Idiopathic or Primary RCM
Idiopathic or primary RCM, often due to hereditary contractile protein mutations, represents approximately 50% of cases and occurs more commonly in older women than men. Wall thickness is commonly increased by echocardiography, and biopsy typically reveals myocyte hypertrophy often with patchy endocardial fibrosis involving both ventricles. Idiopathic diagnosis can only be established in the absence of other identifiable causes (ie, storage, infiltrative, and inflammatory diseases), many of which induce thick ventricular walls and infiltrative/storage damage on biopsy.
Amyloidosis is the prototypical RCM, arising from a group of disorders resulting in multisystem infiltrative disease with organ involvement, including heart, dependent on the underlying amyloid precursor protein entity. Cardiac amyloid is typically silent until tissue infiltration is extensive, leading to RCM with symptomatically progressive biventricular diastolic dysfunction. Imaging modalities, biochemical tests, and tissue samples establish definitive diagnosis. Echo documentation of thick walls, small cavities, and granular speckled “hyperrefractile” myocardial pattern is nearly diagnostic. Cardiac magnetic resonance imaging (MRI) shows diffuse late gadolinium enhancement throughout both ventricles, particularly the subendocardium. To exclude amyloid of the AL type, monoclonal gammopathy may be evident on urine and serum protein electrophoresis, although immunofixation and assays for serum free light chains are more sensitive. Amyloid deposits can be documented by biopsy of myocardium (by histology, Congo Red staining delineates amyloid deposits between cardiac myocytes); tissue specimens can also be obtained from fat pad or rectum. The general treatment approach is as with any RCM. The mainstay is diuretics to decongest within the limits tolerated by hypotension. These patients are at high risk of thromboembolism, especially with atrial fibrillation, but even in its absence, anticoagulation should be strongly considered. Untreated patients with AL amyloid have a median survival < 6 months after onset of heart failure. Aggressive chemotherapy and stem cell transplantation, followed by cardiac transplantation, have shown promising potential in a small number of cases, but transplantation mortality rate is high and randomized data are lacking.
Cardiac iron overload, due to heritable disorder or chronic and excessive iron administration, is always associated with involvement of multiple organs, giving rise to the classic clinical presentation of heart failure, cirrhosis, impotence, and diabetes. At pathology, hearts are dilated and ventricular walls thickened. Echo shows a nonspecific mixed pattern of systolic and diastolic dysfunction. The condition is commonly complicated by and may be announced by arrhythmias. Laboratory evaluation is usually diagnostic (marked elevations of plasma iron, serum ferritin, and transferrin saturation, but lower normal total iron binding capacity). Cardiac MRI is a sensitive marker of iron deposition and predictive of future events. Endomyocardial biopsy is definitive, but usually not necessary when biochemical testing is diagnostic. Chelation therapy is appropriate and may limit further damage but is unlikely to reverse existing organ dysfunction.
This systemic inflammatory condition results in multiorgan noncaseating granulomatous infiltration, typically in the lungs, reticuloendothelial system, and skin. The heart is involved in 20–30% of cases at autopsy, with patchy granulomatous infiltration in discrete areas of the ventricular walls with a predilection for the posterior LV free wall, basal septum, and conduction system. Cardiac infiltrate may result in fibrotic scars and “microaneurysm” formation. Cardiac sarcoid most commonly presents clinically with conduction block or malignant arrhythmias and less commonly with heart failure due to RCM. The electrocardiogram (ECG) may reveal atypical infarction patterns and various degrees of AV block. Echo varies according to disease activity, with wall thickening due to granulomatous expansion but later wall thinning due to fibrosis. Segmental hypokinesia most commonly localizes to mid and basal segments of the LV free wall and upper septum. Owing to patchy involvement, endomyocardial biopsy provides diagnostic evidence in only 25–50% of autopsy-confirmed cases. Cardiac MRI and positron emission tomography (PET) are more sensitive and correlate with disease severity. If treated early, when inflammation predominates and fibrosis is less advanced, anti-inflammatory therapy (steroids and cyclophosphamide [Cytoxan]) may improve cardiac function. In those with arrhythmias, pacemaker and defibrillator therapy should be considered.
Storage Disorders Due to Heritable Diseases
RCMs may result from heritable metabolic disorders resulting in myocardial accumulation or infiltration of abnormal metabolic products, producing classic RCM. The recent availability of enzyme replacement in some disorders makes early diagnosis increasingly essential. The most common are glycogen storage disorders (Gaucher and Fabry disease) resulting from lysosomal accumulation in the heart and other organs. Gaucher disease commonly presents with RCM in childhood and is responsive to enzyme replacement therapy or, in extreme cases, hepatic transplantation. In Fabry disease, cardiac involvement is typically manifest in the third or fourth decade of life; the thick ventricular walls mimic hypertrophic cardiomyopathy; differentiation by MRI may be helpful. Other less common heritable storage disorders that may result in RCM include the mucopolysaccharidoses, myocardial oxalosis (related to underling primary hyperoxaluria), and Friedreich ataxia (an autosomal recessive neurodegenerative disorder associated with RCM and/or dilated cardiomyopathy in 90–100% of cases).
There are two variants of endomyocardial disease, with different pathogenesis but shared and overlapping features. Endomyocardial fibrosis (EMF) refers to a specific syndrome with characteristic geographic epidemiologic features. Other cardiomyopathy syndromes with similar pathologies include Loeffler endocarditis (also called hypereosinophilic endomyocarditis) and other diseases that induce fibrotic changes of the endocardium (eg, carcinoid heart disease).
EMF occurs primarily in tropical regions and in subtropical zones, presents at a young age, and is the most common form of RCM worldwide. EMF is characterized by fibrosis of the apical endocardium of the ventricles. The clinical manifestations are classic RCM.
Loeffler “Hypereosinophilic” Endomyocarditis
This group of disorders results from sustained overproduction of eosinophils, leading to eosinophilic infiltration and mediator release, which damages multiple organs. Diagnosis is established by eosinophil counts > 1500 for at least 6 months. The disease may be primary, but it is essential to search for secondary and potentially treatable causes including leukemia, reactive disorders such as parasite infection, allergies, granulomatous syndromes, hypersensitivity, and neoplastic disorders. Eosinophil-mediated heart damage, detected by echo or MRI, evolves through three stages: (1) an acute necrotic stage; (2) an intermediate phase characterized by thrombus formation along the damaged endocardium; and (3) a fibrotic stage. Treatment is aimed at the underlying disease.
Carcinoid tumors metastatic to the liver elaborating circulating serotonin (and 5-hydroxyindolacetic acid, its primary metabolite) induce fibrous endocardial plaques in 50% of patients. By echo, plaques are typically seen on the endocardium downstream of the TV, commonly resulting in stenotic and regurgitant valvular lesions (especially TV). The observation that the right heart is preferentially affected reflects inactivation of these toxic substances in the lung. Management of the underlying carcinoid is the focus of treatment. Identical pathology results from exposure to the anorectic drug fenfluramine and its related medications.
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