Continuing Education Activity

Restrictive cardiomyopathy (RCM) is characterized by diastolic dysfunction of a non-dilated ventricle. Multiple types of restrictive cardiomyopathies exist and vary in their pathogenesis, clinical presentation, diagnostic evaluation, treatment, and prognosis. Three of the leading causes of RCM are cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis. This activity reviews restrictive cardiomyopathy with particular emphasis on these three major etiologies and outlines the role of team-based interprofessional care for affected patients.

Objectives:

• Define restrictive cardiomyopathy.
• Review the types of restrictive cardiomyopathies and their causes.
• Review the management strategies for restrictive cardiomyopathies.
• Describe how enhanced coordination of the interprofessional team can lead to more rapid detection of restrictive cardiomyopathy and subsequently allow for more prompt treatment when indicated.

Introduction

Restrictive cardiomyopathy (RCM) is distinguished by diastolic dysfunction in a non-dilated ventricle. Multiple types of restrictive cardiomyopathies vary according to pathogenesis, clinical presentation, diagnostic evaluation, treatment, and prognosis. Three of the leading causes of RCM include cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis.[1] In this article, a comprehensive review of RCM will be presented, including a particular emphasis on the three major etiologies of RCM.

Etiology

There are several causes of restrictive cardiomyopathy, including infiltrative diseases, storage diseases, and a variety of systemic diseases. Infiltrative diseases are pathologies that lead to a build-up of a substance in the myocardium. These diseases include amyloidosis (AL, ATTRm, ATTRwt, ApoA-I), sarcoidosis, hereditary hemochromatosis, as well as primary hyperoxaluria.[1] Amyloidosis is the most common infiltrative disease. Storage diseases are rare congenital abnormalities in metabolism. Storage diseases include Anderson-Fabry disease, Gaucher disease, glycogen storage, mucopolysaccharidosis type II (Hurler cardiomyopathy), Niemann-Pick, Danon disease, and Friedrich ataxia. Several different systemic diseases can also lead to restrictive cardiomyopathy. Some of these pathologies include diabetes, scleroderma, myofibrillar myopathies, pseudoxanthoma elasticum, Werner syndrome, sarcomeric protein disorders, carcinoid cardiomyopathy, idiopathic fibrosis, hypereosinophilic fibrosis, chronic eosinophilic leukemia fibrosis, endocardial fibroelastosis, and metastatic malignancies. Other causes of restrictive cardiomyopathy include idiopathic causes, including radiation therapy and various pharmaceuticals.[2] Some drugs known for causing restrictive cardiomyopathy include anthracycline, busulfan, ergotamines, methysergide, mercurial agents, and serotonin-containing agents.[3][4]

Epidemiology

RCM is a fairly rare disease, but it does account for approximately 5% of all cases of cardiomyopathy. The three major cardiomyopathies are dilated, hypertrophic, and restrictive. RCM is the least common form. Most causes of RCM are acquired. Its prevalence varies depending on regionality, ethnicity, age, and gender.[5] Below are some examples of specific statistics for individual etiologies:

• Amyloidosis: The most common cause of RCM in the United States. It affects men and women equally. AL amyloidosis most common cause of RCM. Several different types of amyloidosis. The wild-type transthyretin amyloidosis is most often found in the elderly population. The V1221 mutant transthyretin has a higher rate of symptomatic heart failure.[6][3]

• Sarcoidosis: More common in women than men. The highest prevalence is among black women. The highest incidence worldwide is in Japan.[1][7]

• Hemochromatosis: Affects men and women equally. The prevalence is 1 per 200 individuals. Men are more likely to have cirrhosis associated with hemochromatosis. The predominant gene mutation HFE C282Y. It is inherited in an autosomal recessive pattern. Another common mutation seen in hemochromatosis is the H63D.[8]

• Loffler endocarditis: Common in tropical climates and sub-Saharan Africa. Up to twenty percent of heart failure in this region is thought to be secondary to endomyocardial fibrosis.[9]

There are several other causes of restrictive cardiomyopathy, each of which has its unique epidemiology. They all vary by region, gender variance, incidence, prevalence, and mutation affected. These conditions are not mentioned in detail here as they are much rarer than the above. If any of the above does not fit the patient's diagnosis, then the recommendation is to consult a specialist if one is not already involved.

Pathophysiology

Most restrictive cardiomyopathies are due to infiltration of abnormal substances between myocytes, storage of abnormal metabolic products within myocytes, or fibrotic injury.

Infiltrative (Between Myocytes)

• Amyloidosis
• Primary (light chain amyloid)
• Familial (abnormal transthyretin)
• Senile (normal transthyretin or atrial peptides)
• Inherited metabolic defects

Storage (Within Myocytes)

• Hemochromatosis (iron)
• Inherited metabolic defects
• Fabry disease
• Glycogen storage disease (II, III)

Fibrotic

• Radiation
• Scleroderma

Endomyocardial

• Possibly related fibrotic diseases
• Tropical endomyocardial fibrosis
• Hypereosinophilic syndrome (Löffler endocarditis)
• Carcinoid syndrome
• Radiation
• Drugs: e.g., serotonin, ergotamine

Histopathology

The histology of restrictive cardiomyopathies varies depending on etiology. It is specifically useful with infiltrative cardiomyopathies and some of the storage diseases. A list of common histology associations are listed below:[10][11][12][13][14][15][16]

• Amyloidosis: positive congo red stain 
• Sarcoidosis: granulomatosis reaction
• Primary hyperoxaluria: oxalate deposition
• Niemann-Pick: foam cells
• Mucopolysaccharidosis type II: glycosaminoglycans
• Glycogen storage dicarboxylic acids
• Hereditary hemochromatosis (iron)
• Gaucher: Gaucher cells (lipid-laden macrophages)
• Fabry: ceramide trihexoside

History and Physical

Patients with RCM primarily present with advanced disease and obvious signs of cardiopulmonary compromise, but in some circumstances, the diagnosis is incidental. It is important to suspect RCM in any patient with a normal or close to normal systolic function and evidence of diastolic dysfunction with a restrictive filling pattern on echocardiogram. For those that present symptomatically, there is a wide range of presentations. Some may present in full-blown heart failure (jugular venous distension, ascites, lower extremity edema, and less commonly pulmonary edema). Some may complain of poor exercise tolerance or be newly diagnosed with an arrhythmia such as atrial fibrillation. In the less fortunate cases, some present as sudden cardiac arrest (SCD). Other less common presentations include ischemia, thrombus, and misdiagnosed as hypertrophic cardiomyopathy with left ventricular outflow obstruction. When performing the evaluation and physical in a patient suspected of RCM, it is essential to look for extracardiac manifestations such as carpal tunnel, which may be present in amyloidosis or bilateral hilar infiltrates seen in sarcoidosis.[17] Hemochromatosis may present with the classic bronze skin, cirrhosis, arthralgias, and endocrinopathies such as diabetes mellitus.[18]

The cardiac impulse is less displaced than in dilated cardiomyopathy and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than a third heart sound in sinus rhythm, but atrial fibrillation is common. Jugular venous pressures often show rapid Y descents and may increase during inspiration (positive Kussmaul’s sign).

Evaluation

Electrocardiogram (ECG) is one of the first tools used when a cardiac diagnosis is suspected. For example, a low-to-normal voltage in the QRS complex despite thickened cardiac muscle in the absence of valvular or hypertensive disease may lead one to suspect amyloidosis. However, the absence of low voltage does not exclude the diagnosis.[19]

The echocardiogram is the primary radiographic diagnostic test for identifying patients with RCM. It may help aid in differentiating RCM from some of its common imitators, such as constrictive pericarditis. The echocardiogram may also provide information to suggest a specific diagnosis. Cardiac magnetic resonance (CMR) imaging can also aid in the diagnosis. Endomyocardial biopsy (EMB) may help establish the diagnosis in some cases if the primary workup has not been able to do so. Cardiac MRI can be useful to gain ancillary evidence to support a diagnosis of RCM, specifically in amyloidosis, where a gadolinium enhancement pattern is highly suggestive of amyloid. Nuclear imaging can also be used to aid in diagnosis as it also demonstrates an affinity for amyloid.[3] Biomarkers such as troponin T, B-type natriuretic peptide (BNP), and pro-BNP are also useful diagnostic and prognostic factors. 

For a definitive diagnosis, a biopsy or aspirate is required. EMB is the gold standard for the diagnosis of cardiac amyloidosis.[19] Fat pad aspiration is positive in about 50% of cases. Mass spectrometry, the gold standard for typing the tissue, is done following biopsy to evaluate further the disease process. Mutation analysis can diagnose hereditary hemochromatosis, especially due to the strong association with the HFE C282Y and H63D. 

Treatment / Management

Treatment for RCM includes treating the underlying cause and heart failure symptoms that may arise secondary to the disease. Currently, there is no cure for RCM, but there are some treatments available to alleviate the symptoms of the disease. For heart failure symptoms, diuretics are the mainstay of treatment to reduce volume overload but must be monitored closely to prevent excessive diuresis as patients with RCM rely on high filling pressures to maintain cardiac output. The use of beta-blockers or calcium channel blockers is sometimes introduced to increase the filling time.[4] They may also be beneficial in treating dysrhythmias, which are common in this patient population. Angiotensin-receptor blockers may also be used, especially if concurrent systolic heart failure develops.

For sarcoidosis, antiarrhythmics are a common therapy choice due to the high incidence of conduction disease. Immunosuppressive agents such as corticosteroids and steroid-sparing agents are also sometimes used to treat sarcoidosis. For hemochromatosis, the treatment of choice is therapeutic phlebotomy. Advanced heart failure treatment, such as cardiac transplant or left ventricular assist devices, may be appropriate for some patients.[3] Ultimately, the choice of a specific therapy depends on the clinical condition, the risk of dangerous events, and the ability of the patient to tolerate the therapy.

Differential Diagnosis

There are several differential diagnoses to keep in mind when evaluating a patient for restrictive cardiomyopathy (RCM).[3] A few of the common ones are:

• Constrictive pericarditis
• Acute or chronic heart failure
• Hypertensive heart disease
• Hypertrophic cardiomyopathy
• Acute or chronic pericarditis

Constrictive pericarditis (CP) is the most commonly mistaken for restrictive cardiomyopathy (RCM) out of the list above. That is why it is essential to explore the similarities and differences in more detail. The two diseases present almost identically, except for a few key signs and symptoms. Juglar venous distension, Kussmaul sign, and diastolic sounds are both seen in RCM and CP. However, there are some subtle differences. For example, S3 and elevated BNP are far more common in RCM. Whereas a pericardial knock, pericardial calcifications on chest x-ray, pericardial thickening on imaging, and BNP levels less than 100 are more likely seen in constrictive pericarditis. Furthermore, one clear difference between the two diseases is the presence of ventricular interdependence. Ventricular dependence seen only in CP is described as an increased filling of one of the ventricles only, with a reciprocal decreased filling of the other ventricle.[20]

Prognosis

Similar to the other cardiomyopathies, restrictive cardiomyopathy (RCM) has a very poor prognosis, having the worst prognosis as compared to all other cardiomyopathies. Statistical studies report only a 2 to 5 year survival rate.[3] 

Complications

Complications of RCM may include the following:[21][3] 

• Thromboembolism
• Dysrhythmias
• Heart failure
• Cardiac cirrhosis
• Extra-cardiac manifestations depending on etiology

Consultations

Restrictive cardiomyopathy is such a complex diagnosis it is best to consult or refer the patient to a cardiologist. Other consults that may merit consideration will depend on the extent of the disease; these consults include palliative care, hospice, and possibly advanced heart failure specialist.

Deterrence and Patient Education

Proper and thorough patient education is essential with a diagnosis of restrictive cardiomyopathy. Ultimately, most forms of this disease are fatal. The patient must understand this fact, as modern medicine has no cure for RCM. The key steps which should be made early in the disease course, including educating the patient and their loved ones regarding the disease course and prognosis. Then a heart transplant evaluation should be obtained, followed by a heart failure consult, possible palliative care consult, and possible hospice consult depending on the patient's wishes.[22]

Enhancing Healthcare Team Outcomes

Early diagnosis followed by immediate initiation of an interprofessional approach, including a heart failure nurse, heart failure specialist, palliative care, specialized cardiac pharmacist, the patient's primary care provider, and multiple other specialists, is the key to enhancing outcomes.[23] Cardiology nurses and pharmacists educate patients about compliance, medication side effects and provide updates to the team. It would be optimal to discuss all aspects of the disease with the patient as well as include them in the team discussions. Studies have shown patients live longer, have fewer hospital admissions, and are overall more satisfied with their healthcare with this approach.