Angina Pectoris

Angina pectoris is the result of myocardial ischemia caused by an imbalance between myocardial blood supply and oxygen demand. Angina is a common presenting symptom (typically, chest pain) among patients with coronary artery disease. A comprehensive approach to diagnosis and to medical management of angina pectoris is an integral part of the daily responsibilities of healthcare professionals.

Causes of angina pectoris include the following:

• Decrease in myocardial blood supply due to increased coronary resistance in large and small coronary arteries

• Increased extravascular forces, such as severe LV hypertrophy caused by hypertension, aortic stenosis, or hypertrophic cardiomyopathy, or increased LV diastolic pressures

• Reduction in the oxygen-carrying capacity of blood, such as elevated carboxyhemoglobin or severe anemia (hemoglobin, < 8 g/dL)

• Congenital anomalies of the origin and/or course of the major epicardial coronary arteries

• Risk factors

• Precipitating factors

• Preventive factors

Decrease in myocardial blood supply due to increased coronary resistance in large and small coronary arteries

Causes of such decreases in myocardial blood supply include the following:

• Significant coronary atherosclerotic lesion in the large epicardial coronary arteries (ie, conductive vessels) with at least a 50% reduction in arterial diameter

• Coronary spasm (ie, Prinzmetal angina)

• Abnormal constriction or deficient endothelial-dependent relaxation of resistant vessels associated with diffuse vascular disease (ie, microvascular angina) ^[1]

• Syndrome X

• Systemic inflammatory or collagen vascular disease, such as scleroderma, systemic lupus erythematous, Kawasaki disease, polyarteritis nodosa, and Takayasu arteritis

Congenital anomalies of the origin and/or course of the major epicardial coronary arteries

These include structural abnormalities of the coronary arteries (congenital coronary artery aneurysm or fistula, coronary artery ectasia, coronary artery fibrosis after chest radiation, coronary intimal fibrosis following cardiac transplantation).

Risk factors

Major risk factors for atherosclerosis include a family history of premature coronary artery disease, cigarette smoking, diabetes mellitus, hypercholesterolemia, or systemic hypertension.

Other risk factors include LV hypertrophy, obesity, and elevated serum levels of homocysteine, lipoprotein (a), plasminogen activator inhibitor, fibrinogen, serum triglycerides, or low high-density lipoprotein (HDL).

Metabolic syndrome has been characterized by the presence of hyperinsulinemia (fasting glucose level, ≥100 mg/dL), abdominal obesity (waist circumference, >40 in for men or >35 in for women), decreased HDL cholesterol levels (< 40 mg/dL for men or < 50 mg/dL for women), hypertriglyceridemia (>150 mg/dL), and hypertension (≥130/85 mm Hg). Based on data from the 2000 US census, an estimated 47 million Americans have the metabolic syndrome. Patients with the metabolic syndrome have a 3-fold increased risk for coronary atherosclerosis and stroke compared with those without this syndrome. ^[2]

Precipitating factors

These include factors such as severe anemia, fever, tachyarrhythmias, catecholamines, emotional stress, and hyperthyroidism, which increase myocardial oxygen demand.

Preventive factors

Factors associated with reduced risk of atherosclerosis are a high serum HDL cholesterol level, physical activity, estrogen, and moderate alcohol intake (1-2 drinks/d).

Myocardial ischemia develops when coronary blood flow becomes inadequate to meet myocardial oxygen demand. This causes myocardial cells to switch from aerobic to anaerobic metabolism, with a progressive impairment of metabolic, mechanical, and electrical functions. Angina pectoris is the most common clinical manifestation of myocardial ischemia. It is caused by chemical and mechanical stimulation of sensory afferent nerve endings in the coronary vessels and myocardium. These nerve fibers extend from the first to fourth thoracic spinal nerves, ascending via the spinal cord to the thalamus, and from there to the cerebral cortex.

Studies have shown that adenosine may be the main chemical mediator of anginal pain. During ischemia, ATP is degraded to adenosine, which, after diffusion to the extracellular space, causes arteriolar dilation and anginal pain. Adenosine induces angina mainly by stimulating the A1 receptors in cardiac afferent nerve endings. ^[3]

Heart rate, myocardial inotropic state, and myocardial wall tension are the major determinants of myocardial metabolic activity and myocardial oxygen demand. Increases in the heart rate and myocardial contractile state result in increased myocardial oxygen demand. Increases in both afterload (ie, aortic pressure) and preload (ie, ventricular end-diastolic volume) result in a proportional elevation of myocardial wall tension and, therefore, increased myocardial oxygen demand. Oxygen supply to any organ system is determined by blood flow and oxygen extraction. Because the resting coronary venous oxygen saturation is already at a relatively low level (approximately 30%), the myocardium has a limited ability to increase its oxygen extraction during episodes of increased demand. Thus, an increase in myocardial oxygen demand (eg, during exercise) must be met by a proportional increase in coronary blood flow.

The ability of the coronary arteries to increase blood flow in response to increased cardiac metabolic demand is referred to as coronary flow reserve (CFR). In healthy people, the maximal coronary blood flow after full dilation of the coronary arteries is roughly 4-6 times the resting coronary blood flow. CFR depends on at least 3 factors: large and small coronary artery resistance, extravascular (ie, myocardial and interstitial) resistance, and blood composition.

Myocardial ischemia can result from (1) a reduction of coronary blood flow caused by fixed and/or dynamic epicardial coronary artery (ie, conductive vessel) stenosis, (2) abnormal constriction or deficient relaxation of coronary microcirculation (ie, resistance vessels), or (3) reduced oxygen-carrying capacity of the blood.

Atherosclerosis is the most common cause of epicardial coronary artery stenosis and, hence, angina pectoris. Patients with a fixed coronary atherosclerotic lesion of at least 50% show myocardial ischemia during increased myocardial metabolic demand as the result of a significant reduction in CFR. These patients are not able to increase their coronary blood flow during stress to match the increased myocardial metabolic demand, thus they experience angina. Fixed atherosclerotic lesions of at least 90% almost completely abolish the flow reserve; patients with these lesions may experience angina at rest.

Coronary spasm can also reduce CFR significantly by causing dynamic stenosis of coronary arteries. Prinzmetal angina is defined as resting angina associated with ST-segment elevation caused by focal coronary artery spasm. Although most patients with Prinzmetal angina have underlying fixed coronary lesions, some have angiographically normal coronary arteries. Several mechanisms have been proposed for Prinzmetal angina: focal deficiency of nitric oxide production, ^[4] hyperinsulinemia, low intracellular magnesium levels, smoking cigarettes, and using cocaine.

Approximately 30% of patients with chest pain referred for cardiac catheterization have normal or minimal atherosclerosis of coronary arteries. A subset of these patients demonstrates reduced CFR that is believed to be caused by functional and structural alterations of small coronary arteries and arterioles (ie, resistance vessels). Under normal conditions, resistance vessels are responsible for as much as 95% of coronary artery resistance, with the remaining 5% being from epicardial coronary arteries (ie, conductive vessels). The former is not visualized during regular coronary catheterization. Angina due to dysfunction of small coronary arteries and arterioles is called microvascular angina. Several diseases, such as diabetes mellitus, hypertension, and systemic collagen vascular diseases (eg, systemic lupus erythematosus, polyarteritis nodosa), are believed to cause microvascular abnormalities with subsequent reduction in CFR.

The syndrome that includes angina pectoris, ischemia-like ST-segment changes and/or myocardial perfusion defects during stress testing, and angiographically normal coronary arteries is referred to as syndrome X. Most patients with this syndrome are postmenopausal women, and they usually have an excellent prognosis. ^[5] Syndrome X is believed to be caused by microvascular angina. Multiple mechanisms may be responsible for this syndrome, including (1) impaired endothelial dysfunction, ^[6] (2) increased release of local vasoconstrictors, (3) fibrosis and medial hypertrophy of the microcirculation, (4) abnormal cardiac adrenergic nerve function, and/or (5) estrogen deficiency. ^[7]

A number of extravascular forces produced by contraction of adjacent myocardium and intraventricular pressures can influence coronary microcirculation resistance and thus reduce CFR. Extravascular compressive forces are highest in the subendocardium and decrease toward the subepicardium. Left ventricular (LV) hypertrophy together with a higher myocardial oxygen demand (eg, during tachycardia) cause greater susceptibility to ischemia in subendocardial layers.

Myocardial ischemia can also be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as is observed with severe anemia (hemoglobin, < 8 g/dL), or elevated levels of carboxyhemoglobin. The latter may be the result of inhalation of carbon monoxide in a closed area or of long-term smoking.

Ambulatory ECG monitoring has shown that silent ischemia is a common phenomenon among patients with established coronary artery disease. In one study, as many as 75% of episodes of ischemia (defined as transient ST depression of 1 mm or above persisting for at least 1 min) occurring in patients with stable angina were clinically silent. Silent ischemia occurs most frequently in early morning hours and may result in transient myocardial contractile dysfunction (ie, stunning). The exact mechanism(s) for silent ischemia is not known. However, autonomic dysfunction (especially in patients with diabetes), a higher pain threshold in some individuals, and the production of excessive quantities of endorphins are among the more popular hypotheses. ^[8]

United States statistics

An estimated 10.8 (3.9%) million US adults aged 20 years and older experience angina annually. ^[9]  The overall prevalence of coronary heart disease is 7.1% (20.5 million; males: 8.7%, females: 2.1%) and that of myocardial infarction (MI) is 3.2% (9.3 million; males: 4.5%; females: 2.1%). ^[9]

About 720,000 Americans will have a new coronary event (first hospitalized MI or coronary heart disease death), and approximately 335,000 will have recurrence. ^[9] The estimate of annual incidence of MI is 605,000 new attacks, with 200,000 recurrences; of these first and recurrent attacks, about 170,000 are silent.

Race-and sex-related demographics

Prevalence of angina pectoris in US males aged 20 and older ^[9] :

• Non-Hispanic White: 4.7%
• Non-Hispanic Black: 2.7%
• Hispanic: 3.6%
• Non-Hispanic Asian/Pacific Islander: 2.7%

Prevalence of angina pectoris in US females aged 20 and older ^[9] :

• Non-Hispanic White: 3.5%
• Non-Hispanic Black: 4.1%
• Hispanic: 4.3%
• Non-Hispanic Asian/Pacific Islander: 2.7%

Although angina pectoris has a slightly higher prevalence among US men (4.3%) than women (3.6%), ^[9] it is more often the presenting symptom of coronary artery disease in women than in men. The frequency of atypical presentations is also more common among women compared with men. Women have a slightly higher mortality from coronary artery disease compared with men, in part because of an older age at presentation and a frequent lack of classic anginal symptoms. The estimated age-adjusted prevalence of angina is greater in women than in men.

Prevalence of coronary heart disease [and MI] in US males aged 20 and older ^[9] :

• Non-Hispanic White: 9.4% [4.8%]
• Non-Hispanic Black: 6.2% [4.0%]
• Hispanic: 6.8% [3.1%]
• Non-Hispanic Asian: 5.2% [2.8%]

Prevalence of coronary heart disease [and MI] in US females aged 20 and older ^[9] :

• Non-Hispanic White: 5.9% [2.2%]
• Non-Hispanic Black: 6.3% [2.3%]
• Hispanic: 6.1% [1.9%]
• Non-Hispanic Asian: 3.9% [0.5%]

Age-related demographics

The prevalence of angina pectoris increases with age, which is a strong independent risk factor for mortality. The prevalence among individuals aged 20-39 years is less than 1% relative to over 9% in those aged 80 years and older. ^[9] However, there appears to be an increasing trend toward individuals younger than 75 (45-74 years old) dying from MI. ^[9]

Important prognostic indicators in patients with angina pectoris include LV function, severity and location of atherosclerotic lesions, and response of symptoms to medical treatment. 

LV function is the strongest predictor of long-term survival. Elevated LV end-diastolic pressure and volume along with reduced LV ejection fraction ( (< 40%) are poor prognostic signs. Note the following:

• Critical lesions of left main and proximal left anterior descending coronary arteries are associated with a greater risk. Mortality rates are also directly associated with the number of epicardial arteries involved.

• Unstable angina, recent MI, or both is a sign of atherosclerotic plaque instability, which is a strong predictor of increased risk of short-term coronary events.

Epicardial adipose tissue thickness (EAT) can also be used to predict major adverse cardiac events. ^[10]  In a study of 200 patients hospitalized with stable angina pectoris, unstable angina pectoris, or acute MI who underwent coronary angiography, patients with a baseline EAT of more than 7 mm suffered significantly more revascularizations, nonfatal MI, and cardiovascular death. ^[10]

A number of signs during noninvasive testing are predictive of a higher risk of coronary events, including ST-segment depression of more than 2 mm at a low workload, ST-segment depression that persists for more than 5 minutes after termination of exercise, and failure of blood pressure to rise or an actual drop in blood pressure.

Patients who continue to smoke after an MI have a 22-47% increased risk of reinfarction and death.

In general, Prinzmetal angina and syndrome X are associated with excellent long-term prognoses.

Complications

Complications of angina pectoris include unstable angina, MI, and death.