Restrictive cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare type of cardiomyopathy characterized by marked diastolic dysfunction, normal (or near-normal) systolic function, and normal ventricular volumes. RCM occurs as a result of myocardium distortion due to proliferation of abnormal tissue or the deposition of abnormal compounds. Many diseases, both primary and acquired, cause RCM. Regardless of the etiology, RCM manifests with congestive heart failure (CHF), often with pronounced right-sided symptoms. Echocardiography is the first-line diagnostic test and is often followed by advanced imaging, including cardiac MRI. Initial management focuses on the treatment of CHF followed by identification and treatment of the underlying cause. In severe or refractory cases, heart transplantation may be necessary.

See also “Cardiomyopathy” for other cardiomyopathy types.

• RCM is the least common form of cardiomyopathy (2–5% of all cardiomyopathies). ^[1][2][3]
• Heart failure occurs in over 80% of patients with RCM. ^[4]

Epidemiological data refers to the US, unless otherwise specified.

RCM can be classified into four categories based on the underlying pathology; there is some overlap between the categories.

“PLEASe Help!”: Causes of restrictive cardiomyopathy include Postradiation/Postsurgery fibrosis, Löffler endocarditis, Endocardial fibroelastosis, Amyloidosis, Sarcoidosis, and Hemochromatosis.

Infiltrative cardiomyopathy ^[1][2][5]

• Amyloidosis: caused by an accumulation of abnormal proteins in the myocardium
• Sarcoidosis: secondary to deposition of granulomas in the myocardium
• Primary hyperoxaluria: secondary to oxalate deposits in the myocardium

Amyloidosis is the most common cause of restrictive cardiomyopathy in high-income countries. ^[6]

Storage disorders ^[1][2]

• Hereditary hemochromatosis; : increased absorption of iron from GI tract (more commonly causes dilated cardiomyopathy)
• Iron overload: increased systemic iron from repeated blood transfusions
• Congenital enzyme abnormalities
  • Lysosome storage diseases
    • Anderson-Fabry disease
    • Mucopolysaccharidosis type I
    • Gaucher disease
  • Glycogen storage disorders

Some storage disorders, e.g., Gaucher disease, can also cause infiltrative cardiomyopathy. ^[1]

Endomyocardial disorders ^[5]

• Endomyocardial fibrosis: caused by autoantibodies against myocardial proteins
  • Most common form of RCM worldwide; primarily found in sub-Saharan Africa ^[5]
  • Mainly affects children and young adults
  • Possible initiating factors ^[7]
    • Exposure to the element cerium
    • Chronic eosinophilia
    • Viral and parasitic infections
    • Magnesium deficiency
• Hypereosinophilia (Löffler endocarditis): eosinophilic infiltration of the myocardium ^[5]
• Endocardial fibroelastosis: a diffuse thickening of the left ventricle endocardium from the proliferation of fibrous and elastic tissue
  • Most commonly occurs in the first two years of life
  • Can be primary (with unknown etiology) or secondary (associated with congenital heart conditions, e.g., aortic stenosis, aortic atresia, coarctation of the aorta, patent ductus arteriosus) ^[8]
• Malignancy: carcinoid heart disease or metastatic tumor
• Iatrogenic
  • Radiotherapy to the chest: causes radiation-induced fibrosis ^[5]
  • Chemotherapy ^[9]
    • Multiple chemotherapy agents have been associated with cardiac damage.
    • Anthracyclines (e.g. doxorubicin) are most commonly associated with RCM ^[9]
  • Cardiac surgery: postoperative scarring

Noninfiltrative restrictive cardiomyopathy

• Idiopathic RCM: may be sporadic or familial
• Systemic sclerosis (scleroderma): Microvascular ischemia creates reperfusion injury with secondary fibrosis.

• Infiltration (e.g., abnormal proteins, glycogen, eosinophils, granulomas, iron) or proliferation of connective or fibrotic tissue → ↓ elasticity of myocardium → ↓ ventricular compliance (severe diastolic dysfunction) → ↓ ventricular filling in diastole → ↑ left and right-sided filling pressures → ↑ atrial size → ↑ pulmonary and systemic venous congestion → late-stage ↓ in LV systolic function → hypotension ^[2][4]

Symptoms ^[1][4][5]

• Dyspnea on exertion (most common symptom)
• Leg swelling
• Palpitations
• Syncope
• Sudden cardiac death

Physical examination ^[1]

• Features of right-sided heart failure
  • Jugular venous distention
  • Peripheral edema
  • Hepatomegaly and ascites
  • Kussmaul sign
• Auscultatory findings
  • Prominent S4 gallop
  • Possible murmur of mitral regurgitation and/or tricuspid regurgitation
  • Possible dysrhythmia: Atrial fibrillation is common.
  • Signs of heart failure (e.g., crackles or dullness secondary to pleural effusion) ^[4]
• Features of the underlying disease, e.g.: ^[2]
  • Amyloidosis: carpal tunnel syndrome , large tongue
  • Hemochromatosis: bronze skin
  • Sarcoidosis: erythema nodosum

The symptoms and signs of heart failure are the most common clinical features of RCM. ^[1]

Approach

• Order initial studies (basic laboratory studies, ECG, x-ray chest, and echocardiogram) to confirm the diagnosis of RCM.
• Screen patients for associated complications.
• If the underlying etiology remains unclear, consider advanced studies (e.g., cardiac MRI or endomyocardial biopsy).

Initial studies ^[1]

• ECG
  • Low voltage QRS complexes: classic but insensitive finding in infiltrative disease (e.g., amyloidosis) ^[10]
  • Conduction disorders (AV block, LBBB, RBBB) and atrial fibrillation
  • Large P wave: consistent with biatrial enlargement
  • May also be normal
• X-ray chest (PA and lateral)
  • X-ray findings of left atrial enlargement
  • X-ray features of pulmonary congestion
  • Evidence of underlying disease (e.g., hilar adenopathy in sarcoidosis)
• Laboratory studies
  • CBC with differential: Eosinophil count > 1.5 × 10⁹/L is consistent with hypereosinophilic heart disease. ^[4]
  • Comprehensive metabolic panel: Nephropathy and hepatopathy are common in amyloidosis.
  • Troponin and NT-proBNP: to establish the extent of heart failure and establish a baseline for treatment monitoring ^[2][4][11]
• Transthoracic echocardiography ^[1][2][12]
  • TTE is the preferred initial test. ^[1]
  • Characteristic findings of RCM ^[1]
    • Severe diastolic dysfunction (high early diastolic filling velocities and low late diastolic filling velocities) ^[1][13]
    • Normal right and left ventricular volumes
    • Preserved ejection fraction (may be reduced in late-stage disease)
    • Typically normal ventricular wall thickness (may be increased in amyloidosis, sarcoidosis, and lysosomal storage disease)
    • Left atrial or biatrial enlargement
  • Findings of underlying disease, e.g.:
    • In amyloidosis: reflective myocardium (speckling) ^[14]
    • In sarcoidosis: regional wall motion abnormalities that do not match coronary blood flow distribution ^[2][5]

Echocardiography is the preferred first-line test for RCM because of its high sensitivity and specificity for this disease. ^[1][15]

Additional diagnostic studies

Assessment for associated disease states

• Ambulatory ECG monitoring (e.g., holter monitor): Indicated for patients with an abnormal ECG, symptomatic patients, and those with a history of sarcoidosis. ^[5][16]
• Cardiac catheterization: used to assess for ischemic heart disease or constrictive pericarditis ^[1]
  • Indications
    • Prominent chest pain
    • Regional wall abnormalities on echocardiography ^[12]
    • Diagnostic uncertainty between RCM and constrictive pericarditis
  • Findings
    • May show concurrent ischemic heart disease
    • High right atrial pressure
    • Abnormal ventricular pressure: diastolic pressure is usually slightly higher in the left ventricle compared to the right ^[1][2][12]
    • Early decrease in ventricular diastolic pressure followed by a rapid rise
• Evaluation of secondary end-organ damage: Consider if found during initial studies, e.g., doppler ultrasound for cardiac cirrhosis, urine analysis and renal ultrasound in renal impairment

Screening studies for the suspected underlying cause

• Hemochromatosis: elevated ferritin and transferrin saturation ^[2]
• Sarcoidosis
  • Angiotensin-converting enzyme levels may be elevated. ^[5]
  • FDG-PET scan: shows increased uptake in early disease and reduced uptake in advanced disease ^[2]
• Amyloidosis: serum free light chains and serum and urine electrophoresis ^[1]
• Lysosomal storage diseases: enzyme and genetic testing ^[1]

Advanced studies for RCM

• Cardiac MRI (CMR) ^[1][17][18]
  • Can establish a definitive diagnosis
  • Can help guide chronic management of RCM by quantitating myocardial disease
• Endomyocardial biopsy (EMB) ^[2]
  • EMB provides tissue for a definitive histological diagnosis (e.g., fibrosis, amyloidosis, iron deposition, granulomas, eosinophilic infiltrates in Löffler endocarditis).
  • Guided biopsy with electroanatomic mapping or CMR or PET is recommended. ^[2][19]
  • The use of EMB has decreased as cardiac MRI technology has improved. ^[1]

Approach

• Start symptomatic treatment of heart failure, including education on lifestyle modification.
• Screen for and treat associated diseases (e.g., arrhythmias, thromboembolism).
• Treat the underlying cause, when possible.
• Patients with severe or refractory symptoms:
  • Consider heart transplant.
  • If the patient is not a suitable candidate for transplant, refer early to palliative care, as symptoms can be challenging to manage.

RCM is the most challenging form of cardiomyopathy to manage because treatment options are limited and morbidity and mortality are high. ^[20]

Symptom management

Treatment of congestive heart failure ^[2][21]

• The initial management of RCM is the treatment of congestive heart failure symptoms.
• The unique physiology of RCM and its underlying disease processes may necessitate modifications to the standard treatment of CHF.

Start at very low doses when prescribing beta blockers, CCBs, ACEIs, or ARBs for patients with RCM; life-threatening hypotension may occur.

Management of associated arrhythmias ^[1][5]

• Treat atrial fibrillation.
  • Early cardioversion: Tachycardia can precipitate acute heart failure and hypotension. ^[4]
  • Medical therapy: Consider beta blockers (e.g., sotalol) or amiodarone (see “Rate control for atrial fibrillation” for further information including dosages). ^[22]
• Consider the following, depending on ECG and Holter monitor findings:
  • Pacemaker placement: Patients with RCM frequently develop high-grade symptomatic AV blocks. ^[1]
  • AICD: Patients with RCM are at high risk for sudden cardiac death from ventricular dysrhythmias. ^[2]

Digoxin should be avoided in patients with RCM because it can worsen symptoms of several of the underlying etiologies (e.g., amyloidosis, sarcoidosis). ^[2]

Anticoagulation

• Anticoagulation is indicated for patients with a known thrombus, a high risk of thrombogenesis, or atrial fibrillation. ^[1][2][5]
• See “Anticoagulation in atrial fibrillation” for further information on anticoagulation, including dosages.

Disease-specific treatment

Definitive treatment depends on the specific etiology (see “Etiology” section).

Management of severe or refractory RCM

• In patients who are unresponsive to medical therapy, consider mechanical circulatory support (e.g., LVAD), either as a destination therapy or a bridge to transplant. ^[25]
• Consider referral for a heart transplant (or heart and liver transplant in amyloidosis). ^[4]
• For patients who are not candidates for a heart transplant, refer to palliative care.

• RCM and constrictive pericarditis have similar clinical presentations. Distinguishing between the two diseases is critical to determining the appropriate management.
• See also “Cardiomyopathy” article.

Echocardiography is the initial test of choice to distinguish RCM from constrictive pericarditis. ^[1]

The differential diagnoses listed here are not exhaustive.

• The prognosis for RCM is generally poor. ^[4]
• Adult patients: The overall 5-year survival rate is approximately 50%.
• Pediatric patients: over 50% experience sudden cardiac death shortly after diagnosis