Cocaine and the heart – bad news for risk/reward

Due to its unique combination of local anaesthesia and vasoconstriction, cocaine at one time had an important clinical use in ear, nose and throat procedures. However, the drug is embedded in public consciousness for entirely different reasons: its central nervous system stimulant action and concomitant addiction and abuse potential. Indeed, in Sir Arthur Conan Doyle's “Sign of Four” (1890), we witness Sherlock Holmes' singular vice: a predilection to inject a 7 % solution of cocaine during times of boredom and professional inactivity. As Watson remonstrated, Holmes justified his habit as follows “My mind … rebels at stagnation. Give me problems, give me work… I abhor the dull routine of existence. I crave for mental exaltation.” Whether it is through the world's most famous fictional detective, the unhinged Patrick Bateman in Brett Easton Ellis' American Psycho, or any number of films in which crack-cocaine use has been depicted, cocaine has become notorious for its addictive, CNS stimulant effects. In parallel, dangers in its use have long been known. Indeed, in the Sign of Four, Watson admonished Holmes “Count the cost! Your brain may, as you say, be roused and excited, but it is pathological and morbid process which involves increased tissue-change and may at last leave a permanent weakness.” Watson, no doubt, would have seized upon the real-world evidence in the work of Saleem and colleagues in this volume of JMCC Plus to appeal further to Holmes, citing the findings of this new study that potentially damaging myocardial effects of cocaine can be observed with even short-term repeated cocaine use [1].

It is well-established that acute coronary events tend to occur within minutes to hours of taking cocaine [2]. This arises due to the sympathetic stimulatory effects of cocaine that can lead to coronary vasoconstriction and acute hypertension, which in turn can predispose to acute myocardial infarction [2]. Longer term effects of cocaine include vascular disease and cardiomyopathy [2]. The present study by Saleem et al. aimed to ascertain whether a relatively short period of regular cocaine self-administration suffices to produce measurable adverse changes to the heart structure and gene expression [1]. The experimental design draws on well-established methods for studying operant conditioning in rodents, involving self-administration of cocaine. Such methods have been used previously to demonstrate transient hypertension and heart rate responses in rodents that self-administer cocaine, with development of tolerance over time also observed [3,4].

Here, following surgery for superior vena cava implantation of a catheter to enable i.v. self-administration, rats were initially trained to lever-press to administer a food reward (in the form of sucrose pellets) and were then allowed to self-administer a solution containing cocaine or, for control animals, saline [1]. The acquisition phase involving progression of a fixed-ratio reinforcement of 4 (FR4) for cocaine rats and FR1 for saline rats; the maintenance phase duration was 14 days. Addictive behaviour was evidenced in cocaine treated rats by the significantly larger number of self-administered infusions compared to control rats. Animals were sacrificed after 14 days and sympathetic stimulation was evidenced by increased expression of tyrosine hydroxylase (a key control point in catecholamine synthesis) in the adrenal glands of cocaine treated rats [1].

Remarkably, with short term cocaine exposure, H&E staining showed some wall thickening in hearts from cocaine self-administration rats and results of Masson Trichome staining were consistent with initiation of a fibrotic response. Perhaps the most novel findings of the study are gene expression changes identified from a combination of RNA-seq and KEGG analysis, with further supportive RT-PCR analysis: changes were observed in genes linked to glycolytic, cardiac adrenergic signalling and neuroactive ligand-receptor interaction pathways. RT-PCR confirmed reductions in Pfkp (which encodes the platelet form of phosphofructokinase) and Epor (which encodes the erythropoietin receptor that can contribute to cell protection in non-haematopoietic cells). Biomarkers for key parts of the mitochondrial electron transport chain were reduced by cocaine and mRNA for Bax (responsible for Bcl-2-associated X protein which promotes apoptosis) was increased. TUNEL staining revealed significant cardiomyocyte cell death in tissue from self-administered cocaine animals [1].

It seems, then, that in addition to its sympathomimetic actions cocaine can, even with short term use, produce undesirable cardiac molecular reprogramming. The question that arises from these observations is what are the consequences of such changes for heart function? The authors acknowledge that this issue now needs to be addressed. Future work needs to establish the extent to which the changes observed in this study negatively impact functional mechanical and electrical activity and, additionally, whether or not adverse changes reported here following short-term repeated exposure can be reversed on cessation of cocaine administration.

It is also important to highlight that acute cocaine exposure is already known to be associated with other, well-established direct actions that are additional to those reported in this new study. Given its local anaesthetic properties, there is perhaps no surprise that cocaine can inhibit cardiac Nav1.5 channel current [5], due to a combination of resting and use-dependent channel inhibition [5]. Moreover, cocaine has long been known to produce prolongation of QT and rate-corrected QT (QTc) intervals and to augment QTc dispersion (e.g. [6,7]) and it is listed in the “CredibleMeds” database as having a “known risk” of Torsades de Pointes arrhythmia. In line with this, experiments on hERG potassium channels, which are crucial for normal ventricular repolarization, have demonstrated acute hERG current inhibition with cocaine exposure [8,9]. Thus, there are known ion channel blocking effects of cocaine that can occur promptly with acute cocaine exposure.

Cocaine is often taken alongside other drugs and concomitant alcohol use is common [2]. Cocaethylene is a cocaine metabolite that forms in the presence of alcohol and it has been shown to inhibit hERG channels over a similar concentration range to the parent compound, while other cocaine metabolites were seen either to block hERG at much higher concentrations (methylecgonidine) or to produce minimal inhibition (ecgonine methylester or benzoylecgonine) [8,10]. Interestingly, an analysis of patients attending a Spanish emergency department with symptoms of cocaine intoxication showed a clear link between cocaine use and QTc prolongation, but that benzoylecgonine levels and QTc intervals were not correlated [7]. These observations highlight the relevance and value of considering potential effects of cocaine metabolites when contemplating cocaine cardiotoxicity. In the study by Saleem et al. [1], while rats self-administered cocaine, the drug would have undergone some metabolism and so the overall effects observed in this new study are presumably due to the combination of those caused by the parent compound and those due to relevant metabolites. The contribution of particular metabolites to the main effects seen remains to be established. Similarly, it may be instructive in the future to co-administer cocaine with ethanol to determine whether that drug combination exacerbates the negative effects reported here. Potentially, such information could be of value to both clinicians and users.

In summary, the report by Saleem et al. in this volume of JMCC Plus [1] provides a clear demonstration that a relatively short period of repeated cocaine self-administration can induce adverse cardiac structural changes including cell death as well as transcriptome changes that are anticipated to negatively impact mitochondrial function and neuro-humoral signalling. While these changes would be predicted to impair cardiac function, future work should address that issue directly, as well as the role of cocaine versus its metabolites in the overall effects observed and the extent to which changes can be reversed on cocaine cessation. Overall, this valuable new study adds further to the weight of evidence that, quite aside from any ethical or legal considerations, cocaine is bad news from a cardiac health point of view and that restricting use to the short term is no guarantee against potential harms.

CRediT authorship contribution statement

Jules C. Hancox: Conceptualization, Writing – original draft. Andrew F. James: Conceptualization, Writing – original draft.

Declaration of competing interest

The authors have no conflicts of interests to declare.