Cocaine and the Heart

In this review, we examined the detrimental effects of cocaine and its metabolites on the cardiovascular system. Moreover, we accented to the role of oxidative stress (OS) in the pathology of cocaine-induced cardiotoxicity. The review aims to develop methods for diagnosing acute and chronic cocaine toxicity by determining OS levels in biological samples used mainly in emergency medicine and toxicology clinics. While the published literature has demonstrated an association between cocaine use and cardiovascular disease, there is still a lack of research regarding to whether prolonged use of cocaine would lead to conspicuous increase of plaque burden. The present study aimed to determine the relationship between total coronary plaque volume throughout the entire coronary vasculature in relationship to years of cocaine use in asymptomatic individuals with or without HIV.

High levels of catecholamines disrupt calcium homeostasis and increase the activity of NAD(P)H oxidase and xanthine oxidase. As a result, additional amounts of ROS and RNS are generated in the mitochondria, which cause mitochondrial dysfunction. High ROS levels damage cellular macromolecules (DNA, lipids, and proteins) and adversely affect myocardial calcium function, causing arrhythmias, increasing cardiac remodeling, and leading to hypertension, necrosis, and apoptosis 47. Lipid peroxidation is a major cause of myocardial membrane phospholipid damage and leads to glutathione depletion in chronic cocaine use 119. Calcium and OS overload cause cardiomyocyte death in both the apoptotic and necrotic pathways.

Cocaine Cardiotoxicity in Human Studies

Volkow et al. 64 were the first to document that CUD had profound decreases in CBF as evidenced by decreased brain uptake of water. Cocaine doses within the range self-administered by drug abusers can markedly decrease CBF (approximately by 70%) within 2–3 min after administration, lasting in some arteriolar branches for over 45 min 5. Thus, cocaine induces microischemia in various types of vessels and arteriolar branches that is exacerbated with repeated use and is likely to be a contributor to its neurotoxic effects 5. Furthermore, chronic cocaine-use reduces capillary flows in brain and may be responsible for cerebrovascular small-vessel ischemic disease (e.g. cocaine-induced leukoaraiosis), possibly involving genetic factors 65,66. The mechanism of cocaine toxicity involves the expression of enzymes and compromise of mitochondrial function through direct or indirect action of cocaine on endothelial cells.

Concomitant Drug Use and Lifestyle

Cocaine and its significantly more toxic metabolite cocaethylene lead to ion channel blockade (the Na+ and K+ channels), prolonged QT interval, early postdepolarization, and ventricular tachyarrhythmia 89. In combination with high levels of catecholamines, it can cause acidosis and electrolyte abnormalities, which increases the likelihood of cardiac arrhythmias 49. In the event of sudden cardiac death due to cardiac arrhythmias and/or prolonged QT interval, no structural changes in the heart were observed 83. We did not include historical reviews and articles that are not in English and are not directly related to cocaine-induced pathological changes in the cardiovascular system. Scientific publications describing the effects of various narcotic substances (amphetamine, methamphetamine, heroin, methadone, marijuana, etc.) were not considered.

As mentioned previously, cocaine inhibits the reuptake of dopamine by interacting with the dopamine transporter, resulting in increased levels of dopamine in the central nervous system. Subsequently, changes in dopamine levels affect eating behavior and body weight 103,104,105. Increased dopaminergic neurotransmission suppresses overall food intake whereas it increases fat-rich food intake 106.

Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. The etiology underlying cocaine’s acute and chronic vascular effects is multifactorial, spanning hypertension, impaired homeostasis and platelet function, thrombosis, thromboembolism, and alterations in blood flow. Early detection of vascular disease in cocaine addiction by multimodality imaging is discussed. Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding β-blockers. The drug transesterification in the presence of ethanol (EtOH) results in the formation of a potent pharmacologically active metabolite cocaethylene (ethylbenzoylecgonine) (Figure 2) 74,75, which shows direct cardiotoxicity, with a proven high risk of heart attack 76. Ethanol enhances and prolongs the effects of cocaine on the cardiovascular system, and the combination of cocaine and ethanol is acute and chronic effects of cocaine on cardiovascular health pmc more cardiotoxic than any other.

• There is also evidence that the cardiovascular actions of cocaine are mediated in part by dopamine 20, via central and peripheral mechanisms 21.
• Acute coronary syndrome and acute myocardial infarction are two common cardiovascular issues that arise in cocaine users (6).
• A review found that a single dose of cocaine increases a resting heart rate by 30 beats/minute and raises blood pressure by 20/10 mmHg (8).
• Underlying this addiction is CUD’s association with abnormal brain morphology 11 and function involving inefficiencies in circuits that coordinate reward and self-control processes 12.
• Concomitant use of cocaine and nicotine significantly exacerbates the harmful effects of the drug on the heart by disrupting the supply of oxygen to the myocardium by potentiating coronary arterial vasoconstriction 78.
• Basnet et al. reported a healthy 17-year-old adolescent who presented to the emergency room complaining of burning chest pain radiating to the jaw that awoke him from sleep.30 He admitted to marijuana use and denied cocaine use.

Results

• Although the role of OS in the pathogenesis of cardiotoxicity in cocaine intoxication is well known, to date, the potential use of nitroxide radicals as redox-sensitive detectors to determine OS levels in cocaine-induced cardiotoxicity has not been considered.
• Calcium and OS overload cause cardiomyocyte death in both the apoptotic and necrotic pathways.
• Cocaine-induced cardiotoxicity can result in deleterious effects on the heart and vessels through multifactorial pathophysiological mechanisms, as described above.
• Numerous studies have also shown various physiologic mechanisms linking depression and CVD.82 One possible mechanism uses stress as a possible factor.
• The mechanism of cocaine toxicity involves the expression of enzymes and compromise of mitochondrial function through direct or indirect action of cocaine on endothelial cells.
• Cocaine was reported as a strong vasoconstrictor and can be detected in the blood and urine even 4 days after use.

The prevailing low socio-economic status, limited awareness of health issues, lack of sleep, and poor nutrition, could further hasten vascular disease 43,44. Additionally, genetic factors leading to variability in reaction to cocaine can enhance hemodynamic responsiveness, incidence of coronary vasoconstriction, and vascular damage 16. There is growing evidence of the influence of oxidative stress on the pathogenesis of cardiotoxicity in cocaine abusers. Oxidative stress (OS) occurs when the production of reactive oxygen and nitrogen exceeds the antioxidant defense systems of cells 102. As a result of an imbalance between the generation and elimination of ROS and RNS, changes in redox homeostasis are achieved 103.

2.2. Atherosclerosis

After cocaine use, populations at high risk for CAD experienced coronary atherosclerosis whereas those at low risk did not experience CAD, suggesting that the chronic effects of cocaine were more likely to be prominent among individuals with higher CAD risk. Studies also suggested that risky behaviors and cardiovascular risks may affect the association between cocaine use and mortality. Our study findings highlight the need for education regarding the deleterious effects of cocaine, and access to interventions for cocaine abusers. In recent years, there have been increasing scientific reports of cocaine-induced cardiac dysfunction as a result of nitrosative/oxidative stress after cocaine use and mitochondrial dysfunction as a result of oxidative damage to cellular structures 17,18,117,118. Cocaine directly inhibits the mitochondrial electron transport chain by increasing intramitochondrial Ca2+ overload and depleting adenosine triphosphate (ATP) production.

Long-term cocaine use is associated with increased coronary plaque burden – a pilot study

Advanced atherosclerosis of intracranial vessels 32 is noted as the cause of cocaine-induced stroke in numerous studies 4,29. Although the role of OS in the pathogenesis of cardiotoxicity in cocaine intoxication is well known, to date, the potential use of nitroxide radicals as redox-sensitive detectors to determine OS levels in cocaine-induced cardiotoxicity has not been considered. In the context of their redox properties, they can find wide application in determining the severity and consequences of acute and chronic drug intoxication.

Histamine released from mast cells increases endothelial permeability, which leads to leukocyte migration 67. As such, cocaine has complex effects on endothelial cell dysfunction, facilitates low-density lipoprotein and leukocyte migration, and increases intimal smooth muscle cells, all of which contribute to atherosclerosis in long-term users. The effects of chronic cocaine use on the cardiovascular system have been reported in the literature (5–7). A review found that a single dose of cocaine increases a resting heart rate by 30 beats/minute and raises blood pressure by 20/10 mmHg (8).

Future directions: urgent need for early detection of a complex disease process in a vulnerable and aging population

Histological specimens examination of chronic cocaine users shows the presence of scattered foci of necrosis with loss of cardiac myofibrils, myocyte degeneration, and edema. Inflammatory cells that infiltrate necrotic tissue and remarkable mononuclear infiltration around cardiomyocytes can be seen 82. Our study demonstrated a strong tendency towards overall more pronounced atherosclerosis in chronic cocaine users and the longer the cocaine use, the greater the plaque burden. Additional research is needed to uncover if plaque progressions among coronary territories were heterogeneous in cocaine users as well as its detrimental health consequences. The relationships between total plaque volume (a) and left anterior descending artery (LAD) plaque volume (b) versus cocaine years use in the unadjusted data presented for illustrative purposes.

1. The Basic Pathways of Cocaine Cardiotoxicity

Chronic cocaine use was defined as administration via any route for a period of 6 months and at least 4 times/month, based on self-report and confirmed by a urine test during initial study visit. As evident from this review, there is ample data on cocaine-induced endothelial dysfunction, vasoconstriction, and accelerated atherosclerosis. The first line of treatment for cocaine induced sodium channel blockade is alkalization with hypertonic sodium bicarbonate. In patients with acute manifestation of cerebrovascular events it is essential to perform a toxicological drug screening also in presence of normal blood pressure and with spontaneous subcortical hemorrhagic stroke and negative anamnesis for drug abuse at admission 95.

We present the main mechanisms of acute and chronic cocaine-induced toxicity on vessels, brain and heart (Fig. 1) and the common vascular and systemic effects of cocaine use in humans (Fig. 2). Particular attention was given to the imaging studies that measured cocaine-induced changes to the human heart, brain, and arteries (Table 1), since these methods are gaining a central role as markers of inflammatory disease. The aim of our study was to examine the role of oxidative stress in cocaine-induced cardiomyopathy. A preliminary review of the literature was conducted, with a focus on the involvement of free radicals in the mechanisms of induction of pathological changes in the cardiovascular system in cocaine users.

In addition, acute vessel damage induces platelet aggregation/blood clots through increased fibrinogen and von Willebrand factor, leading to acute heart damage due to reduced blood flow 21. Taken together, cocaine induces acute hypertension, coronary spasm, which may lead to subsequent myocardial infarction. Cerebral vasospasm is pharmacologically induced via cocaine’s potent sympathomimetic properties 32 and an increase of endothelin-132,34. In addition, cocaine induces disruption of cerebral autoregulation of blood flow (maintaining relatively constant blood flow despite changes in perfusion pressure) and global reduction in cerebral glucose metabolism 31. Abnormalities in the expression of transcription factors in cells and changes of brain neurotransmitter systems have been reported 31.