Andres Schuster and W. H. Wilson Tang
MYOCARDITIS
The concept of myocarditis was first introduced by Corvisart in 1812. The term is broadly defined by an inflammatory infiltration of the myocardium with associated necrosis and/or degeneration.1 The disease is also known as “myocarditis with cardiac dysfunction” when left ventricular systolic dysfunction is evident. Although there is a tremendously wide spectrum of clinical presentation, it is frequently associated with acute-onset profound cardiac dysfunction leading to rapidly progressive heart failure (HF) and arrhythmia development in an otherwise healthy young person. Myocarditis is also one of the major causes of sudden cardiac death in patients < 20 years old.2
Epidemiology and Classification
The exact incidence and prevalence of myocarditis is unclear because the majority of cases of myocarditis may be subclinical in presentation. Nevertheless, myocarditis usually affects younger individuals (median age of 42 years), with a slight predominance of men.3 The estimated incidence of myocarditis is 1 to 10 per 100,000 persons from military recruits and autopsy studies, and about 1% to 5% of patients with acute viral infections may have some involvement in the myocardium.4 The incidence of biopsy-proven myocarditis ranges from 9% to 11% in adults and up to 38% in children with acute-onset HF5. The presence of viral genome in biopsies of patients with idiopathic dilated cardiomyopathy (IDCM) is up to 65% of the individuals, suggesting that viral subclinical myocarditis could be more frequent than suspected and may be the cause of many of the IDCM cases considered “idiopathic.”6
The classification of myocarditis is confusing but is often defined according to the description of the disease course as “fulminant,” “acute,” or “chronic” (Table 19.1).7 With the availability of endomyocardial biopsy techniques in the 1970s, a technical (histologic) definition has been standardized by pathologists:
TABLE
19.1 Clinicopathological Classification of Myocarditis
aLong-term survival data from 147 biopsy-proven myocarditis cases followed at the Johns Hopkins Hospital from 1984 to 1997.
IDCM, idiopathic dilated cardiomyopathy; LVD, LV dysfunction; LV, left ventricular.
Adapted from McCarthy RE III, Boehmer JP, Hruban RH, et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med. 2000;342:690-695, and Lieberman EB, Hutchins GM, Herskowitz A, et al. Clinicopathologic description of myocarditis. J Am Coll Cardiol. 1991;18:1617-1626.
1. The Dallas criteria (1987)8 describe the quantity and distribution patterns of lymphocyte infiltrates, and classify into three main types: (a) myocarditis (with or without fibrosis), (b) borderline myocarditis, and (c) no myocarditis. The availability of a second follow-up biopsy may allow further stratification into “ongoing myocarditis,” “resolving/healing myocarditis,” or “resolved myocarditis.”
2. The World Heart Foundation Marburg Criteria (1996)9 added a quantitative assessment of lymphocyte density (with the cutoff at 14 cells/mm2) for the stratification of the biopsies. Newer histologic criteria rely on immunohistologic quantification and characterization of immunocompetent infiltrates and cell adhesion molecule expression like anti-CD3, anti-CD4, anti-CD20, and anti-CD28. Criteria based on cellular staining have better sensitivity and could guide immunomodulatory therapy and also have a prognostic value.10,11
Etiologies and Pathophysiology
Many infectious and noninfectious agents can cause myocarditis (Table 19.2).4,12 Viral infection is the most common cause in North America and Europe, with enterovirus (including coxsackievirus) and adenovirus being classically the most frequently identified viruses.13,14 Recent data has raised the importance of parvovirus B19 (PVB19) and human herpesvirus-6 as causative agents, not only in biopsies from acute myocarditis patients15 but also when subjects with IDCM are studied. Pankuweit et al.16 described the persistence of viral genome of PVB19 in up to 33% of endomyocardial biopsy samples from patients with IDCM, ejection fraction (EF) < 45%, and persistent inflammation in their histology. A recent publication from Stewart et al. showed that PVB19 was the only virus isolated from tissue samples in adult HF patients referred for endomyocardial biopsy but in a lower rate than previously described (12%). Furthermore, they did not support a causative role for PVB19 persistence in the development of HF as there was a lack of correlation between PVB19 genome and HF progression in these patients.17 Otherwise, two or more viruses have also been described in more than 25% of patients with IDCM,6suggesting a simultaneous synergic effect of the different viruses.
TABLE
19.2 Causes of Myocarditis
The precise pathogenic mechanisms of the disease are generally not well understood and may vary according to the causative agent and host factors. The majority of the cases are presumed to be due to a common pathway of host autoimmune-mediated injury. Direct cytotoxic effects of the causative agent plus damage due to myocardial cytokine expression and direct endothelium injury seem to be the key factors. Clinically, myocardial damage follows the expected course of inflammatory response (Fig. 19.1).4
FIGURE 19.1 Classification of primary cardiomyopathies predominantly involving the heart. (From Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807-1816, with permission.)
Acute phase (0 to 3 days) is characterized by myocyte destruction and cardiac proteins exposure as a direct consequence of the offending agent. There is also cytokine expression and macrophage activation, leading to cell-mediated cytotoxicity and cytokine release that contribute to myocardial damage and dysfunction. In viral myocarditis, viremia is often present, although detection may sometimes be difficult.
Subacute phase (4 to 14 days): Most patients recover after the acute phase but a subgroup progresses to this second stage that consists of an adaptive immune response. In addition to the continued cytokine production and myocyte destruction by nonspecific autoimmune-mediated injury (through cytotoxic T-and natural killer cells), antibodies are produced against viral proteins (in the subgroup patients with viral myocarditis) and cardiac proteins (including β1 receptor and cardiac myosin).
Chronic phase (>14 days) involves a repair process characterized by fibrosis, and downregulation of the immune response. Some patients may have persistence of autoantibodies and also persistence of viral genome in myocardium. It has been estimated that between 20% and 50% of patients with acute myocarditis can progress to this chronic phase and develop cardiac dilatation and chronic HF.18 Those cases where inflammation persists on endomyocardial biopsy are considered as “chronic active myocarditis” or “persistent myocarditis.” A subclassification of the cardiomyopathy cases with persistent viral genome has been proposed. The patients in which viral clearing fails and have inflammatory disease in the biopsy would be referred as “viral inflammatory cardiomyopathy.” Those cases with dilated cardiomyopathy where inflammation is absent would correspond to a “viral cardiomyopathy.”19
In viral myocarditis, viral isolates differ in tissue tropism and virulence. For example, coxsackie A9 is a self-limiting myocarditis, whereas coxsackie B3 causes severe myocarditis with a high mortality. In addition, the induction of the coxsackie-adenovirus receptor (CAR) and the complement deflecting protein decay accelerating factor (DAF, CD55) may allow efficient internationization of the viral genome.20These key molecular determinants for cardiotropic viral infections can be found in up to two-thirds of patients with IDCM. Viral replication may lead to further disruption of metabolism and perturbation of inflammation and its response. More recent evidence of dystrophin disruption by expression of enteroviral protease 2A points to yet another unique pathogenic mechanism.21 Also, endothelial cells have been recognized as a target for PVB19 infection if they express blood group P antigen, which serves as a cellular receptor for this virus. Therefore, initial parvovirus infection of endothelial cells of small coronary arteries may cause endothelial dysfunction, vasospasm, and ischemia. This may be a cofactor for myocardial damage progression and could also mimic myocardial infarction presentation, what has been called “parvomyocarditis.”22 Interestingly, other investigators have not found histopathologic signs of chronic ischemic disease like subendocardial fibrosis and vacuolization on endomyocardial biopsy of HF patients with a positive tissue PCR for PVB19. These findings contradict the theory of endothelial and ischemic damage related to PVB19.17
Clinical Presentation
Myocarditis can be totally asymptomatic or can present with a chest pain syndrome ranging from the mild persistent chest pain of acute myopericarditis (35%) to severe symptoms that resemble myocardial ischemia.4 About 60% of patients may have history of arthralgias, malaise, fevers, sweats, or chills consistent with viral infections (pharyngitis, tonsillitis, upper respiratory tract infection) usually about 1 to 2 weeks prior to onset. The hallmark symptoms of acute or fulminant myocarditis are those of acute-onset HF in a person without known cardiac dysfunction or with low cardiovascular risks. The diagnosis is usually presumptive, based on patient demographics and the clinical course (spontaneous recovery following supportive care or death). Patients with an acute HF presentation usually will have tachycardia with a S3 gallop, jugular venous distension, and peripheral edema. An audible pericardial friction rub may accompany in cases of myopericarditis. In some instances, patients may present with arrhythmia in the form of palpitations caused by supraventricular or ventricular tachyarrhythmia, syncope caused by heart block (“Stokes–Adams attack”) or sudden cardiac death.
Additional findings may accompany specific forms of myocarditis. In patients with acute rheumatic fever, associated signs include erythema marginatum, polyarthralgia, chorea, and subcutaneous nodules (Jones criteria for rheumatic fever). In cases of sarcoid myocarditis, lymphadenopathy and arrhythmias are common (up to 70% of affected individuals). Chagas acute infection may present with arrhythmias and cardiac conduction abnormalities. Hypersensitive or eosinophilic myocarditis is often associated with a pruritic maculopapular rash (and history of offending drug use) and eosinophilia in their blood work. The typical presentation of a patient with giant-cell myocarditis involves sustained ventricular tachycardia and rapidly progressive HF leading to cardiogenic shock. These features have low specificities but are often useful and may raise the suspicion of underlying myocarditis.
Evaluation
Inflammation is the hallmark feature of myocarditis. Clinically, an early onset of fever, tachycardia, hypotension, reduced ventricular function, elevated acute phase reactants (erythrocyte sedimentation rate or C-reactive protein), leukocytosis, and increased cardiac enzymes (CK-MB/cardiac troponins) are predictive of myocarditis. However, the prevalence of an increased troponin T in biopsy-proven myocarditis is only 35% to 45%.23 A lower level of troponin I at admission has been associated with an increased risk for death, heart transplantation, or persistent ventricular dysfunction in patients with fulminant myocarditis.24 The presence of eosinophilia may suggest hypersensitive (eosinophilic) myocarditis. Novel inflammatory markers that are still under investigation include tumor necrosis factor (TNF)-α, interleukin (IL)-10, serum-soluble Fas, and soluble Fas-ligand levels.25,26 Elevation of these markers portends a worse prognosis, although they are rarely used in the clinical setting. Serum viral antibody titers are usually increased fourfold or more in the acute phase and gradually fall during convalescence. However, measurement of viral antibody titers is infrequently indicated due to the usual low viral levels at the time of HF presentation and the lack of evidence for antiviral therapy. Because of their low specificity, measurement of anticardiac antibody titers is not indicated (only 62% of myocarditis cases have titers ≥1:40). Screening antinuclear antibodies and rheumatoid factor are often indicated to rule out common rheumatologic problems. Disease-specific testing is indicated if particular conditions such as systematic lupus erythematosus, polymyositis, Wegner granulomatosus, or scleroderma are suspected.
The electrocardiogram generally reveals sinus tachycardia, although sometimes ST-segment deviation can be found, making it necessary to rule out ischemia especially in patients with cardiovascular risk factors. In some cases, fascicular block, atrioventricular conduction disturbances, or ventricular tachyarrhythmias may be hemodynamically significant. A complete echocardiogram is a standard procedure for patients with suspected myocarditis to (a) exclude alternative causes of HF-like valvular disease, (b) quantify the degree of left ventricular dysfunction to monitor response to therapy, and (c) detect the presence of intracardiac thrombi. Occasionally, focal wall motion abnormalities and presence of pericardial fluid may prompt further workup or intervention. Fulminant myocarditis is often characterized by near normal diastolic dimensions and increased septal wall thickness, whereas acute myocarditis often has increased diastolic dimensions but normal septal wall thickness.27 Coronary angiography is often performed to rule out coronary disease as cause of new-onset HF in patients with risk factors or with a clinical presentation that mimic myocardial ischemia ("pseudoinfarct pattern"). This is especially relevant in the presence of focal wall motion abnormalities on echocardiography and localizing electrocardiographic changes. Several specialized imaging procedures are available to detect the presence of myocarditis, although they are rarely used clinically. Antimyosin scintigraphy using indium-III monoclonal antimyosin antibody provides identification of myocardial inflammation, with a high sensitivity (91% to 100%) and negative predictive value (93% to 100%) but relatively low specificity (28% to 33%) of detecting myocarditis. Gallium scanning has been utilized to identify severe myocardial cellular infiltration with high specificity (98%) but low sensitivity (36%).4
Gadolinium-enhanced cardiac magnetic resonance imaging (MRI) is being used with increasing frequency for noninvasive evaluation of patients with suspected myocarditis. Cardiac MRI can assess different markers of tissue injury, including intracellular and interstitial edema, capillary leakage with hyperemia, and cellular necrosis with fibrosis. The International Group on Cardiovascular Magnetic Resonance in Myocarditis recommended to perform a cardiac MRI when the patient was symptomatic, if the clinical suspicion of myocarditis was high, and if the MRI result will likely impact clinical management. The authors proposed three tissue markers (the “Lake Louise Criteria”) to confirm the diagnosis of myocarditis (Table 19.3). If all sequences can be performed and two or more of the three tissue-based criteria are positive, myocardial inflammation can be predicted with a diagnostic accuracy of 78%; if only late gadolinium enhancement imaging is performed, the diagnostic accuracy falls to 68%.28
TABLE
19.3 Cardiac MRI Diagnostic Criteria for Myocarditis
Reprinted from Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol. 2009;53(17):1475-1487, with permission from Elsevier.
Histology remains the gold standard for the diagnosis of myocarditis, although endomyocardial biopsy is insensitive and not without risks. False negative rates are high29 (even with multiple biopsy samples) due to the small number of lymphocytes reviewed, difficulties in distinguishing cell types, wide interobserver variability, and the patchy distribution of myocardial inflammation in most patients. Guided biopsy using delay enhancement in contrast MRI was evaluated by Mahrholdt et al., where 21 patients in whom biopsy was obtained from the region of contrast enhancement. In these patients, histopathologic analysis revealed active myocarditis in 19 patients (PVB19, n = 12; human herpes virus type 6, n = 5). In contrast, the remaining 11 patients in whom biopsy could not be taken from the region of contrast enhancement, active myocarditis was found only in one case.30
In patients with suspected myocarditis, endomyocardial biopsy is generally reserved for suspected etiology in whom a positive histologic diagnosis will determine a specific treatment, such as giant-cell and sarcoid myocarditis. Giant-cell myocarditis, which can be suspected in subjects presenting with rapidly progressive HF symptoms despite conventional therapy and new-onset frequent ventricular tachyrrhythmia or conduction disturbances, could benefit from immunosuppressive therapy. In most cases, the histologic criteria only provide confirmation of the diagnosis and perhaps some prognostic information. It is also important to recognize that as the interval from illness onset to the time of the biopsy increases, the yield of the procedure gets lower. A negative endomyocardial biopsy can not convincingly exclude underlying myocarditis or sarcoidosis due to its patchy process and biopsy sampling error and therefore clinical correlation is necessary.
Treatment and Prognosis
There are no hard-and-fast rules for managing myocarditis once the acute events have occurred. In general, patients are treated in the same manner as if they have chronic HF. Clinical follow-up should be close, as persistent chronic inflammation may lead to dilated cardiomyopathy (initially 1 to 3 month intervals for medication and physical activity titration). Serial echocardiographic assessment of ventricular structure and function is often performed, although there is no agreement regarding the frequency of echocardiographic assessment following myocarditis. There is a theoretical increased risk of myocardial inflammation and necrosis, cardiac remodeling, and death with exercise in animal models.31 Therefore, patients suffering from myocarditis are usually advised to abstain from vigorous exercise for several months in order to limit myocardial demands. Depending on the clinical presentation, standard HF therapy with diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists should be used to delay or reverse disease progression of cardiac dysfunction. Although not proven in human studies, proarrhythmic properties of digoxin have been observed in animal models of myocarditis, and therefore should be avoided. Anticoagulation is usually recommended and indicated to prevent thromboembolic events in patients with apical aneurysm and thrombus (such as in Chagas cardiomyopathy), atrial fibrillation, and prior embolic episodes. Permanent pacemakers should be implanted for persistent heart block or bradyarrhythmia. Implantable cardioverter defibrillators (ICDs) are indicated only after acute phase resolution, in patients with primary and secondary indication of sudden cardiac death prevention. Inotropic therapy often is reserved for those experiencing severe hemodynamic compromise (particularly in fulminant myocarditis). Sometimes, intra-aortic balloon counterpulsation can be used for hemodynamic support and afterload reduction to prevent further deterioration. Mechanical assist devices (left ventricular assist device [LVAD]) and even extracorporeal membrane oxygenation (ECMO) have been used in cases of fulminant myocarditis with the hope for recovery and/or bridge to transplantation. Early consideration for cardiac transplantation should be given especially in severe, progressive, biopsy-proven giant-cell myocarditis and peripartum cardiomyopathy. Registry data have suggested that patients with myocarditis may have increased rejection and reduced survival after heart transplantation as compared to those without, and myocarditis may recur in the allograft in less severe forms.
Table 19.4 summarizes the major clinical trials on immunosuppression therapy for myocarditis and inflammatory cardiomyopathy. Routine immunosuppression therapy (including steroids), antiviral regimen, and nonsteroidal anti-inflammatory agents are not warranted based on current clinical evidence. The findings from the Myocarditis Treatment Trial (with oral prednisone and cyclosporine)32 and the IMAC study (with intravenous immunoglobulin)5indicated that routine immunosuppression therapy may not be effective. The more recently published TIMIC-randomized controlled trial showed positive results with prednisone and azathioprine therapy in 85 patients with virus-negative chronic inflammatory cardiomyopathy, where 88% of them improved their left ventricular ejection fraction (LVEF) and had reverse cardiac remodeling after 6 months of treatment.33 It seems that the duration of symptoms appears to be a major determinant in the response to immunosuppression. A recent meta-analysis of immunosuppression in patients with IDCM suggested that acute HF (symptoms duration of < 6 months) was associated with a lack of response to immunomodulation and immunosuppression therapy when compared to patients with symptoms for more than 6 months.34 At present, there is no FDA-approved regimen to treat acute or chronic myocarditis. Immunosuppression or immunomodulation therapy is reserved for the refractory patients with chronic myocarditis and those with biopsy-proven giant-cell myocarditis; in fact, patients with fulminant myocarditis should not be routinely being immunosuppressed but rather supported. Some reports have suggested that eosinophilic or sarcoid myocarditis may respond to highdose steroid therapy. Also, specific therapy for underlying collagen vascular diseases may be used.
TABLE
19.4 Major Clinical Trials of Myocarditis and Inflammatory Cardiomyopathy
LV, left ventricular; IVIG, intravenous immunoglobulin, HLA, human leukocyte antigen; IDCM, idiopathic dilated cardiomyopathy; EF, ejection fraction; NHLBI, National Heart, Lung & Blood Institute; EMB, endomyocardial biopsy
Recent studies have suggested potential benefits of targeted therapy with azathioprine and prednisone in patients with recent onset IDCM. An ongoing multicenter European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) may provide some further insight.38 There is likely a category of patients who have an active immune process for whom immunosuppression, immune absorption, or immune regulation will ultimately provide benefit.
Many patients may have full spontaneous clinical recovery, even after weeks of medical and mechanical support (including intra-aortic balloon counterpulsation and mechanical assist devices). In the Myocarditis Treatment Trial, 1-year mortality was 20%, and 4-year mortality was 56%.30 Interestingly, long-term outcomes do not differ significantly between active and borderline myocarditis by the Dallas criteria. Severe heart block requiring permanent pacemaker placement occurs in approximately 1% of patients. Unfavorable factors for survival include extremes of age (very old or very young), New York Heart Association (NYHA) class at presentation, electrocardiographic abnormalities (QRS alterations, atrial fibrillation, low voltage), syncope, and specific etiologies (peripartum cardiomyopathy, giant-cell myocarditis). Favorable factors for survival include preserved cardiac function, shorter clinical history, or survivors of fulminant presentation at onset. In fact, the prognosis of patients with secondary myocarditis, when compared with patients with idiopathic myocarditis, seems most affected by the primary disease processes.39For unclear reasons, survivors of fulminant myocarditis experienced better long-term outcomes than those presenting with acute myocarditis.40 Adults may present with HF years after the initial index event of myocarditis (up to 12.8% of patients with IDCM had presumed prior myocarditis in one case series). Up to half of patients with myocarditis develop subsequent IDCM over a range of 3 months to 13 years.
Specific Forms of Cardiomyopathy Related to Myocarditis
Chagas Heart Disease
It is estimated that 16 to 18 million persons are infected with Trypanosoma cruzi in South and Central America. While most patients resolve from the acute inflammatory phases of the infection, cardiac involvement usually appears decades after inoculation and is the leading cause of death in persons aged 30 to 50 years in endemic areas. The hallmark of Chagasic cardiomyopathy is arrhythmia that often presents with symptoms of palpitation, syncope, chest pain, and subsequently HF.41 Frequent complex ectopic beats and ventricular tachyarrhythmias occur in 40% to 90% affected, with sudden cardiac death occurring in 55% to 65% affected. Right bundle-branch block is also frequently seen, sometimes with bradyarrhythmias and high-grade atrioventricular block requiring pacemaker placement. HF is predominantly right-sided, and can be found in 25% to 30% of patients, and sometimes with cerebral or pulmonary thromboembolism. Apical left ventricular aneurysm, ventricular dilatation, and cardiac fibrosis are commonly found at autopsy. There are several types of serologic tests to confirm the presence of exposure to T. cruzi.Cardiac lesions can be confirmed by in situ polymerase chain reaction in biopsy specimens. Echocardiographic findings may include left ventricular aneurysm with or without thrombi, posterior basal akinesis or hypokinesis with preserved septal contraction, and diastolic dysfunction. Antibiotic therapy in the acute phase with benznidazole or nifurtimox may help to reduce parasitemia and prevent complications.
Giant-Cell Myocarditis
Giant-cell myocarditis (also known as pernicious myocarditis, Fiedler myocarditis, granulomatous myocarditis, or idiopathic interstitial myocarditis) is a rare disorder with unclear etiology. The hallmark feature is the presence of fused, multinucleated (>20 nuclei) epithelioid “giant cells” of histocytic origin within a diffuse, intramyocardial inflammatory infiltrate with lymphocytes. Giant-cell myocarditis often presents with an aggressive clinical course with progression over days to weeks. Rapidly progressive HF transpires in 75% affected, and sustained ventricular tachyarrhythmia is seen in more than 50% affected. Giant-cell myocarditis is often refractory to standard medical therapy, although small observational studies have suggested potential benefits of immunosuppressive therapy.42,43 Recently, a prospective study with steroids, cyclosporine and OKT3 monoclonal antibody therapy in 11 GCM patients showed a survival free of transplant in 8 of 11 patients at 1 year.44 Consideration for early cardiac transplantation is appropriate (71% 5-year survival following successful transplantation). Often, mechanical support may be required as a temporary bridge to recovery or transplantation. The prognosis is often dismal without intervention such as cardiac transplant (up to 80% 1-year mortality, with a median survival of 5.5 months from symptom onset). Therefore, early identification of giant-cell myocarditis by means of endomyocardial biopsies may facilitate prompt referral for cardiac transplantation. A 20% to 25% rate of histologic recurrence in surveillance endomyocardial biopsies has been observed following transplantation, but without substantial impact on the clinical course.45
Hypersensitive/Eosinophilic Myocarditis
Eosinophilic endomyocardial disease (also known as Loffler endomyocardial fibrosis) occurs as a major complication of idiopathic hypereosinophilic syndrome, as a result of direct toxic damage caused by eosinophil granule proteins within the heart.46 Drug-induced eosinophilic myocarditis is independent of cumulative dose and duration of therapy. Common inciting agents include catecholamines, chemotherapeutic agents, ampicillin, and tetanus toxoid (see Table 19.2).47 The absence of peripheral eosinophilia does not rule out eosinophilic myocarditis. Although observational series suggest potential clinical benefits of corticosteroid therapy, the best strategy is to remove the causative agent once identified.
DILATED CARDIOMYOPATHY
In 1995, the World Health Organization (WHO) defined dilated cardiomyopathy as a myocardial disease characterized by dilatation and impaired contraction of the left ventricle (LV) or both left ventricle and right ventricle (RV) (Table 19.5).1 It is a common and largely irreversible form of heart muscle disease with an estimated prevalence of 1:2,500. It is the third most common cause of HF and the most frequent of heart transplantation. In the new 2006 classification (see Fig. 19.1), dilated cardiomyopathy has been classified within the group of primary cardiomyopathies of mixed origin (genetic and nongenetic) together with the primary restrictive nonhypertrophied cardiomyopathy.48
TABLE
19.5 Major Forms of Cardiomyopathy and their Classification
Adapted from Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841–842.
Often synonymous with “nonischemic cardiomyopathy,” dilated cardiomyopathy is a heterogeneous disease, and shares the same common pathophysiologic processes of myocyte apoptosis and necrosis, fibrosis, and neurohormonal upregulation with specific cardiomyopathies. Clinical presentation of dilated cardiomyopathy ranges from asymptomatic to overt HF, stroke from thromboembolism, arrhythmias, and sudden cardiac death, almost parallel to that of myocarditis. While classification schemes are largely academic and the general diagnostic and therapeutic strategy follows that of all HF etiologies, several specific forms of cardiomyopathy are worth mentioning because they have unique clinical features and specific treatment options that are noteworthy.
Strict diagnostic criteria and epidemiology for IDCM are lacking because many cases go undiagnosed, and many patients who experienced HF do not undergo extensive workup. It has been estimated that the prevalence of IDCM is 0.4 per 1,000 in the general population. However, as more diagnostic techniques become available, specific causes of dilated cardiomyopathy can be identified and fewer cases will be deemed “idiopathic.” For example, histologic evidence of myocarditis is seen in 4% to 10% of endomyocardial biopsies of IDCM patients. It is estimated that dilated cardiomyopathy may develop in up to 50% of patients with acute myocarditis18 and molecular diagnosis of viral involvement have even suggested a viral etiology in up to two-thirds of IDCM cases.6
Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders, and storage diseases. Certain metabolic deficiencies such as selenium, carnitine, phosphate, calcium, and vitamin B deficiencies can all result in dilated cardiomyopathy, as often seen in patients with anorexia nervosa. Many endocrine disorders (adrenocortical insufficiency, thyroid abnormalities, acromegaly, and pheochromocytoma) also cause secondary cardiomyopathies. However, in cases of metabolic cardiomyopathies such as hemochromatosis, amyloidosis, glycogen storage diseases, and Fabry–Anderson disease, restrictive physiology is the hallmark presentation. Identification of the underlying etiology may aid the appropriate treatment (e.g., phlebotomy and chelation therapy for hemochromatosis, α-galactosidase replacement therapy for Fabry cardiomyopathy).
Several forms of dilated cardiomyopathy may develop early in childhood. Noncompacted myocardium occurs as a result of an arrested endomyocardial morphogenesis, and usually presents in childhood with persisting myocardial sinusoids, prominent trabeculations, and evidence of patchy “spongy” morphology of the embryonic heart. Endocardial fibroelastosis can lead to thickening of LV and left-sided cardiac valves, leading to dilated or restrictive cardiomyopathy.
Inherited Forms of Dilated Cardiomyopathy
Although familial dilated cardiomyopathy accounts for at least 20% to 30% of the cases of dilated cardiomyopathy, genetic screening is rarely performed. Mutations in genes encoding for cytoskeletal proteins (lamin A/C, phospholamban, dystrophin) as well as sarcomeric proteins (myosin heavy chain, cardiac troponin T, actin) have been described.49-51 Interestingly, the latter mutations are similar to those found in hypertrophic cardiomyopathy. Furthermore, patients with ion channelopathy (such as long and short QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachyarrhythmia) often develop dilated cardiomyopathy. The autosomal form of familial dilated cardiomyopathy is the most prevalent. The clinical expression and penetrance of these inherited gene defects is variable and may encompass skeletal myopathies (including Duchenne, Becker-type, and myotonic dystrophies), neuromuscular disorders (include Friedreich ataxia, Noonan syndrome, and lentiginosis), cardiac conduction system abnormalities, and progression to end-stage HF. The risk of sudden cardiac death is less clearly defined as compared with hypertrophic cardiomyopathy, but appears to be increased, particularly in patients with sarcomeric protein mutations. Family members may be asymptomatic early in the course of disease, but identification of affected individuals with serial echocardiography is important as early treatment may improve prognosis. Patients with familial dilated cardiomyopathy, particularly in those with inherited forms of systolic dysfunction with minimal dilatation (without restrictive physiology), may carry a poor prognosis.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) emerged as a unique entity in the 1995 WHO classification scheme. It is an autosomal dominant disease predominantly affecting the right ventricle by massive or partial replacement of myocardium by fatty or fibro-fatty tissue, and can be detected by MRI or by endomyocardial biopsy (often sparing the trabeculae and the septum).52 Over 50% of cases are inherited with an autosomal dominant pattern, and mutations in the plakoglobin and desmoplakin genes (recessive form of ARVC known as Naxos disease) have been associated with familial ARVC. Residual islands or strands of myocytes are often electrically unstable, leading to widespread ventricular tachyarrhythmias and sudden death of young individuals. Clinically, they may present in early adulthood with tachyarrhythmias or with right-sided HF (sometimes extending to the LV). Echocardiography may demonstrate a localized RV aneurysm or isolated RV failure, and the electrocardiogram may show slurred ST segments and inverted T waves in anterior leads (epsilon waves) without right bundle branch block. An ICD and treatment with antiarrhythmic drugs are indicated; radiofrequency ablations may be a useful intervention. HF is difficult to manage, and cardiac transplantation can be considered in selective cases.
Mitochondrial cardiomyopathy represents a special form of maternally inherited cardiomyopathy due to mutations in mitochondrial DNA with resultant abnormalities in oxidative phosphorylation. Indeed, the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome) can manifest as a cardiomyopathy. Electron microscopy of muscle biopsy specimens may demonstrate giant mitochondria, concentric crystae, and intramitochondrial inclusions. There have also been reports of the association of mutations of the hereditary hemochromatosis (HFE) gene with IDCM.
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QUESTIONS AND ANSWERS
Questions
1. A 45-year-old female came to see you because of intermittent chest pain and progressive shortness of breath for the last 3 days. She was seen last week by her primary physician because of sinusitis and was placed on azithromycin for 5 days without relief.
Exam: BP 110/80 mm Hg, pulse 110 bpm regular, JVP 10 cm H2O, bibasilar rales, S3 gallop, 1 to 2+ pedal edema.
ECG: sinus tachycardia, nonspecific T wave changes.
Echocardiography: left ventricular ejection = 25% 1 to 2+ mitral regurgitation
Which of the following is not an appropriate next course of action?
a. Cardiac catheterization
b. Endomyocardial biopsy to rule out acute lymphocytic myocarditis
c. Start diuretics and angiotensin-converting enzyme (ACE) inhibitors
d. Blood testing for thyroid function tests
2. Her blood work and autoimmune workup were negative. Cardiac catheterization revealed normal coronary arteries. Her clinical course rapidly deteriorated over the course of the next few days, requiring hospital admission for decompensated heart failure (HF). She was found to be in cardiogenic shock, requiring inotropic support for stabilization. An endomyocardial biopsy was performed, and the preliminary results suggested acute lymphocytic myocarditis according to the Dallas criteria. Her cardiac index and hemodynamics were stable other than frequent nonsustained ventricular tachyarrhythmia. Based on this information what is the appropriate therapeutic intervention?
a. Intravenous Solu Medrol
b. Implantable cardioverter defibrillator (ICD)
c. Plasmapheresis
d. No additional therapy at this point
3. What would be her 5-year prognosis if she survives this acute event?
a. 93%
b. 80%
c. 65%
d. 45%
4. Which of the following patients would have a worse prognosis?
a. A 29-year-old man with giant-cell myocarditis
b. A 27-year-old woman with fulminant myocarditis
c. A 35-year-old man with idiopathic restrictive cardiomyopathy
d. A 25-year-old woman with postpartum cardiomyopathy
Answers
1. Answer B: New-onset HF in a relatively young patient who had a recent bout of upper respiratory tract infection can be a potential clinical presentation of acute myocarditis. That being said, the usual course of action should involve cardiac catheterization to rule out coronary ischemia, blood testing to rule out reversible causes of HF such as hypoor hyperthyroidism, and start therapy with diuretics, ACE inhibitors, and beta-adrenergic blockers. Routine endomyocardial biopsy, even though it may elucidate the definitive diagnosis, does not change the management at this point, and should be reserved only when patients require further evaluation due to decompensation.
2. Answer D: The patient now presents with fulminant myocarditis, requiring inotropic support. She should remain on supportive therapy, and there is no supporting evidence to recommend immunosuppression therapy at this stage. It would also be inappropriate for her to receive an ICD in this acute setting.
3. Answer A: McCarthy and colleagues compared the long-term prognosis between fulminant and acute myocarditis and found a 93% survival for those suffering from fulminant myocarditis at 1-year follow-up, which maintained for the next 10 years.16. This is significantly better from those presenting with acute myocarditis (45% at 11 years).
4. Answer A: All the choices possess a poor prognosis except for fulminant myocarditis if supported, but giant-cell myocarditis has the worst prognosis, and cardiac transplantation should be considered.