Fibrous Plaque.

The fibrous plaque stage is the beginning of progressive changes in the endothelium of the arterial wall. These changes can appear in the coronary arteries by age 30 and increase with age.

Normally the endothelium repairs itself immediately. This does not happen in the individual with CAD. LDLs and growth factors from platelets stimulate smooth muscle proliferation and thickening of the arterial wall. Once endothelial injury has taken place, lipoproteins (carrier proteins within the bloodstream) transport cholesterol and other lipids into the arterial intima. Collagen covers the fatty streak and forms a fibrous plaque with a grayish or whitish appearance. These plaques can form on one portion of the artery or in a circular fashion involving the entire lumen. The borders can be smooth or irregular with rough, jagged edges. The result is a narrowing of the vessel lumen and a reduction in blood flow to the distal tissues (Fig. 34-1, C).

Complicated Lesion.

The final stage in the development of the atherosclerotic lesion is the most dangerous. As the fibrous plaque grows, continued inflammation can result in plaque instability, ulceration, and rupture. Once the integrity of the artery’s inner wall is compromised, platelets accumulate in large numbers, leading to a thrombus. The thrombus may adhere to the wall of the artery, leading to further narrowing or total occlusion of the artery. Activation of the exposed platelets causes expression of glycoprotein Ilb/IIIa receptors that bind fibrinogen. This, in turn, leads to further platelet aggregation and adhesion, further enlarging the thrombus. At this stage the plaque is referred to as a complicated lesion (Fig. 34-1, D).

Age, Gender, and Ethnicity.

The incidence of CAD and MI is highest among white, middle-aged men. After age 65, the incidence in men and women equalizes, although cardiovascular disease causes more deaths in women than men. Additionally, CAD is present in African American women at rates higher than those of their white counterparts.¹ (See Cultural & Ethnic Health Disparities box for additional differences in CAD among ethnic groups.)

Heart disease kills almost 10 times more women than breast cancer and is the leading cause of death in women. Yet most women do not consider CAD their greatest health risk.⁴ (Cardiovascular disease mortality trends for both men and women are shown in eFig. 34-2, available on the website for this chapter.) On average, women with CAD are older than men who have CAD, and women are more likely to have co-morbidities (e.g., hypertension, diabetes). Most women have atypical symptoms of angina rather than MI when they experience their first cardiac event⁴ (see Gender Differences box).

Elevated Serum Lipids.

An elevated serum lipid level is one of the four most firmly established risk factors for CAD.⁶ The risk of CAD is associated with a serum cholesterol level greater than 200 mg/dL (5.2 mmol/L) or a fasting triglyceride level greater than 150 mg/dL (3.7 mmol/L). (See Table 32-6 for normal serum lipid values.)

For lipids to be used and transported by the body, they must become soluble in blood by combining with proteins. Lipids combine with proteins to form lipoproteins. Lipoproteins are vehicles for fat mobilization and transport, and vary in composition. They are classified as high-density lipoproteins (HDLs), LDLs, and very-low-density lipoproteins (VLDLs).

HDLs contain more protein by weight and fewer lipids than any other lipoprotein. HDLs carry lipids away from arteries and to the liver for metabolism. This process of HDL transport prevents lipid accumulation within the arterial walls. Therefore high serum HDL levels are desirable and lower the risk of CAD.

There are two types of HDLs: HDL₂ and HDL₃. They differ by their density and apolipoprotein composition. Apolipoproteins are found on lipoproteins and activate enzyme or receptor sites that promote the removal of fat from plasma. Several types of apolipoproteins exist (e.g., apo A-I, apo B-100, apo C-I). Women produce more apo A-I than men, and premenopausal women have HDL₂ levels approximately three times greater than men. This is thought to be related to the protective effects of natural estrogen. After menopause, women’s HDL₂ levels decrease and quickly near those of men.

In general, HDL levels are higher in women, decrease with age, and are low in persons with CAD. Physical activity, moderate alcohol consumption, and estrogen administration increase HDL levels.

LDLs contain more cholesterol than any of the lipoproteins and have an attraction for arterial walls. VLDLs contain both cholesterol and triglycerides, and may deposit cholesterol directly on the walls of arteries. Elevated LDL levels correlate closely with an increased incidence of atherosclerosis and CAD. Therefore low serum LDL levels are desirable.6,7

Certain diseases (e.g., type 2 diabetes, chronic kidney disease), drugs (e.g., corticosteroids, hormone therapy), and genetic disorders have been associated with elevated triglyceride levels. Lifestyle factors that can contribute to elevated triglycerides include high alcohol consumption, high intake of refined carbohydrates and simple sugars, and physical inactivity. When a high triglyceride level is combined with a high LDL level, a smaller, denser LDL particle is formed, which favors deposition on arterial walls. People with insulin resistance often have this pattern.

Guidelines for treating elevated LDL cholesterol are based on a person’s 10-year risk for having a nonfatal MI or dying from a coronary event and his or her LDL levels. The following information generates a risk score: (1) age, (2) gender, (3) use of tobacco, (4) systolic BP, (5) use of BP medications, (6) total cholesterol, and (7) HDL cholesterol level.⁷ A 10-year risk calculator is available at http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof.

In general, individuals with no or only one risk factor are considered at low risk for the development of CAD, and the LDL goal is less than 160 mg/dL (4.14 mmol/L). Those at very high risk have CAD and multiple risk factors. The LDL goal for this group is less than 70 mg/dL (1.8 mmol/L).⁷

Hypertension.

The second major risk factor in CAD is hypertension, which is defined as a BP greater than 140/90 mm Hg or greater than 130/80 mm Hg if the patient has diabetes or chronic kidney disease.⁸ Hypertension increases the risk of death from CAD 10-fold in all people. In postmenopausal women, hypertension is associated with a higher incidence of CAD than in men and premenopausal women.

Blood pressure is classified as (1) normal (BP less than 120/80 mm Hg), (2) prehypertension (BP of 120 to 139/80 to 89 mm Hg), (3) stage 1 hypertension (140 to 159/90 to 99 mm Hg), and (4) stage 2 hypertension (BP greater than 160/100 mm Hg).⁸ The cause of hypertension in 90% of those affected is unknown, but it is usually controllable with diet and/or drugs. Therapeutic lifestyle changes should begin in people with prehypertension. Those with stage 1 or 2 hypertension often require more than one drug to reach therapeutic goals⁸ (see Table 33-7). Teach all people with elevated systolic or diastolic BP the importance of achieving and maintaining target BP goals.

The stress of an elevated BP increases the rate of atherosclerotic development. This relates to the shearing stress that causes endothelial injury. Atherosclerosis, in turn, causes narrowed, thickened arterial walls and decreases the distensibility and elasticity of vessels. More force is required to pump blood through diseased arteries, and this increased force is reflected in a higher BP. This increased workload results in left ventricular hypertrophy and decreased stroke volume with each contraction. Salt intake positively correlates with elevated BP, adding volume and increasing systemic vascular resistance (SVR) to the cardiac workload. (See Chapter 33 for a complete discussion of hypertension.)

Tobacco Use.

A third major risk factor in CAD is tobacco use. The risk of developing CAD is two to six times higher in those who smoke tobacco or use smokeless tobacco than in those who do not. Further, tobacco smoking decreases estrogen levels, placing premenopausal women at greater risk for CAD. Risk is proportional to the number of cigarettes smoked. Changing to lower nicotine or filtered cigarettes does not affect risk.

Nicotine in tobacco smoke causes catecholamine (i.e., epinephrine, norepinephrine) release. These neurohormones cause an increased heart rate (HR), peripheral vasoconstriction, and increased BP. These changes increase the cardiac workload. Tobacco smoke is also related to an increase in LDL level, a decrease in HDL level, and release of toxic oxygen radicals. All of these add to vessel inflammation and thrombosis.²

Carbon monoxide, a byproduct of combustion found in tobacco smoke, affects the oxygen-carrying capacity of hemoglobin by reducing the sites available for oxygen transport. Thus the effects of an increased cardiac workload, combined with the oxygen-depleting effect of carbon monoxide, significantly decrease the oxygen available to the myocardium. There is also some indication that carbon monoxide is a chemical irritant and causes injury to the endothelium.

The benefits of smoking cessation are dramatic and almost immediate. CAD mortality rates drop to those of nonsmokers within 12 months. However, nicotine is highly addictive, and often intensive intervention is required to assist people to quit. Individual and group counseling sessions, nicotine replacement therapy, smoking cessation medications (e.g., bupropion [Zyban], varenicline [Chantix]), and hypnosis are examples of smoking cessation strategies. (See Chapter 11, Tables 11-4 through 11-6 for information on smoking cessation.)

Chronic exposure to environmental tobacco (secondhand) smoke also increases the risk of CAD.⁶ People who live in the same household as the patient should be encouraged to stop smoking. This reinforces the individual’s effort and decreases the risk of ongoing exposure to environmental smoke. Pipe and cigar smokers, who often do not inhale, have an increased risk of CAD similar to those exposed to environmental tobacco smoke.

Physical Inactivity.

Physical inactivity is the fourth major modifiable risk factor. Physical inactivity implies a lack of adequate physical exercise on a regular basis. An example of health-promoting regular physical activity is brisk walking (3 to 4 miles per hour) for at least 30 minutes five or more times a week.⁹

The mechanism by which physical inactivity predisposes a person to CAD is mostly still unknown. Physically active people have increased HDL levels. Exercise improves thrombolytic activity, thus reducing the risk of clot formation. Exercise may also encourage the development of collateral circulation in the heart.

Exercise training for those who are physically inactive decreases the risk of CAD through more efficient lipid metabolism, increased HDL production, and more efficient oxygen extraction by the working muscles, thereby decreasing the cardiac workload. For those individuals with CAD, regular physical activity reduces symptoms, improves functional capacity, and improves other risk factors such as insulin resistance and glucose intolerance.

Obesity.

The mortality rate from CAD is statistically higher in obese persons. Obesity is defined as a body mass index (BMI) of greater than 30 kg/m² and a waist circumference more than 40 inches for men and more than 35 inches for women. BMI is a measure of body fat based on height and weight. It can be calculated online (http://nhlbisupport.com/bmi/bmicalc.htm).

The increased risk for CAD is proportional to the degree of obesity. Obese persons may produce increased levels of LDLs and triglycerides, which are strongly related to atherosclerosis. Obesity is often associated with hypertension. There is also evidence that people who tend to store fat in the abdomen (an “apple” figure) rather than in the hips and buttocks (a “pear” figure) have a higher incidence of CAD (see Table 41-2). As obesity increases, the heart grows and uses more oxygen. In addition, there is an increase in insulin resistance in obese individuals.²

Diabetes Mellitus.

The incidence of CAD is two to four times greater among persons who have diabetes, even those with well-controlled blood glucose levels, than the general population. The patient with diabetes manifests CAD not only more frequently but also at an earlier age.² There is no age difference between male or female patients with diabetes in the onset of symptoms of CAD. Diabetes virtually eliminates the lower incidence of CAD in premenopausal women.

Undiagnosed diabetes is frequently discovered at the time a person has an MI. The person with diabetes has an increased tendency toward endothelial dysfunction. This may account for the development of fatty streaks in these patients. Diabetic patients also have alterations in lipid metabolism and tend to have high cholesterol and triglyceride levels. Management of diabetes should include lifestyle changes and drug therapy to achieve a glycosylated hemoglobin (A1C or Hb A1C) level of less than 7%.⁶

Metabolic Syndrome.

Metabolic syndrome refers to a cluster of risk factors for CAD whose underlying pathophysiology may be related to insulin resistance. These risk factors include obesity as defined by increased waist circumference, hypertension, abnormal serum lipids, and an elevated fasting blood glucose² (see Table 41-10). These interrelated risk factors of metabolic origin appear to promote the development of CAD. (Chapter 41 discusses metabolic syndrome.)

Psychologic States.

The Framingham study provided early evidence that certain behaviors and lifestyles contribute to the development of CAD. Several behavior patterns correlated with CAD. However, the study of these behaviors remains controversial and complex. One type of behavior, referred to as type A, includes perfectionism and a hardworking, driven personality. The type A person often suppresses anger and hostility, has a sense of time urgency, is impatient, and creates stress and tension. This person may be more prone to MIs than a type B person, who is more easygoing, takes upsets in stride, knows personal limitations, takes time to relax, and is not an overachiever. However, findings from studies regarding these relationships are inconsistent.

Studies now are focusing on specific psychologic risk factors thought to increase risk of CAD. These include depression, acute and chronic stress (e.g., poverty, serving as a caregiver), anxiety, hostility and anger, and lack of social support.10,11 In particular, depression is a risk factor for both the development and worsening of CAD. Depressed patients have elevated levels of circulating catecholamines that may contribute to endothelial injury and inflammation and platelet activation. Higher levels of depression are also associated with an increased number of adverse cardiac events.¹⁰ More research on the treatment of depression and other negative psychologic states (e.g., anger) in patients with or at risk for CAD is needed to improve these patients’ emotional and physical health.

Stressful states correlate with the development of CAD.¹² Sympathetic nervous system (SNS) stimulation and its effect on the heart are the physiologic mechanism by which stress predisposes one to the development of CAD. SNS stimulation causes an increased release of catecholamines (i.e., epinephrine, norepinephrine). This stimulation increases HR and intensifies the force of myocardial contraction, resulting in increased myocardial oxygen demand. Also, stress-induced mechanisms can cause elevated lipid and glucose levels and changes in blood coagulation, which can lead to increased atherogenesis.