Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

Introduction

A classification serves to bridge the gap between ignorance and knowledge. J.F. Goodwin

Historically, restrictive cardiomyopathies were among the three primary forms of idiopathic heart muscle diseases, characterized by the World Health Organization as “restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function.” This early grouping of cardiomyopathies highlighted the readily evident morphologic and functional features of these disorders, which were largely of unknown cause. With advances in diagnostic testing (biochemistry, genetics, immunology, and pathology) and cardiac imaging techniques (echocardiography, computed tomography [CT], magnetic resonance imaging [MRI]), the etiology of many cardiomyopathies can now be identified. The classification proposal of the American Heart Association (AHA) defines primary (involving predominantly the heart) and secondary (related to systemic disorders) cardiomyopathies. Using this classification, except for primary restrictive cardiomyopathy, the entity of “restrictive cardiomyopathy” no longer exists, and most infiltrative and storage disorders are considered specific secondary cardiomyopathies (i.e., amyloid cardiomyopathy). With increasing genetic knowledge and availability of genetic testing, a new phenotype-genotype classification scheme—the MOGE(S) classification—has been endorsed by the World Heart Federation. This system involves notation of five cardiomyopathy characteristics:

• M: Morphofunctional or phenotype

• O: Organ involvement

• G: Genetic transmission

• E: Etiology

• (S): Functional status (This last attribute is optional.)

However, the clinical applicability of this new classification scheme has not yet been established.

From the point of view of the clinician, however they are compiled, these are disorders in which diastolic dysfunction is at least initially the predominant pathophysiologic derangement. They are uncommon diseases, generally with a poor prognosis, and often presenting with advanced right-sided or left-sided heart failure. Much of the data regarding these diseases are based on observational retrospective studies from tertiary centers with little prospective and randomized information. Although a cardiologist will often initiate testing, a multidisciplinary team of geneticists, pathologists, radiologists, hematologists, and oncologists is often required to refine the diagnosis and determine management strategies. Since infiltrative and storage cardiomyopathies occur as part of a multisystem disorder, treatments with chemotherapeutic agents, stem cells, and enzyme replacement are increasingly becoming options.

This chapter will review primary restrictive cardiomyopathy and the most prevalent forms of infiltrative and storage disorders encountered among patients surviving into adulthood. A practical approach to diagnosis, differentiation, and exclusion of other more common disorders with similar pathophysiology and structural appearance will be presented along with current treatment options.

Pathophysiology

Most primary restrictive cardiomyopathies are characterized by at most mild degrees of increased wall thickness on gross inspection. Cardiac biopsy will distinguish whether at the cellular level there is myocyte hypertrophy (increased myocyte diameter and nuclear area), endocardial and interstitial fibrosis (increased collagen to muscle ratio), or both ( Fig. 23.1 ). Exclusion of fiber disarray, inflammation, eosinophilia, lymphocytes, amyloid or iron deposits, and pericardial disease via light and electron microscopy is required to distinguish primary restrictive diseases from secondary cardiomyopathies or pericardial diseases that may also manifest with advanced stages of diastolic dysfunction. Absence of an endocardial fibrotic shell with extension into the myocardium excludes endomyocardial disease.

Structural characteristics of primary restrictive cardiomyopathies include (a) biatrial enlargement, (b) nondilated or reduced left ventricular (LV) cavity size, and (c) normal or mildly increased wall thickness. The LV ejection fraction (EF) is usually normal during early stages but often declines with disease progression. Strain imaging also demonstrates abnormal LV and left atrial (LA) contractility almost universally in these patients (see Chapters 4 , 12 , and 29 ). The pathogenesis of diastolic impairment may be secondary to myocyte abnormalities, including abnormal calcium handling, accumulation of desmin (a cytoskeletal component), myocyte hypertrophy, and extracellular matrix interstitial fibrosis with proliferation of collagen fibers and elastic elements. A marked increase in stiffness of the myocardium or endocardium causes the ventricular pressure to rise dramatically with only small changes in volume, causing an upward shift of the LV pressure-volume relationship and a dip-and-plateau or square-root hemodynamic pattern. Both ventricles are affected by the process, but usually the pressures are higher on the left than the right, which may reflect the relatively decreased compliance of the left ventricle compared with the right ventricle.

Secondary infiltrative and storage cardiomyopathies result from the presence of myocardial cellular or extracellular substances that impair diastolic function. In infiltrative diseases, there is localization to the interstitium (between myocardial cells), as with cardiac amyloidosis; whereas in storage disorders, the deposits are within cells, as with hemochromatosis and Fabry disease. The infiltrative and storage cardiomyopathies may have heterogeneous morphologic and hemodynamic findings, depending on the specific underlying process and the stage of disease, which often involves LV dysfunction, increased wall thickness, and nonrestrictive diastolic filling patterns.

Clinical Relevance

Primary Restrictive Cardiomyopathies

Case Study 1

A 23-year-old woman presents to her family physician complaining of fatigue, exercise intolerance, muscle aches, and dyspnea with exertion. No other past medical history (PMH) is present. Family history is significant for an aunt with hypertrophic cardiomyopathy (HCM). On examination, she is found to be tachycardic. The cardiac exam is notable for an elevated jugular venous pressure of 10 cm H ₂ O, an S ₃ gallop, and 1+ lower extremity pitting edema. An electrocardiogram (ECG) shows first-degree atrioventricular (AV) block with a P-R interval of 240 msec. A chest x-ray (CXR) shows mild pulmonary congestion. Brain natriuretic peptide (BNP) level is 750 pg/mL, and the creatine phosphokinase (CPK) level is 280 units/L. An echocardiogram shows normal LV and right ventricular (RV) size and function, with moderately dilated atria, grade III diastolic dysfunction (restrictive filling pattern), E/e′ of 15, and a delayed color M mode slope of 35 cm/sec. Cardiac MRI shows normal pericardial thickness and near normal LV wall thickness. Subsequent cardiac catheterization is notable for pressures (mmHg) as follows: right atrial, 15; right ventricular end diastolic, 17; left ventricular end diastolic, 24; pulmonary artery systolic pressure, 55; pulmonary capillary wedge pressure, 25; and cardiac index, 2.3 L/min/m ² . Cardiac biopsy confirms idiopathic restrictive cardiomyopathy and excludes specific infiltrative and storage diseases.

Diagnosis

Primary (or idiopathic) restrictive cardiomyopathy (RCM) is a rare disorder of advanced diastolic impairment, often leading to biventricular diastolic heart failure and sudden cardiac death. It was first described by Benotti et al. in nine patients with heart failure, elevated RV and LV filling pressures, normal systolic function, and dip-and-plateau hemodynamic tracing. In children, the disease is more common in females, and the prognosis is worse compared with adults. Familial autosomal dominant transmission and the association with skeletal myopathies (predominantly distal) and heart block have been reported in several generations of families. Other associations include family members with HCM and Noonan syndrome. Genetic sequence analysis studies in patients with idiopathic RCM have shown mutations in approximately 60% of patients, including in the MYH7, DES, FLNC, MYBPC3, LMNA, TCAP, TNNI3, TNNT2, TPM1, and LAMP2 loci.

The clinical signs and symptoms of primary restrictive cardiac disease relate closely to the degree of LA hypertension required to compensate for reduced ventricular filling. Initially, there is exercise intolerance and fatigue, progressing to dyspnea with minimal effort. Exertional chest pain is usually absent. Atrial fibrillation is common due to atrial enlargement. Ventricular arrhythmias or heart block are commonly present in advanced cases and are often the causes of death. Symptoms of proximal or distal myopathy may be present. Cardiac examination may reveal pulmonary congestion, jugular venous distention with a prominent x and y descent, and S ₃ depending on the filling characteristics. Right heart failure with hepatomegaly, ascites, peripheral edema, and anasarca are present in advanced cases. Kussmaul sign can be detected, while apical retraction (as in constrictive pericarditis) is not seen.

Laboratory testing may provide supportive information. BNP levels are elevated proportional to the degree of elevation in filling pressures and grade of diastolic dysfunction. Elevated BNP levels also may aid in excluding constrictive physiology. CPK levels may be elevated with concomitant myopathy. No data are available on troponin levels in patients with idiopathic restrictive cardiomyopathy.

Echocardiography is often the first-line test and may be virtually diagnostic. Atrial enlargement with nondilated ventricles with near normal systolic function is uniformly present on echocardiography. Mild LV dysfunction may develop among patients with advanced disease requiring transplantation. Generally, if hypertrophy is present, it is mild (<15 mm). The pathophysiologic findings of advanced diastolic dysfunction are evident with a comprehensive echocardiographic Doppler study (elevated filling pressures ± restrictive physiology). Restrictive physiology may not be present, depending on the grade of diastolic dysfunction and loading conditions, but abnormal diastolic function should be evident by evaluation of mitral and tricuspid inflow patterns, pulmonary and hepatic venous flows, and isovolumic relaxation time (IVRT). Tissue Doppler echocardiography (TDE) e′ and a′ annular velocities are low, with mitral E/e′ annular ratios elevated, consistent with high filling pressures. Concomitantly, the color M mode propagation slope is slow. Tissue Doppler imaging and color M mode, along with pulsed Doppler flow patterns with a respirometer, can help distinguish restrictive from constrictive physiology (see 10, 11, 26 ).

MRI and CT may be useful to exclude increased pericardial thickness, septal bounce, or conical compression. Cine MRI may show abnormal filling patterns in early and advanced stages of restrictive cardiomyopathy similar to echocardiography. MRI is capable of distinguishing tissue characteristics and shows a diffuse reduction in signal intensity due to fibrosis in idiopathic restrictive cardiomyopathy, with more specific patterns in other infiltrative processes such as amyloidosis or hemochromatosis.

Cardiac catheterization is often used as a confirmatory test. Using strict criteria, either right-sided or left-sided filling pressures are elevated, with a typical dip-and-plateau RV and LV filling pattern and an M-shaped or W-shaped venous filling pattern with prominent x and y descents. LV diastolic pressures are greater than 5 mmHg more than RV filling pressures. Cardiac index is reduced, and pulmonary artery pressure is greater than 50 mmHg in most patients with a ratio of RV systolic to diastolic pressure greater than 1:3. Often RV endomyocardial biopsy is done at the same time as hemodynamic assessment and importantly excludes other specific etiologies.

Management

The prognosis of idiopathic restrictive cardiomyopathy depends most on the age of the patient and presenting hemodynamic factors. Although variable, the course is usually progressive and generally poor among the pediatric population, with survival rates of less than 50% over 2 years, in some studies. A serial study of 18 children (9 male; mean age, 4.3 years) evaluated over a course of 31 years at Texas Children’s Hospital found that predictors of sudden death included female sex, chest pain, syncope, and ischemia on Holter monitor. The annual mortality rate was 7%, with sudden death occurring in 28% of patients. Other predictors of poor outcome in the pediatric population include decreased cardiac index, pulmonary venous congestion, and elevated pulmonary vascular resistance.

Beta blockers are the primary therapy to reduce the risk of sudden death. Additional medical therapy includes diuretics for symptomatic relief and consideration of antiplatelet agents or anticoagulation, due to the high risk of atrial fibrillation and embolism reported in some series. Vasodilators should be used cautiously unless LV dysfunction is present, since they may cause hypotension. Pacemakers are often required for heart block. Implantable cardioverter-defibrillators are recommended for any patients with ischemic manifestations, along with listing for transplantation. Transplantation can substantially improve survival and is usually required within 4 years of diagnosis, optimally before pulmonary vascular resistance is irreversibly high. Heart-lung transplantation is an option for some children. When concomitant skeletal myopathy is present, the benefits of transplantation may be partial.

Idiopathic restrictive cardiomyopathy may also be diagnosed in adults after exclusion of secondary causes of restrictive physiology. A large series of 94 patients (mean age, 64 years) was identified from 1979 to 1996 at the Mayo Clinic, with typical structural and hemodynamic features of restrictive cardiomyopathy. At follow-up of 68 months, 50% of patients had died, primarily from cardiac causes, and four patients required heart transplantation. Using multivariate analysis, predictors of death included male sex, LA dimension greater than 60 mm, age older than 70 years, and advanced New York Heart Association (NYHA) class ( Fig. 23.2 ).