31 - 269 Dilated Cardiomyopathies

269 Dilated Cardiomyopathies

unexplained. Without curative therapy, the initial inflammatory necro­ sis can lead to thrombosis, valve disease, and progressive endomyocar­ dial fibrosis with restrictive physiology, termed Loeffler endocarditis, which presents as a restrictive cardiomyopathy. Myocarditis is often associated with systemic inflammatory diseases, such as polymyositis and dermatomyositis, which can affect cardiac as well as proximal skeletal muscle and are usually diagnosed from autoantibodies. Myocarditis with lymphocytic infiltrates on endomyo­ cardial biopsy can be seen in some patients with systemic lupus erythe­ matosus, but multiple cardiac manifestations also include accelerated coronary artery disease, valvular involvement from sterile endocarditis, pericarditis, vasculitis, and chloroquine cardiotoxicity. Vaccines have occasionally been implicated in myocarditis. This has been best studied after the smallpox vaccine in military popula­ tions. As this is a live vaccine, it is unclear whether this is direct injury, but it is generally assumed to be a hypersensitivity response. More recent concern relates to COVID-19 vaccines, after which the overall rate of myocarditis is estimated to be about 1/100,000 vaccine doses (increased to 2–3/100,000 for recipients age 18–39 years). Most cases of vaccine-induced myocarditis resolve without hospitalization. Male adults under 40 are at highest risk of myocarditis from the COVID-19 vaccines, as they are for primary infectious myocarditis after COVID19 and other viruses. The risk for men under 40 increases after repeat COVID-19 vaccines, for which the benefit/risk for individuals should be considered. The most dramatic form of noninfectious inflammatory myocarditis is that seen with combined immune checkpoint inhibitors. Targeted monoclonal antibody therapy to unblock the host immune response has produced remarkable remission of multiple advanced tumors. Inhibitory receptors on T lymphocytes (such as CTLA-4 and PD-1) and the programmed death ligands, such as PD-L1, interact in nor­ mal self-regulation to inhibit overactivation of immune responses. Tumor cells can upregulate these ligands to hide from immune recognition. Therapeutic antibodies against these inhibitory recep­ tors or ligands can heighten host defenses against the tumor but also unleash immune attack against host tissues expressing PD-L1, which include skeletal and cardiac muscle, endothelial cells, and multiple other organs, such as lung, liver, pancreas, thyroid, and skin. With cardiac involvement, troponin is often elevated, B-type natriuretic peptide may be elevated, and creatine phosphokinase may be high, particularly with skeletal involvement. The diagnosis should be suspected immediately with acute cardiac presentation in patients treated with checkpoint inhibitors. Admission to the coronary care unit is currently recommended for an elevated troponin levels and ECG changes, which may be nonspecific but can also include conduc­ tion blocks and bizarre arrhythmias. Echocardiography may suggest myocardial edema, but initial ejection fraction may not be markedly reduced. Initial care should generally not be delayed for endomyocar­ dial biopsy, which typically shows extensive lymphocytic infiltration. Patients may also present initially with other acute organ system involvement, which warrants urgent multidisciplinary management in intensive care. Therapy with high-dose glucocorticoids should be initiated rapidly and may be followed soon by more targeted immune inhibition. Reports of fatality in checkpoint inhibition myocarditis were initially very high, but outcomes are improving with earlier recognition and therapy. ■ ■FURTHER READING Ammirati E et al: Management of acute myocarditis and chronic inflammatory cardiomyopathy. Circ Heart Failure 13:e007405, 2020. Drent M et al: Challenges of sarcoidosis and its management. N Engl J Med 385:1018, 2021. Fairweather D et al: COVID-19, myocarditis and pericarditis. Circ Res 132: 1302, 2023. Moslehi J, Salem JE: Immune checkpoint inhibitor myocarditis treatment strategies and future directions. JACC CardioOncol 4:704, 2022.

Neal K. Lakdawala, Lynne Warner Stevenson,

Joseph Loscalzo

Dilated

Cardiomyopathies CHAPTER 269 As described in Chap. 266, the phenotype of dilated cardiomyopathy (DCM) is characterized by decreased left ventricular systolic function, typically with increased left ventricular dimensions, although dilation may be minimal in some cases. Multiple causes and contributing fac­ tors have been implicated (Table 269-1). Dilated Cardiomyopathies As discussed in Chaps. 267 and 268, many cases are attributed to prior myocarditis, and an increasing number are associated with pathogenic genetic variants, but other causes include toxic and meta­ bolic disorders and peripartum cardiomyopathy, which are discussed in this chapter, along with takotsubo cardiomyopathy, which has a distinct presentation and phenotype that often resolves. Despite the multiple etiologies and variable initial presentations, DCM often progresses into a convergent clinical phenotype similar to that of other injury such as acute myocardial infarction. Some myo­ cytes may die early in the course, while others survive only to have later programmed cell death (apoptosis), and remaining myocytes develop hypertrophy in response to increased wall stress. Local and circulating neurohormonal factors stimulate deleterious secondary responses that contribute to progression of disease. Dynamic remod­ eling of the interstitial scaffolding affects diastolic function and the amount of ventricular dilation. Mitral regurgitation commonly devel­ ops as the ventricle dilates and the valvular apparatus is distorted and is commonly moderate to severe by the time heart failure is advanced. There is increasing evidence for the role of chronic inflammation in disease progression even when not initially implicated. Many cases that present “acutely” have progressed silently through these stages of injury over months to years. Dilation and decreased function of the right ventricle may result directly from the initial injury but more often develop later in response to elevated afterload presented by sec­ ondary pulmonary hypertension and in relation to mechanical interac­ tions with the failing left ventricle. The secondary responses are often modifiable or reversible. Almost a third of patients with recent-onset cardiomyopathy in the absence of coronary artery disease demonstrate substantial spontaneous recovery to normal ejection fraction. Partial recovery to left ventricular ejec­ tion fraction (LVEF) >0.40 (“heart failure with improved ejection fraction”) is common in chronic DCM during recommended therapy with neurohormonal modulation, cardiac resynchronization therapy for left bundle branch block, and diuretics as needed to maintain fluid balance, as recommended for other heart failure with reduced LVEF (Chap. 265) regardless of the initial cause of DCM. Additional aspects of diagnosis, therapy, and outcomes for specific etiologies of DCM other than the infectious, inflammatory, and genetic cardiomyopathies are discussed below. CARDIOTOXICITY AND CARDIOMYOPATHY Cardiotoxicity has been reported with multiple environmental and pharmacologic agents. Often these associations are seen only with very high levels of exposure or acute overdoses, in which acute elec­ trocardiographic and hemodynamic abnormalities may reflect both direct drug effect and systemic toxicity. Alcohol is the most common toxin implicated in chronic DCM. Although excess consumption may contribute to >10% of cases of heart failure, including exacerbation of heart failure with structural heart disease, alcoholic cardiomyopa­ thy is relatively rare and remains a diagnosis of exclusion. Moreover, Mendelian randomization studies have not identified a link between genetically predicated alcohol consumption and heart failure, sug­ gesting that the population attributable risk of alcohol to the overall heart failure epidemic is modest. Alcoholic cardiomyopathy causes

TABLE 269-1  Major Causes of Dilated Cardiomyopathy

(with Common Examples) Inflammatory Myocarditis (see Chap. 268) Infective   Viral (coxsackie,a adenovirus,a COVID-19, HIV) PART 6 Disorders of the Cardiovascular System   Parasitic (Trypanosoma cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis)   Bacterial (diphtheria)   Spirochetal (Borrelia burgdorferi—Lyme disease)   Rickettsial (Q fever)   Fungal (with systemic infection) Noninfective   Granulomatous inflammatory disease     Sarcoidosis     Giant cell myocarditis   Eosinophilic myocarditis   Polymyositis, dermatomyositis   Collagen vascular disease   Checkpoint inhibitor chemotherapy   Transplant rejection Toxic Alcohol Catecholamines: amphetamines, cocaine Chemotherapeutic agents (anthracyclines, trastuzumab) Interferon Other therapeutic agents (hydroxychloroquine, chloroquine) Drugs of misuse (testosterone and other anabolic steroids emetine) Heavy metals: lead, mercury Occupational exposure: hydrocarbons, arsenicals Metabolica Nutritional deficiencies: thiamine, selenium, carnitine Electrolyte deficiencies: calcium, phosphate, magnesium Endocrinopathy   Thyroid disease   Pheochromocytoma   Diabetes mellitus Obesity Hemochromatosis Inherited metabolic pathway defects (see Chap. 267) Familiala (see Table 267-1) Cardiomyopathies without extracardiac involvement Cardiomyopathy with skeletal myopathy, for example:   Dystrophin-related dystrophy (Duchenne’s, Becker’s)   Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) Hemochromatosis Susceptibility to immune-mediated myocarditis Associated with other systemic diseases Miscellaneous (Shared Elements of Above Etiologies) Arrhythmogenic ventricular cardiomyopathy Peripartum cardiomyopathy Left ventricular noncompactiona Tachycardia-related cardiomyopathy   Supraventricular arrhythmias with uncontrolled rate   Very frequent nonsustained ventricular tachycardia or high burden of premature ventricular complexes aSome specific cases can be linked now to specific genetic mutation in a familial cardiomyopathy; others with similar phenotypes that appear to be acquired or idiopathic may represent genetic factors not yet identified.

many more hospital admissions in men than women, but prevalence is similar between men and women with alcoholism, with left ventricular dysfunction detected in about a third of asymptomatic patients. Esti­ mates of the alcohol intake necessary to cause cardiomyopathy have been 3–4 ounces or ≥60–80 g of pure ethanol daily for ≥5 years, about 750 mL of wine, 6 beers, or a half pint of hard liquor, although women may develop cardiomyopathy with lower amounts of consumption. Frequent binge drinking may also be sufficient. Toxicity is attributed both to alcohol and to its primary metabolite, acetaldehyde. Chronic heavy exposure may cause neurohormonal activation and alter metab­ olism, protein synthesis, substrate utilization, and oxidative stress. Polymorphisms of the genes encoding alcohol dehydrogenase and the angiotensin-converting enzyme may influence the likelihood of alco­ holic cardiomyopathy. Superimposed vitamin deficiencies and toxic alcohol additives are rarely implicated currently. Mutations in TTN and other DCM disease genes can be identified in ~10% of patients with presumed alcohol cardiomyopathy. Many patients with alcoholic cardiomyopathy are fully functional in their daily lives without apparent stigmata of alcoholism. The cardiac impairment in severe alcoholic cardiomyopathy is the sum of both permanent damage and a substantial component that is reversible after cessation of alcohol consumption. Atrial fibrillation occurs commonly both early in the disease (“holiday heart”) and in advanced stages. Medical therapy includes conventional guideline-directed medical therapies with neurohormonal, mineralocorticoid receptor, and β adr­ enoreceptor antagonists as well as sodium-glucose cotransporter 2 inhibitors with diuretics as needed for fluid management and careful attention to electrolyte repletion. Withdrawal should be supervised to avoid exacerbations of heart failure or arrhythmias and ongoing sup­ port arranged. Even with severe disease, marked improvement can occur within 3–6 months of abstinence, but the prognosis is grim if heavy alcohol consumption continues. Cocaine, amphetamines, and related catecholaminergic stimulants can produce chronic cardiomyopathy as well as acute ischemia, tachyarrhythmias, malignant hypertension, aortic dissection, and stroke. Cardiac pathology reveals microinfarcts consistent with small vessel ischemia, similar to those seen with pheochromocytoma, and thrombosis secondary to endothelial dysfunction in the case of cocaine. Regular cannabis use has been linked to increased risk of atrial fibrillation, myocardial infarction, and stroke in patients with and without other known risk factors. Cannabis is not specifically implicated as a cause of cardiomyopathy in population studies but is of concern as the potency of both inhaled and edible products continues to increase. Chemotherapy agents are the most common drugs implicated in toxic cardiomyopathy. Judicious use balances risks of the malignancy and the risks of cardiotoxicity presented not only by the drug regimens but also by the patient’s cardiovascular profile and possibly genetic factors influencing myocyte response to injury. Receipt of cardiotoxic drugs or radiation may warrant designation as “stage B” heart failure, with asymptomatic changes in cardiac structure and biomarkers. Clini­ cal recognition can be delayed as some symptoms can overlap with cancer and the prognosis with heart failure may be worse than for the underlying cancer. Anthracyclines (e.g., doxorubicin) cause characteristic histologic changes of vacuolar degeneration and myofibrillar loss. Multiple mech­ anisms have been implicated, involving reactive oxygen species and iron compounds, mitochondrial damage, transcription factors such as hypoxia-induced factor, and, most recently, inhibition of topoisomer­ ase II involved in DNA repair. Risk for cardiotoxicity increases with older age, obesity, hypertension, diabetes mellitus, preexisting cardiac disease, higher doses or combination therapies, and left chest irradia­ tion. Systolic dysfunction can occur acutely with symptoms of heart failure noted soon after drug administration, but more often is detected by surveillance echocardiography during the first year after exposure. Doxorubicin cardiotoxicity generally does not result in marked left ventricular dilation, such that stroke volume and systemic perfusion can be low with only a modest reduction of ejection fraction. Therapy

for reduced ejection fraction due to anthracycline therapy includes β-adrenergic receptor blockade and inhibition of the renin-angiotensin system, with conflicting data on whether these agents decrease toxicity when given in parallel with chemotherapy. The use of dexrazoxane, an intracellular iron chelating agent, can prevent anthracycline cardio­ myopathy, but there is no consensus on when it should be used owing to concerns that it might attenuate the efficacy of cancer therapies. Once thought to have an inexorable downward course, many patients with symptomatic heart failure can improve to near-normal function with careful management, including prevention of “second-hit” insults such as atrial fibrillation or hypertension. The course differs for some children treated with these agents before puberty, in whom inadequate growth of the heart may lead to refractory heart failure as they reach their twenties. Trastuzumab (Herceptin) is one of the humanized monoclonal anti­ bodies that interfere with human epidermal growth receptor 2 (HER2), which is crucial for growth of some tumors, such as breast cancer, and for cardiac adaptation. Cardiotoxicity is highest when anthracyclines are administered in conjunction with trastuzumab; however, less toxic­ ity is seen now when these agents are combined compared with the toxicity observed previously with paclitaxel for breast cancer. Although more often reversible than anthracycline cardiotoxicity, trastuzumab cardiomyopathy may persist in about a third of affected patients and can progress to clinical heart failure and death. For cardiotoxicity with anthracyclines or trastuzumab, therapy is recommended as for other causes of reduced ejection fraction. Cardiotoxicity with cyclophosphamide and ifosfamide generally occurs acutely and with very high doses. 5-Fluorouracil, cisplatin, and some other alkylating agents can cause recurrent coronary spasm that occasionally leads to depressed contractility. Acute administration of interferon-α, interleukin 2, and other cytokine-based therapies can cause pericarditis, hypotension, and arrhythmias. Clinical heart failure occurring during their chronic administration usually resolves after discontinuation. Vascular endothelial growth factor (VEGF), produced endogenously or by tumors, enhances angiogenesis by activating the VEGF signaling pathways. Monoclonal antibodies and many small-molecule tyrosine kinase inhibitors that affect VEGF are in use for different malignancies. Although these agents are “targeted” at specific tumor receptors or pathways, the biologic conservation of signaling pathways means that some of these drugs also find targets in the cardiovascular and other organ systems. Blood pressures increase in most patients during ther­ apy, attributed to an imbalance between endogenous vasodilators and vasoconstrictors and alteration of glomerular function. Hypertension and proteinuria can develop with these agents, similar to preeclampsia, and presentation is associated with increased risk of future cardiac disease. Recognition of cardiotoxicity during therapy with these agents is complicated because they occasionally cause peripheral fluid accumulation (ankle edema, periorbital swelling, pleural effusions) due to local factors rather than elevated central venous pressures. Therapeutic approaches include management of associated hyperten­ sion, withdrawal of the tyrosine kinase inhibitor (when possible), and conventional treatment for heart failure. Newer tyrosine kinase inhibi­ tors effective against multiple kinases may have more complex offtarget effects. This includes the Bruton tyrosine kinase inhibitors (e.g., ibrutinib), which are used as primary therapy for lymphoid malignan­ cies, with predominant cardiovascular risks of atrial and ventricular arrhythmias in addition to heart failure. Proteasome inhibitors used to treat multiple myeloma are associated with an increased risk of hypertension, ischemic events, thromboem­ bolism, and heart failure. The more potent agent, carfilzomib, appears more cardiotoxic than bortezomib. Other treatments for myeloma include immunomodulatory drugs including lenalidomide and tha­ lidomide, which may cause heart failure in addition to risks of venous thromboembolism. Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors used for metastatic melanoma may cause hypertension and cardiomyopathy, especially when co-administered with rapidly accelerated fibrosarcoma (RAF) inhibitors.

The most dramatic toxicity of contemporary cancer therapy results from combined immune checkpoint inhibitors, which block the natu­ ral counterregulatory T-cell suppression and unleash potentially fatal inflammation directed toward multiple organs that can include the heart and vessels. These are discussed in Chap. 268 on noninfectious myocarditis.

CHAPTER 269 Other therapeutic drugs that can cause cardiotoxicity during chronic use include tumor necrosis factor α antagonists for rheumatologic conditions, and carbamazepine, clozapine, and lithium for neurologic and psychiatric diagnoses. Antiretroviral therapies for HIV have been implicated in cardiomyopathy. Chloroquine and hydroxychloroquine, which are widely used for systemic lupus erythematosus and rheuma­ toid arthritis, can decrease ejection fraction with either restrictive or dilated phenotype, often in association with conduction block. The presumed mechanism of toxicity is impaired lysosomal function, with accumulation of inclusion bodies that can be seen on cardiac biopsy. Dilated Cardiomyopathies Toxic exposures can cause arrhythmias or respiratory injury acutely during accidents. Chronic exposures implicated in cumulative car­ diotoxicity include cobalt, arsenicals, lead, and mercury. Treatment for these disorders includes removing exposure to the toxin and stan­ dard medical therapy for heart failure with reduced ejection fraction. Cardiomyopathy secondary to cobalt toxicity may be secondary to impaired myocardial energetics and is more common in the setting of hypothyroidism and dietary protein and thiamine deficiency. Cobalt cardiomyopathy usually presents with polycythemia, hypothyroid­ ism, and goiter due to the effects of cobalt on red cell production and thyroxine. Most historical causes of pathologic cobalt exposure are no longer relevant (e.g., treatment of anemia associated with end-stage disease, beer foam stabilization), and recent cases have been attributed to industrial exposures and cobalt alloy prosthetic hips. Diagnosis occurs in the setting of cobalt exposure and can be confirmed by the presence of electron microscopy dense intramitochondrial particles. PERIPARTUM CARDIOMYOPATHY Peripartum cardiomyopathy (PPCM) develops during the last trimes­ ter or within the first 5–6 months after pregnancy, most commonly within the first 2 weeks after delivery. Between 1:1000 and 1:4000 deliveries in the United States are affected. Risk factors include older maternal age, increased parity, twin pregnancy, malnutrition, and tocolytic therapy for premature labor. Up to half of cases occur in the setting of hypertensive disorders of pregnancy, including preeclampsia. Risk of PPCM is fourfold higher in black women, in whom recovery of normal LVEF takes longer and is less likely than in white women. Several of the risk factors contribute to antiangiogenic signaling through secreted inhibitors of VEGF, such as soluble FLT1 (sFLT1), high levels of which predict worse outcome. An abnormal cleavage fragment of the nursing hormone prolactin has also been implicated in decreased vascular response during oxidative stress, and investi­ gation is ongoing with the prolactin inhibitor bromocriptine after mixed results of small trials. Multiple other hormonal changes of pregnancy and secretory products from the placenta may interact to cause cardiac dysfunction, suggesting a “vasculohormonal model” in the development of PPCM. Genetic contribution has also been rec­ ognized. Similar to other DCM populations, truncating mutations in TTN are found in ~15% of cases of PPCM and associated with lower rates of recovered systolic function. Pregnancy thus represents another environmental trigger for accelerated phenotypic expression of genetic cardiomyopathy. PPCM usually presents with evidence of congestion, and criteria generally include an LVEF ≤0.45 presenting toward the end of preg­ nancy in the absence of another cardiac diagnosis. Pregnancy can unmask previously unrecognized heart disease but usually does so by the second trimester, when the major circulatory changes have already occurred. Toward the end of pregnancy, edema and dyspnea may be mistakenly attributed to the pregnancy itself, but elevated levels of brain natriuretic peptide or troponin or evidence of elevated central venous pressures are clues to cardiac dysfunction, particularly in the setting of hypertension. Echocardiography is usually sufficient for

diagnosis, but in complex cases, cardiac magnetic resonance imaging (MRI) can be considered, but gadolinium should not be used.

Most cases of PPCM present within the first week after delivery, usually with increasing edema and dyspnea when urine output does not keep up with mobilization of fluid. Both atrial and ventricular arrhythmias can occur. It is important to exclude other complications of pregnancy such as pulmonary emboli and coronary artery dissec­ tion. Genetic testing should be considered as the results may impact the mother, in whom positive genetic testing predicts less recovery, and also other family members, too. PART 6 Disorders of the Cardiovascular System Initial treatment for PPCM includes loop diuretics as needed to restore normal volume status. Prior to delivery, close collaboration with the maternal-fetal medicine team is necessary to adjust therapies to stabilize the gravid mother while protecting the fetus. Digoxin and beta blockers can be used if needed for arrhythmias, and hydrala­ zine/nitrate combinations can be used for hypertension, but reninangiotensin system inhibitors should not be given due to adverse fetal effects. Hemodynamic instability may require ongoing hemodynamic monitoring, and plans should be in place for emergency delivery if nec­ essary. When the mother is hemodynamically stable in the postpartum period, metoprolol tartrate, enalapril, and spironolactone have been shown to be compatible with breastfeeding. PPCM with LVEF <0.35 or marked dilation carries increased incidence of left ventricular throm­ bus and embolic risk, so anticoagulation is usually prescribed for the first 6 weeks once obstetric bleeding has resolved. Breastfeeding was once prohibited but now is generally encouraged in patients in whom fluid balance can be maintained through the high oral fluid intake required. For patients who are not breastfeeding, there is an ongoing large, randomized trial to determine the impact of bromocriptine on PPCM outcomes. Improvement of LVEF to ≥0.50 occurs in 50–80% of PPCM, often within 6 months, when other cardiac diagnoses have been carefully excluded. Recovery is less likely with LVEF <0.30, left ventricular enddiastolic dimension ≥0.60, black race, and presentation >6 weeks after delivery. Elevated levels of natriuretic peptides, troponin, and sFLT1 have also been associated with less recovery. Patients with LVEF <0.35 have a higher risk of life-threatening arrhythmias during initial presen­ tation and early after discharge, for which consideration of wearable defibrillators is reasonable. This is burdensome both physically and psychologically to a new mother, and more data are needed to help stratify risk. One-year mortality rates after PPCM have ranged in the United States from 4% in one study to 11% in a population of black women, and have been reported as up to twofold higher in Africa. METABOLIC CAUSES OF CARDIOMYOPATHY Endocrine disorders affect multiple organ systems, including the heart. Hyperthyroidism and hypothyroidism do not often cause clinical heart failure in an otherwise normal heart but commonly exacerbate heart failure. Clinical signs of thyroid disease may be masked, so tests of thyroid function are part of the routine evaluation of cardiomyopathy. Hyperthyroidism should always be considered with new-onset atrial fibrillation or ventricular tachycardia or atrial fibrillation in which the rapid ventricular response is difficult to control. The most common current reason for thyroid abnormalities in the cardiac population is the treatment of tachyarrhythmias with amiodarone, a drug with sub­ stantial iodine content. Hypothyroidism should be treated with very slow escalation of thyroid supplements to avoid exacerbating tachyar­ rhythmias and heart failure. Hyperthyroidism and heart failure create a dangerous combination that merits very close supervision, often hos­ pitalization, during titration of antithyroid medications, during which decompensation of heart failure may occur precipitously and fatally. Pheochromocytoma is rare but should be considered when a patient has heart failure and very labile blood pressure and heart rate, sometimes with episodic palpitations (Chap. 399). Patients with pheochromocytoma often have postural hypotension. In addition to α-adrenergic receptor antagonists, definitive therapy requires surgi­ cal extirpation. Very high renin states, such as those caused by renal

artery stenosis, can lead to modest depression in ejection fraction with little or no ventricular dilation and markedly labile symptoms with flash pulmonary edema, related to sudden shifts in vascular tone and intravascular volume. Controversies remain regarding whether diabetes mellitus and obesity are sufficient to cause cardiomyopathy with reduced ejection fraction. Most heart failure in diabetes mellitus results from epicardial coronary disease, with further increase in coronary artery risk due to accompanying hypertension and renal dysfunction. Cardiomyopathy may result in part from insulin resistance and increased advancedglycosylation end products, which impair both systolic and diastolic function. However, much of the dysfunction can be attributed to scat­ tered focal ischemia resulting from distal coronary artery tapering and limited microvascular perfusion even without proximal focal stenoses. Diabetes mellitus is a typical factor in heart failure with “preserved” ejection fraction, along with hypertension, advanced age, and female gender. The existence of a cardiomyopathy due to obesity is generally accepted, but the overlap is not well defined with the syndrome of heart failure with preserved ejection fraction (HFpEF). In addition to cardiac involvement from associated diabetes mellitus, hypertension, and vascular inflammation of the metabolic syndrome, obesity alone is associated with impaired excretion of excess volume load, which, over time, can lead to increased wall stress and secondary adaptive neuro­ humoral responses. Fluid retention may be aggravated by large fluid intake and the rapid clearance of natriuretic peptides by adipose tissue. In the absence of another obvious cause of cardiomyopathy in an obese patient with systolic dysfunction without marked ventricular dilation, effective weight reduction is often associated with major improvement in ejection fraction and clinical function. Improvement in cardiac function has been described after successful bariatric surgery, although all major surgical therapy poses increased risk for patients with heart failure. Postoperative malabsorption and nutritional deficiencies, such as calcium and phosphate deficiencies, may be particularly deleterious for patients with cardiomyopathy. Nutritional deficiencies can occasionally cause DCM but are not commonly implicated in developed countries. Beriberi heart disease due to thiamine deficiency can result from poor nutrition in under­ nourished populations and in patients deriving most of their calories from alcohol and has been reported in teenagers subsisting only on highly processed foods. This disease is initially a vasodilated state with very-high-output heart failure that can later progress to a low-output state; thiamine repletion can lead to prompt recovery of cardiovascu­ lar function. Abnormalities in carnitine metabolism can cause dilated or restrictive cardiomyopathies, usually in children. Deficiency of trace elements such as selenium can cause cardiomyopathy (Keshan’s disease). Calcium is essential for excitation-contraction coupling. Chronic deficiencies of calcium, such as can occur with hypoparathyroidism (particularly postsurgical) or intestinal dysfunction (from diarrheal syndromes and following extensive resection), can cause severe chronic heart failure that responds over days or weeks to vigorous cal­ cium repletion. Phosphate is a component of high-energy compounds needed for efficient energy transfer and multiple signaling pathways. Hypophosphatemia can develop during starvation and early refeeding following a prolonged fast and occasionally during hyperalimentation. Hemochromatosis is variably classified as a metabolic or storage disease (Chap. 426). It is included among the causes of restrictive car­ diomyopathy, but the clinical presentation is often that of a DCM. The autosomal recessive form is related to the HFE gene. With up to 10% of the population heterozygous for one mutation, the clinical prevalence might be as high as 1 in 500. The lower observed rates highlight the limited penetrance of the disease, suggesting the role of additional genetic and environmental factors such as alcoholism affecting clinical expression. Cardiac siderosis can also be acquired from iron overload due to hemoglobinopathies in patients treated with recurrent transfu­ sions. Excess iron is deposited in the perinuclear compartment of car­ diomyocytes, with resulting disruption of intracellular architecture and

FIGURE 269-1  Hemochromatosis. Microscopic image of an endomyocardial biopsy showing extensive iron deposition within the cardiac myocytes with the Prussian blue stain (400× original magnification). (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) mitochondrial function. A diagnosis of systemic iron overload is made from measurement of serum iron and transferrin saturation, with a threshold of >60% for men and >45–50% for women. MRI is used to quantitate iron stores in the liver and heart. While endomyocardial biopsy tissue can be stained for iron (see Chap. 270 and Fig. 269-1), a diagnosis of cardiac iron overload is made principally by MRI and biopsy is not usually needed. If diagnosed early, hemochromatosis can often be managed by repeated phlebotomy to remove iron. For more severe iron overload, iron chelation therapy with desferrioxamine (deferoxamine) or deferasirox can help to improve cardiac function if myocyte loss and replacement fibrosis are not too severe. Inborn disorders of metabolism occasionally present with DCM, although they are most often associated with restrictive cardiomyopa­ thy (Chap. 267, Table 267-1). FIGURE 269-2  Takotsubo cardiomyopathy. Four-chamber view of cardiac magnetic resonance imaging demonstrating a mildly dilated left ventricle in diastole (left panel) with diffuse hypokinesis of the mid and apical segments and relative sparing of the basal segment wall motion at end systole (right panel) with left ventricular ejection fraction 46%. (Image courtesy of Raymond Kwong, MD, and Zariyat M. Mannan, MD, Cardiovascular Imaging, Brigham and Women’s Hospital, Boston.)

TAKOTSUBO SYNDROME OR CARDIOMYOPATHY Apical ballooning or “takotsubo” syndrome, also referred to as stressinduced cardiomyopathy or “broken heart syndrome,” is often clas­ sified as a cardiomyopathy, although its distinct acute presentation, typical ventricular shape, and frequent rapid recovery differ from most other cardiomyopathies. It occurs typically in older women after sudden intense emotional or physical stress. The ventricle shows global ventricular dilation with basal contraction, forming the shape of the narrow-necked jar (takotsubo) used in Japan to trap octopuses. Originally described in Japan, it is well recognized elsewhere during emergency cardiac catheterization and intensive care unit admissions for noncardiac conditions. Presentations include pulmonary edema, hypotension, and chest pain with electrocardiogram (ECG) changes mimicking an acute infarction. The left ventricular dysfunction extends beyond a specific coronary artery distribution and generally resolves within days to weeks. Animal models and ventricular biop­ sies suggest that this acute cardiomyopathy may result from intense sympathetic activation with heterogeneity of myocardial autonomic innervation, diffuse microvascular spasm, and/or direct catecholamine toxicity. Cardiac MRI (Fig. 269-2) demonstrates diffuse myocardial edema without necrosis and abnormal myocardial calcium handling. Coronary angiography may be required to rule out acute coronary occlusion.

CHAPTER 269 Dilated Cardiomyopathies A similar picture to takotsubo can also be caused a coronary embolus in the absence of atherosclerotic coronary artery disease. No therapies have been proven beneficial, but reasonable strategies include nitrates for pulmonary edema; combined alpha and beta blockers rather than selective beta blockade if hemodynamically stable; and magnesium for arrhythmias related to QT prolongation. An intra-aortic balloon pump is occasionally employed to improve critically low cardiac output, but only if there is no left ventricular outflow tract obstruction. The longterm prognosis is generally good, with the lowest mortality associated with episodes triggered by emotional rather than physical triggers. In-hospital complications and mortality are similar to those with acute myocardial infarction. Recurrence occurs in 10% of patients at an esti­ mated rate of 2%/year.