The Pathophysiology of Myocardial Infarction

Myocardial infarction ("heart attack") is the irreversible damage of myocardial tissue caused by prolonged ischemia and hypoxia. This most commonly occurs when a coronary artery becomes occluded following the rupture of an atherosclerotic plaque, which then leads to the formation of a blood clot (coronary thrombosis). This event can also trigger coronary vasospasm. If a vessel becomes completely occluded, the myocardium normally supplied by that vessel will become ischemic and hypoxic. Without sufficient oxygen, the tissue dies. The damaged tissue is initially comprised of a necrotic core surrounded by a marginal (or border) zone that can either recover normal function or become irreversibly damaged. The hypoxic tissue within the border zone may become a site for generating arrhythmias. Collateral blood flow is an important determinant of infarct size and whether or not the border zone becomes irreversibly damaged. Infarcted tissue does not contribute to tension generation during systole, and therefore can alter ventricular systolic and diastolic function and disrupt electrical activity within the heart. After several weeks, the infarcted tissue forms a fibrotic scar. Long-term consequences include ventricular remodeling of the remaining myocardium (e.g., development of compensatory hypertrophy or dilation), ventricular failure, arrhythmias and sudden death.

Myocardial infarctions produce clinical symptoms that include intense chest pain that may radiate into the neck, jaw or arms (i.e., referred pain), a sense of substernal heaviness, squeezing or pressure, shortness of breath (dyspnea), fatigue, fainting (syncope), nausea, sweating (diaphoresis), anxiety, sleeplessness, hypertension or hypotension (depending in part on the extent of cardiac damage), tachycardia and arrhythmias. Recent clinical research indicates that the symptoms may be very different between men and women. Chest pain less common in women. Instead, their most common symptoms are weakness, fatigue and dyspnea.

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The pathophysiology of acute myocardial infarction is complex. Loss of viable myocardium impairs global cardiac function, which can lead to reduced cardiac output, and if damage is severe, to cardiogenic shock. Systolic and diastolic dysfunction are associated with ischemic myocardium. If left ventricular function is significantly impaired, pulmonary congestion and edema can occur. Ischemia can also precipitate abnormal cardiac rhythms and conduction blocks that can further impair function and become life-threatening in some cases. Reduced cardiac output and arterial pressure can elicit baroreceptor reflexes that lead to activation of neurohumoral compensatory mechanisms (e.g., activation of sympathetic nerves and the renin-angiotensin-aldosterone system) similar to what occurs during

heart failure. The pain and anxiety associated with myocardial infarction further activates the sympathetic nervous system, which causes systemic vasoconstriction and cardiac stimulation (this explains why some patients become hypertensive and have tachycardia). While sympathetic activation helps to maintain arterial pressure, it also leads to a large increase in myocardial oxygen demand that can lead to greater myocardial hypoxia, enlarge the infarcted region, precipitate arrhythmias, and further impair cardiac function. Sympathetic activation is responsible for the diaphoresis (sweating) experienced by the patient. Renal hypoperfusion and sympathetic activation stimulate renin release, which leads to increased plasma levels of angiotensin II and aldosterone that enhance renal retention of sodium and water.

Rationale for Drug Therapy in Myocardial Infarction

The most important goal of drug therapy early in the course of acute myocardial infarction is to improve the oxygen supply/demand ratio for the heart. The reduction in this ratio that occurs when coronary flow is compromised is the primary reason cardiac function is impaired, which leads to the clinical signs associated with myocardial infarction (see above). There are two strategies to improve the coronary supply/demand ratio, 1) restore normal coronary blood flow, and 2) decrease myocardial oxygen consumption. Restoring Normal Coronary Blood Flow. The two major approaches for restoring normal cardiac perfusion are 1) percutaneous transluminal angioplasty (PCTA), often coupled with the placement of an intracoronary stent, and 2) administering a thrombolytic drug to induce clot lysis. Both of these procedures include anticoagulant drugs to inhibit new clot formation. Patients are also treated with anti-platelet drugs, which helps to prevent recurrent thrombosis. Because coronary vasospasm can also contribute to the reduced perfusion, vasodilators such as nitroglycerine are often given to prevent or reverse vasospasm. Decreasing Myocardial Oxygen Consumption. Myocardial oxygen demand can be decreased by decreasing 1) heart rate, 2) contractility (inotropy), 3) ventricular afterload, and 4) ventricular preload. Because the heart is being stimulated by increased sympathetic activity and circulating catecholamines during infarction, drugs such as beta-blockers that inhibit sympathetic activity (sympatholytics) are commonly given. Systemic vasodilators are sometimes given to reduce systemic vascular resistance; however, care must be taken not to cause hypotension because this would reduce coronary perfusion pressure and blood flow. Finally, venous dilator drugs such as nitroglycerin are used to reduce ventricular preload, which reduces oxygen demand. Other Drugs. Pain management is an important consideration because pain and associated anxiety stimulates sympathetic activity, which can be deleterious to the heart. Therefore, analgesic drugs such as morphine are often given in the acute setting to reduce pain. Morphine also has other beneficial effects as a vasodilator. Antiarrhythmic drugs are administered particularly when their are serious ventricular rhythm disturbances. Diuretics may also be given depending on the degree of heart failure and fluid retention.

Long-Term Treatment. Because myocardial infarctions usually occur because of coronary artery disease, most patients will be placed on long-term anti-platelets therapy. Additionally, most post-infarct patients are treated with a beta-blocker because they have been shown to reduce cardiac remodeling and reduce mortality following infarction. Angiotensin converting enzyme inhibitors have a similar beneficial effect.

Classes of Drugs Used to Treat Myocardial Infarction

Classes of drugs used in the treatment of myocardial infarction are given below. Clicking on the drug class will link you to the page describing the pharmacology of that drug class.

Vasodilators (dilate arteries and veins) - nitrodilators - angiotensin converting enzyme inhibitors (ACE inhibitors) - angiotensin receptor blockers (ARBs)

Cardiac depressant drugs (reduce heart rate and contractility) - beta-blockers Antiarrhythmics (if necessary) Anti-thrombotics (prevent thrombus formation) - anticoagulant - anti-platelet drugs Thrombolytics (dissolve clots - i.e., "clot busters") - plasminogen activators Analgesics (reduce pain) - morphine