Cocaine Cardiotoxicity

As cocaine abuse has become widespread, the number of cocaine related cardiovascular events, such as angina pectoris, myocardial ischemia and infarction, cardiac myopathy, left ventricular hypertrophy, and sudden death has increased substantially [1-15], These occur in young subjects, a significant percentage of whom had no evidence of atherosclerotic coronary artery disease on subsequent angiography [10,11,18-21]. Twice as many men as women experience cocaine related cardiac ischemic events, at least partly caused by a greater frequency of cocaine use in men. The concomitant use of cigarettes and/or ethanol is pervasive, with up to 75% of cocaine users admitting to each. Although myocardial ischemia, infarction, and sudden death are most likely to occur in chronic cocaine users, they have been reported in first time users as well. These events can occur from any route of administration and with a large or small amount of the drug [3,4,8,9,20-29], It is thought that the pathophysiology of cocaine-related myocardial ischemia and infarction is most likely multidimensional, and that it is caused by individual and/or combined conditions including increased myocardial oxygen demand in the setting of limited or fixed supply, marked coronary artery vasoconstriction, and enhanced platelet aggregation and thrombus formation [1],

These hypotheses are supported by a variety of previous studies. In humans, the intracoronary infusion of cocaine in amounts sufficient to achieve a high drug concentration in coronary sinus blood causes a deterioration of left ventricular systolic and diastolic performance [30], Even a small amount (2 mg/kg)of cocaine causes 'inappropriate' coronary arterial vasoconstriction, meaning that myocardial oxygen supply fell in the setting of increased demand [31]. Cocaine-induced thrombosis is an important mechanism in the development of myocardial infarction in the presence of normal or diseased coronary arteries [32], Autopsies following cocaine-related deaths have complete thrombotic occlusions of normal and atherosclerotic coronary arteries [8,12,25,33]. Coronary artery thrombosis and subsequent ischemia in these cases may be attributed to alterations in platelet and endothelial cell functions [34], Endothelial damage may occur at the site of vascular spasm resulting in thrombus formation, and cocaine may cause coronary artery thrombosis by initiating coronary artery spasm [18,35,36], In vitro studies have demonstrated that cocaine activates platelets, increases platelet aggregation, and potentiates platelet thromboxane production [37-39], The idea that cocaine exerts pro-coagulant effects is further supported by findings of combined protein C and antithrombin III depletion in patients with cocaine-related arterial thromboses [40], Levels of both anticoagulants returned to normal following discontinuation of cocaine use. Similarly, cocaine users have increased risk of developing upper extremity deep vein thrombosis (Paget-Schroetter syndrome) [41].

Cocaine causes central and peripheral adrenergic stimulation by blocking the presynaptic reuptake of norepinephrine and dopamine, thus increasing their postsynaptic concentrations [42], The coronary arteries have both a and ^-adrenergic receptors. Stimulation of a-adrenergic receptors causes vascular smooth muscle contraction, while ^-adrenergic stimulation induces the opposite. The cardiovascular effects of cocaine are partially mediated by a-adrenergic stimulation, since they were reversed by phentolamine, an a-adrenergic antagonist [31].

Some researchers have advocated the use of ^-adrenergic blocking agents in patients with acute cocaine ingestion [43,44], Indeed, previous studies have shown that ^-adrenergic receptor antagonists such as propranolol have been effective at lessening the pressor, positive inotropic, and heart rate responses to cocaine intoxication [43,45-50], However, since ^-adrenergic stimulation causes coronary vasodilation, ^-adrenergic blockade may allow for unopposed a-adrenergically mediated coronary arterial vasoconstriction. This hypothesis has been vindicated in a previous study demonstrating that cocaine increases myocardial oxygen demand while simultaneously reducing supply, as reflected by a decrease in coronary sinus blood flow and coronary arterial diameter. The study went on to describe how the cocaine-induced fall in myocardial oxygen supply is actually exacerbated by propranolol. Therefore, ^-adrenergic blockade may actually increase the magnitude of cocaine-related myocardial ischemia, and thus should not be used in patients with cocaine intoxication. We hypothesize, vis a vis the treatment of cocaine intoxication in humans, it is more important to reverse the vasoconstriction than it is to decrease heart rate, i.e., slow the heart down. A significant amount of patients suffering from cocaine-associated angina pectoris or myocardial infarction report the onset of symptoms several hours after drug administration, when the blood concentration of cocaine is low or undetectable [3,51]. This delay in experiencing symptoms may be caused not by the cocaine itself, but by the drug's major metabolites, benzoylecgonine and ethyl methyl ecgonine [52], Further study of the cardiotoxic effects of cocaine in humans, indicate that patients with atherosclerotic coronary artery disease are probably at increased risk of having an ischemic event in response to cocaine when compared against patients not suffering such malady. This may occur because diseased coronary arterial segments usually exhibit pronounced endothelial dysfunction such as greatly impaired or absent production of endothelium-derived relaxing factors [53,54],

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