Restrictive Cardiomyopathy 

Updated: Aug 30, 2017
Author: Lindsay Reardon, MD; Chief Editor: Henry H Ooi, MD, MRCPI 

Overview

Practice Essentials

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium and is the least common of the three clinically recognized and described cardiomyopathies.[1, 2] It is characterized by diastolic dysfunction with restrictive ventricular physiology, whereas systolic function often remains normal. Atrial enlargement occurs due to impaired ventricular filling during diastole, but the volume and wall thickness of the ventricles are usually normal. RCM accounts for approximately 5% of all cases of diagnosed cardiomyopathies.[3]

Signs and symptoms

Symptoms may include the following:

  • Gradually worsening shortness of breath
  • Progressive exercise intolerance
  • Orthopnea
  • Fatigue
  • Weight loss, cardiac cachexia
  • Paroxysmal nocturnal dyspnea
  • Abdominal discomfort or liver tenderness
  • Chest pain, primarily in patients with amyloidosis or due to angina
  • Palpitations

Physical examination

Search for extracardiac manifestations of a systemic disorder that may cause secondary restrictive cardiomyopathy (eg, hemochromatosis, amyloidosis, sarcoidosis, or scleroderma).

General examination findings:

  • Increased jugular venous pressure
  • Decreased pulse volume
  • Ascites and pitting edema of the lower extremities
  • Hepatomegaly due to fluid or amyloid infiltration
  • Easy bruising, periorbital purpura, macroglossia, and other systemic findings (eg, carpal tunnel syndrome) may be evidence of amyloidosis

Cardiovascular system examination findings:

  • Normal S 1 and S 2 heart sounds, with a normal S 2 split
  • Loud early diastolic filling sound (S 3)
  • A fourth heart sound (S 4) is almost never present
  • Murmurs due to mitral and tricuspid valve regurgitation (usually not hemodynamically significant)

Respiratory system examination findings:

  • Breath sounds are often decreased due to pleural effusions, frequently bilateral and large in amyloidosis
  • Crepitations or rales are rarely heard

See Clinical Presentation for more detail.

Diagnosis

Establishing the diagnosis of RCM and excluding constrictive pericarditis are imperative. The workup in a patient with suspected restrictive cardiomyopathy may include the following:

  • Complete blood cell (CBC) count
  • Blood gas analysis
  • Serum electrolyte, blood urea nitrogen (BUN), and creatinine levels
  • Liver function profile
  • Serum iron concentrations and other possible indicators of hemochromatosis
  • Serum brain natriuretic peptide (BNP) levels
  • Radiography
  • Angiography
  • Echocardiography
  • Cardiac catheterization
  • Electrocardiography
  • Radionuclide imaging
  • Cardiovascular magnetic resonance imaging (CMRI)
  • Computed tomography (CT) scanning to exclude diagnosis of restriction
  • Ventricular biopsy
  • Liver biopsy for diagnosis of hemochromatosis

See Workup for more detail.

Management

RCM has no specific treatment. However, therapies directed at individual causes of RCM have been proven to be effective.

Pharmacologic therapy may include:

  • Beta blockers
  • Amiodarone
  • Cardioselective calcium channel blockers
  • Diuretics
  • Anticoagulants for patients with atrial fibrillation
  • Digoxin (use with caution)
  • Melphalan (for antiplasma cell therapy in systemic amyloidosis)
  • Chemotherapy (in amyloidosis)
  • Corticosteroids, cytotoxic agents (eg, hydroxyurea), and interferon (in Loeffler endocarditis)
  • Chelation therapy or therapeutic phlebotomy (in hemochromatosis)

Other treatments:

  • Pacemaker implantation
  • Endomyocardectomy
  • Cardiac transplantation
  • Novel therapies (eg, RNA interference or gene silencing molecules that target abnormal protein production in familial amyloidosis)

See Treatment for more detail.

Background

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium and is the least common of the three clinically recognized and described cardiomyopathies.[1, 2]  It is characterized by diastolic dysfunction with restrictive ventricular physiology, whereas systolic function often remains normal. Atrial enlargement occurs due to impaired ventricular filling during diastole, but the volume and wall thickness of the ventricles are usually normal. RCM accounts for approximately 5% of all cases of diagnosed cardiomyopathies.[3]

RCM may be idiopathic or secondary to other diseases (ie, amyloidosis and endomyocardial disease with or without hypereosinophilia). The course of RCM varies, depending on the pathology and treatment. RCM has been found to be a significant cause of heart failure with preserved ejection fraction, although there is a high clinical overlap between RCM and other forms of heart failure.[4] RCM therefore presents a diagnostic challenge, and multiple modalities are usually required to make a final diagnosis.

See the images below.

Restrictive cardiomyopathy. Axial double inversion Restrictive cardiomyopathy. Axial double inversion-recovery magnetic resonance image of the heart in a 30-year-old woman with sarcoidosis demonstrates a normal pericardium.
Restrictive cardiomyopathy. Axial contrast-enhance Restrictive cardiomyopathy. Axial contrast-enhanced computed tomography scan through the heart (same patient as in the previous image) shows a thin pericardium without calcification. Note the cardiophrenic and internal mammary lymph nodes. The patient had extensive mediastinal and hilar adenopathy, as well as interstitial lung changes.

Pathophysiology

Restrictive cardiomyopathy (RCM) can be idiopathic or secondary to a heart muscle disease that manifests as restrictive physiology.[1, 5] Both inherited and acquired forms of the disease exist and affect men and women equally. Increased stiffness of the myocardium causes ventricular pressures to rise precipitously with small increases in volume. Thus, accentuated filling occurs in early diastole and 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.[6]

Patients typically have reduced compliance (increased diastolic stiffness), and the left ventricle cannot fill adequately at normal filling pressures. Reduced left ventricular filling volume leads to a reduced cardiac output. Early in the disease process, systolic function usually remains normal. Wall thickness may be increased in cases of infiltrative processes such as amyloidosis, but the increase is usually not as pronounced as that observed in hypertrophic cardiomyopathy.

As the disease progresses, a variable reduction in systolic function may develop with symptoms of reduced cardiac output, such as fatigue and lethargy, becoming evident. Increased filling pressures can manifest as pulmonary and systemic congestion. RCM affects both ventricles and therefore may cause signs and symptoms of both left-sided and right-sided heart failure. Some patients may have complete heart block as a consequence of fibrosis encasing the sinoatrial or the atrioventricular nodes.

RCM is one of the cardiomyopathies that is known to have a genetic cause, although only a few RCM-causing mutations have been described.[7, 8, 9] The Heart Failure Society of America (HFSA) issued updated guidelines on the genetic evaluation of cardiomyopathy in 2010.[10]

Based on pathology findings, RCM can further be classified as obliterative (ie, thrombus-filled ventricles) or nonobliterative. Idiopathic (primary) RCM is nonobliterative, as progressive fibrosis of the myocardium occurs but no thrombus forms. This entity also is said to lack specific histopathologic changes.

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.

Etiology

Restrictive cardiomyopathy (RCM) may be caused by various local and systemic disorders; many of them are rare and unlikely to be observed in the United States. 

According to World Health Organization (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.[11]

The etiologies of RCM may be grouped into broad categories as follows:

The specific pathophysiologies of the more common causes of RCM will be described in detail below.

Primary (idiopathic) RCM

Both genetic and sporadic cases of primary (idiopathic) RCM have been described. This is a rare condition that can present in children and adults,[13] and males and females are affected equally. However, the prognosis appears to be worse in children than in adults. Genetic cases show autosomal dominant inheritance with incomplete penetrance. The mutation appears to occur in the genes encoding sarcomeric proteins, including troponin I, troponin T, alpha cardiac actin, and beta-myosin heavy chain.[13] A history of familial RCM is reported in approximately 30% of RCM cases.[3]  

A subset of patients has heart muscle disease of unknown cause that is manifested by heart failure and restrictive hemodynamics, but without significant ventricular hypertrophy, endocardial thickening or fibrosis, associated eosinophilia, or other diagnostically distinct histopathologic changes.

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. An observational study suggests that poor left ventricular function may be a hallmark for pediatric restrictive cardiomyopathy even in the presence of normal diastolic parameters.[14]

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 patients and extensive in others.

Eosinophilic cardiomyopathy (Loeffler endocarditis) and EMF

EMF is the most common global cause of RCM, affecting an estimated 12 million people worldwide. This condition is observed in equatorial Africa and, less frequently, in tropical and subtropical Asia and South America. 

Severe prolonged eosinophilia from any cause (eg, allergic, autoimmune, parasitic, leukemic, or idiopathic) can lead to eosinophilic infiltration of the myocardium. Eosinophilic cardiomyopathy, also known as Loeffler endocarditis, begins with an acute inflammatory phase characterized by fever and pancarditis. Left ventricular and right ventricular thrombus formation occurs in the intermediate phase and, after months to years, the final stage includes development of endocardial fibrosis. The intracytoplasmic granular content of activated eosinophils is believed to be responsible for the toxic damage to the heart.[13]

EMF was originally believed to be the end stage of eosinophilic endomyocarditis. However, chronic EMF is currently considered a separate entity because it does not exhibit eosinophilia. EMF demonstrates pathology that is similar to that of Loeffler endocarditis.

Both EMF and Loeffler endocarditis are categorized as types of obliterative RCM. Intraventricular thrombus formation leads to obliteration of the ventricular cavity in the late stages. Echocardiography may show endomyocardial thickening, ventricular apical obliteration, and tethering of mitral and tricuspid leaflets.[13]

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

Secondary RCM

Infiltrative cardiomyopathy

Infiltrative cardiomyopathies are characterized by deposition of abnormal substances (ie, amyloid proteins, noncaseating granulomas, iron) within the heart tissue. Infiltration causes the ventricular walls to stiffen, leading to diastolic dysfunction. Disease occurs in a wide variety of age groups and, given the systemic nature of the underlying disease, extracardiac manifestations are common. Restrictive physiology predominates in the early stages, causing conduction abnormalities and diastolic heart failure. Adverse remodeling may lead to systolic dysfunction and ventricular arrhythmias in advanced cases.[15]

Confirmatory evidence of infiltrative cardiomyopathy is often obtained by endomyocardial biopsy, echocardiography, or cardiac magnetic resonance imaging (CMRI). Depending on the etiology and extent of involvement, medications, device therapy, and transplantation can be effective, although treatment is largely supportive in many cases.[15]

Amyloidosis

Amyloidosis is the most common cause of RCM in the United States. Due to advancements in noninvasive diagnostic modalities, relatively recent studies have shown that there may be a higher prevalence of amyloidosis among elder patients with heart failure with preserved ejection fraction than previously recognized.[4]

Amyloidosis is characterized by the multisystem deposition of proteins known as amyloid fibrils, and it typically presents as a systemic disorder, with infiltration of the liver, kidneys, bowel, nerves, skin, and tongue.[13] Cardiac involvement is common and the major source of associated morbidity and mortality. The myocardial wall thickens and becomes firm, rubbery, and noncompliant as amyloid accumulates in tissues. These changes lead to abnormalities of contractility, conduction, and coronary blood flow. Interestingly, amyloid deposition in the bundle branches is rare. Biventricular diastolic dysfunction causes intracardiac pressures to rise, and it may progress to systolic dysfunction in advanced disease.[15] The heart typically does not collapse when removed from the chest during autopsy. 

Amyloidosis is classified into the following four major clinical types based on the composition of amyloid protein:

  • Primary or amyloid light-chain (AL): This is the most common form, often associated with multiple myeloma; prognosis is poor, with a median 1-year survival from diagnosis.

  • Secondary amyloidosis or amyloid A (AA): This type is secondary to chronic diseases, especially inflammatory conditions.

  • Senile amyloidosis or wild-type transthyretin (wt-TTR) amyloidosis: This form is seen in 25-36% of patients older than 80 years; it is caused by deposition of wt-TTR.[16] The median survival is 6 years.

  • Familial amyloidosis or hereditary mutant TTR (m-TTR)/hereditary transthyretin-derived (ATTR) amyloidosis: This type is a systemic autosomal dominant disorder due to tissue deposition of various proteins. Cardiac involvement is rare. 

The cardiac involvement in primary amyloidosis is most commonly associated with restrictive physiology. 

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. Restrictive diastolic dynamics strongly predict cardiac death in patients with amyloidosis. Studies have shown that patients with elevated cardiac biomarkers such as troponin (Tn) and B-type natriuretic peptide (BNP) have a worse prognosis.[15]

On histologic examination, amyloid may deposit within any part of the heart, including the myocardium, vessels, endocardium, valves, epicardium, and parietal pericardium. The ventricular walls are typically thickened, sometimes with disproportionate septal thickening, and may mimic the appearance of hypertrophic cardiomyopathy. Atrial dilatation develops as a consequence of increased ventricular filling pressures and restrictive physiology.[17] Involvement of the valves may create regurgitant lesions, but a hemodynamically and clinically significant degree of regurgitation is unusual.

Cardiac biopsy is needed to confirm the diagnosis if doubt remains after noninvasive tests. Classically, the deposition of insoluble fibrillary protein displays as apple-green birefringence under polarized light microscopy with Congo Red staining.[13]

Classic two-dimensional echocardiography findings include an increased left ventricular and right ventricular wall thickness, normal or small left ventricular cavity size with preserved ejection fraction, and biatrial enlargement. Up to one third of patients can present with normal left ventricular wall size. Pericardial effusion and thickening of both valves and papillary muscles is common. A granular and speckled appearance of the ventricular myocardium is suggestive of amyloidosis, but it is no longer considered specific.[15]

Other less common forms of infiltrative RCM include:

  • Sarcoidosis: Presence of noncaseating granulomas (cardiac involvement: 25-30%)
  • Hemochromatosis and iron overload cardiomyopathy: Excess deposition of iron
  • Fabry disease: Lysosomal storage disorder with accumulation of glycosphingolipid
  • Danon disease: Deficiency in lysosome-associated membrane protein 2 (LAMP2)
  • Friedreich ataxia: Mutation of frataxin gene ( FXN)

Treatment-induced RCM

Postirradiation fibrosis

Radiation-induced myocardial and endocardial fibrosis is a cause of noninfiltrative RCM. Fibrosis causes endothelial cell damage and subsequent microvascular dysfunction. An increase in total collagen concentration leads to decreased distensibility of the ventricular tissue. Radiation affects the coronary vessels, valves, and pericardium.[13] This complication of radiotherapy, as with pericardial constriction, is evident several years after treatment. Differentiating between constriction and restriction may be particularly difficult in these patients because the two conditions may coexist. Echocardiography may show normal left ventricular wall thickness with abnormal left ventricular filling, valvular calcification, and pericardial constriction.[13]

Drug induced

Drug-induced RCM is a rare disorder that has been described with long-term use of the antimalarial medications chloroquine and hydroxychloroquine. Common findings include conduction abnormalities and valvular thickening.[13]

Epidemiology

Idiopathic restrictive cardiomyopathy (RCM) is observed primarily in the United States. Loeffler endocarditis is common in the temperate zone, whereas chronic endomyocardial fibrosis (EMF) is observed exclusively in tropical and subtropical Africa, Asia, and South America. EMF occurs most commonly in children and young adults in Uganda and Nigeria[18] ; this condition may account for up to one fourth of deaths due to cardiac disease in those areas.

Prognosis

Restrictive cardiomyopathy (RCM) has the poorest prognosis among all types of heart muscle diseases, with 2- and 5- year mortality rates of 50% and 70%, respectively, and the highest rate of sudden cardiac death. Due to restrictive physiology, patients with RCM ultimately develop heart failure and pulmonary hypertension.[3]

The course of RCM varies depending on the pathology, and treatment is often unsatisfactory. The prognosis is generally poor in the adult population, as RCM shows 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 whose condition is refractory to supportive therapy usually die of low-output cardiac failure unless cardiac transplantation is an option.

Complications

Complications of RCM may include the following:

  • Thromboembolism
  • Dysrhythmias
  • Cardiac cirrhosis
  • Progressive deterioration of cardiac function
 

Presentation

History

Patients with restrictive cardiomyopathy (RCM) often present at an advanced stage of disease with pronounced cardiopulmonary symptoms. They complain of gradually worsening shortness of breath, progressive exercise intolerance, orthopnea, and fatigue. Paroxysmal nocturnal dyspnea may be reported.

Right-sided heart failure typically results in profound bilateral lower extremity edema, hepatomegaly, right upper quadrant pain, and ascites. Abdominal discomfort or liver tenderness may be reported.

Chest pain is rare, but it may be occur in amyloidosis or secondary to angina. Chest pain that mimics myocardial ischemia may be due to myocardial compression of small vessels. Patients may complain of frequent palpitations, as idiopathic RCM commonly causes atrial fibrillation.[19]

As many as one third of patients with idiopathic RCM may present with thromboembolic complications, especially pulmonary emboli secondary to blood clots in the legs. If atrial fibrillation is present, a high risk of left atrial clots and systemic emboli may also be present.

Patients may have a history of syncopal attacks from a variety of causes, but orthostatic hypotension secondary to a peripheral and/or autonomic neuropathy should be excluded. Syncope and sudden death are common in primary (amyloid light-chain [AL]) amyloidosis, but ventricular arrhythmias are uncommon. Electrical-mechanical dissociation is more usual. Conduction disturbances are particularly common in some forms of infiltrative RCM, but not in amyloidosis.

Depending on the etiology, patients may have a prior history of radiation therapy, heart transplantation, chemotherapy, or a systemic disease.

Physical Examination

A careful physical examination must be conducted to search for extracardiac manifestations of a systemic disorder that may cause secondary restrictive cardiomyopathy (eg, hemochromatosis, amyloidosis, sarcoidosis, or scleroderma).[11, 12] Particular attention should be paid to the cardiovascular and respiratory systems.

General examination

Patients may be more comfortable in the sitting position because of fluid in the abdomen or lungs, and they frequently have ascites and pitting edema of the lower extremities. The liver is usually enlarged and full of fluid, which may be painful. Weight loss and cardiac cachexia are not uncommon. Easy bruising, periorbital purpura, macroglossia, and other systemic findings, such as carpal tunnel syndrome, should be an indication for the clinician to consider amyloidosis. Amyloid infiltration may cause the liver to be enlarged and firm, but splenomegaly is rare.

Increased jugular venous pressure is present, with rapid x and y descents, and the most prominent finding is usually the rapid y descent. The degree of elevation of the jugular venous pressure indicates the severity of impaired filling of the right ventricle.

In constrictive pericarditis, the jugular venous pulse fails to fall during inspiration and may actually rise (Kussmaul sign). Although less common in restrictive cardiomyopathy (RCM), Kussmaul sign cannot be used as an absolute means to distinguish RCM and constrictive pericarditis. The pulse volume is decreased, consistent with decreased stroke volume and cardiac output.

Cardiovascular system examination

Heart sounds S1 and S2 are normal, with a normal S2 split. A loud early diastolic filling sound (S3) may be present, but it is uncommon in amyloidosis. A fourth heart sound (S4) is almost never present, possibly secondary to amyloid infiltration of the atria. Murmurs due to mitral and tricuspid valve regurgitation may be heard, but they are secondary to the myocardial disease and usually not hemodynamically significant.

Respiratory system examination

Breath sounds are often decreased due to pleural effusions, frequently bilateral and large in amyloidosis. Crepitations or rales are rarely heard, even in advanced heart failure of amyloidosis.

 

DDx

Diagnostic Considerations

All causes of diastolic dysfunction are included in the differential diagnosis of restrictive cardiomyopathy (RCM). The more common forms of heart failure with preserved ejection fraction are typically related to advanced age, diabetes, obesity, coronary artery disease (CAD), and left ventricular hypertrophy. Some specific characteristics may help distinguish RCM as a cause, such as low-normal blood pressure, younger age, elevated B-type natriuretic protein (BNP) that is out of proportion to the clinical presentation, persistent positive troponin in the absence of CAD, low voltage-mass ratio on electrocardiography (ECG), increased left ventricular mass, and pericardial effusion. The high prevalence of clinical overlap between RCM and other causes of heart failure, however, continue to make it a diagnostic challenge.[4, 20]

Differentiating RCM from constrictive pericarditis (CP) is imperative. Although RCM has no specific therapy, CP is potentially curable with surgical pericardectomy.[21] Both processes show reduced left ventricular chamber compliance, but RCM is caused by abnormal elastic properties of the myocardium, whereas CP is constrained externally by the pericardium. Myocardial relaxation is impaired in RCM, whereas it remains normal in CP.[13]

The etiology of RCM has been confused with that of CP because of the similarity of their presenting symptoms and diagnostic findings. With respect to their history and clinical profile, pericardial constriction and RCM are often indistinguishable. In addition, the two conditions can coexist in the same patient; for example, radiation therapy affects the myocardium as well as the pericardium. There are certain clinical features, however, that help to differentiate the two conditions (see Table 1 below). 

Table 1. Clinical Features of Constrictive Pericarditis and Restrictive Cardiomyopathy (Open Table in a new window)

Clinical Features

Constrictive Pericarditis

Restrictive Cardiomyopathy

History

Prior history of pericarditis or condition that causes pericardial disease

History of systemic disease (eg, amyloidosis, hemochromatosis)

General examination

Peripheral stigmata of systemic disease

Systemic examination - Heart sounds

Pericardial knock, high-frequency sound

Presence of loud diastolic filling sound S3, Low-frequency sound

Murmurs

No murmurs

Murmurs of mitral and tricuspid insufficiency

Prior chest radiograph

Pericardial calcification

Normal results of prior chest radiograph

In the past, cardiac catheterization findings were not always conclusive, and the diagnosis of RCM was often made during surgery. Currently, as noninvasive imaging techniques continue to advance, the correct diagnosis can be strongly suggested by structural, mechanical, and hemodynamic findings on echocardiography and cardiac magnetic resonance imaging (CMRI). More advanced tissue tracking software allows myocardial functional data to be determined from both echocardiography and CMRI with equal ease and accuracy. Echocardiography and CMRI are comparable in their ability to differentiate RCM from CP.[22]

Echocardiographic findings consistent with RCM include normal or thickened right ventricular and left ventricular walls, normal or small left ventricular cavity size, and enlarged atria. Doppler ultrasonography shows a restrictive filling pattern of transmitral flow and reduced tissue Doppler peak early-diastolic mitral-annular velocities. In contrast, CP echocardiographic findings may show a plethoric (distended) inferior vena cava (IVC), abnormal septal wall motion, and respiratory variation of left ventricular inflow velocities.[22]

Other conditions to be considered include systemic hypertension, valvular aortic stenosis, and hypertrophic cardiomyopathy, all of which cause impaired diastolic distensibility secondary to left ventricular hypertrophy. The thickened left ventricle could be confused with amyloidosis on echocardiography, but the clinical findings are completely different. The final diagnosis of RCM is most commonly made on the basis of biopsy of fat tissue, such as abdominal wall fat.

Differential Diagnoses

 

Workup

Approach Considerations

The accurate diagnosis of restrictive cardiomyopathy (RCM) is difficult given the similar clinical and hemodynamic presentation of constrictive pericarditis, but it is of utmost importance for treatment and prognosis. In years past, the diagnosis of RCM was often not made until surgical biopsy. However, with advances in diagnostic imaging, the necessity of surgical intervention for diagnosis should decrease. Investigative modalities that may aid in the differentiation of RCM and constrictive pericarditis appear in Table 2 below. 

A full evaluation of the heart often necessitates a multimodality approach, including radiography, echocardiography, computed tomography (CT) scanning, magnetic resonance imaging (MRI), and invasive angiography.[23]  With the current availability of nuclear imaging and cardiac MRI (CMRI), the diagnosis of RCM can be made noninvasively with a high degree of accuracy, but echocardiography remains the “front line” for diagnosis in early cases. Early diagnosis is crucial, given the advancements in therapeutic possibilities.[24]

See also Imaging in Restrictive Cardiomyopathy.

Table 2. Investigation of Constrictive Pericarditis and Restrictive Cardiomyopathy (Open Table in a new window)

Investigation

Constrictive Pericarditis

Restrictive Cardiomyopathy

Chest radiograph

Pericardial calcification

Atrial dilation causing increased cardiothoracic ratio; normal ventricular size

CT scanning/MRI

Pericardial thickening

No pericardial thickening

Echocardiography

Normal-sized ventricles and atria; pericardial effusion may be observed

Nondilated, normally contracting, nonhypertrophied ventricles and marked dilation of both atria

Doppler flow velocities on echocardiography

Respiratory changes (ie, decreased peak transmitral diastolic flow) during inspiration; equalization of the right- and left-sided filling pressures

No respiratory changes; greater elevation in the left-sided filling pressures

Catheterization hemodynamics:

1) RVSP

2) RVEDP:RVSP ratio

3) RVEDP/LVEDP equalization

 

1) = 50 mm Hg

2) = 0.33

3) = 5-mm Hg difference

 

1) = 50 mm Hg

2) = 0.33

3) = 5-mm Hg difference

Cardiac biopsy

Normal myocardium

Often diagnostic, showing abnormal myocardium

CT = computed tomography; LVEDP = left ventricular end-diastolic pressure; MRI = magnetic resonance imaging; RVEDP = right ventricular end-diastolic pressure; RVSP = right ventricular systolic pressure.

Laboratory Studies

A complete blood cell (CBC) count with peripheral smear helps to establish eosinophilia. Blood gas analysis is performed to monitor hypoxia. Serum electrolyte, blood urea nitrogen (BUN), and creatinine levels should be obtained, as well as a liver function profile.

Serum iron concentrations, percentage saturation of total iron-binding capacity, and serum ferritin levels are all increased in hemochromatosis.

Serum brain natriuretic peptide (BNP) levels should be assessed. Data suggest that serum BNP levels are nearly normal in patients with constrictive physiology of heart failure and grossly elevated in patients with restrictive physiology, despite a nearly identical clinical and hemodynamic presentation.[25]

Electrocardiography

The findings on electrocardiography (ECG) depend on the stage of the disease and the specific diagnosis. The ECG recording is abnormal in more than 90% of patients with restrictive cardiomyopathy (RCM), especially idiopathic RCM. The ECG may be normal, however, or only show nonspecific ST-T wave changes. Rhythm disorders are common, and up to 74% of patients have atrial fibrillation. Case reports have shown Torsades de pointe. Significant ST depression mimicking ischemia has also been reported, especially in idiopathic RCM.[26]

In infiltrative disease, low-voltage QRS complexes have been described.[19] Conduction abnormalities are uncommon in amyloidosis. A pseudoinfarct pattern is possible, secondary to myocardial infiltration and/or small vessel–induced ischemia or infarction.

Radiography and Angiography

Chest radiography typically shows a normal cardiac silhouette and manifestations of pulmonary venous hypertension and pulmonary congestion. There may be other signs of congestive heart failure, such as pleural effusions.[19]  There is typically no pericardial calcification, which is seen in constrictive pericarditis.

Angiography may show a small, thick-walled cavity in eosinophilic endomyocardial disease, which may be distorted significantly by a mural thrombus.

Echocardiography

Two-dimensional imaging

There is a significant body of literature demonstrating the utility and availability of two-dimensional transthoracic echocardiography (TTE). Therefore, it is a primary diagnostic modality in suspected restrictive cardiomyopathy (RCM).[27] In noninfiltrative RCM, TTE shows a left ventricle that is nondilated, nonhypertrophied, and normally contracting. There is typically marked dilatation of both atria.

In infiltrative RCM, such as amyloidosis and glycogen storage diseases, the primary finding is a concentrically increased left ventricular wall thickness with a normal or reduced chamber cavity size. Interatrial septal thickening is more specific to infiltrative cardiomyopathies. These changes are caused by myocardial amyloid deposition rather than true myocyte hypertrophy. Left atrial thrombi may occur in cardiac amyloidosis even in sinus rhythm.[24] Other common findings include biatrial dilatation, valvular thickening, and pericardial effusion. The ejection fraction (EF) typically remains preserved until advanced stages of the disease, and reduced EF is a marker of poor prognosis.[27]

The ratio of stroke volume to left ventricular myocardial volume, called myocardial contraction fraction, is a novel metric of left ventricular remodeling that has demonstrated prognostic significance superior to left ventricular EF in infiltrative disease.[27]

A granular myocardial appearance, or “sparkling” was initially reported using older ultrasonographic techniques. With current harmonic imaging, this finding is no longer validated and is considered nonspecific for infiltrative disease.[27]

Obliterative cardiomyopathy may reveal a mural thrombus and cavity obliteration. In contrast, dilated cardiomyopathy shows dilatation of all the chambers of the heart. Increased wall thickness, especially of the ventricular septum, is observed in hypertrophic cardiomyopathy.

Pericardial thickening is not reliably observed on echocardiography; magnetic resonance imaging (MRI) is suggested for exclusion of a thick pericardium.

Doppler imaging

Doppler echocardiography shows restriction of diastolic filling, as diastolic dysfunction precedes reductions in left ventricular EF in infiltrative disease. Studies have shown the degree of diastolic dysfunction correlates to the extent of wall thickening in amyloid infiltration.[24, 27] Accentuated early diastolic filling of the ventricles (E), shortened deceleration time, and diminished atrial filling (A) results in a high E-to-A ratio on mitral inflow velocities. Variations of this diastolic (transmitral) blood flow with respiration help differentiate between constrictive pericarditis and RCM.

In infiltrative disease, all valves are often thickened. However, color flow Doppler studies have revealed that valvular dysfunction is usually mild and rarely contributes to heart failure. In contrast, the progressive and severe diastolic dysfunction leads to low EF and restrictive Doppler filling patterns, which demonstrated a worse prognosis.[24]

In constrictive pericarditis, both ventricles are encased in a common constricting pericardial sac. An inspiratory increase in inflow to the right ventricle causes a reciprocal reduction in the transmitral inflow to the left ventricle. Thus, a pattern of respiratory variation with a diminished peak transmitral diastolic flow during inspiration is characteristic of pericardial constriction, but not of RCM. In contrast, in RCM, the left-sided filling pressures are elevated further in inspiration.

Pulsed-wave tissue Doppler imaging

The use of pulsed-wave Doppler imaging may be used as a noninvasive approach to distinguish RCM from constrictive pericarditis. In addition to the information obtained by standard Doppler imaging, pulsed-wave Doppler studies can determine the myocardial velocity gradient, which is a measure of myocardial contraction and relaxation. Small studies have suggested that the myocardial velocity gradient is a specific measurement to differentiate restrictive and constrictive physiology.

Strain imaging and speckle tracking

Strain imaging is a method of measuring myocardial deformation, and it has demonstrated high sensitivity for detecting more subtle changes in contractile function. Specific myocardial strain patterns may reveal earlier stages of a variety of cardiovascular disorders. Longitudinal systolic strain (deformation along the long-axis of the left ventricle) is particularly sensitive for detecting early changes of amyloidosis.[27]

Speckle-tracking echocardiography measures both global and segmental ventricular strain, and therefore evaluates different contractile directions beyond the longitudinal axis. This is yet another imaging method to differentiate amyloidosis from other conditions that cause increased myocardial wall thickness, such as hypertrophic cardiomyopathy. Amyloid infiltration shows a characteristic pattern of reduced basal and mid-wall left ventricular longitudinal systolic strain with relative preservation at the apex.[27]

Cardiac Catheterization

Ventricular pressure tracings of increased right heart pressures, a typical venous wave pattern, and the dip-and-plateau or square-root contour of the ventricular diastolic pressures (deep and rapid early decline in ventricular pressure at the onset of diastole, with a rapid rise to a plateau in early diastole) obtained by cardiac catheterization are the same in pericardial constriction and in restrictive cardiomyopathy (RCM). This dip-and-plateau or square-root sign of ventricular pressure is manifested in the atrial pressure tracing as a prominent descent followed by a rapid rise to a plateau.

A few criteria favor the pericardial disorder, as follows:

  • Equalization of the left and right ventricular filling pressures, with a difference of no more than 5 mm Hg between the two sides

  • Right ventricular end-diastolic pressure (RVEDP) equal to or exceeding one third of the level of the right ventricular systolic pressure (RVSP)

  • RVSP lower than 50 mm Hg

  • Persistence of diastolic equalization of pressures under stress or exercise or fluid challenge

In RCM, the variance between the right and left ventricular diastolic pressures is more likely to be greater than 5 mm Hg, RVEDP is more likely to be less than one third the RVSP, and RVSP is more likely to be higher than 50 mm Hg.

Other Imaging Studies

Radionuclide imaging

Radionuclide imaging shows increased diffuse uptake of technetium-99m (99mTc) pyrophosphate and indium-111 (111In) antimyosin in cardiac amyloidosis.

Cardiovascular magnetic resonance imaging (CMRI)

CMRI can be used to evaluate the myocardial structure/orientation, perfusion, function, and viability in cardiomyopathy, providing information such as the left ventricular mass, volume, and regional contractility, as well as myocardial strain analysis, tissue mapping, and extracellular volume estimation.[28]  

CMRI has been used to assess abnormal myocardial interstitium, and it has been shown to reliably identify the morphologic findings of cardiac amyloidosis.[27] Preliminary reports suggest a characteristic pattern of global subendocardial late gadolinium enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics in restrictive cardiomyopathy (RCM). Dynamic cine imaging provides a clear, unobstructed view of all cardiac chambers, which allows for high quality visualization and tracking of both the endocardial and epicardial borders in addition to valvular disease.[27]

CMRI-based strain analysis, like echocardiography, is a promising modality to improve the diagnostic sensitivity of early infiltrative disease and the specificity of imaging findings in the hypertrophic stage.[27]

Cardiac computed tomography (CCT) scanning

CCT scanning has primarily been used to investigate coronary artery disease in select RCM patients with anginal chest pain, and its diagnostic role has thus far been limited. Similar to CMRI, however, CCT scanning can track contrast medium distribution to healthy and unhealthy tissues. Despite the disadvantages with regard to renal insufficiency and radiation exposure, CCT scanning may be an alternative modality if CMRI is contraindicated or unavailable.[27]

Biopsy

Ventricular biopsy obtained from either the right or the left ventricle has proven to be useful in certain cases to establish whether endocardial or myocardial disease is present. Growing experience in this technique indicates a high diagnostic yield in diseases that may present with restriction hemodynamics when noninvasive studies have failed to establish a clear-cut diagnosis.

Amyloidosis demonstrates apple-green birefringence, stained with Congo red, when viewed under a polarizing microscope. Fine-needle aspiration of abdominal fat is easier and safer to perform than myocardial biopsy for the determination of amyloidosis. Confirmation of the diagnosis of primary or amyloid light-chain (AL) amyloidosis demands a search for a plasma cell dyscrasia.

Liver biopsy is performed for diagnosis of hemochromatosis.

 

Treatment

Approach Considerations

Restrictive cardiomyopathy (RCM) has no specific treatment. However, therapies directed at individual causes of RCM have been proven to be effective. Examples of this include corticosteroids for sarcoidosis and Loeffler endocarditis, endocardiectomy for endomyocardial fibrosis and Loeffler endocarditis, phlebotomy and chelation for hemochromatosis, and chemotherapy for amyloidosis. Familial amyloidosis has been shown to respond to novel therapies such as RNA interference or gene silencing molecules that target abnormal protein production.[29] Budesonide has been studied as a potential effective anti-inflammatory with fewer side effects than other oral corticosteroid therapy.[30]

The mainstays of medical treatment include diuretics, vasodilators, and angiotensin-converting enzyme inhibitors (ACEIs) as indicated, as well as anticoagulation (if not contraindicated).[19]

In selected patients, permanent pacing, left ventricular assist device (LVAD) therapy, and transplantation (heart or heart-liver) may be considered.

Pharmacologic Therapy

The goal of treatment in restrictive cardiomyopathy (RCM) is to reduce symptoms by lowering elevated filling pressures without significantly reducing cardiac output. Beta blockers and cardioselective calcium channel blockers (eg, verapamil, diltiazem) may be of benefit by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation. In addition, low-medium dose diuretics reduce preload and may provide symptomatic relief. Small initial doses should be administered to prevent hypotension because patients are frequently extremely sensitive to alterations in left ventricular volume. Higher doses may be needed if the serum albumin level is low secondary to concomitant nephrotic syndrome.

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II inhibitors (angiotensin II receptor blockers [ARBs]) are poorly tolerated in patients with amyloidosis. Even small doses may result in profound hypotension, which is likely secondary to an autonomic neuropathy. Beta-blockers and calcium channel blockers have not been shown to improve day-to-day symptoms or to favorably alter the natural history in patients with diastolic heart failure. No published data are available on the use of intravenous (IV) inotropic or vasodilator drugs.

Patients with a history of atrial fibrillation should be anticoagulated, and the heart rate should be adequately controlled. Atrial contraction acts to increase the efficiency of ventricular filling and ejection; thus, if removed, existing diastolic dysfunction may worsen. Likewise, rapid ventricular response may further compromise diastolic filling, creating a crisis. Therefore, maintaining sinus rhythm is important, and medications such as amiodarone and beta-blockers are often used.

Digoxin should be used with caution because it is potentially arrhythmogenic, particularly in patients with amyloidosis.

Antiplasma cell therapy with melphalan may slow the progress of systemic amyloidosis by stopping production of the paraprotein responsible for the formation of amyloid. The prognosis of patients with primary systemic amyloidosis remains poor, with a median survival of approximately 2 years despite intervention with alkylating-based chemotherapy in selected cases. In specific cases, chemotherapy has dramatic benefits, with improvement in systemic and cardiac manifestations.

The treatment of Loeffler endocarditis consists of correctly identifying the condition before the end-stage fibrosis occurs. Medical therapy with corticosteroids, cytotoxic agents (eg, hydroxyurea), and interferon to suppress the intense eosinophilic infiltration of the myocardium is appropriate during the early phase of Loeffler endocarditis and improves symptoms and survival. Conventional heart failure medication is also given.

Chelation therapy or therapeutic phlebotomy is effective in patients with hemochromatosis to decrease the iron overload.

Pacemaker Implantation

Patients with idiopathic restrictive cardiomyopathy (RCM) may have fibrosis of the sinoatrial and atrioventricular nodes that result in complete heart block and, therefore, require permanent pacing. If cardioversion to treat atrial fibrillation is attempted, particularly in patients with amyloidosis, the abnormal sinus node may fail as an effective pacemaker. Patients with sinus node dysfunction and/or advanced conduction system disease also require treatment with implantation of a pacemaker.

Endomyocardectomy

As noted earlier, treatment of Loeffler endocarditis depends on correctly identifying the condition before the end-stage fibrosis occurs, and it typically involves early pharmacotherapy (see Pharmacologic Therapy).

In the fibrotic stage of Loeffler endocarditis, surgical therapy, with excision of the fibrotic endocardium and replacement of the mitral and tricuspid valves, is palliative but may provide symptomatic improvement. The operative mortality is in the range of 15% to 25%.

Cardiac Transplantation

Cardiac transplantation or ventricular mechanical support (left ventricular assist device [LVAD]) therapy can be considered in highly selected patients with refractory symptoms who have idiopathic or familial restrictive cardiomyopathy (RCM) and amyloidosis. Elevated pulmonary vascular resistance excludes patients from cardiac transplantation, and LVAD implantation may be required as a bridge to transplantation.[31] LVAD has successfully been used as a bridge to heart transplantation in infants and children.[32] When noncardiac organ involvement is absent, a few patients with amyloidosis have undergone successful cardiac transplantation in combination with postoperative high-dose chemotherapy to abolish recurrent amyloid production.

Cardiac transplantation is a widely accepted treatment to improve long-term survival in patients with advanced RCM. Unfortunately, patients face long waiting periods. Many develop irreversible pulmonary hypertension and die from heart failure complications before they can receive a donor heart. Persistent right heart failure, thickened left ventricular walls and small left ventricular chamber sizes make LVAD implantation challenging in RCM. A 2015 study by Grupper et al found that LVAD implantation is technically feasible in patients with advanced RCM, and it is associated with improved survival as compared with medical therapy, regardless of RCM etiology.[33] Left ventricular dimensions were an important predictor for outcome. The investigators showed a 1-year survival of 64% with LVAD implantation, which is higher than the reported natural history of advanced RCM. Although the cohort consisted of 28 patients, the results also showed improved long-term survival of those who underwent LVAD implantation as a bridge to transplantation.[33]

Combined heart and liver transplantation in patients with heart and liver failure due to hemochromatosis has been successful in small numbers of patients.[34] However, early morbidity and mortality are higher in dual-organ transplantation than in single-organ transplantation.

Transplantation is a treatment option for cardiac sarcoidosis, but recurrence of sarcoid granulomas can occur in the transplanted heart.

A surgical approach carries a potential for significant morbidity for RCM, but it may offer a cure for pericardial constriction. Thus, establishing a clear diagnosis is crucial, aided by the advent of sophisticated imaging technology (see Workup). Fewer patients now need exploratory open-heart surgery to establish the correct diagnosis. Finally, it is uncertain whether patients who have radiation-induced cardiac diseases are candidates for heart transplantation. This stems from data that have shown these patients have poor early and late outcomes after cardiac transplantation related to fibrosis, procedural complications, and new or recurrent malignancies.[35]

Novel Therapies

Advancements in chemotherapy regimens and the use of autologous hematopoietic cell transplantation in some patients have been shown to improve survival for primary or amyloid light-chain (AL) amyloidosis. Mortality at 1 year, however, remains greater than 50% for those with advanced cardiac involvement.[27] Stem cell transplantation used in conjunction with high-dose chemotherapy is still considered experimental by most cardiologists. Its routine use has not yet been established.

Novel protein-specific strategies are emerging for the treatment of amyloidosis, including nonsteroidal anti-inflammatory agents (NSAIDs), novel compounds and micro-RNA inhibitors. Other treatments target the reduction of gene expression and amyloid degrading agents.[27] There are ongoing studies testing agents that block hepatocyte production of transthyretin, stabilize the tetramer in plasma, or promote clearance of already deposited fibrils.[36]  

 

Medication

Medication Summary

Treatment of restrictive cardiomyopathy (RCM) is symptomatic. Treatment goals include reducing systemic and pulmonary congestion, lowering ventricular filling pressure, augmenting systolic pump function, and reducing the risk for embolism.[19]

Diuretics

Class Summary

Diuretics are used to reduce pulmonary and systemic congestion. Symptomatic treatment may improve symptoms of venous congestion through elimination of retained fluid and preload reduction. Initiate therapy with a low dose because relatively high levels of ventricular filling pressure must be maintained for adequate diastolic filling.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Furosemide (Lasix)

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dose must be individualized to the patient. Depending on response, administer furosemide at increments of 20-40 mg no sooner than 6-8 hours after the previous dose until the desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until a satisfactory effect is achieved.

Nitrates

Class Summary

Nitrates are used to reduce preload in diastolic dysfunction.

Nitroglycerin PO

Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure. This agent is available as lingual pump spray, sublingual tablets, oral tablets, patches, and ointments.

Beta-Blockers, Alpha Activity

Class Summary

May improve symptoms by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation.

Carvedilol (Coreg, Coreg CR)

Nonselective beta- and alpha-adrenergic blocker. Also has antioxidant properties. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.

Calcium Channel Blockers

Class Summary

May improve symptoms by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation.

Verapamil (Calan, Isoptin)

Nondihydropyridine calcium-channel blocker that inhibits extracellular calcium ion influx across membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction and thereby dilating main coronary and systemic arteries.

Diltiazem (Cardizem, Cardizem CD, Dilacor Tiazac)

Nondihydropyridine calcium-channel blocker that inhibits extracellular calcium ion influx across membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction and thereby dilating main coronary and systemic arteries.

Vasodilators

Class Summary

Vasodilators are used to reduce ventricular filling pressure. Avoid excessive decrease in preload and diastolic filling.

Hydralazine

Hydralazine decreases systemic resistance through direct vasodilation of arterioles.

Isosorbide dinitrate/hydralazine (BiDil)

A fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), which is a predominantly arterial vasodilator. Based on the results of the African American Heart Failure Trial, isosorbide dinitrate/hydralazine is indicated for heart failure in black patients.

Two previous trials in the general population of patients with severe heart failure found no benefit, but it suggested a benefit in patients who are black. In comparison with placebo, this combination showed a 43% reduction in mortality, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure among black patients.

Anticoagulants, Cardiovascular

Class Summary

Anticoagulants are used to prevent embolism from ventricular thrombus.

Warfarin (Coumadin)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Heparin

Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents reaccumulation of clot after spontaneous fibrinolysis.

Inotropic Agents

Class Summary

Cardiac glycosides are used to treat atrial fibrillation and systolic dysfunction in RCM. Digitalis and other positive inotropic agents generally are not indicated unless systolic pump function and contractility are impaired. Digitalis must be used with caution in patients with amyloid cardiomyopathy; such patients may be digoxin sensitive (arrhythmogenic) because of amyloid fibril binding of digoxin.

Digoxin (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.