Outline
Definition, 269
Epidemiology of Dilated Cardiomyopathy, 270
Natural History of Dilated Cardiomyopathy, 270
Pathophysiology, 272
Diagnostic Strategies in Dilated Cardiomyopathy, 273
General Management Strategies of Dilated Cardiomyopathy, 273
Myocardial Diseases Presenting as Dilated Cardiomyopathy, 273
Idiopathic Dilated Cardiomyopathy, 274
Familial/Genetic Cardiomyopathies, 274
Cardiomyopathy Due to Cardiotoxins, 275
Alcoholic Cardiomyopathy, 275
Cocaine Cardiomyopathy, 276
Cardiomyopathy Related to Other Stimulant Drugs, 276
Chemotherapy, 277
Other Myocardial Toxins, 277
Inflammation-Induced Cardiomyopathy, 277
Infectious Causes, 277
Acquired Immunodeficiency Syndrome, 277
Noninfectious Causes, 278
Hypersensitivity Myocarditis, 278
Systemic Lupus Erythematosus, 278
Scleroderma, 278
Rheumatoid Arthritis, 278
Sarcoidosis, 278
Peripartum Cardiomyopathy, 279
Autoimmune Mechanisms, 281
Endocrine and Metabolic Causes of Cardiomyopathy, 281
Obesity, 281
Diabetic Cardiomyopathy, 282
Hyperthyroidism, 282
Hypothyroidism, 282
Acromegaly and Growth Hormone Deficiency, 283
Nutritional Causes of Cardiomyopathy, 283
Hematologic Causes of Cardiomyopathy, 284
Cardiomyopathy Due to Iron Overload: Hemochromatosis and Thalassemia, 284
Hemodynamic and Stress-Induced Cardiomyopathy, 285
Tachycardia-Induced Dilated Cardiomyopathy, 285
Premature Ventricular Contractions and Cardiomyopathy, 285
Stress-Induced Cardiomyopathy, 285
Summary and Future Directions, 285
Definition
The term dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders ( Table 20.1 ) that are characterized by ventricular dilation and depressed myocardial contractility in the absence of abnormal loading conditions (such as hypertension or valvular disease) or ischemic heart disease sufficient to cause global systolic impairment. Such a definition with emphasis on anatomic description has been challenging, as there could be heterogeneity of expression of the same disease with different phenotypes, or a phenotype may progress from one to another during clinical course (e.g., hypertrophic or infiltrative cardiomyopathies may progress to a dilated form). Although DCM is recognized as a final common pathway for a myriad of cardiac disorders that either damage the heart muscle or, alternatively, disrupt the ability of the myocardium to generate force and subsequently cause chamber dilation, this anatomical characterization fails to emphasize etiology. From a pathologic standpoint, the term DCM is traditionally used to designate an idiopathic or unknown process, but the morphological categorization should not undermine the necessity of search for an etiology and a specific diagnosis. It is likely that the term “dilated cardiomyopathy” will gradually be replaced with specific diagnoses underlining the etiology.
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Recent proposed classifications, such as MOGE(S), describe ( Fig. 20.1 ) the morphofunctional phenotype (M), organ involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association (NYHA) functional class. This approach does not dichotomize the classification as dilated versus hypertrophic cardiomyopathies; recognizes the flexibility of potential transitions between morphofunctional types; defines involvement of different cardiac structures and extra cardiac organs; emphasizes etiology such as genetic causes, progression of symptomatology, and functional status; and provides more precision for diagnosis and prognosis.
In clinical practice and multicenter trials, heart failure has often been categorized into ischemic and nonischemic cardiomyopathy, and the term DCM has been interchangeably used with nonischemic cardiomyopathy. Though this approach may be practical, it is overly simplistic and fails to recognize that the term “nonischemic cardiomyopathy” may include cardiomyopathies due to volume or pressure overload—such as hypertension or valvular heart disease—that are not conventionally accepted under the definition of DCM, and also fails to recognize specific etiologies of DCM.
Epidemiology of Dilated Cardiomyopathy
Due to challenges and changes in approaches to definition and diagnosis, geographical, environmental, and genetic variation, the reported incidence of DCM varies in publications. In Western populations, the annual incidence of DCM is about 5 to 8 cases per 100,000 of the population. The prevalence is considerably higher in underdeveloped and tropical countries due to various infectious and environmental factors. As populations go through epidemiological, socioeconomic transitions, health care modifications, and changes in exposure to cardiotoxic agents, the prevalence of DCM will continue to change. Changes in patterns of drug and substance abuse, development of chemotherapy and biological agents with cardiotoxicity, the development of obesity, new metabolic and dietary trends globally, and the success in treatment of protozoal diseases in Latin America will continue to play a dynamic role in the epidemiology of DCM. The true incidence may be underestimated also due to underreporting or underdetection of asymptomatic cases of DCM.
In most multicenter, randomized trials in heart failure, approximately 30% to 40% of the enrolled patients have nonischemic DCM. According to the Acute Decompensated Heart Failure National Registry (ADHERE), 47% of the patients admitted to the hospital with heart failure have nonischemic cardiomyopathy, but the true incidence of DCM is unknown.
Compared with whites, blacks have almost a threefold increase in risk for developing DCM, not explained solely by differences in hypertension, cigarette smoking, alcohol use, or socioeconomic factors. Moreover, the risk of mortality is almost twofold higher among blacks compared with age-matched whites with DCM. While the reasons for these differences are not exactly known, potential explanations include differences in genetic predisposition, etiology, risk factors, comorbidities, lack of access to medical care, and differences in response to therapy.
Epidemiological data suggesting sex-related differences in the occurrence and prognosis of DCM are conflicting and confounded by differing etiologies and underrepresentation of women in clinical trials, though the “true” incidence of DCM in women independent of hypertension is not well known. In some studies, women with idiopathic DCM had more advanced heart failure (HF) and a trend toward worse survival compared with men.
Natural History of Dilated Cardiomyopathy
DCM represents a heterogeneous spectrum of myocardial disorders that may each progress at different rates. Furthermore, diagnosis may be delayed as the onset may be insidious, particularly in the case of familial and/or idiopathic dilated cardiomyopathies. Approximately 4% to 13% of the patients with DCM will present with asymptomatic left ventricular dysfunction and left ventricular dilatation. Once symptomatic, prognosis is relatively poor, with 25% mortality at 1 year and 50% mortality at 5 years ( Fig. 20.2 ). The cause of death appears to be primarily pump failure in approximately 70%, whereas sudden cardiac death accounts for approximately 30% of all deaths. The existing clinical studies suggest that patients with idiopathic DCM have a lower total mortality than ischemic cardiomyopathy. The absence of a rigorous definition of DCM in many studies may account for this discrepancy and make interpretation of the results difficult. Further studies targeting specific etiologies of heart failure could be particularly important to achieve benefit above and beyond conventional treatment strategies that target heart failure as a single disease entity.
Since addition of guideline directed therapies, prognosis may be more favorable, perhaps reflecting earlier diagnosis and better treatment. Approximately 25% of DCM patients with the recent onset of symptoms of heart failure will improve spontaneously. This statement notwithstanding, patients with longer duration of symptoms and/or with severe clinical decompensation and advanced disease generally have less chance of recovery.
As shown in Table 20.2 , there are a number of other parameters that predict a poor prognosis in patients with DCM, including biventricular enlargement, reduced left and right ventricular ejection fraction, persistent S 3 gallop, right-sided heart failure, elevated left ventricular (LV) filling pressures, moderate to severe mitral regurgitation, pulmonary hypertension, ECG findings of left bundle branch block, recurrent ventricular tachycardia, renal and hepatic dysfunction, elevated levels of natriuretic peptides, persistently elevated cardiac troponin levels, peak oxygen consumption less than 10 to 12 mL/kg/min, serum sodium less than 137 mmol/L, advanced NYHA class, and age over 64 years.
| Advanced New York Heart Association class (NYHA Class III or IV) |
| Recurrent heart failure hospitalizations |
| Advanced age (>64 years) |
| LV enlargement |
| RV enlargement |
| Reduced LV and/or RV ejection fraction |
| Elevated LV filling pressures |
| Persistent S 3 gallop |
| Right-sided heart failure |
| Pulmonary hypertension |
| Hypotension |
| Moderate-severe mitral regurgitation |
| ECG findings of LBBB, persistent tachycardia, wide QRS |
| Recurrent ventricular tachycardia |
| Reduced heart rate variability |
| Late potentials of QRS in signal average ECG |
| Myocytolysis on endomyocardial biopsy |
| Elevated levels of natriuretic peptides (NT-proBNP or BNP) |
| Elevated levels of proinflammatory cytokines and other inflammatory biomarkers |
| Elevated cardiac injury markers; serum cardiac troponin T, troponin I levels |
| Peak oxygen consumption <10–12 mL/kg/min |
| Reduced contractile response |
| Serum sodium <137 mmol/L |
| Impaired kidney function (elevated creatinine, reduced EGFR) |
| Impaired liver function (elevated transaminases, elevated bilirubin) |
Pathophysiology
DCM may be viewed as a progressive disorder initiated after an “index event” that either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of acute exposure to toxins; or it may have a gradual or insidious onset, as in the case hemodynamic pressure or volume overloading; or it may be hereditary, as in the case of many of the familial cardiomyopathies. Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all, in some manner, produce a decline in pumping capacity of the heart.
The anatomic and pathophysiological abnormalities that occur in LV remodeling are discussed in Chapter 12 . Patients with DCM generally present with dilation of all four chambers of the heart ( Fig. 20.3 ). Despite the fact that there is thinning of the left ventricular wall in patients with DCM, there is massive hypertrophy at the level of the intact heart, as well as at the level of the cardiac myocyte, which has a characteristic elongated appearance that is observed in myocytes obtained from hearts subjected to chronic volume overload ( Fig. 20.4 ). The coronary arteries are usually normal in DCM, although it should be emphasized the end-stage “ischemic cardiomyopathies” ( see also Chapter 19 ) may also present with a dilated phenotype. The cardiac valves are anatomically normal; however, there is usually left ventricular dilation, global hypokinesis ( Fig. 20.5 ), tricuspid and mitral annular dilatation due to cavity enlargement, distortion of subvalvular apparatus, and stretching of the papillary muscles giving rise to valvular regurgitation. Intracavitary thrombi are common usually in the ventricular apex ( Fig. 20.6 ).
Diagnostic Strategies in Dilated Cardiomyopathy
Patients with DCM should undergo appropriate diagnostic evaluation for specific etiology with an aim toward individualized and targeted management strategies according to etiology. A common diagnostic and management approach for patients with heart failure with reduced ejection fraction (HFrEF) may be appropriate for most, but further diagnostic and treatment strategies should target specific etiologies in patients with DCM. A diagnostic algorithm approach for evaluation of a patient with DCM is summarized in Fig. 20.7 .
General Management Strategies of Dilated Cardiomyopathy
Patients with DCM should be treated according to guideline-directed management and treatment (GDMT) strategies for patients with HFrEF, as most treatment strategies for HFrEF are appropriate for patients with DCM ( see Chapter 37 ). In addition, however, when a specific treatment strategy is available or preferred for a specific etiology, that specific management strategy should be considered first, and/or in addition to GDMT for HFrEF.
In most large-scale clinical trials in HFrEF, DCM has not been captured as a specific etiology, and subgroups for etiology have been usually divided into two general groups: ischemic or nonischemic. The differential treatment benefit seen in nonischemic patients compared with patients with ischemic cardiomyopathy that has been observed in several earlier randomized clinical trials such as with digoxin or amiodarone suggested that there may be therapeutic differences between ischemic and nonischemic heart failure. Contrarily, earlier reports of survival benefit with β-blockers or amlodipine in patients with nonischemic but not ischemic cardiomyopathy have not been reproduced in subsequent large-scale randomized trials, in which the benefit was similar in both the ischemic and nonischemic heart failure patients. Currently, it is accepted that guideline-directed medical and device therapies, including implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) for HF, are beneficial in both in ischemic and nonischemic HF patients, including DCM. Thus it is appropriate to achieve optimization of therapies according to the general guidelines for HFrEF patients, and specific management strategies for specific etiologies of DCM should be considered when appropriate.
Myocardial Diseases Presenting as Dilated Cardiomyopathy
The most common causes of DCM are genetic, idiopathic, toxic, inflammatory, infectious, or metabolic. However, it should be recognized that the exact prevalence of the various forms of DCM will vary based on the demographics of the patient population and the ability to identify a specific etiology. In the section that follows, we will review that various specific etiologies that lead to the development of DCM.
Idiopathic Dilated Cardiomyopathy
Although the term idiopathic DCM has become synonymous with that of DCM in some heart failure parlance, the term “idiopathic” was originally intended to characterize the subset of DCM patients in whom no known etiological cause for ventricular dilation and depressed myocardial contractility was apparent. However, with increasing sophistication in diagnostic testing, clinicians have become aware that most cases of so-called idiopathic DCM may occur as the result of inherited and/or spontaneous mutations of genes that regulate cardiac structure and/or function ( see also Chapter 24 ), such as the genes for cytoskeletal proteins, or in some cases a consequence of undiagnosed hypertension, autoimmune diseases, toxins (such as cardiotoxic chemotherapy, alcohol, or illicit drugs), or viral myocarditis. Nonetheless, in the context of the present chapter, we use the terminology of idiopathic DCM to refer to those patients with DCM whose etiological cause remains unknown. It is likely that the proportion of patients with idiopathic DCM will diminish with increased sophistication in detection of genetic cardiomyopathies and other specific cardiomyopathies.
Familial/Genetic Cardiomyopathies
There is growing evidence that many cases of previously diagnosed “idiopathic” dilated cardiomyopathies have a genetic basis. It is estimated that at least 30% of DCM cases are familial or genetic. Such causes, including noncompaction cardiomyopathies; dystrophin, titin-related, or other sarcomere, cytoskeleton, nuclear lamina–related genetic cardiomyopathies; X-linked cardiomyopathies; muscular dystrophy–associated cardiomyopathies; other familial dilated cardiomyopathies; and arrhythmogenic right ventricular cardiomyopathies, are discussed in detail in Chapter 24 .
Cardiomyopathy Due to Cardiotoxins
Alcoholic Cardiomyopathy
Alcoholism is an important cause of DCM. The clinical diagnosis of alcoholic cardiomyopathy is suspected when biventricular dysfunction and dilation are noted in an individual with a long and heavy alcohol abuse history, in the absence of other known causes for myocardial disease. Alcoholic cardiomyopathy most commonly occurs in men 30 to 55 years of age who have been heavy consumers of alcohol for more than 10 years. Women represent approximately 14% of the alcoholic cardiomyopathy cases, but may develop cardiomyopathy with a less total lifetime exposure to alcohol compared with men. Mortality rates due to alcoholic cardiomyopathy are greater in men compared with women, and in blacks compared with white. Even before the clinically overt symptoms of heart failure, left ventricular systolic dysfunction and atrial fibrillation are common. The point at which these abnormalities appear during the course of an individual’s lifetime of drinking, such that the abnormalities can be called a DCM, is not well established and is highly individualized.
The risk of developing alcoholic cardiomyopathy appears to be related to both the amount and duration alcohol intake. In general, alcoholic patients consuming greater than 90 g of alcohol a day (approximately seven to eight standard drinks per day) for more than 5 years are at risk for the development of asymptomatic alcoholic cardiomyopathy. On the other hand, mild to moderate alcohol consumption has been reported to be protective against development of heart failure in the general population. These paradoxical findings (i.e., alcohol may be protective against development of heart failure in certain populations when used in moderation, but detrimental in others, especially when used in excess over longer periods of time) suggest that duration of exposure and individual genetic susceptibility play an important role in pathogenesis. Persistent DCM develops in only a small percentage of chronic drinkers, and the role of genetic predisposition, or the presence of synergistic cardiovascular factors such hypertension or arrhythmias in the development of alcohol-related cardiomyopathy, are not clear at the present time.
Studies in experimental animals have demonstrated that both acute and chronic ethanol administration impairs cardiac contractility. Alcohol results in acute as well as chronic depression of myocardial contractility, even when ingested by normal individuals in quantities consumed during social drinking. Compensatory mechanisms such as vasodilation or sympathetic stimulation may mask the direct acute myocardial depressant effects of alcohol.
Despite the known deleterious effects of alcohol, it has been difficult to produce heart failure in animal models in which ethanol has been administered. Thus the direct causal relationship between alcohol consumption and the development of cardiomyopathy has not been rigorously demonstrated in experimental models, despite the long-recognized clinical relationship between alcohol consumption and the development of DCM. Potential mechanisms invoked to explain the depressed myocardial function include the direct toxic effects of alcohol on striated muscle (most alcoholics have manifestations of skeletal myopathy and cardiomyopathy); shifts in the relative expression of the α-myosin heavy chain to β-MHC; alterations in cellular calcium, magnesium, or phosphate homeostasis; and formation of fatty acid ethyl esters impairing mitochondrial oxidative phosphorylation. In acute ethanol toxicity, free radical damage and/or ischemia may occur, possibly due to increased xanthine oxidase activity or β-adrenergic stimulation, respectively. Both autopsy and endomyocardial biopsy specimens from alcoholic cardiomyopathy patients reveal marked mitochondrial swelling, fragmentation of cristae, swelling of endoplasmic reticulum, entrance of mitochondria into the nucleus potentially promoting attack of mitochondria by nuclear proteins and the attack of nuclear DNA by proteins of the mitochondrial intermembrane space, and cytoskeletal disorganization and destruction of myofibrils ( Fig. 20.8 ). Several studies suggest that heavy drinking alters both lymphocyte and granulocyte production and function, raising the possibility that myocardial damage may occur secondary to inflammatory and autoimmune mechanisms comparable to those observed in myocarditis. The point at which the changes in mitochondrial, sarcoplasmic reticulum, contractile protein, and calcium homeostasis culminate in intrinsic cell dysfunction is not completely understood. Application of insulin-like growth factor (IGF)-1 has been reported to attenuate the apoptotic effects of ethanol in primary neonatal myocyte cell cultures.
Genetic traits such as multiple point mutations in the mitochondrial DNA have been reported to influence the occurrence, pathogenesis, and progression of alcoholic cardiomyopathy, which may explain interindividual variations in the sensitivity of the myocardium to alcohol-induced myocardial damage. In addition, nutritional deficiencies, such as thiamine deficiency, may play an additive role to the direct myocardial damage of ethanol. Thus the cardiomyopathy that develops following chronic alcohol consumption appears to be multifactorial in origin.
The management of patients with alcohol cardiomyopathy begins with total abstinence from alcohol, in addition to the conventional management of heart failure. There are currently no studies of specific pharmacotherapies in patients with alcoholic cardiomyopathy other than the standard therapy of heart failure; however, there are numerous reports that detail the reversibility of depressed left ventricular dysfunction after the cessation of drinking. Many heart failure programs limit alcoholic beverage consumption to no more than one or two alcoholic beverage servings daily for all patients with left ventricular dysfunction, regardless of the etiology. Even if the depressed left ventricular function does not normalize completely, the symptoms and signs of congestive heart failure improve after abstinence. However, the overall prognosis remains poor, with a mortality of 40% to 50% within 3 to 6 years, if the patient is not abstinent. Survival is significantly lower for patients who continue to drink compared with patients with idiopathic DCM or alcoholic cardiomyopathy patients who abstain.
Cocaine Cardiomyopathy
Long-term abuse of cocaine, a drug that causes postsynaptic norepinephrine reuptake blockade, can result in DCM, even without presence of coronary artery disease, vasculitis, or regional myocardial injury. This has been termed as “cocaine related cardiomyopathy” and likely reflects the direct toxicity of the cocaine on the myocardium. In patients with cocaine abuse, depressed LV function has been reported in 4% to 18% of the screened patients without heart failure symptoms.
Electrocardiogram may reveal increased QRS voltage, early repolarization, ischemic or nonspecific ST-T changes, or pathologic Q waves. Episodes of ST elevation may be seen during Holter monitoring. Echocardiogram usually reveals left ventricular hypertrophy, depressed left ventricular ejection fraction, and dilation. Segmental wall motion abnormalities usually suggest myocardial injury; however, approximately 18% to 20% of patients with cocaine abuse manifest global hypokinesia. Cardiac catheterization in these patients may reveal normal coronaries or mild coronary artery disease not significant enough to explain the extent of myocardial dysfunction. Accelerated coronary atherosclerosis, coronary vasculitis, coronary spasm, or coronary thrombosis can also be seen in cocaine-related heart disease.
Cocaine may produce left ventricular dysfunction through its direct toxic effects on the myocardium, by provoking coronary arterial spasm (and hence myocardial ischemia), and by causing increased release of catecholamines, which may be directly toxic to cardiac myocytes. These effects will decrease myocardial oxygen supply and may increase demand if heart rate and blood pressure rise. The vasoactive effects of cocaine are further complicated with enhanced platelet aggregation, anticardiolipin antibody formation, and endothelial release of potent vasoconstrictors such as endothelin-1. Up regulation of tissue plasminogen activator inhibitors, increased platelet aggregation, and decreased fibrinolysis by cocaine predispose to coronary thrombosis and/or microvascular disease. Myocarditis with inflammatory lymphocyte and eosinophils has also been reported, raising the possibility of hypersensitivity myocarditis due to cocaine or associated contaminants. Scattered foci of myocyte necrosis, contraction band necrosis, and foci of myocyte fibrosis have been reported in patients with cocaine abuse. In addition, experimental studies and clinical case reports suggest that cocaine may cause lethal arrhythmias. Cocaine prolongs repolarization by a depressant effect on potassium current and may generate early after depolarizations.
Other than abstinence, very little is known about the treatment of cocaine-induced cardiac dysfunction. Indeed, there are case reports of reversibility of cardiac function after cessation of drug use. In patients who develop cardiomyopathy, the traditional therapy for LV dysfunction is appropriate. Given that some of the toxicity of cocaine is caused by catecholamine excess and/or myocardial ischemia, the use of β-adrenergic blocking agents appeared to be a logical treatment, both in terms of preventing further disease progression, as well as for treating the ventricular arrhythmias that are prone to develop in this setting. Two decades ago, the treatment of cocaine-induced cardiovascular effects favored the use of β-blockers, especially propranolol. As the clinical use of propranolol increased, reports of accentuation of cocaine-induced hypertension and myocardial ischemia began to surface, blaming the unopposed alpha effects of the β-blockers. Although these reports were isolated, the routine use of propranolol and subsequently all β-blockers were considered relatively contraindicated in treating cocaine-induced cardiovascular emergencies. The end result is that an entire generation of potent and selective β-adrenergic blocking agents have been overlooked, both for acute and chronic treatment of cocaine-related cardiac disease, due to the possibility of “unopposed alpha effects.” The focus of treatment shifted from the cardiovascular effects to combating central nervous stimulation. As a result, benzodiazepines have been the drug of choice in treating the cerebrovascular and subsequent systemic hyperadrenergic complications of cocaine, and nitroprusside or phentolamine being advocated for peripheral vasodilatory effects. It is now becoming apparent that treatment of cardiovascular effects of cocaine should involve a multifactorial approach to combat both central nervous system and peripheral vasospastic effects of cocaine. An observational study demonstrated that β-blocker treatment did not result in any a major adverse cardiovascular in patients with HFrEF, and there were no significant differences in HF readmissions or mortality rates compared with β-blocker treatment in HFrEF patients with and without cocaine use. Within HF patients with cocaine use, mortality rates were not significantly different between patients treated with non-cardioselective versus cardioselective β-blockers. According to the AHA Scientific Statement on Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies, it is considered reasonable to treat patients with cocaine-related cardiomyopathy who have demonstrated abstinence for more than 6 months with standard therapy for LV dysfunction including β-blockers. In patients at risk for relapse for cocaine abuse, a nonselective β-blocker treatment with α 1 , β 1 , β 2 receptor antagonism is reasonable because of potential protection against the unopposed alpha agonism effects of cocaine with β 1 -receptor antagonist treatment alone. It should also be noted that β-blockers are not recommended to be used in the acute setting of cocaine-related acute coronary syndrome.
Cardiomyopathy Related to Other Stimulant Drugs
Especially among adult patients, crystal amphetamine and methamphetamine abuse have been associated with reports of myocardial infarction, pulmonary edema, and cardiomyopathy cases. Methamphetamine users have an almost fourfold increased risk of developing cardiomyopathy compared with nonusers. Methamphetamine-associated cardiomyopathy may be reversible with appropriate medical therapy and cessation of use. By some reports, late gadolinium enhancement cardiovascular MR has been helpful to identify the magnitude of fibrosis and likelihood of recovery in methamphetamine-associated cardiomyopathy cases. Although rare, misuse or overdose of drugs used for attention-deficit/ hyperactivity disorder (ADHD) such as methylphenidate, dextroamphetamine, and dextroamphetamine-amphetamine have been associated with myocardial infarction, cardiomyopathy, and sudden death in case reports.
Over the past decade, novel or atypical drugs have emerged and have been associated with cardiovascular toxicity. Cardiostimulant drugs such as ecstasy (3,4-methylenedioxy-N-methylamphetamine [MDMA]); “bath salts” containing synthetic cathinones such as mephedrone methylenedioxypyrovalerone, which have amphetamine/ cocaine-like properties; and khat chewing, which contains cathinone, have cardiotoxic effects and have been implicated in cases of myocardial infarction, arrhythmia, cardiac arrest, and cardiomyopathy. Synthetic cannabinoids have been reported to result in acute congestive heart failure from myocardial stunning, respiratory failure, and death.
Chemotherapy (See Also Chapter 46 )
Cardiotoxicity is a well-known side effect of several cytotoxic drugs, especially of the anthracyclines, and can lead to long-term morbidity. Anthracyclines, such as doxorubicin and daunorubicin, produce cardiac toxicity possibly by increasing oxygen free radical generation, platelet activating factor, prostaglandins, histamine, calcium and C-13 hydroxy metabolites, or by interfering with sarcolemmal sodium potassium pump and mitochondrial electron transport chain. Formation of oxygen free radicals that are generated by iron-catalyzed pathways appears to be the most important pathway in the pathogenesis of anthracycline-induced cardiomyopathy, as it has been noted that iron-chelating agents that prevent generation of oxygen free radicals, such as dexrazoxane, are cardio-protective. The prognosis of anthracycline induced cardiomyopathy relates to the time course of treatment and preexisting additional risk factors for myocardial injury such as radiation, coexisting coronary artery disease, and preexisting cardiac dysfunction. Prior XRT to the heart/mediastinum also increases the risk of doxorubicin-induced cardiomyopathy. In general, patients with anthracycline-induced cardiomyopathy have a worse survival than that seen with idiopathic DCM ( Fig. 20.9 ). Other chemotherapeutic agents in cancer associated with cardiac toxicity complication are the monoclonal antibody trastuzumab (herceptin), high-dose cyclophosphamide, taxoids, mitomycin-C, 5-fluorouracil, certain antivascular endothelial growth factor (VEGF) inhibitors and proteasome inhibitors, such as bortezomib and carfilzomib, and interferons. In contrast to anthracycline-induced cardiac toxicity, trastuzumab-related cardiac dysfunction does not appear to increase with cumulative dose or to be associated with ultrastructural changes in the myocardium, and is generally reversible. This topic is discussed in further detail in Chapter 46 .
