Restrictive Cardiomyopathy (RCM)

Monogenic (Mendelian): a minority: sarcomeric (TNNI3, TNNT2, MYH7), desmin, hereditary ATTR^[1]

Acquired: commonest, infiltrative: AL amyloidosis, haemochromatosis, sarcoidosis, endomyocardial fibrosis, radiation, hypereosinophilic disease^[1]

Complex (likely polygenic): limited; most non-genetic RCM has an identifiable infiltrative or secondary cause^[1]

Inheritance: Predominantly autosomal dominant; first-degree relatives have a 50% risk of inheriting the pathogenic variant. Penetrance variable (30–70% depending on gene), meaning not all carriers develop disease.^[1]

Familial proportion: Approximately 30% of idiopathic RCM cases have an identifiable pathogenic variant; family history of cardiomyopathy is present in a significant minority. After excluding infiltrative causes (amyloidosis, Fabry, Pompe), most remaining idiopathic RCM is sarcomere-gene related.^[1]

Genetic yield: ~30% in idiopathic RCM (after excluding infiltrative causes)

Genetic forms with penetrance:

• Sarcomeric (most common genetic cause): TNNI3 (~20-30%, penetrance 60-80%), TNNT2 (~10-15%, high penetrance), MYH7 (~5-10%), ACTC1 (<5%) - overlap with HCM genetics; can be restrictive phenotype
• Desmin-related: DES (~5%, penetrance 50-70%), CRYAB (~1-2%) - often with skeletal myopathy, cardiomyocyte protein aggregates
• Other: FLNC, BAG3, MYL2, MYL3 (rare) - variable phenotypes

Gene frequencies and penetrance figures derive largely from referral cohorts and vary with variant class and ascertainment; treat them as indicative rather than fixed.

Pathophysiology: Gene-dependent mechanisms → myocardial fibrosis, increased myocardial stiffness → impaired ventricular relaxation and filling → elevated filling pressures, biatrial dilation → restrictive physiology. Sarcomeric mutations: altered calcium sensitivity and diastolic dysfunction. Desmin mutations: protein aggregation and cardiomyocyte dysfunction.

Infiltrative/storage causes to exclude (NOT genetic RCM):

• Amyloidosis (most common cause of restrictive physiology in adults) - AL, ATTR, AA types
• Anderson-Fabry disease (GLA gene, X-linked) - lysosomal storage
• Hemochromatosis (HFE gene), glycogen storage diseases (Danon, Pompe)
• Endomyocardial fibrosis, hypereosinophilic syndrome

Rarest form of cardiomyopathy, accounts for approximately 2–5% of all cardiomyopathies.^[1]

Estimated incidence 2–5 cases per million population per year; exact prevalence uncertain due to rarity.^[1]

Can present in childhood or adulthood; childhood-onset typically more severe with higher transplant requirement.

High mortality without transplantation, median survival 2–5 years from diagnosis.

Mandatory work-up, RCM is a phenotype, so the underlying cause must be actively sought because it dictates treatment: echocardiography shows restrictive filling with preserved systolic function and biatrial enlargement; CMR (± invasive haemodynamics) helps exclude constrictive pericarditis. Screen systematically for a cause, cardiac amyloidosis (bone scintigraphy + serum free light chains/immunofixation), iron overload (ferritin, transferrin saturation, CMR T2*), Fabry disease (α-galactosidase A ± GLA), sarcoidosis (imaging/biopsy) and hypereosinophilic/endomyocardial disease (eosinophil count).^[1]

Diagnostic Criteria:

• Restrictive filling pattern with impaired ventricular filling
• Normal or near-normal systolic function
• Normal or reduced ventricular volumes
• Biatrial enlargement (often marked)
• Exclude constrictive pericarditis (key differential)

Clinical Features:

• Progressive dyspnea, exercise intolerance
• Right heart failure signs (ascites, edema, elevated JVP)
• Atrial arrhythmias common (especially atrial fibrillation)
• Thromboembolic risk elevated

Essential investigations:^[1]

• Echocardiography, biatrial enlargement, restrictive filling pattern, normal LV size and systolic function
• Cardiac MRI, exclude infiltration, characterise fibrosis pattern, exclude constrictive pericarditis
• Cardiac catheterisation, dip-and-plateau pattern, exclude constriction (discordant RV/LV pressure on respiration)
• Endomyocardial biopsy, if infiltrative cause suspected

Exclude secondary causes:^[1]

• Serum/urine protein electrophoresis, free light chains (amyloid)
• Alpha-galactosidase levels (Fabry, males), genetic testing (females)
• Iron studies, ferritin (haemochromatosis)

Medical management:

• Diuretics for congestion (cautious - preload dependent)
• Anticoagulation if AF or high thromboembolic risk
• Treat underlying cause if identified (e.g., iron chelation, enzyme replacement)

Advanced therapies:

• Heart transplantation - definitive treatment for idiopathic RCM
• Consider early referral given poor prognosis

• Progressive restrictive (diastolic) heart failure: often advanced at presentation, with limited disease-modifying options and an early transplant pathway^[1]
• Atrial fibrillation and atrial enlargement: with thromboembolism in the low-flow state
• Conduction disease and arrhythmia: aetiology-dependent (e.g. amyloid, sarcoid)
• Pulmonary hypertension: from chronically raised filling pressures

Poor prognostic features:

• NYHA class III-IV symptoms
• Severe biatrial enlargement
• Pulmonary hypertension
• Refractory atrial arrhythmias
• Progressive deterioration despite therapy

Based on ESC 2023 Cardiomyopathy guidelines^[1].

Advanced / complicated = progressive heart failure, significant atrial enlargement or AF, conduction disease, or a device in situ.

	Uncomplicated / Stable	Advanced / Complicated
Frequency	Every 6–12 months	Every 3–6 months
Clinical review	Symptoms, NYHA, fluid status	As above + device check
ECG	Annual 12-lead (conduction disease)	Each visit
Echocardiography	Every 6–12 months (diastolic function, atria)	6-monthly
Holter / ambulatory	Annual (AF, conduction, arrhythmia)	6-monthly
Bloods	Annual (renal, NT-proBNP) + aetiology-specific	Each visit
Family screening	If familial/genetic aetiology confirmed	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Always exclude constrictive pericarditis - different prognosis and treatment (surgical)^[1]
• Screen for infiltrative causes - treatment available for some (Fabry, amyloid, hemochromatosis)
• Avoid negative inotropes - can worsen filling
• Anticoagulate if AF - high stroke risk^[1]
• Early transplant referral - median survival 2-5 years without transplant^[1]