Atherosclerosis is a major cause of disability and the ravages of atherosclerosis can markedly impair quality of life. Depression, which is associated with stroke, can lead to problems with compliance and worse outcomes in persons with heart disease.

Atherosclerosis: The History

Atherosclerosis comes from athero = gruel and sclerosis = hardening. The term was introduced by Marchand in 1904.

Aristotle was the first to recognize calcifications in the heart.

The picture below is of Wupfer's atherosclerotic aorta, as drawn by his son-in-law, Johann Brunner.

Premature Aging Syndrome

Atherosclerosis is commonly associated with premature aging syndromes.

The Burden of Atherosclerosis

Atherosclerosis accounts for 44% of mortality in the USA and costs $259 billion annually. As shown in the two figures below, both coronary heart disease prevalence and death by myocardial infarction increase with age. The Framingham study has stated that death due to myocardial infarction may be over reported by about 10%.

Multiple studies have suggested that altherosclerosis is a universal phenomenon with fatty streaks being present as early as 10 years of age and clinical manifestations becoming apparent in the fourth and fifth decade.

Preclinical signs of atherosclerosis are found with increasing prevalence with age.

Atherosclerosis in one organ is associated with atherosclerosis in other organs as we demonstrated in our study of the two-year outcomes in persons presenting with vascular impotence.

40% of persons over 80 years had none of the three major coronary arteries narrowed more than 75% by plaque at post-mortem. These persons tended to die from pulmonary embolism, falls, cancer, and infection. Identification of those who seem to be protected from atherosclerotic disease represents an important research area in the future.

Pathogenesis of Early Atherosclerosis

Injury to the endothelial wall leads to the release of a variety of chemotactic and adhesion molecules resulting in monocytes being attracted to the endothelial surface. The monocytes pass through the endothelium and as macrophages, take up oxidized LDL through two receptors, SRA-A and CD-36. The SRB-1 receptor, when bound to HDL, pumps LDL out of the macrophage. Activation of the macrophage results in the production of growth factors that produce smooth muscle proliferation. Eventually, the macrophage becomes a lipid-laden foam cell. This is shown diagrammatically in the figure below.

Cholesterol in the Elderly

The 4S Study clearly demonstrated an advantage of lowering cholesterol for secondary prevention following myocardial infarction in persons up to 75 years of age.

In a meta-analysis, statins also reduced strokes.

Statins produce these effects not only by lowering cholesterol, but also by improving endothelial function, reducing inflammation, and stabilizing atherosclerotic plaques.

The structures of the statins are given below. Alongside each is the maximum approved dose and the reduction in LDL-cholesterol achieved by this dose.

Despite the results of the WOSCOPS study, the cost-effectiveness of primary prevention in the old and in the old-old remains controversial. Two studies in the old-old have suggested that low cholesterol is associated with increased mortality, perhaps due to an association with malnutrition and cytokine-related disease.

Other studies have also suggested a J-shaped mortality curve in older subjects.

Regardless of when to treat cholesterol in older persons, when the decision is made, treatment should be with drugs. There is little evidence of effectiveness of therapeutic diets as shown by the normal plasma cholesterol in an 88- year- old man who ate 25 eggs a day(1) and a number of studies have demonstrated that therapeutic diets can lead to malnutrition in older persons.(2)

Obesity

There is an epidemic of obesity among middle aged Americans. This is due predominantly to a decrease in exercise. Obesity, but particularly visceral obesity, is related to an increase in atherosclerotic events. In older persons, the primary cure for obesity must be exercise (vide infra).

Cigarette Smoking

Exercise

There is increasing evidence that both endurance and resistance exercise protect against coronary artery disease.

In older persons, the exercise prescription should include all five modalities of exercise.

Hypertension

Hypertension is a major risk factor for atherosclerotic-associated disease.

Diabetes

Diabetes is the diabetic sword of Damocles. Aggressive treatment of atherosclerosis shows dramatic improvements in diabetic outcomes.

Homocysteine

Homocysteine levels increase with aging and are associated with folate and vitamin B₁₂ levels, as well as renal disease, hypothyroidism,, and estrogen lack.

Homocysteine produces endothelial dysfunction.

Elevated homocysteine levels are a risk factor for coronary artery disease.

Estrogen

Estrogen appears to be good for primary, but not secondary, prevention of coronary artery disease.

Estrogen lowers homocysteine.

Phytoestrogens are mildly protective against atherosclerosis.

Testosterone

Testosterone in older males seems to protect against atherosclerosis.

Infection and Atherosclerosis

Numerous infections have been associated with an increase in atherosclerotic heart disease. C-reactive protein has become a marker for increased risk of coronary artery disease. Infection appears to accelerate the risk of atherosclerosis by releasing cytokines.

Chlamydia pneumonia has been strongly associated with atherosclerosis in seroepidemiological studies. Bacterial antigen is found in plaques. Rabbits infected with chlamydia have accelerated atherosclerosis. Azithromycin has been shown to decrease clinical cardiac events.(3) The role of antibiotic treatment of atherosclerosis must await the outcomes of the WIZARD trial.

The Unstable Plaque

Plaque disruption is 1.3 to 3.0 times more common as a cause of a coronary event than is high grade stenosis. There are multiple factors involved in the pathogenesis of the unstable plaque.

Plaque disruption can be prevented by:

Thrombus Formation

A variety of factors result in the formation of a thrombus:

Thrombus prevention agents include:

The Future