Which of the following heart muscle diseases is unrelated to other cardiovascular disease?

Myocardial Diseases: Cardiomyopathy and Myocarditis

Cardiomyopathy refers to a diverse group of myocardial diseases with multiple causes. These are rare disorders that account for only approximately 1% of childhood cardiac disease. In 1995, the World Health Organization classified cardiomyopathies into hypertrophic, dilated, restrictive, and mixed type.63 This classification is based on the pathophysiology of the disease. However, with rapid evolution of molecular genetics in cardiology, the American Heart Association in 2006 has classified cardiomyopathies into two major groups based on predominant organ involvement and etiology.48 Primary cardiomyopathies are those solely or predominantly confined to heart muscle and are relatively few in number (Fig. 76.3). Secondary cardiomyopathies show pathologic myocardial involvement as part of a large number and variety of generalized systemic (multiorgan) disorders (Box 76.1).48 Myocarditis, an inflammatory, usually infectious process affecting the myocardium, may also result in either a dilated (common) or restrictive (rare) cardiomyopathy.

Dilated cardiomyopathy is characterized by left ventricular enlargement, with systolic dysfunction of either the left ventricle or both ventricles causing variable degrees of congestive heart failure. The patient's cardiac output (heart rate × stroke volume) is often decreased, and ventricular filling pressures are increased. Total ventricular mass is increased, but chamber volume is disproportionately enlarged. These neonates present with symptoms of poor cardiac output, including pallor, irritability, poor feeding, respiratory distress, and diaphoresis. Physical signs include tachypnea, tachycardia, narrow pulse pressure, and hepatomegaly. Decompensated infants will present with shock and cardiovascular collapse. Cardiac auscultation often reveals muffled heart sounds with a gallop rhythm (S3, S4). Occasionally, a murmur of mitral regurgitation can be auscultated. Arrhythmias, although rare, are an ominous, often undetected presentation.64 The electrocardiogram in a patient with dilated cardiomyopathy shows flattening of the T waves with possible depression of the ST segments. The chest x-ray often shows cardiomegaly with pulmonary edema. Echocardiogram is diagnostic, illustrating dilation of the ventricle(s) and poor cardiac contractility. Cardiac MRI is increasingly part of the diagnostic work-up, often demonstrating myocardial fibrosis and scarring. MRI has become useful in differentiating dilated cardiomyopathy from acute myocarditis, both of which can appear clinically and echocardiographically nearly identical. An extensive family history is essential when evaluating neonates, specifically asking for the first-degree relatives with dilated cardiomyopathy, metabolic disorders, degenerative neurologic diseases, or diseases of mitochondria. The management of these patients involves targeting the body's neurohormonal activation during heart failure, including spironolactone and loop diuretics, angiotensin-converting enzyme inhibitors or receptor blockers, and inotropes for acute decompensation. There is conflicting data in neonates and infants for use of beta-blockers in management of dilated cardiomyopathy, with many experienced institutions continuing to add carvedilol to augment medical management.58 The primary goal of therapy is to relieve symptoms and prolong survival. Often, these patients may require the use of extracorporeal membrane oxygenation (ECMO) and/or ventricular assist device (VAD) as a bridge to recovery or transplant. As mechanical support technology has improved, ventricular assist devices have demonstrated improvement in survival over ECMO.26 All forms of mechanical support have a high incidence of adverse event rates, particularly hemorrhage and thrombosis events in children under 10 kg.46

Cardiomyopathies—diseases of heart muscle—may result from an array of factors, mainly genetic, that will impair myocardial function leading to heart failure (HF). With the development of new sequence technologies following the human genome project (HGP), genetic evaluation of cardiomyopathies has exponentially increased. Numerous mutations have been identified as etiological factors in the more prevalent types of cardiomyopathy, that is, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and also recently in other, more uncommon phenotypes, such as restrictive cardiomyopathy (RCM), arhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC), noncompaction LV (NLVCM), stress cardiomyopathy (SCM), mitochondrial cardiomyopathy (MCM), and Danon cardiomyopathy (DCM). Increasingly, genetic defects have been also found in metabolic cardiomyopathies (i.e., diabetes), which often present with extracardiac manifestations. These genetic defects involve numerous intracellular pathways and they share a number of critical features as well as distinct elements fostering the various cardiomyopathic phenotypes, such as those arising from sporadic and acquired cardiomyopathies resulting from infection (e.g., viral induced), toxins (e.g., alcohol), and ischemic insult. In this chapter, we will review recent and contemporary research on CMs, including their etiology, mechanisms, clinical diagnosis, and potential therapies.

Myocardial Disease

A substantial minority of cases of heart failure result from familial (genetic) or nonfamilial (acquired) disorders, which can be confined to the heart or be multisystem disorders. The termcardiomyopathy refers to myocardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease (Chapter 64), hypertension (Chapter 70), valvular disease (Chapter 66), or congenital heart disease (Chapter 61) sufficient to cause the observed myocardial abnormality. Cardiomyopathies are classified according to ventricular morphology and pathophysiology into four major types: dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy (Table 54-1 andFig. 54-1). Diseases that do not fit into these groups (such as endocardial fibroelastosis and left ventricular noncompaction) are termed unclassified cardiomyopathies. Mixed phenotypes can exist; for example, patients with hypertrophic and dilated cardiomyopathies frequently have a restrictive left ventricular physiology or develop ventricular dilation.

OVERVIEW

Cardiomyopathies, diseases of heart muscle, may result from an array of factors that damage the heart and other organs and impair myocardial function, including infections, toxins, and cardiac ischemia. Over the past decade, the significance of inherited gene defects in the pathogenesis of primary cardiomyopathies has been recognized, with numerous mutations identified as etiological factors in the more prevalent types of cardiomyopathy (i.e., hypertrophic cardiomyopathy [HCM] and dilated cardiomyopathy [DCM]) and more recently in more uncommon phenotypes such as restrictive cardiomyopathy (RCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC). Moreover, genetic defects are increasingly implicated in the pathogenesis of metabolic cardiomyopathies (often associated with extracardiac presentations), including the mitochondrial cardiomyopathies and the cardiomyopathy associated with diabetes. These genetic defects involve numerous intracellular pathways sharing a number of critical features, as well as displaying distinct elements, in fostering the various cardiomyopathic phenotypes, including those arising in sporadic and acquired cardiomyopathies resulting from infection (e.g., viral-induced), toxins (e.g., alcohol), and ischemic insult. The primary pathophysiological mechanisms implicated in cardiomyopathy include defective force generation caused by mutations in sarcomeric protein genes; defective force transmission caused by mutations in cytoskeletal protein genes; myocardial energy deficits caused by mutations in both nuclear and mitochondrial DNA encoded genes; and abnormal Ca++ homeostasis caused by altered availability of Ca++ and altered myofibrillar Ca++ sensitivity.

A leading premise of ongoing research on cardiomyopathy is defining the role(s) of a plurality of genes in cardiac function and explaining the mechanisms by which mutations in these genes lead to hypertrophy, dilation, and contractile failure and, hopefully, to discover successful therapeutic strategies.

Cardiomyopathy and Left Ventricular Abnormalities

The incidence of HIV-associated cardiomyopathy has decreased dramatically from the pre-ART era, from 25.6 cases per 1000 person-years to 3.9 cases, according to one review (seeChapter 79).80 Additionally, in the pre-ART era, HIV-associated cardiomyopathy was defined as symptomatic, systolic dysfunction with left ventricular dilation, and was seen almost exclusively in patients with advanced HIV disease and AIDS; in the post-ART era, the diagnosis often refers to systolic or diastolic dysfunction detected by echocardiography in asymptomatic HIV patients.

The pathophysiology of HIV-associated cardiomyopathy is likely multifactorial, with proposed causes including direct HIV infection of the myocardium with or without myocarditis, coinfection with other viruses such as coxsackievirus B3 and cytomegalovirus, toxicity from ART, autoimmune factors, opportunistic infections, and nutritional disorders. When HIV-associated cardiomyopathy consisted of severe, dilated cardiomyopathy, the cause was believed to be opportunistic infections or myocarditis. Now that the disease has changed to more nuanced myocardial dysfunction, the understanding of mechanisms has become more nuanced as well.

Infection of the heart with the HIV virus is thought to cause impaired systolic function. HIV gene products, such as tat (transactivator of transcription, can also contribute. Proinflammatory cytokines such as interleukin-1β and tumor necrosis factor have also been shown to depress systolic function.80 Some types of ART cause mitochondrial toxicity, which may impair ventricular function. In sub-Saharan Africa and other poor areas, nutritional deficiencies may contribute to HIV-associated cardiomyopathy. HIV-associated heart failure has been reported in low- and middle-income countries.81 Most studies of HIV patients have been performed in developed countries with readily available access to ART, so a different spectrum of CV diseases may be observed in developing countries.

Left ventricular hypertrophy is more common in HIV-infected patients than in controls). In one study, HIV-infected participants had a left ventricular mass index that was 8 g/m2 (the mean) larger than the mass index in controls (P = 0.001).82 The higher left ventricular mass index was independently associated with a lower nadir CD4 T-cell count, suggesting that immunodeficiency may play a role in this process. After adjustment for age and traditional risk factors, HIV patients were 2.4 times more likely to have diastolic dysfunction than controls. Another study compared left ventricular mass in patients with and without HIV infection and with and without hypertension.83 In both hypertensive and normotensive persons, HIV patients had a greater left ventricular mass and more diastolic dysfunction than uninfected controls.

Cardiomyopathy

Cardiomyopathy is any structural and functional abnormality of the heart muscle unattributable to specific causes or disease processes such as coronary artery disease (CAD), congenital heart disease, or valvular disease. Over the years, classification of this condition has been updated by the rapid advancement of genetic, imaging, and clinical investigation. In 2006 in association with the American Heart Association (AHA), the classification of heart muscle disease was updated with an intention to bridge the gap between rapidly expanding genetic knowledge and existing clinical experience. An expert panel proposed this definition:

Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure–related disability.1

This new classification divided cardiomyopathies into two major groups—primary and secondary—based on the predominant organ involvement. It retained the common clinical cardiomyopathies synonymous with worsening myocardial performance due to diastolic or systolic dysfunction, but for the first time included diseases with electrical abnormalities that cause life-threatening arrhythmias (differentiated by their specific molecular nature). Primary cardiomyopathies include those conditions with only or mostly myocardial involvement (genetic, mixed, acquired) (Fig. 18-1). This places a traditional cardiomyopathy like hypertrophic cardiomyopathy (HCM) with disorders that cause tachyarrhythmias because of genomic changes that encode for ion channel dysfunction.1 Secondary cardiomyopathies are defined as the result of any disease process that includes the heart but is not limited to the heart. These were previously referred to as specific cardiomyopathies or specific heart muscle diseases. Box 18-1 lists some of the major disease processes that may be associated with cardiomyopathy but are not considered “primary” cardiomyopathies under the new classification. Also excluded are cardiomyopathies due to myocardial conditions such as valvular, congenital heart, and atherosclerotic disease. The common use of “ischemic cardiomyopathy” is excluded.

The importance of echocardiography in cardiomyopathy diagnosis, research, and patient care is evident. Using the AHA classification of cardiomyopathies, this chapter will first provide an overview of primary cardiomyopathy in the adult in association with a range of echocardiographic imaging, including during the perioperative period. This patient population may need a wide range of cardiac surgical procedures (including heart transplantation) that will necessitate perioperative transesophageal echocardiography (TEE). TEE may be especially valuable for optimal care in this patient population during noncardiac surgical procedures, such as cholecystectomy or hip replacement.

Enormous work has been done identifying genetic causes for cardiomyopathies. Genetic testing is advancing rapidly to identify disease-causing mutations in family members at risk but asymptomatic.2 The primary cardiomyopathies have a very complex genetic profile, with mutations that affect clinical expression of the same disease. The result is heightened clinical surveillance and possibly earlier intervention and prevention of the sequelae of cardiomyopathies. At this time, genetic testing is not 100% sensitive, so it is usually performed once the disease has been diagnosed and confirmed clinically. Genetic screening’s greatest use is to identify carriers within a family. This may allow family members that carry the same genetic mutation to be followed, since they may have a reduced penetrance that leads to a lesser form of the disease or even asymptomatic expression.3

Most inherited cardiomyopathies demonstrate a mendelian autosomal dominant inheritance. It has been accepted that HCM is largely a genetic defect of the contractile proteins. In contrast, the genetic trail of dilated cardiomyopathy (DCM) is really only solid as it pertains to familial DCM. The more common sporadic DCM has not been found to have a genetic basis. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is primarily related to genetic mutations that encode proteins of the desmosome. Desmosomes, cell-cell adhesion organelles, are especially abundant in heart tissue.4 A genetic basis for restrictive cardiomyopathy (RCM) has not been identified, but a familial form exists and is caused by mutations in the troponin I gene.5 The genetic basis for left ventricular noncompaction (LVNC) has not been found (and the diagnostic criteria for LVNC continue to be debated),6 but it is frequently familial, with at least 25% of asymptomatic relatives having a range of echocardiographic abnormalities.5 More extensive information about the genetics of primary cardiomyopathies is available.7-10

Etiology

Cardiomyopathies with a hypertrophic phenotype have in common the genetic etiology. However, the pathways leading to the phenotypic expression and the clinical and morphologic features vary widely, according to the gene (or class of genes) involved. Increased ventricular thickness is a common finding of sarcomeric HCM, mitochondrial disorders, metabolic or storage disease, familial transthyretin-related amyloidosis, Friedreich' ataxia, and Noonan/LEOPARD syndrome. Clues in the differential diagnosis include the pattern of inheritance, age of onset, and clinical presentation (syndromic vs. nonsyndromic disease), pattern of hypertrophy (symmetric vs. nonsymmetric), electrocardiographic abnormalities, laboratory tests, and histopathologic findings. These allow the identification of “red flags” that can guide the genetic analysis for identification of specific subsets of cardiomyopathies [5].

Definition

The World Health Organization defines cardiomyopathies (CMs) as myocardial diseases associated with cardiac dysfunction. They are classified by the dominant pathophysiology or, if known, by causative factors. Thus, CM may be dilated, hypertrophic, restrictive, or a special type called arrhythmogenic right ventricular cardiomyopathy (or arrhythmogenic right ventricular dysplasia). If the cause of a CM is known (i.e., secondary CM), it may be ischemic, valvular, hypertensive, inflammatory, metabolic, or peripartum in origin. CMs can also be associated with systemic disease, neuromuscular disorders, or exposure to toxins.

ANNOTATED REFERENCES

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Elliott P, Andersson B, Arbustini E, et al: Classification of the cardiomyopathies: A position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–276.

This recent report from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases provides a comprehensive classification of the cardiomyopathies.

Nugent AW, Daubeney PE, Chondros P, et al: The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003;348:1639–1646.

Lipshultz SE, Sleeper LA, Towbin JA, et al: The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;348:1647–1655.

These two population-based studies provide novel epidemiological and aetiological data on childhood cardiomyopathies.

Ahmad F, Seidman JG, Seidman CE: The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet 2005;6:185–216.

This is an excellent and comprehensive review of the genetic basis of cardiomyopathies.

Elliott PM, Poloniecki J, Dickie S, et al: Sudden death in hypertrophic cardiomyopathy: Identification of high risk patients. J Am Coll Cardiol 2000;36:2212–2218.

This study reports a non-invasive risk stratification algorithm for identifying patients with hypertrophic cardiomyopathy at risk of sudden death. Although the data is derived from adults, it has been extrapolated to children with some success.

Maron BJ, Shen WK, Link MS, et al: Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000;342:365–373.

This large study demonstrates that implantation of cardioverter-defibrillators prevents sudden death in a population of patients, mostly adults, with hypertrophic cardiomyopathy.

Mason JW, O’Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269–275.

This randomised controlled trial of 111 adults with myocarditis showed no improvement in survival in patients given immunosuppressive therapy, suggesting that the routine use of immunosuppressive drugs in patients with myocarditis is not warranted.

Rosenthal D, Chrisant MR, Edens E, et al: International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. J Heart Lung Transplant 2004;23:1313–1333.

These practical guidelines for the management of cardiac failure in children provide an excellent and comprehensive review of the evidence for different drugs available for therapeutic use in children and adults.

Towbin JA, Lowe AM, Colan SD, et al: Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296:1867–1876.

This population-based report provides data on the epidemiology, aetiology, and outcome of children with dilated cardiomyopathy in the current era.

Shaddy RE, Boucek MM, Hsu DT, et al: Carvedilol for children and adolescents with heart failure: A randomized controlled trial. JAMA 2007;298:1171–1179.

This is the first randomised controlled trial of medication for the management of cardiac failure in children. Although not statistically significant, the results suggested a trend towards improved survival when patients were treated with carvedilol.

Metabolism

CMR allows the semiquantitative assessment of several nuclei, and numerous studies have been published on 1H and 31P CMR spectroscopy (CMRS) in cardiomyopathies. Changes of high-energy phosphates as studied by 31P CMRS in cardiomyopathies have been reported for DCM31–33 and HCM.34,35 However, CMRS is still an experimental approach. Whereas 1H CMRS is characterized by a strong signal from water-bound protons and difficulties of spectral interpretation, 31P CMRS is limited by the weakness of the phosphorus signal. Thus, voxels have to be too large to cover circumscribed myocardial regions, and spectra are often altered by blood or adjacent tissue (e.g., skeletal muscle). Furthermore, CMRS requires extensive experience of the investigator, strong physicist support, and sophisticated hardware and software. Therefore, the number of centers with access to this promising tool is currently limited.