Various substances have been associated with cardiomyopathies. This includes legally available substances, illicit substances of abuse, and prescribed medications. The epidemiology, pathophysiology, and outcomes of substance-induced cardiomyopathy are varied. In addition to guideline-directed medical therapy, identification of the offending substances and prompt cessation are key features in the management of substance abuse cardiomyopathy.

Although widely consumed, only a small subset of patients with long-standing abuse of ethanol develop a dilated cardiomyopathy. Those with consumption of greater than 90 g/day of ethanol for greater than 5 years are at the highest risk for developing cardiomyopathy, although individual genetic predisposition also plays a role. As ethanol exposure increases, so does the risk of cardiomyopathy, with those ingesting greater than 200 g/day of ethanol having the highest risk of developing cardiomyopathy.

The pathogenesis of alcoholic cardiomyopathy includes various mechanisms, such as direct toxic effects on cardiomyocytes, mitochondrial dysfunction, disruption of calcium homeostasis, increased β-adrenergic tone, increased arrhythmogenic potential, and inappropriate activation of the renin-angiotensin-aldosterone (RAAS) axis. Ethanol’s effects on cardiomyocyte mitochondria have been well-documented, leading to free radical generation. Ethanol also disrupts the sarcoplasmic reticulum causing inappropriate calcium release and derangement of calcium metabolism.¹ This in turn leads to aberrant cardiac remodeling and increased arrhythmogenic tendencies including reentry dependent tachycardias, atrial fibrillation, ventricular tachycardia and ventricular fibrillation.² Finally, RAAS and sympathetic tone is increased by various mechanisms including fluid shifts, poor nutrition, inappropriate systemic vasodilation, and aberrant hormonal signaling. Abstinence of ethanol can often reverse these changes; however, when dose exposure increases, left ventricular dysfunction often becomes irreversible.³

Clinical manifestations of alcoholic cardiomyopathy, as well as treatment, are similar to idiopathic dilated cardiomyopathy, but long-term outcomes are more favorable, especially if the patient maintains abstinence.³ Observational data demonstrate that at 140 months of follow-up, between 35% and 85% of patients with alcoholic cardiomyopathy will be alive as compared to 40% to 70% with idiopathic dilated cardiomyopathy. However, several characteristics portend a poor outcome including continued ethanol use, atrial fibrillation, and electrocardiographic QRS duration greater than 120 ms. Patients with these risk factors have poor outcomes ranging from 0% to 65% survival at 12 years, with accumulating risk factors associated with the worst outcomes. Identifying and modifying these risk factors are key components in the management of alcoholic cardiomyopathy, with ethanol cessation forming the basis of treatment.

Cocaine is a semisynthetic alkaloid derived from the leaves of the Erythroxylum coca plant. It can be consumed in a variety of manners including inhalation, intravenous injection, insufflation, and ingestion. Cocaine acts on dopaminergic and sympathetic receptors in the brain as well as in the periphery and exerts a variety of effects including euphoria. After ethanol, cocaine is the second most commonly used drug and the most commonly encountered drug in patients presenting with chest pain. Postmortem data suggest that up to 28% of regular cocaine users have significant coronary artery disease even among those of young age at the time of death (ie, median age 34 years).⁴

Cocaine exerts its effects by excessively stimulating the dopaminergic and sympathetic nervous systems. This in turn has multiple effects on the heart through hypertension, tachyarrhythmias, cardiomyocyte toxicity, coronary vasospasm, and dissection. In addition, cocaine causes accelerated atherosclerosis as well as microvascular ischemia through inappropriate platelet activation, which contributes to myocardial dysfunction. Hypertension is a well-documented effect of sympathetic activation. In one series, up to 47% of documented cocaine users developed severe, chronic hypertension.⁴ The resultant increased afterload on the heart causes multiple downstream effects including left ventricular hypertrophy, microvascular disease, and maladaptive remodeling through neurohormonal pathways. In addition, cocaine users are at higher risk of developing tachyarrhythmias, most notably atrial fibrillation but also ventricular tachyarrhythmias. This is in part caused by increased sympathetic activation brought on by cocaine use, as well as myocardial remodeling. Cocaine is also directly toxic to cardiomyocytes, causing oxidative damage, free radical generation, disruption of calcium stores, and eventually myonecrosis.
Finally, cocaine exerts direct toxic effects on the vasculature by causing endothelial disruption. This in turn leads to vascular inflammation, plaque formation and erosion, and intra-arterial thrombosis through direct platelet aggregation induced by cocaine and its metabolites.

The outcomes of cocaine-induced cardiomyopathy are directly linked to continued cocaine abuse. Cocaine cessation often results in reversal of cardiomyopathy, although up to 30% of patients will not recover cardiac function.⁵

Amphetamines are a class of semisynthetic chemicals with profound dopaminergic and sympathetic activity. In controlled settings, amphetamines and their derivatives provide relief from multiple conditions including attention deficit disorder, but when consumed in excess, methamphetamine exhibits short- and long-term consequences to the cardiovascular system. Methamphetamine ingestion provides a long-lasting high that has proven resistant to substance abuse counseling and treatment, leading to a significant dependency on the substance. Data from hospital diagnosis codes reveal that up to 5% of admissions for heart failure (HF) exacerbations are caused by methamphetamine use. Patients with methamphetamine-associated cardiomyopathy are typically younger (ie, average age at diagnosis is 49.7 years) than individuals with idiopathic dilated cardiomyopathy and with significant left ventricular dysfunction, with up to 30% of patients having left ventricular ejection fractions (LVEF) less than 40% at the time of diagnosis. Those with the highest amounts of methamphetamine consumption have more severely depressed LVEF.⁶

Methamphetamine exerts numerous effects on the cardiovascular system, which in turn promote aberrant remodeling, myocardial loss, and ultimately cardiomyopathy. Methamphetamine abuse results in catecholamine excess, increased reactive oxygen species, direct myocardial toxic effects, mitochondrial dysfunction with aberrant coupling of the electron transport chain, and coronary vasospasm and ischemia. In addition, catecholamine excess causes increased left ventricular afterload, aberrant cardiac remodeling, and myocyte necrosis. Endomyocardial biopsy of methamphetamine users demonstrates extensive fibrosis, with higher levels of fibrosis corresponding to more severe left ventricular dysfunction. In addition to left ventricular dysfunction, methamphetamine use is emerging as a significant cause of pulmonary arterial hypertension (PAH). Long-standing PAH can lead to right ventricular failure. Direct endothelial injury by methamphetamine results in aberrant pulmonary vascular remodeling. Methamphetamine also causes dysfunction of key modulators of vascular function including endothelin, carboxylesterase 1, and bone morphogenetic protein receptor type 2. Although pulmonary vasodilators can provide some relief, early intervention and methamphetamine cessation are key in preventing the progression of PAH. However, even with cessation, return of normal pulmonary vascular function may not occur.

In a case series in Germany, 57% of patients presenting with decompensated HF attributed to methamphetamine with continued abuse had high mortality; median time to death was approximately 6 months. Furthermore, survivors demonstrated persistent left ventricular dysfunction and repeated admissions for HF exacerbations. However, in those who were able to cease methamphetamine abuse, 80% were alive at 26 months. Moreover, these patients saw drastic increases in their left ventricular function: mean LVEF increased from 23% on initial discharge to 47% at follow-up. In comparison, those with continued methamphetamine use had a decline in LVEF from 19% to 17%, despite similar prescription rates of guideline-directed medical therapy.⁷

Several prescription medications have been associated with cardiomyopathy. A limited list of drugs associated with cardiomyopathy is provided in Table 74.1.

Chloroquine and its derivatives are immunomodulators used in the treatment of a variety of rheumatologic conditions including rheumatoid arthritis. Chloroquine and derivatives are increasingly recognized as cardiomyocyte toxic agents leading to drug-induced cardiomyopathy. Frequently a restrictive cardiomyopathy occurs, although dilated and hypertrophic variants have been described as well. In addition to direct cardiomyocyte toxicity, chloroquine can exert toxic effects on the cardiac conduction system including the sinoatrial and atrioventricular nodes. Cardiomyopathy may become evident within weeks of the beginning of therapy or manifest after years of treatment. Cessation of chloroquine can reverse cardiomyopathy; however, persistent myocardial dysfunction requiring advanced therapies including transplantation has been reported.⁸ Although endomyocardial biopsy is the gold standard for diagnosis, a careful history and review of the medication list can often provide clues. Endomyocardial biopsy reveals vacuolization of cardiomyocytes, confirming the diagnosis.

Clozapine is a dopamine antagonist most commonly used in schizophrenic spectrum psychiatry disorders. Although agranulocytosis is the most commonly associated adverse effect of clozapine, IgE-mediated myocarditis resulting in cardiomyopathy is a recognized complication. Although most often encountered in the first few weeks of treatment, clozapine-induced myocarditis can also present later, even years after clozapine treatment. In addition to a careful review of the medication list, laboratory assessments of C-reactive protein and troponin I or T levels may provide clues to a developing cardiomyopathy. Prompt cessation of clozapine often results in reversal of the cardiomyopathy.

Drug-induced cardiomyopathies are an important cause of non-ischemic cardiomyopathy. Prompt detection and cessation of offending drugs is key in reversing myocardial dysfunction.
The fundamentals of cardiomyopathy treatment remain similar, namely neurohormonal blockade and fluid management to treat congestive symptoms. It is unclear whether treatment must be continued after cessation of the offending agent and myocardial recovery is observed. More research is needed to help guide specific therapies as well as identify potential causes of cardiomyopathy as the list of pharmacologic agents ever expands.

Advances in chemotherapy, novel immune- and targeted therapies have been lifesaving for patients with cancer. These treatments are not thought of as “toxins” per se, but they do have the potential for adverse cardiac side effects. For example, treatment of breast cancer involves chemotherapy with anthracycline-containing regimens, targeted therapy with antihuman epidermal growth factor receptor 2 (HER2) agents, and radiation therapy. The use of these agents may result in treatment-associated cardiotoxicity. Furthermore, the presence of concomitant cardiovascular risk factors and comorbidities can affect the timing, severity, and potentially the reversibility of cancer therapy-related cardiotoxicities. Cardiotoxic effects of chemotherapeutics can occur immediately upon exposure or years later depending on the anticancer therapy.

Cancer therapy-related cardiomyopathy may present as asymptomatic left ventricular systolic dysfunction, subclinical diastolic dysfunction, symptomatic HF, and even cardiogenic shock. Chemotherapy-induced cardiomyopathy is estimated to affect up to 10% of cancer survivors and has among the poorest prognosis compared to other causes of cardiomyopathy.

Anthracyclines have been used for a variety of cancers including solid (eg, breast cancer, sarcoma, lung cancer) and hematologic (eg, leukemia, lymphomas) malignancies. Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin, and mitoxantrone) were first implicated as potential culprits for cardiomyopathy in 1967 when daunomycin was being used for leukemias.

In the Childhood Cancer Survivor Study, administration of less than or equal to 250 mg/m² anthracycline therapy was associated with 2.4× increased risk for developing HF, but that rose to a 5.2× risk if greater than 250 mg/m² doxorubicin was administered. In contrast, some patients have received doses as high as 1000 mg/m² without significant cardiac events, whereas others developed cardiac dysfunction after doses as low as 100 mg/m².⁹ Overall, the risk of cardiotoxicity increases with cumulative doses of anthracycline; for instance, with doxorubicin, there is an approximately 5% risk at a cumulative dose of 400 mg/m², a 26% risk at a dose of 550 mg/m², and up to a 48% risk at a cumulative dose of 700 mg/m².¹⁰ Factors
associated with an increased incidence of anthracycline-induced cardiomyopathy include total dose, dose fractions, concomitant therapies (ie, other chemotherapy or radiotherapy), female sex, cardiovascular risk factors (including tobacco use, hypertension, dyslipidemia, obesity, diabetes mellitus, underlying left ventricular dysfunction), and age (>65 years or <4 years).¹¹,¹² Genetic factors may also play a role. Decreased expression of topoisomerase 2b has been associated with a variant of the retinoic receptor g gene, which predicts predisposition to cardiotoxicity in childhood cancer patients receiving anthracycline therapy.¹³