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REVIEW ARTICLE
Epedimiology and angiographic studies of hypercholesterolemia and atherosclerosis
1930- Relation between and elevated serum cholesterol level and
atherosclerosis was first described by Muller et al
- excessive prevalence of premature coronary artery disease and MI
among hereditary Xanthomatosis
1971- Kannel and coworkers confirmed these and strong direct correlation
between the total cholesterol level and the development of ischemic
heart disease in more than 5000 subjects in the Framingham heart
studies
1986- MRFIT involved studies of 400000 men and confirme unequivocal
relation between base-line serum cholesterol levels and mortality
from cardiovascular disease and increase risk with cholesterol as
low as 4.68mmol per litre
Later epidimiology studies found similar correlation in young men, women, blacks and elderly as well as those already got CHD.
1987- EAS ( European Atherosclerosis Society) and National Institue
concluded that there is sufficient evidence to demonstrate a casual
relation between hypercholesterolaemia with CHD.
CHOLESTEROL REDUCTION AND CARDIOVASCULAR DISEASE
PRIMARY PREVENTION TRIAL
1984- Lipid Research clinics coronary Primary Prevention Trial includes
3806 middle-age men who recieved dietary midification and
cholestyramine or dietary modification and placebo
- combination gp. reduced TC =11.8% and LDLchol= 18.9%
- placebo gp. reduced TC=5% and LDLchol = 8.6%
- 19% reduction in non-fatal MI and 24% reduction in cardiovascular
mortality
1988- Helsinki Heart Study includes 4081 men assigned randomly to
gemfibrozil or placebo
- 10% reduction in TC and 11% reduction in LDL chol. and 11% inc.
in HDL
- 34% reduction in combined death from cardiac disease, nonfatal
and fatal MI
- inc. in HDL chol was the strongest predictor of a reduction in CVS
death
SECONDARY PREVENTION TRIALS
1988- Stockholm Ischaemic Heart Disease Secondary Prevention Study
recruits survivors from MI and assigned randomly to combination of
clofibrate and nicotinic acid or clofibrate with placebo
- 13% reduction in TC and 36 % reduction in mortality from CHD
1990- Program on the Surgical control of Hyperlipidemias assigned post
MI patients to receive partial ileal bypass surgery plus diet of diet
alone
- 23% reduction in total cholesterol
- 27% fewer CVS death and 35% fewer cardiac events
1994- Scandinavian Simvastatin Survival Study ( 4S )
- recruits 4444 patients with angina or previous MI
- assigned to treatment with simvastatin or placebo
Metaanalysis by Yusuf and colleahues evaluated effect of cholesterol reduction on major cardiacoutcomes in 22 primary and secondary prevention trials.
these investigators calculated that 10% reduction in serum cholesterol resulted in a 20% reduction in mortality from cardiac disease and 17% reduction in MI.
ANGIOGRAPHIC STUDIES OF CHOLESTEROL REDUCTION
1984- National Heart, Lung and Blood Institute Type II Coronary Intervention Study
- 116 men with inc LDL chol assigned to treatment with diet plus
cholestyramine or dietary modification plus placebo
- Coronary Angiogram performed before and five years after
treatment
- 17% reduction in TC in treatment gp. and 1% in placebo gp.
- but actual proportion of lesions that progressed was similar in both
groups
Many subsequent studies only showed minimal regression of stenosis after a period of treatment with lipid lowering drugs and this minimal regression is unlikely to be able to explain the significant reduction in cardiac events in both primary and secondary prevention trials.
Hypercholesterolemia, Plaque Rupture and Lesion Activation
Falk, Fuster et al, have developed the concept of lesion 'activation' in quiescent atherosclerotic plaque which becomes susceptible to undergo rupture and thrombosis precipitating MI and unstable angina. Cholesterol reduction may decrease incidence of lesion activation..
1980- DeWood and colleagues studies 79 patients with AMI undergoing
catheterization and coronary bypass surgery.
- 59 pts. had angiograhic evidence of coronary thrombosis
- other studies suggested that lipid-laden plaques are most likely to
rupture when exposed to inc. shear rate
- progressive accumulation of lipids may destabilize plaques and
make it more prone to rupture
- in animal studies Administration of HDL chol results in a
significant decrease in the formation of atherosclerotic, lipid-laden
lesions and a reduction in the size of preexisting lesions.
Hypercholesterolemia, Atherosclerosis and Endothelial Dysfunction
Acetylcholine caused dilatation of angiographically normal coronary arteries and paradoxical constriction of arteries with early or advance atherosclerotic lesions.
Studies showed that an impairement of endothelium-dependent dilatation contributes
to the pathogenesis of myocardial ishaemia in pts with stable CHD
Endothelial vasomotor dysfunction also implicated in the pathogenesis of unstable coronary syndromes in which platelet aggregation and thrombin formation have a
more prominent role
Okumura and colleagues- demonstrate that response of infusion of acetylcholine was more impaired in infarct-related arteries than in other arteries with similar stenoses.
Studies of Cholesterol Reduction and Endothelial Function
Egashira and coworkers- examined the effect of treatment with Pravastatin on endothelial vasomotor function in pts with hypercholesterolemia undergoing angiography
- 31% reduction in TC
- 80% reduction in the constrictor response with acetycholine
Treaure and colleagues studies - got similar conclusion by using lavostatin
Anderson and colleagues- recent evidence suggests that inc. oxidative
stress is a mechanism of endothial dysfunction in
hypercholesterolemia
- pts randomly assigned to a lipid lowering diet,
lovastatin and cholestyramine, or lovastatin and
probucol (antioxidant)
- greater improvement in endothelial vasomotor
dysfunction in the last gp,. raised the possibility
of addition of an antioxidant increases the
beneficial effect of lipid lowering drugs.