© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The cardiac cocaine connection
c.grohe{at}uni-bonn.de
See article by Moritz et al. [9] (pages 834–843) in this issue.
Cocaine (benzoylmethylecgonine) is increasingly used as an illegal stimulatory and hallucinogenic drug. This abuse is associated with a large array of clinically relevant cardiovascular side effects that after long-term use may lead from myocardial hypertrophy and necrosis to progressive left ventricular dysfunction [1]. To further dissect the underlying mechanisms, two pathophysiological entities have to be taken into account and deserve further attention: the acute effects and the biochemical and cellular changes in the myocardium after chronic abuse.
Cocaine was introduced as the first local anaesthetic agent at the end of the 19th century. Its local anaesthetic effect originates in from a blockade of voltage-gated Na+ channels. This is accompanied by a sympathomimetic influence of the drug due to central stimulation of sympathetic outflow and inhibition of norepinephrine reuptake into sympathetic nerve terminals. The sympathomimetic property supports the local anaesthetic influence by inducing local vasoconstriction and thus preventing fast dilution of the drug.
In the cardiovascular system, acute cocaine application prolongs QRS duration, increases heart rate and myocardial contractility, and elicits intense vasoconstriction in coronary and peripheral vascular beds [1]. Inhibition of cardiac Na+ current by cocaine is voltage- and frequency-dependent. Reduced Na+ current leads to a depression of Vmax in the action potential (AP) that reduces AP propagation in the heart, consistent with the finding of a prolonged QRS complex. The reduction of Vmax is accompanied by a biphasic influence on AP duration (APD); at cocaine concentrations <100 µM APD was prolonged up to 20% and at higher concentrations (100–300 µM) cocaine induces a shortening of APD [2]. Prolongation of the APD may be due to reduction of repolarizing K+ currents. A reduction of IKr but not IKs by low concentrations of cocaine has been shown in guinea pig ventricular myocytes [3]. This is in accordance with the finding that cocaine is an antagonist of human HERG channels (Kd 7.2 µM) conducting IKr; KvLQT1+mink conducting IKs seems to be insensitive to cocaine [4,5]. Even a metabolite of cocaine and ethanol, cocaethylene, inhibits HERG channels [6]. The shortening of the APD obtained at higher cocaine concentrations may be explained by a reduction of L-type Ca2+ current and blockade of non-inactivated TTX-sensitive Na+ channels [3]. However, in rat ventricular myocytes, low concentrations of cocaine have been found to potentiate L-type Ca+ current (up to 80%) in a concentration-dependent fashion by increasing the mean open time and the open probability of the single channel [7].
These cocaine-induced effects on isolated cardiac cells have to be reconciled with the in vivo situation, as a potent sympathomimetic influence has to be taken into consideration [1]. This will in part enhance the direct cocaine effects, such as potentiation of ICa,L, or may also reduce them, e.g. by reducing the APD. Furthermore, cocaine has been shown to release endothelin-1 from cultured endothelial cells [8], which in turn may augment cocaine-induced vascular constriction.
Taken together, these observations support the hypothesis that a variety of different cellular responses such as alterations of the ionic currents, vasoconstriction, and paracrine hormone (angiotensin/endothelin) release is triggered by cocaine in the myocardium. Depending on the subject studied and the dosage used, this may ultimately explain why the clinical picture after acute cocaine administration displays such a great variability. However, this leaves behind the integrative rationale as to how the stunning of the myocardium progresses after repetitive use.
In the study of Moritz et al. [9] in this issue, another player in the cardiac cocaine connection is pursued. An excessive amount of circulating catecholamines is known to induce cardiomyopathy not only through cardiac adrenergic receptors, but possibly also by increased reactive oxygen species (ROS) [10]. As cocaine leads to a catecholamine surplus, Moritz et al. [9] hypothesized that cocaine administration may also induce formation of ROS. Moritz et al. [9] demonstrate that lipid peroxidation, antioxidant enzyme activity, and NADPH-driven superoxide production are significantly elevated after short-term cocaine administration. Elevated biochemical parameters were associated with increased gp91phox and p22phox mRNA expression (encoding NADPH genes). However, the authors did not detect any changes in ventricular function and hemodynamic parameters after short-term cocaine application, which may in part be due to the low dose of cocaine that was injected (2x7.5 mg/kg/day) and to the 3-h time interval between the last injection and the monitoring of the hemodynamic parameters.
Blood pressure and heart rate remained unchanged even after 8 days of cocaine administration (2x7.5 mg/kg/day), but the ventricular function assessed by echocardiography was impaired. Fractional shortening as well as the cardiac index were significantly reduced and left ventricular end-systolic diameter as well as left ventricular mass were increased. No differences in indexed myocardial fibrosis and necrosis were observed. Although this study does not concentrate on microfocal myocardial necrosis that is a hallmark of catecholamine myotoxicity, the findings extend earlier observations of cocaine-induced cardiac stress. Moreover, it has already been demonstrated that both cocaine and norepinephrine can induce cardiomyocyte apoptosis [11,12]. After 8 days of cocaine administration, catalase as well as superoxide dismutase activity decreased while NADPH values remained elevated. Elevated NADPH activity points to a central role of this oxidase system in the progression of cocaine-related cardiac hypertrophy. Earlier studies showed that gp91phox-deficient mice exhibit a blunted response to angiotensin-induced hypertrophy [13]. The induction of ROS reported by Moritz et al. [9] extends the findings of earlier reports [14]. Application of higher doses of cocaine (40 mg/kg/30 day) resulted in a decrease of glutathione accompanied by an increase of oxidised glutathione and mimicked the effects that were obtained in animals treated with norepinephrine [14].
Cotreatment with antioxidants (vitamin E 100 U/kg/day and vitamin C 100 mg/kg/day) and cocaine lead to biochemical changes of ROS but not to significant alterations of cardiac function nor to hypertrophy. This is consistent with the finding that norepinephrine- as well as cocaine-induced cardiac stress and cardiomyocyte apoptosis is prevented by antioxidant treatment [10,11]. The potential benefit of antioxidant therapy strategies such as superoxide dismutase mimetics therefore deserves further attention despite the poor outcome of clinical studies that used standard antioxidant treatments [15].
Which mechanisms lead to the progressive left ventricular dysfunction in the study of Moritz et al.? Cocaine is rapidly degraded to benzoylecgonine, ecgonine methyl ester, and norcocaine in the liver. These metabolites have a prolonged half life compared to cocaine and are only slowly excreted from the body. They possess sympathomimetic activities and can lead to hypertension. It is well conceivable that the accumulation of these metabolites leads to a reduction of the antioxidant defense system and a sustained lipid peroxidation leading to cardiac stress. At the dose of cocaine chosen by Moritz et al. [9], neither an increase in heart rate nor in blood pressure was detected. Thus, the cardiac hypertrophy observed does not seem to be an adaptation to an increased peripheral resistance. Most probably, it is a consequence of the increased ROS itself. This observation is of importance to a wider part of the population than cocaine users.
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