Another case reported by Gunawardena et al. described a 29-year-old male who presented with acute coronary syndrome following consumption of marijuana. He had dynamic ST-segment elevation in different leads and a markedly elevated troponin.28 Coronary angiography did not elucidate any occlusive atherosclerotic disease. There was evidence of slow flow in the left anterior descending artery, which improved with intracoronary nitrate therapy. A diagnosis of coronary vasospasm was made, and it was inferred that cannabis consumption was the primary cause. In both reports, coronary angiography did not demonstrate occlusive atherosclerotic disease.

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

In cell line studies, ROS was found to have a primarily direct effect on cardiac cells by activating mitogen-activated protein kinase (MAPK) and NOX2. These results in acute myocardial oxidative stress, oxidative damage to cardiomyocytes, and cell death in a mouse model 120,121. The first mechanism is the activation of the MAPK-beta-adrenergic receptor after calcium overload and subsequent phosphorylation of a multitude of calcium-containing cyclic proteins. The second mechanism is based on the redox cycle and takes place in the mitochondria 122. It is also known that high levels of oxidative stress can cause mitochondrial transition pore opening, leading to the generation of abnormal ROS levels and so-called ROS-induced ROS release.

• Lipid peroxidation is a major cause of myocardial membrane phospholipid damage and leads to glutathione depletion in chronic cocaine use 119.
• As a result of an imbalance between the generation and elimination of ROS and RNS, changes in redox homeostasis are achieved 103.
• Sudden increases in arterial pressure can induce aneurysms (a localized widening of an artery or vein, resulting from weakening of vessel wall), arteriovenous malformations (abnormal connection between arteries and veins, bypassing the capillary system) and hemorrhagic strokes 55.
• Cocaine releases endothelin-145, which is found to be elevated in CUD and declines with detoxification 36,46,47.
• Another case reported by Gunawardena et al. described a 29-year-old male who presented with acute coronary syndrome following consumption of marijuana.

Cocaine and the Heart

• Finally, causal relations cannot be assessed in this cross-sectional study, and generalizability of the results from this study should be evaluated in a large cohort.
• And R.M.; supervision, E.G. and G.N.; project administration, E.G. and G.N.; funding acquisition, E.G. and G.N.
• “Crack-Cocaine” was introduced in the mid-1980s involving a new route of administration, smoking (as opposed to sniffing), which enhances vascular toxicity.
• Conceptualization, E.G.; methodology, E.G.; software, E.G.; validation, E.G., Y.K., R.M., H.A.
• In addition to the limbic region, stimulants exert their effects on the brain by increasing the release of norepinephrine in the prefrontal cortex 30.

It is assumed that the action of methylphenylamine also depends on its concentration; furthermore, the dose is crucial for determining the effects of abuse of amphetamine and/or its analogs. Thus, at low concentrations, AMPH acts primarily as a DAT blocker, while high concentrations increase and promote DAT-mediated back transport of dopamine from the cytoplasm to the synaptic cleft 22,43,44. There is a lack of research regarding whether prolonged use of cocaine would lead to increase of coronary plaque burden. Drugs or substances in this schedule have a high potential for abuse, which may lead to severe psychological or physical dependence. Approximately 40% of all emergency department visits related to drug misuse and abuse were attributed to cocaine 8.

Cocaine-Related Sudden Cardiac Death

Cocaine treatments in rats (20, 30, 40, and 50 mg/kg) resulted in significant reductions in the maternal weight gain and food consumption in a dose-dependent manner. However, maternal water consumption was significantly increased in the cocaine-exposed animals possibly because of the increased locomotor activity and diuretic effect. Furthermore, cocaine provoked diarrhea in some of animals that received high doses, suggesting that cocaine, as a gastrointestinal irritant, might cause malabsorption and loss of electrolytes and nutrients, which ultimately can lead to malnutrition. Maceira et al. 45 found that cocaine abusers had increased LV end-systolic volume, LV mass index, and right ventricular (RV) end-systolic volume, with decreased LV ejection fraction and RV ejection fraction.

The mechanism involves an increase in extracellular dopamine and prolongation of DA-receptor signaling in the striatum 41,42. Both cocaine and amphetamines increase the time interval in which DA remains at the postsynaptic receptor 33. Chest pain 8,13,76 and cerebrovascular events 5,31,63 may occur within minutes to just a few hours from cocaine use. Atherosclerosis, however, develops during prolonged periods of chronic cocaine use and in its early stages usually does not create symptoms or signs. Indeed, silent disease progression is particularly pronounced in CUD who remain asymptomatic until they reach the emergency room with acute events 8,24,73. Therefore, the ability to identify plaques before luminal stenosis develops is fundamental for early disease detection 99.

Over 550 clinical, laboratory, epidemiological studies and literature reviews related to stimulant use and cocaine-induced cardiotoxicity were studied, from which we selected 137 articles directly related to our topic (Scheme 1). Globally, their use reaches epidemiological proportions and is one of the most common causes of death in many countries. The use of illicit drugs has negative effects on the cardiovascular system and is one of the causes of serious cardiovascular pathologies, ranging from abnormal heart rhythms to heart attacks and sudden cardiac death.

Dopamine accumulates in the synaptic cleft and causes increased activity of postsynaptic receptors, eliciting an enhanced response in the host cell (Figure 1) 34. Retention of the cocaine molecule by DAT leads to overstimulation of dopaminergic neurons and excessive synaptic metabolism of the neurotransmitter 35. Increasing the DA absolute concentration at the synapse and the time interval in which the neurotransmitter remains at the site of the postsynaptic receptor disturbs the balance between the release of DA and the reuptake of the dopamine molecule 33. Cocaine inhibits the reuptake of the monoamine neurotransmitter 5-hydroxytryptamine (5-HT) by blocking the action of SERTPR, enhancing the secretion of adrenaline and noradrenaline from the adrenal cortex, which enhances the effect of norepinephrine. As a result, sustained supraphysiological extracellular levels of various catecholamines were observed 37, which defines the drug as a potent sympathomimetic agent with a direct cardiotoxic effect 38. Depending on the dose and the presence of concomitant cardiovascular disease, the clinical effects vary widely and include vasoconstriction, arrhythmia, tachycardia, aortic dissection, heart attack, myocardial ischemia, etc. 11,12.

1.3. Acute Myocardial Infarction

Chronic cocaine use causes repetitive damages to the heart and vessels by interacting with norepinephrine transporters 68. Alpha-2 adrenergic receptors induce vasoconstriction of coronary arteries through contraction of vascular smooth muscle cells 34, leading to prothrombotic effects caused by increased von Willebrand factor 21. Cocaine induces vasospasm through stimulation of adrenergic receptors on coronary arteries 69. In addition, long-term use of cocaine induces endothelial injury, vascular fibrosis 73,74, and subsequent vessel wall weakening 75, resulting in apoptosis of vascular smooth muscle cells and cystic medial necrosis 76,77. According to previous reports, cocaine sometimes induces coronary and carotid aortic dissections 78,79,80. Thus, cocaine causes coronary artery diseases through multifactorial mechanisms including vasoconstriction, intracoronary thrombosis, and accelerated atherosclerosis.

Especially important for the drug’s amplified effects is the way they are administered (intravenous, intranasal, and smoking). Volkow et al. determine the rate at which cocaine enters the brain as a key parameter in its effectiveness in blocking DAT. Using 11C-labeled cocaine and positron emission tomography (PET), they found a significant blockade of the dopamine transporter in all modes of cocaine administration. A dose-dependent effect was observed with intravenous and intranasal administration but not with cocaine smoking 39. Moreover, for the enhancing properties of the drug, the involvement of a “phasic” dopamine firing is particularly important, which is characterized by sharp fluctuations in neurotransmitter levels 40. Similar to cocaine, amphetamine (AMPH) acts on DAT by activating the mesolimbic dopaminergic pathway.

Cocaine also enhances coronary spasm/vasoconstriction and platelet adherence/thrombosis, leading to reduced myocardial oxygen supply 34. At high doses, cocaine-induced local anesthesia results in decreased left ventricular (LV) contractibility and prolongation of QRS and QT intervals in electrocardiograms acute and chronic effects of cocaine on cardiovascular health pmc by blocking sodium transport and norepinephrine uptake in the myocardium 4. In vessels, cocaine contributes to MI by increasing endothelin-1 36 and reducing nitric oxide production in endothelial cells 37. When vessels are stressed, acute damages/ruptures can occur, which promotes thrombosis by increasing platelet activity/aggregation 38,39 and elevating fibrinogen levels 40 and plasminogen activator inhibitor activity 41,42. These cellular and molecular cascades result in reduced cardiac blood flow, leading to acute MI and possibly atherosclerosis and coronary thrombosis in the long term 43,44.

The short-term physical effects of cocaine include sensitivity to environmental factors, increased energy, and mental alertness. There is a wide range of physiological effects from increased heart rate to narrowing of blood vessels. Long term use can lead to negative health consequences such as cardiovascular problems, coma, and seizures (2,3). Even though the rates of cocaine use have remained steady over the past decade, cocaine is still a widely used substance in the United States.

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. The Electrocardiogram (ECG) demonstrated ST-segment elevation in the lateral leads followed by a blood troponin of 0.23 U/l (normal, 0.00–0.04 U/l). Cardiac magnetic resonance imaging was performed, and it was suggested that symptoms and objective cardiac findings were secondary to transient myocardial ischemia. This report was one of the first to describe coronary vasospasms in an adolescent likely from marijuana abuse.

Fig. 1. Cocaine’s acute and chronic toxicity mechanisms.

Also, the authors found that current marijuana users smoked more cigarettes and consumed higher amount of sodas and alcohol, when compared to their counter cohort. It was also reported that marijuana smokers had less folate and carotenoids in their blood possibly secondary to increased oxidation from both marijuana and tobacco smoke inhalation. Cocaine-induced cardiotoxicity can cause a variety of structural and functional damage to cardiac tissue 48.

However, the accelerated development of vascular disease remains mostly undetected and asymptomatic presentation of vascular pathology in CUD results in silent disease progression. Cocaine use, and especially crack cocaine abuse, creates a rare but extremely fatal aortic dissection condition, probably due to decreased aortic elasticity and sudden and profound hypertension and tachycardia 102. Chronic treatments for CUD with cardiovascular problems include antiplatelet and antithrombin agents, statins and diuretics. Conceptualization, E.G.; methodology, E.G.; software, E.G.; validation, E.G., Y.K., R.M., H.A. And G.N.; formal analysis, E.G.; investigation, E.G. and G.N.; resources, E.G. and G.N.; data curation, E.G., Y.K., R.M., H.A.