Restrictive cardiomyopathy (RCM) is a group of mixed cardiomyopathies characterized by restrictive ventricular filling dysfunction. It has a poor prognosis, with a 5-year survival rate of only about 30%.
Etiology and Classification
The etiology of RCM is highly complex and includes genetic, sporadic, and systemic diseases.
RCM can be classified into myocardial and endomyocardial types.
Myocardial type can be further divided into:
- Infiltrative/storage diseases: Abnormal accumulation of intracellular or interstitial substances, including amyloidosis, sarcoidosis, Gaucher disease, glycogen storage diseases, Fabry disease, Danon disease, and hemochromatosis
- Non-infiltrative forms: Such as familial RCM, which may overlap phenotypically with mild dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM)
Endomyocardial type can be further divided into:
- Obstructive forms: Classic RCM primarily involving the endocardium, seen in endomyocardial fibrosis, hypereosinophilic syndrome, radiation injury, and anthracycline toxicity
- Non-obstructive forms: Often caused by tumorlike or malignant infiltration
Cardiac amyloidosis (CA) is the most common infiltrative form of RCM. More than 30 pathogenic proteins have been identified, with two major subtypes affecting the light-chain cardiac amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA can be further classified into mutated (ATTRm-CA) and wild-type (ATTRwt-CA) subtypes based on the presence or absence of transthyretin (TTR) gene mutations.
Pathology and Pathophysiology
The etiology and pathological changes of RCM are diverse. The hallmark pathological changes of classic RCM include endocardial fibrosis, calcification, mural thrombi, subendocardial myocardial degeneration, necrosis, and scar formation. Each type of RCM has its own pathological features. For instance, in CA, amyloid deposits stain with Congo red and exhibit apple-green birefringence under polarized light microscopy. These changes lead to stiff ventricular walls, severely restricted ventricular filling, and congestion of both systemic and pulmonary circulations.
Clinical Presentation
Symptoms
In the early stages, symptoms are primarily related to heart failure with preserved ejection fraction (HFpEF), such as reduced exercise tolerance and dyspnea. As the disease progresses, symptoms such as anorexia, abdominal distension, and edema may develop. Prominent right-sided heart failure symptoms are characteristic of classic RCM.
Signs
A fourth heart sound (S4 gallop) may be heard. Low blood pressure often indicates a poor prognosis. Signs of right-sided heart failure, such as jugular vein distension, hepatomegaly, ascites, and lower limb edema, are also prominent in this condition.
Auxiliary Examinations
Laboratory Tests
Laboratory abnormalities related to the underlying disease may be present. For suspected CA, serum free light chain and serum/urine immunofixation electrophoresis should be performed to identify evidence of plasma cell disorders. Biomarkers such as brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin are indicators of disease severity in CA and are associated with prognosis.
Electrocardiography (ECG)
Findings may include low QRS voltage, abnormal Q waves, ST-T changes, and various arrhythmias. A mismatch between diffuse low voltage on ECG and imaging findings of myocardial hypertrophy is a distinctive feature of CA.
Chest X-ray/CT
Marked atrial enlargement may be seen, and calcification of the endocardium may occasionally be observed. CT is particularly useful for identifying endocardial or pericardial calcifications.
Transthoracic Echocardiography (TTE)
TTE combined with Doppler imaging is an important diagnostic tool. Typical findings include severely restricted ventricular filling, significantly impaired diastolic function, and marked biatrial enlargement. Diffuse myocardial thickening with a speckled ground-glass appearance suggests CA. Strain imaging (showing reduced longitudinal strain peak values) can detect early systolic dysfunction. A characteristic apical sparing pattern, where longitudinal strain is reduced in the basal and mid-left ventricular segments but preserved at the apex, is a key feature that helps differentiate CA from other causes of left ventricular hypertrophy.
Cardiac Magnetic Resonance Imaging (CMR)
Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) can identify the presence and nature of endocardial, myocardial, and pericardial lesions, such as inflammation, fibrosis, and scarring. In cardiac amyloidosis (CA), CMR often reveals an amyloid LGE pattern. Subendocardial LGE is commonly observed in AL-CA, while transmural LGE is more typical of ATTR-CA.
Cardiac Nuclear Imaging
99mTc-pyrophosphate (99mTc-PYP) scintigraphy or single-photon emission computed tomography (SPECT) is valuable for diagnosing ATTR-CA. Studies have shown that in patients with suspected CA, if 99mTc-PYP imaging demonstrates myocardial uptake graded as level 2 (equal to bone uptake) or level 3 (greater than bone uptake) and serum/urine monoclonal immunoglobulins are negative, ATTR-CA can be diagnosed. This technique can detect myocardial involvement even before abnormalities are evident on echocardiography or CMR.
Cardiac Catheterization
The diastolic ventricular pressure curve typically shows an early dip followed by a plateau, resembling the pattern seen in constrictive pericarditis. However, RCM has distinct features, including:
- Significantly elevated pulmonary artery systolic pressure (often >50 mmHg)
- Relatively lower right ventricular diastolic pressure compared to constrictive pericarditis, where it often exceeds 1/3 of the systolic pressure
- A difference >5 mmHg between the end-diastolic pressures of the left and right ventricles
Endomyocardial Biopsy (EMB)
EMB is the gold standard for determining the etiology of RCM. It helps distinguish infiltrative, storage, deposition cardiomyopathies, and endomyocardial diseases. Congo red staining is the most common pathological method for detecting amyloidosis. Immunohistochemistry, laser microdissection, and/or mass spectrometry can be used to confirm the precursor protein type of amyloid fibrils.
Genetic Testing
Familial RCM is often inherited in an autosomal dominant manner. Pathogenic mutations are most found in genes encoding cardiac troponin I (TNNI3) and β-myosin heavy chain 7 (MYH7). Genetic testing is recommended for ATTR-CA patients to differentiate between ATTRm-CA and ATTRwt-CA, aiding in prognosis, treatment selection, family screening, and genetic counseling.
Diagnosis
RCM should be considered in patients presenting with predominant right-sided heart failure and arrhythmias, along with marked atrial enlargement, after secondary causes have been excluded. Restrictive ventricular filling dysfunction on transthoracic echocardiography is the primary diagnostic criterion.
Differential Diagnosis
First, etiological differentiation among various types of RCM is essential. This process is complex and requires reference to relevant literature. Clinically, etiological differentiation can be guided by imaging features on TTE and CMR, with EMB performed when necessary. Second, RCM must be differentiated from constrictive pericarditis. Although their clinical and hemodynamic presentations are similar, imaging studies and cardiac catheterization pressure characteristics can help distinguish between the two conditions.
Treatment
Most types of RCM lack specific therapies, and treatment is primarily symptomatic. For some RCMs with identified causes, targeted therapies may be applied.
Hypereosinophilic Syndrome
Glucocorticoids and cytotoxic drugs can effectively reduce eosinophil levels and prevent endomyocardial fibrosis.
AL-CA
The first-line treatment is autologous hematopoietic stem cell transplantation. For patients ineligible for transplantation, anti-plasma cell chemotherapy and anti-amyloid therapies may be used, though outcomes are often unsatisfactory.
ATTR-CA
Current drug treatments focus on inhibiting TTR synthesis and stabilizing TTR.
Small interfering RNA (siRNA) and antisense oligonucleotides can suppress TTR gene expression and reduce TTR protein production.
Tafamidis, a TTR stabilizer, is the first-line treatment and has been shown to reduce all-cause mortality by 30%.
Drugs targeting the clearance of TTR amyloid fibrils are also under development.
For RCM caused by hereditary enzyme deficiencies, such as Fabry disease, enzyme replacement therapy (ERT) or gene therapy is the preferred treatment. Specific therapies for Fabry disease include ERT (e.g., agalsidase alfa and agalsidase beta), molecular chaperone therapy, and gene therapy.
Diuretics and vasodilators can reduce cardiac preload, alleviate congestion in the pulmonary and systemic circulation, and relieve symptoms. However, they should be started at low doses to avoid reducing ventricular filling and impairing cardiac output. Non-dihydropyridine calcium channel blockers may improve ventricular compliance. Beta-blockers can slow the heart rate, prolong ventricular filling time, reduce myocardial oxygen consumption, and improve diastolic function. For patients with rapid atrial fibrillation (AF) or heart failure, low-dose digitalis may be used. Anticoagulation is indicated for patients with mural thrombi or thromboembolic events.
** Endomyocardial Fibrosis**
Severe cases may require endocardial decortication.
Mural Thrombi
Thrombectomy may be performed.
Device Implantation
Cardiac pacemakers may be implanted when indicated.
Heart Transplantation
This may be considered for eligible patients with end-stage disease.