MKSAP 17Cardiovascular MedicineReference Ranges

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Chapter 01: Epidemiology and Risk FactorsRelated QuestionsPrevious: Return to Cardiovascular Medicine

Epidemiology and Risk Factors

Overview

In the United States, the mortality rate from cardiovascular disease (CVD), including heart disease,stroke, peripheral vascular disease, hypertension, and heart failure has steadily declined over the pastdecade—33% from 1999 to 2009, likely as a result of better prevention and acute care efforts.Nonetheless, CVD is the leading killer of both men and women, and although mortality of CVD isdecreasing, CVD prevalence is increasing. By 2030, according to the American Heart Association'sHeart Disease and Stroke Statistics, more than 40% of the U.S. population is projected to have someform of CVD. More than one in three American adults currently have some form of CVD, and theprevalence increases from more than 10% in those aged 20 to 39 years to more than 70% in thoseaged 60 to 79 years. Based on data from the Framingham Heart Study, two out of three men and oneout of two women will develop CVD in their lifetime. Despite the decreasing mortality,hospitalizations for cardiovascular­related diseases have steadily continued to rise. There were nearly6 million hospital discharges for cardiovascular­related diseases in 2009, with an estimated cost of$312.6 billion.

The prevalence of heart failure continues to rise, with a predicted prevalence in the United States of25% by 2030. It is estimated that 5.1 million Americans older than 20 years have a diagnosis of heartfailure. Currently, the incidence is 1/100 annually in those older than 65 years. Most of these patientshave a history of hypertension. Both systolic dysfunction and diastolic dysfunction are associated withthe development of symptomatic heart failure, and the prevalence of heart failure with preservedejection fraction (diastolic dysfunction) is increasing. Mortality in heart failure is quite high—nearly50% mortality at 5 years.

Cardiovascular Disease in Women

Since 1984, the number of deaths from CVD has been greater for women than men and highest amongblack women. More than 400,000 women died of CVD in 2009, 51% of all CVD deaths. Women havea higher mortality rate after myocardial infarction: 26% in women versus 19% in men older than 45years. The death rate for women with heart failure is higher than among men, although women areoften older. Incidence of and mortality from stroke is highest among women, with the highest amongblack women.

Women have a higher prevalence of risk factors for CVD, including elevated cholesterol levels,diabetes mellitus, hypertension, and inactivity. Only tobacco use is higher among men.

More women present with angina than men, but women often have other symptoms in addition tochest pain. Women have “atypical” symptoms more frequently than men, including nausea, shortnessof breath, and unusual fatigue. More than two thirds of women who die suddenly from coronary heart

disease either did not recognize the symptoms or had no previous symptoms. Women undergo fewerrevascularization procedures than men, with 25% of coronary artery bypass surgeries and nearly 33%of percutaneous coronary interventions occurring in women.

Ethnicity and Cardiovascular Disease

The prevalence of CVD and risk factors in the United States vary by ethnicity. American Indians andAlaska Natives have the highest rate of heart disease (12.7%), followed by whites (11.1%), blacks orAfrican Americans (10.7%), Hispanics or Latinos (8.6%), and Asians (7.4%). Peripheral arterialdisease affects nearly 8.5% of Americans older than 40 years, and prevalence is highest among olderpersons, non­Hispanic blacks, and women. The population most affected by heart failure is AfricanAmericans, at a rate of 4.6/1000 person­years, followed by Hispanic, white, and Chinese Americans.

Cardiovascular risk factors also vary among ethnicities. Blacks have the highest rate of hypertension,at 33.4% (higher in black women), followed by American Indians or Alaska Natives (25.8%), whites(23.3%), Hispanics or Latinos (22.2%), and Asians (18.7%). Blacks have the highest prevalence oftwo or more cardiovascular risk factors (48.7%). The prevalence of risk factors is increased withdecreasing levels of education and income. Obesity and lack of physical activity are highest amongHispanic/Latino adults and non­Hispanic blacks.

Environmental influences on cardiovascular risk factors are changing the prevalence of CVD incertain populations. In countries with previously low rates of CVD, rates of disease are increasingwith the adoption of Western eating habits and increasing tobacco use. With declining rates of infantmortality and death from infectious diseases, the influence of urbanization and change in traditionallifestyles are resulting in increasing rates of CVD.

Genetics in Cardiovascular Disease

Family history of premature (male <45 years; female <55 years) coronary artery disease (CAD)significantly increases risk of CVD. Having a parent with premature CAD doubles risk of myocardialinfarction in men and increases risk in women by 70%. CAD in a sibling increases risk by 50%.Genetic predisposition as well as shared environment may contribute to increased risk in familymembers. Although prediction models based on the genetics of CVD are not yet available, researchcontinues at a rapid pace.

Lifestyle Risk Factors

Related Question

Question 17

As much as 90% of the risk for myocardial infarction has been attributed to modifiable risk factors,with elevated cholesterol levels, smoking, and psychosocial stressors accounting for a significantportion of the attributable risk. The attributable risk for myocardial infarction is highest for cholesterollevels, followed by current smoking, psychosocial stressors, diabetes, hypertension, abdominalobesity, no alcohol intake, inadequate exercise, and irregular consumption of fruits and vegetables.

Elevated cholesterol levels increase the risk of CVD, and multiple studies have shown that reductionsin cholesterol levels, particularly LDL cholesterol, reduce risk. Nearly 14% of adults older than 20years have total cholesterol levels greater than 240 mg/dL (6.21 mmol/L); approximately 6% of adultsare estimated to have undiagnosed hypercholesterolemia. Elevated LDL cholesterol and low HDLcholesterol levels are independent risk factors for CVD. For every 1% decrease in LDL cholesterol

level, there is a corresponding 1% decrease in risk for coronary artery disease. The risk reduction iseven greater with changes in HDL cholesterol, with a risk reduction of 2% to 3% for every 1%increase in HDL cholesterol level. However, randomized clinical trials evaluating pharmacologictherapies that raise HDL cholesterol levels in patients with well­treated LDL cholesterol levels havenot shown reduction in clinical endpoints. Long­standing guidelines (Adult Treatment Panel III [ATPIII]) have provided treatment goals for LDL and non­HDL cholesterol levels based on cardiovascularrisk factors and Framingham risk score. In 2013, the American College of Cardiology and theAmerican Heart Association (ACC/AHA) published revised guidelines that treat lipid blood levelsaccording to cardiovascular risk, rather than LDL cholesterol targets (see MKSAP 17 General InternalMedicine, Dyslipidemia).

The use of tobacco has declined over the past few decades, but despite this decline, in 2011, morethan 21.3% of men, 16.7% of women, and 18% of high school students were smokers. The rates werehighest among American Indian/Alaska Natives and non­Hispanic black males and lowest amongHispanic females. Tobacco use increases the risk of CVD, including coronary heart disease, stroke,and peripheral vascular disease, for which smoking is a major risk factor, and increases CVDmortality by 2 to 3 times. The risk of coronary artery disease is increased by 25% in women whosmoke. Smoking increases the risk of stroke by 2 to 4 times. Secondhand smoke is also a risk factorfor CVD, increasing the risk by 25% to 30%. Smoking cessation substantially reduces cardiovascularrisk within 2 years, and this risk returns to the level of a nonsmoker within 5 years. Efforts to assesssmoking status and provide assistance with cessation should be made at every encounter (seeMKSAP 17 General Internal Medicine, Routine Care of the Healthy Patient).

Nearly one in three adults in the United States older than 20 years has hypertension, and the rates areequal among men and women. Nearly 30% of adults older than 20 years have prehypertension(systolic blood pressure 120­139 mm Hg; diastolic blood pressure 80­89 mm Hg). The rates increasewith age, with a prevalence greater than 70% in persons older than 65 years. Treatment ofhypertension reduces risk for cardiovascular events, including stroke, and reduces end­organ damagesuch as heart failure and kidney disease. Although the prevalence of blood pressure control (that is,blood pressure within recommended ranges) has improved in the United States from less than 30%two decades ago (1988­1994), it still is only 50% (2007­2008).

Sedentary lifestyle, poor diet, and obesity contribute to increased cardiovascular risk and increasedrisk for diabetes. Nearly one third of all U.S. adults report no leisure time activity, and less than 30%of high school students engaged in 60 minutes of daily physical activity; this rate was lowest amonggirls. Between 1971 and 2004, total energy consumption increased by 22% in women and 10% inmen. Average fruit and vegetable consumption was 2.4 to 4 servings daily (recommended, >5 daily)and was lowest among blacks. The increased caloric intake coupled with decreased physical activityhas led to an increased incidence of obesity. More than two thirds of the American population olderthan 20 years are overweight (BMI 25­29.9) with more than one third obese (BMI >30). In childrenand adolescents between the ages of 2 and 19 years, nearly 33% are obese or overweight and 17% ofthese children are obese.

Psychosocial stressors are an important contributor to cardiovascular risk. These include depression,anger, and anxiety, and are associated with worse outcomes. Depression has been associated withhigher risk for cardiovascular events, and psychosocial stressors also affect the course of treatmentand adherence to healthy lifestyles after an event. Awareness of these factors and appropriatetherapies may improve outcomes in these individuals.

Impaired glucose control is a significant component of the metabolic syndrome, which ischaracterized by elevated glucose, central obesity, low HDL cholesterol, elevated triglycerides, andhigh blood pressure. More than 34% of adults older than 20 years meet the criteria for metabolicsyndrome (three of the five components). The presence of metabolic syndrome is associated with anincreased risk of CVD. This risk increases with an increased number of components and also appearsto be higher among women. The National Diabetes Prevention Program found that in persons at high

risk for diabetes, improved food choices and at least 150 minutes of exercise weekly led to 5% to 7%weight loss and reduced the risk of developing diabetes by 58%, but no interventions have shown areduction in CVD events to date.

Key Point

Elevated cholesterol levels, smoking, and psychosocial stressors are the greatest modifiable riskfactors for cardiovascular disease.

Specific Risk Groups

Diabetes Mellitus

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Question 8Question 40

The presence of diabetes mellitus is associated with increased cardiovascular risk, particularly amongwomen. Persons with diabetes have a 2 to 4 times increased risk of CVD, with more than two thirds ofthose with diabetes eventually dying of heart disease. The risk of stroke is increased 1.8­ to 6­fold inpersons with diabetes. The presence of diabetes in those older than 65 years is nearly 27%. In thoseaged 12­19 years, the prevalence of diabetes and prediabetes is increasing, from 9% to 23% from1999­2007. Diabetes is often undiagnosed, and is frequently diagnosed at the time of an acute eventsuch as myocardial infarction. Appropriate treatment of cardiovascular risk factors in persons withdiabetes is associated with reduced cardiovascular risk. The most recent cholesterol guidelinesrecommend moderate­ or high­intensity statin therapy in patients aged 40 to 75 years with diabetes.Patients with diabetes aged 40 to 75 years with a 10­year atherosclerotic cardiovascular disease(ASCVD) risk greater than or equal to 7.5% should receive high­intensity statin therapy because oftheir increased risk. In patients with diabetes in this age group with a 10­year risk below 7.5%,moderate­intensity statin therapy is recommended.

Chronic Kidney Disease

Chronic kidney disease (CKD) is associated with higher cardiovascular mortality, and more patientswith kidney disease will die of CVD than will go on to have end­stage kidney disease requiringdialysis. Chronic kidney disease shares many of the same risk factors for CVD such as hypertension,diabetes, and smoking. The exact etiology of the high death rate in patients with CKD is uncertain andmay be related to a higher incidence of fatal arrhythmias, lack of adequate therapies at the time of anacute cardiovascular event, or multi­organ changes related to kidney failure.

Systemic Inflammatory Conditions

Patients with systemic inflammatory conditions, such as systemic lupus erythematosus (SLE) andrheumatoid arthritis, have an increased risk of CVD. Most deaths in persons with SLE and nearly 40%of deaths in those with rheumatoid arthritis are cardiovascular and, in particular, heart failure related.The risk of CVD increases with the duration of the underlying inflammatory condition. The risk ofCVD increases from two times that of the general population to three times after 10 years' duration ofrheumatoid arthritis. The increased atherosclerotic burden is likely a result of both the inflammatoryprocess of the systemic disease, including a prothrombotic state, as well as the presence of traditionalcardiovascular risk factors.

Calculating Cardiovascular Risk

Cardiovascular risk scores should be utilized to stratify patients for appropriate prevention targets.Traditionally, the Framingham risk score has been used to estimate the 10­year risk of a majorcardiovascular event (myocardial infarction or coronary death). An online Framingham risk calculatoris available at http://cvdrisk.nhlbi.nih.gov/calculator.asp. Using this method, a 10­year risk of ASCVDof less than 10% is considered low risk, 10% to 20% is classified as intermediate risk, and above 20%is designated as high risk. Age is the component that drives most of the risk, with increasing agereflected in increased risk. The Framingham risk score underestimates risk in women and minoritypopulations. In an effort to account for the underestimation in women, the Reynolds risk score wasdeveloped, which is a sex­specific score for both men and women that includes family history andhigh­sensitivity C­reactive protein (hsCRP) levels (www.reynoldsriskscore.org).

The Pooled Cohort Equations are a new risk assessment instrument developed from multiplecommunity­based cohorts (including the Framingham study) that includes a broader range of variablesthan the Framingham score when evaluating 10­year ASCVD risk. Its use as a primary riskassessment tool was recommended in the 2013 ACC/AHA Guideline on Assessment ofCardiovascular Risk. The ACC/AHA CV risk calculator includes age, sex, race, total and HDLcholesterol levels, systolic blood pressure, blood pressure–lowering medication use, diabetes status,and smoking status. Using this method, a 10­year risk of ASCVD of below 5% is considered low risk,5% to below 7.5% is classified as intermediate risk, and 7.5% or above is designated as high risk. Thenew risk calculator can be accessed athttp://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention­Guidelines_UCM_457698_SubHomePage.jsp.

Key Point

Cardiovascular risk scores should be utilized to stratify patients for appropriate preventiontargets; risk assessment tools include the Framingham risk score, the Reynolds risk score, andthe American College of Cardiology/American Heart Association's cardiovascular riskcalculator based on the Pooled Cohort Equations.

Emerging Risk Factors

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Question 2Question 83

Because atherosclerotic disease is thought to be in part an inflammatory process, hsCRP measurementhas been investigated for enhancing risk prediction. Current guidelines do not support the use ofhsCRP evaluation in the general population. However, hsCRP testing may be used in intermediate­risk patients (Framingham 10­year risk score of 10%­20%) in whom choice of therapy may beaffected by reclassification of risk. Elevated hsCRP levels should be rechecked within 2 weeks, andother potential causes of infection or inflammation should be ruled out. Although statin therapy hasbeen shown to lower hsCRP levels, therapy targeting hsCRP alone is not appropriate as patientsshould be treated according to cardiovascular risk.

Although elevated levels of Lp(a) lipoprotein and homocysteine have been associated with elevatedcardiovascular risk, these tests should not be routinely performed. Interventions to reducehomocysteine levels with folic acid supplementation have not been shown to reduce cardiovascularevents. Although epidemiologic evidence supports the association between elevated levels of Lp(a)

lipoprotein and cardiovascular events, to date no trials have shown that treatment to lower Lp(a)lipoprotein levels lowers risk. There is currently no role for the evaluation of lipid particle size andnumber. No studies to date have shown that treatment targeted to particle size and number affectsoutcomes.

The evaluation of subclinical disease with coronary artery calcium (CAC) scoring may be appropriateto further risk stratify intermediate­risk patients but is not a component of routine risk assessment.Evidence of calcification of coronary vessels is indicative of atherosclerotic disease, but the absenceof calcification does not rule out the presence of soft plaque.

Key Points

Current guidelines do not support the use of high­sensitivity C­reactive protein (hsCRP)evaluation in the general population, but hsCRP testing may be used in intermediate­riskpatients in whom choice of therapy may be affected by reclassification of risk.There is currently no role for the routine measurement of Lp(a) lipoprotein levels orhomocysteine levels or evaluation of lipid particle size as these tests are expensive and nostudies to date have shown that treatment targeted to these levels affects outcomes.The evaluation of subclinical disease with coronary artery calcium scoring may be appropriateto further risk stratify intermediate­risk patients but is not a component of routine riskassessment.

Aspirin for Primary Prevention

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Question 88

Aspirin is a powerful agent for both primary and secondary prevention of coronary artery disease.Aspirin for secondary prevention is discussed under Coronary Artery Disease. For primary preventionof myocardial infarction, data suggest that there is greater benefit in men, particularly those older than45 years. For women, benefit outweighs risk of aspirin therapy after the age of 65 years. Between theages of 55 and 65 years, the risk of stroke is reduced in women on aspirin therapy. Guidance for usingaspirin for primary prevention of myocardial infarction and stroke is provided in Table 1 and Table 2.

It is important to balance the benefits of aspirin therapy with the risks of gastrointestinal (GI)bleeding. The risk of serious bleeding is greatly increased in patients with a history of GI ulcers andwho use NSAIDs, and these factors should be considered when assessing the benefits and harms ofusing aspirin in the individual patient.

Aspirin should not be routinely given to patients with diabetes who are at low risk for CVD (men <50years and women <60 years with no major additional CVD risk factors; 10­year CVD risk <5%). It isreasonable to give low­dose aspirin to adults with diabetes and no previous history of vascular diseasewho are at increased CVD risk (10­year Framingham risk >10%) and without increased risk forbleeding.

Key Points

In men ages 45 to 79 years, aspirin for primary prevention of myocardial infarction isrecommended if the benefit of treatment outweighs the risk of gastrointestinal bleeding.In women ages 55 to 79 years, aspirin for primary prevention of stroke is recommended if thebenefit of treatment outweighs the risk of gastrointestinal bleeding.

Aspirin should not be routinely given to patients with diabetes who are at low risk; that is, menyounger than 50 years and women younger than 60 years with no major additionalcardiovascular risk factors.

Bibliography

Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascular disease. Curr AtherosclerRep. 2008 Apr;10(2):128­33. PMID: 18417067Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee andStroke Statistics Subcommittee. Heart disease and stroke statistics–2013 update: a report fromthe American Heart Association. Circulation. 2013 Jan 1;127(1):e6­e245. Erratum in:Circulation. 2013 Jan 1;127 (1). Erratum in: Circulation. 2013 Jun 11;127(23):e841. PMID:23239837Greenland P, Alpert JS, Beller GA, et al; American College of Cardiology Foundation;American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular riskin asymptomatic adults: a report of the American College of Cardiology Foundation/AmericanHeart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010 Dec14;56(25):e50­103. PMID: 21144964Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascularevents in people with diabetes: a position statement of the American Diabetes Association, ascientific statement of the American Heart Association, and an expert consensus document ofthe American College of Cardiology Foundation. Circulation. 2010 Jun 22;121(24):2694­701.PMID: 20508178Schoenfeld SR, Kasturi S, Costenbaker KH. The epidemiology of atherosclerotic cardiovasculardisease among patients with SLE: a systematic review. Semin Arthritis Rheum. 2013Aug;43(1):77­95. PMID: 23422269U.S. Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease.www.uspreventiveservicestaskforce.org/uspstf/uspsasmi.htm. Updated October 2013. AccessedOctober 1, 2014.Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Effect of potentiallymodifiable risk factors associated with myocardial infarction in 52 countries (theINTERHEART study): case­control study. Lancet. 2004 Sep 11­17;364(9438):937­52. PMID:15364185Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases. Part II: Variationsin cardiovascular disease by specific ethnic groups and geographic regions and preventionstrategies. Circulation. 2001 Dec 4;104(23):2855­64. PMID: 11733407

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Chapter 010 NotesEpidemiology and Risk FactorsQuestionsReference Ranges