What are additional findings on the pathophysiology of cocaine toxicity in rat studies?

Updated: Dec 31, 2020
  • Author: Lynn Barkley Burnett, MD, EdD, JD; Chief Editor: Sage W Wiener, MD  more...
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In rat studies, long-term use markedly increased norepinephrine content of the left ventricle. This theoretically suggests that long-term cocaine users could be at increased risk of malignant arrhythmia if excess norepinephrine also accumulates in the human left ventricle. Of note, coincident with the increase in ventricular catecholamine concentration, the rate of catecholamine synthesis was reduced, reflecting physiologic attempts to decrease sympathetic tone secondary to chronic cocaine stimulation.

Alterations in cardiac histology may produce an arrhythmogenic anatomic substrate. Independent of coronary artery disease or clinically documented MI, cocaine use may induce scattered foci of myocarditis, microfocal fibrosis, and contraction band necrosis, the severity of which is correlated with serum and urine concentrations of cocaine. Although common in the hearts of cocaine and other stimulant abusers, such findings are found in only a minority of hearts examined.

Other conditions providing an anatomic arrhythmogenic substrate include the accessory pathways resulting in Wolff-Parkinson-White (WPW) syndrome, and left ventricular enlargement.

In patients with an arrhythmogenic anatomic substrate, even low levels of cocaine can cause tachydysrhythmias. In a study of 19 people who had survived cocaine-related cardiac arrest, 8 had asystolic arrest (5 because of massive overdose) and the remaining 11 had arrest resulting from ventricular fibrillation (VF). Of the latter group, all had an anatomic substrate for the dysrhythmia: 2 patients had an MI, 3 had WPW, and 6 had left ventricular hypertrophy or cardiomyopathy. On subsequent electrophysiologic testing, several patients had dysrhythmias, which were induced only after they had been given cocaine. [10]

Normal electrical conduction may become disrupted in cardiomegaly, which can be observed with chronic cocaine use. Rat studies have demonstrated that cocaine causes genetic changes in cardiac myocytes. Hemodynamic overload results in the production of high levels of atrial natriuretic factor (ANF). Increased levels of mRNA coding for ANF were measurable within 4 hours after rats were injected with 40 mg/kg of cocaine. When that same dose was administered to rats over 28 days, levels of mRNA coding for collagen and heavy-chain myosin increased, and left ventricular mass increased by 20%. Increased collagen production and increased left ventricular mass are independent risk factors for sudden death.

Similar findings also are observed in humans. The hearts of cocaine users are 10% heavier than those of nonusers. In a study of 200 asymptomatic patients in a rehabilitation program who had used cocaine long term, one third had increased QRS voltage, indicative of left ventricular enlargement. Another study of asymptomatic patients in rehabilitation revealed that more than 40% had an echocardiographically demonstrable increased left ventricular mass. [10]

An autopsy study conducted by Darke, Kay, and Duflou compared cardiovascular and cerebrovascular pathology in decedents dying of cocaine toxicity, opioid toxicity, and those dying of hanging who were toxicologically negative for cocaine or opioids. [11] With gender, effects of age, and body mass index (BMI) having been controlled for, 1 in 7 cocaine users were found to have left ventricular hypertrophy, two and one-half times the odds of such a pathologic diagnosis being made in either comparison group. In patients with enlarged hearts due to long-term exposure to high levels of cocaine, even low cocaine levels can be lethal.

Cocaine also has quinidinelike (IC) direct cardiotoxic effects, causing intraventricular conduction delay, as reflected by widening of the QRS and prolongation of the QT segment. In large doses, blockade of the fast sodium channels prolongs the slope of phase 0 of the cardiac action potential, which may result in a negative inotropic response, bradycardia, and, often as a precursor to death, hypotension from decreased contractility and dysrhythmia.

With high blood levels of cocaine, such as those observed in a body packer or body stuffer when a cocaine packet ruptures, or in a binge user with large cocaine supply, the membrane-stabilizing effects of cocaine may cause cardiac arrest from asystole. In such cases, blood levels may exceed 50,000 ng/mL. Cardiac arrest is even more likely if the patient also has been consuming alcohol, with resultant production of cocaethylene. Tolerance rapidly develops to the euphoriant effects of cocaine but not to its local anesthetic effects of membrane stabilization.

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