Restrictive Cardiomyopathy 

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium and is the least common of the 3 clinically recognized and described cardiomyopathies.^[1] Its principal abnormality is diastolic dysfunction—specifically, restricted ventricular filling. RCM accounts for approximately 5% of all cases of primary heart muscle disease.

The World Health Organization (WHO) defines RCM as a myocardial disease characterized by restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function and wall thickness. Increased interstitial fibrosis may be present. This disease may be idiopathic or associated with other diseases (eg, amyloidosis and endomyocardial disease with or without hypereosinophilia). The course of RCM varies, depending on the pathology and treatment, but is often unsatisfactory.

The importance of an accurate diagnosis of RCM is to distinguish this condition from constrictive pericarditis, a clinically and hemodynamically similar entity that also presents with restrictive physiology but is frequently curable by surgical intervention. This distinction is difficult to make but crucial because the treatment options and prognoses for the 2 conditions differ drastically.^[2]

In the past, the correct diagnosis of RCM was frequently not made until surgical inspection demonstrated the pericardium of normal thickness and appearing normal. A subsequent myocardial biopsy would prove the diagnosis of RCM. With the improvement in diagnostic imaging, the necessity of progressing to surgical intervention to confirm the diagnosis of RCM (or constrictive pericarditis) should decrease.

RCM can be idiopathic or secondary to a heart muscle disease that manifests as restrictive physiology.^{[1, 3]} The disease creates increased stiffness of the myocardium, which causes pressure within the ventricles to rise precipitously with small increases in volume. Thus, accentuated filling occurs in early diastole, which terminates abruptly at the end of the rapid filling phase. When pressure tracings are taken at this point, they show a characteristic diastolic “dip-and-plateau” or “square-root” pattern, both similar to constrictive pericarditis.^[4]

Patients typically have diastolic heart failure, meaning that systolic function is normal but the left ventricle has increased diastolic stiffness (reduced compliance) and cannot fill adequately at normal diastolic pressures, leading to reduced cardiac output as a result of reduced left ventricular filling volume. Systolic function usually remains normal, at least early in the disease; wall thickness is typically increased secondary to myocardial infiltration with amyloidosis, but the increase is usually not as pronounced as that observed in hypertrophic cardiomyopathy.

A variable reduction in systolic function may be present as the disease progresses. Reduced left ventricular filling volume leads to reduced stroke volume and low cardiac output symptoms (eg, fatigue, lethargy), whereas increased filling pressures cause pulmonary and systemic congestion. Thus, RCM causes symptoms and signs of left-side failure, right-side failure, or both because it affects both ventricles, but amyloidosis typically presents with dominant right-side fluid retention.

Some patients may have complete heart block as a consequence of fibrosis encasing the sinoatrial or the atrioventricular nodes. Interestingly, amyloid deposition in the bundle branches is rare.

On the basis of pathology, RCM can be classified as obliterative (ie, thrombus-filled ventricles) or nonobliterative/idiopathic.

Obliterative RCM is very rare. It may result from the end stage of the eosinophilic syndromes, in which an intracavitary thrombus fills the left ventricular apex and hampers the filling of the ventricles. The fibrosis of the endocardium may extend to involve the atrioventricular valves and cause regurgitation. Two forms of endomyocardial fibrosis (EMF) exist—an active inflammatory eosinophilia and chronic EMF.

In idiopathic (primary) RCM, progressive fibrosis of the myocardium occurs, but no thrombus forms. This entity also is said to lack specific histopathologic changes.

RCM may be caused by various local and systemic disorders; many of them are rare and unlikely to be observed in the United States. These causes may be grouped into 4 broad categories as follows:

• Idiopathic
• Infiltrative
• Treatment-induced
• Malignancy

According to WHO guidelines, the term “cardiomyopathy” refers to diseases of the myocardium that are idiopathic (ie, primary cardiomyopathies). However, secondary infiltrative myocardial diseases, which are actually cardiac manifestations of systemic diseases, often are grouped together with cardiomyopathies.^[5]

Idiopathic RCM may be caused by EMF or by Loeffler eosinophilic endomyocardial disease. Secondary restrictive cardiomyopathy may be caused by the following:

• Hemochromatosis
• Amyloidosis^[6] (the most common cause of RCM in the United States)
• Sarcoidosis
• Progressive systemic sclerosis (scleroderma)
• Carcinoid heart disease
• Glycogen storage disease of the heart
• Radiation
• Metastatic malignancy
• Anthracycline toxicity

Idiopathic/primary RCM

A subset of patients have heart muscle disease of unknown cause that is manifested by heart failure and restrictive hemodynamics but is not characterized by significant ventricular hypertrophy, endocardial thickening or fibrosis, associated eosinophilia, or other diagnostically distinct histopathologic changes.

Males and females have been affected equally, but the prognosis appears to be worse in children than in adults. Children require relatively high filling pressures for maintenance of systolic output, and the therapeutic margin between volume depletion (leading to low output) and volume overload (leading to congestive heart failure) is narrow. A familial pattern has been noted in some cases.

In addition to the presenting symptoms of right- and left-side heart failure, as many as one third of patients with idiopathic RCM may present with thromboembolic complications. Pathologically, these patients have strikingly dilated atria, which may account for the increased cardiothoracic ratio on chest radiography. Echocardiography shows bilateral atrial enlargement with normal ventricular size but significant diffuse left ventricular hypertrophy, especially with amyloidosis. Histologic features include interstitial fibrosis, which is minimal in some and extensive in others.

Amyloidosis

Amyloidosis is characterized by intercellular accumulation of amyloid material in amounts sufficient to impair the function of the involved organs. On the basis of the amyloid protein composition, amyloidosis is classified into 4 different varieties as follows:

• Primary or myeloma-related amyloidosis
• Secondary amyloidosis (ie, secondary to chronic diseases)
• Senile amyloidosis
• Familial amyloidosis

The cardiac involvement in primary amyloidosis most commonly is associated with restrictive physiology. Amyloid infiltration of the heart is common in the elderly population (systemic senile amyloidosis) and may exhibit impaired diastolic filling properties but has other features that are more typical of a dilated cardiomyopathy.

The myeloma protein fibrils composed of immunoglobulin light chains are deposited diffusely throughout the myocardium and create a firm and rubbery consistency. Typically, the heart does not collapse when removed from the chest during autopsy.

On histologic examination, interstitial deposition of insoluble amyloid fibrils in all 4 cardiac chambers is observed. This can result in increased wall thickness without cavity dilatation.

Involvement of the valves may create regurgitant lesions, but hemodynamically and clinically significant degree of regurgitation is unusual.

The granular sparkling (ie, scintillating) appearance on 2-dimensional echocardiography may be present and is typical, but not diagnostic, of cardiac amyloidosis. Echocardiography more typically shows biventricular thickening out of proportion to current or prior hypertension, biatrial enlargement, a restrictive filling pattern by Doppler echocardiography, and normal systolic function and ejection fraction until late in the disease.

In the early stages of the disease, typical restrictive hemodynamics may not be evident; however, in more advanced cases, typical restrictive hemodynamics are more likely. A corollary of these observations is that restrictive diastolic dynamics strongly predict cardiac death in patients with amyloidosis. Cardiac biopsy is needed to confirm the diagnosis if doubt remains after noninvasive tests.

Eosinophilic cardiomyopathy and EMF

Severe prolonged eosinophilia from any cause (eg, allergic, autoimmune, parasitic, leukemic, or idiopathic) can lead to eosinophilic infiltration of the myocardium. The intracytoplasmic granular content of activated eosinophils is believed to be responsible for the toxic damage to the heart. This eosinophilic cardiomyopathy, also known as Loeffler endocarditis, is associated with dense EMF, intraventricular thrombus formation, and obliteration of the ventricular cavity in its late stages; accordingly, it is included in the category of obliterative RCM.

EMF, which is observed exclusively in equatorial Africa and less frequently in Asia and South America, was believed to be the end stage of eosinophilic endomyocarditis. However, it now is considered a separate entity because it does not exhibit eosinophilia. EMF demonstrates pathology that is similar to that described above (Loeffler endocarditis) and therefore is grouped under obliterative RCM.

The prognosis is poor for patients with diffuse involvement of the heart in EMF, but localized lesions involving the valves are amenable to surgical repair or removal and replacement.

Postirradiation fibrosis

Radiation-induced myocardial and endocardial fibrosis also can cause RCM. However, this complication of radiotherapy, like pericardial constriction, is evident several years after treatment. Differentiating between constriction and restriction may be particularly difficult in these patients because the 2 conditions may coexist.

Idiopathic restrictive cardiomyopathy is observed mainly in the United States. Loeffler endocarditis is common in the temperate zone, and chronic EMF is observed in the tropics. EMF occurs most commonly in children and young adults in tropical and subtropical Africa, primarily in Uganda and Nigeria.^[7] EMF may account for up to one fourth of deaths due to cardiac disease in those areas

The course of RCM varies depending on the pathology, and treatment is often unsatisfactory. Prognosis generally is poor in the adult population, with progressive deterioration. The natural history of RCM is especially poor in children with heart failure. Adults experience a prolonged course of heart failure and may have complications of cardiac cirrhosis and thromboembolism. Patients who are refractory to supportive therapy usually die of low-output cardiac failure unless cardiac transplantation is an option.