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The Present Survival with CAD
Time 0
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Hospital Mortality Post MI
0
5
10
15
20
25
1970 1990 1995
25% 11% 8%
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Follow-up 132 Grafts at 10 Years
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Is This the Best We Can Do?
10 Years Later
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Treatment Goals
in CAD Patients Identify and TreatUnstable Life-ThreateningCoronary Lesions
Antithrombotic Rx Prevent VentricularDilation with ACE Rx
Lower LDL
the More the BetterAfter Lifestyle
smoking
obesity
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Dietary, Exercise & Lifestyle
Modifications
Factors affecting therapyof hyperlipidemia
Modifiable risk factors
Hypertension
Cigarette smoking
Diabetes mellitus
Obesity
Alcohol intake
Other factors
Family history of coronaryheart disease or peripheral
vascular disease
Personal history of early onsetcoronary heart disease
Male sex
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Passive smoking
The incidence of heart disease
among women with smokinghusbands was 14.9 times higherthan that of women with nonsmoking husbands.
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Nutritional Management
of Hypercholesterolemia
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Obesity
Not an independent factor
Strong association with otherrisk factors:
increased blood pressure diabetes
hypercholesterolemia
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Body weight deserves adeliberate attention in any
effort to reducecardiovascular risk.
R l i f B d M I d
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Relation of Body Mass Index,(BMI) to Relative Mortality Risk
BMI Risk Odds
Ratio20 - 30 Desirable 1.0
2530 Mild 1.0 - 1.25
3040 Moderate 1.252.5
40 High > 2.5
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Body Weight
Restoration of normal body weight is mostimportant.
Several studies have shown that decreasing bodyweight decreases the plasma lipids regardless ofthe design of the diet:
decreases LDL Chol decreases TG Increases HDL Chol
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NUTRIENT
AVERAGE
NORTH
AMERICAN
DIET
STEP ONE
DIET
STEP TWO
DIET
MONO
DIET
TOTAL FAT
(% total calories) 35-40%
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CCCC recommendations:Intervention by dietary modification plus exercise
Goals for dietary intervention:
Dietary component % of caloric intakefat < 30%saturated fatty acids < 10%
polyunsaturates < 10%protein 10-15%
In Addition:
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Strategies
Most families have 10-15 recipes thatconstitute their daily diet
It is often more efficient to modify orreplace individual meals, taking into
account: preparation time cost
taste
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Strategies
Reduction of the major and obvious
sources of saturated fatty acid andcholesterol.
Substitute rather than delete.
F
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FAT Saturated fat: Increases total Chol and LDL C Monounsaturated fat: neutral Polyunsaturated fat: decreases total Choland LDL C
Subtracting a certain amount ofsaturated fat has the same effect asadding twice that amount of
polyunsaturated fat. Animal and vegetable fats do not makea complete distinction:
butter, coconut oil: Increase Chol corn oil, whale oil: decrease Chol
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Replace fat in the diet by carbohydrate.
Carbohydrate has less calories than fat.
Increase fiber gradually
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Increase fish intake to two to three90 g servings per week.
Avoid fish oil supplements.
M i P t ti l f Di t Ch t
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Maximum Potential of Dietary Changes toReduce Serum Cholesterol
Dietary Change in Serum Cholesterol
(%)
saturated fat
from 14 to 7% of total calories
15
polyunsaturated fat
from 7 to 10% of total calories
5
cholesterol
from 500 to 250 mg/day
7
fibre (especially soluble)
from 20 to 40 mg/day
8
Total maximum potential effect of dietary
changes:
35%
verage effect of dietary changes:
1.1 1.4 mmol/L decrease in serum cholesterol level
D M d f
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Dietary Modification
Hepatic over productionis a major cause ofincreased plasma lipids
Reduce excess dietary fat& excess caloric load &this will reduce hepaticproduction & reduce
obesity hypertension
diabetes
Chylomicron
Remnant VLDL
Remnant(IDL)
LDL
LPL
HPLHPL
HDL3
LCAT
HDL2
LPL
Intestine
Liver
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Diet modification remains aprincipal therapy for people with
elevated blood lipid levels.
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Lower LDL the More the Better
SUGGESTED APPROACH BASED ON LIPID
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SUGGESTED APPROACH BASED ON LIPIDLEVELS AND RISK FACTORS (RF)
LIPIDPROFILE
if total Chol
DIETTHERAPY
if LDL Chol
DIET, and thenMEDICATION
if LDL Chol GOAL
< 35 yr., no RF > 6.2 > 4.1 > 5.7 4.1
> 35 yr., no RF > 6.2 > 4.1 > 4.9 4.1
> 2 Risk Factors > 5.2 > 3.4 > 4.1 3.4
With CHD > 0 > 2.5 > 3.4 2.6
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+ DRUGS
Li id l i t
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Lipid-lowering agents
1.HMG-CoA reductase inhibitors: Inhibit hepaticcholesterol production
2.Bile acid resins: Bind cholesterol in gut
3.Fibric acid derivatives: cholesterol excretion inbile
4.Probucol: LDL-C breakdown and may inhibitLDL-C oxidation
5.Nicotinic acid: production of VLDL-C
Mechanism of action of Bile Acid Sequestrants
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Mechanism of action of Bile Acid Sequestrants
LDLLDL
LDL
Resins
IIMG CoA
Cholesterol
Bile Acids
IIMG CoA
Cholesterol
Bile Acids
Bile acid Sequestrants in
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Ser
umConcentration(mmol/l)
% Change
8.9
6.87.2
5.0
1.1 1.21.4 1.5
Diet
only
Diet +
Cholestyramine (16g/day)Total CholesterolLDL-CholesterolHDL-Cholesterol
Triglyceride
- 23 - 30.5 + 9.1 + 7.0
Bile acid Sequestrants inPrimary Hypercholesterolaemia
HMG C A R d t I hibit
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HMG CoA Reductase Inhibitors
Ratelimitingcontrol of
cholesterolsynthesis(secretedin lipoproteins)
HMG COAMevastatin
(compactin)
Lovastatin
(mevinolin)
Simvastatin
(Synvinolin)
PrevastatinCS 514,
SQ 31000
Fluvastatin(Fluindostatin,
SRI 62320)
(Lactone form) (Lactone form) (Lactone form)
Statins are pharmacologic targets toReduce hepatic productionPeripheral catabolism
T tm nt f h p h l t l mi
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8
6
4
2
0 4 8 12 16 20 24Weeks on treatment
Cholesterol(mmol/l)
Total LDL HDL
Effect of statin treatment (20 mg/day) on total, LDL and HDLcholesterol concentrations (means +- s.e.m., n=10) in patients
with high plasma cholesterol.
Treatment of hypercholesterolemia
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HMG-CoA Reductase InhibitorsContraindications Active liver disease
Pregnancy and lactation
Hypersensitivity
Relative Contraindications Childhood Concurrent use of cyclosporine, erythromycin, (fibrates, niacin)
Side effects Serum transaminases
CK
Myopathies
Abdominal pain, diarrhea, constipation
Headaches
P i P ti T i l
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Primary Prevention Trials
Trials of DietLA Veterans StudyOslo Primary Prevention Study
Multiple Risk Factor Intervention Trial (MRFIT)
Trials of DrugsWHO Cooperative Trial of Clofibrate
Lipid Research ClinicsCoronary Primary Prevention Trial (LRC-CPPT)
Helsinki Heart Study
OSLO P im P ti T i l
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OSLO Primary Prevention Trial
325
300
275
0 1 2 3 4 5
TC(m
g/dl)
Years
Treatment Group N = 604 Controls N = 628
OSLO P i P ti T i l
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OSLO Primary Prevention TrialNumber of episodes Change Relativ
to ControlsCoronary 19 - 47.2%Heart Disease 36*
All Cardiovascular 22 - 43.6%
Disease 39*
Sudden 3 - 72.7%Death 11
Total CVD Death 8 - 46.7%(inc. Stroke) 15
Total 16 - 33.3%Deaths 24
Treatment Group N = 604 Controls N = 628 * P < 0.05
C nclusi ns fr m Primar
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Conclusions from PrimaryPrevention Studies
1) Elevated blood cholesterol is amajor risk factor for CHD
2) Primary preventative measures cangreatly reduce CHD risk
3) A 1% reduction of blood cholesterolreduces CHD risk by 2%
Atherosclerosis CAN be Reversed
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athero
Atherosclerosis CANbe Reversed
Regression only Progression only Lipid effects
Definite lesion changes in the FATS trial according to the three treatmentgroups. The numbers in the horizontal bars on the graph represent
percentage of patients. The numbers in the squares on the right representthe lipid and lipoprotein changes in each of the corresponding treatment
groups.
Global change score
P = 0.005
-7% 5% 15%
-46% 15% -9%
-32% 43% -29%
LDL HDL TG
-40 -20 0 20 40
Niacin + Colestipol39 25
21Lovastatin + Colestipol32
11 46Conventional
Examples of regression FATS
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Examples of regression - FATSLAD OMB RCA OMB LCx
Mean % Stemosis 100% 39% 48% 69% 44%
Mean % Stemosis 28% 18% 30% 37% 30%
Baseline
After
2.5 years
OBJECTIVES
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OBJECTIVES
Randomised trial of cholesterol lowering in 4444patients with coronary heart disease: TheScandinavian Simvastatin Study (4S)
Lancet 344, 1994
To investigate whether long-term simvastatin
therapy reduces total mortality and coronaryevents in post-MI and angina patients with serumtotal cholesterol levels of 5.5 to 8.0 mmol/L (212-309 mg/dl)
Simvastatin and Platelet Dysfunction
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Simvastatin and Platelet Dysfunction8
6
4
2
0
70
60
50
40
30
20
10
0
B 1 4 8 12 B 1 4 8 12 B 1 4 8 12B 1 4 8 12
mean + SD
* P < 0.01
TAC ADP pM PLATELET TXB2 ng/108 pits
**
* * **
*
Decrease in Ischemia
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Decrease in IschemiaWith Decrease in LDL
Episodesofischemia/48hours
24
17
15
10
5
0
24
17
15
10
5
0Baseline 6 months Baseline 6 months
Placebo
(n = 20)
Treatment
(n = 20)
MAJOR CORONARY EVENTS
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MAJOR CORONARY EVENTS
Proportion
(%)ofpatie
ntswithou
tevents
Coronary death and nonfatal MI
Years since randomization
100
90
80
70
01 2 3 4 5 6
Simvastatin
Placebo
P < 0.0000134%
Risk reduction
Women and older patients
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Women and older patientsBACKGROUND
CHD is the chief cause of death in women
More than 75 percent of deaths from CHD occur in
individuals older than age 65
Few clinical trials have focused on therapeuticintervention in women and the elderly
Subgroups of both women and the elderly (> 60years) were included in the ScandinavianSimvastatin Survival Study
Women
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Women
MAJOR CORONARY EVENTS
Coronary death and nonfatal MI
Numberofpatients
35%Risk reduction
P = 0.01
100
75
50
25
0
91
59
Placebo Simvastatin
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CAD: TherapeuticStrategies for the 2000s
Antiatherogenic Antithrombogenic
Angiogenic
Obesity and Diet
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