Cardiac energy generation is primarily aerobic, and therefore myocardial oxygen consumption is an accurate measure of total cardiac metabolism. Increases in cardiac oxygen consumption are primarily affected by changes in systolic wall tension, contractility, and heart rate (Ardehali & Ports, 1990; Rooke & Fiegel, 1984; Graham et al, 1968).

Systolic wall tension is determined by both stroke volume and systolic pressure generation. These determinants of wall tension have their clinical correlates in preload and afterload. Increases in either parameter result in a greater overall external workload and an increase in myocardial wall tension (Rooke & Fiegel, 1984). By the Laplace relation, myocardial wall tension is decreased by decreasing ventricular size and increased with ventricular dilatation.

Changes in contractility increase both systolic pressure generation and time to peak pressure generation; without significant changes in ventricular volume, these translate into increased myocardial wall tension and increased myocardial oxygen consumption (Ardehali & Ports, 1990; Rooke & Fiegel, 1984; Graham et al, 1968). Positive inotropic agents also enhance excitation–contraction coupling. Increased oxygen requirements then result from greater and more rapid calcium uptake by the sarcoplasmic reticulum. Finally, acceleration of the heart rate increases myocardial oxygen demand by increasing the frequency of tension development per unit of time and simultaneously by increasing contractility (Ardehali & Ports, 1990; Rooke & Fiegel, 1984). Myocardial ischemia is the result when any of these determinants cause increased myocardial metabolic demands without concomitant regulation of oxygen delivery.

Coronary blood flow is the major determinant of myocardial oxygen delivery. Perfusion of the coronary arteries occurs primarily during diastole because of myocardial compression of the intramyocardial and subendocardial arterioles during systole. Approximately 80% of coronary flow to the left ventricle and 50% of flow to the right ventricle occur during diastole. Coronary perfusion pressure, therefore, is determined by both mean aortic pressure and left ventricular end-diastolic pressure.

Autoregulation of the coronary circulation via neurohumoral mechanisms serves to maintain coronary flow fairly constant over a wide range of perfusion pressures. In the presence of fixed coronary stenoses, however, autoregulation cannot further increase regional blood flow to accommodate increases in myocardial oxygen demand. Coronary vessels with fixed atherosclerotic lesions are maximally dilated to maximize distal flow in the setting of luminal obstruction. With further metabolic demands, autoregulation is not possible and regional myocardial ischemia with resultant myocardial dysfunction occurs. Furthermore, in the setting of atherosclerosis, endothelial dysfunction results in impaired ability to generate vasoactive substances such as endothelial-derived relaxing factor and prostacyclin. This results in further impairment of smooth muscle relaxation as well as a loss of platelet aggregation inhibition.

CAD increases linearly with age. The prevalence of CAD is greater in men than women until age 75, at which point it equalizes. The incidence of CAD in persons younger than 55 years of age is three to four times greater in men than women.

The National Cholesterol Education Program defines family history of premature CAD as MI or sudden death in a father or first-degree male relative less than 55 years of age or in a mother or first-degree female relative less than 65 years of age (Summary of the Second Report of NCEP, 1993). Family history is one of the most powerful determinants of CAD independent of other risk factors (Rissanen, 1979; Friedlander, 1994;
Hamstn & De Faire, 1987). Siblings of patients with CAD have an increased risk of dying (5.2 times higher) compared to a control population (Rissanen, 1979). The presence of this very strong nonmodifiable risk factor should prompt the physician to treat aggressively any concomitant risk factors in such a patient.

A variety of psychosocial factors are associated with the development of CAD in the Western world. Social factors such as lower educational level and economic insecurity are associated with increased cardiac risk (Berkman et al, 1992; Kaplan & Keil, 1993). There is an inverse correlation between educational level and the age-adjusted mortality rate from CAD. Neither risk factor modification nor decreased MI rates have been uniform across all socioeconomic groups. The mechanism of increased risk among certain socioeconomic groups may be indirectly related to poor participation in a strict risk factor modification program. Some authors believe that the higher the level of education and socioeconomic status, the greater potential for lifestyle modification.

There is a well-established relation between total blood cholesterol and CAD, with a graded risk down to a cholesterol level of 180 mg/dL (Stamler et al, 1993a; Neaton & Wentworth, 1992). LDLs appear to be most strongly associated with the development of CAD. It has been estimated that with every 1% difference in LDL cholesterol, there is a 2% to 3% difference in the risk for CAD (Summary of the Second Report of NCEP, 1993). The National Cholesterol Education Program has stratified CAD risk according to LDL cholesterol level (Table 9-2) (Summary of the Second Report of NCEP, 1993).

The LDL cholesterol level increases with age and weight. Diets high in saturated fats and cholesterol similarly cause progressive increases in serum LDL concentrations. Conditions such as hypothyroidism, nephrotic syndrome, liver disease, and estrogen deficiency can also be accompanied by increases in serum LDLs. As referred to earlier, oxidative modification of LDLs plays an important role in the accelerated atherogenic process (Berliner et al, 1995; Morris et al, 1994).

There is a strong inverse epidemiologic association between high-density lipoprotein (HDL) cholesterol, and CAD. The Adult Treatment Panel II classified an HDL cholesterol level of less than 35 mg/dL as low and considered the presence of a high HDL cholesterol level to be a negative risk factor for CAD (Summary of the Second Report of NCEP, 1993). For every 1 mg/dL decrease in HDL cholesterol, the relative risk for CAD increases by 2% to 3% (Gordon et al, 1989). HDL cholesterol levels are affected by genetics, tobacco use, obesity, and physical activity. There are no clinical trials that indicate a decreased risk of coronary disease secondary only to an increase in HDL cholesterol. This is most likely because lifestyle and dietary modifications affect multiple lipids simultaneously.

The relation between triglycerides and CAD remains controversial. A 1992 Consensus Development Conference defined a triglyceride level of 200 to 400 mg/dL as borderline high, 400 to 1000 mg/dL as high, and more than 1000 mg/dL as very high (NIH Consensus Development Panel, 1993). In univariate analysis, triglycerides predict coronary disease but lose their power when other lipids (especially HDL cholesterol) are factored into a multivariate analysis. It has been suggested that HDL and triglycerides should not be considered separately when evaluating cardiac risk. Low HDL levels are usually associated with high triglycerides because of the transfer of a cholesterol ester between HDL particles and triglyceride-rich lipoproteins. Lifestyle modifications including weight loss, dietary restriction, decrease in alcohol consumption, smoking cessation, and increased physical activity all decrease triglyceride levels. The reduction in triglyceride levels is associated with the greatest risk reduction in patients with the highest risk—those with low HDL or elevated LDL cholesterol levels.

Although LDL levels are directly associated with CAD, the combination of elevated LDL cholesterol, elevated triglycerides, and low levels of HDL cholesterol places the patient in the highest lipid risk stratification category (Manninen et al, 1992; Assman & Schulte, 1992).

Both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus are major risk factors for the development of CAD. The National Diabetes Data Group defined diabetes as a fasting blood glucose level of more than 127 mg/dL (American Diabetes Association, 1997). Atherosclerosis accounts for 80% of all deaths related to diabetes, and 25% of all heart attacks in the United States occur in persons with diabetes (Diabetes Control & Complications Trial, 1993; Getz, 1993; Schwartz et al, 1992; Stamler, 1987; Butler et al, 1985). The First National Health and Nutrition Examination Survey (NAHANES I) revealed that age-adjusted death rates for men and women with diabetes were twice those seen in persons without diabetes, with 75% of the excess mortality attributed to CAD (Kleinman et al, 1988). The pathogenesis of atherosclerosis in persons with diabetes is multifactorial because there are multiple metabolic derangements in persons with diabetes, including hyperglycemia, insulin resistance, dyslipidemia, and increased platelet aggregation.

The pathogenic role of hyperglycemia is well supported. Observational studies have shown that better metabolic control lowers vascular risk in patients with insulin-dependent diabetes mellitus, but this has not been clearly shown in non-insulin-dependent diabetes mellitus (Diabetes Control & Complications Trial, 1993; Reichard et al, 1993). The secondary complications of diabetes are additive in the risk of atherosclerosis. The development of nephropathy leads to elevated blood pressure and dyslipidemia, which together compound the patient’s cardiac risk.

Hypertension is a major modifiable risk factor. Elevated shear stress and increased myocardial oxygen demand caused by hypertension have been implicated in atherogenesis and arterial injury. Nearly 50 million adult Americans suffer from hypertension, and the level of risk associated with elevated blood pressure varies substantially with gender, race, and age. Elderly people have a greater risk of cardiovascular events at every level of hypertension.

There is a continuous relation between both systolic and diastolic pressures and cardiovascular disease (Joint National Committee, 1993; Stamler et al, 1993b; MacMahon et al, 1990). A meta-analysis of several large prospective studies demonstrated a linear relation between hypertension and CAD, with a relative risk approaching three times the risk at the highest levels of blood pressure (MacMahon et al, 1990).

The risk of hypertension cannot be taken in isolation. It frequently coexists with other risk factors, including physical inactivity, obesity, alcohol use, hyperlipidemia, diabetes, and smoking. The presence of these CAD risk factors appears to be both causal and additive for hypertension.

Cigarette smoking is an independent risk factor for cardiovascular disease. Several independent studies have demonstrated that smoking increases the cardiovascular mortality rate by 40% to 60% (Reducing the health consequences of smoking, 1989; Rigotti & Pasternak, 1996). Nicotine accelerates the process of atherosclerosis by a variety of mechanisms. Inhalation of cigarette smoke produces a transient and reversible prothrombotic increase in fibrinogen levels, increases platelet aggregation, and decreases the ability of endothelial cells to produce or release prostacyclin. Nicotine is also a potent agonist for the adrenergic nervous system, resulting in increased coronary tone and vasoconstriction. The enhanced vasoconstriction results in an imbalance between oxygen supply and demand and has been associated with silent myocardial ischemia (Deanfiels et al, 1986).

Tobacco smoke may augment cardiovascular death from other risk factors. Cigarette smoking adversely affects lipid profiles. Heavy smokers have lower levels of HDL cholesterol and higher levels of LDL cholesterol and triglycerides (Migas, 1988). Smoking has a variable effect on blood pressure. The acute inhalation results in a rise in blood pressure. Epidemiologic studies have shown that chronic smokers tend to have lower blood pressures than nonsmokers, possibly secondary to lower body weight (Green et al, 1986). The Hypertension Detection and Follow-up Program demonstrated that smokers had twice the mortality rate of nonsmokers (Langford et al, 1986). The incidence of MI is definitely diminished after smoking cessation. The risk reduction occurs early and may be demonstrated 12 months after cessation.

CAD presents later in women than in men. Endogenous estrogen protects premenopausal women from coronary disease. Estrogen replacement therapy (ERT) confers a 50% reduction in the risk of developing CAD (Barrett-Conner & Bush, 1991). Estrogen favorably affects both HDL and LDL cholesterol. However, the beneficial effects of estrogen appear to be the result of more than just its improvement in the overall lipid profile. The nonlipid cardioprotective mechanisms of estrogen include direct actions on vessel walls, estrogen-associated calcium antagonist effects, estrogen-associated antioxidant effects, and estrogen-induced genetic changes. The initial clinical presentation of CAD is reduced by 30% to 70% in users of ERT (Barrett-Conner & Bush, 1994; Bush & Korenman, 1990). The Lipids Research Clinic Follow-Up Study demonstrated that after 9 years, estrogen users had a 64% lower risk of coronary death than nonusers (Bush et al, 1987). This was still significant after adjustments for known CAD risk factors, and 50% of the protection was afforded by estrogen-induced increases in HDL levels.

All studies on ERT have been observational in design, raising many questions regarding unrecognized biases that can account for the observed protective effect of estrogen. Some such biases include whether healthier women may be more likely to be prescribed estrogen or whether estrogen users may be more likely to participate in all prevention therapies. Proof of the protective benefit of estrogen awaits the results of prospective randomized clinical trials to answer these questions. One such study is the Women’s Health Initiative, which is a long-range study enrolling more than 165,000 women. Preliminary results from this study are expected over the next several years.

The role of physical activity in the prevention of CAD remains controversial. The exact mechanism of protection is multifactorial. Exercise is important in maintaining ideal body weight, muscle mass, and normal blood pressure as well as optimizing lipid levels. Regular aerobic exercise decreases both systolic and diastolic pressures, improves the myocardial oxygen supply/demand ratio, lowers triglycerides, raises HDL levels, and decreases platelet aggregation.

The greatest risk reduction is achieved in nonactive and moderately active persons. Intense exercise is associated with decreases in total and LDL cholesterol and increases in HDL cholesterol (Seiler et al, 1988). Patients who exercise regularly have a decreased incidence of sudden death, although sedentary patients who begin an exercise regimen may be at increased risk for acute MI or malignant ventricular arrhythmia. Therefore, a thorough physical examination is recommended for people older than 40 years before initiating a vigorous exercise program. Likewise, younger patients with hypertension, diabetes, and other associated CAD risk factors should undergo a thorough assessment before undertaking an aggressive exercise regimen, including a baseline electrocardiogram (ECG). A history of angina or an abnormal ECG result should prompt further diagnostic testing before initiating an intensive exercise program.

The definition of obesity is arbitrary, but it may be defined as an increase of 120% above ideal body weight for height. There is a linear relation between body mass and cardiovascular mortality (Manson et al, 1995). The precise role of obesity as an independent risk factor remains unclear. The increased risk of obesity with CAD is chiefly related to its close association with other risk factors. Obesity has a direct relation with all CAD risk factors except smoking. Obesity is positively correlated with hypertension, hypertriglyceridemia, and hyperinsulinemia and negatively correlated with HDL.

Central obesity is quantified as the waist/hip ratio and has been shown to increase CAD risk. An elevated waist/hip ratio has been associated with hypertension, hypercholesterolemia, elevated levels of fibrinogen, and hypertriglyceridemia. In men, the development of CAD is correlated with the abdominal distribution of fat independent of obesity. In women, abdominal fat deposition constitutes a greater risk than obesity. The waist/hip ratio appears to be a more significant predictor than the total degree of obesity. A waist/hip ratio of less than 0.9 for men and less than 0.8 for women is desirable (Freedman et al, 1990).

The effect of alcohol on coronary disease is dichotomous. Moderate consumption (one to three drinks per day) results in a 40% to 50% reduction of CAD compared to abstinence (Gaziano et al, 1993; Yano et al, 1977). However, excessive consumption results in an overall increased risk (Shaper et al, 1988). Alcohol increases the HDL cholesterol level, which accounts for half of the reduction in MI. However, no beneficial effect of alcohol has been demonstrated in angina pectoris (Yano et al, 1977). Its adverse effects include the development of alcoholic cardiomyopathy, hypertension, and cardiac arrhythmias.

The most notorious psychosocial factor associated with CAD is the “Type A personality.” Type A people are characterized as highly competitive, ambitious, and in constant struggle with their environment. There is an increased incidence in the development of angina pectoris but no subsequent increase in fatal cardiac events (Eaker et al, 1989; O’Connor et al, 1995). The increased rate of stable angina could not be explained by the presence of other cardiac risk factors. However, there are no data available that have clearly proven that this behavior itself, nor any modifications, changes the overall cardiac risk.

A newer, independent risk factor for atherosclerosis is an elevated plasma level of the amino acid homocysteine. A plasma homocysteine concentration of more than 15 μmol/L is referred to as hyperhomocysteinemia. Such elevated homocysteine levels can induce pathologic changes in the arterial wall, with a subsequent increased risk for CAD, peripheral vascular disease, cerebrovascular disease, and venous thrombosis. There is increasing evidence that homocysteine may affect the coagulation cascade and the resistance of the endothelium to thrombosis (Nygard et al, 1997). It may also interfere with the vasodilator and antithrombotic effects of nitric oxide. Although several epidemiologic studies have established the relation between total homocysteine level and CAD, studies are still ongoing to determine whether lowering homocysteine levels can prevent vascular occlusive events.

Fifty percent of patients with chronic stable angina have normal ECG tracings at rest, but they may have severe CAD. However, the 12-lead ECG during a provoked episode of substernal chest pain or during an attack of angina may reveal downward or horizontal sloping depression of the ST segment, T-wave peaking, or inversion. These ECG changes accompanied by chest discomfort may signal the possibility of coronary stenosis.

Exercise treadmill ECG has been the most studied noninvasive test for the evaluation of CAD in both men and women. Stress testing increases overall cardiac work and heart rate. This increased work results in an increase in myocardial oxygen demand and a subsequent requirement for increased oxygen delivery via an increase in coronary flow. If narrowed or obstructed lesions prevent the required increase in coronary blood flow, chest pain or ECG changes may arise. In both sexes the exercise ECG is most accurate in patients who are able to exercise to 85% of their maximal predicted heart rates (Severi & Michelassi, 1991). However, this goal can be modified based on the characteristics of the patient being evaluated. A young patient with a low risk for CAD will have a much more sensitive result should he or she reach the maximal heart rate target or exercise to exhaustion. An older, high-risk patient, on the other hand, may reveal clinically meaningful information at lower cardiac workloads.

Criteria for determining a positive ECG stress test vary among different institutions. Depression or downsloping of the ST segment 0.08 seconds after the J point of the ECG is the typical ischemic change sought as a positive result (Fig. 9-4). However, the degree of ST-segment depression defined as positive can range anywhere from 0.5 mV to 2 mV. Using the lower end of this range will produce a test that is more sensitive but less specific, whereas the higher end produces a result that is less sensitive but more specific. Most centers use a 1-mm ST depression as a criterion for positivity. If typical chest discomfort occurs during the test associated with an ST depression of more than 1 mm, the predictive value for the detection of CAD is 90% (Wilson et al, 1991). ST depressions of more than 2
mm in the setting of typical chest discomfort are virtually diagnostic of CAD.