Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 2

Pereira NL, Grogan M, Dec GW.
Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 2 of a 2-Part Series. J Am Coll Cardiol 2018;71:1149-1166.

The following are summary points from part 2 of a 2-part series on the spectrum of restrictive and infiltrative cardiomyopathies:

  1. Endomyocardial diseases are another rare cause of restrictive cardiomyopathy (RCM); the most common is endomyocardial fibrosis (EMF). Several conditions share the pathologic phenotype, but a variety of distinct causes have been identified. Other diseases are endocardial fibroelastosis (EFE), hypereosinophilic syndromes, and carcinoid heart disease.
  2. Endomyocardial fibrosis: EMF is the most common cause of RCM affecting >12 million people worldwide, but rare in North America. It is commonly seen in equatorial countries such as Uganda, Nigeria, and Brazil; it accounts for approximately 20% of heart failure (HF) cases and 15% of cardiac deaths in equatorial Africa. Other conditions such as hypereosinophilic syndrome may mimic this disorder. EMF typically affects impoverished young adults with a bimodal distribution peaking at 10 and 30 years of age. The natural history of EMF includes: a) an active phase with inflammation and eosinophilia that progresses to a chronic phase leading to restrictive heart disease, and b) the chronic phase where biventricular involvement is the most common presentation (>50% of cases), followed by isolated right-sided heart involvement. When right ventricular (RV) restriction predominates, chronic venous hypertension often results in facial edema and exophthalmos, marked jugular venous distention, hepatomegaly, and ascites (the latter is often seen out of proportion to peripheral edema). The presence of ascites with lymphocytic exudates and peritoneal fibrosis suggests that EMF is a systemic syndrome with periods of active peritoneal inflammation. Atrial fibrillation occurs in >30% of patients, and embolic complications are common. Therapeutic options include sodium and fluid restriction, diuretics, and aspirin or anticoagulation in view of the potential for intracardiac thrombi. Long-term outcome for medical therapy in advanced stages is very poor, with 75% mortality reported at 2 years. Where surgical expertise exists, EMF may be successfully treated with surgical endocardectomy and valve repair or replacement. Survival rates as high as 70% at 10 years have been reported.
  3. Endocardial fibroelastosis: EFE is extremely rare and is characterized by diffuse thickening of the left ventricular (LV) endocardium secondary to proliferation of fibrous and elastic tissue. Two forms have been described: a dilated form (dilated cardiomyopathy [DCM] phenotype), in which the LV is enlarged, and a “contracted” form (RCM phenotype), in which the LV cavity is small. A familial pattern is seen in the majority with presentation commonly during infancy. The primary form of EFE invariably affects the LV with significant involvement of the mitral and aortic valves. Isolated RV involvement is rare. The “contracted” form produces restrictive hemodynamics and a clinical picture of left-sided obstructive disease, particularly if the mitral valve is involved. EFE may respond to surgery.
  4. Hypereosinophic syndromes affecting the heart (formerly known as Loeffler’s endocarditis), although very rare, can cause substantial morbidity and mortality through the release of substances that damage the endothelium and myocardium that leads to eosinophilic myocarditis. Most patients are diagnosed between the ages of 20 and 50 years. Etiology of hypereosinophilia (an absolute peripheral blood eosinophil count that is >1500 cells/L and persists for longer than a month or pathologic evidence of hypereosinophilic tissue invasion) is variable and includes helminthic and parasitic infections, malignancies, eosinophilic leukemia, allergic drug reactions, idiopathic causes or associated with genetic aberrations (for example, gene for platelet-derived growth factor alpha [PDGFRA] or platelet-derived growth factor beta [PDGFRB]). Other etiologies include hypersensitivity, and eosinophilic granulomatsosis with polyangiitis. Eosinophilic heart disease has been categorized into three stages: an acute necrotic phase, an intermediate phase with thrombus formation, and a fibrotic stage characterized by impaired cardiac function, HF due to RCM, and/or fibrotic deformation of chordal structures leading to mitral and tricuspid regurgitation. Therapy can be effective in the early stages of disease. Corticosteroids alone or in combination with cytolytic therapies (hydroxyurea, inferon alpha) have been shown to improve the acute necrotic stage of disease with substantial increases in LV ejection fraction (LVEF) and decreased symptoms. The role for systemic anticoagulation in the management of patients with documented intracardiac thrombi remains controversial, but should be instituted for patients who have sustained a prior embolic event. The presence of a documented thrombus may not be sufficient to justify anticoagulation, as treatment failures are not uncommon. The fibrotic stage may occasionally require cardiac surgery, which may include resection of endocardial scar as well as subchordal repair and/or valve repair or replacement. The need for cardiac surgery has declined during the last decade due to aggressive management strategies aimed at preventing unregulated eosinophil proliferation. Surgical replacement of the mitral or aortic valves must be accompanied by pharmacologic measures designed to control ongoing eosinophilia. Bioprosthetic valves are preferable to mechanical valves due to the thrombotic tendency of HES patients. Prosthetic valve obstruction occurs when marked hyper-eosinophilia is not adequately controlled on pharmacologic therapy.
  5. Iron overload cardiomyopathy (IOC) is characterized in early stages by an RCM with prominent early diastolic dysfunction that inevitably progresses to an end-stage DCM. Excess iron accumulation usually occurs due to increased iron absorption by the gastrointestinal tract (e.g., hemochromatosis) or high parenteral iron administration, generally due to frequent red blood cell transfusions, especially in hereditary anemias such as thalassemia major and sickle cell disease. In iron overload, iron in the circulation typically exceeds serum transferrin iron-binding capacity, leading to the appearance of non-transferritin bound iron, leading to an expansion of the labile intracellular iron pool, and pathologic iron deposition initially begins in the epicardium, extends to the myocardium and finally to the endocardium, which partially explains preservation of systolic function until late in the disease. Cardiac magnetic resonance imaging (MRI) is the only available noninvasive method with the potential to accurately quantitatively assess iron load. Iron’s paramagnetic effect produces changes in the MR signal intensity, shortens the T2-weighted relaxation time, and darkens the image more quickly. T2 relaxation time is an excellent measure of myocardial iron deposition and is useful for serial assessment of response to iron chelation therapy. The mainstay of treatment for excessive iron deposition in patients with hemochromatosis is phlebotomy. Other options include control of dietary intake of iron and chelation.
  6. Sarcoidosis is a multisystem, granulomatous disease of unknown etiology. Non-caseating granulomas are the pathologic hallmark of the disease and are most often associated with pulmonary and lymph node involvement; however, the heart is also frequently involved. The annual incidence of sarcoidosis in the United States is estimated at 10.9 per 100,000 in whites and 35.5 per 100,000 in African-Americans. Most disease (70%) occurs in patients between 25 and 60 years of age; it is rarely observed in patients <15 or >70 years of age. Familial clustering indicates a strong genetic element in sarcoidosis. The clinical spectrum is highly varied and includes asymptomatic cardiac involvement, atrial or ventricular arrhythmias including sudden cardiac death, varying degrees of atrioventricular block, LV dysfunction (either restrictive [less common] or dilated [more common] phenotype), or overt HF. Echocardiographic abnormalities have been reported in 14-56% of patients and findings are highly variable, but not specific for cardiac sarcoidosis. Cardiac MRI has proven extremely useful in the initial diagnosis and subsequent follow-up of patients with cardiac sarcoidosis. While T2 imaging can identify myocardial edema associated with active inflammation, no specific pattern of late gadolinium enhancement (LGE) has been shown to be diagnostic for cardiac sarcoidosis; its distribution is usually patchy and multifocal with sparing of the endocardium. Positron emission tomographic (PET) imaging with 18F-fluorodeoxyglucose has been shown to correlate with histologic activity of sarcoidosis. Management of cardiac sarcoidosis involves both immunosuppressive therapy as well as cardiac-specific treatments for ventricular dysfunction and heart rhythm abnormalities.
  7. Radiation-induced heart disease (RIHD): Manifestations are myriad and may include accelerated coronary artery disease, valvular dysfunction, RCM, aortopathy, and constrictive pericarditis. It had been recognized since the 1960s that substantial doses of radiation (>30 Gray or Gy) that were initially employed during mantle radiotherapy for Hodgkin’s lymphoma were cardiotoxic. However, evidence from the past decade suggests that RIHD also occurs following doses substantially below 20 Gy. RIHD typically occurs with a latent period of 10-15 years. Management is symptomatic and consists largely of diuretics to control volume overload. In advanced cases, cardiac transplantation has been successful in a limited number of radiation-induced RCM patients with actuarial survival rates in a single-center experience at 5 and 10 years of 75% and 47%, respectively. However, multicenter 5-year post-transplant survival reported in the United Network for Organ Sharing database was 58% and was lower when compared to transplant for other types of RCM likely related to the presence of concomitant mediastinal fibrosis and radiation lung disease and prior cardiac surgeries leading to increased early postoperative deaths.

Note: Most of the text in this summary is verbatim from the original manuscript.

Keywords: Anemia, Sickle Cell, Aspirin, Atrial Fibrillation, Atrioventricular Block, Carcinoid Heart Disease, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Cardiomyopathy, Restrictive, Cardiotoxicity, Chelation Therapy, Coronary Artery Disease, Death, Sudden, Cardiac, Diuretics, Echocardiography, Edema, Endocardial Fibroelastosis, Endomyocardial Fibrosis, Endothelium, Heart Failure, Heart Transplantation, Hemochromatosis, Hepatomegaly, Hypertension, Leukemia, Magnetic Resonance Imaging, Myocarditis, Pericarditis, Constrictive, Positron-Emission Tomography, Sarcoidosis, Thrombosis, Transferrins, Ventricular Dysfunction

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