Key Facts

Restrictive cardiomyopathy (RCM) is characterised by impaired ventricular filling due to increased stiffness of the myocardium, with normal or near-normal systolic function and wall thickness. It is the least common form of cardiomyopathy.

Epidemiology

• Rarest form of cardiomyopathy (<5% of all cardiomyopathies)
• Amyloidosis is the most common infiltrative cause
• ATTR amyloidosis: increasingly recognised, especially in elderly (wild-type ATTR in ~13% of elderly patients with HFpEF)
• Endomyocardial fibrosis: most common cause in tropical countries

Aetiology

Infiltrative:

• Amyloidosis: AL (light-chain), ATTR (transthyretin — hereditary or wild-type)
• Sarcoidosis
• Haemochromatosis
• Glycogen/lysosomal storage diseases (Fabry, Gaucher, Danon)

Non-infiltrative:

• Idiopathic RCM
• Scleroderma
• Radiation-induced
• Diabetic cardiomyopathy

Endomyocardial:

• Endomyocardial fibrosis (tropical)
• Loeffler endocarditis (hypereosinophilic syndrome)
• Carcinoid heart disease

Pathophysiology

• Infiltration or fibrosis of the myocardium → increased myocardial stiffness
• Impaired diastolic relaxation and filling → elevated filling pressures → systemic and pulmonary congestion
• Systolic function preserved initially but may decline in late stages
• Biatrial dilatation from chronic elevated filling pressures → AF
• Unlike constrictive pericarditis, the myocardium itself is diseased (not the pericardium)

Typical Presentation

• Heart failure with preserved (or mildly reduced) ejection fraction
• Right heart failure predominates: peripheral oedema, ascites, hepatomegaly
• Dyspnoea, exercise intolerance
• AF and atrial arrhythmias common

Specific Features by Cause

• Amyloidosis: macroglossia, periorbital bruising, neuropathy, nephrotic syndrome, carpal tunnel syndrome (bilateral — especially ATTR)
• Sarcoidosis: conduction disease (heart block), ventricular arrhythmias, pulmonary involvement
• Haemochromatosis: skin pigmentation, diabetes, liver disease, arthropathy

Red Flags

• Disproportionate right heart failure with normal LV size
• LVH with low-voltage ECG (amyloidosis — voltage-mass mismatch)
• Bilateral carpal tunnel syndrome in elderly man (ATTR amyloidosis)
• Heart failure not responding to standard therapy

Bedside

• ECG: low-voltage QRS (amyloidosis — despite increased wall thickness), AF, conduction abnormalities, pseudo-infarct pattern

Bloods

• BNP/NT-proBNP: markedly elevated (helps differentiate from CP)
• Troponin: may be chronically elevated (ongoing myocyte damage in amyloidosis)
• Serum free light chains, serum protein electrophoresis: AL amyloidosis
• Iron studies, ferritin, transferrin saturation: haemochromatosis
• ACE level, calcium: sarcoidosis
• Eosinophil count: hypereosinophilic syndrome/Loeffler
• Alpha-galactosidase A: Fabry disease

Imaging

• Echocardiography: normal LV cavity, increased wall thickness (if infiltrative), biatrial dilatation, restrictive filling (E/A >2, short DT), sparkling/granular myocardium (amyloidosis)
• Cardiac MRI: LGE pattern (diffuse subendocardial in amyloidosis, patchy in sarcoidosis), elevated T1 mapping, raised ECV
• DPD/PYP nuclear scintigraphy: highly sensitive and specific for ATTR amyloidosis (Perugini grade ≥2)
• CT chest: pericardial calcification (excludes CP)

Special Tests

• Endomyocardial biopsy: definitive for infiltrative causes (Congo red staining + apple-green birefringence for amyloid)
• Fat pad/rectal biopsy: less invasive for amyloid detection
• Genetic testing: TTR gene for hereditary ATTR amyloidosis; Fabry disease genes
• Cardiac catheterisation: restrictive filling haemodynamics; differentiation from CP
  • Equalised diastolic pressures (but concordant ventricular pressure changes with respiration — discordant in CP)

Non-pharmacological

• Sodium and fluid restriction
• Treat underlying cause
• Exercise as tolerated

Pharmacological

Supportive HF management:

• Diuretics: for congestion; use cautiously (patients are preload-dependent)
• Rate control: for AF (beta-blockers, amiodarone — avoid digoxin in amyloidosis as it binds amyloid fibrils)
• Anticoagulation: for AF (warfarin or DOACs)
• ACEi/ARBs: use cautiously; may cause hypotension (especially in amyloidosis)

Cause-specific:

• AL amyloidosis: chemotherapy (bortezomib, cyclophosphamide, dexamethasone — VCD), autologous stem cell transplant
• ATTR amyloidosis: tafamidis 80mg OD (TTR stabiliser; ATTR-ACT trial — reduced mortality and hospitalisation; NICE TA696)
  • Patisiran (RNAi) and inotersen (antisense oligonucleotide) for hereditary ATTR with neuropathy
• Haemochromatosis: venesection, iron chelation
• Sarcoidosis: corticosteroids ± steroid-sparing agents
• Fabry disease: enzyme replacement therapy (agalsidase alfa/beta) or chaperone therapy (migalastat)

Surgical/Interventional

• Heart transplantation: for end-stage RCM (careful evaluation for systemic disease)
• Pacemaker: for conduction disease (especially sarcoidosis, amyloidosis)
• ICD: for ventricular arrhythmias (sarcoidosis, advanced RCM)

Referral Criteria

• All suspected RCM: specialist cardiology/cardiomyopathy centre referral
• Amyloidosis: National Amyloidosis Centre (NAC) at Royal Free Hospital, London
• Sarcoidosis: joint cardiac-respiratory clinic
• Genetic evaluation for hereditary causes

• AL amyloidosis: median survival ~6-12 months from cardiac involvement without treatment; improving with modern chemotherapy (~3-5 years)
• Wild-type ATTR: median survival ~3-5 years from diagnosis; improved with tafamidis
• Hereditary ATTR: variable; ~5-15 years depending on mutation
• Cardiac sarcoidosis: variable; improved with immunosuppression; conduction disease and VT are poor prognostic markers
• Haemochromatosis: good prognosis if treated early (cardiac function can improve with iron removal)
• Idiopathic RCM: poor prognosis; ~50% 10-year survival
• Heart transplant: improves survival in selected patients

Restrictive vs Constrictive: Key Differentiators

Types of Cardiac Amyloidosis