ANGINA PECTORIS

EPIDEMIOLOGY

The 2010 Heart Disease and Stroke Statistics update of the American Heart Association reported that 17.6 million persons in the United States have coronary heart disease (CHD), including 8.5 million with MI and 10.2 million with angina pectoris.⁽¹⁾. Approximately 9.8 million Americans are estimated to experience angina annually, with 500,000 new cases of angina occurring every year. An additional 195,000 silent first myocardial infarctions are estimated to occur each year.⁽²⁾

In Pakistan, mortality from coronary heart disease is 410/100000.⁽³⁾ Low and middleincome countries including the South Asian countries of India and Pakistan contribute significantly to the global burden of cardiovascular diseases accounting for 75% of all deaths and 86.3% of all loss of disability adjusted life years attributable to this cause.⁽⁴⁾

PATHOPHYSIOLOGY:

Myocardial ischemia, and consequently angina, occurs whenever myocardial oxygen demand exceeds oxygen supply.

MYOCARDIAL OXYGEN DEMAND: There are four major factors that determine myocardial work and therefore myocardial oxygen demand:

• Heart rate
• Systolic blood pressure (the clinical marker of afterload)
• Myocardial wall tension or stress (the product of ventricular end-diastolic volume or preload and myocardial muscle mass)
• Myocardial contractility

MYOCARDIAL OXYGEN SUPPLY: The major determinants of oxygen supply are the oxygen carrying capacity of the blood, which is affected by a variety of factors including oxygen tension and the hemoglobin concentration; the degree of oxygen unloading from hemoglobin to the tissues, which is related to 2,3 diphosphoglycerate levels; and the coronary artery blood flow delivered to the myocardium. The latter is influenced by:

• Coronary artery diameter and tone (resistance)^(5,6).
• Collateral blood flow.
• Perfusion pressure. This is determined by the pressure gradients from the aorta to the coronary arteries. Coronary blood flow from the epicardium to endocardial capillaries is determined by the left ventricular end-diastolic pressure.
• Heart rate, which affects the duration of diastole; importantly, coronary artery flow primarily occurs during diastole. The percent of diastolic time decreases as the heart rate increases. Thus, heart rate is a determining factor for both oxygen demand and supply.

The mechanisms responsible for the sensation of angina are complex and not entirely understood. An important feature is that myocardial ischemia results in the development of acidosis and also reduces the formation of adenosine triphosphate (ATP), the loss of the normal ATP sodium-potassium pump, the loss of myocardial membrane integrity, and the release of chemical substances that stimulate chemosensitive and mechanoreceptive receptors innervated by unmyelinated nerve cells found within cardiac muscle fibers and around the coronary vessels.⁽⁷⁾ The substances that are released include lactate, serotonin, bradykinin, histamine, reactive oxygen species, and adenosine.^(8-10) In addition, there are substances released from platelets, which often spontaneously aggregate in the area of a coronary artery stenosis, which may also be responsible for myocardial ischemia and angina. These include serotonin, thromboxane A2, and 5-hydroxytyrptamine.^(11,12)

There is substantial evidence that the primary mediator of angina is adenosine, via stimulation of the A1 adenosine receptor.^(13-16) It is also possible that venodilation as a response to ischemia can activate these receptors. The nerve fibers travel along the sympathetic afferent pathways from the heart and enter the sympathetic ganglia in lower cervical and upper thoracic spinal cord (C7-T4). Impulses are then transmitted via the ascending spinothalamic pathways to the medial and lateral thalamus and ultimately activate several areas of the cerebral cortex.⁽⁷⁾

Angina is a discomfort that is referred to the corresponding dermatomes that supply sympathetic afferent nerves to the same segments of the spinal cord as the heart (i.e. C7-T4).⁽⁷⁾ Furthermore, stimulation of sensory receptors in different myocardial regions results in the transmission via the same neural pathway.⁽¹⁶⁾  These characteristics account for two typical features of angina: It is often a diffuse discomfort felt in the chest, neck, lower jaw, and down the arm (typically the left arm, although some patients experience right arm discomfort). Most patients experience angina in the same distribution, regardless of which area of the myocardium is ischemic.⁽¹⁶⁾ An exception is often post-cardiac surgery, as this may interrupt and alter the neural supply to the heart, which may affect the distribution of angina.

CLINICAL ENTITIES ASSOCIATED WITH MYOCARDIAL ISCHEMIA: As mentioned above, any significant imbalance between myocardial oxygen supply and demand can lead to myocardial ischemia and angina. Patients may have a supply or a demand problem, but many have both.

DECREASED SUPPLY: In most of the world, atherosclerotic obstruction of one or more coronary arteries (coronary artery disease) is the most common cause of myocardial ischemia. Other clinical conditions associated with a decrease in supply due to disease in one or more coronary arteries include coronary artery vasospasm, coronary microvascular disease, myocardial bridging, fibrosis, embolism, dissection, and arteritis. Left ventricular hypertrophy may result in a reduction in subendocardial blood flow and oxygen supply; this may result in angina. This may be particularly important with the development of arterial hypertension, which may increase left ventricular end-diastolic pressure, resulting in impairment of capillary flow in the subendocardium.

Other examples of inadequate supply include shock (any cause), hypoxemia, anemia, and postprandial angina resulting from a redistribution of blood flow away from territories supplied by severely stenosed coronary arteries to those supplied by less diseased or normal arteries (i.e. a steal phenomenon).^(17,18)

INCREASED DEMAND: Clinical conditions associated with an increase in myocardial oxygen demand include any situation in which there are increased catecholamines or sympathetic tone, as with vigorous exertion or mental stress, tachycardia for any reason, hypertension, left ventricular hypertrophy (with hypertensive heart disease or aortic stenosis), and right ventricular hypertrophy (with pulmonary hypertension).⁽¹⁹⁾

NATURAL HISTORY:

Most patients with myocardial ischemia will present with classic angina pectoris as the primary clinical manifestation. Classic angina pectoris is described as a pressure, heaviness, tightness, or constriction in the center or left of the chest that is precipitated by exertion and relieved by rest. It is generally not described as pain (sharp or dull), ache, or needles and pins. However, in some patients, myocardial ischemia may be silent.

Elements of the history that are critically important include characteristics of the discomfort, associated symptoms, precipitating factors, and information about social and family history.

SIGNS AND SYMPTOMS:

ATYPICAL FEATURES: Specific chest pain characteristics can be used to help differentiate cardiac from noncardiac causes.

In two systematic reviews, the following characteristics were found to be more typical of non-ischemic chest discomfort:^(20,21)

• Pleuritic pain, sharp or knife-like pain related to respiratory movements or cough.
• Primary or sole location in the mid or lower abdominal region.
• Any discomfort localized with one finger.
• Any discomfort reproduced by movement or palpation.
• Constant pain lasting for days.
• Fleeting pains lasting for a few seconds or less.
• Pain radiating into the lower extremities or above the mandible.

In addition, some patients who appear to have a non-cardiac cause of chest pain have other serious conditions including acute aortic dissection, pulmonary embolism, tension pneumothorax, myocarditis, perforating peptic ulcer, and esophageal rupture.⁽²²⁾ It is essential to consider these alternate diagnoses to avoid potentially dangerous errors in management, such as the administration of thrombolytic therapy to a patient with an aortic dissection.

ASSOCIATED SYMPTOMS: Angina is often associated with other symptoms. The most common is shortness of breath or wheezing, which may reflect mild pulmonary congestion.^(23,24) Pulmonary congestion is due to an elevation in left ventricular end diastolic pressure related to failure of the myocardium to relax normally in diastole (as relaxation or lusitropy is energy dependent). The resulting diastolic "stiffness" or diastolic dysfunction results in an increase in left ventricular end diastolic pressure, left atrial pressure, and pulmonary venous pressure, which is transmitted to the pulmonary vessels.

Other symptoms may include belching, nausea, indigestion, diaphoresis, dizziness, lightheadedness, clamminess, and fatigue. However, these symptoms may be seen with other etiologies for chest pain, especially gastrointestinal causes.

INCREASE IN HEART RATE: Ischemia can raise the heart rate even if the patient is receiving a beta blocker or calcium channel blocker. The increase in heart rate is induced by reflex sympathetic nervous system activation as a response to ischemia.

ELEVATION IN BLOOD PRESSURE: Ischemia often causes a hypertensive blood pressure response.

NEW HEART SOUNDS: Ischemia-induced myocardial dysfunction can lead to changes in the normal heart sounds. The second heart sound may become paradoxically split due to delayed relaxation of the left ventricular myocardium and delayed closure of the aortic valve. There may also be a third or fourth heart sound.

NEW/CHANGED MURMURS: Impaired myocardial function may result in a new mitral regurgitation murmur, which appears to be due to papillary muscle dysfunction causing apical tethering or tenting of the leaflets, or changes in the intensity or timing of pre-existing murmurs.

PRECORDIAL PULSATION: Palpation of the chest wall may reveal abnormal pulsations that correlate with transient left ventricular dysfunction.

DIAGNOSTIC TESTS:

The diagnosis of myocardial ischemia can often be made with a high likelihood based on the history, physical examination, and electrocardiogram. Such patients have classic angina, either a normal physical examination or features consistent with myocardial ischemia and an electrocardiogram that is normal in the absence of ongoing ischemia.

For some patients, additional testing is necessary to secure the diagnosis with certainty. Testing, particularly stress testing, is of value when the history is not completely consistent with angina or in a high-risk patient with symptoms that are atypical for ischemia.

PHYSICAL EXAMINATION: For most patients with stable angina, physical examination findings are normal. Diagnosing secondary causes of angina, such as aortic stenosis, is important. A positive Levine sign (characterized by the patient's fist clenched over the sternum when describing the discomfort) is suggestive of angina pectoris. It is significant to look for physical signs of abnormal lipid metabolism (e.g. xanthelasma, xanthoma) or of diffuse atherosclerosis (e.g. absence or diminished peripheral pulses, increased light reflexes or arteriovenous nicking upon ophthalmic examination, carotid bruit).

Examination of patients during the angina attack may be more helpful. Useful physical findings include third and/or fourth heart sounds due to LV systolic and / or diastolic dysfunction and mitral regurgitation secondary to papillary muscle dysfunction.

LABORATORY TESTS: For patients in whom the history and physical examination raise the possibility of myocardial ischemia as the cause of chest discomfort, an electrocardiogram should be obtained. An electrocardiogram obtained when the chest discomfort is present will often show J point and ST segment depression, which indicates subendocardial ischemia. When the patient is asymptomatic, the electrocardiogram may be entirely normal.

ELECTROCARDIOGRAPHY: Approximately 50% of patients with angina pectoris have normal findings after a resting ECG. However, abnormalities such as evidence for prior MI, intraventricular conduction delay, various degrees of atrioventricular block, arrhythmias, or ST-T–wave changes may be seen.

CHEST RADIOGRAPHY: A chest radiograph is often ordered but is not likely to confirm or refute the diagnosis of myocardial ischemia. Chest radiograph findings are usually normal in patients with angina pectoris. However, they may show cardiomegaly in patients with previous MI, ischemic cardiomyopathy, pericardial effusion, or acute pulmonary edema. Calcification of coronary arteries frequently correlates with major coronary artery disease.⁽²⁵⁾

CARDIAC BIOMARKERS: (e.g. troponin) are often obtained in patients with angina. However, they are unlikely to be elevated in patients with intermittent and relatively brief angina episodes. They may be useful when the anginal episode is more prolonged.

EXERCISE STRESS TESTING: Exercise stress testing can be performed alone and in conjunction with echocardiography or myocardial perfusion scintigraphy tests. Exercise stress testing alone generally has somewhat lower sensitivity and specificity, but it is cheaper and therefore is a reasonable choice in those with a low probability of disease.⁽²⁶⁾
These test results must be interpreted in the context of the likelihood of the presence of coronary artery disease determined from the patient's history and physical examination findings. In a population with low prevalence, the predictive abilities of these tests are low; however, in patients with a high likelihood of coronary artery disease, the predictive value is much higher.

The frequency of infarction or death is 1 case per 10,000 stress tests. Absolute contraindications include symptomatic cardiac arrhythmias, severe aortic stenosis, acute MI within the previous 2 days, acute myocarditis, or pericarditis. Discontinue the exercise stress test in the presence of chest pain, a drop in systolic blood pressure of more than 10 mm Hg, severe shortness of breath, fatigue, dizziness or near syncope, ST depression of more than 2 mm, ST elevation of at least 1 mm without diagnostic Q waves, or development of ventricular tachyarrhythmia

STRESS ECHOCARDIOGRAPHY: Stress echocardiography can be used to evaluate segmental wall motion during exercise. It detects changes in regional wall motion that occur during myocardial ischemia. Normal myocardium becomes hyperdynamic during exercise; ischemic segments become hypokinetic or akinetic. Stress echocardiography has the advantage of simultaneous evaluation of LV function, cardiac dimensions, and valvular disease. It is especially useful in patients with baseline ECG abnormalities and those with systolic murmurs suggestive of aortic stenosis or hypertrophic cardiomyopathy.
It is also helpful for localizing ischemia and evaluating its severity. Signs of severe coronary artery disease during exercise stress echocardiography include LV dilation, a decrease in global systolic function, and new or worsening mitral regurgitation.

NUCLEAR IMAGING:

MYOCARDIAL PERFUSION SCINTIGRAPHY: Thallium Tl 201 and technetium Tc 99m sestamibi are the most frequently used myocardial perfusion scintigraphy tests. These tests are especially useful in patients with baseline ECG abnormalities, to localize the region of ischemia, and as prognostic indicators. The presence of increased lung uptake upon thallium imaging is associated with a poor prognosis. Increased lung uptake, together with poststress dilation of the LV and multiple perfusion defects, is suggestive of either left main coronary artery disease or severe 3-vessel disease. The number of affected myocardial segments is predictive of long-term survival. Smaller perfusion defects are usually associated with peripheral coronary artery lesions, which are associated with a better prognosis. The absence of perfusion defects even in the presence of symptoms indicates an excellent prognosis.

COMPUTED TOMOGRAPHY SCANNING: In relatively recent years, coronary artery calcium (CAC) scoring by fast computed tomography (CT) has become more popular in clinical practice for risk assessment of patients with chest pain. Currently, electron-beam computed tomography (EBCT) and multi-detector computed tomography (MDCT) are the primary fast CT methods for CAC measurement. However, some controversy exists about the usefulness of this test.⁽²⁷⁾

CT ANGIOGRAPHY: Bamberg et al found that, in patients with acute chest pain and an inconclusive initial evaluation (non-diagnostic electrocardiographic findings, negative cardiac biomarkers), age and gender can serve as simple criteria to select patients who would derive the greatest diagnostic benefit from coronary computed tomographic angiography (CTA).

PATIENT SELECTION FOR TREATMENT:

For patients with suspected myocardial ischemia, timely diagnosis and treatment is necessary to treat symptoms and possibly also reduce morbidity and mortality. Rapid diagnosis is particularly important in patients with a possible acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction, or ST-elevation myocardial infarction).

TREATMENT OPTIONS:

GENERAL MEASURES:

Smoking cessation results in a significant reduction of acute adverse effects on the heart and may reverse, or at least slow, atherosclerosis. Strongly encourage patients to quit smoking, and take an active role in helping them to achieve this goal.

Treat risk factors, including hypertension, diabetes mellitus, obesity, and hyperlipidemia.

DIET AND ACTIVITY:

A diet low in saturated fat and dietary cholesterol is the mainstay of the Step I and Step II diet from the American Heart Association.

The level of activity that aggravates anginal symptoms is different for each patient. However, most patients with stable angina can avoid symptoms during daily activities simply by reducing the speed of activity.

SURGICAL CARE:

REVASCULARIZATION THERAPY: (i.e. coronary revascularization) can be considered in patients with left main artery stenosis greater than 50%, 2 or 3-vessel disease and LV dysfunction (ejection fraction, < 45%), poor prognostic signs during noninvasive studies, or severe symptoms despite maximum medical therapy. The 2 main coronary revascularization procedures are percutaneous transluminal coronary angioplasty, with or without coronary stenting, and coronary artery bypass grafting (CABG).

LASER TRANSMYOCARDIAL REVASCULARIZATION: Laser transmyocardial revascularization has been used as an experimental therapy for the treatment of severe, chronic, stable angina refractory to medical or other therapies.⁽²⁸⁾ This technique has been performed with either an epicardial surgical technique or by a percutaneous approach. In both approaches, a series of transmural endomyocardial channels are created to improve myocardial perfusion. The surgical transmyocardial revascularization technique has been associated with symptomatic relief for end-stage chronic angina in the short term. However, no published data address the long-term efficacy of surgical transmyocardial revascularization. Nonetheless, this technique appears to provide at least symptomatic relief for end-stage chronic angina in the short term.⁽²⁹⁾

HUMAN CD34+ STEM CELLS: A subgroup of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Some studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium enhancing perfusion and function.

INCREASED CORONARY SINUS PRESSURE: Increased coronary sinus pressure has been suggested to reduce myocardial ischemia by redistribution of blood from nonischemic to ischemic areas. The Coronary Sinus Reducer is a percutaneous implantable device designed to establish coronary sinus narrowing and to elevate coronary sinus pressure.

ANTIANGINAL THERAPY:

There are three classes of anti-ischemic drugs commonly used in the management of angina pectoris: beta blockers, calcium channel blockers, and nitrates.⁽³⁰⁾ Often, a combination of these agents is used for control of symptoms.

BETA BLOCKERS: 2012 American College of Cardiology Foundation / American Heart Association / American College of Physicians / American Association for Thoracic Surgery / Preventive Cardiovascular Nurses Association / Society recommend for Cardiovascular Angiography and Interventions / Society of Thoracic Surgeons guideline for the diagnosis and management of patients with stable ischemic heart disease (SIHD), which recommends beta blockers as first line therapy to reduce anginal episodes and improve exercise tolerance.^(31,32)

Beta blockers relieve anginal symptoms by reducing both heart rate and contractility. Since beta blockers reduce the heart rate-blood pressure product during exercise, the onset of angina or the ischemic threshold during exercise is delayed or avoided. All types of beta blockers appear to be equally effective in exertional angina. Beta blockers should not be used in patients with vasospastic or variant (Prinzmetal) angina. In such patients, they are ineffective and may increase the tendency to induce coronary vasospasm from unopposed alpha-receptor activity.

CALCIUM CHANNEL BLOCKERS: In general, calcium channel blockers are used in combination with beta blockers when initial treatment with beta blockers is not successful or as a substitute for a beta blocker when beta blockers are contraindicated or cause side effects. Calcium channel blockers improve anginal symptomatology by causing coronary and peripheral vasodilatation and reducing contractility.⁽³³⁾ The degree to which these changes occur varies with the type of calcium channel blocker given.

Long-acting diltiazem or verapamil or a second generation dihydropyridine (amlodipine or felodipine) are preferred. Short-acting dihydropyridines, especially nifedipine, should be avoided unless used in conjunction with a beta blocker in the management of Stable Ischemic Heart Disease (SIHD) because of evidence of an increase in mortality after a myocardial infarction and an increase in acute myocardial infarction in hypertensive patients.

NITRATES: Nitrates, usually in the form of a sublingual preparation, are the first-line therapy for the treatment of acute anginal symptoms. Patients should be instructed to use them at the onset of angina. They may also be recommended for the prophylaxis of anginal episodes.

Long-acting nitrates are added to beta blockers (with or without calcium channel blockers) to control stable angina. In patients with exertional stable angina, chronic nitrate therapy using oral or dermal preparations improves exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta blockers or calcium channel blockers, nitrates produce greater antianginal and anti-ischemic effects compared to those drugs without nitrates. However, the long-term utility of nitrates is limited by the induction of nitrate tolerance.

NEWER THERAPIES: A number of newer medical and invasive therapies have been evaluated for use in patients with stable angina. Of these, ranolazine, a late sodium channel blocker, is the most widely used.⁽³⁴⁾ Ranolazine is used either in combination with a beta blocker or as a substitute in patients who cannot receive one.

NICORANDIL: Nicorandil, a potassium channel activator, is used for the treatment of angina in a number of countries. It has multiple actions that are beneficial in coronary artery disease. It is an arterial and venous dilator and improves coronary blood flow due to potassium channel opening and nitrate effect. Since ATP-dependent potassium channels play a role in ischemic preconditioning, nicorandil may also mimic a natural process of ischemic preconditioning, protecting the heart from subsequent ischemic attacks.

GOALS OF THERAPY:

The main goals of treatment in angina pectoris are to relieve the symptoms, slow the progression of disease, and reduce the possibility of future events, especially MI and premature death.

GUIDELINES:

Recommendations made in this topic, including those for follow-up, are consistent with those made in the 2013 European Society of Cardiology guidelines on the management of stable coronary artery disease.⁽³⁵⁾

www.escardio.org/guidelines.

CONSULTATION AND LONG TERM MONITORING:

Approximately 1-3 months after the acute phase of unstable angina, the risk of major adverse events typically declines to that observed in patients with chronic stable angina. The goals are to prepare patients for resumption of their normal activities as safely as possible, to preserve left ventricular function, and to prevent future events.

SMOKING CESSATION: Aggressive attempts should be made to convince the patient and the rest of his or her household to cease smoking. The target is for the patient and his or her cohabitants to abstain completely from all tobacco products for 12 months or longer.

LIPID LOWERING: The target is an LDL-C level of 70 mg/dL or lower, high-density lipoprotein cholesterol (HDL-C) level higher than 35 mg/dL, and a triglyceride level below 200 mg/dL.

CONTROL OF HYPERTENSION: The target blood pressure is below 140/90 mm Hg or below 130/80 mm Hg if the patient has diabetes mellitus or chronic kidney disease. Diet modification, moderation of sodium and alcohol intake, exercise, smoking cessation, and pharmacotherapy are indicated.

DIABETES MELLITUS MANAGEMENT: The American College of Cardiology Foundation/American Heart Association 2011 update to the UA/NSTEMI guideline states that it is reasonable to achieve and maintain glucose levels lower than 180 mg/dL for hospitalized patients, avoiding hypoglycemia.⁽³⁶⁾ Diet modification, exercise, pharmacotherapy (including ACE inhibitor therapy), preventive counseling regarding foot care, and ophthalmic examinations are indicated.

WEIGHT MANAGEMENT AND NUTRITIONAL COUNSELING: The target body mass index (BMI) is below 25 kg/m2, in conjunction with a waist circumference of less than 40 inches in men and of less than 35 inches in women. Diet modification with adequate intake of fruits and vegetables, exercise, and behavioral modification and counseling are indicated.

PSYCHOSOCIAL MANAGEMENT: The targets in psychosocial management are lifestyle modification, recognition and treatment of substance abuse (whether involving alcohol or psychotropics), management of depression or hostile attitude, and compliance with health maintenance. Education, counseling, support groups, and social or religious resources are indicated.

ACTIVITY MANAGEMENT: Patients at risk for MI should avoid sudden strenuous activities, especially in cold weather (e.g. shoveling snow).

FOLLOW-UP: Patients with chronic stable angina require follow-up on a regular basis. Every 6 to 12 months follow up is recommended. At each visit, a detailed history should be obtained and physical examination performed. In particular, it is important to establish:

• A change in physical activity
• Any change in the frequency, severity, or pattern of angina
• Tolerance of and compliance with the medical program
• Modification of risk factors
• The development of new or worsened comorbid illnesses

In addition to laboratory studies such as blood glucose or a lipid profile, an electrocardiogram should be obtained if medications are altered or if the history or physical examinations have changed.

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