4: Prevention

Overview

This chapter reviews risk factors for cardiovascular disease and atherosclerotic risk assessment. The pathophysiology,contribution to cardiovascular disease, and treatment of risk factors including lipids, nutrition, obesity, smoking, diabetes and themetabolic syndrome, are discussed. Gender differences in cardiovascular disease prevention and the role of exercise indisease prevention are also covered.

Authors

Patrick T. O'Gara, MD, FACC Editor­in­Chief

Thomas M. Bashore, MD, FACC Associate Editor

James C. Fang, MD, FACC Associate Editor

Glenn A. Hirsch, MD, MHS, FACC Associate Editor

Julia H. Indik, MD, PhD, FACC Associate Editor

Donna M. Polk, MD, MPH, FACC Associate Editor

Sunil V. Rao, MD, FACC Associate Editor

4.1: Atherosclerotic Risk Assessment

Author(s): Emil M. deGoma, MD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Calculate the 10­year coronary heart disease (CHD) and general cardiovascular disease (CVD) Framingham risk scores(FRS) for primary prevention patients to estimate cardiovascular risk.

2. Recognize the limitations of both clinical risk scores and novel risk prediction tools to optimize strategies forcardiovascular risk assessment.

3. Identify intermediate­risk patients for whom additional tests such as coronary artery calcium (CAC) scanning, carotidintima­media thickness (CIMT) assessment, ankle­brachial index (ABI), or high­sensitivity C­reactive protein (hs­CRP)measurement may be appropriate to refine cardiovascular risk.

Rationale for Risk Assessment

Matching the intensity of management to the degree of cardiovascular risk has long

served as a central tenet of preventive cardiovascular medicine.1,2 The fundamentalrole of global risk assessment as a gatekeeper in preventive cardiologyacknowledges the costs associated with escalating therapy. On a patient level, thedemonstrated benefits of statin administration, for example, must be weighedagainst the financial cost of the medications itself, as well as the burden of long­term monitoring and the risk of side effects including muscle­related symptoms.From a population perspective, use of risk assessment methods promotes efficientallocation of limited health care resources.

Analysis of the number needed to treat (NNT), that is, the number of patientsrequiring treatment in order to avoid a single adverse cardiovascular event over aspecified time frame, captures the logic of risk assessment in therapeutic decisionmaking. For a given intervention, lower NNTs or greater reductions in absolute riskhave been consistently observed among higher­risk populations compared to lower­

risk groups (Tables 1, 2).3­5 These data support the intuitively appealing approach ofbuilding preventive management strategies starting from sound cardiovascular riskassessment.

This module reviews clinical approaches to cardiovascular risk stratification andsummarizes the current state of cardiovascular risk refinement measures includingCRP, ABI, CAC scanning, and CIMT evaluation.

Table 1

Table 2

NNT to Prevent One Cardiovascular Event Over 5 YearsTable 1Estimates of the number needed to treat (NNT) to prevent one hard cardiovascular event over 5 years by reducing low­density lipoproteincholesterol (LDL­C) from 160 mg/dl to 130 mg/dl, 130 mg/dl to 100 mg/dl, or 100 mg/dl to 70 mg/dl in the presence or absence of diabetes,cardiovascular disease (CVD), coronary artery disease (CHD), diabetes, or impaired fasting glucose (IFG).

Reference:

1. Robinson JG Stone NJ. Identifying patients for aggressive cholesterol lowering: the risk curve concept. Am J Cardiol 2006;98:1405­8.

5­Year Number Needed to Treat to Prevent One Myocardial Infarction (MI) or Stroke (CVA) Stratified by Baseline RiskTable 2References:

1. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascular risk: a review forclinicians. J Am Coll Cardiol 2009;54:1209­27.

2. Jackson R, Lawes CM, Bennett DA, Milne RJ, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based onan individual's absolute cardiovascular risk. Lancet 2005;365:434­41.

Clinical Risk Scores for Primary Prevention(1 of 2)

10­Year Coronary Heart Disease Framingham Risk Score

A variety of clinical risk equations have been developed for use in the primaryprevention setting, each derived from multivariable regression analyses of largeprospectively followed cohorts (Table 3). Because clinical risk scores achievemoderate discrimination in predicting cardiovascular events, are cost­effective, andutilize widely available data, they provide the foundation for cardiovascular riskassessment and are provided a Class I recommendation by the American Collegeof Cardiology Foundation/American Heart Association (ACCF/AHA) 2010 Guideline

for Assessment of Cardiovascular Risk in Asymptomatic Adults.3,6

Published in 1998, the 10­year FRS for hard CHD events (fatal CHD and myocardial

infarction [MI]) represents the first clinical cardiovascular risk equation developed.7

Input variables include age, sex, total cholesterol, high­density lipoproteincholesterol (HDL­C), current smoking, systolic blood pressure, and the use ofantihypertensive medications. Online tools as well as tables are available tofacilitate calculation of the 10­year CHD FRS(http://www.framinghamheartstudy.org/risk/hrdcoronary.html).

One of the primary reasons the 10­year hard CHD FRS remains the dominantmethod of risk assessment in the United States is due to its incorporation into theNational Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)

guidelines.8 A 10­year CHD FRS >20%, observed in 25% of US adults,9 isconsidered high risk. The intermediate­risk category is alternatively defined as a

CHD FRS of 10­20%6 or 5­20%,9 the latter comprising 40% of the adult population.9

The most recent consensus document detailing cardiovascular risk assessment in

asymptomatic adults proposed an intermediate­risk category of 10­20%.6 Finally, a

risk score of <10% or <5%, observed in 35% of US adults, 9 classifies patients intothe low­risk category.

These risk thresholds, though arbitrarily defined,10 provide the structure to identifypatients who warrant intensification of lipid­lowering therapy. The 2004 NCEP ATP IIIupdate recommended minimum LDL­C targets for high­risk, intermediate­risk, and

low­risk groups of <100 mg/dl, <130 mg/dl, and <160 mg/dl.11

Weaknesses of the 10­year hard CHD FRS include its focus on CHD events to theexclusion of other atherothrombotic outcomes; the limited generalizability of findingsfrom a single­center, predominantly Caucasian study exposed to a different riskfactor milieu than contemporary cohorts; the dominant effect of age leading tounderestimation of risk in younger groups and overestimation of risk in the elderly;the relatively short 10­year time frame given the slow evolution of atherosclerosisover decades; and the exclusion of known causative risk factors such as family

history and obesity.12

Arguably the most worrisome limitation of the 10­year hard CHD FRS lies in itssuboptimal detection of high­risk patients who go on to suffer an MI, individuals inwhom failure to implement intensive preventive therapy represents a significantmissed opportunity. In a retrospective study of 222 younger patients hospitalized for

acute MI, only 12% were deemed at high risk by 10­year hard CHD FRS.13 In a

second study examining 355 consecutive patients presenting with ST­elevation MI,14

only 6% were classified as high risk using the 10­year hard CHD FRS.

Table 3

Summary of Selected Clinical Risk ScoresTable 3CHD = coronary heart disease; CVD = cardiovascular disease; FRS = Framingham risk score; HDL­C = high­density lipoprotein cholesterol; MI =myocardial infarction.

References:

1. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factorcategories. Circulation 1998;97:1837­47.

2. D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study.Circulation 2008;117:743­53.

3. Pencina MJ, D'Agostino RB Sr, Larson MG, Massaro JM, Vasan RS. Predicting the 30­year risk of cardiovascular disease: theFramingham heart study. Circulation 2009;119:3078­84.

4. Lloyd­Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.Circulation 2006;113:791­8.

Clinical Risk Scores for Primary Prevention(2 of 2)

Risk Scores Incorporating Broader Endpoints and Longer Time Frames

In an effort to expand the applicability of the clinical risk score, a more extensiveinclusion of risk factors such as family history as well as broadly defined endpointsmay better illustrate individual risk. The 10­year FRS for general CVD overcomesseveral of the limitations of the hard CHD FRS by using a more inclusive endpoint,incorporating not only fatal CHD and MI but coronary insufficiency, angina,cerebrovascular disease (ischemic stroke, hemorrhagic stroke, transient ischemicattack), peripheral artery disease (intermittent claudication), and heart failure (Figure

1).15

Inputs into the algorithm include diabetes as well as the independent variables ofthe 10­year hard CHD FRS. Tables are available online to facilitate calculation(http://www.framinghamheartstudy.org/risk/gencardio.html).Use of anencompassing metric acknowledges shared risk factors and similar preventivemeasures for the component CVDs. Moreover, such an approach may improve riskcommunication and avoid undertreatment of patients at high risk for noncoronaryevents. For example, female hypertensive smokers may exhibit a 10­year generalCVD FRS over three times higher than a 10­year hard CHD FRS due to the

contribution of excess heart failure and stroke.16

More recently developed risk indices incorporate a longer­term perspective in orderto motivate younger at­risk patients to initiate and adhere to lifestyle changes and,when needed, pharmacotherapy (Figure 1).The 30­year FRS for hard CVD estimatesthe 30­year risk for the development of coronary death, MI, and stroke based on the

standard risk factors of the 10­year general CVD FRS.17 Lifetime risk scores extendthe follow­up duration further, providing estimates of the risk of atherosclerotic CVD

assuming a baseline age of 50 years and survival to 95 years.18 Also derived fromFramingham cohort data, the lifetime risk algorithm utilizes gender, systolic bloodpressure, diastolic blood pressure, smoking status, total cholesterol, and diabetesstatus to calculate the risk of cardiovascular death, MI, coronary insufficiency, anginapectoris, atherothrombotic stroke, and intermittent claudication.

Discrepancies between long­ and short­term risk estimates can be striking. Forexample, for a 25­year­old female hypercholesterolemic smoker, the 10­yeargeneral CVD FRS is only 1.4%, but the corresponding 30­year hard CVD FRS

reaches 12%.17 A 50­year­old nonsmoking, nondiabetic man with total cholesterolof 250 mg/dl, HDL­cholesterol of 60 mg/dl, and untreated systolic blood pressure of160 mm Hg has an estimated 10­year hard CHD FRS of 7%, but an average lifetime

risk for CVD approaching 70%.18 Simple online tools are not yet available forcalculating 30­year hard CVD or lifetime CVD risk.

Figure 1

Cardiovascular Risk Assessment for a Hypothetical Case Using Framingham Risk Scores for 10­Year General CVD and 30­Year Hard CVDFigure 1BP = blood pressure; CVD = cardiovascular disease; HDL = high­density lipoprotein; HTN = hypertension; RF = risk factor.

Reproduced with permission from Vasan RS, Kannel WB. Strategies for cardiovascular risk assessment and prevention over the life course:progress amid imperfections. Circulation 2009;120:360­3.

Limitations of Clinical Risk Scores

Limitations of the 10­year hard CHD FRS were described earlier. Clinical risk equations utilizing broader endpoints andlonger time horizons appear to offer advantages over the traditional risk assessment approach. However, it remainsuncertain how these newer methods should be incorporated into clinical management, including which numericalthresholds may be assigned to define treatment­relevant risk categories. Long­term risk estimates may be most usefulfor promoting lifestyle modification among younger patients and for identifying appropriate target populations for publichealth initiatives. Finally, although use of clinical risk equations represents a well­accepted approach, there is limiteddirect evidence from randomized clinical trials that calculation and communication of global clinical risk scores alterspatient and physician behavior or improves patient outcomes compared to risk factor counting or an ad hoc unifactor­

based approach.19

Coronary Heart Disease Risk Equivalents

The NCEP ATP III introduced the concept of CHD risk equivalents, disease states conferring a risk of incident MI equal to

the risk of recurrent MI among patients with established CHD, that are greater than 2% per year.8 In addition to a 10­yearhard CHD FRS above 20%, four diseases were deemed CHD risk equivalents based on numerous observational cohortstudies indicating an annual CHD event rate exceeding 2%: lower extremity peripheral artery disease, symptomaticcarotid artery disease, asymptomatic carotid artery disease with stenosis exceeding 50%, diabetes mellitus, andabdominal aortic aneurysm.

The CHD risk equivalent designation was created to increase awareness of noncoronary conditions at high­risk for CHDevents and to intensify management among this group to a secondary prevention approach, including setting aggressivelow­density lipoprotein cholesterol (LDL­C) goals of 70­100 mg/dl or below. While randomized controlled clinicaloutcome trials do not exist supporting these targets among patients with asymptomatic carotid artery disease andabdominal aortic aneurysm, such an approach seems justified in light of the central tenet of prevention, matchingintensity of therapy to degree of risk.

Emerging Risk Refinement Methods(1 of 2)

The past decade has witnessed a proliferation of adjunctive risk prediction toolsaiming to further improve cardiovascular risk assessment. Subclinicalatherosclerosis imaging techniques, circulating inflammatory biomarkers,noninvasive metrics of endothelial function, additional lipoprotein testing, and mostrecently panels of genetic variations or single nucleotide polymorphisms have been

advanced as potential methods to address the so­called “detection gap”1 in CVDprognosis. Four of the best studied risk refinement tools are described later.Guidelines are provided in Table 4, and test characteristics are summarized inTable 5. No randomized controlled trials have yet established the benefit (or harm)associated with management guided by these tests compared to treatment basedon clinical risk scores described earlier.

C­Reactive Protein

CRP is a 110 kDa protein predominantly synthesized by hepatocytes in response tothe inflammatory cytokines interleukin (IL)­6 and IL­1. Most studies havedemonstrated a statistical relationship between CRP and cardiovascular events,although the weight of evidence thus far argues against a causative role in

atherosclerosis.20 As with measures of cholesterol, CRP displays a degree ofintraindividual variability for which two serial measurements are recommended for agiven patient to better assess the true homeostatic setpoint prior to making

therapeutic decisions.21 Values higher than 3 mg/L define the high­risk category

according to an earlier consensus statement.21

Since then, results have been published for the JUPITER (Justification for the Use ofStatins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, whichutilized an hs­CRP of 2 mg/L or greater as an inclusion criterion. In the JUPITERtrial, treatment with rosuvastatin 20 mg daily for a median of 1.9 years wasassociated with a significant 46% reduction in the incidence of cardiovascular death,MI, stroke, hospitalization for unstable angina, and revascularization compared toplacebo. Of note, the study was not designed to test the incremental value of hs­CRP for risk assessment compared to traditional risk factors alone.

CRP is modestly associated with worsened cardiovascular outcomes with amultivariable­adjusted risk ratio for CHD and nonfatal MI of 1.6, comparing highest tolowest hs­CRP tertile values. Discrimination and net reclassification data areprovided in Table 5. A clinical risk score that includes CRP, called the “Reynolds

Risk Score,” has been developed.22,23

Other inputs include age, sex, smoking status, systolic blood pressure, totalcholesterol, and HDL­C as well as a parental history of MI before the age of 60.Statistically significant but modest improvements in discrimination and riskreclassification were reported compared to traditional risk factors alone (Table 5). Anonline calculator for the Reynolds Risk Score can be found athttp://www.reynoldsriskscore.org/.

Critics of the Reynolds Risk Score cite too much weight placed on a score thatincludes CRP, which has a relatively small incremental prognostic value comparedto traditional risk factors. An additional concern is the fluctuation observed in serialCRP measures.

Ankle­Brachial Index

ABI, an integral component of the diagnostic evaluation of lower extremity peripheralartery disease, yields important cardiovascular prognostic information in addition todescribing limb morbidity. As discussed in Chapter 9, Peripheral Artery Disease, ABIfor the right (or left) lower extremity is by convention defined as the higher of thesystolic pressures in the right (or left) dorsalispedis and posterior tibial arteriesdivided by the higher of the systolic pressures in the right and left brachial artery. Inhealthy individuals, distal pulse wave reflection causes ankle systolic pressures tobe 10­15 mm Hg higher than brachial systolic pressures; therefore, the normal ABI

Table 4

Table 5

exceeds 1.0.24 On the other end of the spectrum, a “supranormal” ABI above 1.4also portends a worse cardiovascular prognosis. Ankle pressures elevated to thisdegree may be observed in noncompressible, calcified vessels due to diffuseatherosclerosis or diabetes.

A large international meta­analysis examining 16 population cohort studies, 24,955men, and 23,339 women clarified the incremental value of ABI above and beyond the

traditional FRS.25 Compared with an ABI of 1.11­1.4, an ABI below 0.9 wasassociated with a hazard ratio for cardiovascular mortality and major events of 2.34for men and 2.35 for women after adjustment for the FRS. Adding ABI data to theFRS significantly improved discrimination among women, increasing the area underthe curve from 0.605 to 0.658. No change was noted among men.

Inclusion of the ABI in cardiovascular risk stratification using the FRS would result inreclassification of the risk category and modification of treatment recommendationsin approximately 19% of men and 36% of women. The prevalence of an abnormalABI among asymptomatic adults without CVD or diabetes has been estimated at

13% among subjects with an intermediate FRS.26

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendations for Risk Refinement MethodsTable 4CHD = coronary heart disease; FRS = Framingham risk score; LDL­C = low­density lipoprotein cholesterol.

Reproduced with permission from Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk inasymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JAm Coll Cardiol 2010;56:e50­103.

Overview of Test Characteristics of hs­CRP, ABI, CACS, and CIMTTable 5

ABI = ankle­brachial index; AUC = area under the curve; CACS = coronary artery calcium score; CHD = coronary heart disease; CIMT = carotidintima­media thickness; cNRI = clinical net reclassification index; FRS = Framingham risk score; hs­CRP = high­sensitivity C­reactive protein; RR =relative risk.

aComparing hs­CRP >3 and <1 mg/L. Endpoint: CHD death, nonfatal myocardial infarction. bcNRI was 15% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10 to <20%, ≥20%. cNRI was9% among participants with 10­year hard CHD FRS 5­20% using three risk categories: <5%, 5 to <20%, ≥20%. Endpoint: myocardial infarction,coronary revascularization, stroke, and cardiovascular death. ccNRI was 16% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10 to <20%, ≥20%. cNRI was12% among participants with 10­year hard CHD FRS 5­20% using three risk categories: <5%, 5 to <20%, ≥20%. Endpoint: myocardial infarction,coronary revascularization, stroke, and cardiovascular death. dComparing ABI <0.9 to 1.11­1.4. Endpoint: cardiovascular mortality and major events. eNo significant difference in AUC among men. fNet reclassification index calculated from published data, defining abnormal ABI as <0.9 and >1.4 and utilizing three Framingham risk strata(<10%, 10­20%, >20%). The percentages of patients in whom ABI would reclassify risk and modify treatment recommendations were 19%among men and 36% among women. gComparing top and bottom quantile, usually quartile. Endpoint: coronary death, nonfatal myocardial infarction, surgical or percutaneous coronaryrevascularization procedures, nonhemorrhagic stroke, and peripheral arterial surgery. hAmong participants with 5­year hard CHD FRS 3­10% using three risk categories: <3%, 3% to <10%, ≥10%. Endpoint: CHD death, myocardialinfarction, cardiac arrest, angina, and coronary revascularization. iAmong participants with 10­year hard CHD FRS 10­20% using three risk categories: <10%, 10­20%, >20%. jComparing top and bottom quantile, usually quartile. Endpoint: variable, systematic review included studies of myocardial infarction alone, strokealone, and all cardiovascular outcomes. kcNRI was 22% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10­20%, >20%. Endpoint:CHD death, myocardial infarction, and coronary revascularization.

References:

1. Buckley DI, Fu R, Freeman M, Rogers K. Helfand M. C­reactive protein as a risk factor for coronary heart disease: a systematic reviewand meta­analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:483­95.

2. Cook NR, Buring JE, Ridker PM. The effect of including C­reactive protein in cardiovascular risk prediction models for women. Ann InternMed 2006;145:21­9.

3. Ridker PM, Paynter NP, Rifai N, Gaziano JM. Cook NR. C­reactive protein and parental history improve global cardiovascular riskprediction: the Reynolds Risk Score for men. Circulation 2008;118:2243­51.

4. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Scoreto predict cardiovascular events and mortality: a meta­analysis. JAMA 2008;300:197­208.

5. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart diseaseprediction. JAMA 2010;303:1610­6.

6. Nambi V, Chambless L, Folsom AR, et al. Carotid intima­media thickness and presence or absence of plaque improves prediction ofcoronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol 2010;55:1600­7.

Emerging Risk Refinement Methods(2 of 2)

Coronary Artery Calcium

CAC scanning quantifies the aggregate amount of calcium deposited in the walls ofthe epicardial coronary arteries and serves as a proxy for the extent of coronary

atherosclerosis (Figure 2).27 Calcification of the coronary arteries is synonymouswith intimal atherosclerosis with two infrequent exceptions: 1) medial calcificationrarely observed in patients with diabetes or chronic kidney disease, and 2)calcification of the internal elastic lamina seen in patients with the human

immunodeficiency virus.28 Of note, pathologic examination and intravascularultrasound of atheroma have demonstrated that calcified plaque accounts for only20% of total plaque burden, the remainder attributed to lipid deposition and

fibrosis.29

Electron beam computed tomography (EBCT), so­called “ultrafast CT,” was the firstimaging modality used to measure CAC. The acquisition protocol involvesnonoverlapping 3 mm slices from the carina to the caudal extent of the heart. Thereference Agatston method defines an area of calcification as an area within the

coronary arteries measuring at least 1 mm2 with a density of 130 Hounsfield units(HU) or greater. Each area is multiplied by a factor of 1­4 depending on peak. Thetotal CAC score is then obtained through summation of scores for all transaxialimages.

Improvements in scanner technology now permit CAC evaluation using multi­detector CT (MDCT). A similar acquisition and quantification method, called the“Agatston algorithm for MDCT,” provides scores comparable to that of EBCT. CACscores exceeding 100 Agatston units (AU) or 75th percentile are considered highrisk for coronary events, and values above 400 AU or 90th percentile are classified

as very high risk.29

Test characteristics for CAC are summarized in Table 5. A consistent finding in largepopulation studies has been the long­term, benign prognostic profile of patients witha zero CAC score. The absence of CAC as quantified by the Agatston methodconfers a very low risk of events, an annualized cardiovascular event rate of 0.11%

over 4 years,30 and a mortality rate of 0.5% over 10 years.31

Radiation exposure represents the leading concern with CAC scanning.Prospectively triggered acquisition yields effective doses of 0.9­1.1 mSv, although

higher doses may result from retrospective imaging.27 Very low­dose protocols havebeen developed that reduce radiation exposure below 1 mSv.

One multicenter study of clinical practices indicated a higher average radiation

exposure of 2.3 mSv (0.8­10.5 mSv).32 Appropriate use of CAC requires constantvigilance to minimize radiation exposure, tailoring image acquisition protocols toeach and every patient. A second important issue is that macrocalcification detectedby CT is a relatively late finding in the atherosclerotic process. As a result, thesensitivity of CAC score for subclinical disease is highly dependent on patient age.

In one study of younger patients (mean age 49 years) without documented CVD,subclinical atherosclerosis by carotid ultrasound was detected in 47% of patients

with a zero CAC score.33 The proposed minimum age thresholds for the use of CAC

is 45 years for men and 55 years for women34; however, appropriate age cutoffsremain uncertain. In addition to younger patients, patients with diabetes may alsodevelop coronary plaque without significant calcification.

Carotid Intima­Media Thickness

Screening carotid ultrasound for cardiovascular risk refinement incorporates both

measurement of CIMT and assessment for carotid plaque.35 IMT is measured asthe distance between the lumen­intima interface and the media­adventitia interface,visualized as two parallel echobright lines on ultrasound (Figure 3). Current

Figure 2

Table 5

Figure 3

guidelines from the American Society of Echocardiography and the Society ofVascular Medicine recommend measurement of IMT in the far wall of the distal 1 cm

of the common carotid arteries.35 Although the earliest development ofatherosclerosis frequently occurs at the carotid bulb and the origin of the internalcarotid artery, the common carotid artery was chosen as the target segmentbecause the site is frequently easier to visualize and to acquire images for IMTassessment.

Plaque is defined as either a focal wall thickening at least 50% greater than that ofthe surrounding arterial wall or a focal region of IMT thickening greater than 1.5 mmthat protrudes into the lumen and is distinct from the adjacent boundary. Thepresence of any carotid plaque or an IMT exceeding the 75th percentile using anage­, sex­, and ethnic­specific reference population confers a higher risk of CVD,independent of traditional risk factors. Test characteristics are provided in Table 5.

The primary limitation of CIMT is the required technical proficiency to achieveconsistent submillimeter measurements. One study, however, demonstrated theability of nonsonographer clinicians to perform accurate CIMT assessment using

semiautomated border detection software after a brief 2­day training program.36

An additional concern has been the biological dissimilarity between IMT and

atherosclerosis.37 IMT is largely driven by medial thickening, attributed tohypertension and age, whereas early atherosclerosis is an intimal process. Thehigher frequencies required to isolate the thin intimal layer, however, cannotpenetrate to the depth needed to assess the carotid artery. Medial layer aside,pathology of atherosclerotic lesions at various stages of evolution suggests thatpathologic intimal thickening, characterized by the formation of lipid pools, does notnecessarily progress to plaque, a phenotype defined by the formation of a necroticcore. On the other hand, provided CIMT tracks well with cardiovascular outcomes,the effectiveness of the surrogate marker need not rely on identicalpathophysiological underpinnings.

Representative Multi­Detector Computed Tomography Axial Image Taken From a Patient With a High­Risk Coronary Artery Calcium Score of 250Figure 2Reproduced with permission from Rumberger JA. Coronary artery calcium scanning using computed tomography: clinical recommendations forcardiac risk assessment and treatment. Semin Ultrasound CT MR 2008;29:223­9.

Overview of Test Characteristics of hs­CRP, ABI, CACS, and CIMTTable 5ABI = ankle­brachial index; AUC = area under the curve; CACS = coronary artery calcium score; CHD = coronary heart disease; CIMT = carotidintima­media thickness; cNRI = clinical net reclassification index; FRS = Framingham risk score; hs­CRP = high­sensitivity C­reactive protein; RR =relative risk.

a. Comparing hs­CRP >3 and <1 mg/L. Endpoint: CHD death, nonfatal myocardial infarction.b. cNRI was 15% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10 to <20%, ≥20%.c. NRI was 9% among participants with 10­year hard CHD FRS 5­20% using three risk categories: <5%, 5 to <20%, ≥20%. Endpoint:

myocardial infarction, coronary revascularization, stroke, and cardiovascular death.d. cNRI was 16% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10 to <20%, ≥20%.

cNRI was 12% among participants with 10­year hard CHD FRS 5­20% using three risk categories: <5%, 5 to <20%, ≥20%. Endpoint:myocardial infarction, coronary revascularization, stroke, and cardiovascular death.

e. Comparing ABI <0.9 to 1.11­1.4. Endpoint: cardiovascular mortality and major events.f. No significant difference in AUC among men.g. Net reclassification index calculated from published data, defining abnormal ABI as <0.9 and >1.4 and utilizing three Framingham risk

strata (<10%, 10­20%, >20%). The percentages of patients in whom ABI would reclassify risk and modify treatment recommendationswere 19% among men and 36% among women.

h. Comparing top and bottom quantile, usually quartile. Endpoint: coronary death, nonfatal myocardial infarction, surgical or percutaneouscoronary revascularization procedures, nonhemorrhagic stroke, and peripheral arterial surgery.

i. Among participants with 5­year hard CHD FRS 3­10% using three risk categories: <3%, 3% to <10%, ≥10%. Endpoint: CHD death,myocardial infarction, cardiac arrest, angina, and coronary revascularization.

j. Among participants with 10­year hard CHD FRS 10­20% using three risk categories: <10%, 10­20%, >20%.k. Comparing top and bottom quantile, usually quartile. Endpoint: variable, systematic review included studies of myocardial infarction alone,

stroke alone, and all cardiovascular outcomes.l. cNRI was 22% among participants with 10­year hard CHD FRS 5­20% using four risk categories: <5%, 5 to <10%, 10­20%, >20%.Endpoint: CHD death, myocardial infarction, and coronary revascularization.

References:

1. Buckley DI, Fu R, Freeman M, Rogers K. Helfand M. C­reactive protein as a risk factor for coronary heart disease: a systematic reviewand meta­analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:483­95.

2. Cook NR, Buring JE, Ridker PM. The effect of including C­reactive protein in cardiovascular risk prediction models for women. Ann InternMed 2006;145:21­9.

3. Ridker PM, Paynter NP, Rifai N, Gaziano JM. Cook NR. C­reactive protein and parental history improve global cardiovascular riskprediction: the Reynolds Risk Score for men. Circulation 2008;118:2243­51.

4. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Scoreto predict cardiovascular events and mortality: a meta­analysis. JAMA 2008;300:197­208.

5. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart diseaseprediction. JAMA 2010;303:1610­6.

6. Nambi V, Chambless L, Folsom AR, et al. Carotid intima­media thickness and presence or absence of plaque improves prediction ofcoronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol 2010;55:1600­7.

Example of Carotid Intima­Media Thickness Measurement Performed in the Far Wall of the Distal Common Carotid ArteryFigure 3cIMT = carotid intima­media thickness; RCCA = right common carotid artery.

Reproduced with permission from Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease andevaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima­Media ThicknessTask Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93­111.

Future Directions

Further research will determine the appropriate clinical role of newer risk equations, including assessment oflifetime risk.Future clinical risk scores may offer additional advantages such as exclusion of age within the risk model bylimiting analysis to narrow windows of age or inclusion of multiple ethnicities, as in the MESA (Multi­Ethnic Studyof Atherosclerosis).Randomized clinical trials comparing clinical outcomes and cost­effectiveness of various risk assessmentstrategies, including those incorporating subclinical atherosclerosis imaging modalities, are needed.

Key Points

Global cardiovascular risk assessment, the cornerstone of preventive care, serves to guide the intensity ofmedical management.Limitations of the 10­year hard CHD FRS as a clinical risk assessment technique include its focus on CHDevents to the exclusion of other atherothrombotic outcomes; the limited generalizability of findings from a single­center, predominantly Caucasian study exposed to a different risk factor milieu than contemporary cohorts; thedominant effect of age leading to underestimation of risk in younger groups; the relatively short 10­year time framegiven the slow evolution of atherosclerosis over decades; and the exclusion of known causative risk factors suchas family history.Newer clinical risk scores, such as the 10­year general cardiovascular risk score and lifetime risk assessment,incorporate broader endpoints and longer time frames to overcome several limitations of the traditional FRS.Lower extremity peripheral artery disease, symptomatic carotid artery disease, asymptomatic carotid arterydisease with stenosis exceeding 50%, diabetes mellitus, and abdominal aortic aneurysm are noncoronarydiseases designated as CHD risk equivalents warranting intensive preventive therapy akin to secondaryprevention groups.Hs­CRP levels greater than 3 mg/L define the high­risk category.ABIs below 1.1 or above 1.4 are associated with an increased risk for cardiovascular events.CAC scores exceeding 100 AU or 75th percentile are considered high risk for coronary events.The presence of any carotid plaque or an IMT exceeding the 75th percentile defines the high­risk category for CVD.

References

1. Pasternak RC, Abrams J, Greenland P, Smaha LA, Wilson PW, Houston­Miller N. 34th Bethesda Conference:Task force #1­­Identification of coronary heart disease risk: is there a detection gap? J Am Coll Cardiol2003;41:1863­74.

2. Vasan RS, Kannel WB. Strategies for cardiovascular risk assessment and prevention over the life course:progress amid imperfections. Circulation 2009;120:360­3.

3. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascularrisk: a review for clinicians. J Am Coll Cardiol 2009;54:1209­27.

4. Jackson R, Lawes CM, Bennett DA, Milne RJ, Rodgers A. Treatment with drugs to lower blood pressure and bloodcholesterol based on an individual's absolute cardiovascular risk. Lancet 2005;365:434­41.

5. Robinson JG, Stone NJ. Identifying patients for aggressive cholesterol lowering: the risk curve concept. Am JCardiol 2006;98:1405­8.

6. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk inasymptomatic adults: a report of the American College of Cardiology Foundation/American Heart AssociationTask Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50­103.

7. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart diseaseusing risk factor categories. Circulation 1998;97:1837­47.

8. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol EducationProgram (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III) final report. Circulation 2002;106:3143­421.

9. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment in asymptomaticpeople: role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863­7.

10. Lloyd­Jones DM. Cardiovascular risk prediction: basic concepts, current status, and future directions. Circulation2010;121:1768­77.

11. Grundy SM, Cleeman JI, Merz CN, et al.; on behalf of the National Heart, Lung, and Blood Institute; AmericanCollege of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for theNational Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227­39.

12. Lloyd­Jones DM. Short­term versus long­term risk for coronary artery disease: implications for lipid guidelines.Curr Opin Lipidol 2006;17:619­25.

13. Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the firstplace: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41:1475­9.

14. Sposito AC, Alvarenga BF, Alexandre AS, et al.; on behalf of the Brasilia Heart Study Group. Most of the patientspresenting myocardial infarction would not be eligible for intensive lipid­lowering based on clinical algorithms orplasma C­reactive protein. Atherosclerosis 2011;214:148­50.

15. D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: theFramingham Heart Study. Circulation 2008;117:743­53.

16. Marma AK, Lloyd­Jones DM. Systematic examination of the updated Framingham heart study generalcardiovascular risk profile. Circulation 2009;120:384­90.

17. Pencina MJ, D'Agostino RB Sr, Larson MG, Massaro JM, Vasan RS. Predicting the 30­year risk of cardiovasculardisease: the Framingham heart study. Circulation 2009;119:3078­84.

18. Lloyd­Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factorburden at 50 years of age. Circulation 2006;113:791­8.

19. Sheridan SL, Crespo E. Does the routine use of global coronary heart disease risk scores translate into clinicalbenefits or harms? A systematic review of the literature. BMC Health Serv Res 2008;8:60.

20. Elliott P, Chambers JC, Zhang W, et al. Genetic Loci associated with C­reactive protein levels and risk of coronaryheart disease. JAMA 2009;302:37­48.

21. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application toclinical and public health practice: A statement for healthcare professionals from the Centers for Disease Controland Prevention and the American Heart Association. Circulation 2003;107:499­511.22.

22. Cook NR, Buring JE, Ridker PM. The effect of including C­reactive protein in cardiovascular risk prediction modelsfor women. Ann Intern Med 2006;145:21­9.

23. Ridker PM, Paynter NP, Rifai N, Gaziano JM. Cook NR. C­reactive protein and parental history improve globalcardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 2008;118:2243­51.

24. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheralarterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborativereport from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for CardiovascularAngiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, andthe ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management ofPatients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and

Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlanticInter­Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239­312.

25. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined withFramingham Risk Score to predict cardiovascular events and mortality: a meta­analysis. JAMA 2008;300:197­208.

26. Dhangana R, Murphy TP, Ahn SH. Prevalence of abnormal ankle­brachial index among subjects with low­intermediate Framingham risk score. Society of Interventional Radiology 35th Annual Scientific Meeting, Tampa,FL: 2010;Abstract 43.

27. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computedtomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imagingand Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging,Council on Clinical Cardiology. Circulation 2006;114:1761­91.

28. Alexopoulos N, Raggi P. Calcification in atherosclerosis. Nat Rev Cardiol 2009;6:681­8.29. Rumberger JA. Coronary artery calcium scanning using computed tomography: clinical recommendations for

cardiac risk assessment and treatment. Semin Ultrasound CT MR 2008;29:223­9.30. Sarwar A, Shaw LJ, Shapiro MD, et al. Diagnostic and prognostic value of absence of coronary artery calcification.

JACC Cardiovasc Imaging 2009;2:675­88.31. Blaha M, et al. Absence of coronary artery calcification and all­cause mortality. JACC Cardiovasc Imaging

2009;2:692­700.32. Kim KP, Einstein AJ, Berrington de Gonzalez A. Coronary artery calcification screening: estimated radiation dose

and cancer risk. Arch Intern Med 2009;169:1188­94.33. Lester SJ, Eleid MF, Khandheria BK, Hurst RT. Carotid intima­media thickness and coronary artery calcium score

as indications of subclinical atherosclerosis. Mayo Clin Proc 2009;84:229­33.34. Naghavi M, Falk E, Hecht HS, et al. From vulnerable plaque to vulnerable patient­­Part III: Executive summary of the

Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol 2006;98:2H­15H.35. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and

evaluate cardiovascular disease risk: a consensus statement from the American Society of EchocardiographyCarotid Intima­Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am SocEchocardiogr 2008;21:93­111; quiz 189­90.

36. Korcarz CE, Hirsch AT, Bruce C, et al. Carotid intima­media thickness testing by non­sonographer clinicians: theoffice practice assessment of carotid atherosclerosis study. J Am Soc Echocardiogr 2008;21:117­22.

37. Finn AV, Kolodgie FD, Virmani R. Correlation between carotid intimal/medial thickness and atherosclerosis: apoint of view from pathology. Arterioscler Thromb Vasc Biol 2010;30:177­81.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.2: Lipid Management

Author(s): Elizabeth A. Jackson, MD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Recall current guidelines/statements relevant to lipid management.2. Describe landmark trials of lipid­lowering therapies.3. Discuss clinical implications of current recommendations and evidence in regard to lipid management.

Introduction

An estimated 16.2% of adults residing in the United States have total cholesterol levels of 240 mg/dl or greater.1 Thistranslates into over 33 million adults with elevated cholesterol, placing them at increased risk for cardiovascular disease.Although the number of adults who report having had their lipids checked has increased from 68.6% in 1999­2000 to74.8% in 2005­2006, there remain substantial gaps in patients' awareness of having elevated cholesterol. Women and

minorities remain less aware of their condition compared to men and nonminorities.1,2 Among patients with heartdisease, currently <20% are at their recommended low­density lipoprotein cholesterol (LDL­C) goal, and <50% of

patients with symptomatic coronary heart disease (CHD) are taking lipid­lowering therapy.1

Adult Treatment Program III Guidelines

The National Cholesterol Educational Panel (NCEP) has published guidelines for

lipid management periodically, starting in 1988.3­5 The most currentrecommendations, the Adult Treatment Program III (ATP III), were published in 2001

and updated in 2004.5,6 The current guidelines are based on a large body ofevidence, which demonstrates that lowering LDL­C results in statistically significantreductions in cardiovascular events. Based on these trials, guidelines includeestablished criteria for risk assessment and treatment of adults.

The following section will outline the key points of ATP III related to risk assessmentand related treatment goals. Key trials upon which the ATP III recommendationswere based, in addition to key trials published since the publication of ATP III, will bereviewed. Last, this section will review pharmacotherapy related to LDL­C and non­high­density lipoprotein (HDL) management and the use of additional testing whereappropriate.

Risk Assessment and Low­Density Lipoprotein Cholesterol Goals

For both primary and secondary prevention, LDL­C is the primary target for themajority of patients. Major clinical trials that support LDL­C lowering to reducecardiovascular disease events include: HPS, PROSPER, ALLHAT­LLT, ASCOT­LLA,PROVE IT­TIMI 22, VA­HIT, TNT, REVERSAL, IDEAL, and ASTERIOD.

The ATP III guidelines categorize patients into three risk categories: 1) establishedCHD and CHD risk equivalents, 2) multiple risk factors, and 3) 0­1 risk factor. CHDrisk equivalents include diabetes, symptomatic carotid artery disease, peripheralarterial disease (including the aorta), and multiple risk factors, with a 10­year risk forCHD of >20%. Major risk factors include cigarette smoking, hypertension, low HDLcholesterol (HDL­C), a family history of premature CHD, and age (Table 1).

Use of the Framingham risk score (FRS) is central to the identification of those athigh risk and intermediate risk of CHD. Patients with either CHD or CHD riskequivalents are considered high risk, and therefore, have a recommended goalLDL­C of <100 mg/dl. Among patients considered very high risk (i.e., those with bothCHD and risk factors such as diabetes, or with uncontrolled risk factors such assmoking), the ATP III update recommended that a reasonable goal would be anLDL­C level <70 mg/dl (Table 2).

For patients without clinically apparent CHD, but with two or more risk factors, theupdated ATP III guidelines call for the use of the FRS to determine which of thosepatients would be considered high risk. Patients with 2+ risk factors who have a 10­year risk of CHD >20% are considered to have a CHD risk equivalent, and therefore,are at high risk. For such patients, a goal LDL­C <100 mg/dl is reasonable.

Patients with 2+ risk factors who have a 10­year risk of CHD <20% are furthercategorized into intermediate risk (FRS between 10% and 20%) and low risk (FRS<10%). For both groups, an LDL­C goal ≤130 mg/dl is appropriate. In such patients,guidelines allow for initiation of lipid­lowering medications such as statins after atrial of dietary therapy. If the 10­year risk of CHD is <10%, LDL­C therapy can beconsidered if the LDL is ≥160 mg/dl on maximal dietary therapy.

The majority of patients with 0­1 risk factors have a low FRS (i.e., <10%). For theselow­risk adults, a goal LDL­C <160 mg/dl is considered reasonable. Diet therapyshould be initiated when the LDL­C is ≥160 mg/dl, and if the LDL­C is ≥190 mg/dlafter a trial of dietary modification, then pharmacotherapy should be considered. ATPIII guideline authors suggested that in the presence of a "severe risk factor," earlierinitiation of lipid­lowering medication can be considered.

Non­Low Density Lipoprotein Goals

Although LDL­C remains the primary target of therapy for a majority of patients, oncethe LDL­C goal has been met, consideration of non­HDL targets is the secondtherapeutic concern among patients with triglyceride levels ≥200 mg/dl. Non­HDL­Cincludes both very LDL (VLDL) and LDL, which represent potential additional risk

Table 1

Table 2

Table 3

Table 4

due to atherogenic remnant lipoproteins.

Non­HDL goals are 30 mg/dl above the LDL­C goal. For example, a patient whoseLDL­C goal is <100 mg/dl would have a non­HDL goal of <130 mg/dl. A patient withan LDL­C goal of <70 mg/dl would have a non­HDL goal of <100 mg/dl. At the time ofpublication, the ATP III authors did not believe that there was enough evidence forinclusion of a goal HDL­C. Current management options for increasing HDL­Cbeyond lifestyle include fibrates and nicotinic acid, both of which will be describedlater in this module.

The primary exception to an initial LDL­C target is among patients with elevatedtriglycerides. Among patients with triglyceride levels ≥500 mg/dl, triglyceridesbecome the initial target, while LDL­C is considered as a secondary target. Themainstay of therapy is dietary intervention, which can result in substantialimprovement in triglyceride levels (Table 3).

Factors associated with elevated triglycerides include obesity, uncontrolleddiabetes, physical inactivity, cigarette smoking, and excessive alcohol intake.Lifestyle modification can lead to a significant reduction in triglyceride levels. Forpatients with high triglycerides, 2­4 grams of eicosapentaenoic acid (EPA) +docosahexaenoic (DHA) found in fish oil, together with dietary modification, canassist in lowering triglyceride levels.

Alcohol consumption should be limited to 1 drink for women and 1­2 drinks for men.Increased intake of alcohol can contribute to increased triglyceride levels; therefore,accurate assessment of both alcohol intake and dietary factors should be includedin clinician discussions regarding prevention efforts.

Additionally, drugs such as corticosteroids, estrogens, retinoids, and beta­blockerscan contribute to elevations in triglycerides. These factors also are associated withreductions in HDL­C as well. Therefore, a careful history of comorbidities,medications, and lifestyle factors is recommended among all patients, andparticularly those with elevated triglycerides.

The Metabolic Syndrome

The ATP III guidelines placed increased emphasis on the metabolic syndrome withgood reason. The presence of components of the metabolic syndrome significantly

increases the risk for both diabetes and heart disease.6 Calculation of non­HDL orthe total cholesterol to HDL­C ratio can assist in identifying patients with themetabolic syndrome because these patients often have a lower HDL­C and thuselevated non­HDL cholesterol.

For example, a male patient at intermediate cardiovascular disease risk who has anLDL of 125 mg/dl, HDL of 30 mg/dl, and total cholesterol of 200 mg/dl has met hisLDL goal of <130 mg/dl. However, his non­HDL of 170 mg/dl is above his goal of160 mg/dl. His low HDL is one criterion for the metabolic syndrome. By measuringfasting glucose, waist circumference, and triglycerides, his health care provider mayconfirm additional criteria of the metabolic syndrome. The clinician should be awareof the criteria and be able to easily identify patients who meet criteria of themetabolic syndrome, as they constitute a group at risk for CHD regardless of theirFRS (Table 4).

Major Risk Factors That Modify LDL Cholesterol Goals (Adult Treatment Panel III)Table 1CHD = coronary heart disease; HDL = high­density lipoprotein; LDL = low­density lipoprotein

Three Categories of Risk for CHD That Modify Goals and Modalities of LDL­C Lowering TherapyTable 2CHD = coronary heart disease; LDL­C = low­density lipoprotein cholesterol

Lifestyle Recommendations to Lower TriglyceridesTable 3BMI = body mass index

Clinical Identification of the Metabolic SyndromeTable 4HDL­C = high­density lipoprotein cholesterol

Diet and Exercise Guidelines/Recommendations

The American Heart Association (AHA) Scientific Statement on Diet and Lifestyle

Recommendations Revision 2006,7 provides recommendations on diet related tolipid modification. In brief, this statement recommends a balanced caloric intake,together with regular physical activity, to assist in the achievement of a healthy bodyweight. A diet rich in vegetable and fruits, whole grains, and high fiber isrecommended. Saturated fats should be limited to <7% of energy. Trans fats shouldbe avoided whenever possible (Table 5). The strongest dietary factors associatedwith increased LDL include dietary saturated fats and trans fats.

Soluble fiber and soy protein can modestly reduce LDL­C. Plant stanols/sterols havebeen shown to lower LDL­C up to 15%. Maximum effects are observed with intakesof approximately 2 g/day. Red yeast rice, a fermented rice product that containsmonacolins which have hydroxy­methyl­glutaryl coenzyme A (HMG­CoA) reductaseinhibitor activity, has been shown to reduce LDL­C compared to placebo. The totalmonacolin content can vary significantly in different available preparations, and thelack of long­term safety data and regulation by the US Food and Drug Administration(FDA) limit potential for inclusion in future guideline recommendations.

Low HDL levels are often related to lifestyle factors including excess weight(particularly central obesity), smoking, and sedentary behaviors. Very low fat diets(<10% fat) have also been linked to lowering HDL levels. For patients with low HDL,recommendations for weight loss, regular exercise (increasing the dose of exerciseover time), and smoking cessation are central to raising HDL levels through lifestylemodification. As discussed previously, for patients with elevated triglycerides,addition of fish oil and/or fiber, together with reduction (or avoidance) of alcohol andcontrol of glucose, will assist in lowering triglycerides. Additional recommendationsinclude consuming low­fat dairy products such as milk, while limiting beverageswith added sugar, which is central to reducing empty calories.

Table 5

Examples of Dietary Patterns Consistent With AHA RecommendationsTable 5*DASH = Dietary Approaches to Stop Hypertension.†TLC = Therapeutic lifestyle changes. #Whole­grain foods are recommended for most grain servings to meet fiber recommendations.§This number can be less or more depending on other food choices, to meet 2,000 calories.

Adapted with permission from Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statementfrom the American Heart Association Nutrition Committee. Circulation 2006;114:82­96, Table 4.

Major Clinical Trials Upon Which the ATP III 2004 Update WasBased

Landmark trials upon which current ATP III guidelines were based include the HPS

(Heart Protection Study),8 PROSPER (PROspective Study of Pravastatin in the

Elderly at Risk),9 ALLHAT­LLT (Antihypertensive and Lipid­Lowering Treatment to

Prevent Heart Attack Trial­Lipid Lowering Trial),10 ASCOT­LLA (Anglo­Scandinavian

Cardiac Outcomes Trial­Lipid Lowering Arm),11 and PROVE IT­TIMI 22 (Pravastatin

or Atorvastatin Evaluation and Infection­Thrombolysis in Myocardial Infarction 22).12

These trials formed the basis for the updates to ATP III, published in 2004.6 It isbeyond the scope of this module to discuss all the major studies; therefore, a briefdiscussion of trials upon which the ATP III 2004 updates were based will beprovided, in addition to some of the key trials published since 2004.

HPS (Heart Protection Study)

The HPS was a clinical trial included 20,536 adults, ages 40­80 years, who were

considered high risk for cardiovascular disease events.8 Subjects included thosewith a history of CHD and CHD risk equivalents (noncoronary occlusive arterialdisease and diabetes). Subjects were randomized to 40 mg of simvastatin orplacebo and followed for a primary outcome of total mortality, and secondaryoutcomes of fatal and nonfatal vascular events. Average lipid values at baselinewere total cholesterol 228 mg/dl, triglycerides 186 mg/dl (nonfasting), HDL­C 41mg/dl, non­HDL­C 187 mg/dl, and direct LDL­C 131 mg/dl.

Among subjects randomized to simvastatin, total mortality was reduced by 13% (p =0.003). Reductions were observed for major vascular events (­24%), coronary death(­18%), nonfatal myocardial infarction (MI) and cardiac death (­27%), nonfatal or fatalstroke (­25%), and cardiovascular revascularization (­24%), as compared toplacebo. The benefits were observed for both the primary prevention group (i.e.,those with no prior history of CHD) and the secondary prevention group (i.e., thosewith a history of CHD). Similar reductions were noted for both men and women, andfor those under and over 70 years of age at baseline.

A key finding of the HPS was the risk reduction observed with simvastatin at allbaseline levels of LDL­C, including subjects with LDL­C levels <100 mg/dl. Anadditional important finding was the significant risk reduction observed amongdiabetics. In 2,426 diabetic subjects with a pretreatment LDL­C <116 mg/dl, eventrates were 27% lower in the simvastatin group compared to the placebo group. Nosignificant adverse effects of simvastatin therapy were reported, including anysignificant increase in myopathy, cancer incidence, or hospitalization for any othernonvascular cause (Figure 1).

PROSPER (Prospective Study of Pravastatin in the Elderly at Risk)

The major aim of the PROSPER trial was to examine the potential for CVD risk

reduction related to statin therapy among the elderly.9 A total of 5,804 men andwomen, ages 70­82 years, with a history of vascular disease or cardiovasculardisease risk factors, were randomized to pravastatin 40 mg/day or placebo. Theprimary endpoint was combined coronary death, nonfatal MI, and fatal or nonfatalstroke. Over an average follow­up of 3.2 years, pravastatin reduced LDL­C levels by34%. The primary endpoint was reduced by 15% among the pravastatin groupcompared to the control group (p = 0.014).

Risk reductions were observed for secondary endpoints, including major coronaryevents (i.e., nonfatal MI and CHD death). CHD mortality was reduced by 24% in thestatin group compared to the placebo group. No reduction in stroke was observed;however, transient ischemic attacks (TIAs) were reduced by 25%. Diagnosis of newcancer was unexpectedly found to be 25% more often in subjects on pravastatintreatment (p = 0.020). Pravastatin therapy did not improve cognitive function, nor didit retard progression of cognitive­related disabilities. The key finding of PROSPERwas the significant benefit of statin therapy in the high­risk elderly.

Figure 1

ASCOT­LLA (Anglo­Scandinavian Cardiac Outcomes Trial­Lipid Lowering Arm)

In the ASCOT­LLA study, 19,342 hypertensive patients, ages 40­79 years old, withthree or more cardiovascular risk factors in addition to hypertension, were

randomized to one of two antihypertensive regimens.11 A total of 10,305 subjectswere also randomly assigned to atorvastatin 10 mg/day or placebo. LDL­C levelsaveraged 132 mg/dl at baseline and were reduced by an average of 42 mg/dl (29%)in the atorvastatin­treated group at the end of the study.

The trial was stopped early for a significant reduction in the primary combinedendpoint of nonfatal MI and fatal CHD. At that time, 100 primary events had occurredin the atorvastatin group compared with 154 events in the placebo group (hazardratio [HR], 0.64; p = 0.0005). In the atorvastatin group, fatal and nonfatal stroke werereduced by 27% (p = 0.024), total cardiovascular events by 21% (p = 0.0005), andtotal coronary events by 29% (p = 0.0005). There was a nonsignificant trend toward areduction in total mortality in the atorvastatin group (13%; p = 0.16).The key finding ofASCOT­LLA was the significant benefit of statin therapy in primary prevention amongpatients with hypertension.

PROVE IT­TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy­Thrombolysis in Myocardial Infarction 22) Trial

The PROVE IT­TIMI 22 study was designed to compare intensive LDL­C loweringcompared to standard therapy to reduce major coronary events among high­risk

patients (i.e., recent acute coronary syndrome [ACS]).12 The intensive therapy armwas atorvastatin 80 mg/day compared to standard therapy of pravastatin 40 mg/day.A total of 4,162 patients recently hospitalized for an ACS (within the preceding 10days) were randomized to two treatment arms. The primary endpoint of the trial wasa composite of death from any cause, MI, documented unstable angina requiringrehospitalization, revascularization (performed at least 30 days after randomization),and stroke. Mean follow­up time was 24 months.

A greater reduction in LDL­C level was attained in the group randomized to 80 mg ofatorvastatin (62 mg/dl), as compared to those who received pravastatin 40 mg (95mg/dl). At the end of 2­year follow­up, a significant reduction in the primarycomposite cardiovascular endpoint was observed for the atorvastatin groupcompared to the pravastatin group (p < 0.005). Nonsignificant trends were observedin patients on atorvastatin therapy for total mortality (p < 0.07) and for death or MI (p <0.06). The high dose of atorvastatin was well tolerated, and no case of severemyopathy (rhabdomyolysis) was observed in either treatment group. Greater thanthreefold elevations of alanine aminotransferase (ALT) were observed in 3.3% ofpatients treated with atorvastatin versus 1.1% on pravastatin (p < 0.003).

The key finding of the PROVE IT­TIMI 22 study was the reduction in cardiovasculardisease events among patients with recent ACS events randomized to intensive­dose statin therapy.

The Heart Protection Trial: Major Vascular Events by LDL CholesterolFigure 1CI = confidence interval; LDL = low­density lipoprotein; SE = standard error.

Reproduced with permission from Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 20,536 high­risk individuals: a randomised placebo­controlled trial. Lancet 2002;360:7­22.

Landmark Trials Since the Adult Treatment Panel III Update

REVERSAL (Reversal of Atherosclerosis With Aggressive Lipid Lowering) Trial

Subjects (n = 502) in the REVERSAL trial were randomized to either aggressive lipid­lowering therapy with atorvastatin 80

mg/day or moderate lipid­lowering with pravastatin 40 mg/day.13 Intravascular ultrasound (IVUS) was performed atbaseline and at 18 months. Mean LDL­C levels at baseline were similar in both arms (152.2 mg/dl), while follow­up LDL­C was lower in the aggressive therapy arm (79 mg/dl vs. 110 mg/dl). By IVUS, atheroma volume had significantlyincreased in the group randomized to pravastatin 40 mg/day, whereas subjects randomized to atorvastatin 80 mg/daydemonstrated no change.

In a post­hoc analysis among subjects randomized to pravastatin whose LDL was <100 mg/dl, the percent change inatheroma still demonstrated progression of atherosclerosis. C­reactive protein (CRP) levels decreased more in theatorvastatin arm, as compared with the pravastatin arm (36.4% vs. 5.2%, p < 0.0001). No difference was observed inadverse events, death, or MI between the two treatment groups. This study suggests that although no difference wasobserved for hard endpoints such as MI (the trial was not powered to detect such endpoints), intensive­dose statinsprevent progression of atheroma, as measured by IVUS.

IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial

The IDEAL study compared high­dose statins with more moderate dosing.14 The IDEAL study found no difference in theprimary composite endpoint of major coronary events or secondary endpoints of CHD death, or cardiac arrest betweenthose randomized to atorvastatin 80 mg/day or simvastatin 20 mg/day. Lower rates of nonfatal MI were observed forsubjects on atorvastatin compared with subjects on simvastatin.

TNT (Treating to New Targets) Trial

The TNT study randomized subjects to either atorvastatin 80 mg/day or atorvastatin 10 mg/day (after completion of an 8­

week open­labeled run­in period where all subjects were on atorvastatin 10 mg/day).15 On­treatment mean LDL­C was77 mg/dl among those randomized to atorvastatin 80 mg/day and 101 mg/dl among those randomized to atorvastatin 10mg/day.

The primary endpoint (CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke) was lower in theintensively treated group, as compared to those treated with atorvastatin 10 mg/day (8.7% vs. 10.9%, p < 0.001).Secondary endpoints, including nonfatal MI and stroke, were also reduced in the group randomized to atorvastatin 80mg/day. These data suggest that intensive statin doses may be beneficial among patients with stable coronary arterydisease.

JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin)

The JUPITER trial, a randomized trial of rosuvastatin in the prevention of cardiovascular events among 17,802 apparently

healthy men and women with elevated levels of high­sensitivity CRP (hs­CRP), was a landmark trial published in 2008.16

Subjects with low LDL­C (<130 mg/dl) and hs­CRP ≥2 mg/L were randomized to either rosuvastatin 20 mg/day orplacebo. Additional inclusion criteria were age ≥50 years for men, ≥60 years for women, and no cardiovascular diseaseor diabetes. The trial was stopped early due to a significant reduction in the primary endpoint (MI, stroke, unstableangina/revascularization, and cardiovascular death) observed in the rosuvastatin group compared to placebo (hazardratio [HR], 0.56; 95% confidence interval [CI], 0.46­0.69).

Reductions in nonfatal and fatal MI, stroke, and revascularization were observed among those randomized to statintherapy. The benefits of rosuvastatin were noted for all subgroups. A modest increase in development of diabetes wasobserved with statin therapy (HR, 1.25; 95% CI, 1.05­1.54). The key finding of JUPITER was the benefit of statin therapyfor primary prevention among patients without significant elevations of LDL­C at baseline.

ACCORD (Action to Control Cardiovascular Risk in Diabetes) Trial

The ACCORD study examined combination therapy with a statin plus fibrate compared to statin therapy alone to reduced

cardiovascular disease events among subjects with type 2 diabetes.17 A total of 5,518 subjects were randomized toopen­label simvastatin with either masked fenofibrate or placebo. The primary outcome was first occurrence of nonfatalMI, nonfatal stroke, or cardiovascular disease mortality. Mean follow­up was 4.7 years.

The combination of fenofibrate and statin did not reduce rates of fatal cardiovascular disease events, nonfatal MI, ornonfatal stroke compared to statin therapy alone. These data suggest that for a majority of diabetic patients, addition of afibrate to statin therapy is not associated with significant benefit in terms of reducing future cardiovascular diseaseevents.

Pharmacotherapy for Low­Density Lipoprotein

Based on ATP III guidelines, the primary goal for most patients focuses on LDL­Clevels. Based on the presence or absence of coronary artery disease and/orcoronary artery disease risk equivalent, and concomitant risk factors, an LDL targetis determined. The results of studies such as HPS and PROVE IT support a lowerLDL­C goal than had been recommended in earlier guidelines. Thus, for patients atvery high risk such as those patients with coronary artery disease and diabetes, it isreasonable to target LDL for a goal of <70 mg/dl. Statin therapy is the first­line agentfor LDL lowering based on the numerous trials, several of which are outlined in thismodule.

After initiation of statin therapy, a repeat LDL­C and liver enzyme tests are performed.Statin dose is adjusted or combination therapy is initiated if the patient is not at goal(Table 6). After the target LDL­C levels are obtained, LDL levels and liver enzymesare checked every 4­6 months thereafter. All patients should be instructed intherapeutic lifestyle including regular exercise, and a diet high in fiber and low insaturated fats, along with maintenance of a healthy weight and avoidance ofsmoking, which are central to lipid management.

When patients cannot achieve their LDL goal with statins as monotherapy,consideration for combination therapy is recommended. Options for combinationtherapy include use of ezetimide, bile acid sequestrants, or nicotinic acid. Additionalnonpharmacologic interventions include the use of plant stanols/sterols incombination with a statin. Addition of fiber and soy may also be considered.

Bile acid sequestrants bind to bile acids in the gut, thus reducing reabsorption. Thesubsequent reduction in intrahepatic cholesterol leads to an increase in thesynthesis of apo B/E receptors, which bind LDL from the plasma, thus resulting infurther reductions in LDL­C. Bile acid can be used in combination with statins,nicotinic acid, and psyllium to achieve recommended LDL goals. Side effectsincluding gastrointestinal symptoms (nausea, bloating, and cramping), and theeffects on absorption of other drugs such as warfarin, limit its use. Liver enzymesshould be monitored every 4­6 months or with changes in medications. Nicotinicacid and fibrates are discussed in the following section.

Ezetimide is also used in combination with statins for lowering LDL­C. However, todate, data for ezetimide have not been shown to reduce significant outcomes, suchas MI. Given evidence of nonsignificant changes in intima­media thicknessmeasures with ezetimide and simvastatin compared to simvastatin alone, currentrecommendations call for ezetimide as a second­ or third­line agent, rather than aninitial treatment choice.

Table 6

LDL­C Average Reduction With Standard Doses of Currently Available StatinsTable 6LDL­C = low­density lipoprotein cholesterol

Pharmacotherapy for Non­High­Density Lipoprotein

Although current guidelines do not identify HDL­C levels for specific treatment goals, low HDL­C levels are associatedwith increased cardiovascular disease risk and are a key component of the metabolic syndrome. A combination of statinwith niacin can result in a reduction in LDL­C along with a rise in HDL­C. The concurrent LDL lowering with HDLincreasing results in a significant CHD risk reduction. Prior clinical trials support the use of niacin to both reduce LDL andincrease HDL.

Niacin

The HATS (HDL­Atherosclerosis Treatment Study) trial randomized subjects to four treatment arms; 1) simvastatin/niacin,

2) antioxidants, 3) simvastatin/niacin + antioxidants, and 4) placebo.18 LDL and HDL levels did not change in theantioxidant group or the placebo group. In the simvastatin/niacin group, LDL levels decreased by 42%, whereas HDLlevels increased by 26%. Similar changes were observed among those randomized to antioxidants withsimvastatin/niacin. Cardiovascular disease events were significantly lower among those randomized tosimvastatin/niacin (3%), compared to antioxidant + simvastatin/niacin (14%), antioxidants alone (21%), amd placeboalone (24%).

These findings support the use of combination statin/niacin for cardiovascular disease risk reduction, while addingfurther data to suggest antioxidants do little to reduce cardiovascular disease risk. As a result of these data and otherstudies, the FDA has approved a statin/niacin combination.

Niacin inhibits VLDL synthesis in the liver, resulting in lower LDL­C levels. It also raises HDL­C by reducing the transferof cholesterol from HDL to VLDL, and by reducing HDL clearance. A major side effect of niacin is prostaglandin­medicated flushing. Pretreatment of aspirin 30 minutes prior to taking niacin can reduce symptoms of flushing, andpruritus. Flushing often diminishes over a 7­ to 10­day period after initiation or dose increase. Liver enzymes should bemonitored with dose changes or every 4­6 months. Increase in uric acid precipitating gout is possible; thus, amongpatients with a history of gout, nicotinic acid should be avoided or used with caution. Patients and their providers shouldalso be aware of the potential for increase in glucose levels with nicotinic acid.

No flush over­the­counter preparations are ineffective for HDL raising (or LDL lowering), as they contain nicotinamide, theinactive form of the vitamin, rather than nicotinic acid. Nicotinic acid should be used with caution in patients with liverdisease, and may not be appropriate for those with gout or peptic ulcer disease.

Fibrates

Prior clinical trials with fibrates suggested a risk reduction for CHD events in patients with high triglycerides and low HDL­

C, particularly among patients with diabetes or criteria for the metabolic syndrome.19 However, recent results from

the ACCORD study do not confirm such benefits among patients with type 2 diabetes.17

Risk for adverse events, in particular myopathy, related to statin use increases with use of combination therapy such asfibrates. Fenofibrate is recommended since it does not interfere with the catabolism of statins, and thus, reduces the riskfor myopathies in patients on statin therapy. Caution should be used when prescribing fibrates in patients with liver orrenal dysfunction, and those with gallbladder disease.

Lipid Treatment Adverse Effects

Absolute contraindications to statin therapy include active liver disease and pregnancy, whereas relativecontraindications include use of cyclosporine, gemfibrozil, macrolide antibiotics, antifungals, and cytochrome P450inhibitors. For patients taking cyclosporine, pravastatin is the preferred statin. Monitoring for adverse effects includeschecking liver function tests (ALT/AST) at baseline, 6­8 weeks after dose changes, and 4­6 months when on a stabledose.

Elevated hepatic transaminases can be seen in up to 2% of patients taking statins. Abnormal levels are associated withincreased doses of statins, and can normalize with reduced doses or holding statin therapy. Statins have not beenassociated with poor outcomes among patients with hepatitis B or C. However, active or chronic liver disease isconsidered a contraindication to statin therapy. Pregnancy is also an absolute contraindication for statin therapy. Forwomen of childbearing age, counseling prior to conception is recommended, with cessation of the statin prior toconception.

The American College of Cardiology (ACC)/AHA/National Heart, Lung, and Blood Institute (NHLBI) Clinical Advisory on theUse and Safety of Statins recommends that clinicians be aware of factors that can increase risk for statin­associated

myopathy.20 These factors include advance age, particularly in women, small body frame and frailty, multisystem diseaseincluding chronic renal insufficiency due to diabetes, hypothyroidism, and multiple medications. Concomitant use ofmedications, including fibrates, cyclosporine, azole antifungals, itraconazole and ketoconazole, macrolide antibiotics,

erythromycin and clarithromycin, human immunodeficiency virus protease inhibitors, nefazodone, verapamil,amiodarone, and alcohol abuse, can increase the risk for myopathy. Intake of grapefruit juice over one quart per day canalso increase the risk for statin­associated myopathy.

Creatine phosphokinase (CPK) should be drawn at baseline, with repeat measures only when significant muscle achesare reported. Statin dose should be reduced or discontinued for a CPK level >10 times normal. Since a hypothyroid statecan predispose patients to myopathy, a thyroid stimulating hormone (TSH) should be checked. Rhabdomyolysis is rare,and is associated with an increased risk of mortality (~10%). Only 1 per 3,000 deaths occurred in patients taking both astatin and fibrate. Nonspecific muscle aches with minor or no CPK elevations are present in approximately 5% ofpatients, which is a similar rate observed among subjects randomized to placebo in several trials. In the past, concernhas been raised regarding potential dangers of reducing LDL­C to very low levels; however, in a large body of clinicaltrials, no significant side effects from LDL lowering have been identified.

Key Points

Patients are categorized by ATP III into three risk categories: 1) established CHD and CHD risk equivalents, 2)multiple (2+) risk factors, and 3) zero to one risk factor. CHD risk equivalents include noncoronary forms of clinicalatherosclerotic disease, diabetes, and multiple risk factors (2+) with a 10­years risk for CHD >20%. All personswith CHD or CHD risk equivalents can be called high risk.LDL­C remains the primary target of lipid treatment. Randomized controlled trials using statins suggest asignificant benefit to statin therapy to lower LDL­C. Recent trials suggest benefit to intensive­dose statin therapyfor patients at high or very high risk for cardiovascular disease events.Recent trials suggest a benefit to intensive­dose statin therapy for patients at high or very high risk forcardiovascular disease events. Thus, evidence is applicable to patient groups including women, the elderly,diabetics, minorities, and those with hypertension.Lipid treatment that fails to produce a sizable LDL­C reduction will not yield a significant reduction incardiovascular disease risk. For those at high risk, an LDL­C goal of <70 mg/dl is reasonable.Therapeutic lifestyle changes including exercise, dietary modification, and smoking cessation can lead tosubstantial improvements in lipids. All patients should be counseled regarding a healthy lifestyle.Current ATP III guidelines recommend that clinicians place increased emphasis on the metabolic syndrome inpatients who are already receiving LDL­C lowering therapy by additionally targeting the lowering of triglyceridesand raising HDL­C.The combination of a statin with niacin can produce a marked reduction in LDL­C, along with a significant risk inHDL­C, leading to reductions in CHD risk.

References

1. Roger VL, Go AS, Lloyd­Jones DM, et al., on behalf of the American Heart Association Statistics Committee andStroke Statistics Subcommittee. Heart disease and stroke statistics­­2011 update: a report from the AmericanHeart Association. Circulation 2011;123:e18­e209.

2. Pleis J, Lucas, L. Summary Health Statistics for US Adults; National Health Interview Survey, 2007. Hyattsville, MD:US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center forHealth Statistics, 2010. Vital and Health Statistics, Series 10, No. 249, DHHS publication No. 2009­1568.

3. [No authors listed]. Cholesterol treatment recommendations for adults. Highlights of 1987 report, NationalCholesterol Education Program Adult Treatment Panel. Md Med J 1988;37:24­5.

4. [No authors listed]. Summary of the second report of the National Cholesterol Education Program (NCEP) ExpertPanel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).JAMA 1993;269:3015­23.

5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary ofthe Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486­97.

6. Grundy SM, Cleeman JI, Merz CN, et al., on behalf of the National Heart, Lung, and Blood Institute; AmericanCollege of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for theNational Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227­39.

7. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientificstatement from the American Heart Association Nutrition Committee. Circulation 2006;114:82­96.

8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 20,536 high­risk individuals: a randomised placebo­controlled trial. Lancet 2002;360:7­22.

9. Shepherd J, Blauw GJ, Murphy MB, et al., on behalf of the PROSPER Study Group. PROspective Study ofPravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): arandomised controlled trial. Lancet 2002;360:1623­30.

10. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid­Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic,hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid­LoweringTreatment to Prevent Heart Attack Trial (ALLHAT­LLT). JAMA 2002;288:2998­3007.

11. Sever PS, Dahlof B, Poulter NR, et al., on behalf of the ASCOT Investigators. Prevention of coronary and strokeevents with atorvastatin in hypertensive patients who have average or lower­than­average cholesterolconcentrations, in the Anglo­Scandinavian Cardiac Outcomes Trial­­Lipid Lowering Arm (ASCOT­LLA): amulticentre randomised controlled trial. Lancet 2003;361:1149­58.

12. Cannon CP, Braunwald E, McCabe CH, et al., on behalf of the Pravastatin or Atorvastatin Evaluation and InfectionTherapy­Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering withstatins after acute coronary syndromes. N Engl J Med 2004;350:1495­504.

13. Nissen SE, Tuzcu EM, Schoenhagen P, et al., on behalf of the REVERSAL Investigators. Effect of intensivecompared with moderate lipid­lowering therapy on progression of coronary atherosclerosis: a randomizedcontrolled trial. JAMA 2004;291:1071­80.

14. Pedersen TR, Faergeman O, Kastelein JJ, et al., on behalf of the Incremental Decrease in End Points ThroughAggressive Lipid Lowering (IDEAL) Study Group. High­dose atorvastatin vs usual­dose simvastatin for secondaryprevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437­45.

15. LaRosa JC, Grundy SM, Waters DD, et al., on behalf of the Treating to New Targets (TNT) Investigators. Intensivelipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425­35.

16. Ridker PM, Danielson E, Fonseca FA, et al., on behalf of the JUPITER Study Group. Rosuvastatin to preventvascular events in men and women with elevated C­reactive protein. N Engl J Med 2008;359:2195­207.

17. Ginsberg HN, Elam MB, Lovato LC, et al., on behalf of the ACCORD Study Group. Effects of combination lipidtherapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563­74.

18. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for theprevention of coronary disease. N Engl J Med 2001;345:1583­92.

19. Keech A, Simes RJ, Barter P, et al. Effects of long­term fenofibrate therapy on cardiovascular events in 9795people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849­61.

20. Pasternak RC, Smith SC Jr, Bairey­Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisoryon the Use and Safety of Statins. Circulation 2002;106:1024­8.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.3: Nutrition and Obesity

Author(s): Amit Khera, MD, MSc, FACC Anand Rohatgi, MD, MSCS, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Apply the 2006 American Heart Association (AHA) diet and lifestyle recommendations to improve risk factors and health

outcomes in patients with cardiovascular disease (CVD) and those at risk for CVD.1

2. Recognize which dietary factors are and are not recommended for improving cardiovascular (CV) health.3. Utilize the National Institutes of Health (NIH) Practical Guide recommendations for promoting weight loss in overweight

and obese patients.2

4. Describe the appropriate use of pharmacologic therapy and bariatric surgery as therapeutic options for obesitymanagement.

Introduction

Despite major advances in medical therapies for reducing CV events, diet and lifestyle changes remain the most effectiveways to reduce the burden of CVD in the general public. Unfortunately, current dietary patterns, along with decreasingphysical inactivity, have led to epidemics in obesity and diabetes. Obesity and diabetes are both major risk factors forCVD.

A majority of the research has focused on individual nutrients, but it has become increasingly clear that overall healthyeating patterns ensure adequate nutrient intake and energy balance. Consistent with these findings, the AHA has set

goals for optimal healthy eating behaviors.1 In addition, the National Heart, Lung, and Blood Institute (NHLBI) has

synthesized the evidence to provide practical recommendations for the approach to obesity management.2

Nutrition Guidelines

In 2006, the AHA Nutrition Committee revised the diet and lifestylerecommendations to emphasize an overall healthy eating pattern, rather than

focusing on a specific nutrient or food.1 In addition to consuming a healthy diet, othergoals to reduce CV risk include: 1) aiming for a healthy body weight; 2) maintainingrecommended levels of low­density lipoprotein cholesterol (LDL­C), high­densitylipoprotein cholesterol (HDL­C), and triglycerides; and 3) maintaining normal bloodpressure (BP) and blood glucose levels. Other recommendations include: 1) beingphysically active, and 2) avoiding exposure to tobacco products. The specific dietaryrecommendations are shown in Table 1. These consist of a balanced diet with thefollowing limitations: 1) saturated fat intake to <7% of daily calories, 2) trans fat to<1% of daily calories, and 3) cholesterol to <300 mg/day. The recommendationsencourage increased consumption of oily fish, vegetables, fruits, and whole grain.Salt and alcohol consumption should be limited.

Goals for a healthy body weight target a body mass index (BMI) in the normal range

(i.e., 18.5­24.9 kg/m2) (Table 2). Increasing emphasis has been placed onprevention of weight gain during childhood and the subsequent adult years. This isbecause obesity is a strong risk factor for the development of CVD risk factors andfor CVD itself, and because weight loss can be challenging.

LDL­C levels are linearly related to an increasing CVD risk, and LDL remains theprimary lipoprotein target for CV risk reduction. Optimal LDL­C levels are <100 mg/dl(Table 2). Borderline high levels are 130­159 mg/dl, high levels are 160­189 mg/dl,and very high levels are ≥190 mg/dl. The strongest dietary determinants of LDL­Clevels are dietary saturated fatty acid and trans fatty acid intake. HDL­C andtriglycerides are also affected by dietary patterns and body weight. The criteria for themetabolic syndrome include HDL­C levels <40 mg/dl in men and <50 mg/dl inwomen, as well as triglyceride levels >150 mg/dl.

Optimal BP is a systolic BP <120 mm Hg and a diastolic BP <80 mm Hg (Table 2).However, the risk of CVD and renal disease increases throughout the range of BPswithout a specific threshold. Dietary factors have a central role in affecting BP, asdiscussed in the following sections. The optimal blood glucose level is ≤100 mg/dl,with diabetes defined as a fasting glucose level ≥126 mg/dl. Modest weight lossthrough reducing caloric intake and increasing physical activity can improve glucosecontrol, delay the onset of diabetes, and possibly prevent the incidence of diabetes

by more than 50%.3

Table 1

Table 2

American Heart Association 2006 Diet and Lifestyle Recommendations for Cardiovascular Disease Risk ReductionTable 1Reproduced with permission from Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientificstatement from the American Heart Association Nutrition Committee. Circulation 2006;114:82­96.

Optimal Targets for Reducing Cardiovascular Disease RiskTable 2BMI = body mass index; BP = blood pressure; LDL­C = low­density lipoprotein cholesterol.

Reproduced with permission from Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientificstatement from the American Heart Association Nutrition Committee. Circulation 2006;114:82­96.

Cardiovascular Effects of Specific Dietary Patterns

Low­Fat Diet

Observational studies and smaller randomized trials have suggested that diets lower in fats, particularly saturated fats,could result in improved CV outcomes. The largest randomized trial to date to test this hypothesis is the Women’s HealthInitiative Dietary Modification Trial. This trial included approximately 48,000 women who were randomized to a diet

targeting reduced total fat intake, as well as increased fruits, vegetables, and grains, versus no dietary change.4 Despitean 8.2% lower fat intake, women in the dietary intervention arm had no significant difference in rates of CV events. Thesenull results may be attributed to insufficient reductions in saturated fats (i.e., 2.9%) in the intervention arm, during an erawith generally lower overall saturated fat intake. However, it was also suggested that a global dietary pattern change maybe necessary to impact CV events, rather than a primary focus on one macronutrient.

Mediterranean Diet

Several large observational studies have demonstrated a reduction in total mortality and CVD mortality with theMediterranean style diet. This diet consists of an increased intake of monounsaturated fat, plant protein, whole grains,and fish; moderate consumption of alcohol; and low consumption of red and processed meat, whole­fat dairy products,and sweets.

In addition to observational studies, the randomized secondary prevention Lyon Heart Study demonstrated fewer fatal and

nonfatal CV events with the Mediterranean diet, as compared with the low­fat diet.5 Several recent substudies of theongoing randomized PREDIMED (Prevencion con Dieta Mediterranean) trial of two Mediterranean diets versus a low­fatdiet have elucidated the salutary effects of the Mediterranean diet on CV risk factors. This dietary pattern resulted insignificantly lower plasma glucose levels, lower systolic and diastolic BP, and a lower total cholesterol to HDL­C ratio, but

little change in LDL­C.6 More recently, the PREDIMED investigators also reported greater resolution of the metabolic

syndrome and a lower incidence of diabetes in those assigned to the Mediterranean diet.7

Dietary Approaches to Stop Hypertension Diet

The original randomized DASH (Dietary Approaches to Stop Hypertension) trial compared a control diet to a diet rich infruits, vegetables, and low­fat dairy foods, and with reduced saturated and total fat intake. The results demonstrated thatthose on the DASH diet had a significantly greater reduction in systolic and diastolic BP (i.e., 5.0 and 3.5 mm Hg,

respectively).8 The reduction was more substantial among those with diagnosed hypertension (i.e., 11.4 and 5.5 mm Hg,respectively). Subsequently, the DASH study group demonstrated that a low sodium diet and the DASH diet each had

beneficial effects on BP, but that the effects were greatest when both diets were combined.9

The most recent dietary guidelines from the US Department of Health and Human Services recommend a daily sodiumintake of <2300 mg/day for all adults, and <1500 mg/day for those who have hypertension or are at risk of hypertension.The at­risk groups include those over the age of 50, African Americans, and those with diabetes or chronic kidney

disease.10 However, a daily intake of <1500 mg may be a reasonable target for everyone.

Dietary Factors Potentially Affecting Risk Factors and Cardiovascular Risk

Omega­3 Fatty Acids

Multiple observational studies have consistently documented the association between fish intake and a decreased risk ofCVD. The AHA recommends that individuals without coronary heart disease (CHD) consume fish at least twice weekly,specifically oily fish such as tuna, mackerel, trout, or salmon. For patients with CHD, a total of 1 g of long­chain omega­3fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day is recommended, through

consumption of oily fish and/or supplements.1 Higher doses of 2­4 g daily of EPA/ DHA are required for treatment ofhypertriglyceridemia.

Fiber

In observational studies, increased total dietary fiber consumption has been associated with a reduced risk of CHD and

coronary death.11 Soluble or viscous fiber found in oats, barley, flax, psyllium, beans, peas, and nuts can modestly lowerLDL­C levels. This is accomplished by increasing short­chain fatty acid synthesis and thus reducing endogenous

cholesterol synthesis, as well as by increasing bile acid production.12 Insoluble fiber found in whole wheat, whole grains,green beans, and leafy vegetables, can enhance satiety and slow gastric emptying. Currently, >25 g/day of total fiber isrecommended for possibly improving CVD outcomes, and 10­25 g/day of soluble fiber is recommended for lipid­lowering

therapy. The AHA recommendations call for at least half of the grain intake to come from whole grains.1

Plant Stanols/Sterols

Plant sterols are chemically similar to animal cholesterol and can lower LDL­C by up to 15%, primarily by reducingcholesterol absorption in the intestines, but also through downstream biochemical effects of receptor binding. The

maximal effective intake is approximately 2 g/day.1 Plant stanols/sterols are available in a number of different types offood products with varying caloric and nutrient content. Whether intake of plant stanols/sterols is associated withdecreased risk remains to be determined. For example, a rare genetic form of a disease involving severely increasedplant sterol levels, sitosterolemia, results in premature CHD.

Alcohol

While alcohol use is not encouraged, for those currently consuming alcohol, the AHA recommends a limited intake of 2

servings/day in men and 1 serving/day in women.1 One serving equates to one­half ounce of alcohol, which is the contentof one 12 oz. bottle of beer, a 4 oz. glass of wine, and a 1.5 oz shot of 80­proof spirits. Epidemiologic data suggest thatthis quantity of alcohol may be associated with a lowered risk of CVD. However, it is not known whether initiating

consumption of alcohol in those who have previously abstained will lower CVD events.12

Dietary Factors With Unproven Effects

Antioxidant Supplements

Observational studies suggest there is a benefit of a high intake of antioxidant vitamins for lowering CVD risk. However,clinical trials of antioxidant supplements including vitamins C and E have not confirmed this benefit, despite witnessing

significantly higher blood levels in those randomized to taking these supplements.13 Importantly, some antioxidants havebeen associated with an increased risk of lung cancer (i.e., beta carotene) as well as heart failure and total mortality (i.e.,

vitamin E).14 While the use of antioxidant supplements is not supported, food sources containing antioxidant nutrients

are recommended. These include fruits, vegetables, whole grains, and vegetable oils.1

Folic Acid and Other B vitamins

Higher homocysteine levels have consistently been linked to modestly higher rates of CVD.15 Nevertheless, a recentmeta­analysis of eight large, randomized trials involving 37,485 individuals found no significant effect of folic acidsupplementation (with or without vitamins B12 and B6) on any of the CVD endpoints, even though there was an average

25% reduction in homocysteine levels in these studies.16 Thus, the AHA does not recommend folic acid and B vitamin

supplementation for CVD risk reduction.1

Soy Protein

Early studies suggested a favorable effect of soy protein on improving LDL­C levels. This was possibly because soyprotein replaced animal protein that was rich in saturated fat, or due to favorable effects on LDL receptors. However, theaggregate of evidence, including newer studies, demonstrates that even large amounts of soy protein consumption haveminimal effects on LDL­C (approximately 3% reduction) as compared to milk and other proteins. It has no significant

effect on HDL­C, triglycerides, lipoprotein, or BP.17 Similarly, soy isoflavones have not been found to have any significantCV benefits in randomized studies. Nevertheless, soy protein may be a good vegetable­based protein and an alternativeto animal and dairy products which contain higher saturated fat.

Omega­6 Polyunsaturated Fatty Acids Restriction

Linoleic acid is the primary dietary form of omega­6 polyunsaturated fatty acid (PUFA) (i.e., vegetable oils). It is convertedto arachidonic acid, which is the substrate for a host of both pro­ and anti­inflammatory molecules. Decreased intake oflinoleic acid has been advocated by some to reduce arachidonic acid production and thereby reduce the inflammatorystimulus for atherosclerosis and CHD.

However, evidence from both randomized trials and observational studies consistently shows that an intake of 5­10% ofenergy from omega­6 PUFA results in a decreased CHD risk compared with lower intake. Studies also show that a

higher intake is safe and possibly more beneficial.18 The AHA recommends at least 5­10% of energy in the form ofdietary omega­6 PUFAs. The 2001­2002 National Health and Nutrition Examination Survey found that the average USintake of linoleic acid, based on a 2000 kcal/day diet, was 6.7% of energy (14.8 g/day).

Obesity(1 of 2)

Obesity is termed an epidemic due to its dramatic rise in prevalence over the past 4

decades, from just 15% of the population to now over 30% of the population.19

Current classification schemes use BMI categories of 18.5 to <25 kg/m2 as normal

weight, ≥25 to <30 kg/m2 as overweight, and ≥30 kg/m2 as obese, with furthersubcategories of the obese group. These schemes have been developed by the NIH

and supported by the AHA and World Health Organization (WHO) (Table 3).20

The most recent estimates for the adult US population demonstrate that the overallprevalence of obesity is now 33.9%, with a higher prevalence among women ascompared with men (35.5 % vs. 32.2 %). The highest rates of obesity are amongAfrican Americans (44%), followed by Hispanics (38%), and then Caucasians

(33%).21 Importantly, overweight and obesity rates together comprise over two­thirds(68%) of the population.

While BMI is the most commonly used anthropometric measurement, waistcircumference can also identify those at a higher risk of adverse metabolicconsequences of adiposity. This is due to its close correlation with total abdominaland visceral fat. The NHLBI defines higher risk waist circumference values as those

>102 cm (40 inches) for men and >88 cm (35 inches) for women.20

Cardiovascular Consequences of Obesity

Several CV risk factors track with obesity and contribute to the increased risk of CVDevents in obese patients. Obese individuals are approximately three times morelikely to have hypertension and type 2 diabetes mellitus than normal weightindividuals, and they also more often have dyslipidemia, metabolic syndrome, and

obstructive sleep apnea.22,23 Independent of these risk factors, obesity conveys an

increased risk of all­cause mortality, CV death, stroke, and CHD.24 These

associations are manifest even with obesity measured in adolescence.25

However, in patients with known coronary artery disease or myocardial infarction,overweight and obesity may be associated with improved outcomes, particularly for

the overweight group. This observation is termed “the obesity paradox.”26 Additionalphysiologic changes accompanying obesity include increased circulating bloodvolume and cardiac output, higher cardiac wall stress, and increased fillingpressures. As such, obese individuals are more prone to left ventricular hypertrophy,

diastolic filling abnormalities, atrial fibrillation, and cardiomyopathy.27

Guideline Recommendations

Dietary Therapy

The Practical Guide developed by the NHLBI in 2000 remains the mainstay for

weight loss recommendations.2 This guide recommends weight loss therapy for all

individuals with a BMI >30 kg/m2. Weight loss therapy is also recommended for

those with a BMI 25­29.9 kg/m2, or an increased waist circumference and two ormore risk factors. The initial target goal for weight loss is 10% of body weight over 6months, accomplished by losing 1­2 pounds per week. This amount can beachieved by reducing calorie intake by 500­1000 kcal/day (i.e., 500 kcal/day x 7 days= 3500 kcal = 1 pound). This results in a target calorie intake of 1000­1200 kcal/dayfor most women, and 1200­1600 kcal/day for most men. After the initial weight lossperiod, the main goal is weight maintenance, with possible additional weight lossafter a period of stability.

Behavioral Therapy

In addition to dietary therapy, behavior therapy and increased physical activity are themajor components of weight loss therapy. Several behavioral strategies have beenevaluated, and the evidence suggests that weight loss success involves

Table 3

incorporating two or more strategies. These strategies include goal setting, selfmonitoring, feedback and reinforcement, enhancing self­efficacy, problem solving,

modeling behavior, and frequent and prolonged contact.28 One particularly effectivebehavioral strategy is motivational interviewing which involves eliciting the motivationto change, rather than imposing it, upon the individual. This is done by having thecounselor help direct the individual to resolve his or her own ambivalence.

Physical Activity

Current recommendations specify that all adults should engage in at least 30minutes a day of moderate­intensity physical activity at least 5 days a week. Thisamount of physical activity can both improve CV health and contribute towards a

negative calorie balance for weight loss.29 However, 60 minutes or more may be

required daily for weight loss or weight maintenance.29 This volume of physicalactivity may be accumulated in brief increments throughout the day rather than in onesetting.

Severely obese individuals or those who lead a very sedentary lifestyle may need tostart with very light or light activities, such as household chores or slow walking. Itshould be noted, however, that more weight loss occurs due to reducing caloricintake than increased physical activity; the latter may be more effective in preventing

weight gain.2

Classification of Overweight and Obesity by Body Mass Index Waist Circumference CategoriesTable 3† Disease risk for type 2 diabetes, hypertension, cardiovascular disease.* Increase waist circumference is >102 cm (40 inches) in men and >88 cm (35 inches) in women.

** Increased waist circumference can stratify risk primarily among those with body mass index (BMI) 25­34.9 kg/m2, and can also be a marker forincreased risk even in persons of normal weight.

Reproduced with modification from National Institutes of Health. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweightand Obesity in Adults­­The Evidence Report. Obes Res 1998;6 (Suppl 2):51S­209S.

Obesity(2 of 2)

Weight Loss Diets

Although caloric reduction is the major dietary contributor to weight loss, there ismuch interest in whether diets involving specific macronutrient patterns will result inmore weight loss than others. Several recent studies have directly compared diets ofvarying macronutrient composition. The A to Z Study (A to Z: A Comparative WeightLoss Study) compared four commercially available diets: Atkins (very lowcarbohydrate), Zone (low carbohydrate), LEARN (low fat, high carbohydrate), andOrnish (low fat, very high carbohydrate). The subjects were 311 overweight andobese postmenopausal women. The study reported that the Atkins diet led to the

most weight loss at 12 months.30

The DIRECT (Dietary Intervention­Randomized Controlled Trial) study comparedthree dietary patterns, rather than commercial diets. These were: 1) Mediterranean,restricted calorie; 2) low­fat, restricted calorie; and 3) low­carbohydrate, nonrestricted

calorie. The subjects were 322 overweight/obese individuals.31 After 2 years, theMediterranean and low­carbohydrate groups lost significantly more weight than thelow­fat diet group. The greatest increases in HDL and reductions in triglyceridesoccurred in the low­carbohydrate group. However, the low­carbohydrate groupactually had lower caloric intake than the others, and the low­fat group had higher fatintake than advised.

A more recent randomized trial evaluated the impact of four diets with varyingamounts of fat, protein, and carbohydrates in 811 overweight/obese men andwomen over a 2­year period. Similar foods were used in the diets to maintain the

double­blind design.32 The overall weight loss was similar between the differentdiets regardless of nutrient composition. However, across the groups, there was astrong association between adherence to group counseling sessions and weightloss. It can be concluded from this trial that the macronutrient composition of a dietprobably is not as critical as caloric restriction and adherence to a weight lossprogram. CV risk factors improve in general with diverse weight loss diets, despiteminor differences in risk factor changes related to the specific composition of thediet.

Currently, there are no large randomized studies evaluating the effects of weightloss on clinical CVD outcomes. However, the Look AHEAD (Action for Health in

Diabetes) trial of 5,100 individuals with diabetes and a BMI >25 kg/m2 (mean BMI

~36 kg/m2) has provided some valuable insight into the potential improvements in

CVD risk factors with intensive lifestyle interventions.33 As compared with usualcare, the intensive intervention resulted in a mean 8.6% weight loss at 1 year, whichwas accompanied by significantly greater improvements in glycated hemoglobin (­0.50%), systolic BP (­4.0 mm Hg), HDL­C (+2.0 mg/dl) and triglycerides (­15.7mg/dl). Thus, a modest amount of weight loss with diet and lifestyle interventionscan be associated with meaningful beneficial changes in multiple metabolicparameters.

Pharmacologic Therapy

Pharmacotherapy can be considered for those with a BMI ≥30 kg/m2. It can also be

considered for those with a BMI of 27 kg/m2 and a weight­related comorbidity, who

do not have sufficient weight loss after 6 months of lifestyle changes (Table 4).2

Currently, only one medication, orlistat, is approved by the US Food and Drug

Administration (FDA) for long­term treatment of obesity.34 The other agent previouslyapproved, sibutramine, was recently withdrawn from the market by the FDA due toevidence of increased CV risk in patients with established CVD. Orlistat and its lesspotent over­the­counter form, Alli, work by inhibiting gastric and pancreatic lipase,thus reducing dietary fat absorption by approximately 30%. This therapy results in amodest ~3% weight loss. Compared with a placebo, orlistat has been shown toslightly improve LDL­C levels, BP, and fasting glucose. However, the commongastrointestinal side effects from fat malabsorption limit its long­term tolerability.

Table 4

Figure 1

Several sympathomimetic agents are FDA approved only for short­term treatment ofobesity (i.e., ≤12 weeks). Phentermine and diethylpropion are the most commonly

prescribed of these agents.34 These amphetamine derivatives help suppress theappetite by enhancing the release of dopamine and norepinephrine. They arecontraindicated in individuals with CVD and moderate to severe hypertension,hyperthyroidism, and glaucoma. Recently, three different agents in development forpotential weight loss indications failed to gain FDA approval, due to side effects orlack of long­term safety data.

Bariatric Surgery

Currently, the NIH supports bariatric surgery as an option for patients with a BMI >40

kg/m2. It is also an option for patients with a BMI >35 kg/m2 who have seriouscomorbid conditions including hypertension, diabetes, sleep apnea, and coronary

artery disease.20 It is most appropriate in those who have failed attempts at lifestyleand medical therapy, and who are at acceptable operative risk.

The operations include either restrictive procedures that reduce the gastric size anddelay gastric emptying, or malabsorptive procedures that bypass portions of thesmall intestine. The three most common procedures include the laproscopicadjustable gastric banding, vertical sleeve gastrectomy, which are both restrictiveprocedures, and Roux­en­Y gastric bypass, which is a combined restrictive and

malabsorptive procedure (Figure 1).35 In general, all three procedures arereasonably safe, with a major complication rate of approximately 4%. There is aslightly higher risk of mortality with the gastric bypass and vertical sleeve

gastrectomy (0.5%), as compared with the adjustable band procedure (0.1%).35

However, weight loss is usually slower and of a lesser amount with the adjustableband procedure.

In addition to meaningful weight loss, bariatric surgery leads to notableimprovements in BP, lipids, and especially diabetes. For example, severalobservational studies have demonstrated a three­ to four­fold greater resolution ofclinical diabetes in those undergoing bariatric surgery as compared with usual care,

with approximately 75% showing remission in the early period.36 Triglycerides arealso significantly reduced and HDL­C is modestly increased, but there is littlechange in LDL­C levels with these procedures.

A few recent large, observational studies have confirmed and extended the findingsof prior smaller studies, which showed that bariatric surgery may confer a survivalbenefit. The SOS (Swedish Obese Subjects) study was a prospective, matched,observational study of 4,047 subjects. The study demonstrated a 27% relative riskreduction in death in the bariatric surgery group after a mean of 10.9 years, with a

numerical reduction in CV deaths.37 Due to the salutary effects on weight, riskfactors, and possibly mortality, there is interest in extending the scope of bariatric

surgery to include the BMI category of 30­34.9 kg/m2. However, current data areinsufficient to firmly support this practice. 

Recommendations for Treatment Strategies by Body Mass Index CategoryTable 4Reproduced with permission from National Institutes of Health; National Heart, Lung, and Blood Institute; and North American Association for theStudy of Obesity. 2000.The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Available at:http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf. Accessed 11/07/2011.

Common Types of Bariatric Surgery ProceduresFigure 1Reproduced with permission from DeMaria EJ. Bariatric surgery for morbid obesity. N Engl J Med 2007;356:2176­83.

Key Points

The AHA Diet and Lifestyle Recommendations emphasize an overall healthy eating pattern, rather than focusingon a specific nutrient or food.Specific dietary recommendations consist of a balanced diet with limitations of saturated fat intake to <7% of dailycalories, trans fat to <1% of daily calories, and cholesterol to <300 mg/day. Recommendations also includeincreased consumption of oily fish, vegetables, fruits, and whole grain, and limitation of salt and alcohol.All adults should consume 2 servings of oily fish per week that are rich in long­chain omega­3 fatty acids (EPAand DHA). One gram per day of EPA and DHA is recommended in those with established CHD.Antioxidant vitamin supplements (i.e., vitamins C and E) and folic acid supplementation have not been shown toreduce CV events and are not recommended for CV risk reduction.

Obesity is defined as a BMI >30 kg/m2, while overweight is defined as 25­29.9 kg/m2, and normal weight is

defined as 18.5­24.9 kg/m2.An increased waist circumference of >40 inches for men and >35 inches for women is associated with a higherrisk of adverse metabolic consequences of adiposity, even in those who are not obese.According to the NHLBI Practical Guide, an initial approach to weight loss should include a goal of 1­2 lbs perweek by reducing caloric intake by 500­1000 kcal/day, with an initial weight loss goal of 10% of body weight in 6months.Caloric restriction and adherence to a weight loss program are more important than the specific macronutrientcomposition of a weight loss diet.In addition to dietary therapy, behavioral therapy and increased physical activity are the major components ofweight loss therapy.

Pharmacologic therapy may be appropriate for those with a BMI >27 kg/m2 with comorbidity, or for those with a

BMI >30 kg/m2. Orlistat is currently the only FDA­approved agent for long­term weight loss.

Bariatric surgery is considered an appropriate option for patients with a BMI >40 kg/m2 or those with a BMI >35

kg/m2 with serious comorbid conditions including hypertension, diabetes, sleep apnea, and coronary arterydisease.Bariatric surgery can lead to significant improvements in body weight, lipids, and particularly in diabetes, withpossible improvements in mortality.

References

1. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientificstatement from the American Heart Association Nutrition Committee. Circulation 2006;114:82­96.

2. National Institutes of Health; National Heart, Lung, and Blood Institute; and North American Association for theStudy of Obesity. 2000.The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity inAdults. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf. Accessed 11/07/2011.

3. Knowler WC, Barrett­Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyleintervention or metformin. N Engl J Med 2002;346:393­403.

4. Howard BV, Van Horn L, Hsia J, et al. Low­fat dietary pattern and risk of cardiovascular disease: the Women'sHealth Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295:655­66.

5. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha­linolenic acid­rich diet in secondary prevention ofcoronary heart disease. Lancet 1994;343:1454­9.

6. Estruch R, Martínez­González MA, Corella D, et al. Effects of a Mediterranean­style diet on cardiovascular riskfactors: a randomized trial. Ann Intern Med 2006;145:1­11.

7. Salas­Salvadó J, Bulló M, Babio N, et al. Reduction in the incidence of type 2 diabetes with the Mediterranean diet:results of the PREDIMED­Reus nutrition intervention randomized trial. Diabetes Care 2011;34:14­9.

8. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASHCollaborative Research Group. N Engl J Med 1997;336:1117­24.

9. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the DietaryApproaches to Stop Hypertension (DASH) diet. DASH­Sodium Collaborative Research Group. N Engl J Med2001;344:3­10.

10. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines forAmericans, 2010. 7th Edition, Washington, DC: U.S. Government Printing Office, December 2010.

11. Pereira MA, O'Reilly E, Augustsson K, et al. Dietary fiber and risk of coronary heart disease: a pooled analysis ofcohort studies. Arch Intern Med 2004;164:370­6.

12. Van Horn L, McCoin M, Kris­Etherton PM, et al. The evidence for dietary prevention and treatment of cardiovasculardisease. J Am Diet Assoc 2008;108:287­331.

13. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitaminsupplementation in 20,536 high­risk individuals: a randomised placebo­controlled trial. Lancet 2002;360:23­33.

14. Miller ER III, Pastor­Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta­analysis: high­dosage vitaminE supplementation may increase all­cause mortality. Ann Intern Med 2005;142:37­46.

15. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta­analysis. JAMA 2002;288:2015­22.

16. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovasculardisease, cancer, and cause­specific mortality: Meta­analysis of 8 randomized trials involving 37 485 individuals.Arch Intern Med 2010;170:1622­31.

17. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris­Etherton P, Winston M. Soy protein, isoflavones, andcardiovascular health: a summary of a statement for professionals from the american heart association nutritioncommittee. Arterioscler Thromb Vasc Biol 2006;26:1689­92.

18. Harris WS, Mozaffarian D, Rimm E, et al. Omega­6 fatty acids and risk for cardiovascular disease: a scienceadvisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity,and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation2009;119:902­7.

19. Kumanyika SK, Obarzanek E, Stettler N, et al. Population­based prevention of obesity: the need for comprehensivepromotion of healthful eating, physical activity, and energy balance: a scientific statement from American HeartAssociation Council on Epidemiology and Prevention, Interdisciplinary Committee for Prevention (formerly theexpert panel on population and prevention science). Circulation 2008;118:428­64.

20. National Institutes of Health. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight andObesity in Adults­­The Evidence Report. Obes Res 1998;6 (Suppl 2):51S­209S.

21. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999­2008.JAMA 2010;303:235­41.

22. Brown CD, Higgins M, Donato KA, et al. Body mass index and the prevalence of hypertension and dyslipidemia.Obes Res 2000;8:605­19.

23. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity­related health risk factors,2001. JAMA 2003;289:76­9.

24. Kurth T, Gaziano JM, Berger K, et al. Body mass index and the risk of stroke in men. Arch Intern Med2002;162:2557­62.

25. Tirosh A, Shai I, Afek A, et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Engl J Med2011;364:1315­25.

26. Romero­Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and withcardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006;368:666­78.

27. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of

weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and HeartDisease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation2006;113:898­918.

28. Artinian NT, Fletcher GF, Mozaffarian D, et al. Interventions to promote physical activity and dietary lifestyle changesfor cardiovascular risk factor reduction in adults: a scientific statement from the American Heart Association.Circulation 2010;122:406­41.

29. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults fromthe American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081­93.

30. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change inweight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: arandomized trial. JAMA 2007;297:969­77.

31. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low­carbohydrate, Mediterranean, or low­fat diet. N EnglJ Med 2008;359:229­41.

32. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight­loss diets with different compositions of fat, protein, andcarbohydrates. N Engl J Med 2009;360:859­73.

33. Look AHEAD Research Group, Pi­Sunyer X, Blackburn G, et al. Reduction in weight and cardiovascular diseaserisk factors in individuals with type 2 diabetes: one­year results of the look AHEAD trial. Diabetes Care2007;30:1374­83.

34. Powell TM, Khera A. Therapeutic approaches to obesity. Curr Treat Options Cardiovasc Med 2010;12:381­95.35. Poirier P, Cornier MA, Mazzone T, et al. Bariatric surgery and cardiovascular risk factors: a scientific statement from

the American Heart Association. Circulation 2011;123:1683­1701.36. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and

meta­analysis. Am J Med 2009;122:248­256.37. Sjöström L, Narbro K, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N

Engl J Med 2007;357:741­52.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.4: Smoking Cessation

Author(s): Donna M. Polk, MD, MPH, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Discuss the contribution of tobacco abuse as a modifiable cardiovascular risk factor in the development ofatherosclerosis and cardiovascular events.

2. Explain how to improve abstinence rates through systematic identification of smokers and through providing tools to helpsmokers quit.

3. Identify the pharmacologic agents used to help improve abstinence rates.

Introduction

Tobacco use is associated with significant morbidity and mortality, and in the United States, over 435,000 deaths are

attributed to its use annually.1 Although the number of smokers in the United States has declined over the last decade,nearly 19.3% of all adults over the age of 18 are current cigarette smokers, with significant regional, age, gender, and

ethnic differences.2 More men than women are current smokers (21.5% vs. 17.3%).2

Among various ethnic groups, American Indian or Alaskan Native adults (31.4%) have the highest rates of smoking,

whereas Asian (9.2%) and Hispanic adults (12.5%) are the least likely to smoke cigarettes.2 Adults ages ≥65 years arethe least likely to be current smokers (9.5%). With more than 70% of current smokers having expressed a desire to quit,the systematic identification, assistance with cessation, and follow­up of smokers allows the clinician a tremendousopportunity to greatly impact the health of smokers.

Smoking and Cardiovascular Risk

Cigarette smoking is a major modifiable risk factor in the development of atherosclerosis, myocardial infarction (MI), and

mortality after revascularization.3­5 Smoking cessation improves outcomes in patients post­MI and postrevascularization.

In the OASIS (Organization to Assess Strategies in Acute Ischemic Syndromes) trial, which included >18,000 patientswith acute coronary syndrome, quitting smoking was associated with an odds ratio (OR) of 0.57 (95% confidence interval

[CI], 0.36­0.89) for MI as compared with continued smoking.6 In patients with left ventricular dysfunction after MI, patientswho stopped smoking had a 40% lower hazard of all­cause mortality and a 30% lower hazard of death or recurrent MI or

death or heart failure hospitalization at 42­month follow­up in the SAVE (Survival and Ventricular Enlargement) trial.7

In a long­term follow­up of 1,521 patients after MI, there was a hazard ratio (HR) of 0.63 (95% CI, 0.48­0.82) for patientswho quit after the MI, and a reduction in mortality for those who reduced the amount they smoked: an 18% decline in

mortality for every reduction of five cigarettes.8 In patients who have been revascularized, there is a higher total mortalityrate (all­cause mortality relative risk [RR], 1.68; 95% CI, 1.33­2.13; and cardiac death risk, RR, 1.75; 95% CI, 1.30­2.37),as well as higher rates of repeat revascularization (RR, 1.41; 95% CI, 1.02­1.94), as seen in a 20­year follow­up study

after coronary artery bypass grafting.9

Over time, quitting smoking after MI reduces the risk of recurrent events to that of a nonsmoker within 3 years.10 In asystemic review by Critchley and colleagues, the reduction of all­cause mortality from smoking cessation holds true

regardless of age, gender, type of cardiac event, and country studied.11

Pathophysiology

There are several mechanistic pathways whereby cigarette smoking, either active orpassive exposure, leads to the development of atherosclerosis and cardiovasculardisease (CVD). These include vasomotor and endothelial dysfunction, inflammatoryresponses, adverse effect on lipids, platelet dysfunction, and changes in

coagulation (Figure 1).3,12­20

Endothelial dysfunction is a precursor to atherosclerosis and exposure to tobacco

impairs nitric oxide availability and endothelial function.3,12,13 This dysfunction is

associated with acute, chronic, and passive exposure to tobacco smoke.12,13

Smoking cessation leads to improved endothelial function, as well as reduced

arterial stiffness.14,15 Acute exposure to cigarette smoking can cause acutevasospasm and increased total coronary vascular resistance, and thus, increase

the myocardial oxygen demand in smokers.16

Inflammation also plays a role in the activation of leukocytes and the development of

atherosclerosis.3 Circulating leukocytes and multiple inflammatory markersincluding C­reactive protein (CRP), interleukin­6, and tumor necrosis factor are

elevated in smokers.3,17 Exposure to tobacco smoke also increases the levels ofvascular cell adhesion molecule (VCAM)­1, intercellular adhesion molecule (ICAM)­1, and E­selectin, thus increasing the cell­to­cell interaction, recruitment of

leukocytes, and the development of atherosclerosis.3

The fibinolytic/thrombogenic balance is also impaired in smokers.3 Plateletsbecome activated, fibrinogen levels are increased, endothelial cells produce lesstissue plasminogen activator and plasminogen activator inhibitor­1, and there is

reduced thrombolytic capacity during acute coronary events in smokers.3,18,19

Cigarette smoking is associated with a less favorable lipid profile, with smokershaving higher total cholesterol, triglycerides, low­density lipoprotein cholesterol

(LDL­C) levels, and lower high­density lipoprotein cholesterol (HDL­C) levels.3,20

There are increased levels of oxidized LDL­C particles and antibodies against

oxidized LDL­C in smokers.3,21 Smoking cessation improves levels of HDL­C, but

not the LDL­C number or particle size.20

Figure 1

Potential Pathways and Mechanisms for Cigarette Smoking­Mediated Cardiovascular DysfunctionFigure 1METC = mitochondial electron transport chain; NADPH = nicotinamide adenosine dinucleotide phosphate; NO = nitric oxide; NOS = nitric oxidesynthase; ONOO = peroxinitrate.

Reproduced with permission from Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: An update. JAm Coll Cardiol 2004;43:1731­7.

Smoking Cessation

Of the more than 43 million smokers in the United States, nearly 70% want to quit

smoking.2,22 Unaided, their success rate is only 4­7%.22 Smokers with recentdiagnoses of stroke, cancer, lung disease, heart disease, or diabetes mellitus were3.2 times more likely to quit smoking and those with multiple diagnoses were 6.1

times more likely to quit.23 Assistance with cessation in the form of quit lines, groupand individual counseling, nicotine, and prescription agents can significantlyincrease quit rates. Each interaction a smoker has with the health care provider isan opportunity to promote smoking cessation. A physician's advice to quit smoking

increases cessation rates by 30%.22

Tobacco use is a chronic health issue, and smokers often make multiple attemptsat quitting, so it is important for each interaction with the health care system toidentify smokers and their readiness to quit. A systematic approach to all smokerscan improve cessation rates. The "5 A's" (ask, advise, assess, assist, and arrange

follow­up) is an effective model for this purpose (Table 1).24

Patients should be asked at every encounter about tobacco use. The identification ofsmokers is the first step in smoking cessation. Often, systemic reminders arerequired to help identify smokers for the busy health care provider. One example isto include smoking status in the vital signs so that smoking status is readily

identifiable (Table 2).24 Documentation of smokers through electronic health record

reminders significantly increased the identification of smokers (17% vs. 11%; p 25

The next step is to advise every smoker to quit, with personalized informationregarding the health benefits of cessation.

The next critical step in successful smoking cessation is to assess the smoker'sreadiness to quit. The Prochaska stages­of­change model for behavior change is a

useful tool in assessing a smoker's ability to quit.26 Individuals are described asbeing at a point in the stages­of­change model from precontemplation,contemplation, preparation, action, to maintenance. It is important to identify wherethey are to help them advance to successful cessation.

In the precontemplation stage, individuals do not intend to make a change in thenext 6 months. Contemplation is the next stage, where a smoker is seriouslythinking about changing in the next 6 months. Those in preparation intend to changein the next month. Often these individuals have tried to quit within the last year andare taking steps toward action, such as cutting down on tobacco use. Those thathave quit smoking within the last 6 months are in the action stage and are atgreatest risk for relapse. Maintenance is the continuation of a healthier lifestyle.

Identification of the stage a smoker is in will help focus the provider's intervention,such as education of a precontemplator or providing counseling and/orpharmaceutic therapies to a person in the preparation stage. It is important tocontinually assess the readiness of the patients to make lifestyle changes and toassist them as they move along the spectrum of the stages­of­change model. Forthose smokers who are not ready to quit, clinicians should assess barriers tochange as well as provide information about the relevance, risks, and rewards that

result from smoking cessation (Table 3).24

The next step in the "5 A's" model is to assist the patient in quitting throughresources, counseling, and medication. Setting a quit date in the near future canhelp focus the action strategy. Preparations, such as making the home smoke­free,can help with a smoker's successful quit attempt. Clinicians can help smokersutilize the time prior to the quit date to identify triggers and challenges and to developcoping strategies for them. If pharmacologic therapy is part of the quit plan, it shouldbe started during this phase.

Arranging follow­up for smokers who are quitting is critical in helping them remainabstinent. Most relapses occur within the first 3 months. Early contact within the firstweek, either by phone or in person, should be arranged with a second follow­up in

the first month to maximize success rates.22

Table 1

Table 2

Table 3

The “5 A’s” Model for Treating Tobacco Use and DependenceTable 1Reproduced with permission from Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Quick referenceguide for clinicians. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2009.

Identification of Tobacco UsersTable 2a Repeated assessment is not necessary in the case of the adult who has never used tobacco or has not used tobacco for many years and forwhom this information is clearly documented in the medical record.

b Alternatives to expanding the vital signs include using tobacco use status stickers on all patient charts or indicating tobacco use status viaelectronic medical records or computerized reminder systems.

Reproduced with permission from Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Quick referenceguide for clinicians. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2009.

Enhancing Motivation to Quit Tobacco—The “5 R’s”Table 3Reproduced with permission from Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Quick referenceguide for clinicians. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2009.

Smoking Cessation Support

Physical dependence as well as psychosocial factors contributes to the addictive nature of tobacco, and the combinationof pharmacotherapy and counseling can be effective for smoking cessation. Counseling alone can improve quit rates

and can be as little as a brief counseling session by a physician during an office visit.27 Cessation rates can be

increased by 30% with 3 minutes or less of counseling.22 Effective counseling can be performed by trained counselors

individually or in groups, face to face, by phone, phone and Internet, or via mobile text messaging.22,28­30

In a meta­analysis of 16,050 smokers and 13,499 controls, there was a significant effect of web­based and computer­based interventions on increasing cessation rates (RR, 1.44; 95% CI, 1.27­1.64) with long­term (12­month) cessation

rates of 9.9% (95% CI, 8.9­10.9) versus 5.7% (95% CI, 5.1­6.3).30

Although some studies show higher abstinence rates with more comprehensive interventions, not all counseling studies

have shown increased long­term quit rates.31 In 16 randomized controlled trials reviewed, there was heterogeneitybetween trials, but overall 6­ to 12­month abstinence rates were improved with behavioral therapies and self­help

materials (OR, 1.44; 95% CI, 0.99­2.11).32 The addition of pharmacologic treatment increases long­term abstinence

rates in smokers.22,31

Pharmacotherapy

Nicotine Replacement

The Food and Drug Administration (FDA) has approved five different types of nicotinereplacement therapy (NRT): transdermal patch, gum, lozenge, nasal spray, andinhaler. These have been the mainstay of smoking cessation aids because they arereadily available over the counter. The use of these therapies can double long­termabstinence rates and, as with all pharmacotherapies used to assist smoking

cessation, success is enhanced with the addition of counseling.22,33

Cigarettes deliver a spike of nicotine to the smoker and thus reinforce the addictivenature of nicotine (Figure 2). Nicotine replacements deliver nicotine in lower levelsand in a more time­released fashion. Nicotine patches come in several doses andan effective starting dose can be estimated by the number of cigarettes used perday. The most common side effects are local skin reactions, insomnia, and vividdreams. Patches should be placed on the skin each morning and can be removedat bedtime for individuals who experience side effects. Duration of treatment is 8weeks.

Nicotine gum can be used alone or in conjunction with a nicotine patch. There aretwo doses available: a 2 mg dose appropriate for those who smoke <25 cigarettes a

day, and a 4 mg dose for those who smoke >25 cigarettes per day.22 Smokers havebetter success if they use the gum in a scheduled manner (at least 1 piece every 1­2

hours).34 It is important to instruct patients in the proper use of the nicotine gum inorder to prevent the most common side effects, such as mouth soreness, jaw ache,dyspepsia, and hiccups. The gum should be chewed slowly until a peppery taste issensed, and then parked between the cheek and the gum for a few minutes, then

chewed again over a 30­minute period.22 Duration of treatment is 8­12 weeks.

Nicotine lozenges can be used with or without concurrent transdermal nicotine. It isavailable in 2 or 4 mg doses and should be dissolved in the mouth. Recommendeddose is nine lozenges a day, with a maximum of 20 per day and tapered over time.Most common side effects are dyspepsia, hiccups, nausea, headache, and cough.Recommended duration of treatment is up to 12 weeks.

The nicotine nasal spray has an initial spike of nicotine that is lower than thatdelivered by a cigarette but faster than any of the nicotine delivery systems (Figure 2).

Because of rapid delivery of nicotine, it has the highest dependency potential.22 It isavailable by prescription only. The dose is 1 mg (0.5 mg per nostril), with 1­2 dosesper hour. Maximum treatment is eight doses per day. Most common side effects arenasal congestion, nasal irritation, and changes in taste and smell, all of whichusually improve after the first week of treatment. Duration of treatment is up to 6months.

Nicotine inhaler is available by prescription only, and vaporized nicotine is deliveredto the buccal mucosa with each puff. It takes approximately 80 puffs over 20 minutesto deliver 2­4 mg of nicotine, and the recommended daily dose is 6­16 cartridges perday. The most common side effects are local irritation and cough. Recommendedduration of use is up to 6 months.

NRT is not associated with increased CV risk in patients with and without coronary

artery disease.22,35,36 The NRT package inserts do, however, caution the use ofthese products in individuals within 2 weeks after MI, in unstable angina, or in

patients with serious arrhythmias.22

Non­Nicotine Therapy

Sustained­Release Bupropion

Bupropion is a monocyclic antidepressant that inhibits the reuptake of dopamineand norepinephrine, and is FDA approved for smoking cessation. Initial therapyshould be started at 150 mg/d for 3 days, and then increased to 150 mg twice daily.Bupropion therapy should begin 1 week prior to the quit date, but can be used within

Figure 2

the first 2 weeks after an MI.22 It is contraindicated in individuals with a history ofseizures or eating disorders. Most common side effects are insomnia, dry mouth,and occasional hypertension. Duration of treatment is 7­12 weeks, but can be usedin lower doses for up to 6 months.

Varenicline

Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist that is FDA

approved for use in smoking cessation.37 Initial therapy, started 1 week before thequit date, is 0.5 mg once daily for 3 days, then 0.5 mg twice daily for 4 days, and then1 mg twice daily. Patients with kidney disease or who are on dialysis should receive

lower doses.22

An additional warning has been added by the FDA to alert health care providers tochanges in mood, behavior, or suicidal ideation. Side effects include nausea,trouble sleeping, and vivid dreams. Varenicline has recently been studied in patients

with CVD and did not increase CV events or mortality.38 Duration of therapy is 3months, but this may be extended to 6 months.

Clonidine

Clonidine is a second­line agent for the treatment of tobacco abuse and is not FDAapproved for this use. It can be given orally (0.15­0.75 mg/d) or transdermally (0.1­

0.2 mg/d) starting up to 3 days before the quit date.22 It should not be stoppedabruptly in order to avoid rebound hypertension. Side effects include dry mouth,

drowsiness, dizziness, and constipation.22

Nortriptyline

Nortriptyline is a tricyclic antidepressant that can be used as a second­line agent forsmoking cessation, but is not FDA approved for this use. The usual dose is 75­150mg/d. Most common side effects are dry mouth, sedation, and dizziness. Because ofthe risk of cardiac arrhythmias, it should be used with caution with patients withCVD. Usual duration of therapy is 12 weeks, but this can be extended to 6 months.

Plasma Nicotine LevelsFigure 2Plasma nicotine levels after a smoker has smoked a cigarette, received nicotine nasal spray, begun chewing nicotine gum, or applied a nicotinepatch. The amount of nicotine in each product is given in parentheses. The pattern produced by the use of the nicotine inhaler (not shown) issimilar to that for nicotine gum.

Reproduced with permission from Rigotti NA. Treatment of tobacco use and dependence. N Engl J Med 2002;346:506­12.

Abstinence Rates

NRT nearly doubles the abstinence rate over placebo both as a monotherapy and incombination with prescription therapies, as seen in a meta­analysis by Fiore and

colleagues (Table 4).22 The highest quit rates at 6 months were in smokers whoused long­term nicotine patches (>14 weeks) with ad lib nicotine gum or spray (OR,

3.6; 95% CI, 2.5­5.2).22 The average 6­month abstinence rate in these three studies

Table 4

3.6; 95% CI, 2.5­5.2). The average 6­month abstinence rate in these three studieswas 36.5% (95% CI, 28.6­45.3). The use of varenicline as a monotherapy produced

quit rates of 33.2% (95% CI, 28.9­37.8), with an OR of 3.1 (95% CI, 2.5­3.8).22

The lowest quit rates were seen in the 15 studies that utilized nicotine gum with anOR of 1.5 (95% CI, 1.2­1.7). In a recent study comparing the effectiveness of fivesmoking cessation pharmacotherapies, patch plus lozenge resulted in 6­monthcarbon dioxide confirmed abstinence of 40.1% as compared with 33.2% forbupropion plus lozenge, 34.4% for patch, 33.5% for lozenge, 31.8% for bupropion,

and 22.2% for placebo.39 Regardless of the intervention utilized, from briefcounseling to pharmacologic therapy, abstinence rates are increased in smokerswho are identified and offered assistance in their efforts to quit.

Meta­Analysis: Effectiveness and Abstinence Rates for Smoking Cessation TherapiesTable 4Go to www.surgeongeneral.gov/tobacco/gdlnrefs.htm for the articles used in this meta­analysis.

CI = confidence interval; NRT = nicotine replacement therapy; SR = sustained relief.

Reproduced with permission from Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Quick referenceguide for clinicians. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2009.

Opportunities for Intervention

In addition to office visits, there are other opportunities to promote reduced use of tobacco, such as in the work place,through community smoking bans, or at the time of hospitalization. In a matched controlled study, Seo and Torabishowed that there was a significant decrease in hospitalizations for acute MI in nonsmokers in the 44 months after public

smoking ban ordinance was enacted.40 Smokers who are hospitalized are often motivated to quit regardless of theirdiagnosis at the time of presentation.

Assessment of smoking status is a requirement by the Joint Commission on Accreditation of Healthcare Organizations,and through identification of smokers, it provides an opportunity for intervention. In a meta­analysis of 33 trials by Rigottiet al., cessation success in hospitalized patients was related to the intensity of the intervention and to the critical

component of follow­up greater than 1 month postdischarge.41

Those who received the lowest intensity intervention (brief inpatient intervention) had an OR of 1.16 (95% CI, 0.08­1.67) ofquitting, whereas those with longer inpatient contact but no follow­up had an OR of 1.08 (95% CI, 0.89­1.29), a strategythat was no more effective than usual care. The six studies that looked at patients with inpatient intervention and follow­upfor up to 1 month after discharge did not show increased quit rates (OR, 1.09; 95% CI, 0.91­1.30). It was those patientsthat received the most intensive intervention and follow­up for longer than 1 month postdischarge that had improved quitrates (OR, 1.65; 95% CI, 1.44­1.77), thus illustrating that arranging for outpatient follow­up after hospitalization is crucialin improving quit rates in hospitalized smokers.

In the PREMIER (Prospective Registry Evaluating Outcomes After Myocardial Infarction) study, hospital­based smoking

cessation programs and cardiac rehabilitation were strongly associated with increased cessation rates.42

Summary

Despite the decreasing number of smokers in the United States, over 435,000 deaths are attributed to tobacco annually.Tobacco use is the leading modifiable cause of the development of atherosclerosis, as well as a contributor to acutecoronary events. Smoking cessation is associated with a lower risk of CVD, and efforts to promote cessation andabstinence should be addressed at each encounter with the health care provider.

Assessing the patient's readiness to change can help the provider provide appropriate counseling, resources, andfollow­up to enhance long­term abstinence. Use of over the counter and prescription NRTs and pharmacologic agents,such as bupropion and varenicline, significantly improve quit rates.

Key Points

Tobacco use is a leading preventable cause of morbidity and mortality and contributes to >435,000 deathsannually in the United States.Cigarette smoking is associated with increased inflammation, endothelial dysfunction, unfavorable changes inthe lipid profile, and increased thrombotic factors.Identification of tobacco users is the first step in improving rates of abstinence.The "5 A's" (ask, advise, assess, assist, and arrange follow­up) is an effective tool to systematically identify andpromote smoking cessation.NRTs can double abstinence rates.Combination therapy with nicotine patch and supplemental nicotine or bupropion and NRT significantly increasequit rates.

References

1. Centers for Disease Control and Prevention. Annual smoking­attributable mortality, years of potential life lost, and productive losses­United States, 1997­2001. MMWR Morb Mortal Wkly Rep 2005;54:625­8.

2. Centers for Disease Control and Prevention. Vital Signs: Current Cigarette Smoking Among Adults Aged ≥18 Years­United States, 2005­2010. MMWR Morb Mortal Wkly Rep 2011;60:1207­12.

3. Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol2004;43:1731­7.

4. Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ1994;309:901­11.

5. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR Jr. Effect of smoking status on the long­term outcome after successfulpercutaneous coronary revascularization. N Engl J Med 1997;336:755­61.

6. Chow CK, Jolly S, Rao­Melacini P, Fox KA, Anand SS, Yusuf S. Association of diet, exercise, and smoking modification with risk of earlycardiovascular events after acute coronary syndromes. Circulation 2010;121:750­8.

7. Shah AM, Pfeffer MA, Hartley LH, et al. Risk of all­cause mortality, recurrent myocardial infarction, and heart failure hospitalizationassociated with smoking status following myocardial infarction with left ventricular dysfunction. Am J Cardiol 2010;106:911­6.

8. Gerber Y, Rosen LJ, Goldbourt U, Benyamini Y, Drory Y, on behalf of the Israel Study Group on First Acute Myocardial Infarction. Smokingstatus and long­term survival after first acute myocardial infarction: A population­based cohort study. J Am Coll Cardiol 2009;54:2382­7.

9. van Domburg RT, Meeter K, van Berkel DF, Veldkamp RF, van Herwerden LA, Bogers AJ. Smoking cessation reduces mortality aftercoronary artery bypass surgery: a 20­year follow­up study. J Am Coll Cardiol 2000;36:878­83.

10. Rea TD, Heckbert SR, Kaplan RC, Smith NL, Lemaitre RN, Psaty BM. Smoking status and risk for recurrent coronary events aftermyocardial infarction. Ann Intern Med 2002;137:494­500.

11. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: asystematic review. JAMA 2003;290:86­97.

12. Neunteufl T, Heher S, Kostner K, et al. Contribution of nicotine to acute endothelial dysfunction in long­term smokers. J Am Coll Cardiol2002;39:251­6.

13. Kallio K, Jokinen E, Saarinen M, et al. Arterial intima­media thickness, endothelial function, and apolipoproteins in adolescentsfrequently exposed to tobacco smoke. Circ Cardiovasc Qual Outcomes 2010;196:196­203.

14. Johnson HM, Gossett LK, Piper ME, et al. Effects of smoking and smoking cessation on endothelial function: 1­year outcomes from arandomized clinical trial. J Am Coll Cardiol 2010;55:1988­95.

15. Jatoi NA, Jerrard­Dunne P, Feely J, Mahmud A. Impact of smoking and smoking cessation on arterial stiffness and aortic wave reflectionin hypertension. Hypertension 2007;49:981­5.

16. Quillen JE, Rossen JD, Oskarsson HJ, Minor RL Jr, Lopez AG, Winniford MD. Acute effect of cigarette smoking on the coronarycirculation: constriction of epicardial and resistance vessels. J Am Coll Cardiol 1993;22:642­7.

17. Asthana A, Johnson HM, Piper ME, Fiore MC, Baker TB, Stein JH. Effects of smoking intensity and cessation on inflammatory markers ina large cohort of active smokers. Am Heart J 2010;160:458­63.

18. Barua RS, Ambrose JA, Saha DC, Eales­Reynolds LJ. Smoking is associated with altered endothelial­derived fibrinolytic andantithrombotic factors: an in vitro demonstration. Circulation 2002;106:905­8.

19. Newby DE, McLeod AL, Uren NG, et al. Impaired coronary tissue plasminogen activator release is associated with coronaryatherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 2001;103:1936­41.

20. Gepner AD, Piper ME, et al. Effects of smoking and smoking cessation on lipids and lipoproteins: outcomes from a randomized clinicaltrial. Am Heart J 2011;16:145­51.

21. Zaratin A, Gidlund M, Boschcov P, Castilho L, de Faria EC. Antibodies against oxidized low­density lipoprotein in normolipidemicsmokers. Am J Cardiol 2002;90:651­3.

22. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD:U.S. Department of Health and Human Services. Public Health Service. May 2008.

23. Keenan PS. Smoking and weight change after new health diagnoses in older adults. Arch Intern Med 2009;169:237­42.24. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Quick Reference Guide for Clinicians.

Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. April 2009.25. Linder JA, Rigotti NA, Schneider LI, Kelley JH, Brawarsky P, Haas JS. An Electronic health record­based intervention to improve tobacco

treatment in primary care: a cluster­randomized controlled trial. Arch Intern Med 2009;169:781­7.26. Prochaska JO, Goldstein MG. Process of smoking cessation. Clin Chest Med 1991;12:727­35.27. Rigotti NA. Clinical practice. Treatment of tobacco use and dependence. N Engl J Med 2002;346:506­12.28. Graham AL, Cobb NK, Papandonatos GD, et al. A randomized trial of Internet and telephone treatment for smoking cessation. Arch

Intern Med 2011;171:46­53.29. Free C, Knight R, Robertson S, et al. Smoking cessation support delivered via mobile phone test messaging (tst2stop): a single­blind,

randomised trial. Lancet 2011;378:49­55.30. Myung SK, McDonnell DD, Kazinets G, Seo HG, Moskowitz JM. Effects of web­ and computer­based smoking cessation programs: meta­

analysis of randomized controlled trials. Arch Intern Med 2009;169:929­37.31. Ranney L, Melvin C, Lux L, McClain E, Lohr KN. Systematic review: smoking cessation intervention strategies for adults and adults in

special populations. Ann Intern Med 2006;145:845­56.32. Barth J, Critchley JA, Bengel J. Psychosocial interventions for smoking cessation in patients with coronary heart disease. Cochrane

Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006886. Available at:http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006886/abstract;jsessionid=00C2B20E5890515B1DC112B75C318CE7.d02t04.Accessed 02/22/2012.

33. Fiore MD, Smith SS, Jorenby DE, Baker TB. The effectiveness of the nicotine patch for smoking cessation: a meta­analysis. JAMA1994;271:1940­7.

34. Goldstein MG, Niaura R. Methods to enhance smoking cessation after myocardial infarction. Med Clin North Am 2000;84:63­80.35. Greenland S, Satterfield MH, Lanes SF. A meta­analysis to assess the incidence of adverse effects associated with the transdermal

nicotine patch. Drug Saf 1998;18:297­308.36. Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac

disease. N Engl J Med 1996;335:1792­8.37. Hayes JT, Ebbert JO. Varenicline for tobacco dependence. N Engl J Med 2008;359:2018­24.38. Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with

cardiovascular disease: a randomized trial. Circulation 2010;121:221­9.39. Piper ME, Smith SS, Schlam TR, et al. A randomized placebo­controlled clinical trial of 5 smoking cessation pharmacotherapies. Arch

Gen Psychiatry 2009;66:1253­62.40. Seo DC, Torabi MR. Reduced admissions for acute myocardial infarction associated with a public smoking ban: matched controlled

study. J Drug Educ 2007;37:217­26.41. Rigotti NA, Munafo MR, Stead LF, et al. Smoking cessation interventions for hospitalized smokers: a systematic review. Arch Intern Med

2008;168:1950­60.42. Dawood N, Vaccarino V, Reid KJ, Spertus JA, Hamid N, Parashar S; PREMIER Registry Investigators. Predictors of smoking cessation

after a myocardial infarction: the role of institutional smoking cessation programs in improving success. Arch Intern Med 2008;168:1961­7.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.5: Diabetes

Author(s): Steven P. Marso, MD

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Describe the risk of coronary heart disease (CHD) associated with type 2 diabetes mellitus (T2DM).2. Recognize the goals of hypertension and hyperlipidemia management in patients with T2DM.3. Describe the clinical benefits of managing chronic hyperglycemia in patients with T2DM.

Introduction

Diabetes is the seventh leading cause of death in the United States and is associated with an increased hazard for

cardiovascular (CV), non­CV, and cancer deaths.1 The overall risk of death in patients with diabetes is twice that ofpatients without diabetes. While CV disease (CVD) is the most frequent cause of death among all individuals in theUnited States, people with diabetes are disproportionately affected. Heart disease is noted on the death certificates ofnearly 70% of patients with diabetes.

Epidemiology

Diabetes mellitus (DM) affects 25.8 million people (8.3% of the population) in theUnited States, including 7 million undiagnosed individuals. The frequency ofdiabetes increases with age. Over 25% of patients ≥65 years have diabetes. Eachyear in the United States, 2 million new cases develop in individuals >20 years ofage. Diabetes is the leading cause of kidney failure, nontraumatic lower limbamputations, and new cases of blindness. It is a major determinant of heartdisease and stroke.

DM is a metabolic disorder characterized by insufficient insulin secretion necessaryto maintain normal plasma glucose values. There are three distinct classificationsfor diabetes: 1) T2DM, which accounts for more than 90% of all cases; 2) type 1 DM(T1DM), which generally develops in the young; and 3) gestational diabetes, whichdevelops during pregnancy.

Gestational diabetes complicates about 4% of pregnancies in the United States.Women who develop gestational diabetes have an increased risk of developingT2DM, as compared with those who have normal glycemia throughout pregnancy.The relative risk (RR) is approximately 7.4. The risk is measurable within 5 years,with a RR of approximately 4.7. The risk more than doubles to 9.3 in those women 5

years postpartum.2 The absolute risk of developing T2DM in a meta­analysis by

Bellamy L and colleagues was 12.5% in patients with gestational diabetes.2

The current diagnostic criteria for diabetes and prediabetes are listed in Table 1. Ingeneral, glycated hemoglobin (HbA1c) is used as a screening test for diagnosis.

Either fasting plasma glucose or an oral glucose tolerance test (OGTT) should beused for a definitive diagnosis when diabetes is suspected based on an elevatedHbA1c value.

Prediabetes is a state indicating increased risk for development of diabetes. It ischaracterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose(IFG). In addition to the criteria in Table 1, an HbA1c of 5.7­6.4% also qualifies as

prediabetes.

Special Populations

The frequency of diabetes varies in certain minority populations. It has been

estimated that 14.2% of American Indians and Alaska Natives have diabetes.3 Whilethe frequency is 10.2% in non­Hispanic whites >20 years old, it is 18.7% in non­

Hispanic black individuals of the same age.3

T2DM is increasing in prevalence, particularly among younger people in the UnitedStates. Approximately 0.18% of individuals under age 20 have either T1DM or T2DM(i.e., 1 in 523). According to Search for Diabetes in Youth, a multistate registrytracking all new cases of diabetes in adolescents and children 0­19 years old,

15,600 patients were diagnosed with T1DM and 3,600 with T2DM from 2002­2005.4

During each year, 18.6 per 100,000 new cases of T1DM were diagnosed inadolescents ages 10­19. In the same age group, 8.5 per 100,000 new cases ofT2DM were diagnosed. The frequency of T2DM in the young is increasing, and isdisproportionately higher among young Pacific Islanders and American Indians. Incontrast, new cases of T1DM are diagnosed to a greater extent in non­Hispanic

white youths.4

Cost of Diabetes

Medical expenditures associated with diabetes are more than two times that ofpeople without diabetes. Total annual medical costs in 2003 were estimated to be$174 billion, including $116 billion in direct costs. Indirect costs totaled $58 billion,

and included disability, lost productivity, and premature mortality.6

Table 1

Diagnostic Criteria for Diabetes and PrediabetesTable 1

References:

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011;34 Suppl 1:S62­9.2. World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF

Consultation. Geneva: World Health Organization; 2006.

Metabolic Syndrome and Diabetes Risk

Metabolic syndrome (MetSyn), originally described over 80 years ago, is thepresence of multiple cardiometabolic disorders, also referred to in the literature asSyndrome X or insulin resistance syndrome. While several clinical definitions forMetSyn exist, insulin resistance is a central component. In 2001, the NationalCholesterol Education Program (NCEP) Adult Treatment Panel developed clinicallyuseful criteria for identifying MetSyn in clinical practice, and the panel updated the

criteria in 2005 (Table 2).6

The prevalence of MetSyn increases with age, affecting as many as 40% ofindividuals older than age 60. However, it is increasingly being observed in young

and obese individuals.7 While prevalence estimates vary according to the definitionused, data from the National Health and Nutrition Examination Survey suggest thatnearly 50 million people (i.e., 24% of the population) in the United States have

MetSyn.7

MetSyn is associated with an excess risk of developing diabetes and CVD,8 which isnot surprising, since MetSyn includes IFG and multiple factors associated with CVrisk. In the DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnosticcriteria in Europe) study, there was an approximate twofold increase in risk for all­

cause and CV mortality.9 Others have reported an association with both myocardial

infarction (MI) and stroke.10 Treatment is primarily focused on risk factormodification, since no specific MetSyn therapies currently exist. Similar to those withdiabetes, MetSyn patients often have atherogenic dyslipidemia consisting ofelevated triglycerides and apolipoprotein­B, small low­density lipoprotein (LDL)particles, and low high­density lipoprotein (HDL) levels.

Table 2

NCEP Adult Treatment Panel III Diagnostic Criteria for Metabolic SyndromeTable 2*For people of European ethnicity, the International Diabetes Federation recommends cutpoints of >94 cm for men and >80 cm for women. Forpeople of Asian descent, the recommended cutoffs are >90 cm for men and >80 cm for women.

HDL = high­density lipoprotein; NCEP = National Cholesterol Education Program

Reference:

1. The IDF Consensus Worldwide Definition of the Metabolic Syndrome. Brussels: International Diabetes Federation, 2006. Available at:http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf. Accessed: 12/27/2011.

Coronary Heart Disease Risk

In patients with diabetes, the 10­year risk of CHD events (MI or death) is nearly equalto that of patients with a known history of CHD, but without diabetes. Accordingly,

diabetes is recognized as a CHD risk equivalent.11 Further underscoring thisassociation, CHD is the primary cause of death in many patients with diabetes. Inaddition, fatalities following MI are excessive in patients with DM, and their long­term

survival in general is poor once diagnosed with CHD.11 It is the combination ofthese CV risk factors, rather than hyperglycemia alone, that raises diabetes to thelevel of a CHD risk equivalent.

Management of concomitant CV risk factors is requisite in patients with DM. Giventhat DM is a CHD risk equivalent, many risk factor thresholds and treatment goalsare similar to those for patients with known CHD (Table 3). Attainment of thesegoals is a clinical priority.

Table 3

Risk Factors and Treatment Goals for Reducing CHD Risk in Patients With DiabetesTable 3CHD = coronary heart disease; HbA1c = glycated hemoglobin; HDL = high­density lipoprotein; LDL = low­density lipoprotein.

Adapted with permission from Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelinesfor Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17 Suppl 2:1­53.

Prevention

Diabetes is a preventable chronic disease that can be avoided or delayed througheffective lifestyle management, including reducing caloric, carbohydrate, and fatintake to reach ideal body weight, engaging in physical activity, and avoidingsmoking. Specific prevention strategies include a 5­10% reduction in body weight,moderate exercise, and selective use of metformin. Since obesity is a significant riskfactor for the development of diabetes, weight loss through diet, exercise, andpharmacotherapy may be appropriate.

Gastric bypass surgery is also indicated for morbidly obese (i.e., body mass index

[BMI] >40 kg/m2) patients without diabetes. It is also recommended for those who

have a BMI >35 kg/m2 with high­risk comorbidities, including diabetes.12 Specificrisk factors for diabetes are shown in Table 4.

Lifestyle modification is particularly effective at delaying or preventing the onset ofdiabetes. In the DPS (Finnish Diabetes Prevention Study), 522 overweight/obese

subjects with a mean BMI of 31 kg/m2 and IGT were randomized to an interventionconsisting of dietary and exercise counseling to reduce body weight versus a control

group.13 Over 4 years of follow­up, the cumulative incidence of diabetes was 58%lower in the intervention group compared with controls (11% vs. 23%, p < 0.001).

The DPP (Diabetes Prevention Program) trial included 3,234 overweight patients

with a mean BMI of 34 kg/m2 and IFG or IGT. Patients were randomly assigned toeither lifestyle intervention (i.e., >7% weight loss and >150 minutes weekly physical

activity), metformin (i.e., 850 mg bid), or placebo.14 Over 3 years of follow­up, lifestylemodification was associated with a 58% reduction in the incidence of diabetescompared with placebo (4.8 vs. 11.0 cases per 100 person­years), while metforminwas associated with a 31% reduction compared with placebo (7.8 vs. 11.0 casesper 100 person­years). The cumulative frequency of diabetes at 3 years is shown inFigure 1.

In the STOP­NIDDM (Study to Prevent Non­Insulin­Dependent Diabetes Mellitus)trial, 1,429 IGT patients were randomized to the alpha glucosidase inhibitoracarbose (100 mg three times daily) or placebo. Patients received annual OGTTs to

assess the incidence of progression to DM.15 Treatment with acarbose wasassociated with a 25% reduction in RR of diabetes compared with placebo over amean follow­up of 3.3 years (32% vs. 42%, p = 0.0015). Furthermore, more patientswho were randomized to acarbose experienced a reversal of IGT to normoglycemiaversus patients who were randomized to placebo (p < 0.001).

Table 4

Figure 1

Risk Factors for Diabetes MellitusTable 4Adapted with permission from Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelinesfor Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17 Suppl 2:1­53.

Three­Year Cumulative Incidence of Diabetes in Diabetes Prevention Program TrialFigure 1Reference:

1. Knowler WC, Barrett­Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEngl J Med 2002;346:393­403.

Glucose Management

By definition, normoglycemic individuals have preprandial glucose values <99 mg/dl or postprandial values <120 mg/dl.Epidemiological studies have demonstrated elevated glucose to be associated with greater risk for microvascular andmacrovascular complications. A number of these studies have shown a linear increase in CVD and mortalitycorresponding with increasing values for fasting plasma glucose, postprandial glucose, and HbA1c.

Glucose control is fundamental to the management of DM. According to the current glucose guidelines from the AmericanDiabetes Association (ADA), the target HbA1c threshold for DM patients is <7.0%, but should be individualized based on

patient characteristics. A lower target can be considered in highly selected individuals who are at lower risk forhypoglycemia. Less stringent treatment goals may also be appropriate for adults with limited life expectancy or advancedvascular disease.

Microvascular Complications

Two prospective, randomized, controlled trials of intensive versus standard glucose control were the DCCT (DiabetesComplications and Control Trial) in T1DM patients and the UKPDS (United Kingdom Prospective Diabetes Study) in

T2DM patients.16,17 These trials definitively showed that improved glucose control was associated with a significantreduction in microvascular complications, namely retinopathy and nephropathy.

Follow­up of the DCCT and UKPDS has demonstrated long­term benefits of intensive glucose control with respect tomicrovascular complications. A number of trials of intensive glucose control that were designed to demonstrate areduction in macrovascular events have also confirmed a reduction in microvascular complications. A curvilinearrelationship exists between HbA1c and microvascular complications, suggesting that the greatest magnitude of benefit in

reducing microvascular complications is in very poorly controlled patients (e.g., HbA1c 8­10%). Although there continues

to be a limited benefit for reducing microvascular complications by lowering HbA1c from 7% to 6%, the absolute benefit is

much smaller.

Macrovascular Complications

The association between intensive glucose control and macrovascular complications has also been examined in severallarge­scale randomized controlled trials. In contrast to the consistent association between glycemic control andmicrovascular complications, intensive glucose control has not been consistently linked to improved CV outcomes inthese trials. There was much heterogeneity in the results. An overview of the methodology and findings from a few ofthese studies follows.

DCCT­EDIC (Diabetes Complications and Control Trial­Epidemiology of Diabetes Interventions and

Complications)18: There were 1,441 patients with T1DM and without existing CVD who were randomized tointensive glucose control (i.e., three times daily insulin to achieve preprandial glucose 70­120 mg/dl andpostprandial glucose 180 mg/dl) versus conventional glucose control. Patients were treated for 6.5 years andwere followed for an additional 10 years without extending the treatment assignment. Over 90% of patients werefollowed for a total of 17 years, at which time there was a 42% RR reduction in CV events in the intensivetreatment group compared with conventional therapy (0.38 vs. 0.80 events per 100 patient­years, p = 0.02) and a57% reduction in risk of nonfatal MI, stroke, or CV death (p = 0.02).

UKPDS: In over 4,200 T2DM patients randomized to intensive glucose control (i.e., sulfonylurea, insulin, ormetformin) or conventional glucose control, 3,277 were monitored for an additional 10 years but were not required

to continue treatment according to their original randomization scheme.19 During 10 years of follow­up,sulfonylurea­insulin was associated with a 13% reduction (RR, 0.87; 95% confidence interval [CI], 0.79­0.96) inall­cause mortality and a 15% reduction (RR, 0.85; 95% CI, 0.74­0.97) in MI compared with controls. In themetformin group, the RR reductions in all­cause mortality and MI compared with conventional treatment were 27%(RR, 0.73; 95% CI, 0.59­0.89) and 33% (RR, 0.57; 95% CI, 0.51­0.89).

ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release ControlledEvaluation): 11,140 T2DM patients with existing macrovascular or microvascular disease were randomized toglicazide with or without metformin, thiazolidinediones(TZDs), acarbose, or insulin to achieve HbA1c <6.5% versus

standard glucose control.20 Although intensive control resulted in a 10% reduction in combined macrovascularand microvascular events (hazard ratio [HR], 0.90; 95% CI, 0.82­0.98), this benefit was mostly driven by astatistically significant reduction in nephropathy (HR, 0.79; 95% CI, 0.66­0.93). There was no significant reductionin overall macrovascular events (HR, 0.94; 95% CI, 0.84­1.06), including nonfatal MI (HR, 0.98; 95% CI, 0.78­1.23).These patients typically had advanced stages of diabetes relative to UKPDS.

ACCORD (Action to Control Cardiovascular Risk in Diabetes): This trial was prematurely discontinued due to an

excess hazard of mortality associated with intensive glucose control.21 In 10,251 T2DM patients with HbA1c >7.5%

and existing CVD, intensive glucose control was defined as a target HbA1c <6%, while standard therapy was a

target of 7­7.9%. Although the composite occurrence of death, nonfatal MI, or nonfatal stroke was 10% lower inpatients randomized to intensive glucose control (HR, 0.90; 95% CI, 0.78­1.04), there were 257 deaths from all­causes in the intensive group compared with 203 deaths in controls (HR, 1.22; 95% CI, 1.01­1.46). Aftertermination of intensive therapy, these patients were followed for 5 additional years. During this time, mean HbA1cincreased from 6.4% to 7.2% in the intensive arm. Although the risk of nonfatal MI continued to be lower in theintensive group (HR, 0.82; 95% CI, 0.70­0.96), a statistically significant hazard for mortality persisted in these

patients (HR, 1.19; 5% CI, 1.03­1.38).22

VADT (Veteran's Affairs Diabetes Trial): In this cohort of US Military veterans who had T2DM for a mean duration of11.5 years, intensive glucose control was defined as an absolute reduction in HbA1c >1.5% as compared with a

control group.23 There were 1,791 patients randomized. The mean HbA1c was 9.4% at baseline in both groups.

After 6 months, HbA1c was reduced to 6.9% in the intensive group and 8.4% in the control group. Over a median

follow­up of 5.6 years, intensive therapy was associated with a nonsignificant 12% reduction in primary compositemajor adverse CV events (MACE) (HR, 0.88; 95% CI, 0.74­1.05). The risk of all­cause mortality was numericallygreater in the intensive therapy group but did not rise to the level of statistical significance (HR,1.07; 95% CI, 0.81­1.42).

Due to the uncertainty and heterogeneity in results from individual trials, several meta­analyses have recently beenpublished that combined results from these trials. One of these meta­analyses included over 33,000 patients andshowed a 17% reduction in RR for nonfatal MI associated with intensive glycemic control (odds ratio [OR], 0.83; 95% CI,0.75­0.93) and a 15% reduction in CHD events (OR, 0.85; 95% CI, 0.77­0.93). There was no effect on stroke or all­cause

mortality.24 Two additional meta­analyses supported these findings.24,26

Diabetes Medications

According to the Centers for Disease Control and Prevention report, among patients with diabetes in the United States,

58% use oral medications, 14% use insulin and oral medications, 12% use insulin only, and 16% use no medications.3

Clinical trial data remain incomplete on specific CV effects of many classes of these drugs. The ADA suggests lifestyle

intervention or metformin as the first­line therapy to manage hyperglycemia.27

Thiazolidinediones

TZDs bind to and activate the nuclear receptor known as peroxisome proliferator­activated receptor (PPAR)­α, which isresponsible for regulating the expression of several metabolic genes. TZDs stimulate insulin sensitivity throughincreased insulin­dependent glucose disposal and reduced hepatic glucose output. Although their precise mechanismof action is unknown, it is believed that the enhanced insulin action produced by TZDs is mediated by transcriptionalchanges in gene expression. Both rosiglitazone and pioglitazone are associated with increased fluid retention and risk ofcongestive heart failure, as well as a numerical excess in the risk of bone fractures.

Studies have shown that pioglitazone and rosiglitazone exert differential effects on plasma lipids. Specifically,rosiglitazone use is associated with several adverse effects on lipids, as shown in a prospective study of 800 patientswith T2DM who were randomized to either pioglitazone or rosiglitazone for 24 weeks. Patients randomized torosiglitazone demonstrated increased triglyceride levels, lower increases in HDL cholesterol levels, greater increases inLDL cholesterol levels, and increased LDL particle concentration. In contrast, patients randomized to pioglitazone hadreduced triglyceride levels, greater increases in HDL cholesterol, lower increases in LDL cholesterol, reduced LDL

particle concentration, and increased LDL particle sizes.28 Other general effects of TZDs include reduced bloodpressure, markers of inflammation, carotid intima medial thickness, as well as reduced bone mineralization.

The CV safety of rosiglitazone has been described in several meta­analyses.29­34 In general, an excess risk as high as

1.43 for nonfatal MI has been demonstrated.31 Others have reanalyzed this work and demonstrated HRs ranging from

1.26­1.43 for nonfatal MI and 1.17­1.64 for CV death.32,34 Marketing of rosiglitazone was suspended by the EuropeanMedicines Agency in late 2010, and the US Food and Drug Administration (FDA) issued a "black box" warning forrosiglitazone in late 2007. This warning stated that its use is associated with an excess risk of heart failure andmyocardial ischemia and is specifically contraindicated in patients with New York Heart Association class III or IV heartfailure. Subsequently, in early 2011 the warning was revised to state that rosiglitazone is associated with increased riskof MI while no comparable increase in risk has been demonstrated with use of pioglitazone. At the same time, use ofrosiglitazone was restricted to only patients currently using it or those not achieving adequate glucose control with otherantidiabetic medications.

Metformin

Metformin is recommended as the first­line therapy in overweight patients with newly­diagnosed T2DM.17 However, itsuse is contraindicated in stage 4 and 5 chronic kidney disease. Although it is associated with weight loss, it is alsoassociated with dyspepsia and diarrhea. In the UKPDS, monotherapy with metformin was associated with a 30% RRreduction in macrovascular events, including statistically significant reductions in MI (RR, 0.61; 95% CI, 0.41­0.89) andall­cause mortality (RR, 0.64; 95% CI, 0.45­0.91). However metformin plus sulfonylurea was associated with a 96%

increase in risk of diabetes­related death (p = 0.039) and a 60% increase in risk of all­cause mortality (p = 0.041).17

Sulfonylureas

The glucose­lowering effects of sulfonylureas are maximal at 6 months and taper off over the course of 3 years.Combined with any other glucose lowering agent, sulfonylureas are associated with a multifold increase in risk ofhypoglycemia. They are also associated with weight gain comparable to that of TZDs.

Other Novel Agents

Dipeptidyl peptidase­IV (DPP­IV) is an enzyme expressed in multiple organs and cells. It inactivates the gut hormoneglucagon­like­peptide­1 (GLP­1), which is responsible for insulin stimulation, suppression of glucagon, and delayed

gastric emptying.35 Several orally­administered DPP­IV inhibitors (i.e., sitagliptin, vildagliptin, saxagliptin) have recentlybeen developed. These drugs do not lead to weight gain, are not associated with hypoglycemia, and can beadministered in patients with renal insufficiency. GLP­1 receptor agonists (i.e., exenatide and liraglutide) also increasephysiologic levels of insulin and decrease glucagon, resulting in lower fasting and post­prandial glucose. They areassociated with delayed gastric emptying, increased satiety, decreased fluid intake, and weight loss of 4­5% withoutincreased hypoglycemia. Side effects include nausea and vomiting. The CV safety of these agents are currently beingtested in large scale clinical trials.

Antiplatelet Treatment

Aspirin is remarkably effective in reducing CV morbidity and mortality in high risk patients (including DM) with a priorhistory of MI or stroke. Thus, aspirin is universally indicated as an appropriate therapy in CHD patients for secondary

prevention.36 The benefit of aspirin therapy in a primary prevention cohort is controversial, both for patients with and

without DM. Based on current evidence and a joint position statement from the ADA and American Heart Association,37

aspirin has a modest relative effect on CV event rates, in the range of approximately 10%. The magnitude of benefit isrelated to the absolute risk of events in the population. The main adverse effects from aspirin therapy are related to anincreased risk for gastrointestinal bleeding, which approaches 1­5 per 1,000 patients per year. Given that this level ofbleeding risk is approximately equal to the expected benefit in patients at low CVD risk, aspirin therapy is only

recommended for higher risk patients. Specific recommendations are as follows37:

1. Low­dose aspirin (75­162 mg/dl) is reasonable in patients with DM and without vascular history who are atincreased CVD risk (i.e., approximately 1% per year) if there is not an increased risk for bleeding, due to a priorhistory of bleeding or use of nonsteroidal anti­inflammatory drugs or warfarin. In general, DM individuals with >1major risk factor and age >50 for men or >60 for women, would qualify as high risk.

2. Aspirin is not recommended for patients with DM who are at a low CVD risk (i.e., CHD risk <0.5% per year).3. Low­dose aspirin might be considered in patients at intermediate risk, which is defined as 0.5­1% CHD risk per

year.

A number of risk calculators are available to estimate CHD risk, including the UKPDS risk engine, which can be found on­

line at http://www.dtu.ox.ac.uk/riskengine/index.php. The Framingham risk score provides another risk calculator.38

Hypertension

Coexisting hypertension in DM is particularly common and is associated with high risk. Epidemiologic data have

suggested an increased hazard for CV events with a systolic blood pressure >115 mm Hg.39 Individuals with elevated

blood pressure are also 2.5 times more likely to develop DM within 5 years.40 The presence of hypertension also greatly

increases the likelihood of progression of nephropathy and retinopathy in DM patients.41 The UKPDS trial demonstratedthat for each 10 mm Hg reduction in blood pressure, there was a 15% reduction in DM­related mortality, an 11%reduction in MI, and a 13% reduction in microvascular complications, including retinopathy or nephropathy.

A number of randomized controlled trials of hypertensive patients have demonstrated improved outcomes associatedwith blood pressure control. These include: UKPDS, HOT (Hypertension Optimal Therapy), SHEP (Systolic Hypertensionin the Elderly Program), SYST­EUR (Systolic Hypertension in Europe), HOPE (Heart Outcomes Prevention Evaluation),

and LIFE (Losartan Intervention For Endpoint reduction in hypertension).41­46 These trials included large populationswith DM. The Joint National Committee (JNC) 7 recommendations support a targeted blood pressure of <130/80 mm Hg

in DM patients.47 The ADA recommendations also support this target. However, evidence for this low target is limited.

The ACCORD trial targeted a systolic blood pressure <120 mm Hg compared with a target of 130­140 mm Hg. Therewas a nonsignificant reduction in the composite outcome of MI, stroke, and CV death (HR, 0.88; 95% CI, 0.73­1.06), but astatistically significant reduction in stroke for the <120 mm Hg cohort (HR, 0.59; 95% CI, 0.39­0.89).

Blood pressure should be measured at every office visit. Systolic blood pressure ≥130 mm Hg or diastolic pressure ≥80mm Hg on two separate days is used to confirm the diagnosis of hypertension. If systolic pressure is ≥140 mm Hg ordiastolic pressure is ≥90 mm Hg, patients should receive both lifestyle therapy and pharmacologic treatment. Lifestyleintervention includes the DASH (Dietary Approaches to Stop Hypertension) diet, with reduced sodium intake, increasedpotassium intake, increased physical activity, and moderation of alcohol consumption.

According to the JNC 7, a compelling case exists for the use of many classes of antihypertensive agents, includingdiuretics, beta­blockers, angiotensin­converting enzyme inhibitors (ACEIs), angiotensin­receptor blockers (ARBs), andcalcium channel blockers (CCBs) in patients with DM. Patients most often require multidrug treatment regimens, oftenneeding at least three classes of agents. Most pharmacologic strategies include the use of either ACEIs or ARBs, withARBs substituted for ACEIs if not tolerated.

The ADA currently recommends ACEIs in DM patients >55 years old and at high risk for CVD, and both ACEIs and ARBs

in T2DM patients with nephropathy. Thiazide diuretics are preferred if glomerular filtration rate (GFR) >30 ml/min/1.73 m2,

while loop diuretics are preferred if GFR <30 ml/min/1.73 mm2. Beta­blockers are beneficial in DM patients as part of amultidrug regimen, but their efficacy as monotherapy is less clear. An exception would be in patients with a prior history ofMI. Beta­blockers can decrease insulin sensitivity and mask the epinephrine­mediated symptoms of hypoglycemia.

Nevertheless, they are not contraindicated in DM patients.48 In CHF patients in the ABCD (Appropriate Blood pressure

Control in Diabetes) trial, nitrendipine was inferior to lisinopril in reducing MACE.48

Dyslipidemia

Lipoprotein abnormalities are common in DM individuals. The typical profile of DM dyslipidemia is often referred to asatherogenic dyslipidemia, which includes elevated triglycerides, low HDL, and modestly elevated LDL particle size. DMpatients have more small, dense LDL particles, which are thought to be more atherogenic than other LDL moieties.Atherogenic dyslipidemia is also typically seen in patients with cardiometabolic risk, including T2DM, familial combined

hyperlipidemia, familial hypoalphalipoproteinemia, and polycystic ovary syndrome.49 Patients with cardiometabolic riskoften have central adiposity, insulin resistance, dyslipoproteinemia, and hypertension.

Management of dyslipidemia in patients with DM includes the following treatment goals:

In adults, annual measurement of lipids is appropriate. Low­risk individuals <40 years of age without CV riskfactors may be assessed every 2 years.In patients >40 years of age without CVD, the target LDL is <100 mg/dl.

In high­risk patients with established CVD, an alternative LDL target of <70 mg/dl is reasonable.50

Lifestyle modification should include reduced intake of saturated fat and cholesterol, weight loss if overweight,increased dietary fiber intake, and increased physical activity. Pharmacologic intervention is indicated whentargets are not achieved with lifestyle changes.

Although the primary target for DM dyslipidemia is LDL, there is a secondary target for non­HDL (i.e., total cholesterolminus HDL) when triglycerides are 200­499 mg/dl. The target is 30 mg/dl higher than the LDL goal. When triglyceridesare >500 mg/dl, providers should initiate therapy with diet and either a fibrate or niacin, prior to initiating other LDL­specific therapies.

Evidence to support lowering LDL in DM patients is provided by several randomized controlled trials, including the HPS(Heart Protection Study) and the CARDS (Collaborative Atorvastatin Diabetes Study). Among over 20,000 patients enrolled

in HPS who were randomized to 40 mg daily simvastatin or placebo, 5,963 had T2DM.51 Over 5 years of treatment, therewas a 22% reduction in major vascular events (i.e., nonfatal MI, coronary death, stroke, or revascularization) in DMpatients randomized to simvastatin compared with placebo (20.2% vs. 25.1%, p < 0.0001).

CARDS enrolled 2,800 T2DM patients without previous CVD who were randomized to atorvastatin 10 mg/day or

placebo.52 The atorvastatin treated arm was associated with an approximate 30­40% reduction in LDL as well as a 37%reduction in primary composite acute coronary syndrome, revascularization, or stroke (HR, 0.63; 95% CI, 0.48­0.83).

The efficacy of statins on reducing LDL and major vascular events was also recently summarized in a meta­analysis of

18,700 patients with DM (including 92% with T2DM) enrolled in 14 large­scale randomized controlled trials.53 Trials wereincluded if they met the following criteria: at least one of their primary objectives was to modify lipid levels through statintreatment, >1,000 patients were enrolled, and duration of treatment was >2 years. Mean duration of treatment was 4.3years.

The meta­analysis found that for each 1 mg/dl decrease in LDL, statin therapy was associated with a 9% reduction in all­cause mortality (RR, 0.91; 99% CI, 0.82­1.01), including CHD mortality (RR, 0.88; 99% CI, 0.75­1.03) and vascularmortality (RR, 0.87; 99% CI, 0.76­1.00). There was also a statistically significant 21% reduction in MACE for each 1 mg/dldecrease in LDL (RR, 0.79; 99% CI, 0.72­0.86), including MI or coronary death (RR, 0.78; 99% CI, 0.69­0.87), coronaryrevascularization (RR, 0.75; 99% CI, 0.64­0.88), and stroke (RR, 0.79; 95% CI, 0.67­0.93). It is noteworthy that 63% of allpatients included in this meta­analysis did not have a history of vascular disease.

Future Directions

There are a number of ongoing randomized clinical trials designed to evaluate the safety of newer antidiabetic therapies.Since the US FDA requires formal evaluation of the CV safety of antidiabetic therapies, there will likely be a sharpincrease in the number of large­scale CV outcome trials. For example, there are four ongoing trials which are testing theadministration of incretin mimetic agents in patients with T2DM.

The TECOS (Trial to Evaluate Cardiovascular Outcomes after treatment with Sitagliptin) includes patients with T2DM andinadequate glycemic control on mono­ or dual­combination oral anti­hyperglycemic therapy. The trial is evaluating the CVefficacy and safety of sitagliptin. TECOS is a long­term, event­driven, noninferiority study enrolling approximately 14,000diabetic patients at risk for CV events. The primary objectives are to determine whether sitagliptin added to usual carereduces the composite CV endpoint of CV death, nonfatal MI, nonfatal stroke, or unstable chest pain requiringhospitalization. Patient recruitment commenced in 2008 and results are expected in 2014.

The EXAMINE (EXAMination of CV outcomes: aldogliptIN versus standard of care) trial in patients with T2DM and acutecoronary syndrome is evaluating alogliptin as an adjunct to diet and exercise. This trial will enroll approximately 5,400patients, with the primary endpoint being CV death, nonfatal MI, or stroke. Enrollment began in 2009 and results areexpected in 2014.

The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) trial is an event­driven, large­scale, randomized, controlled trial evaluating the CV safety of liraglutide. LEADER is enrolling high­riskT2DM patients. Recruitment began in 2010, and results are expected in 2016.

The EXSCEL (EXnatide Study of Cardiovascular Event Lowering) trial is examining the CV safety of a once­weeklyadministration of exenatide added to usual care in patients with T2DM. The primary composite endpoint is CV death,nonfatal MI, or nonfatal stroke. Approximately 9,500 T2DM patients will be enrolled and followed for at least 4 years.Recruitment began in 2010 and study completion is expected in 2017.

Additional targets for therapy include sodium­glucose co­transporters (SGLT2) inhibitors such as dapagliflozin, whichprevent reabsorption of glucose in the kidney. The kidney plays a deterministic role in glucose homeostasis. Specifically,glucose reabsorption occurs in the proximal convoluted tubules. In a normal state, <1% of glucose is excreted in urine.

Glucose transport is accomplished by SGLTs, which are a family of membrane bound proteins responsible fortransporting a number of moieties across the brush border membranes of the proximal renal tubules. SGLT2 is a high­capacity transporter expressed mostly in the kidney, and accounts for 90% of glucose reabsorption. SGLT2 inhibitorsblock the reabsorption of filtered glucose, leading to glycosuria. Thus, SGLT2 inhibitors are candidate targets to managehyperglycemia in the setting of T2DM.

Dapagliflozin is an SLGT2 inhibitor, likely with the most clinical data accumulated currently. Dapagliflozin haddemonstrated sustained and dose­dependent glucose excretion over 24 hours. Preliminary studies have shown it to besafe and generally well tolerated. In initial clinical studies, it was associated with an approximate 0.5­1.0% reduction inHbA1c as well as a 1­2 kg loss in weight over 12 weeks. Overall, the rate of hypoglycemia was low (<2%), and it was

associated with a 2­6 mm Hg reduction in systolic blood pressure as well as a mild diuretic effect. Nevertheless, there is

a concern that SGLT2 inhibitors may be associated with an increased risk of urinary tract and genital infections.54,55

Key Points

DM is growing in prevalence and is currently the seventh leading cause of death in the United States.Nearly 70% of patients with diabetes die of CV causes, and the risk of an MI in a diabetic patient without existingheart disease is nearly equal to that of a nondiabetic patient with existing disease.MetSyn is a clustering of three or more risk factors associated with an increased risk of developing diabetes.General prevention strategies for diabetes consist of lifestyle management, including: caloric, carbohydrate, andfat reductions to reach ideal body weight, increased physical activity, and smoking avoidance.Hyperglycemia is associated with an excess risk of CV events. While the association between intensive glucosecontrol and a reduction in microvascular complications has been established in randomized trials, intensiveglucose control has not been consistently linked to improved macrovascular outcomes.Lifestyle intervention and/or metformin are indicated as the first­line therapy in newly diagnosed patients withdiabetes. Additional agents include TZDs, sulfonylureas, DPP­IV inhibitors, and GLP­1 agonists and analogs.Low­dose aspirin can be considered in diabetic patients at elevated CHD risk who do not have a history ofvascular events.The target blood pressure for diabetic patients is systolic <130 mm Hg and diastolic <80 mm Hg. Thiazidediuretics, ACEIs, beta­blockers, and CCBs are acceptable therapies, depending on individual patientcharacteristics.Management of dyslipidemia in diabetic patients includes statin therapy and/or lifestyle modification to achieve anLDL cholesterol level <100 mg/dl, or <70 mg/dl in patients with established CVD. Other therapies may be initiatedin patients with excessively high triglyceride levels. These include dietary modification, fibrates, and/or niacin.

References

1. Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause­specific death.N Engl J Med 2011;364:829­41.

2. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematicreview and meta­analysis. Lancet 2009;373:1773­9.

3. CDC. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes inthe United States, 2011. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Controland Prevention, 2011.

4. Liese AD, D'Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalenceestimates from the SEARCH for Diabetes in Youth Study. Pediatrics 2006;118:1510­8.

5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2002. Diabetes Care 2003;26:917­932.

6. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an AmericanHeart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735­52.

7. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the thirdNational Health and Nutrition Examination Survey. JAMA 2002;287:356­9.

8. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415­28.9. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch­Johnsen K, Pyorala K. Prevalence of the metabolic syndrome and its

relation to all­cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med2004;164:1066­76.

10. Ninomiya JK, L'Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome withhistory of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey.Circulation 2004;109:42­6.

11. NCEP. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation2002;106:3143­421.

12. Gastrointestinal Surgery for Severe Obesity. NIH Consensus Development Conference Statement. Bethesda, MD:U.S. Department of Health and Human Services, 1991. Available at:http://consensus.nih.gov/1991/1991gisurgeryobesity084html.htm. Accessed 12/27/2011.

13. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle amongsubjects with impaired glucose tolerance. N Engl J Med 2001;344:1343­50.

14. Knowler WC, Barrett­Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyleintervention or metformin. N Engl J Med 2002;346:393­403.

15. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetesmellitus: the STOP­NIDDM randomised trial. Lancet 2002;359:2072­7.

16. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications StudyResearch G. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N EnglJ Med 2005:2643­53.

17. Effect of intensive blood­glucose control with metformin on complications in overweight patients with type 2diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854­65.

18. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patientswith type 1 diabetes. N Engl J Med 2005;353:2643­53.

19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10­year follow­up of intensive glucose control in type 2diabetes. N Engl J Med 2008;359:1577­89.

20. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients withtype 2 diabetes. N Engl J Med 2008;358:2560­72.

21. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med2008;358:2545­59.

22. Gerstein HC, Miller ME, Genuth S, et al. Long­term effects of intensive glucose lowering on cardiovascularoutcomes. N Engl J Med 2011;364:818­28.

23. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2diabetes. N Engl J Med 2009;360:129­39.

24. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes anddeath in patients with diabetes mellitus: a meta­analysis of randomised controlled trials. Lancet 2009;373:1765­72.

25. Marso SP, Kennedy KF, House JA, McGuire DK. The effect of intensive glucose control on all­cause andcardiovascular mortality, myocardial infarction and stroke in persons with type 2 diabetes mellitus: a systematicreview and meta­analysis. Diab Vasc Dis Res 2010;7:119­30.

26. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2diabetes. Diabetologia 2009;52:2288­98.

27. American Diabetes Association. Standards of medical care in diabetes­­2011. Diabetes Care 2011;34 Suppl1:S11­61.

28. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone androsiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547­54.

29. Diamond GA, Kaul S. Rosiglitazone and cardiovascular risk. N Engl J Med 2007;357:938­9; author reply 939­40.30. Home PD, Pocock SJ, Beck­Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes­­an interim

analysis. N Engl J Med 2007;357:28­38.31. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular

causes. N Engl J Med 2007;356:2457­71.32. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta­analysis of risk for myocardial infarction and

cardiovascular mortality. Arch Intern Med 2010;170:1191­1201.33. Singh S, Loke YK, Furberg CD. Long­term risk of cardiovascular events with rosiglitazone: a meta­analysis. JAMA

2007;298:1189­95.34. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and

cardiovascular death. Ann Intern Med 2007;147:578­81.35. Drucker DJ, Nauck MA. The incretin system: glucagon­like peptide­1 receptor agonists and dipeptidyl peptidase­4

inhibitors in type 2 diabetes. Lancet 2006;368:1696­705.36. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease:

collaborative meta­analysis of individual participant data from randomised trials. Lancet 2009;373:1849­60.37. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with

diabetes: a position statement of the American Diabetes Association, a scientific statement of the American HeartAssociation, and an expert consensus document of the American College of Cardiology Foundation. Circulation2010;121:2694­701.

38. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart diseaseusing risk factor categories. Circulation 1998;97:1837­47.

39. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560­72.

40. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factorsfor type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000;342:905­12.

41. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascularcomplications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412­9.

42. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood­pressure lowering and low­dose aspirin inpatients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOTStudy Group. Lancet 1998;351:1755­62.

43. Franse LV, Pahor M, Di Bari M, Somes GW, Cushman WC, Applegate WB. Hypokalemia associated with diureticuse and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension 2000;35:1025­30.

44. Staessen JA, Fagard R, Thijs L, et al. Randomised double­blind comparison of placebo and active treatment forolder patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst­Eur) TrialInvestigators. Lancet 1997;350:757­64.

45. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of theHOPE study and MICRO­HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet2000;355:253­9.

46. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in theLosartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.Lancet 2002;359:1004­10.

47. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure. Bethesda, MD: National Institutes of Health, 2004.

48. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as comparedwith enalapril on cardiovascular outcomes in patients with non­insulin­dependent diabetes and hypertension. NEngl J Med 1998;338:645­52.

49. Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab2004;89:2601­7.

50. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol EducationProgram Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720­32.

51. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol­lowering withsimvastatin in 5963 people with diabetes: a randomised placebo­controlled trial. Lancet 2003;361:2005­16.

52. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin intype 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo­controlled trial. Lancet 2004;364:685­96.

53. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol­lowering therapy in 18,686 people with diabetesin 14 randomised trials of statins: a meta­analysis. Lancet 2008;371:117­25.

54. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who haveinadequate glycaemic control with metformin: a randomised, double­blind, placebo­controlled trial. Lancet2010;375:2223­33.

55. Neumiller JJ, White JR, Jr., Campbell RK. Sodium­glucose co­transport inhibitors: progress and therapeuticpotential in type 2 diabetes mellitus. Drugs 2010;70:377­85.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.6: Metabolic Syndrome

Author(s): Nathan D. Wong, PhD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Recall the pathophysiology, key components, and definitions used for describing the metabolic syndrome (MetS).2. Describe the guidelines and approaches for lifestyle management of MetS.3. Discuss the guidelines, approaches, and therapies used for clinical management of MetS, including treatment of

atherogenic dyslipidemia, elevated blood pressure, obesity, and elevated glucose.

Pathophysiology

In 1988, Reaven proposed that insulin resistance was central to the pathophysiologyof type 2 diabetes mellitus, hypertension, and coronary artery disease. Insulin is ahormone that facilitates glucose uptake in the adipocytes, hepatocytes, and skeletalmuscle, and helps to regulate hepatic glucose production and lipolysis (Figures 1a,b). The condition of insulin resistance with associated metabolic abnormalitiesassociated with increased cardiovascular disease (CVD) risk has been referred to

by various names, including the metabolic syndrome (MetS).1

Insulin resistance is closely related to the other components of the MetS, namelyabdominal obesity, dyslipidemia, glucose intolerance, and elevated blood pressure.Moreover, insulin resistance is associated with abnormal uric acid metabolism,hemostatic abnormalities such as elevated fibrinogen and plasminogen activatorinhibitor­1 levels, endothelial dysfunction, and reproductive issues such as

polycystic ovary syndrome.2,3

The MetS originates from dysfunctional energy balance, characterized fromincreased triglycerides resulting from food energy intake exceeding energy output,which overwhelms storage available in small peripheral adipocytes. This results inincreased free fatty acids in the plasma affecting endocrine and paracrine function inthe adipocytes. While plasma free fatty acids suppress insulin­stimulated glucoseuptake, insulin resistance leads to insuppressible fatty acid release. The resultingeffect is the atherogenic lipoprotein phenotype of elevated triglycerides, low high­density lipoprotein (HDL), and small­dense low­density lipoprotein (LDL) derivingprimarily from an increased flux of free fatty acids. Also, elevated blood pressureresults in part via angiotensinogen synthesized by adipocytes and from effects of

free fatty acids on central organs and blood vessels.3

Figure 1a

Figure 1b

Pathophysiology of the Metabolic Syndrome (Insulin Resistance) (1 of 2)Figure 1aFree fatty acids (FFAs) are released in abundance from an expanded adipose tissue mass. In the liver, FFAs produce an increased productionof glucose, triglycerides, and secretion of very low­density lipoproteins (VLDLs). Associated lipid/lipoprotein abnormalities include reductions inhigh­density lipoprotein (HDL) cholesterol and an increased density of low­density lipoproteins (LDLs). FFAs also reduce insulin sensitivity inmuscle by inhibiting insulin­mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increasedlipid accumulation in triglyceride. Increases in circulating glucose and to some extent FFA, increase pancreatic insulin secretion, resulting inhyperinsulinemia. Hyperinsulinemia may result in enhanced sodium reabsorption and increased sympathetic nervous system activity andcontribute to the hypertension, as might increased levels of circulating FFA.

Adapted with permission from Eckel RH, Grundy SM, Zimmett PZ. The metabolic syndrome. Lancet 2005;365:1415­28.

Pathophysiology of the Metabolic Syndrome (Insulin Resistance) (2 of 2)Figure 1bSuperimposed and contributory to the insulin resistance produced by excessive FFA is the paracrine and endocrine effect of theproinflammatory state. Produced by a variety of cells in adipose tissue including adipocytes and monocyte­derived macrophages, the enhancedsecretion of interleukin­6 (IL­6) and tumor necrosis factor­alpha (TNF­α) among others, results in more insulin resistance and lipolysis of adiposetissue triglyceride stores to circulating FFA. IL­6 and other cytokines also are increased in the circulation and may enhance hepatic glucoseproduction, the production of VLDL by the liver, and insulin resistance in muscle. Cytokines and FFA also increase the production of fibrinogenand plasminogen activator inhibitor­1 (PAI­1) by the liver that complements the overproduction of PAI­1 by adipose tissue. This results in aprothrombotic state. Reductions in the production of the anti­inflammatory and insulin sensitizing cytokine adiponectin are also associated withthe metabolic syndrome and may contribute to the pathophysiology of the syndrome.

Adapted with permission from Eckel RH, Grundy SM, Zimmett PZ. The metabolic syndrome. Lancet 2005;365:1415­28.

Definitions of Metabolic Syndrome

The MetS comprises a constellation of inter­related risk factors of metabolic origin that promote the development ofdiabetes and atherosclerotic CVD. The most widely recognized are atherogenic dyslipidemia, elevated blood pressure,and elevated plasma glucose. Several definitions have been proposed to define MetS, which differ in their criteria; most

commonly cited include those proposed by the National Cholesterol Education Program (NCEP),4,5 and the International

Diabetes Federation (IDF).6

The 2005 American Heart Association (AHA)/National Heart, Lung, and Blood Institute update of the NCEP definition,5

defines the presence of MetS on the basis of demonstrating three or more of the following five abnormalities:

1. Abdominal obesity, as determined by a waist circumference >88 cm in women or >102 cm in men;2. Elevated blood pressure based on a systolic blood pressure of 130 mm Hg or greater, a diastolic blood pressure

of 85 mm Hg or greater, or being on antihypertensive treatment;3. Low HDL cholesterol (HDL­C) defined as <40 mg/dl in men or <50 mg/dl in women, or taking medication to raise

levels of HDL­C;4. Elevated fasting triglycerides defined as 150 mg/dl or greater, or taking medication to lower levels of elevated

triglycerides, or nonfasting triglycerides of 400 mg/dl or greater; and5. Impaired fasting glucose of 100 mg/dl or greater, or taking medication to lower glucose levels. Alternatively, a

nonfasting glucose of 140 mg/dl or greater could be considered equivalent to this level for being defined as acriterion of MetS, with 200 mg/dl or greater defining diabetes.

The IDF definition is closely related in using the same criteria with the same cutpoints6; however, it requires the presenceof abdominal obesity (as defined earlier) plus two of the other factors in the NCEP definition. Importantly, the IDFdefinition differs from the NCEP definition by indicating lower waist circumference cut points to define abdominal obesityamong European Caucasians (≥80 cm for women and ≥ 94 cm for men) and for certain Asian groups and Hispanics(≥80 cm for women and ≥90 cm for men). The vast majority (>75%) of people with MetS, even in the absence of diabetes, have increased waist circumference,blood pressure, and triglycerides, and depressed HDL­C levels; of note, however, is that 58% of men and 63% of women

with MetS also have LDL­C levels of 130 mg/dl or higher7

Prevalence and Epidemiology

Data from US adults in 1999­2002 show a prevalence of MetS of 33.7% among men and 35.4% among women

according to the NCEP definition, with higher estimates of 39.9% and 38.1%, respectively, using the IDF definition.8

These figures are substantially higher than that previously reported in the preceding decade, when prevalence rates were

well under 30%.9,10

Wide variations in the prevalence of MetS are observed across other parts of the world, and depend on the definitionused. For instance, among Hong Kong Chinese, the prevalence of MetS varied from 9.6% using the NCEP definition to

13.4% using the World Health Organization (WHO) definition.11 In a large United Kingdom population­based study, SouthAsians had the highest prevalence of MetS (29% in men and 32% in women using the NCEP definition), and European

women had the lowest (14%),12 and in a large study involving 11 European cohorts, prevalence using a modified WHO

definition was slightly higher in men (15.7%) than in women (14.2%).13

Metabolic Syndrome and Cardiovascular Risk

Among US adults, a twofold greater risk of mortality from coronary heart disease

(CHD) and CVD in persons with MetS was observed in one study 14; even those withMetS but without diabetes and those with only one or two MetS risk factors are at anincreased risk of death from CHD and CVD. Moreover, those with diabetes in theabsence of CVD had a similar risk of total mortality as those with pre­existing CVD,hence supporting the concept of diabetes as a CVD risk equivalent. Those with bothdiabetes and pre­existing CVD have the highest risk (Figure 2). Other reports alsodocument the prognostic importance of the MetS among men in the West of

Scotland study,15 and in Finnish adults.16

In a meta­analysis of risks for all­cause mortality, CVD, and diabetes, Ford et al.,17

noted that among studies that used the exact NCEP definition of the MetS, relativerisks (and 95% confidence intervals) associated with the MetS were 1.27 (0.90­1.78)for all­cause mortality, 1.65 (1.38­1.99) for CVD, and 2.99 (1.96­4.57) for diabetes.The authors concluded that MetS may attribute to 6­7% of all­cause mortality, 12­

17% of CVD, and 30­52% of diabetes.17

Finally, in a large meta­analysis of longitudinal studies, which included over 170,000individuals among 43 cohorts, a relative risk of cardiovascular events and death of1.78 (1.58­2.00) was reported, with a stronger effect seen in women compared with

men (relative risk, 2.63 vs. 1.98; p = 0.09) (Figure 3).18

Persons with diabetes are considered to be a CHD risk equivalent, according to the

National Cholesterol Education Program (NCEP),5 warranting aggressive treatmentguidelines similar to those with known CHD. In the absence of prior myocardialinfarction, they have a similar risk of future CV mortality as persons with a priormyocardial infarction without diabetes. The presence of both diabetes and prior

myocardial infarction is associated with an even higher risk of CV mortality.19

Figure 2

Figure 3

Cardiovascular Disease (CVD) and Total Mortality in US Men and Women Ages 30­74Figure 2

Cardiovascular disease (CVD) and total mortality in US men and women ages 30­74: Age, gender, and risk­factor adjusted Cox regression,National Health and Nutrition Examination Survey (NHANES) II follow­up (n = 6,255), compared to those with neither metabolic syndrome (MetS),diabetes, nor CVD. MetS: p < 0.05 for coronary heart disease (CHD) mortality and p < 0.01 for CVD mortality; diabetes, CVD, and CVD plusdiabetes: p < 0.001 for CHD, CVD, and total mortality.

Data adapted with permission from Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heartdisease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245­50.

Relative Risk and 95% Confidence Interval for Metabolic Syndrome and Incident Cardiovascular Events and DeathFigure 3Studies are listed in chronological order by year that their cohorts were created (except for the last study listed, which includes multiplecohorts). Results are for available analyses of incident cardiovascular disease and death, and may differ from the results of the total studypopulations. Boxes represent the relative risk (RR), and lines represent the 95% confidence interval (CI) for studies. The diamond represents thepooled RR, and its width represents its 95% CI.

Adapted with permission from Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: asystematic review and meta­analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403­14.

Evaluation and Assessment of Risks in the Metabolic Syndrome

Given a wide spectrum of CHD risk associated with MetS, intensified efforts toscreen and adequately treat persons with the MetS are needed. The NCEP has

provided a clinically useful definition of the MetS,5 which has been widelydisseminated through the medical community and has been subsequently

updated.4

An initial evaluation of MetS can be done by standard laboratory tests, or by efficientpoint­of­care instruments assessing triglycerides, HDL­C, and glucose, in additionto blood pressure and waist circumference measurement. As most persons withMetS have elevated triglycerides, a direct LDL­C measurement is recommended, asuse of the Friedewald formula for calculating LDL­C would result in LDL­C beingunderestimated in many cases due to elevated triglycerides.

Additionally, a proper measurement of waist circumference and at least twoconsistent measures of blood pressure (taking the average of the two) shouldprovide the required information to diagnose MetS. Importantly, the measurement ofglycated hemoglobin (HbA1c) has also been designated in recent American College

of Cardiology Foundation (ACCF)/AHA as being reasonable for CV risk assessmentin asymptomatic adults without a diagnosis of diabetes (Class IIa, Level of Evidence

B).20

Given the significant heterogeneity in estimated risk of persons with MetS, initialevaluation of risk in persons with MetS and without diabetes, can utilize Framingham

risk scores to estimate total CVD risk in 10­years (Table 1).21 Moreover, the use ofglobal risk scores for risk assessment is an ACCF/AHA Class I, Level of Evidence Brecommendation for all asymptomatic adults without a history of CHD to help target

preventive interventions.20 While some 40% are actually at low risk of CHD (<6% in10 years), fully one­third are at high risk based on pre­existing diabetes, CVD, or

>20% 10­year risk of CHD.22 Older persons or those who are smokers or haveincreased total or LDL­C levels, even if only minimal elevations of defined MetS riskfactors are present, may be at intermediate or higher risk of CHD.

Furthermore, there is interest as to whether the addition of newer risk factors suchas C­reactive protein (CRP), fibrinogen, and small­dense LDL will further add topredicting risk in persons with MetS. For instance, the Nurses’ Health Study hasshown that among those with MetS, age­adjusted incidence rates of future CVDevents were 3.4 and 5.9 per 1,000 person­years for those with CRP levels of ≤3 and>3 mg/L, with additive effects of higher CRP levels also seen for those with 4­5 MetS

risk factors.23 It has also been recommended that CRP be considered for

measurement in intermediate­risk individuals,20,24 and in men ages 50 and over or

women ages 60 and over without CHD, but who have an LDL­C <130 mg/dl,20 whichmay comprise many persons with MetS.

The presence of subclinical atherosclerosis such as carotid ultrasound intimal

medial thickness,25 ankle­brachial index (although a low ankle­brachial index <0.9

is diagnostic of peripheral arterial disease, a CHD risk equivalent),26­27 or coronary

artery calcium (CAC),28­30 may also identify individuals with higher CV risk based ontheir demonstrated independent prognostic value (Figure 4). This may haveimportant implications for persons with MetS (especially in the absence of diabetes),given the uncertainty of risk assessment on the basis of global risk assessmentalone.

Recent ACCF/AHA guidelines recommend considering atherosclerosis screening(e.g., by CAC testing) in those with a 10­20% 10­year CHD risk (Class IIa, Level of

Evidence B).20 The guidelines state that those found to have clinically significantatherosclerosis could have their risk level “stratified upwards,” (e.g., reclassifying anintermediate­risk individual as high risk); thus, such screening may haveimplications for refining risk assessment in many persons with MetS. It isnoteworthy that these recommendations have now been extended to those withdiabetes who are age ≥40 years for CV risk stratification (Class IIa, Level of

Evidence B).20 A finding of significant calcification in such individuals could in fact bea potent motivator on both the part of the physician and patient to more aggressivelycontrol the multiple CVD risk factors that often present in patients with MetS.

Table 1

Figure 4

Framingham Risk Score: What is this patient’s risk cardiovascular disease?Table 1Adapted with permission from D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: theFramingham Heart Study. Circulation 2008;117:743­53.

Computed Tomography Scan Showing Significant Coronary Artery Calcium (score > 400)Figure 4

Management of the Metabolic Syndrome(1 of 2)

Lifestyle Management

Initial management of the MetS should focus on reversing the root causes of

atherogenic diet, sedentary lifestyle, and overweight or obesity.31 Weight control, inparticular, can beneficially modify all key cardiometabolic risk factors, includingglucose, LDL­C, HDL­C, triglycerides, blood pressure, insulin levels, andinflammatory measures such as high­sensitivity CRP.

In one study, subjects assigned to a low­carbohydrate diet compared with a low­fatdiet showed greater weight loss and greater reductions in triglycerides, a lesser

decrease in HDL­C, and improved insulin sensitivity.32 Comparison of a low­carbohydrate, high­protein, high­fat (Atkins) approach with a conventional low­calorie, high­carbohydrate, and low­fat diet showed greater initial weight loss on the

former; however, after 12 months, there was little difference in weight loss.33

The most effective way to manage the MetS appears to be overall lifestyle changeprograms. For instance, the DPP (Diabetes Prevention Program) trial’s lifestyleintervention arm (involving a 7% weight loss and exercise of 150 minutes/week)showed a 58% reduction in new diabetes onset compared to placebo (with even the

metformin arm only showing a 31% reduction compared to placebo).34 The FinnishDiabetes Prevention Study also showed a 58% reduction in new diabetes onset asa result of lifestyle intervention involving reduction in weight, saturated fat intake, and

increases in fiber intake and exercise.35

Lifestyle management guidelines focus on the management of underlying riskfactors predisposing to the development of MetS, namely overweight/obesity,

physical inactivity, and dietary modifications that are needed (Table 2).1 Thisincludes recommendations for modest reductions of 500­1,000 calories per day toprovide a 7­10% reduction in body weight over the first year, with a reduction of body

mass index to <25 kg/m2.

Regular and continuous moderate­intensity physical activity of at least 30 minutes(preferably 60 minutes) at least 5 days per week (and daily if possible) is alsorecommended, although the greatest benefit occurs from a difference betweensome versus no physical activity. In particular, the combination of weight reductionand increased physical activity can significantly reduce the incidence of new­onsetdiabetes in persons with prediabetes.

Furthermore, for treatment of MetS, dietary recommendations consistent with AdultTreatment Panel (ATP) III recommendations for a low intake of saturated fats, transfats, and cholesterol; reduced consumption of simple sugars; and increasedintakes of fruits, vegetables, and whole grains are reasonable, with an overall intakeof saturated fat of <7% of calories, dietary cholesterol of <200 mg/day, and total fat

intake of 25­35% of calories.5 Moreover, recently updated recommendations alsoindicate sodium restriction at <1500 mg/day.

Clinical Management

General recommendations are also given for the management of clinical riskfactors, including atherogenic dyslipidemia, elevated blood pressure, elevated

glucose, and a proinflammatory state (Table 2).1 Importantly, it can be demonstratedthat approximately 80% of CHD events could be potentially averted in persons withMetS if blood pressure, LDL­C, and HDL­C were controlled to optimal levels (Figure

5).7

Atherogenic Dyslipidemia

Besides the vast majority of persons with MetS having elevated triglycerides (85% ofmen and 73% of women) as well as low HDL­C (83% of men and 87% of women),

many (58% of men and 63% of women) have suboptimal LDL­C levels.7 Importantly,

Table 2

Figure 5

this LDL­C in many persons with MetS is likely to be of the small­dense pattern B

phenotype, which is well­documented to be highly atherogenic.4,36,37 Control of

LDL­C remains the primary target of therapy,1 and subgroup analyses of patientswith MetS from several large­scale trials have shown that important reductions in

CHD with statin therapy support these recommendations.38­40

Also of importance, the ACCORD (Action to Control Cardiovascular Risk in Diabetes)trial in persons with type 2 diabetes failed to show an added benefit of fenofibrate

therapy to reduce CVD risk beyond that of a statin alone,41 although there wasbenefit seen specifically in the subgroup of persons with both elevated triglyceridesand low HDL­C. Whether these findings would extend to persons with MetS withoutdiabetes mellitus, however, is unclear.

Recommended goal levels for LDL­C are <100 mg/dl for high­risk patients, <130mg/dl for moderate­ and moderately high­risk patients, and <160 mg/dl for lower­risk

patients) (Table 2).4 For those patients with pre­existing CVD, recent guidelines

suggest an optional goal for LDL­C of <70 mg/dl.42 Moreover, a secondarytherapeutic target relevant for most patients with MetS (many who will have fastingtriglycerides of ≥200 mg/dl) is non­HDL­C, with these targets being 30 mg/dl higher

than LDL­C targets (Table 2).4 A tertiary target is low HDL­C, and while no specificgoal has been recommended, it would be reasonable to consider efforts to raise theHDL­C above those cut points defining it as a criterion for MetS (40 mg/dl in men or50 mg/dl in women).

Although lifestyle modalities (as described earlier) are mandatory to adequatelyaddress dyslipidemia in MetS, it is recognized that many persons will requiremultiple pharmacologic therapies to reach recommended goals for LDL­C, withconcomitant improvements in HDL­C and triglycerides. The major statins prescribedat moderate to maximal dosages will lower LDL­C by 40% or greater, along withlowering triglycerides by 25% or more and raising HDL­C by 5­10% on average,

based on a large study conducted in persons with MetS.43

However, once LDL­C goal is reached and additional improvements in triglyceridesand/or HDL­C are needed, fibrates (particularly fenofibrate, which can be combinedsafely with statins) or niacin should be added (or used as monotherapy if low HDL­Cor elevated triglycerides are the principal problem and LDL­C is already at goal).or elevated triglycerides are the principal problem and LDL­C is already at goal).Evidence from several trials suggests benefits in terms of reduced CV risk or

atherosclerosis from fibrates, niacin, or when these are combined with statins.44­48

Therapeutic Goals and Recommendations for Clinical Management of Metabolic SyndromeTable 2CHD = coronary heart disease; HDL­C = high­density lipoprotein cholesterol; HbA1c = glycated hemoglobin; LDL­C = low­density lipoproteincholesterol.

Adapted with permission from Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an AmericanHeart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735­52.

Proportion of CHD Events Potentially Preventable From Optimal Control of BP, LDL­C, and HDL­CFigure 5Optimal control of blood pressure (BP; to <120 mm Hg / <80 mm Hg), low­density lipoprotein cholesterol (LDL­C; to <100 mg/dl), and high­densitylipoprotein cholesterol (HDL­C; to >60 mg/dl) in men and women.

CHD = coronary heart disease.

Data adapted with permission from Wong ND, Pio JR, Franklin SS, et al. Preventing coronary events by optimal control of blood pressure andlipids in patients with the metabolic syndrome. Am J Cardiol 2003;91:1421­6.

Management of the Metabolic Syndrome(2 of 2)

Elevated Blood Pressure

Hypertension is the leading MetS risk factor predisposing to increased risk for CV morbidity and mortality, the associationof elevated blood pressure to MetS being strongly linked through the causative pathway of obesity. Hyperactivity of thesympathetic nervous system and renin­angiotensin­aldosterone system is associated with increased blood pressure,

insulin resistance, and endothelial dysfunction, which are all often found in persons with MetS.49 It has beendemonstrated that elevated blood pressure is present in 84% of men and 77% of women with MetS in the absence of

diabetes.7 The goal for antihypertensive therapy in those without overt diabetes or chronic kidney disease is <140/90 mm Hg, and ifthese conditions are present, <130/80 mm Hg; however, in persons with type 2 diabetes, the ACCORD trial did not showoverall CV events to be significantly reduced from more versus less intensive control of blood pressure, except for stroke

prevention.50 Despite elevated blood pressure of 130­139 mm Hg systolic or 85­89 mm Hg diastolic fitting the definitionof being a criterion for MetS, these patients would only qualify for lifestyle modification per Joint National Committee 7

(JNC 7) recommendations 51; however, European Society of Hypertension guidelines would supplement lifestylemodification with antihypertensive drug therapy for these persons when at least three of the following CV risk factors arepresent: male >55 years of age or female >65 years of age, dyslipidemia, smoking, family history of premature CVD, left

ventricular hypertrophy, and microalbuminuria.52

Certainly, mild elevations of blood pressure can be controlled with lifestyle modifications, especially weight control,increased physical activity, alcohol moderation, sodium reduction, and increased consumption of fresh fruits and

vegetables, in accordance with the Dietary Approaches to Stop Hypertension (DASH) diet.53 In those with overthypertension, pharmacologic therapy will often be required to reach goal levels of blood pressure, and while someinvestigators have supported the use of angiotensin­converting enzyme (ACE) inhibitors (or angiotensin­receptorblockers [ARBs] in ACE­intolerant patients) given their documented renoprotective role in persons with diabetes or kidneydisease, no clinical trials specifically conducted in persons with MetS to support such an approach exists.

Given the difficulty of controlling hypertension, often requiring two or three medications for its control, the JNC 7recommends initiation with two drugs (or a two­drug combination) for those with stage 2 hypertension (systolic bloodpressure of 160 mm Hg or higher or diastolic blood pressure of 100 mm Hg or higher); those with diabetes or chronickidney disease (or other high­risk MetS patients) would require such polypharmacy at lower levels (e.g., 150 mm Hgsystolic or higher) to achieve the lower recommended goals for these patients.

Elevated Glucose

Elevated fasting glucose in persons with MetS is defined as ≥100 mg/dl, and includes both impaired fasting glucose anddiabetes. The role of lifestyle management, particularly weight reduction and/or increased physical activity in delaying the

onset of type 2 diabetes in those with impaired fasting glucose, is well established from results of the DPP trial,34 and

the Finnish Diabetes Prevention Study.35 For persons with established type 2 diabetes mellitus, pharmacologic therapy

is needed to reach a goal level of HbA1c of <7% to reduce the risk of microvascular complications.4 Such a regimen may

also prevent macrovascular complications, although data are currently limited.

The UKPDS (United Kingdom Prospective Diabetes Study) showed a borderline significant (p = 0.052) 16% reduction inCV events as a result of “intensive” glycemic control, resulting in a median HbA1c level of 7.0%, compared to 7.9% in the

conventionally treated arm,54 although a subgroup of overweight patients randomized to metformin did show significant

reductions in microvascular complications and myocardial infarction.55

More recently, the ACCORD and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron ModifiedRelease Controlled Evaluation) clinical trials, however, have provided mixed results regarding the efficacy of intensiveglycemic control (compared to a more moderate regimen) to reduce CV events; however, the results were suggestive of a

benefit in those without known macrovascular disease at baseline.56,57

For persons with MetS but without diabetes, data are limited regarding therapeutic benefits of antiglycemic medications.In the DPP trial, while metformin use in impaired glucose­tolerant patients was associated with a 31% reduction of newdiabetes onset compared to placebo, this benefit was not as great as the 58% reduction seen in those assigned to

aggressive lifestyle management alone.34

Most recently and perhaps of greatest interest are the results from the DREAM (Diabetes Reduction Assessment WithRamipril and Rosiglitazone Medication) study, where the thiazolidinedione rosiglitazone was associated with a significant

(p < 0.001) 60% reduction in the incidence of new diabetes or death compared to placebo over a 3­year follow­up period;however, overall CV events were similar, and there was a higher incidence of heart failure (0.5% vs. 0.1%, p = 0.01) in the

rosiglitazone­treated subjects.58

A substantial reduction in risk of developing new diabetes was also shown in a similar trial ACT­NOW (Actos Now for the

Prevention of Diabetes) involving pioglitazone.59 It is unknown whether the reduction in new­onset diabetes will translateinto reduced macrovascular event rates in the future. At present, despite these promising data, neither metformin northiazolidinediones are recommended solely for the purpose of preventing diabetes because their cost­effectiveness,

overall benefits, and long­term safety over nonpharmacologic approaches have not been documented.4

Prothrombotic/Proinflammatory States

Increased levels of fibrinogen, plasminogen activator inhibitor­1, and other coagulation factors are seen in persons withMetS. While aspirin therapy is typically recommended in high­risk persons, including those with diabetes or pre­existingCVD, low­dose aspirin is a consideration for persons who are at moderately high risk (e.g., 10­20% risk of a CHD event

in 10 years), which will include many, but not all persons with MetS.4

A proinflammatory state exhibited by elevated cytokines (e.g., tumor necrosis factor­alpha and interleukin­6) and acute

phase reactants (e.g., CRP, fibrinogen) is frequently seen in persons with MetS.4 The AHA/Centers for Disease Controland Prevention has recommended measurement of high­sensitivity CRP as a reasonable test to identify a

proinflammatory state in intermediate­risk individuals.23 A level of >3 mg/L can be used to define a high­risk state,

supporting the need for lifestyle changes, particularly weight reduction, which has been shown to reduce CRP levels.60

Although no drugs are known to specifically reduce levels of inflammation other than aspirin, drugs used to treat otherrisk factors such as statins, nicotinic acid, fibrates, ACE inhibitors, and thiazolidinediones have been shown to reducelevels of CRP; however, there are currently no guidelines indicating the use of any medications specifically to reduce a

proinflammatory state apart from their approved indications for controlling other risk factors.4

Conclusion

The MetS is associated with an increased risk of future diabetes and CVD. While persons with diabetes are CHD riskequivalents and warrant aggressive clinical management, a wide spectrum of global risk is present in persons withMetS, necessitating careful assessment of CV risk. While initial global risk assessment utilizing Framingham or otherrisk algorithms is appropriate, consideration of novel risk markers and screening for subclinical atherosclerosis mayimprove risk stratification and identify those at greatest risk for future CVD events and mortality.

Both primary care and subspecialty physicians should assess for the presence of MetS in each patient. Identification ofMetS will also get physicians accustomed to simultaneous treatment of multiple risk factors (particularly abdominalobesity, dyslipidemia, and elevated blood pressure), instead of the traditional model of treatment of risk factors inisolation. Most importantly, intensified efforts at lifestyle therapies, including effective dietary and physical activityinterventions guided by trained individuals, are crucial if a significant impact is to be made on MetS and its futurecomplications. Inclusion of other members of the health care team, such as registered dietitians and exercisephysiologists, to provide the needed time to help educate patients on healthy lifestyles and their adherence, is critical toachieve success in management of MetS.

Key Points

The MetS is a clustering of risk factors associated with insulin resistance known to promote or increase the riskfor development of diabetes and CVD.In conjunction with increases in obesity worldwide, the prevalence of MetS continues to increase; approximatelyone­third of the adult population in developed countries can be characterized with MetS by different definitions.MetS, even in the absence of diabetes, is associated with an increased risk of CVD and total mortality. Those withdiabetes are considered a CV risk equivalent, and are at greater risk of CVD and mortality.Efficient and rapid determination of MetS requires an assessment of blood glucose, triglycerides, and HDL­C,which can be performed by a clinic laboratory or point­of­care instrument, as well as waist circumference andblood pressure. Additional assessment of LDL­C and cigarette smoking will give a more complete evaluation ofglobal cardiometabolic risk. Finally, optional screening for subclinical atherosclerosis can further complement CVrisk assessment.The AHA and National Heart, Lung, and Blood Institute have released guidelines for the clinical management ofMetS, which focus on lifestyle management for abdominal obesity and physical inactivity, and clinicalmanagement of atherogenic dyslipidemia, elevated blood pressure, elevated glucose, and prothrombotic state.A multidisciplinary team of health care providers, including physicians, nurses/nurse practitioners, dietitians, andexercise specialists, is crucial for achieving success in the management of MetS.

References

1. Eckel RH, Grundy SM, Zimmett PZ. The metabolic syndrome. Lancet 2005;365:1415­28.2. Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: definition, pathophysiology and

mechanisms. Am Heart J 2005;149:33­45.3. Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease.

Circulation 2002;106:286­8.4. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American

Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735­52.5. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation,

and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation2002;106:3143­421.

6. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome­­a new world­wide definition. A Consensus Statement from theInternational Diabetes Federation. Diabet Med 2006;23:469­80.

7. Wong ND, Pio JR, Franklin SS, et al. Preventing coronary events by optimal control of blood pressure and lipids inpatients with the metabolic syndrome. Am J Cardiol 2003;91:1421­6.

8. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults inthe U.S. Diabetes Care 2005;28:2745­9.

9. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the thirdNational Health and Nutrition Examination Survey. JAMA 2002;16:356­9.

10. Lorenzo C, Williams K, Hunt KJ, Haffner SM. Trend in the prevalence of the metabolic syndrome and its impact oncardiovascular disease incidence: the San Antonio Heart Study. Diabetes Care 2006;29:625­30.

11. Ko GT, Cockram CS, Chow CC, et al. High prevalence of metabolic syndrome in Hong Kong Chinese­comparisonof three diagnostic criteria. Diabetes Res Clin Pract 2005;69:160­8.

12. Tillin T, Forouhi N, Johnston DG, McKeique PM, Chaturvedi N, Godsland IF. Metabolic syndrome and coronaryheart disease in South Asians, African­Caribbeans and white Europeans: a UK population­based cross­sectionalstudy. Diabetologia 2005;48:649­56.

13. Hu G, Qiao Q, Tuomilehto J, et al. Prevalence of the metabolic syndrome and its relation to all­cause andcardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004;164:1066­76.

14. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease,cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245­50.

15. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C­reactive protein as a predictor ofcoronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation2003;108:414­9.

16. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolicsyndrome. Diabetes Care 2001;24: 683­9.

17. Ford ES. Risks for all­cause mortality, cardiovascular disease, and diabetes associated with the metabolicsyndrome: a summary of the evidence. Diabetes Care 2005;28:1769­78.

18. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: asystematic review and meta­analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403­14.

19. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects withtype 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med1998;339:229­34.

20. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk inasymptomatic adults: a report of the American College of Cardiology Foundation/American Heart AssociationTask Force on Practice Guidelines. J 2010;56:e50­103.

21. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: theFramingham Heart Study. Circulation 2008;117:743­53.

22. Hoang K, Ghandehari H, Lopez VA, Barboza MG, Wong ND. Global coronary heart disease risk assessment of individuals with the metabolic syndrome in the U.S. Diabetes Care 2008;31:1405­9.

23. Ridker PM, Buring JE, Cook NR, Rifai N. C­reactive protein, the metabolic syndrome, and risk of incidentcardiovascular events: an 8­year follow­up of 14,719 initially healthy American women. Circulation 2003;107:391­7.

24. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application toclinical and public health practice: a statement for healthcare professionals from the Centers for Disease Controland Prevention and the American Heart Association. Circulation 2003;107:499­511.

25. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid­artery intima and mediathickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health StudyCollaborative Research Group. N Engl J Med 1999;340:14­22.

26. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterialdisease. N Engl J Med 1992;326:381­6.

27. Criqui MH, Langer RD, Fronek A, Feigelson HS. Coronary disease and stroke in patients with large­vesselperipheral arterial disease. Drugs 1991; 42(suppl 5):16­21.

28. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnicgroups. N Engl J Med 2008;358: 1336­45.

29. Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin JM. Coronary artery calcium evaluation byelectron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86: 495­8.

30. Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beamcomputed tomography. J Am Coll Cardiol 2000;36:1253­60.

31. Stone NJ, Saxon D. Approach to treatment of the patient with metabolic syndrome: lifestyle therapy. Am J Cardiol2005; 96[suppl]:15E­21E.

32. Samaha FF, Iqbal N, Seshadri P, et al. A low carbohydrate as compared with a low­fat diet in severe obesity. NEngl J Med 2003;348:2074­81.

33. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low­carbohydrate diet for obesity. N Engl J Med2003;348:2082­90.

34. Knowler WC, Barrett­Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyleintervention or metformin. N Engl J Med 2002;346:393­403.

35. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle amongsubjects with impaired glucose tolerance. N Engl J Med 2001;344:1343­50.

36. Austin MA, Rodriguez BL, McKnight B, et al. Low­density lipoprotein particle size, triglycerides, and high­densitylipoprotein cholesterol as risk factors for coronary heart disease in older Japanese­American men. Am J Cardiol2000;86:412­6.

37. Krauss RM. Atherogenicity of triglyceride­rich lipoproteins. Am J Cardiol 1998;81(suppl 4A):13B­17B.38. Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin­treated patients with coronary

heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the ScandinavianSimvastatin Survival Study. Arch Intern Med 1999;159:2661­7.

39. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C­reactive protein as a predictor ofcoronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation2003;108:414­9.

40. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensivepatients who have average or lower­than­average cholesterol concentrations, in the Anglo­Scandinavian CardiacOutcomes Trial—Lipid Lowering Arm (ASCOT­LLA): a multicentre randomised controlled trial. Lancet2003;361:1149­58.

41. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetesmellitus. N Engl J Med 2010;362:1563­74.

42. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary andother atherosclerotic vascular disease: 2006 update endorsed by the National Heart, Lung, and Blood Institute. JAm Coll Cardiol 2006;47:2130­9.

43. Deedwania PC, Hunninghake DB, Bays H. Effects of lipid­altering treatment in diabetes mellitus and themetabolic syndrome. Am J Cardiol 2004;93(suppl):18C­26C.

44. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease : subgroupanalysis from the Department of Veterans Affairs high­density lipoprotein intervention trial (VA­HIT). Arch InternMed 2002;162:2597­604.

45. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healedmyocardial infarction (from the Coronary Drug Project). Am J Cardiol 2005;95:254­7.

46. Keech A, Simes RJ, Barter P, et al. Effects of long­term fenofibrate therapy on cardiovascular events in 9795people with type 2 diabetes mellitus (the FIELD Study): randomised controlled trial. Lancet 2005;366:1849­61.

47. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effectsof Reducing Cholesterol (ARBITER) 2: a double­blind, placebo­controlled study of extended­release niacin onatherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512­7.

48. Volkova N, Deedwania PC. Dyslipidemia in the metabolic syndrome. In: Krentz and Wong, eds. MetabolicSyndrome and Cardiovascular Disease. New York: Informa Healthcare; 2007.

49. Franklin SS. Hypertension in the metabolic syndrome. In: Krentz AJ, Wong ND, eds. Metabolic Syndrome andCardiovascular Disease. New York: Informa Healthcare; 2007.

50. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood­pressure control in type 2diabetes mellitus. N Engl J Med 2010;362:1575­85.

51. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560­72.

52. European Society of Hypertension­European Society of Cardiology Guidelines Committee. 2003 European Societyof Hypertension­European Society of Cardiology guidelines for the management of arterial hypertension. JHypertens 2003;21:1011­53.

53. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the dietary patterns on blood pressure. DASHCollaborative Research Group. N Engl J Med 1997;336:1117­24.

54. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood­glucose control with sulphonylureas or insulincompared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet 1998;352:837­53.

55. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood­glucose control with metformin oncomplications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854­65.

56. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2

diabetes. N Engl J Med 2008;358:2545­59.57. ADVANCE Collaborative Group. Intensive blood glucose and vascular outcomes in patients with type 2 diabetes.

N Engl J Med 2008;358:2560­72.58. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of

rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fastingglucose: a randomized controlled trial. Lancet 2006;368:1096­105.

59. Defronzo RA, Banerji M, Bray GA, et al. Actos Now for the prevention of diabetes (ACT NOW) study. BMC EndocrDisord 2009;9:17.

60. Van Dielen FM, Buurman WA, Hadfoune M, Nijhuis J, Greve JW. Macrophage inhibitory factor, plasminogenactivator inhibitor­1, other acute phase proteins, and inflammatory mediators normalize as a result of weight lossin morbidly obese subjects treated with gastric restrictive surgery. J Clin Endocrinol Metab 2004;89:4062­8.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.7: Cardiovascular Disease Prevention: Considerations for Women

Author(s): Martha Gulati, MD, MS, FACCC. Noel Bairey­Merz, MD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Describe the impact of cardiovascular disease (CVD) on women.2. Explain how to use risk assessment tools to estimate CV risk in women.3. List the major risk factors for CVD in women and identify those that are unique to women.4. Summarize current guidelines related to women regarding CVD prevention.

Introduction

CVD is the leading cause of death for women in the United States.1 CVD prevalence

and mortality is higher in women than in men.1 More women have died of CVD thanof cancer, chronic lower respiratory disease, Alzheimer disease, and accidents

combined.1 The death rate in females from coronary heart disease (CHD) was onthe rise after 1979, when there was a great decline in mortality during the same timeperiod in men. Only in this last decade (since 2000) has there been a decline inmortality from CHD in women, to a rate of 95.7 per 100,000 females in 2007, a third

of what it was in 1980.2,3

The Framingham Heart Study demonstrated a later onset of CVD in women thanmen, with initial manifestation of CVD occurring 10 years later in women compared

with men, and myocardial infarction (MI) as much as 20 years later.4 Despite thelower prevalence of CVD in younger women, the consequences of premature CHDare relatively worse in women, with a twofold increase in mortality after acute MI in

women under the age of 50 years compared with men of the same age (Figure 1).5

The enormity of the problem of CVD in women underscores the need to identify andprevent the development of risk factors for CVD in women, and to consider those riskfactors that are unique to women.

Figure 1

Gender Differences in Death Rates During Hospitalization for Myocardial InfarctionFigure 1Adapted with permission from Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex­based differences in early mortality aftermyocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217­25.

Awareness of Cardiovascular Disease in Women

A barrier to the prevention of CVD in women is lack of awareness of the disease in women and the medical community.Over time, it has been shown that awareness in women of CVD as the leading cause of death in women has increased

from 1997 to 2009, but it has remained stable since 2006, and is disproportionately lower in racial and ethnic minorities.6

In a survey performed in 2004, fewer than one in five physicians recognized that more women than men die each year

from CVD.7

Awareness and symptom recognition impacts mortality from CHD in women. Data from CRUSADE (Can Rapid RiskStratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation) and the NCDRACTION Registry­GWTG (National Cardiovascular Data Registry Acute Coronary Treatment and Interventions OutcomesNetwork­Get With the Guidelines) demonstrated no reduction in time from symptom onset to hospital presentation forwomen with an MI since national awareness campaigns in women were initiated. In addition, women ages 40­60 years

had a 3.46% longer time to presentation than men.8

Risk Stratification

The 2010 American College of Cardiology Foundation (ACCF)/American HeartAssociation (AHA) Guideline for Assessment of CV Risk in Asymptomatic Adultsrecommends assessing a global risk score (such as the Framingham risk score)that uses multiple traditional CV risk factors for all asymptomatic adults without a

clinical history of CHD as a Class I indication.9

Variations of the Framingham risk score exist, with one version including diabetes inthe risk score calculation, and the later version in National Cholesterol EducationProgram Adult Treatment Panel (NCEP ATP) III considers diabetes a CHDequivalent. Endpoints vary as well. Data from the National Health and NutritionExamination Survey (NHANES) showed that a Framingham­type risk model was

useful in women for predicting CV events, with a C­statistic of 0.829.10 However, the

focus on 10­year risk estimates makes risk scoring less useful in women.11

The AHA Effectiveness­Based Guidelines for the Prevention of CVD in Women 2011update recommends stratifying women into three categories: 1) high risk, 2) at risk,

and 3) optimal risk, and places emphasis on the lifetime risk of CVD in women.12

“High risk” status is defined as having one or more high­risk states, which includethe clinical presence of CHD, cerebrovascular disease, peripheral arterial disease,abdominal aortic aneurysm, end­stage or chronic kidney disease, diabetes mellitus,or 10­year predicted CVD risk of ≥10%, which is a significantly lower threshold fordefinition of high risk than the previous cutoff of 20%, used in the prior guidelines

and the NCEP ATP III guidelines.12

“At risk” status is defined as having one or more of the following risk factors:cigarette smoking, systolic blood pressure ≥120 mm Hg, diastolic blood pressure≥80 mm Hg, or treated hypertension, total cholesterol ≥200 mg/dl, high­densitylipoprotein cholesterol (HDL­C) <50 mg/dl, or treated for dyslipidemia, obesity(particularly central adiposity), poor diet, physical inactivity, family history ofpremature CVD occurring in first­degree relatives in men <55 years of age or inwomen <65 years of age, metabolic syndrome, evidence of advanced subclinicalatherosclerosis (e.g., coronary calcification, carotid plaque, or thickened intima­media thickness), poor exercise capacity on treadmill test and/or abnormal heartrate recovery after stopping exercise, systemic autoimmune collagen­vasculardisease (e.g., lupus or rheumatoid arthritis), history of pre­eclampsia, gestational

diabetes, or pregnancy­induced hypertension.12

“Optimal risk” is defined as someone without any of the preceding risk factorspresent, with ideal CV health and behaviors. This includes a total cholesterol under200 mg/dl, blood pressure <120/80 mm Hg, fasting blood glucose <100 mg/dl, body

mass index (BMI) <25 kg/m2, nonsmoker, meeting physical activity goals, and

having a healthy diet (Table 1).12

Other risk scores exist. The Reynolds Risk Score calculates risk in women andmen. It includes high­sensitivity C­reactive protein (hs­CRP) and family history as

risk factors, and considers cerebrovascular events as an outcome.13 The European“SCORE” (Systematic Coronary Risk Evaluation) has been developed, and includesage as a measure of exposure time to risk rather than as a risk factor, andconsidered geographic variability within European countries as the calibration

metric.14

Table 1

Classification of CVD Risk in WomenTable 1CHD = coronary heart disease; CVD = cardiovascular disease; DASH = Dietary Approaches to Stop Hypertension; DBP = diastolic bloodpressure; HDL­C = high­density lipoprotein cholesterol; IMT = intima­media thickness; SBP = systolic blood pressure.

Adapted with permission from Mosca L, Benjamin EJ, Berra K, et al. Effectiveness­based guidelines for the prevention of cardiovascular diseasein women­­2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243­62.

Established Risk Factors for Cardiovascular Disease(1 of 2)

Age

Age is a powerful predictor of CVD, and specifically CHD. The prevalence of CVD

increases with age in both men and women.1 CHD events lag at least 10 years in

women compared to men.4 In contrast to the linear increase in CHD in men as they

age, there is a more exponential increase in CHD in women after the age of 60,15

with one in three women having evidence of CHD after the age of 65 years, in

contrast with one in eight in women ages 45­64 (Figure 2).16 The NCEP ATP IIIconsiders the age of 55 years or above to be a risk factor for women, compared to45 years for men. Despite this, the highest sex difference in CHD mortality isobserved in relatively young middle­aged women, where acute MI mortality is twicethat of age­matched men, compared to no sex difference among elderly women and

men.5

Family History

A history of CHD in a first­degree relative imparts risk on an individual.17 The NCEPATP III and the AHA guidelines for the prevention of CVD in women defines familyhistory of premature CHD as a first­degree relative with CHD before the age of 65

years for women and age 55 years for men.12,18 Premature CHD in first­degreefemale relatives is a relatively more potent family history risk factor compared to

male relatives.19 The 2010 ACCF/AHA Guideline for Assessment of CV Risk inAsymptomatic Adults recommends that family history of atherothrombotic CVD

should be obtained for CV assessment in all asymptomatic adults.9

Hypertension

The prevalence of hypertension overall is higher in women compared to men, butvaries by age. Based on the NHANES data, before the age of 45, more men than

women have hypertension.20 From age 45­64, the prevalence of hypertension inmen and women with hypertension is similar, but at age 65 and above, there is ahigher prevalence of hypertension in women compared with men. For women takingoral contraceptives, hypertension is 2­3 times more common than in women not

taking them.21

The NHANES survey from 1999­2004 demonstrated that hypertensive women weremore likely to be treated than men, but they are less likely to achieve blood pressure

control.22 In addition to a higher prevalence of hypertension in older women, bloodpressure control is also poorer in that age group. In the WHI (Women’s HealthInitiative) observational study, only 29% of hypertensive women ages 70­79 hadblood pressures under 140/90 mm Hg compared with 41% and 37% of those ages

50­59 and 60­69, respectively.23

The presence of hypertension is associated with an increased risk of thedevelopment of congestive heart failure, but this risk appears to be greater inwomen. From the Framingham Heart Study and Framingham Offspring Study, therisk of developing heart failure in those with hypertension compared withnormotensive subjects was about twofold greater in men and threefold greater in

women.24

Women who present with strokes are more likely to have a history of hypertension

than men.25 This is especially important because the lifetime risk of stroke isgreater in women compared with men, related to their greater life expectancy and the

fact that stroke rates increase substantially with age.26,27

Diabetes

Diabetes is such a significant risk factor for CVD that it is considered a CHD risk

equivalent.18 The presence of diabetes is a relatively greater risk factor for CHD in

Figure 2

women compared with men, increasing a woman’s risk of CHD by three­ to

sevenfold with only a two­ to threefold increase in diabetic men.28 In addition, therisk of fatal CHD in a diabetic woman is increased 3.5 times in a nondiabeticwoman, which is higher than seen in diabetic men when compared with nondiabetic

men (relative risk of fatal CHD is twice that of a nondiabetic man).28

The American Diabetes Association suggests that diabetes screening should beconsidered for women and men over the age of 45 years, and then repeated every 3

years if the results are normal.29 For women with a history of gestational diabetes,screening for diabetes should occur 6­12 weeks postpartum, and then every 1­2

years thereafter.30

Incidence of Heart Disease in Women by AgeFigure 2Adapted with permission from Wenger NK. Coronary heart disease: an older woman's major health risk. BMJ 1997;315:1085­90.

Established Risk Factors for Cardiovascular Disease(2 of 2)

Dyslipidemia

Dyslipidemia is common in women, with more than half of American women having a total cholesterol >200 mg/dl and36% with a low­density lipoprotein cholesterol (LDL­C) >130 mg/dl. Women are less likely to have an HDL <40 mg/dl

(13% of women compared to 23% of Americans overall).31 Notably in women, adverse changes in the lipid profileaccompany menopause and include increased levels of total cholesterol, LDL­C, and triglycerides and decreased levels

of HDL­C,32,33 although it remains unclear how much risk factor worsening is related to aging, as opposed to

menopause­related hormonal changes.34

The ATP III guidelines name LDL­C as the primary target of lipid­lowering therapy to reduce risk of CVD.35 Furthermore,the 2010 ACCF/AHA Guideline for Assessment of CV Risk in Asymptomatic Adults does not recommend measurement oflipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond a standard fasting lipid profile

for CV risk assessment in asymptomatic adults.9 However, calculation of non­HDL­C, the difference between totalcholesterol and HDL­C, is recommended, and treatment guidelines for the consideration of pharmacotherapy and

therapeutic targets for non­HDL­C cholesterol are 30 mg/dl higher than the therapeutic target for LDL­C.9 In contrast, theLipoprotein Management in Patients with Cardiometabolic Risk Consensus statement from the American DiabetesAssociation and the ACCF in 2008 recommends that the majority of dyslipoproteinemic patients with cardiometabolic riskfactors be treated with a statin, and that statin therapy be guided with measurement of apolipoprotein B in addition to

LDL­C and non­HDL­C assessments.36

HDL­C is a predictor of CVD in both men and women,37 but may be relatively more predictive in women.38­41 In theFramingham study, men in the lowest quartile for HDL­C (HDL<36 mg/dl) had a 70% greater risk of MI compared withthose in the highest HDL­C quartile (HDL >53 mg/dl). However, this risk was even stronger for women with low HDL­C.Women in the lowest HDL­C quartile (HDL <46 mg/dl) had 6­7 times the rate of coronary events compared with those in

the highest HDL­C quartile (HDL >67 mg/dl), even after adjustment for other risk factors.41 Low levels of HDL­C havealso been shown to be associated with more progression of angiographically significant coronary disease in women

than in men.42 HDL­C levels in women average around 10 mg/dl higher than in men, throughout their lives.41 This isreflected in the Effectiveness­Based Guidelines for the Prevention of CVD in Women 2011 update guidelines and the ATP

III guidelines, as desired HDL­C is recommended to be 50 mg/dl in women, as opposed to 40 mg/dl in men.12,43,44

Smoking

In 2009, 23.1% of men and 18.3% of women reported tobacco use, putting them at increased risk of CVD.45 Cigarettesmoking may be more detrimental in women than men; on average, female smokers die 14.5 years earlier than female

nonsmokers, and male smokers die 13.2 years earlier than male nonsmokers.46 Cessation of smoking substantiallyreduces risk; mortality risk among former smokers decreases nearly to that of never­smokers in 10­14 years after

cessation.47

The use of oral contraceptives and smoking imparts an even greater risk of MI than smoking alone. The risk of smoking25 or more cigarettes a day increases women’s risk by 12­fold, but smoking 25 or more cigarettes a day and taking oral

contraception increases one’s risk by 32­fold.48

Physical Activity/Physical Fitness

Physical inactivity is a common risk factor for CHD, but sedentary behavior is more common in women compared with

men (34.5% vs. 30.3%).45 Between NHANES in 1988­1994 and NHANES in 2001­2006, the proportion of women who

engaged in 12 or more bouts of physical activity per month fell from 49% to 43%.49 Physical inactivity is a risk factor forCVD, given its association with higher blood pressure, worse cholesterol, poorer glucose metabolism, and poorermental health. Inactivity also contributes to obesity.

Physical inactivity is an independent risk factor for acute MI,50 and in the Nurses’ Health Study, it was found that women

who walked 30­45 minutes three times a week reduced their risk of MI by 50%, independent of ages.51 In a meta­analysis of studies of physical activity in women, the relative risk of new CHD decreased across increasing levels ofactivity, with a 43% lower risk of new CHD in women in the highest physical activity group compared to the least active

women.52

Exercise capacity, also known as physical fitness, has been shown to be a strong independent predictor of all­cause

mortality in asymptomatic women.53,54 In the St. James Women Take Heart Project, asymptomatic women who wereunable to achieve 5 metabolic equivalents (METs) on a Bruce protocol had a threefold increased risk of death compared

with women who achieved >8 METs.53 Furthermore, the risk of death among asymptomatic and symptomatic womenwhose exercise capacity was <85% of the predicted value for age was at least twice that of women whose exercise

capacity was at least 85% of their age­predicted value.55 In the Effectiveness­Based Guidelines for the Prevention of CVD

in Women 2011 update, physical inactivity or poor physical fitness is criteria for placing a woman in the “at risk” group.12

Emerging Risk Factors(1 of 2)

Metabolic Syndrome

NHANES data from 2003­2006 indicate that 32.6% of women met the criteria for metabolic syndrome,56 and the

presence of metabolic syndrome is associated with increased risk of the development of diabetes.57 In addition, thosewith the metabolic syndrome are at an increased risk of developing CVD, and this association is strongest in women,with a relative risk of CHD of 2.63, compared to a relative risk of 1.98 in men (compared to their same gender

counterparts without the metabolic syndrome).58

Obesity

Obesity is epidemic in the United States, with the 2007­2008 NHANES estimation of obesity in women at 36%.59 Therising incidence of diabetes is closely associated with obesity. Data from the Framingham Heart Study demonstrate adoubling in the incidence of diabetes over the past 30 years, most dramatically in the 1990s and primarily among

individuals with a BMI >30 kg/m2.60

In the Nurses’ Health Study, obesity was the most powerful predictor of diabetes. Women with a BMI >35 kg/m2 had a

relative risk for diabetes almost 40­fold greater than women with a BMI <23 kg/m2.61

Pattern of obesity appears to be related to CVD. Elevated waist circumference above 35 inches, indicative of visceral

obesity, is related to elevated CVD risk, whereas elevated with BMI alone is not.62 Obesity has also been associated withan increased mortality from CVD, where the NHANES 2004 data demonstrated a 13% increased risk in CV deaths

compared with those with a normal BMI.63

Obesity is also associated with a decrease in life expectancy in women, as demonstrated in the Framingham Heart

Study, where a 40­year­old nonsmoking woman would lose 7.1 years of life expectancy as a result of obesity.64 Despitethese data, obesity is not considered an independent risk factor for CVD, as much/all of the risk is related to traditionalrisk factors, which are worsened with obesity.

Furthermore, obesity may simply be a marker for low physical activity and fitness levels. Prior work in women where bothobesity and physical fitness were measured suggests that obese women who are physically fit are not at elevated risk,

and conversely, lean women who are not physically fit have elevated risk.65

High­Sensitivity C­Reactive Protein

While it is unclear if hs­CRP is an independent risk factor for CVD, it may improve risk detection in women.66­68 In theWomen’s Health Study, it was demonstrated that a global risk predication model that included hs­CRP improved CV risk

prediction in women.66 Furthermore, it has been demonstrated that hs­CRP is a stronger predictor of CV events in

women than LDL­C.68

For women with the metabolic syndrome, hs­CRP may add prognostic information regarding future cardiac risk. In onestudy of apparently healthy women, those women with the metabolic syndrome and a baseline hs­CRP level >3.0 mg/L

had almost twice the risk of future CV events than those with the metabolic syndrome and an hs­CRP <3.0 mg/L.69

Measuring hs­CRP is not recommended in routine risk assessment of women, but rather as an option in those persons

in the intermediate­risk range, based on the Framingham risk score.70 The benefits of assessing hs­CRP or anytreatment based on this strategy remain uncertain.

Autoimmune Disease

Systemic inflammation in autoimmune disease may accelerate atherosclerosis.71 Rheumatoid arthritis and systemic

lupus erythematosus (SLE) have been associated with a significantly increased relative risk for CVD.71

An analysis using data from the California Hospital Discharge Database found that young women between the ages of18 and 44 with SLE are 2.27 times more likely than their age­matched peers without SLE to be hospitalized because ofacute MI, 3.80 times more likely to be hospitalized because of congestive heart failure, and 2.05 times more likely to be

hospitalized because of cerebrovascular accident.72

Traditional risk factors such as smoking, family history of premature disease, hypertension, and elevated cholesterol donot completely account for the increased risk of CHD in patients with SLE. For example, Manzi et al. determined thatwomen in the Framingham Offspring Study ages 35­44 with SLE were 50 times more likely to have an acute MI than

women of the same age.73 In the Effectiveness­Based Guidelines for the Prevention of CVD in Women 2011 update,

systemic autoimmune collagen­vascular disease is now listed as a criterion for the “at risk” risk status.12

Polycystic Ovary Syndrome

Unique to women, polycystic ovarian syndrome (PCOS) is associated with the development of many of the features ofmetabolic syndrome as well as insulin resistance. A recent meta­analysis found that women with PCOS have anincreased prevalence of impaired glucose tolerance, the metabolic syndrome, and diabetes compared to women without

PCOS.74

While it is unclear if PCOS is an independent risk factor for premature CVD in women, recent data suggest elevated risk

independent of established risk factors in older postmenopausal women.75 Furthermore, in the National Heart, Lung,and Blood Institute (NHLBI)­sponsored WISE (Women’s Ischemia Syndrome Evaluation) study of postmenopausalwomen with PCOS, cumulative 5­year CVD event­free survival was 79% for women with PCOS compared to 89% for

women without PCOS.75

Emerging Risk Factors(2 of 2)

Functional Hypothalamic Amenorrhea

It is estimated that up to 10% of premenopausal women have documented ovarian dysfunction, with a larger proportionhaving subclinical hormonal dysfunction that may result in an increased risk of CVD. Functional hypothalamicamenorrhea (FHA) is a cause of a premenopausal ovarian dysfunction and occurs when gonadotropin­releasinghormone increases, thereby increasing luteinizing hormone in a pulse frequency causing amenorrhea andhypoestrogenemia. FHA is induced by psychological stressors or metabolic insult such as caloric restriction or excessiveexercise.

In a large cohort study, women with menstrual irregularities had a 50% increased risk of nonfatal and fatal CHDcompared to women with regular menstrual cycling. Additional data indicate that FHA is associated with premature

coronary atherosclerosis in women undergoing coronary angiography,76 and that use of oral contraceptive therapy may

be protection.77 While these findings suggest that amenorrhea and cycling irregularity may be a risk factor for CVD inwomen, further work is needed.

Pre­Eclampsia and Pregnancy­Associated Hypertension

For women who experience pre­eclampsia, they have a 3.6­ to 6.1­fold greater risk of developing hypertension, and a 3.1­

to 3.7­fold higher risk of developing diabetes, depending on whether the pre­eclampsia was mild or severe.78 Pre­

eclampsia is also a risk factor for future ischemic stroke.79

A recent meta­analysis found that women with a history of pre­eclampsia have approximately double the risk forsubsequent ischemic heart disease, stroke, and venous thromboembolic events over the 5­10 years following the

pregnancy.80 The Effectiveness­Based Guidelines for the Prevention of CVD in Women 2011 update list history of pre­

eclampsia or pregnancy­induced hypertension as criteria for the “at risk” status.12

Gestational Diabetes

Unique to women is the risk factor of gestational diabetes. A history of gestational diabetes doubles the risk of diabetes

in the 4 months postpartum and remains a lifelong risk factor for diabetes.30 Fasting glucose levels of >121 mg/dl during

pregnancy increase the risk for diabetes in the early puerperium by 21­fold.81 The Effectiveness­Based Guidelines for thePrevention of CVD in Women 2011 update incorporated a history of gestational diabetes as an “at risk” criterion, requiringattention to CV risk factors and the implementation of therapeutic lifestyle changes in these women throughout their

life.12

Breast Cancer Therapy

Recent advancements in breast cancer treatment have led to improved survival, but elevated risk of CVD.82 Evidencesuggests that breast cancer therapies are associated with varying degrees of direct CV injury in conjunction with

significant indirect lifestyle changes that also reduce CV reserve.82

While it is uncertain whether breast cancer overall, or specific therapies for breast cancer per se, will emerge as riskfactors for CVD, this is an increasingly important issue in the management of women surviving breast cancer. Furtherwork is needed to glean the relative and absolute risk for CV physicians who will increasingly be called upon to evaluateand treat these women.

Other Issues

Reproductive Hormones

Oral Contraceptive Therapy

The American College of Obstetricians and Gynecologists (ACOG) and the World Health Organization (WHO) have

published guidelines on medical eligibility for contraceptive use.83,84 For most women, who are healthy and free of CVDand CV risk factors, the use of combination estrogen­progestin oral contraceptives is associated with low relative and

absolute risks of CVD.85 Women who are smokers over the age of 35, women with uncontrolled hypertension, andwomen with a history of ischemic heart disease have an unacceptable level of risk associated with oral

contraceptives.85,86

Postmenopausal Hormone Therapy

A majority of CVD occurs after menopause in older women, which is associated with an increased burden of risk factors

for CVD.32 For this reason, it was thought that postmenopause hormone therapy should reduce the risk of CVD, andinitial observational data supported this hypothesis. Nonetheless, randomized trials such as HERS (Heart andEstrogen/Progestin Replacement Study I and II), WHI, and RUTH (Raloxifene Use for The Heart) did not find hormonetherapy or selective estrogen receptor modulators (SERMs) to prevent CVD, in terms of both primary and secondary

prevention.87­90

The AHA Effectiveness­Based Guidelines for the Prevention of CVD in Women 2011 update states that hormonereplacement therapy and SERMS should not be used for the primary or secondary prevention of CVD and are a Class III,

Level of Evidence A, intervention.12

Undertreatment of Women

Women have been shown to receive relatively fewer preventive recommendations, such as lipid­lowering therapy, aspirin,

and lifestyle advice, than similarly scored Framingham risk men.7,91 While hypertensive women are more likely to be

treated than men, they are less likely to have blood pressure at goal.92 Women are less likely to be treated to goal LDL­

C,93 with the largest gender disparity in goal LDL­C amongst female diabetics.94

Key Points

CVD is the leading cause of mortality in women, and CVD prevalence and mortality is higher in women than men.Framingham­type risk models are useful in women for predicting short­term (10­year) and population risk; longer­term risk and individual risk assessment for women require additional information or alternative strategies.There are a number of risk factors for CVD that are unique to women.Postmenopausal hormone therapy should not be used for the prevention of CVD.Women are more likely to be undertreated and receive fewer preventive recommendations, such as lipid­loweringtherapy, aspirin, and lifestyle advice, than do men with similar Framingham risk scores.

References

1. Roger VL, Go AS, Lloyd­Jones DM, et al., on behalf of the American Heart Association Statistics Committee andStroke Statistics Subcommittee. Heart disease and stroke statistics­­2012 update: a report from the AmericanHeart Association. Circulation 2012;125:e2­e220.

2. Xu JQ, Murphy SL, Tejada­Vera B. Deaths: Final Data for 2007. In: National Vital Statistics Reports: StatisticsNCfH, ed.; 2010.

3. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980­2000. NEngl J Med 2007;356:2388­98.

4. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26­year follow­upof the Framingham population. Am Heart J 1986;111:383­90.

5. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex­based differences in early mortality aftermyocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217­25.

6. Mosca L, Mochari­Greenberger H, Dolor RJ, Newby LK, Robb KJ. Twelve­year follow­up of American women’sawareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes2010;3:120­7.

7. Mosca L, Linfante AH, Benjamin EJ, et al. National study of physician awareness and adherence to cardiovasculardisease prevention guidelines. Circulation 2005;111:499­510.

8. Diercks DB, Owen KP, Kontos MC, et al. Gender differences in time to presentation for myocardial infarctionbefore and after a national women's cardiovascular awareness campaign: a temporal analysis from the CanRapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation(CRUSADE) and the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention OutcomesNetwork­Get with the Guidelines (NCDR ACTION Registry­GWTG). Am Heart J 2010;160:80­7, e3.

9. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk inasymptomatic adults: a report of the American College of Cardiology Foundation/American Heart AssociationTask Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50­103.

10. Gaziano TA, Young CR, Fitzmaurice G, Atwood S, Gaziano JM. Laboratory­based versus non­laboratory­basedmethod for assessment of cardiovascular disease risk: the NHANES I Follow­up Study cohort. Lancet2008;371:923­31.

11. Cavanaugh­Hussey MW, Berry JD, Lloyd­Jones DM. Who exceeds ATP­III risk thresholds? Systematicexamination of the effect of varying age and risk factor levels in the ATP­III risk assessment tool. Prev Med2008;47:619­23.

12. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness­based guidelines for the prevention of cardiovascular diseasein women­­2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243­62.

13. Wenger NK. The Reynolds Risk Score: improved accuracy for cardiovascular risk prediction in women? Nat ClinPract Cardiovasc Med 2007;4:366­7.

14. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten­year risk of fatal cardiovascular disease in Europe:the SCORE project. Eur Heart J 2003;24:987­1003.

15. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med 1993;329:247­56.16. Wenger NK. Coronary heart disease: an older woman's major health risk. BMJ 1997;315:1085­90.17. Lloyd­Jones DM, Nam BH, D'Agostino RB, Sr., et al. Parental cardiovascular disease as a risk factor for

cardiovascular disease in middle­aged adults: a prospective study of parents and offspring. JAMA 2004;291:2204­11.

18. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol EducationProgram (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III) final report. Circulation 2002;106:3143­421.

19. Scheuner MT, Setodji CM, Pankow JS, Blumenthal RS, Keeler E. Relation of familial patterns of coronary heartdisease, stroke, and diabetes to subclinical atherosclerosis: the multi­ethnic study of atherosclerosis. Genet Med2008;10:879­87.

20. Centers for Disease Control and Prevention. Health, United States, 2009: With Special Feature on MedicalTechnology. 2010. Available at: http://www.cdc.gov/nchs/data/hus/hus09.pdf. Accessed 12/15/2011.

21. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206­52.

22. Gu Q, Burt VL, Paulose­Ram R, Dillon CF. Gender differences in hypertension treatment, drug utilization patterns,and blood pressure control among US adults with hypertension: data from the National Health and NutritionExamination Survey 1999­2004. Am J Hypertens 2008;21:789­98.

23. Wassertheil­Smoller S, Anderson G, Psaty BM, et al. Hypertension and its treatment in postmenopausal women:baseline data from the Women's Health Initiative. Hypertension 2000;36:780­9.

24. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure.JAMA 1996;275:1557­62.

25. Roquer J, Campello AR, Gomis M. Sex Differences in First­Ever Acute Stroke. Stroke 2003;34:1581­5.26. Reeves MJ, Bushnell CD, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical

care, and outcomes. Lancet Neurol 2008;7:915­26.27. Petrea RE, Beiser AS, Seshadri S, Kelly­Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and

poststroke disability in the Framingham heart study. Stroke 2009;40:1032­7.28. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and

women: meta­analysis of 37 prospective cohort studies. BMJ 2006;332:73­8.29. American Diabetes Association: clinical practice recommendations 2002. Diabetes Care 2002;25 Suppl 1:S1­

147.30. Ratner RE. Prevention of type 2 diabetes in women with previous gestational diabetes. Diabetes Care 2007;30

Suppl 2:S242­5.31. Lloyd­Jones D, Adams RJ, Brown TM, et al., on behalf of the American Heart Association Statistics Committee and

Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the AmericanHeart Association. Circulation 2010;121:e46­e215.

32. Polotsky HN, Polotsky AJ. Metabolic implications of menopause. Semin Reprod Med 2010;28:426­34.33. Jensen J, Nilas L, Christiansen C. Influence of menopause on serum lipids and lipoproteins. Maturitas

1990;12:321­31.34. Gierach GL, Johnson BD, Bairey Merz CN, et al. Hypertension, menopause, and coronary artery disease risk in the

Women's Ischemia Syndrome Evaluation (WISE) Study. J Am Coll Cardiol 2006;47:S50­8.35. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education

Program Adult Treatment Panel III guidelines. Circulation 2004;110:227­39.36. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk:

consensus conference report from the American Diabetes Association and the American College of CardiologyFoundation. J Am Coll Cardiol 2008;51:1512­24.

37. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels,triglycerides, lipoprotein(a), apolipoproteins A­I and B, and HDL density subfractions: The Atherosclerosis Risk inCommunities (ARIC) Study. Circulation 2001;104:1108­13.

38. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study.Ann Epidemiol 1992;2:23­8.

39. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992;70:3H­9H.40. Legato MJ. Dyslipidemia, gender, and the role of high­density lipoprotein cholesterol: implications for therapy. Am

J Cardiol 2000;86:15L­8L.41. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening,

and myocardial infarction. The Framingham Study. Arteriosclerosis 1988;8:207­11.42. Miller M, Mead LA, Kwiterovich PO, Jr., Pearson TA. Dyslipidemias with desirable plasma total cholesterol levels

and angiographically demonstrated coronary artery disease. Am J Cardiol 1990;65:1­5.43. Mosca L, Banka CL, Benjamin EJ, et al. Evidence­Based Guidelines for Cardiovascular Disease Prevention in

Women: 2007 Update. J Am Coll Cardiol 2007;49:1230­50.44. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on

Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA2001;285:2486­97.

45. Roger VL, Go AS, Lloyd­Jones DM, et al., on behalf of the American Heart Association Statistics Committee andStroke Statistics Subcommittee. Heart disease and stroke statistics­­2011 update: a report from the AmericanHeart Association. Circulation 2011;123:e18­e209.

46. Centers for Disease Control and Prevention. 2004 Surgeon General’s Report: The Health Consequences ofSmoking. 2004. Available at: http://www.cdc.gov/tobacco/data_statistics/sgr/2004/index.htm. Accessed12/15/2011.

47. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation in relation to total mortality rates in women. Aprospective cohort study. Ann Intern Med 1993;119:992­1000.

48. Rosenberg L, Palmer JR, Rao RS, Shapiro S. Low­dose oral contraceptive use and the risk of myocardialinfarction. Arch Intern Med 2001;161:1065­70.

49. King DE, Mainous AG, 3rd, Carnemolla M, Everett CJ. Adherence to healthy lifestyle habits in US adults, 1988­2006. Am J Med 2009;122:528­34.

50. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in womenthrough diet and lifestyle. N Engl J Med 2000;343:16­22.

51. Colditz GA, Coakley E. Weight, weight gain, activity, and major illnesses: the Nurses' Health Study. Int J SportsMed 1997;18 Suppl 3:S162­70.

52. Oguma Y, Shinoda­Tagawa T. Physical activity decreases cardiovascular disease risk in women: review andmeta­analysis. Am J Prev Med 2004;26:407­18.

53. Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and the risk of death in women: the St. James WomenTake Heart Project. Circulation 2003;108:1554­9.

54. Mora S, Redberg RF, Cui Y, et al. Ability of exercise testing to predict cardiovascular and all­cause death inasymptomatic women. JAMA 2003;290:1600­7.

55. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl JMed 2005;353:468­75.

56. National Center for Health Statistics. Prevalence of metabolic syndrome among adults 20 years of age and over,by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. National Health StatisticsReports; No. 13. 2009. Available at: http://www.cdc.gov/nchs/data/nhsr/nhsr013.pdf. Accessed 12/15/2011.

57. Ford ES, Schulze MB, Pischon T, Bergmann M, Joost HG, Boeing H. Metabolic syndrome and risk of incidentdiabetes: findings from the European Prospective Investigation into Cancer and Nutrition­Potsdam Study.Cardiovasc Diabetol 2008;7:35.

58. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: asystematic review and meta­analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403­14.

59. Flegal KM, Carroll MD, Ogden CL. Prevalence and trends in the distribution of body mass index among US adults,1999­2010. JAMA 2012;307:491­7.

60. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, D'Agostino RB, Sr. Trends in the incidence of type 2diabetes mellitus from the 1970s to the 1990s: the Framingham Heart Study. Circulation 2006;113:2914­8.

61. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl JMed 2001;345:790­7.

62. Olson MB, Shaw LJ, Kaizar EE, et al. Obesity distribution and reproductive hormone levels in women: a report fromthe NHLBI­sponsored WISE Study. J Womens Health (Larchmt) 2006;15:836­42.

63. Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause­specific excess deaths associated with underweight,overweight, and obesity. JAMA 2007;298:2028­37.

64. Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L. Obesity in adulthood and itsconsequences for life expectancy: a life­table analysis. Ann Intern Med 2003;138:24­32.

65. Wessel TR, Arant CB, Olson MB, et al. Relationship of physical fitness vs body mass index with coronary arterydisease and cardiovascular events in women. JAMA 2004;292:1179­87.

66. Cook NR, Buring JE, Ridker PM. The effect of including C­reactive protein in cardiovascular risk prediction modelsfor women. Ann Intern Med 2006;145:21­9.

67. Ridker PM, Hennekens CH, Buring JE, Rifai N. C­reactive protein and other markers of inflammation in theprediction of cardiovascular disease in women. N Engl J Med 2000;342:836­43.

68. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C­reactive protein and low­density lipoproteincholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557­65.

69. Ridker PM, Buring JE, Cook NR, Rifai N. C­reactive protein, the metabolic syndrome, and risk of incidentcardiovascular events: an 8­year follow­up of 14 719 initially healthy American women. Circulation 2003;107:391­7.

70. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application toclinical and public health practice: a statement for healthcare professionals from the Centers for Disease Controland Prevention and the American Heart Association. Circulation 2003;107:499­511.

71. Salmon JE, Roman MJ. Subclinical atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus.Am J Med 2008;121:S3­8.

72. Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupuserythematosus. Arthritis and rheumatism 1999;42:338­46.

73. Manzi S, Meilahn EN, Rairie JE, et al. Age­specific incidence rates of myocardial infarction and angina in womenwith systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408­15.

74. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndromein polycystic ovary syndrome: a systematic review and meta­analysis. Hum Reprod Update 2010;16:347­63.

75. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevatedandrogen measurements at high risk for worsening cardiovascular event­free survival: results from the NationalInstitutes of Health­­National Heart, Lung, and Blood Institute sponsored Women's Ischemia SyndromeEvaluation. J Clin Endocrinol Metab 2008;93:1276­84.

76. Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoestrogenemia of hypothalamic origin and coronary arterydisease in premenopausal women: a report from the NHLBI­sponsored WISE study. J Am Coll Cardiol2003;41:413­9.

77. Merz CN, Johnson BD, Berga S, Braunstein G, Reis SE, Bittner V. Past oral contraceptive use and angiographiccoronary artery disease in postmenopausal women: data from the National Heart, Lung, and Blood Institute­sponsored Women's Ischemia Syndrome Evaluation. Fertil Steril 2006;85:1425­31.

78. Lykke JA, Langhoff­Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders andsubsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53:944­51.

79. Brown DW, Dueker N, Jamieson DJ, et al. Preeclampsia and the risk of ischemic stroke among young women:results from the Stroke Prevention in Young Women Study. Stroke 2006;37:1055­9.

80. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre­eclampsia and risk of cardiovascular disease and cancer inlater life: systematic review and meta­analysis. BMJ 2007;335:974.

81. Schaefer­Graf UM, Buchanan TA, Xiang AH, Peters RK, Kjos SL. Clinical predictors for a high risk for thedevelopment of diabetes mellitus in the early puerperium in women with recent gestational diabetes mellitus. AmJ Obstet Gynecol 2002;186:751­6.

82. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascularinjury. J Am Coll Cardiol 2007;50:1435­41.

83. ACOG Committee on Practice Bulletins­Gynecology. ACOG Practice Bulletin. The use of hormonal contraceptionin women with coexisting medical conditions. Number 18, July 2000. Int J Gynaecol Obstet 2001;75:93­106.

84. World Health Organization. Improving access to quality care in family planning: medical eligibility criteria forcontraceptive use. Geneva: World Health Organization; 2000.

85. Petitti DB. Clinical practice. Combination estrogen­progestin oral contraceptives. N Engl J Med 2003;349:1443­50.86. Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. J Am Coll Cardiol

2009;53:221­31.87. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary

heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) ResearchGroup. JAMA 1998;280:605­13.

88. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthypostmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA2002;288:321­33.

89. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy:Heart and Estrogen/progestin Replacement Study follow­up (HERS II). JAMA 2002;288:49­57.

90. Barrett­Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer inpostmenopausal women. N Engl J Med 2006;355:125­37.

91. Abuful A, Gidron Y, Henkin Y. Physicians' attitudes toward preventive therapy for coronary artery disease: is there agender bias? Clin Cardiol 2005;28:389­93.

92. Gu Q, Burt VL, Paulose­Ram R, Dillon CF. Gender differences in hypertension treatment, drug utilization patterns,and blood pressure control among US adults with hypertension: data from the National Health and NutritionExamination Survey 1999­2004. Am J Hypertens 2008;21:789­98.

93. Chou AF, Scholle SH, Weisman CS, Bierman AS, Correa­de­Araujo R, Mosca L. Gender Disparities in the Qualityof Cardiovascular Disease Care in Private Managed Care Plans. Women's Health Issues 2007;17:120­30.

94. Bird CE, Fremont AM, Bierman AS, et al. Does Quality of Care for Cardiovascular Disease and Diabetes Differ byGender for Enrollees in Managed Care Plans? Women's Health Issues 2007;17:131­8.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

4.8: Exercise Rehabilitation and Exercise for Prevention

Author(s): Barry A. Franklin, PhD, FAHA

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Describe the impact of exposure to orthostatic or gravitational stress on functional capacity following an acute coronaryevent or revascularization procedure.

2. Define the minimum or threshold intensity for improving cardiorespiratory fitness in cardiac patients, with specificreference to the percentage of oxygen uptake reserve or as a percentage of the highest heart rate achieved during peak orsymptom­limited exercise testing.

3. Explain "the rule of 2 and 3 miles per hour" when prescribing treadmill exercise workloads (metabolic equivalents[METs]) for patients.

4. Summarize the rationale for upper body and resistance exercise training in coronary patients, with specific reference tothe performance of activities of daily living.

5. Review the relationship between cardiorespiratory fitness, expressed as METs, and all­cause and cardiovascular (CV)mortality in patients with established CV disease (CVD).

Introduction

An estimated 80 million Americans (nearly one in three) have CVD; in fact, coronaryheart disease (CHD) and stroke are currently the number 1 and number 4 causes ofmortality, respectively. According to the American Heart Association, CHD causedapproximately one of every six deaths in the United States in 2006. Moreover, 1.3million coronary angioplasty procedures and 448,000 coronary artery bypass graftsurgeries were performed that year, at a cost of over $100 billion. In 2010, anestimated 785,000 Americans experienced a new cardiac event, and approximately470,000 had a repeat acute myocardial infarction (AMI). Accordingly, for literallymillions of previously affected adults in the United States, interventions that havebeen shown to reduce the risk of recurrent CV events, collectively referred to assecondary prevention, include exercise­based cardiac rehabilitation.

Prevention of atherosclerotic CVD can be divided into three types: 1) primordial(prevention of risk factors), 2) primary (treatment of risk factors and their sequelae[subclinical disease]), and 3) secondary (prevention of recurrent CV events) (Figure

1).1

This module reviews the role of structured exercise, increased lifestyle physicalactivity, or both, in the secondary prevention of CHD, with specific reference to earlyconvalescence and exercise­based rehabilitation after AMI, outpatient exerciseprogramming, cardioprotective adaptations to exercise training, cardiorespiratoryfitness as a predictor of mortality, safety of exercise­based cardiac rehabilitation,exertion­related CV events, and counseling strategies to enhance exercisecompliance.

Figure 1

Risk Factor Framework and the Progression of Cardiovascular Disease With Types of Prevention InterventionsFigure 1

Illustrated are primordial, primary, and secondary prevention, which have environmental modulators, including health care access; the builtenvironment; public policy initiatives; and locations where interventions can be made (e.g., personal, family, school, workplace). Cardiovascularhealth markers/interventions include the American Heart Association’s Life’s Simple 7 (smoking status, body mass index, physical activity, healthydiet score, total cholesterol, blood pressure, fasting plasma glucose), pharmacotherapies (e.g., aspirin, beta­blockers, statins, angiotensin­converting enzyme inhibitors) when indicated, and coronary revascularization, when appropriate.

CHF = congestive heart failure; MI = myocardial infarction; PAD = peripheral arterial disease.

Reproduced with permission from Franklin BA, Cushman M. Recent advances in preventive cardiology and lifestyle medicine: a themed series.Circulation 2011;123:2274­83.

Early Convalescence and Exercise­Based Rehabilitation AfterAcute Myocardial Infarction

Prolonged bed rest as advocated before the 1950s is no longer recommended inthe care of uncomplicated patients with AMI. Extended bed rest has been shown toresult in physiologic deconditioning, resting tachycardia, and a significant decrease

in aerobic capacity or maximal oxygen consumption (VO2 max).2 Other

consequences include muscle atrophy, weakness, constipation, urinary retention,thrombophlebitis, pulmonary embolism, hypostatic pneumonia, orthostaticintolerance, and depression.

Armchair Treatment

A classic report from 1952 involving 81 inpatients with AMI who were subjected to"armchair treatment" further prompted liberalization of activity restriction soon after

an acute coronary event.3 There were no complications attributed to the intervention,and the mortality rate of patients treated with chair rest was lower than that of acontrol group who had received conventional therapy (e.g., bed rest). This trial aswell as numerous others changed the management of uncomplicated AMI, and earlymobilization was regarded as a safe practice associated with numerousphysiological, psychological, and economic benefits.

Value of Orthostatic or Gravitational Stress

Because lack of orthostatic stress is largely responsible for many of the deleteriouseffects of prolonged bed rest after AMI, interventions designed to simulategravitational stress, such as intermittent sitting or standing, are increasingly usedduring hospitalization and early convalescence. Nearly three decades ago,researchers measured VO2 max in healthy subjects before and after 14 days of bed

rest using daily treatments with a reverse gradient garment that simulated theeffects of standing. Aerobic capacity decreased only 6% in subjects who receivedvenous pooling treatments, compared with a 15% decrease in nontreated (control)

subjects (Table 1).4 These data have important implications for inpatients and earlypost­hospital discharge activity recommendations after an acute coronary event or

revascularization procedure, especially coronary artery bypass surgery.5

Accordingly, simple exposure to orthostatic or gravitational stress can obviate muchof the deterioration in functional capacity that normally follows an acute coronaryevent or intervention. Electrocardiographically (ECG) monitored low­level treadmill orcycle ergometer exercise for uncomplicated patients, soon after the event, mayprovide more precise quantification of their exercise tolerance and identify exertion­related signs or symptoms of residual myocardial ischemia, threatening ventriculararrhythmias, or both, potentially suggesting additional myocardium in jeopardyand/or electrical instability and the need for additional diagnostic studies orinterventions.

Spontaneous Improvement in Maximal Oxygen Consumption After AcuteMyocardial Infarction

A significant 2­3 metabolic equivalent (MET; 1 MET = 3.5 ml O2/kg/min) increase in

aerobic capacity often occurs between 3 and 11 weeks after clinically uncomplicatedAMI, even in patients who undergo no formal exercise­based cardiac

rehabilitation.6,7 This is presumably because self­care and other out­of­hospitalactivities performed by patients soon after hospital discharge frequently lead tosustained increases in oxygen uptake that can exceed the minimal or "threshold"intensity for training which, for most deconditioned patients with CHD, approximates45% of the oxygen uptake reserve. Nevertheless, improvement in aerobic capacitycan be further augmented by medically directed group (phase II) or home­based

exercise rehabilitation programs soon after an acute coronary event.6

Phase II Cardiac Rehabilitation: Impact on Mortality and Medical Management

Recently, researchers examined the relationship between the number of ECG­

Table 1

monitored exercise sessions attended and subsequent CV events in 30,161

Medicare beneficiaries who had cardiac rehabilitation.8 After correcting for baselinedifferences, patients who attended more sessions, up to a total of 36, demonstrateda dose­dependent reduction in mortality and recurrent MI.

The author's experience suggests that a short­term ECG­monitored phase II cardiacexercise program augments the detection of significant exertion­related arrhythmias,increases patient education and self­confidence, and perhaps more importantly,permits validation of the exercise prescription and verification of the patient's abilityto implement the exercise program safely and effectively.

Mean Changes in Maximal Oxygen Uptake (VO2 max) Before and After Bed Rest

Table 1Adapted with permission from Convertino VA, Sandler H, Webb P, Annis JF. Induced venous pooling and cardiorespiratory responses toexercise after bed rest. J Appl Physiol 1982;52:1343­8.

Outpatient Exercise Prescription: Trainability Modulators(1 of 2)

Structured exercise training sessions should include a preliminary aerobic warm­up(approximately 10 minutes), a continuous or accumulated conditioning phase (≥30minutes or multiple 10­ to 15­minute moderate­to­vigorous intensity exercise bouts),and a cool­down (5­10 minutes), followed by stretching activities.

The warm­up serves as a period of adaptation by increasing blood flow andenhancing the efficiency of working muscle. Moreover, a preliminary aerobic warm­up serves to decrease the susceptibility to injury and the occurrence of cardiac

abnormalities that may be provoked by sudden strenuous activity.9 These includesymptoms or signs of myocardial ischemia (e.g., exertional angina, significant ST­segment depression) and/or electrical instability (ventricular ectopic activity). Theideal warm­up for any endurance activity is the same activity, but at a lower intensity.Hence, individuals who use brisk walking during the endurance phase shouldconclude the warm­up period with a moderate walking pace. Similarly, cycleergometry at 150­300 kgm/min serves as an ideal warm­up for individuals who trainat 450­600 kgm/min.

The cool­down provides a gradual recovery from the intensity of the stress of theendurance phase. Exercises of a muscle­stretching or muscle­lengthening natureare recommended. A walking cool­down enhances venous return during recovery,decreasing the likelihood of hypotension and related adverse sequelae (e.g., post­exercise lightheadedness). It also facilitates the dissipation of body heat, promotesmore rapid removal of lactic acid than stationary recovery, and ameliorates the

potential deleterious effects of the post­exercise rise in plasma catecholamines.10

The most effective exercises for the endurance or conditioning phase includewalking, jogging, running, stationary cycle ergometry, outdoor cycling, swimming,skipping rope, rowing, and combined arm­leg ergometry. The minimum or thresholdintensity for improving cardiorespiratory fitness (VO2 max) in cardiac patients

approximates 45% of the oxygen uptake reserve, which corresponds toapproximately 70% of the highest heart rate achieved during peak or symptom­

limited exercise testing.11 Over time, the exercise intensity should be increased to50­80% of the oxygen uptake reserve (or maximal heart rate reserve) to furtherincrease aerobic fitness. Nevertheless, because symptomatic or silent myocardial

ischemia may be highly arrhythmogenic,12 the prescribed heart rate range forendurance exercise should be set safely below (≥10 bpm) the ischemic ECG or

anginal threshold.13

There are several adjunctive methodologies to regulate the exercise intensity,including the Borg Rating of Perceived Exertion (RPE) scale. The Borg category andcategory­ratio scales consist of 15 and 12 grades, respectively, from 6 to 20 and

from 0 to 10+ (Table 2).14 Exercise rated as 12­15 (6­20 scale), between "somewhathard" and "hard," or 4­6 (0­10 scale), between "somewhat strong and very strong," isgenerally considered appropriate for cardiorespiratory conditioning.

Improvement in aerobic capacity with exercise training generally shows a positivecorrelation to the conditioning frequency, intensity, and duration. The increase in VO2 max among healthy individuals generally shows an inverse relationship with

age, habitual physical activity, and baseline cardiorespiratory fitness.15 Thus, youngto middle­aged sedentary individuals (with low baseline VO2 max) tend to show the

greatest percentage increase in VO2 max with exercise training. However, in cardiac

patients, the relationship is more complex; changes in aerobic capacity may notshow an inverse relationship with initial VO2 max. Some patients with a reduced

exercise capacity are limited because they are deconditioned and thus have greatpotential to improve cardiorespiratory fitness, whereas others are limited by leftventricular (LV) dysfunction and have less potential for improvement.

It has been previously suggested that cardiac patients on beta­blockade do notimprove greatly on exercise training regimens. Although a sustained increase in

Table 2

Table 3

heart rate has traditionally been suggested as a prerequisite to achieving anexercise training response, patients on beta­blockers can still achieve the increase

in metabolic rate necessary for favorable adaptation and improvement.16,17 Thus,patients with CHD who are treated with beta­blockers can derive the expectedenhancement of cardiorespiratory fitness during exercise training, regardless of the

type of beta­blocker that is prescribed.15

Limitations of the MET Concept for Activity Prescription

The metabolic costs of many household, recreational/training (Table 3), andoccupational activities have been defined in terms of oxygen uptake. Consequently,

activity prescription may be made in terms of METs.18 This involvesrecommendation of activities that are sufficiently below the maximal MET levelachieved during peak or symptom­limited exercise testing. The concept is simple,easy to understand, and is sometimes used as a training and activity prescription

guide.19

There are, however, several inherent limitations in using estimated METs in activityprescription. The aerobic requirements of selected physical activities representaverage energy expenditure levels, and these may vary considerably amongindividuals of different age, body habitus, and fitness and skill levels. Moreover, itcannot be assumed that occupational and recreational activities demanding oxygenconsumption equal to that achieved during exercise testing produces similar cardiacdemands. Additional factors at work include the stresses of emotions, excitement,cognition, and environment, as well as the activation of muscle groups not usedduring the exercise tests.

Finally, the oxygen costs listed for many common occupational and domesticactivities were derived from continuous steady­state work, whereas activities of dailylife are predominantly intermittent. If the activity is performed using a work­restapproach, the task can often be accomplished at oxygen consumption levels wellbelow those estimated for it. Thus, using the MET method for prescribing activity mayconsiderably underestimate the patient's capacity for physical work.

In summary, the MET concept has limited applicability in the recommendation ofactivities for coronary patients. Heart rate response and rating of perceived exertion

(Table 2)14 immediately after physical effort usually provide a more objectiveassessment of cardiac and somatic demands than metabolic equivalent tables.

Rating of Perceived ExertionTable 2Reproduced with permission from Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377­81.

Approximate Metabolic Cost of Various Recreational and Training ActivitiesTable 3METs = metabolic equivalents

Adapted with permission from Fox SM 3rd, Naughton JP, Gorman PA. Physical activity and cardiovascular health. 3. The exercise prescription:frequency and type of activity. Mod Concepts Cardiovasc Dis 1972;41:25­30.

Outpatient Exercise Prescription: Trainability Modulators(2 of 2)

The Rule of 2 and 3 Miles per Hour

Because most elderly, deconditioned, overweight/obese, and/or cardiac patients prefer to walk at moderate intensities, itis helpful to recognize that walking on level ground at 2 and 3 mph speeds approximate 2 and 3 METs, respectively.Moreover, at a 2­mph walking speed, each 3.5% increase in treadmill grade adds approximately 1 MET to the grossenergy cost. Patients who desire to walk at a 2­mph pace, but require a 5­MET workload for training would be advised toadd 10.5% grade to this speed. For patients who can negotiate the faster walking speed (3 mph), recognize that each2.5% increase in treadmill grade adds 1 additional MET to the gross energy expenditure. Accordingly, a workload of 3.0mph, 7.5% grade, would approximate an aerobic requirement of 6 METs. Using this practical rule can be helpful toclinicians in prescribing treadmill exercise workloads for their patients, without the need for consulting tables,

nomograms, or for that matter, metabolic formulas or calculations.15

Upper Body Training

Lower extremity training does not necessarily confer training benefit to the upper extremities and vice versa. It is thereforeimportant to recognize the potential benefit of both types of training. Many "real­life" activities require arm work to a greaterextent than leg work. Consequently, cardiac patients who rely on their upper extremities for occupational or recreationalactivities should be advised to train the arms as well as the legs, with the expectation of improved cardiorespiratory and

hemodynamic responses to both forms of effort.20

Although upper­extremity exercise for cardiac patients has been traditionally proscribed, numerous studies have now

demonstrated the safety and effectiveness of arm exercise training in patients with CHD.21 Moreover, it appears that thearms respond to aerobic exercise conditioning in a similar quantitative and qualitative manner as the legs, showingcomparable relative decreases in submaximal rate­pressure product and increases in peak power output and

cardiorespiratory fitness, expressed as METs.22 Guidelines for arm exercise prescription are shown in Table 4, andshould include recommendations regarding three variables: the appropriate exercise heart rate, the workload or power

output that will elicit a safe and effective metabolic load for training, and the proper training equipment or modalities.21

Resistance Training

Cardiac patients often lack the physical strength and/or self­confidence to perform common activities of daily living.Resistance training can provide an effective method for improving muscular strength and endurance, preventing andmanaging a variety of chronic medical conditions, favorably modifying selected coronary risk factors, and enhancing

psychosocial well­being.23 Weight training has also been shown to attenuate the rate­pressure product when any givenload is lifted, which may reduce cardiac demands during daily activities such as carrying groceries or lifting moderate­to­

heavy objects.24 Moreover, there are intriguing data to suggest that strength training can increase muscular endurance

capacity without an accompanying increase in VO2 max.25 Recent studies have also shown that muscular strength is

inversely associated with all­cause mortality and the presence of metabolic syndrome, independent of cardiorespiratory

fitness levels.26,27

Although the traditional weight­training prescription has involved performing each exercise three times (e.g., three sets of10­15 repetitions per set), it appears that one set provides similar improvements in muscular strength and endurance, atleast for the novice exerciser. Consequently, single­set programs performed at least two times a week arerecommended rather than multiset programs, because they are highly effective, less time consuming, and less likely to

cause musculoskeletal injury or soreness.23 Such regimens should include 8­10 different exercises at a load thatpermits 8­15 repetitions per set.

Lifestyle Physical Activity

Despite the "aerobic exercise revolution" and the much heralded Surgeon General's report,28 structured exerciseprograms have been only marginally effective for getting people to be more physically active. Although the benefits ofregular exercise are well documented, recent physical activity prevalence data are particularly troubling. A large proportionof adults fail to achieve the recommended moderate­to­vigorous levels of physical activity (i.e., moderate­intensity aerobic[endurance] physical activity for a minimum of 30 minutes on 5 days each week or vigorous­intensity aerobic physical

activity for a minimum of 20 minutes on 3 days each week).29 For example, walking is the most popular physical activityidentified by adults, but <7% of those whose primary exercise is walking are doing so at the recommended frequency,

intensity, or duration.30

Randomized clinical trials have now shown that an alternative approach to structured exercise (i.e., increased lifestylephysical activity) has similar effects on cardiorespiratory fitness, body composition, and coronary risk factors as a

structured exercise program.31,32 These findings have important implications for public health, suggesting a viablealternative to sedentary people who are not ready to comply with a formal exercise program. Accordingly, physicians andallied health professionals should counsel patients to integrate multiple short bouts of physical activity into their dailylives.

Pedometers can be helpful in this regard, as can programs that use them (e.g., America on the Move33) to enhanceawareness of physical activity by progressively increasing daily step totals. According to one systematic review,pedometer users in varied exercise interventions significantly increased their physical activity by an average of 2,491

steps per day more than their control counterparts.34

Cardioprotective Adaptations to Exercise Training

Regular exercise participation can decrease the risk of initial and recurrent CVevents, presumably from multiple mechanisms, including antiatherosclerotic, anti­

ischemic, antiarrhythmic, antithrombotic, and psychological effects (Table 5).15

Chronic aerobic exercise can result in moderate losses in body weight andmoderate to large losses in body fat. Endurance exercise can promote decreases inblood pressure (particularly in hypertensives), total blood cholesterol, serumtriglycerides, and low­density lipoprotein cholesterol, and increases in the aerobiccapacity and "antiatherogenic" high­density lipoprotein cholesterol subfraction.Exercise also has favorable effects on glucose and insulin homeostasis,inflammatory markers (e.g., C­reactive protein), coagulability, fibrinolysis, andcoronary endothelial function.

Because >40% of the CV risk reduction associated with exercise cannot beexplained by changes in conventional risk factors, a cardioprotective "vascularconditioning" effect has been proposed, including enhanced nitric oxide vasodilatorfunction, improved vascular reactivity, altered vascular structure, or combinations

thereof.35 Decreased vulnerability to threatening ventricular arrhythmias andincreased resistance to ventricular fibrillation have also been postulated to reflectexercise­related adaptations in autonomic control, including reduced sympatheticdrive and increased vagal tone. Moreover, ischemic preconditioning before coronaryocclusion, at least in animal models, has been shown to reduce subsequent infarct

size and/or the potential for malignant ventricular arrhythmias.36,37

Table 5

Potential Cardioprotective Effects of Regular Physical ActivityTable 5CACs = cultured/circulating angiogenic cells; EPCs = endothelial progenitor cells; HDL = high­density lipoprotein; HR = heart rate; LDL = low­density lipoprotein; O2 = oxygen.

Cardiorespiratory Fitness as a Predictor of Mortality

Numerous studies in patients with suspected or known CHD have now identified a low level of cardiorespiratory fitness,

expressed as METs, as an independent risk factor for all­cause and CV mortality.38­49 An exercise capacity <5 METsgenerally indicates a higher mortality group, whereas an exercise capacity >9 METs identifies a cohort with a favorable

long­term prognosis, regardless of the underlying extent of coronary disease.44­48 Using the conventional Brucetreadmill protocol, these fitness levels correspond to failure to complete Stage I (1.7 mph, 10% grade) and the attainmentof Stage III (3.4 mph, 14% grade) or greater, respectively. Moreover, each 1­MET increase in exercise capacity appears to

confer an 8­35% reduction in mortality.50 The importance of exercise capacity in the risk stratification of coronary patientshas historically received inadequate attention because of the tendency for clinicians to focus on signs/symptoms ofmyocardial ischemia, electrical instability, or both, as well as other clinical markers of prognosis (e.g., LV ejection fraction[LVEF]).

Nevertheless, using the well­described primary angioplasty in AMI (PAMI­2) database, investigators recently reported thatexercise capacity more accurately predicts 2­ and 5­year mortality than does LVEF in patients with ST­elevation MI who

were emergently treated with percutaneous intervention.51 Accordingly, physicians and allied health professionalsshould encourage unfit men and women with CHD to improve their exercise capacities by starting and maintaining a

regular exercise program, so as to move them out of the least fit, "high­risk" cohort (bottom 20%; <5 METs).52 On theother hand, if a fitness level >9 METs truly exerts a cardioprotective effect, it has enormous implications for costcontainment and medical care.

Safety of Exercise­Based Cardiac Rehabilitation

Although the incidence of CV complications during exercise is considerably greater among cardiac patients than amongpresumably healthy adults, it is still relatively low. According to one widely cited survey of CV events during outpatientcardiac exercise therapy, the incidence of complications was one cardiac arrest per 111,996 patient­hours, one MI per

293,990 patient­hours, and one fatality per 783,972 patient­hours of exercise.53 However, these data antedate the currentuse of risk stratification procedures, emergent coronary revascularization, newer cardioprotective pharmacotherapies,ablation techniques, ventricular assist devices, and antitachycardia pacemakers and implantable cardioverter­defibrillators. Thus, these complication rates may not necessarily be extrapolated to contemporary cardiac patients.

More recent studies suggest one major CV complication in every approximately 58,000 participant hours of outpatient

cardiac exercise therapy; no fatalities were reported.54­56 At this rate, a typical rehabilitation program with 100 patientsexercising 3 hours per week could expect one CV event every 3.7 years (assuming perfect attendance and nobusiness/holiday closings). It should be emphasized, however, that the absence of fatal events associated with exercise­based cardiac rehabilitation applies only to medically supervised programs equipped with a defibrillator and appropriateemergency drugs. Numerous reports indicate that the vast majority of witnessed, exertion­related cardiac arrests

occurring under such conditions are successfully resuscitated.53­56

Exertion­Related Cardiovascular Events

Vigorous physical exertion may precipitate AMI or cardiac arrest in selected persons with known or occult CHD.57 Byincreasing cardiac demands and simultaneously shortening diastole and coronary perfusion time, exercise may evoke atransient oxygen deficiency at the subendocardial level, which is exacerbated by abrupt cessation of exercise, arterialvasodilatation, or both. Because cardiac demands remain high immediately after exercise, sudden post­exercisedecreases in blood pressure and coronary perfusion may increase the likelihood of a myocardial O2 supply/demand

imbalance.

Ischemia can alter depolarization, repolarization, and conduction velocity, triggering threatening ventricular arrhythmiasthat, in extreme cases, may be harbingers of ventricular tachycardia or fibrillation. Symptomatic or silent myocardialischemia, sodium­potassium imbalance, increased catecholamine excretion, and circulating free fatty acids can alsoheighten electrical instability.

The incidence of CV events during very light­to­moderate intensity activities is extremely low and similar to that expectedat rest. However, vigorous physical exertion (i.e., ≥6 METs), especially when it is sudden, unaccustomed, or involvingshort bursts of high­intensity exercise, appears to transiently increase the risk of AMI and cardiac arrest in susceptible

individuals.57 The aerobic requirements and cardiac demands of these activities may be influenced by team members,opponent expertise, individual skill and fitness levels, and superimposed environmental stressors, including altitude,cold, heat, and humidity, or combinations thereof. Moreover, the excitement of competition may increase sympatheticactivity and lower the threshold to ventricular fibrillation. Recreational and domestic activities that are associated with an

increased incidence of CV events include competitive running, racquet sports, deer hunting, and snow removal.58

Although the relative risk of AMI and sudden cardiac death appears to increase transiently during strenuous physicalexertion compared with the risk at other times, the absolute risk is small. Exercise­related CV events are more likely tooccur among habitually sedentary individuals with known or occult CVD who were performing unaccustomed vigorousphysical activity. On the other hand, the net effect of regular physical activity and/or increased cardiorespiratory fitness isan attenuated risk of exertion­related CV events and a lower overall mortality from CVD.

Recommendations to potentially reduce the risk of exertion­related CV events include: 1) counsel habitually sedentarypatients to avoid unaccustomed, vigorous physical activity (e.g., racquet sports, water skiing, heavy lifting, shovelingsnow); 2) advocate appropriate warm­up and cool­down procedures; 3) promote education of warning signs/symptoms(e.g., chest pain or pressure, lightheadedness, heart palpitations/arrhythmias; unusual shortness of breath); 4)emphasize strict adherence to prescribed training pulse rates; 5) use continuous or instantaneous monitoring inselected coronary patients; 6) minimize competition; 7) modify recreational games to decrease the energy cost and heartrate response to play (e.g., doubles as opposed to singles tennis); and 8) reduce exercise intensities in hot/humid

weather.58

Strategies to Enhance Exercise Compliance

Although many patients can be motivated to initiate an exercise program,maintaining the commitment can be challenging. Unfortunately, negative variablesoften outweigh the positive variables contributing to sustained interest andenthusiasm, including limited supervision/coaching, time inconvenience,musculoskeletal problems, exercise boredom, cost issues, lack of progressawareness, intercurrent illness or injury, and work or family­related conflicts.Collectively, these deterrents often lead to a decline in adherence and exercisedropouts.

The likelihood that patients will or will not engage in a long­term structured exerciseprogram is governed in large part by their expectations or predictions of the effectsand consequences of that behavior in relation to their goals and objectives. TheStages of Change Model (i.e., precontemplation, contemplation, determination,action, maintenance, relapse) can help identify patients who are positively interested

in or, on the other hand, absolutely unwilling to make an exercise commitment.59

For the former subset, motivational interviewing can be used to help encourage abehavioral transformation.

Counterproductive arguments should be avoided at this time and health careproviders should strive to encourage patients to hear themselves express why they

want to (or should) exercise.60 Overcoming inertia (i.e., the patient's sedentarylifestyle) is a major barrier to success. It is also one of the easiest obstacles toovercome. We simply need to get patients to act (e.g., "a thousand mile journeystarts with one small step"). Any action they take, no matter how trivial, may serve asthe catalyst to permanent lifestyle change.

The fervor of the primary physicians' recommendation appears to be the single most

powerful predictor of cardiac rehabilitation participation.61 Accordingly, increasedefforts must be directed at better educating this group (and their cardiologistcontemporaries) regarding the benefits of exercise­based cardiac rehabilitation.Several research­based counseling and motivational strategies may enhancepatient interest and facilitate initiation of and compliance with a structured exerciseprogram, increased lifestyle activity, or both (Table 6).

Table 6

Strategies to Enhance Exercise ComplianceTable 6

Conclusion

The challenge for physicians and other health care providers is to refer increasing numbers of coronary patients to home,club, or medically supervised exercise rehabilitation programs so that many more individuals may realize thecardioprotective and general health benefits that regular physical activity can provide. Nevertheless, to drive utilization,

referrals must be complemented by increasing efforts at enrollment and regular participation.62 Exercise is medicine,and for the vast majority of coronary patients who are not regularly physically active, the prescription remains unfilled.

Future Directions

The American Heart Association/American College of Cardiology Foundation (AHA/ACCF) Guidelines onSecondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic and

Vascular Disease were updated in late 2011.63 The update of the ACCF/AHA Guidelines for the Management of

ST­Elevation Myocardial Infarction is scheduled for publication in 2012.64 Both guidelines address the role ofphysical activity/structured exercise and cardiorespiratory fitness in reducing the risk of recurrent CV events.Contemporary transtelephonic and newer methods of monitoring and surveillance can extend exercise­basedcardiac rehabilitation services to other more convenient settings. A variety of these techniques may be usedbetween patients managed at home and rehabilitation staff, including regular telephone contact, mail or e­mail(e.g., completion of activity logs), use of pedometers and/or ambulatory activity tracking devices, video recording,

Internet, and transtelephonic ECG monitoring.65

Key Points

Exercise­based cardiac rehabilitation includes research­based outcomes (e.g., regular physical activity, improvedcardiorespiratory fitness) that have been shown to reduce the risk of recurrent CV events.Simple exposure to orthostatic or gravitational stress, such as intermittent sitting or standing duringhospitalization and early home convalescence, can obviate much of the deterioration in functional capacity thatnormally follows an acute coronary event or intervention.The minimum or threshold intensity for improving cardiorespiratory fitness in cardiac patients approximates 45%of the oxygen uptake reserve, which corresponds to approximately 70% of the highest heart rate achieved duringpeak or symptom­limited exercise testing.Walking on level ground at 2 and 3 miles per hour (mph) approximates 2 and 3 METs, respectively. At a 2­mphwalking speed, each 3.5% increase in treadmill grade adds approximately 1 MET to the gross energy cost. Forpatients who can negotiate a 3­mph walking speed, recognize that each 2.5% increase in treadmill grade adds 1additional MET to the gross energy expenditure.Structured exercise should be complemented by upper body training, resistance training, and increased lifestylephysical activity (e.g., parking the car farther away from stores when shopping, avoiding elevators/escalators, walkbreaks at work). Using a pedometer can be helpful in tracking daily step totals.Among coronary patients, each 1­MET increase in exercise capacity is associated with an 8­35% reduction inmortality. The reported reductions in mortality are comparable to or greater than those observed for manycardioprotective medications (e.g., aspirin, statins, beta­blockers).The absolute risk of exercise­related CV events during outpatient cardiac exercise therapy is extremely low.Recent studies suggest 1 major CV complication in every 58,000 participant hours of outpatient cardiac exercisetherapy; no fatalities were reported.Recreational and domestic activities that are associated with an increased incidence of CV events in susceptibleindividuals include competitive running, racquet sports, deer hunting, and snow removal.The fervor of the physicians' recommendation appears to be the single most powerful predictor of exercise­basedcardiac rehabilitation participation.

References

1. Franklin BA, Cushman M. Recent advances in preventive cardiology and lifestyle medicine. A themed series.Circulation 2011;123:2274­83.

2. Winslow EH. Cardiovascular consequences of bed rest. Heart Lung 1985;14:236­46.3. Levine SA, Lown B. Armchair treatment of acute coronary thrombosis. JAMA 1952;148:1365­69.4. Convertino VA, Sandler H, Webb P, Annis JF. Induced venous pooling and cardiorespiratory responses to exercise

after bed rest. J Appl Physiol 1982;52:1343­8.5. Convertino VA. Effect of orthostatic stress on exercise performance after bed rest: relation to inhospital

rehabilitation. J Cardiac Rehabil 1983;3:660­3.6. De Busk RF, Houston N, Haskell W, et al. Exercise training soon after myocardial infarction. Am J Cardiol

1979;44:1223­9.7. Savin WM, Haskell WL, Houston­Miller N, et al. Improvement in aerobic capacity soon after myocardial infarction. J

Cardiac Rehabil 1981;1:337­42.8. Hammill BG, Curtis LH, Schulman KA, Whellan DJ. Relationship between cardiac rehabilitation and long­term

risks of death and myocardial infarction among elderly Medicare beneficiaries. Circulation 2010;121:63­70.9. Barnard RJ, MacAlpin R, Kattus AA, Buckberg GD. Ischemic response to sudden strenuous exercise in healthy

men. Circulation 1973;48:936­42.10. Dimsdale JE, Hartley LH, Guiney T, et al. Postexercise peril. Plasma catecholamines and exercise. JAMA

1984;251:630­2.11. Swain DP, Franklin BA. Is there a threshold intensity for aerobic training in cardiac patients? Med Sci Sports Exerc

2002;34:1071­5.12. Hoberg E, Schuler G, Knuze B, et al. Silent myocardial ischemia as a potential link between lack of premonitoring

symptoms and increased risk of cardiac arrest during physical stress. Am J Cardiol 1990;65:583­9.13. American College of Sports Medicine: American College of Sports Medicine’s Guidelines for Exercise Testing and

Prescription, 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000.14. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377­81.15. Franklin BA, Gordon NF. Contemporary Diagnosis and Management in Cardiovascular Exercise. Newtown, PA:

Handbooks in Health Care Company; 2009:74­88.16. Laslett LJ, Paumer L, Scott­Baier P, et al. Efficacy of exercise training in patients with coronary artery disease who

are taking propranolol. Circulation 1983;68:1029­34.17. Pratt CM, Welton DE, Squires WG Jr, Kirby TE, Hartung GM, Miller RR. Demonstration of training effect during

chronic beta­adrenergic blockade in patients with coronary artery disease. Circulation 1981;64:1125­9.18. Fox SM 3rd, Naughton JP, Gorman PA. Physical activity and cardiovascular health. 3. The exercise prescription:

frequency and type of activity. Mod Concepts Cardiovasc Dis 1972;41:25­30.19. Ainsworth BE, Haskell WL, Herrmann SD, et al. 2011 compendium of physical activities: a second update of

codes and MET values. Med Sci Sports Exerc 2011;43:1575­81.20. Fardy PS, Webb D, Hellerstein HK. Benefits of arm exercise in cardiac rehabilitation. Phys Sportsmed 1977;5:30­

41.21. Franklin BA. Aerobic exercise training programs for the upper body. Med Sci Sports Exerc 1989;21(5 Suppl):S141­

8.22. Franklin BA, Vander L, Wrisley D, et al. Trainability of arms versus legs in men with previous myocardial infarction.

Chest 1994;105:262­4.23. Williams MA, Haskell WL, Ades PA, et al. Resistance exercise in individuals with and without cardiovascular

disease: 2007 update: A Scientific Statement from the American Heart Association Council on Clinical Cardiologyand Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572­84.

24. McCartney N, McKelvie RS, Martin J, et al. Weight­training­induced attenuation of the circulatory response of oldermales to weight lifting. J Appl Physiol 1993;74:1056­60.

25. Hickson RC, Rosenkoetter MA, Brown MM. Strength training effects on aerobic power and short­term endurance.Med Sci Sports Exerc 1980;12:336­9.

26. FitzGerald SJ, Barlow CE, Kampert JB, et al. Muscular fitness and all­cause mortality: prospective observations. JPhys Act Health 2004;1:7.

27. Jurca R, Lamonte MJ, Barlow CE, et al. Association of muscular strength with incidence of metabolic syndrome inmen. Med Sci Sports Exerc 2005;37:1849­55.

28. United States Department of Health and Human Services. Physical activity and health: a report of the SurgeonGeneral. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control andPrevention, National Center for Chronic Disease Prevention and Health Promotion; 1996.

29. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults fromthe American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081­93.

30. Rafferty AP, Reeves MJ, McGee HB, Pivarnik JM. Physical activity patterns among walkers and compliance withpublic health recommendations. Med Sci Sports Exerc 2002;34:1255­61.

31. Dunn AL, Marcus BH, Kampert JB, et al. Comparison of lifestyle and structured interventions to increase physicalactivity and cardiorespiratory fitness: a randomized trial. JAMA 1999;281:327­34.

32. Andersen RE, Wadden TA, Bartlett SJ, et al. Effects of lifestyle activity vs structured aerobic exercise in obesewomen: a randomized trial. JAMA 1999;281:335­40.

33. US Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans. Available at:http://www.health.gov/paguidelines/pdf/paguide.pdf. Accessed 01/14/2012.

34. Bravata DM, Smith­Spangler C, Sundaram V, et al. Using pedometers to increase physical activity and improvehealth: a systematic review. JAMA 2007;298:2296­304.

35. Green DJ, O’Driscoll G, Joyner MJ, Cable NT. Exercise and cardiovascular risk reduction: time to update therationale for exercise? J Appl Physiol 2008;105:766­8.

36. Billman GE, Schwartz PJ, Stone HL, et al. The effects of daily exercise on susceptibility to sudden cardiac death.Circulation 1984;69:1182­9.

37. Hull SS, Vanoli E, Adamson PB, et al. Exercise training confers anticipatory protection from sudden death duringacute myocardial ischemia. Circulation 1994;89:548­52.

38. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, et al. Physical fitness and all­cause mortality. A prospective study ofhealthy men and women. JAMA 1989;262:2395­401.

39. Blair SN, Kampert JB, Kohl HW 3rd, et al. Influences of cardiorespiratory fitness and other precursors oncardiovascular disease and all­cause mortality in men and women. JAMA 1996;276:205­10.

40. Wei M, Gibbons LW, Kampert JB, et al. Low cardiorespiratory fitness and physical inactivity as predictors ofmortality in men with type 2 diabetes. Ann Intern Med 2000;132:605­11.

41. Wei M, Kampert JB, Barlow CE, et al. Relationship between low cardiorespiratory fitness and mortality in normal­weight, overweight, and obese men. JAMA 1999;282:1547­53.

42. Church TS, Kampert JB, Gibbons LW, et al. Usefulness of cardiorespiratory fitness as a predictor of all­cause andcardiovascular disease mortality in men with systemic hypertension. Am J Cardiol 2001;88:651­6.

43. Laukkanen JA, Lakka TA, Rauramaa R, et al. Cardiovascular fitness as a predictor of mortality in men. Arch InternMed 2001;161:825­31.

44. Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. NEngl J Med 2002;346:793­801.

45. Vanhees L, Fagard R, Thijs L, et al. Prognostic significance of peak exercise capacity in patients with coronaryartery disease. J Am Coll Cardiol 1994;23:358­63.

46. Kavanagh T, Mertens DJ, Hamm LF, et al. Prediction of long­term prognosis in 12,169 men referred for cardiacrehabilitation. Circulation 2002;106:666­71.

47. Kavanagh T, Mertens DJ, Hamm LF, et al. Peak oxygen intake and cardiac mortality in women referred for cardiacrehabilitation. J Am Coll Cardiol 2003;42:2139­43.

48. Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and the risk of death in women. The St. James WomenTake Heart Project. Circulation 2003;108:1554­9.

49. Lyerly GW, Xuemei S, Lavie CJ, et al. The relationship between cardiorespiratory fitness and all­cause mortality inwomen with impaired fasting glucose or non­diagnosed diabetes. Mayo Clin Proc 2009;84:780­6.

50. Myers J, Herbert W, Ribisl P, Franklin B. Is new science driving practice improvements and better patientoutcomes? Applications for cardiac rehabilitation. Clin Invest Med 2008;31:E400­7.

51. Dutcher JR, Kahn J, Grines C, Franklin B. Comparison of left ventricular ejection fraction and exercise capacity aspredictors of two­ and five­year mortality following acute myocardial infarction. Am J Cardiol 2007;99:436­41.

52. Franklin BA, McCullough PA. Cardiorespiratory fitness: an independent and additive marker of risk stratificationand health outcomes. Mayo Clin Proc 2009;84:776­9.

53. Van Camp SP, Peterson RA. Cardiovascular complications of outpatient cardiac rehabilitation programs. JAMA1986;256:1160­3.

54. Vongvanich P, Paul­Labrador MJ, Merz CNB. Safety of medically supervised exercise in a cardiac rehabilitationcenter. Am J Cardiol 1996;77:1383­5.

55. Franklin BA, Bonzheim K, Gordon S, Timmis GC. Safety of medically supervised outpatient cardiac rehabilitationexercise therapy: a 16­year follow­up. Chest 1998;114:902­6.

56. Pavy B, Iliou MC, Meurin P, et al. Safety of exercise training for cardiac patients. Results of the French registry ofcomplications during cardiac rehabilitation. Arch Intern Med 2006;166:2329­34.

57. Thompson PD, Franklin BA, Balady GJ, et al. Exercise and acute cardiovascular events: placing the risks intoperspective. A Scientific Statement from the American Heart Association Council on Nutrition, Physical Activity, andMetabolism and the Council on Clinical Cardiology. Circulation 2007;115:2358­68.

58. Franklin BA. Cardiovascular events associated with exercise. The risk­protection paradox. J Cardiopulm Rehab2005;25:189­95.

59. Prochaska JO, DiClemente C. Transtheoretical therapy, toward a more integrative model of change. PsychotherTheory Res Pract 1982;19:276­88.

60. Franklin BA, Vanhecke TE. Counseling patients to make cardioprotective lifestyle changes: strategies for success.Prev Cardiol 2008;2:50­3.

61. Ades PA, Waldmann ML, McCann WJ, et al. Predictors of cardiac rehabilitation participation in older coronarypatients. Arch Intern Med 1992;152:1033­5.

62. Boyden T, Rubenfire M, Franklin B. Will increasing referral to cardiac rehabilitation improve participation? PrevCardiol 2010;13:198­202.

63. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy forpatients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the AmericanHeart Association and American College of Cardiology Foundation. Endorsed by the World Heart Federation and

the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol 2011;58:2432­46.64. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST­elevation

myocardial infarction­­executive summary: a report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for themanagement of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671­719.

65. Balady GJ, Ades PA, Bittner VA, et al. Referral, enrollment, and delivery of cardiac rehabilitation/secondaryprevention programs at clinical centers and beyond: a presidential advisory from the American Heart Association.Circulation 2011;124:2951­60.

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.

1.

Which of the following are limitations of the traditional 10­year CHD FRS?

A. Underestimation of cardiovascular risk attributable to age.

B. Overestimation of risk in younger patients.

C. Overweighting of family history.

D. Underestimation of risk among women.

E. Incorporation of expensive testing.

2.

Which statement is TRUE regarding cardiovascular risk assessment?

A. Randomized clinical trials have demonstrated a benefit in clinical outcomesof using global clinical risk scores compared to risk factor counting.

B. Randomized clinical trials have demonstrated a benefit in clinical outcomesof using hs­CRP compared to the traditional FRS.

C. Randomized clinical trials have demonstrated a benefit in clinical outcomesof defining high­, intermediate­, and low­risk 10­year CHD risk factors as >20%,10­20%, and <10%, respectively.

D. Randomized clinical trials have demonstrated the benefit in clinicaloutcomes of designating abdominal aortic aneurysm as a CHD equivalentwarranting aggressive secondary prevention efforts.

E. Prospective cohort studies have demonstrated the incremental prognosticutility of CAC scanning above and beyond clinical risk scores.

3.

Which of the following statements is TRUE regarding the recently proposed lifetimerisk score for cardiovascular risk assessment?

A. It was derived from a multi­ethnic cohort.

B. It improves risk communication to younger individuals.

C. It uses a restrictive clinical endpoint focusing on CHD.

D. It may be calculated via online calculators and tables.

4.

Measurement of CRP for cardiovascular risk refinement is most appropriate inwhich of the following?

Chapter 4 Exam

Visit the online version of the product to see the correct answer and commentary.

A. A 54­year­old woman with diabetes mellitus and an LDL­C of 118 mg/dl.

B. A 50­year­old obese man with hypertension, recurrent gouty flares, and anLDL­C of 105 mg/dl.

C. A 60­year­old woman with hypertension, a family history of premature CHD,rheumatoid arthritis, and an LDL­C of 108 mg/dl.

D. A 46­year­old man with no traditional risk factors and an LDL­C of 102 mg/dl.

E. A 56­year­old man with hypertension, an HDL­C of 33 mg/dl, and an LDL­Cof 118 mg/dl.

5. TN is a 55­year­old woman who is referred to you for lipid management. She isbeing treated for hypertension, but has no history of diabetes mellitus. She had astent to the left anterior descending artery placed 3 years ago for anginal symptomsand a positive stress test. Since that time, she has had no further angina symptoms.She is overweight, but tries to walk on a regular basis. She has been on pravacholsince her stent placement.

Her BMI is 33 kg/m2 and waist circumference is 35 inches. Her blood pressure is125/84 mm Hg and heart rate is 52 bpm.

Her lipid profile: Total cholesterol 190 mg/dl, LDL­C 80 mg/dl, HDL­C 40 mg/dl, andtriglycerides 350 mg/dl.

In addition to lifestyle modifications, which of the following is the appropriate nextstep for this patient?

A. Increase the pravachol dose.

B. Start a fibrate.

C. No change in medications.

D. Add plant stanols/sterols.

6. Your next patient was discharged from the hospital after a non­ST­segmentelevation MI 2 months ago. He is a 55­year­old man with a history of hypertensionand diabetes mellitus. He recently quit smoking 2 months ago. He feels well andhas had no episodes of angina. The patient is currently taking 20 mg of simvastatin.

His blood pressure is 115/84 mm Hg and heart rate is 54 bpm. His BMI is 27 kg/m2.

His lipid profile: Total cholesterol 270 mg/dl, LDL­C 120 mg/dl, HDL­C 40 mg/dl, andtriglycerides 550 mg/dl.

Which of the following should be the primary target for therapy at this time?

A. LDL­C.

B. HDL­C.

C. Triglycerides.

D. Non­HDL­C.

7. Your next patient is an obese male, 55 years of age, without prior history of heartdisease. He has recently undergone an ultrasound exam of his abdomen, whichdemonstrated mild aortic enlargement. He stopped smoking several years ago andleads a sedentary lifestyle. His hypertension is currently well controlled. He has nohistory of diabetes mellitus.

On exam, his blood pressure is 120/80 mm Hg and heart rate is 58 bpm. His BMI is

27 kg/m2. His lungs are clear; heart sounds are normal with no gallops, murmurs,or rubs. Peripheral pulses are equal and 2+ throughout. No peripheral edema isnoted.

His lipid profile: Total cholesterol 240 mg/dl, LDL­C 155 mg/dl, HDL­C 35 mg/dl, andtriglycerides 250 mg/dl.

In addition to lifestyle modification, initial therapy for this patient should be which ofthe following?

A. Statin and fibrate for an LDL­C <130 mg/dl and triglycerides <150 mg/dl.

B. Lifestyle modification only.

C. Statin for an LDL­C <100 mg/dl.

D. Statin for an LDL­C <130 mg/dl.

8. A 64­year­old woman with stent placement in her left anterior descendingcoronary artery 6 months prior presents for follow­up. She has hypertension,diabetes, and coronary artery disease. She denies any anginal symptoms andwalks on the treadmill for 30 minutes daily.

Which of the following is recommended to potentially improve her CV risk factors orCV risks?

A. Consuming 1 g/day of long­chain omega 3 fatty acids.

B. Vitamin C and E supplements.

C. Folic acid and other B vitamins supplements.

D. Reducing her sodium intake to <2300 mg/day.

9. Her physical exam reveals a weight of 180 lbs, BMI of 32 kg/m2, waistcircumference of 37 inches, and BP 128/76 mm Hg on antihypertensive medication.Laboratory studies reveal a total cholesterol of 149 mg/dl, LDL­C of 65 mg/dl, HDL­Cof 46 mg/dl, triglycerides of 190 mg/dl, and a glycated hemoglobin of 7.5%. She hasmade several attempts to lose weight over the past year, but has beenunsuccessful.

Which of the following is an appropriate recommendation for weight loss in thispatient?

A. Bariatric surgery is an appropriate option and can improve her diabetesmanagement.

B. Phenteramine can be considered given her BMI >30 kg/m2 and comorbidconditions.

C. She should increase her exercise to a goal of 60 minutes a day.

D. An appropriate initial goal is 20­lb weight loss over the next 3 months.

10. A 46­year­old man with a strong family history of coronary artery disease, but noother significant past medical history, presents for a general evaluation. His weight

is 210 lbs, BMI 31 kg/m2, waist circumference 40 inches, and BP 135/84 mm Hg.Laboratory studies reveal a total cholesterol of 189 mg/dl, LDL­C of 110 mg/dl, HDL­C of 38 mg/dl, triglycerides of 205 mg/dl, and a fasting glucose of 107 mg/dl. He is anonsmoker and only exercises sporadically.Which of the following is the most appropriate recommendation for him?

A. He should focus on consuming a low fat diet, given his dyslipidemia.

B. He should follow the DASH diet, given his borderline blood pressure values.

C. He should drink 2­3 alcoholic beverages a day to lower his CV risks.

D. He should consume oily fish at least 2 times a week.

11. A 51­year­old man with hypertension and hyperlipidemia is being seen in follow­up for smoking cessation. He is currently on lisinopril 20 mg daily, amilodipine 10mg daily, and varenicline 1 mg twice daily. He has been having trouble sleeping, haspoor appetite, and has lost interest in golfing, which he does every weekend.

Which of the following steps is most appropriate in his care?

A. Stop varenicline.

B. Arrange for follow­up in 1 week.

C. Refer to counseling.

D. Start nicotine gum.

E. Start bupropion.

12.

Which of the following occurs with smoking cessation?

A. Increased CRP.

B. Decreased LDL­C.

C. Increased HDL­C.

D. Increased platelets.

13. A 59­year­old man is being discharged after a recent inferior MI. He wascounseled about quitting smoking and was started on bupropion therapy. Yournurse is scheduled to call him next week to follow­up.

Which of the following will most likely improve his long­term abstinence?

A. Exercise prescription.

B. Follow­up in 6 weeks.

C. Nicotine inhaler.

D. Referral to quit line.

14.

All of the following are valid treatment goals for patients with T2DM, EXCEPT:

A. The target HbA1c is <7%.

B. The target LDL cholesterol level in the setting of prior MI is <70 mg/dl.

C. The target systolic and diastolic blood pressure is <130/80 mm Hg.

D. All adults should be should be on aspirin therapy for the prevention of CVcomplications.

15.

Which of the following statements about the MetSyn is FALSE?

A. Its prevalence increases with age.

B. Insulin resistance is a central component of its pathophysiology.

C. It is associated with increased risk for MI but not for development of T2DM.

D. Its treatment is focused on modification of risk factors such as dyslipidemiaand hypertension.

16.

Which of the following statements about pioglitazone is FALSE?

A. It is among the class of drugs known as TZDs, which bind to and activate thenuclear receptor known as peroxisome proliferator­activated receptor (PPAR)­α.

B. Risks associated with use include increased fluid retention and congestiveheart failure.

C. In early 2011 the US FDA issued a warning stating that it is associated withincreased risk of MI.

D. Other effects include reduced blood pressure, markers of inflammation,

carotid intima medial thickness, and bone mineralization.

17.

Which of the following are not generally considered a feature of the MetS?

A. Elevated triglycerides.

B. Elevated LDL­C.

C. Elevated blood pressure.

D. Impaired fasting glucose.

E. B and C.

18.

Which of the following is NOT true regarding the MetS?

A. Most persons with MetS are at high risk of CHD (based on 10­year risk >20%or having pre­existing CHD).

B. Most persons with MetS have abdominal obesity.

C. Most persons with MetS have suboptimal levels of blood pressure (≥120/80mm Hg).

D. Persons with MetS have a generally lower risk of CHD events than dopersons with diabetes.

E. A and D.

19.

Statin therapy can generally be recommended in persons with MetS if which of thefollowing is/are TRUE?

A. They also have diabetes or CHD.

B. They fall within the NCEP guidelines for initiating therapy based on risk leveland LDL­C.

C. Regardless of LDL­C because of the small­dense pattern LDL­C generallyassociated with their high triglycerides and low HDL­C.

D. A and B.

E. B and C.

20.

Which is the following is FALSE with respect to management of CV risks in the MetSpatient?

A. Blood pressure control can often involve the use of ACE inhibitors and ARBs.

B. Management of prediabetes should include the use of thiazolidinediones,which have been shown to be effective in preventing diabetes.

C. Aspirin may be considered for prevention in those persons with MetS whoare at intermediate risk of CHD.

D. The general target for HbA1c is <7% in persons with MetS who also havediabetes, although a less stringent target may be appropriate for those with long­standing or poorly controlled diabetes or who also have macrovascular disease.

E. B and C.

21.

Based on the findings of the DPP trial, one can generally conclude which of thefollowing?

A. A lifestyle­based regimen that includes weight reduction and physical activityto the degree specified in the study can effectively prevent the onset of newdiabetes in persons with prediabetes

B. Metformin therapy was not effective in the prevention of diabetes.

C. Metformin therapy should be prescribed as an adjunct to diet and exercise inall persons who have prediabetes.

D. CV events can be prevented from a combination of metformin and lifestyletherapy in persons with prediabetes.

E. Both A and D.

22. A 41­year­old G1P1 female is seen in the outpatient clinic. She was initially seenby a cardiologist 3 months prior, while in the hospital, when the diagnosis of pre­eclampsia was made. During the last 2 months of her pregnancy, she waspersistently hypertensive and was started on metoprolol XL 12.5 mg daily. At thetime of her delivery, she developed pre­eclampsia, but her delivery of her child waswithout complications, and within 7 days of delivery, her blood pressure returned tonormal and her obstetrician stopped her medications. She is now 3 monthspostpartum and continues to be off all antihypertensive medications and her bloodpressure at this visit is 122/75 mm Hg.

Which of the following is a TRUE statement?

A. More men than women have hypertension in those over the age of 65 years.

B. Pre­eclampsia increases the risk of future hypertension, stroke, anddiabetes development.

C. Women over the age of 65 with hypertension are more likely to have theirblood pressure controlled when compared with younger women or men of anyage.

D. Pre­eclampsia increases the risk of future development of hypertension andstroke, but not diabetes.

23. A 50­year­old G2P2 female with a history of obesity, hypothyroidism, andgestational diabetes presents for assessment of cardiac risk. Her mother has ahistory of hypertension and stroke at age 70. Her father has diabetes. Her brothershave obesity. Her children are in good health. The patient works as an IT consultantand does not exercise regularly. She has never smoked.

On physical exam, her heart rate is 85 bpm and blood pressure is 125/80 mm Hg. Ingeneral, she is obese. Her cardiovascular exam demonstrates regular rate andrhythm, normal S1 and S2, and no murmurs, rubs, or gallops. She has no edema.

Selected testing is as follows: Her total cholesterol is 180 mg/dl. Her HDL­C is 52mg/dl.

Which of the following is recommended as a measure to prevent CHD?

A. Obtain an assessment of glycemia at a minimum of every 2 years.

B. Place the patient on a daily aspirin.

C. Obtain an hs­CRP level.

D. Obtain an assessment of thyroid function every 2­4 years.

E. Place the patient on folic acid.

24.

Using the Borg category scale (6­20) for perceived exertion, the intensity that isgenerally safe yet appropriate for cardiorespiratory conditioning should approximatewhich of the following?

A. 9 (very light).

B. 11 (fairly light).

C. 13 (somewhat hard).

D. 17 (very hard).

E. 19 (very, very hard).

25.

A patient with coronary disease has a 5­MET capacity, and prefers to exercise on thetreadmill at a comfortable walking speed, which he sets at 2 mph. His cardiologistwants him exercising at 60% of his exercise capacity, which is approximately 3METs. Which of the following is the prescribed percent treadmill grade to achievethis aerobic requirement?

A. 1%.

B. 2%.

C. 2.5%.

D. 3%.

E. 3.5%.

26.

All other factors being equal, patients with coronary disease enrolled in a structuredexercise program are most likely to achieve the greatest relative reduction in CV riskwhen they increase their exercise capacity from the baseline MET value shown, tothe final (higher) value?

A. 4­6 METs.

B. 6­8 METs.

C. 7­9 METs.

D. 11­13 METs.

E. 12­14 METs.

Please visit the online version to engage in this Exam.

1. The correct answer is D. The traditional FRS underestimates cardiovascular risk in women.Choice A is incorrect. Age is the predominant contributor to risk. Choice B is incorrect. Risk inyounger patients is underestimated. Choice C is incorrect. Family history is not included in therisk equation. Choice E is incorrect. One of the advantages of the FRS is the low cost of theinputs needed for its calculation.

2. The correct answer is E. While evidence supports matching intensity of therapy to degree ofrisk, no randomized controlled trials providing outcome data support any of the approachesdescribed in this question. Prospective cohort studies, however, do suggest improveddiscrimination and reclassification using CAC scoring in addition to traditional risk scores.

3. The correct answer is B. One of the principal advantages of the lifetime risk score isimproved risk communication of risk to younger patients. Choice A is incorrect. The lifetime riskscore developed by Dr. Lloyd­Jones was derived from the largely Caucasian Framingham cohort.Choice C is incorrect. The equation calculates risk for the composite cardiovascular endpoint ofcardiovascular death, MI, coronary insufficiency, angina pectoris, atherothrombotic stroke, andintermittent claudication. Choice D is incorrect. To date, there are no available tools to facilitatecalculation of lifetime risk scores.

4. The correct answer is E. Choice A is at high­risk and additional testing is not warranted.Choices B and C represent chronic inflammatory diseases that complicate interpretation of CRP,which is a nonspecific inflammatory marker. Choice D is a low­risk patient, and additional testingis not warranted. Answer E is the only asymptomatic intermediate­risk patient for whom CRP isappropriate.

5. The correct answer is B. Her LDL is acceptable, per current guidelines. However, thepatient's non­HDL is elevated at 150 mg/dl. Her goal non­HDL is <130 mg/dl. Addition of a fibrateor a nitrate, together with lifestyle modification, would assist her in achieving her non­HDL goal.

References

1. Grundy SM, Cleeman JI, Merz CN, et al., on behalf of the National Heart, Lung, and Blood Institute;American College of Cardiology Foundation; American Heart Association. Implications of recentclinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation 2004;110:227­39.

2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. ExecutiveSummary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA 2001;285:2486­97.

6. The correct answer is C. The triglycerides are over 500 mg/dl; therefore, the primary goal oftherapy is to lower the triglycerides. Once the triglycerides are under control, the LDL should belowered.

References

1. Grundy SM, Cleeman JI, Merz CN, et al., on behalf of the National Heart, Lung, and Blood Institute;American College of Cardiology Foundation; American Heart Association. Implications of recentclinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation 2004;110:227­39.

2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. ExecutiveSummary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA 2001;285:2486­97.

7. The correct answer is C. This patient has an abdominal aneurysm, which is a CHDequivalent. Therefore, his primary target is an LDL <100 mg/dl, with an option to lower the LDL to<70 mg/dl.

References

1. Grundy SM, Cleeman JI, Merz CN, et al., on behalf of the National Heart, Lung, and Blood Institute;American College of Cardiology Foundation; American Heart Association. Implications of recentclinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation 2004;110:227­39.

2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. ExecutiveSummary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA 2001;285:2486­97.

8. The correct answer is A. One gram per day of long­chain omega 3 fatty acids (EPA and DHA)is recommended to lower CV risks in those with CHD. Three to four grams a day may be neededto lower triglycerides. Vitamin C and E supplements have not been shown in randomized trials tolower CV risks, although dietary antioxidant consumption in the form of fruits and vegetables areencouraged.

Several randomized studies have failed to show a benefit of folic acid supplementation despitelowering of homocysteine levels. Those with hypertension or those at risk of hypertension (e.g.,African Americans, individuals >50 years, those with diabetes or chronic kidney disease) shouldconsume <1500 mg/day of sodium.

9. The correct answer is C. Bariatric surgery is currently a recommended option for those with a

BMI >40 kg/m2 or a BMI >35 kg/m2 and serious comorbid conditions including hypertension,diabetes, sleep apnea, and coronary artery disease. Phenteramine is sympathomimetic agentapproved for the short­term treatment of obesity (<12 weeks), but is contraindicated in those withCVD. Physical activity goals of 60 minutes a day may be required for weight loss, and especiallyfor weight maintenance after weight loss. According to the NHLBI Practical Guide, the initial goalfor weight loss is 10% of body weight over 6 months, or around 18 lbs in 6 months (rather than 3months) for this patient.

10. The correct answer is D. The AHA recommends oily fish consumption at least 2 times aweek for all adults, but 1 g/day of EPA and DHA for those with CHD. While a low­fat diet maylower his LDL­C levels, the patient also has metabolic syndrome with impaired fasting glucose,borderline blood pressures, and high triglycerides and low HDL­C. Therefore, replacement of fatwith simple carbohydrates could worsen some of these other parameters. Thus, a globalapproach including increased consumption of oily fish, vegetables, fruits, and whole grain, inaddition to lowering saturated fat and cholesterol intake, is recommended.

The DASH diet is most effective for BP lowering in those with hypertension, and the recent

Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart) study,1 showed that a

DASH type diet but with reduced carbohydrates, and greater amounts of plant­based protein ormonounsaturated fats, had more favorable effects on BP and lipids. For men who consumealcohol, 2 or fewer alcoholic beverages per day are recommended, and alcohol consumptioncan further increase triglycerides.

References

Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrateintake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA2005;294:2455­64.

11. The correct answer is A. This patient is exhibiting signs and symptoms of depressionincluding difficulty sleeping, change in eating habits, and anhedonia. This is a known side effectof varenicline. Follow­up and appropriate referrals should be made for his depression, but themost important first step is to discontinue the varenicline.

12. The correct answer is C. One of the benefits of smoking cessation is the increase of HDL­C. There is no change in LDL­C levels. The platelet number does not change, but they are lessactivated and thrombogenic with smoking cessation. CRP levels decrease with smokingcessation.

13. The correct answer is B. Arranging for follow­up is critical in improving the patient's long­term abstinence from tobacco. The highest abstinence rates posthospitalization are seen inpatients seen >1 month after their event. Nicotine should be used in caution in the first 2 weeksafter MI. Referral to cardiac rehabilitation will improve this likelihood of long­term abstinence, aswill referral to a quit line.

14. The correct answer is D.

15. The correct answer is C.

16. The correct answer is C.

17. The correct answer is B.

18. The correct answer is A.

19. The correct answer is D.

20. The correct answer is B.

21. The correct answer is A.

22. The correct answer is B. Pre­eclampsia increases the risk of developing hypertension,

stroke, and diabetes.1­3 It has been shown that women who have had pre­eclampsia have a 3.6­to 6.1­fold greater risk of developing hypertension, and a 3.1­ to 3.7­fold higher risk of developing

diabetes.1 A history of pre­eclampsia doubles the risk of subsequent ischemic stroke and heart

disease over the following 5­10 years after the pregnancy.2,3

Based on the NHANES data, there are more women than men with hypertension over the age of

65.4 This is particularly true for African­American women, who have the highest rate of

hypertension.4 It is also of note that women over the age of 65 are less likely to have their blood

pressure treated to goal.5

References

1. Lykke JA, Langhoff­Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancydisorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother.Hypertension 2009;53:944­51.

2. Brown DW, Dueker N, Jamieson DJ, et al. Preeclampsia and the risk of ischemic stroke among youngwomen: results from the Stroke Prevention in Young Women Study. Stroke 2006;37:1055­9.

3. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre­eclampsia and risk of cardiovascular diseaseand cancer in later life: systematic review and meta­analysis. BMJ 2007;335:974.

4. Roger VL, Go AS, Lloyd­Jones DM, et al., on behalf of the American Heart Association StatisticsCommittee and Stroke Statistics Subcommittee. Heart disease and stroke statistics­­2011 update: areport from the American Heart Association. Circulation 2011;123:e18­e209.

5. Gu Q, Burt VL, Paulose­Ram R, Dillon CF. Gender differences in hypertension treatment, drugutilization patterns, and blood pressure control among US adults with hypertension: data from theNational Health and Nutrition Examination Survey 1999­2004. Am J Hypertens 2008;21:789­98.

23. The correct answer is A. In women with a history of gestational diabetes, the AmericanDiabetes Association and American College of Obstetricians and Gynecologists recommendobtaining an assessment of glycemia 6­12 weeks postpartum. If these are normal, glycemia

should be assessed at a minimum of every 2 years.1,27

This patient falls into the at­risk category, given her history of obesity, physical inactivity, andgestational diabetes.

For the at­risk or healthy woman, aspirin may be useful in women >65 years of age if benefit forischemic stroke and MI prevention is likely to outweigh the risk of gastrointestinal bleeding andhemorrhagic stroke, and may be reasonable for women <65 years of age for ischemic stroke

prevention.2

The Effectiveness­Based Guidelines for the Prevention of Cardiovascular Disease in Women do

not endorse routine screening with hs­CRP.2

Preventive guidelines do not recommend the assessment of thyroid function for CHD prevention.

Folic acid should not be used for the primary or secondary prevention of cardiovascular disease.

References

1. Simmons D, McElduff A, McIntyre HD, Elrishi M. Gestational Diabetes Mellitus: NICE for the U.S.? Acomparison of the American Diabetes Association and the American College of Obstetricians andGynecologists guidelines with the U.K. National Institute for Health and Clinical Excellence guidelines.Diabetes Care 2010;33:34­7.

2. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness­based guidelines for the prevention ofcardiovascular disease in women­­2011 update: a guideline from the American Heart Association.Circulation 2011;123:1243­62.

24. The correct answer is C. Research has shown that exercise rated 12­15 (6­20 scale),between “somewhat hard” and “hard,” is generally considered appropriate for cardiorespiratoryconditioning, approximating 50­75% of the VO2 max. Thus, 13 (somewhat hard) would represent

an appropriate intensity for exercise training.

25. The correct answer is E. According to the “rule of 2 and 3 mph,” at a 2­mph walking speed,each 3.5% increase in treadmill grade adds approximately 1 MET.

26. The correct answer is A. The cohort of patients who seem to derive the greatest benefitfrom an exercise program, are those who move out of the least fit, “high­risk” subset (bottom20%; <5 METs). On the other hand, those with an exercise capacity >9 METs are already in the“lowest­risk” category.