In 1982, Coleman et al. reported an association between cocaine use and myocardial ischemia and infarction. Subsequently, many reports have documented cocaine-related myocardial ischemic events. The risk of acute myocardial infarction is increased by a factor of 24 during the 60 minutes after the use of cocaine in persons who are otherwise at relatively low risk. The occurrence of myocardial infarction after cocaine use is unrelated to the amount ingested, the route of administration, and the frequency of use; it has been reported with doses ranging from 200 to 2000 mg, after ingestion by all routes, and in habitual as well as first-time users.
Persons presenting to the emergency department with nontraumatic chest pain should be questioned about cocaine use, since such pain is the most common symptom in cocaine users. Of patients who come to the emergency department with nontraumatic chest pain, 14 to 25 percent in urban hospitals and 7 percent in suburban hospitals have detectable levels of cocaine or cocaine metabolites in their urine.
Patients with cocaine-related myocardial infarction cannot be distinguished from those without this condition on the basis of such clinical variables as the time of onset of pain, the location of the pain, its quality or duration, the presence or absence of a history of chest pain or myocardial infarction, and the presence or absence of traditional risk factors for atherosclerosis. Most patients with cocaine-related myocardial infarction are young, nonwhite, male cigarette smokers without other risk factors for atherosclerosis who have a history of repeated use of cocaine. About half the patients with cocaine-related myocardial infarction have no evidence of atherosclerotic coronary artery disease on subsequent angiography. Therefore, when patients with no or few risk factors for atherosclerosis, especially those who are young or have a history of substance abuse, present with acute myocardial infarction, urine and blood samples should be analyzed for cocaine and its metabolites.
The accurate identification of patients with cocaine-related myocardial infarction may be difficult for at least two reasons. First, the electrocardiogram may be abnormal in many patients with chest pain after cocaine use, even in the absence of myocardial infarction. The electrocardiogram is reportedly abnormal in 56 to 84 percent of patients with cocaine-related chest pain, and as many as 43 percent of cocaine abusers without myocardial infarction meet the electrocardiographic criterion for the initiation of reperfusion therapy (ST-segment elevation of at least 0.1 mV in two or more contiguous leads). The sensitivity of the electrocardiogram for detecting myocardial infarction is reported to be 36 percent, its specificity 90 percent, its positive predictive value 18 percent, and its negative predictive value 96 percent. The high failure rate of the electrocardiogram in identifying patients with cocaine-related myocardial infarction results, at least in part, from a high incidence of early repolarization abnormalities in young persons in the general population.
The second reason why it is difficult to identify cocaine-related myocardial infarction is that serum creatine kinase concentrations are not a reliable indicator of myocardial injury, since they are elevated in about half of cocaine users who do not have myocardial infarction. This elevation of serum creatine kinase is presumably due to rhabdomyolysis. Accordingly, serum troponin concentrations, which are more sensitive and specific for the detection of myocardial infarction, should be measured in patients in whom cocaine-related myocardial infarction is suspected.
Cardiovascular complications resulting from cocaine-related myocardial infarction are relatively uncommon, with ventricular arrhythmias occurring in 4 to 17 percent of patients hospitalized with cocaine-related myocardial infarction, congestive heart failure in 5 to 7 percent, and death in less than 2 percent. This low incidence of complications is due, at least in part, to the young age of most patients with this condition. Most complications occur within 12 hours after the initial presentation at the hospital. In those who have been discharged from the hospital, continued cocaine use and recurrent chest pain are common, and occasionally a patient has recurrent nonfatal myocardial infarction or dies.
The pathogenesis of cocaine-related myocardial ischemia and infarction is probably multifactorial and includes one or more of the following elements: an increased myocardial oxygen demand in the face of a limited or fixed supply, marked vasoconstriction of the coronary arteries, and enhanced platelet aggregation and thrombus formation. Cocaine induces an increase in the three major determinants of the myocardial oxygen demand: the heart rate, the systemic arterial pressure, and left ventricular contractility. At the same time, the ingestion of even small amounts of the drug causes vasoconstriction of the epicardial coronary arteries - so-called inappropriate vasoconstriction, in that the myocardial oxygen supply decreases even as the demand increases. Although cocaine induces vasoconstriction in both normal and diseased segments of the coronary arteries, its effects are more pronounced in the diseased segments. As a result, cocaine users with atherosclerotic coronary artery disease are probably at greater risk for an ischemic event after cocaine use than are cocaine users without coronary artery disease. Cocaine-induced vasoconstriction of the coronary arteries is primarily a result of the stimulation of coronary arterial α-adrenergic receptors, since it may be reversed with phentolamine (an α-adrenergic antagonist) and is exacerbated by propranolol (a β-adrenergic antagonist). Cocaine also causes increased endothelial production of endothelin (a potent vasoconstrictor) and decreased production of nitric oxide (a potent vasodilator) - effects that may promote vasoconstriction.
Most patients with cocaine-related myocardial ischemia or infarction have chest pain within an hour after they have used cocaine, at a time when the blood cocaine concentration is highest. However, others note the onset of symptoms several hours after the administration of the drug, when the blood concentration of cocaine is low or even undetectable. With cocaine ingestion, the diameter of the coronary arteries decreases as the drug concentration rises, then returns to its base-line measurement as the drug concentration declines. Thereafter, as the concentrations of cocaine’s major metabolites (benzoylecgonine and ecgonine methyl ester) rise, “delayed” (i.e., recurrent) vasoconstriction of the coronary arteries occurs. Thus, the delayed or recurrent vasoconstriction of the coronary arteries appears to be caused by cocaine’s major metabolites, which explains why myocardial ischemia or infarction may occur several hours after the ingestion of cocaine.
In addition to vasoconstriction, cocaine may induce thrombus formation in the coronary arteries. Its use is associated with enhanced platelet activation and aggregability as well as increases in the concentration of plasminogen-activator inhibitor, which may promote thrombus formation. Premature atherosclerotic coronary artery disease has been observed in postmortem studies of long-term cocaine abusers and may provide the nidus for such thrombus formation. In vitro studies have shown that cocaine causes structural defects in the endothelial-cell barrier, increasing its permeability to low-density lipoprotein and enhancing the expression of endothelial adhesion molecules and leukocyte migration, all of which are associated with the progression of atherosclerosis.
As noted above, cocaine-induced vasoconstriction of the coronary arteries can be reversed by phentolamine, an α-adrenergic antagonist. Conversely, propranolol - a β-adrenergic–blocking agent - exacerbates cocaine-induced vasoconstriction of the coronary arteries, and therefore it should not be used in patients with cocaine-related chest pain. Since nitroglycerin and verapamil reverse cocaine-induced hypertension and vasoconstriction of the coronary arteries, they are the agents of choice for patients with cocaine-associated chest pain. Labetalol, which has both α- and β-adrenergic–blocking activity, reverses the cocaine-induced increase in systemic arterial pressure but exerts no demonstrable effect on cocaine-induced vasoconstriction of the coronary arteries. Aspirin should be administered to patients with cocaine-induced myocardial ischemia to inhibit platelet aggregation. Benzodiazepines may also be helpful, since they reduce the heart rate and the systemic arterial pressure; in animals, they also attenuate cocaine’s toxic effects on the heart and the nervous system. Because of the limited experience with thrombolytic therapy in patients with cocaine-related infarction, reports of catastrophic complications associated with its use in cocaine users, and the difficulty involved in using standard electrocardiographic criteria to identify myocardial infarction, we caution against the routine use of thrombolytic therapy in patients who may have cocaine-related infarction. Thrombolytic therapy should be considered only after treatment with oxygen, aspirin, nitrates, and benzodiazepines has failed, and when immediate coronary angiography and angioplasty are not available.
The recently revised guidelines of the American Heart Association for emergency cardiovascular care recommend nitroglycerin and benzodiazepines as first-line agents for patients with cocaine-related myocardial ischemia or infarction and phentolamine as a second-line agent; propranolol is contraindicated. Thrombolysis is not recommended unless evidence of evolving myocardial infarction persists despite medical therapy and an occluded coronary artery is shown to be present on angiography. Thrombolysis is contraindicated if uncontrolled, severe systemic arterial hypertension is present.
From the Cardiovascular Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Address reprint requests to Dr. Hillis at the Department of Internal Medicine, Room CS7.102, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9047.
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Richard A. Lange, M.D., and L. David Hillis, M.D.