David Solkoffand Ronald R. Watson
Cocaine abuse induces coronary vasospasm [1-5], myocardial infarction [6-8], hypertension [9,10], stroke [7,H], and fatal cardiac rhythm disorders, including ventricular fibrillation [12-15], Chronic cocaine abuse has also been shown to cause dilated cardiomyopathy [16,17], and left ventricular hypertrophy in normotensive cocaine users [18-20], It is only since modern electrocardiographic techniques have come into widespread use that the effect of cocaine on cardiac rhythm has been effectively studied. These techniques were the first to demonstrate that cocaine produced severe intractable ventricular arrhythmias that resulted in death during routine nasal surgery ,
Cocaine functions as a strong cardiac stimulant that potentiates the actions of the sympathetic nervous system by inhibiting both peripheral and central neuronal catecholamine uptake [22-24], The resulting changes in cardiac autonomic neural balance may significantly contribute to the formation of arrhythmias, since increased sympathetic activity reduces cardiac electrical stability, thus exposing the heart to ventricular fibrillation [25,26], Therefore parasympathetic activation may oppose these sympathetic effects and thereby protect against cocaine induced malignant arrhythmias [22,23]. Also, high doses of cocaine have caused significant reductions in heart rate variability, which serves as a marker of cardiac vagal tone [27,28], These changes were shown to be increasingly pronounced during myocardial ischemia, when cocaine exacerbated the autonomic response to a coronary artery occlusion , Post cocaine, myocardial ischemia elicited a significantly enhanced tachycardia, resulting from both enhanced sympathetic activation and an increased withdrawal of parasympathetic tone. Thus cocaine-induced changes in autonomic control of the heart play a critical role in the development of ventricular fibrillation during myocardial ischemia.
The previously mentioned cocaine-induced accumulation of catecholamines can hyperactivate a- and fi-adrenergic receptors, thus provoking coronary vasospasm (myocardial infarction and ischemia), increased contractile force resulting in increased metabolic demand and cardiac arrhythmias , ^-Adrenergic receptor antagonists have been shown to lessen many of the hemodynamic effects of cocaine [30-33], Therapeutic doses of propranolol blunt the pressor, positive inotropic, and heart rate responses to cocaine intoxication , Propranolol has also reduced the number of cardiac arrhythmias induced by programmed electrical stimulation after intravenous cocaine , However, propranolol failed to alter the toxic actions of high doses of cocaine , Furthermore, propranolol increased, rather than reduced, the fatal effects of large doses of cocaine [33,39], The conflicting data suggest that additional mechanisms are needed to fully explain the arrhythmogenic action of cocaine.
In the myocardium, there are a large number of a-adrenergic receptors , Activation of these receptors increases cardiac myocyte calcium levels, triggers a delayed after-depolarization, and induces ventricular arrhythmias [40,41], Therefore, cocaine-linked increases in catecholamines, which activate a-adrenergic receptors, may cause ventricular arrhythmias. This hypothesis has received support from a study showing that prazosin, an a ¡-adrenergic receptor antagonist, significantly lessened the incidence of malignant arrhythmias induced by a cocaine, exercise, plus ischemia test , In the same study WB4101, an a1A-adrenergic receptor antagonist, prevented cocaine-provoked arrhythmias. Other studies have shown that paradoxically, the nonselective a-adrenergic receptor antagonist phentolamine augmented, rather than suppressed, the cardiotoxic properties of cocaine [33,43-44], When examined wholistically, these data infer that cocaine-induced activation of adrenergic receptors may be responsible for the disruption in cardiac electrical stability that results in ventricular fibrillation and induction of malignant arrhythmias.
The previously discussed hyperactivation of a- and ^-adrenergic post-synaptic receptors by cocaine-released catecholamines causes increases in intracellular second messengers. These intracellular factors may be responsible for the cellular events that trigger arrhythmias. Adenylate cyclase is activated when myocardial fi-adrenergic receptors are stimulated, and this results in elevated cyclic adenosine monophosphate (cAMP) levels. This has the effect of increasing calcium entry and calcium release from cytosolic stores [45,46], Similarly, a-adrenergic receptors activate the inositol triphosphate second messenger cascade, which also increases cytosolic calcium [45,47], a1A-adrenrgic receptor stimulates the breakdown of phosphoinositides via a pertussin toxin-sensitive G protein, thus stimulating calcium influx , It has therefore been postulated that a- and ^-adrenergic receptor stimulation acts synergistically to increase calcium entry and cytosolic calcium levels. This mechanism represents the end of the pathway that begins with a cocaine-mediated elevation in catecholamine release, and finishes with ventricular fibrillation.
Cardiac arrhythmias result from abnormalities in impulse conduction, impulse generation, or both. Previous studies have shown that these abnormalities may be caused by alterations in cellular calcium [49-50], They have also demonstrated that cocaine raises intracellular calcium levels , and that it also stimulates the release of calcium from the sarcoplasmic reticulum , Furthermore, Kimura et al.  have described cocaine's ability to prolong action-potential duration and to induce after-depolarization, thus triggering extrasystoles in isolated feline cardiomyocytes. They demonstrated that these oscillatory after-potentials were enhanced by catecholamines and suppressed by the calcium channel antagonist verapamil. When compared against those who suffered drug-related deaths not involving cocaine, the heart of individuals who experienced acute fatal cocaine cardiotoxicity displayed myocardial contraction bands more frequently. These pathological changes are thought to indicate abnormalities in calcium homeostasis [49,54], Thus, it has been hypothesized that interventions resulting in a reduction of elevated cytosolic calcium levels may protect against cocaine-linked ventricular fibrillation. Experimental evidence supporting this hypothesis includes a study which found that cocaine-induced ventricular fibrillation was prevented in8ofl2 animals treated with the intracellular calcium-specific chelator BAPTA-AM , The drug also significantly lessened both the pressor and inotropic response to cocaine. Similarly, a number of organic (verapamil, nifedipine, diltiazem, and flunarizine) and inorganic (magnesium) calcium channel antagonists eliminated cocaine-provoked ventricular fibrillation , These antagonists, by suppressing the cocaine-induced accumulation of cytosolic calcium, may prevent oscillatory changes in membrane potential, thus preventing the trigger for malignant arrhythmias. In addition to its sympathomimetic actions, cocaine has potent local anasthetic properties [22,23], Cocaine blocks sodium channels, thus inhibiting action-potential generation and conduction in both nerve and cardiac tissue. Cocaine causes depression ofPurkinje cell automaticity as well as depressed phase 0 of the cardiac action potential (the rapid upstroke due to sodium influx) , Cocaine blocks a calcium dependent potassium channel thereby delaying repolarization , When tested on intact animal preparations in a dose dependent manner, cocaine has been reported to increase QRS duration, prolong P-R interval, and increase the H-V interval on His bundle recordings [29,58-60], For high doses of cocaine, conduction block and asystole have also been reported [15,61], Similarly, cocaine inhibits potassium channels thus prolonging repolarization of isolated cardiac tissue , lengthening the duration of QT interval in intact animals [29,60], The resulting conduction delays and inhomogeneities of repolarization may contribute to the formation of arrhythmias , This inhomogeneity exists when excitability in one area of the heart returns before adjacent areas have repolarized fully. Therefore, the tissue that has remained in a depolarized state longer than the surrounding tissue may act to reexcite the fully repolarized regions and generate a premature impulse. This inhomogeneity of repolarization has been reported for a variety of local anesthetics  and plays an important role in the induction of ventricular fibrillation , These observations suggest that the local anesthetic properties of cocaine may also contribute to the formation of malignant arrhythmias. With respect to the heart, the local anesthetic effects of cocaine are quite obvious following the administration oflarge doses of the drug. These local anesthetic properties may also negatively affect cardiac mechanical function. High doses of cocaine can exert a direct depression of myocardial performance thereby contributing to its cardiovascular mortality , Fraker et al.  found significant reductions in regional left ventricular ejection fraction (as measured by two-dimensional echocardiography) following the administration of a large dose of cocaine (4 mg/kg) to either conscious or pentobarbitol anesthetized instrumented dogs. Similar studies have shown that cocaine infusions caused significant declines in the index of contractility known as left ventricular dP/dT [65,67], This depression was partly normalized by nifedipine, a potent coronary vasodilator, suggesting that the declines in mechanical function may partially result from cocaine-induced reductions in coronary perfusion.
In addition to its actions on cardiac muscle, cocaine can indirectly affect cardiac electrophysiological and mechanical properties by influencing the coronary vasculature. In approximately one-third of the patients studied (myocardial infarction cases resulting from the recreational use of cocaine) the infarction victims possessed normal coronary vessels. The investigators concluded that the cocaine-induced myocardial infarction in these individuals probably involved adrenergically mediated increases in myocardial oxygen consumption and vasoconstriction of the coronary vessels. Thus, the increased release of catecholamines during cocaine intoxication, and the resulting activation of a-adrenergic receptors located on coronary vascular smooth muscle, may be responsible for a powerful vasoconstriction. Many of the fatal consequences of cocaine, including ventricular arrhythmias, may therefore arise secondarily from the resulting myocardial ischemia and infarction. Several previous studies further demonstrate the coronary vasoconstrictive effects of cocaine [68-74], Cocaine produces a dose-dependent vasoconstriction of the coronary vasculature in intact dogs and conscious rats. These actions were prevented by calcium channel antagonists , and a-adrenergic receptor blockade [71,72], Vascular actions of cocaine may create an imbalance between myocardial oxygen supply (coronary vasoconstriction) and oxygen demand (increased heart rate, arterial pressure, and inotropic state), thus increasing the likelihood of ischemic events and the associated reduction in cardiac electrical stability and mechanical performance. It is interesting to note that the deleterious effects of cocaine on myocardial oxygen supply and demand are exacerbated by concomitant cigarette smoking . This combination markedly increases the metabolic requirement of the heart for oxygen but simultaneously decreases the diameter of diseased coronary arterial segments. As to whether ethanol exacerbates the cardiotoxic properties of cocaine, it has been reported that the combination of intranasal cocaine and intravenous ethanol causes an increase in the determinants of myocardial oxygen demand. At the same time, however, it also increases epicardial coronary arterial diameter ,
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