Outline
Restrictive and Infiltrative Cardiomyopathy, 288
Clinical Evaluation, 289
Cardiac Catheterization and Endomyocardial Biopsy, 289
Prognosis, 289
Clinical Manifestations, 290
Laboratory Studies, 290
Inherited and Acquired Infiltrative Disorders Causing Restrictive Cardiomyopathy, 291
Fabry Disease, 291
Cardiac Findings, 291
Gaucher Disease, 291
Hemochromatosis, 291
Glycogen Storage Disease, 292
Inflammatory Causes of Infiltrative Cardiomyopathy, 292
Sarcoidosis, 292
Endomyocardial Disease, 294
Definition and Pathogenesis, 294
Differences Between Löffler Endocarditis and Endomyocardial Fibrosis, 294
Endomyocardial Fibrosis, 295
Pathology, 295
Histologic Findings, 296
Clinical Manifestations, 296
Right Ventricular Endomyocardial Fibrosis, 296
Left Ventricular Endomyocardial Fibrosis, 297
Biventricular Endomyocardial Fibrosis, 297
Endocardial Fibroelastosis, 297
Neoplastic Infiltrative Cardiomyopathy—Carcinoid Heart Disease, 298
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, 298
Presenting Symptoms and Natural History, 298
Pathology, 298
Genetics, 298
Diagnosis, 298
Management, 298
Summary and Future Perspectives, 299
Restrictive cardiomyopathy is the least prevalent of cardiomyopathies relative to dilated ( see Chapter 20 ) and hypertrophic forms ( see Chapter 23 ) of heart muscle diseases. All forms of cardiomyopathy are diseases of heart muscle that result from a myriad of insults, such as genetic defects ( see Chapter 24 ), cardiac myocyte injury, or infiltration of myocardial tissues. Thus cardiomyopathies result from insults to both cellular elements of the heart, notably the cardiac myocyte, and processes that are external to cells, such as deposition of abnormal substances into the extracellular matrix. Disorders that lead to the abnormal deposition of noncompliant materials in the myocardium preferentially lead to the restrictive cardiomyopathy phenotype, the prototypic causes being deposition of excessive fibrosis and amyloid proteins ( see Chapter 22 ). Cardiomyopathies are traditionally defined on the basis of structural and functional phenotypes, notably dilated (characterized primarily by an enlarged ventricular chamber and reduced cardiac performance), hypertrophic (characterized primarily by thickened, hypertrophic ventricular walls and enhanced cardiac performance), and restrictive (characterized primarily by thickened, stiff ventricular walls that impede diastolic filling of the ventricle; cardiac systolic performance is typically close to normal). A fourth, and increasingly appreciated, structural and functional phenotype is a cardiomyopathy that primarily involves the right ventricle—arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). This chapter will review restrictive/infiltrative cardiomyopathies and ARVD/C.
Restrictive and Infiltrative Cardiomyopathy
Relative to the dilated ( see Chapter 20 ) and hypertrophic ( see Chapter 23 ) cardiomyopathies, restrictive cardiomyopathy occurs with lower frequency in the developed world. Specific forms of restrictive cardiomyopathy, such as endomyocardial disease (EMD) ( Table 21.1 ), are important causes of morbidity and mortality common in specific geographic locales, especially in underdeveloped countries. The pathophysiologic feature that defines restrictive cardiomyopathy is the increase in stiffness of the ventricular walls, which causes heart failure because of impaired diastolic filling of the ventricle ( see also Chapter 11, Chapter 23, Chapter 36 ). In early stages of the syndrome, systolic function may be normal, although deterioration in systolic function is usually observed as the disease progresses.
| Myocardial |
| Noninfiltrative |
| Idiopathic cardiomyopathy a Familial cardiomyopathy Hypertrophic cardiomyopathy Scleroderma Pseudoxanthoma elasticum Diabetic cardiomyopathy |
| Infiltrative |
| Amyloidosis a Sarcoidosis a Gaucher disease Hurler disease Fatty infiltration |
| Storage Disease |
| Hemochromatosis Fabry disease Glycogen storage disease |
| Endomyocardial |
| Endomyocardial fibrosis a Hypereosinophilic syndrome Carcinoid heart disease Metastatic cancers Radiation a Toxic effects of anthracycline a Drugs causing fibrous endocarditis (serotonin, methysergide, ergotamine, mercurial agents, busulfan) |
a These conditions are more likely than the others to be encountered in clinical practice.
Restrictive cardiomyopathy must be distinguished from constrictive pericarditis, which is also characterized by normal or nearly normal systolic function but abnormal ventricular filling. Differentiation of these two conditions represents a classic diagnostic challenge and is one of significant clinical importance because pericardial constriction may be treated successfully with pericardiectomy.
Approximately 50% of cases of restrictive cardiomyopathy result from specific clinical disorders, whereas the remainder represent an idiopathic process. The most common specific cause of restrictive cardiomyopathy is infiltration caused by amyloidosis—there are both acquired and genetic causes of amyloid ( see Chapter 22 ). Although there are other specific pathologic presentations associated with restrictive cardiomyopathy, their precise etiology often remains obscure. Like dilated cardiomyopathy (DCM), there are inflammatory and genetic factors important in the cause of restrictive cardiomyopathy. Recently, mutations in the troponin T (TNNT2) , troponin I (TNNI3), α-actin (ACTC), and β-myosin heavy chain (MYH7) genes coding for these sarcomere subunits have been mapped as causes of restrictive cardiomyopathy. The identification of specific infiltrative processes may have prognostic and therapeutic implications. The abnormal diastolic properties of the ventricle are attributable to myocardial fibrosis, infiltration, or scarring of the endomyocardial surface. Myocyte hypertrophy is common, particularly in idiopathic restrictive cardiomyopathy ( Fig. 21.1 ).
Clinical Evaluation
Cardiac Catheterization and Endomyocardial Biopsy
Restrictive Cardiomyopathy Versus Constrictive Pericarditis
A classic diagnostic challenge is to differentiate restrictive cardiomyopathy from constrictive pericarditis, which manifests with similar clinical and hemodynamic features. Cardiac catheterization is a key step in this evaluation ( see also Chapter 31 ). Although there is equalization of diastolic pressures in constrictive pericarditis (pressures differ by no more than 5 mm Hg), they may vary to a greater extent in restrictive cardiomyopathy. Pulmonary hypertension is worse in restrictive cardiomyopathy, with systolic pulmonary pressures often exceeding 50 mm Hg. In constrictive pericarditis, the plateau of right ventricular diastolic pressure is usually at least one-third of peak systolic pressure; in restrictive cardiomyopathy, this is most often lower. Hemodynamically both conditions have a rapid early diastolic pressure decline followed by a rapid rise and plateau in early diastole, the so-called square root sign. The atrial pressure tracing manifests either a classic square root pattern or an M or W waveform when the x descent is also rapid. Both a and v waves are prominent and frequently have the same amplitude. Right- and left-sided atrial filling pressures are elevated, although in the case of restrictive cardiomyopathy the left ventricular filling pressure typically is 5 mm Hg or more than the right ventricular diastolic pressure. This difference may be accentuated by the Valsalva maneuver, exercise, or a fluid challenge.
Endomyocardial biopsy can also be valuable in the evaluation of these patients to exclude an infiltrative process or cardiomyopathic-appearing myocytes and received a class IIa recommendation in the guidelines. A normal-appearing biopsy supports the diagnosis of a pericardial process. Surgical exploration is needed far less often, given the availability of biopsy and imaging technology (see later discussion).
Prognosis
Restrictive cardiomyopathy carries a variable prognosis dependent on the cause ( Fig. 21.2 ). Most often, especially in the case of amyloidosis, it is invariably progressive with an accelerated mortality. Hong and colleagues recently reported in a series of patients ( n = 53) with idiopathic restrictive cardiomyopathy that 5-year survival was 64% and that predictors of mortality were tricuspid regurgitation and smaller left ventricular (LV) chamber size ( Fig. 21.3 ). There is no specific therapy for the idiopathic form of restrictive cardiomyopathy, but intensive fluid and supportive management is required to maintain a patient with a reasonable quality of life. There are ongoing aggressive attempts to devise therapies for secondary forms of restrictive cardiomyopathy tailored to the cause (e.g., iron removal in hemochromatosis or enzyme replacement therapy in Fabry disease).
Clinical Manifestations
Patients with restrictive cardiomyopathy frequently present with exercise intolerance that results from an impaired ability to augment cardiac output during increasing heart rate because of the restriction of diastolic filling. Other notable symptoms are weakness, dyspnea, and edema. Exertional chest pain is reported by some but not all patients. With advancing disease, profound edema occurs that includes peripheral edema, hepatomegaly, ascites, and anasarca. These patients represent the most difficult volume management because of the balance between volume status and hypotension that can result during diuresis because of reduced preload filling of the ventricles. Physical examination is notable for an elevated jugular venous pulse, often with the Kussmaul sign, and a rising jugular pressure during inspiration (because of the restriction to filling). Both S 3 and S 4 gallops are common and the apical pulse is palpable (in contrast to constrictive pericarditis). Patients with restrictive cardiomyopathy are highly prone to developing atrial fibrillation.
Laboratory Studies
Computed tomography and magnetic resonance imaging (MRI) are valuable for differentiating constrictive and restrictive disease. A thickened pericardium supports the diagnosis of pericardial constriction. Other ancillary tests also may be helpful. For example, chest roentgenography may detect pericardial calcification. The electrocardiogram (ECG) may disclose atrial fibrillation. Echocardiography should be routinely performed in patients suspected of restrictive cardiomyopathy or constriction and may reveal biatrial dilation and increasing wall thickness associated with myocardial infiltration, as well as alterations in the appearance of the myocardium (e.g., speckling). Doppler echocardiography supplemented with tissue Doppler reveals evidence of myocardial relaxation with increased early left ventricular filling velocity, decreased atrial filling velocity, and decreased isovolumetric relaxation time. The latter findings are additionally useful for the discrimination from constrictive disease. Brain naturetic peptide (BNP) levels may be used to discriminate between restrictive cardiomyopathy and constrictive disease, with concentrations approximately five times greater in the former compared with the latter.
Inherited and Acquired Infiltrative Disorders Causing Restrictive Cardiomyopathy
The heritable metabolic disorders resulting from the myocardial accumulation or infiltration of abnormal metabolic products represent an important cause of restrictive cardiomyopathy. These disorders produce classic restrictive cardiomyopathy with diastolic impairment and variable degrees of systolic dysfunction. The heritable metabolic disorders include Fabry disease, Gaucher disease, the glycogenoses, and the mucopolysaccharidoses. Early diagnosis is increasingly important because of the availability, in some cases, of effective enzyme replacement therapy.
Fabry Disease
Fabry disease, or angiokeratoma corporis diffusum universale, is an X-linked recessive disorder that results in deficiency of the lysosomal enzyme α-galactosidase A, and the resultant accumulation of glycosphingolipids (most notably globotriaosylceramide) in lysosomes. The major clinical features result from the accumulation of glycolipid substrate in the endothelium. More than 160 different mutations are described that have a varying impact, ranging from the absence of α-galactosidase activity to an attenuated level of activity of this enzyme. Patients with absent α-galactosidase activity exhibit widespread systemic manifestations with prominent kidney and cutaneous manifestations, whereas those with an attenuated level of enzyme activity have atypical variants of Fabry disease that may cause isolated myocardial disease. Histologic evaluation of the heart demonstrates diffuse involvement of the myocardium, vascular endothelium, conduction system, and valves—most notably the mitral valve.
Cardiac Findings
Patients with Fabry disease often experience angina pectoris and myocardial infarction caused by the accumulation of lipid species in the coronary endothelium, although epicardial coronary arteries are angiographically normal. The ventricular walls are thickened and have mildly diminished diastolic compliance with normal systolic function. Mild mitral regurgitation may be present. Diastolic abnormalities detected by Doppler echocardiography may be one of the earlier manifestations preceding cardiac hypertrophy, although cardiac MRI may be the preferred diagnostic method. Males almost always present with symptomatic cardiovascular involvement, whereas female carriers may be completely asymptomatic or have only minimal symptoms. Other common features of the disorder include systemic hypertension, congestive heart failure, and mitral valve prolapse. Echocardiography demonstrates increased ventricular wall thickness, which may mimic hypertrophic cardiomyopathy. Although echocardiography may not be sufficient to do so, cardiac MRI may be able to differentiate Fabry disease from other infiltrative processes such as amyloidosis. The surface ECG may reveal a short PR interval, atrioventricular block, and ST segment and T wave abnormalities. The endomyocardial biopsy and low plasma α-galactosidase A activity offer a definitive diagnosis, which has therapeutic implications because enzyme replacement therapy for Fabry disease is safe and effective ; moreover heart biopsy may be used to monitor response to therapy. Administration of recombinant α-galactosidase A can ameliorate the stores of globotriaosylceramide from the heart and other tissues, leading to symptomatic, clinical, and echocardiographic improvement ( Fig. 21.4 ). Although enzyme reduction therapy is the mainstay of treatment, substrate reduction therapy (upstream inhibition of glycosphingolipids biosynthesis) and gene therapy are also being evaluated.
Gaucher Disease
Gaucher disease results from a heritable deficiency of β-glucosidase, which leads to an accumulation of cerebrosides in diffuse organs including spleen, liver, bone marrow, lymph nodes, brain, and heart. Cardiac disease manifests as a stiffened ventricle caused by reduced chamber compliance, leading to impaired cardiac performance. Other manifestations include left ventricular failure and enlargement, hemorrhagic pericardial effusion, and sclerotic, calcified left-sided valves. Gaucher disease is responsive to enzyme replacement therapy or, in more extreme cases, hepatic transplantation; both therapies contribute to reducing tissue infiltration by cerebrosides and can lead to varying degrees of clinical improvement.
Hemochromatosis
Hemochromatosis results from excessive deposition of iron in a variety of parenchymal tissues, notably the heart, liver, gonads, and pancreas. The classic pentad is a symptom complex of heart failure, cirrhosis, impotence, diabetes, and arthritis. The most frequent form of hemochromatosis is inherited as an autosomal recessive disorder that arises from a mutation in the HFE gene, which codes for a transmembrane protein that is responsible for regulating iron uptake in the intestine and liver. Hemochromatosis may also arise from ineffective erythropoiesis secondary to a defect in hemoglobin synthesis, as well as from chronic liver disease, or may be acquired as a result of chronic and excessive oral or parenteral intake of iron or blood transfusions.
Iron deposition in the heart is almost always accompanied by varying degrees of infiltration of the liver, spleen, pancreas, and bone marrow, although the degrees of different organ system involvement may not parallel each other. Cardiac involvement produces a mixed pattern of systolic and diastolic dysfunction that is often accompanied by arrhythmias. The severity of hemochromatosis is less, and age of onset is later in women because of the menstrual loss of iron. Cardiac toxicity results directly from the free iron moiety, in addition to adverse effects of tissue infiltration. Death results most frequently from cirrhosis and hepatocellular carcinoma, whereas cardiac mortality accounts for an additional one-third of the mortality and is particularly important in the group of male patients who present at relatively younger ages.
Pathology
Grossly the hearts are dilated, and ventricular walls are thickened. Iron deposits locate preferentially in the myocyte sarcoplasmic reticulum, more frequently in ventricular versus atrial cardiomyocytes. Frequently, the conduction system is involved, and loss of myocytes with fibrosis is often present. The degree of iron deposition correlates with the extent of myocardial dysfunction.
Clinical Manifestations
Symptoms at presentation vary widely, and some patients are asymptomatic, although evidence exists for myocardial involvement. Echocardiography reveals increased left ventricular wall thickness, ventricular dilation, and ventricular dysfunction. Both computed tomography and MRI are useful to detect early subclinical myocardial involvement at a time when therapy is most effective. ECG manifestations occur with advancing cardiac involvement and include ST segment and T wave abnormalities, and supraventricular arrhythmias.
Clinical and echocardiographic features usually are diagnostic, and endomyocardial biopsy is confirmatory but because of false negativity cannot definitively rule out the diagnosis. Evaluation of iron metabolism may aid in the diagnosis. Plasma iron levels are elevated, total iron-binding capacity is low or normal, and serum ferritin, urinary iron, liver iron, and especially saturation of transferrin are markedly elevated. Management should include repeated phlebotomies and/or treatment with chelating agents such as desferrioxamine. For advanced disease, cardiac transplantation carries acceptable 5- and 10-year survival rates, and combined liver and heart transplantation is described.
Glycogen Storage Disease
Patients with type II, III, IV, and V glycogen storage diseases may have cardiac involvement. However, survival to adulthood is rare, with the exception of patients with type III disease (glycogen debranching enzyme deficiency). The most typical cardiac involvement is left ventricular hypertrophy, with electrocardiographic and echocardiographic findings, often with the absence of symptoms. A subset of patients may present with overt cardiac dysfunction, arrhythmias, and presentation of a DCM.
Inflammatory Causes of Infiltrative Cardiomyopathy (see also Chapter 20 )
Sarcoidosis
Sarcoidosis is a systemic inflammatory condition characterized by the formation of noncaseating granulomas, most commonly involving the lungs, reticuloendothelial system, and skin. Sarcoid has been reported to involve essentially all tissues, including the heart, which is recognized in 20% to 30% of autopsies of affected patients. Cardiac impairment may also arise secondary to pulmonary sarcoidosis, in which case extensive pulmonary fibrosis leads to advancing right-sided heart failure. The main clinical manifestations of sarcoid heart disease result from infiltration of the conduction system and myocardium, producing heart block, malignant arrhythmias, heart failure, and sudden cardiac death. Patients with cardiac sarcoidosis may also present with a restrictive cardiomyopathy caused by increased ventricular chamber stiffness.
Pathology
Noncaseating granulomas surrounded by multinucleated giant cells are the diagnostic feature of the disorder and are found in multiple organs. In the heart they infiltrate the myocardium and lead to the formation of fibrotic scars. The condition must be separated from two other inflammatory conditions of the heart—chronic active myocarditis and giant cell myocarditis ( see Chapter 28 ). Giant cell myocarditis, which is characterized by diffuse giant cell inflammation in the absence of discrete granulomas, has a much more fulminant course than cardiac sarcoid ( Fig. 21.5 ). In sarcoidosis, the granulomas may involve discrete areas of the ventricular walls in a patchy fashion, increasing the likelihood of a false-negative endomyocardial biopsy result. Granulomas are most commonly observed in the interventricular septum and left ventricular free wall, and patients with conduction system disease typically have involvement of the basal portion of the interventricular septum. Left ventricular aneurysm formation may occur with extensive transmural free wall involvement. In terms of the coronary anatomy, the large conductance vessels are usually spared, but small coronary artery branches may be involved.
