Atherosclerosis

A disorder affecting medium and large arteries in which patchy subintimal deposits of lipids and connective tissue (atherosclerotic plaques) reduce or obstruct blood flow.

Atherosclerosis (collectively termed atherosclerotic cardiovascular disease) includes coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Although atherosclerosis contributes significantly to disability and death in all age groups, its toll is heaviest among the elderly.

Epidemiology

The incidence of all forms of atherosclerosis increases with age, even among the elderly. However, during the last 30 years, the mortality rate for atherosclerosis has markedly and progressively decreased in the USA and in several other industrialized countries. The decreasing mortality rate is probably primarily due to the widespread use of preventive strategies, resulting in decreased prevalence of such risk factors as untreated hypertension, abnormal lipid levels, and cigarette smoking. Improvements in diagnosis and treatment of established atherosclerosis probably have contributed less.

Risk Factors

Many major risk factors increase in prevalence and severity with age. Often, several risk factors coexist, especially in the elderly. Nonmodifiable risk factors include age (>= 45 for men; >= 55 for women), premature menopause without estrogen replacement therapy, male sex, and a family history of premature atherosclerosis (in male relatives before age 55 or in female relatives before age 65). Increased carotid intimal-medial thickness and large vessel stiffness also increase risk.

The following risk factors are modifiable:

Hypertension is strongly correlated with risk of atherosclerosis, particularly for the elderly. For men and women of all ages, the overall risk of atherosclerosis is 2 to 3 times higher in persons with moderate to severe hypertension than in those with normal blood pressure; risk is intermediate for those with mild hypertension. Risk at any given level of blood pressure is 2 to 3 times higher in elderly men and women than in younger ones, and the risk is nearly always higher in men than in women, regardless of age. High diastolic blood pressure is an important risk factor for elderly men but is less important for elderly women.

Abnormal blood lipid levels--ie, a high level of total or low-density lipoprotein (LDL) cholesterol and a low level of high-density lipoprotein (HDL) cholesterol--are strongly correlated with risk of CAD in younger men and women; however, whether the correlation is as strong in the elderly is controversial. A high triglyceride level is a marker for obesity, glucose intolerance, and a low HDL level, all of which are risk factors for CAD.

Cigarette smoking increases the risk of CAD, stroke, peripheral vascular disease, and death. The prevalence of cigarette smoking appears to decrease with age, primarily because smokers tend to die before reaching old age.

High blood glucose level, when chronic, is strongly associated with risk of atherosclerosis.

Obesity, even at an advanced age, is a significant risk factor for atherosclerosis. Progressive increases in body weight correlate with several other risk factors for atherosclerosis: increases in blood pressure and in cholesterol, triglyceride, and blood glucose levels and a decrease in HDL cholesterol level.

Infection and inflammation may be involved in the atherosclerotic process. Several microorganisms, such as herpesviruses (eg, cytomegalovirus), Chlamydia pneumoniae, and Helicobacter pylori, have been identified in atherosclerotic plaques in coronary arteries and other tissues. Elevated titers of antibodies to these microorganisms have been used to predict the recurrence of coronary events after an acute myocardial infarction. Despite these findings, there is no direct evidence that these microorganisms can cause atherosclerotic plaques. However, according to one theory, chronic subclinical infection with these and other microorganisms (eg, those related to chronic periodontal disease) may contribute to an extended but highly variable inflammatory process that could promote atherogenesis and its complications. The observation that C-reactive protein and other nonspecific inflammatory markers are strong predictors of initial and recurrent coronary events supports this theory.

Exacerbating Factors

Several lifestyle choices and conditions can precipitate or exacerbate a cardiovascular event (eg, myocardial infarction, stroke) in persons with atherosclerosis.

Cigarette smoking can exacerbate ischemia because the carbon monoxide derived from cigarette smoke reduces the oxygen-carrying capacity of hemoglobin. Nicotine and other substances derived from cigarette smoke affect vascular smooth muscle and platelets, possibly initiating thrombotic events in persons whose circulation has been compromised by atherosclerosis. Smoking may trigger ventricular arrhythmias, causing sudden cardiac death in vulnerable persons, presumably by enhancing sympathetic tone and reducing the threshold for ventricular fibrillation.

Exercise reduces the overall risk of cardiovascular events; however, risk is increased during and immediately after strenuous exercise, especially for persons who do not exercise regularly. The primary mechanism is temporary elevation of catecholamine levels.

Blood abnormalities may contribute to risk. For elderly men but not for elderly women, a high plasma fibrinogen level increases the likelihood of atherosclerosis-related events. A high white blood cell count, a high Hct, and low vital capacity (which are correlated with the number of cigarettes smoked per day) are markers for increased risk of cardiovascular events and CAD in elderly men whether they smoke or not, but only in women who smoke.

Hyperhomocysteinemia appears to be an independent risk factor for premature atherosclerotic disease and to increase the likelihood of myocardial infarction and stroke, especially for persons with abnormal lipid levels. Homocysteine may accelerate atherosclerosis by affecting blood coagulation and by increasing the atherogenic properties of LDL particles and the proliferation of vascular smooth muscle cells. It is considered to be toxic to vascular endothelium and thereby thrombogenic. Factors that may increase homocysteine levels include advancing age, heavy smoking, renal insufficiency, psoriasis, acute lymphoblastic leukemia, breast cancer, and drugs that interact with vitamin B₆, vitamin B₁₂, and folic acid (eg, methotrexate, carbamazepine, phenytoin) or that interfere with the absorption of homocysteine (eg, colestipol, niacin) or with its metabolism (eg, isoniazid). Homocysteine levels are moderately high in many elderly persons whose diets are high in protein and/or deficient in vitamin B₆, vitamin B₁₂, or folic acid. Atropic gastritis, which occurs in about 35% of women > 80, interferes with B₁₂ absorption and thereby can increase homocysteine levels. Many experts advocate the treatment of hyperhomocysteinemia in patients with CAD and homocysteine levels > 90th percentile of the specific assay used. Supplementation with folic acid, pyridoxine (vitamin B₆), and/or cyanocobalamin (vitamin B₁₂) is effective in decreasing homocysteine levels as well as safe and inexpensive; however, supplementation has not been shown to reduce mortality and morbidity rates.

Left ventricular hypertrophy detected by ECG or echocardiography increases the likelihood of atherosclerosis-related events in elderly persons.

Symptoms and Signs

Patients are asymptomatic until obstruction of the affected artery produces symptoms of ischemia (eg, angina, claudication, transient ischemic attack, stroke) or until a complication (eg, thrombus, embolus, aneurysm) occurs. Typically, onset of symptoms is gradual, as the artery gradually narrows, and acute exacerbation of symptoms occurs during periods of increased demand (eg, during exercise). However, onset may be dramatic, as when an artery is acutely occluded. CAD, cerebrovascular disease, and peripheral vascular disease produce specific symptoms and signs.

Diagnosis and Treatment

The diagnosis is typically based on symptoms and signs. Arterial narrowing may be confirmed by arteriography or Doppler ultrasonography.

Modifiable risk factors should be managed, preferably early in life but also in old age. Treatment of established atherosclerosis depends on the specific type of atherosclerotic disease and the presence of complications. Such treatment includes dietary restriction of fats, weight control, exercise, and lipid-lowering drug therapy.