Restrictive Cardiomyopathy (RCM)

Monogenic (Mendelian): sarcomeric (TNNI3, TNNT2, MYH7) and protein-aggregate genes (DES, FLNC, BAG3)^[1]; about half to 60% of idiopathic RCM in small series^[8][9]

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: RCM is a phenotype with both genetic and non-genetic causes (e.g. iron overload, sarcoidosis, endomyocardial fibrosis, radiation and other infiltrative or acquired processes), it is not a single genetic entity. A 50% risk to each child of a carrier (with risk to parents and siblings set by the pedigree and cascade testing) applies only once an autosomal-dominant pathogenic variant has actually been established in that family; where no genetic cause is identified, or the underlying cause is non-genetic or has a different inheritance pattern, this figure does not apply. Where an autosomal-dominant sarcomeric or related gene variant is found, penetrance is incomplete and variable, so not all carriers develop disease.^[1]

Familial proportion: family history of cardiomyopathy is present in a significant minority, and RCM can occur in families with HCM or DCM.^[1]

Genetic yield: about half to 60% in idiopathic RCM once infiltrative and storage causes are excluded: 19 of 32 adults with end-stage disease^[9] and 13 of 24 in a mixed adult and paediatric series^[8]

Genetic forms (counts from 32 unrelated adults with end-stage idiopathic RCM^[9]):

• Sarcomeric (9 of 32): MYH7 (4), MYBPC3 (2), TNNI3, TNNT2 and TPM1 (1 each); ACTC1 rarely. TNNI3 is generally regarded as the commonest RCM gene^[1]. Overlap with HCM genetics: affected relatives more often had HCM (16, 7 with restrictive filling) than pure RCM (3); penetrance is incomplete^[9]
• Desmin-related: DES (3 of 32^[9]; cardiac disease in 64% of carrier relatives across published DES families^[3]), CRYAB (rare). The classic phenotype is RCM with AV block, often needing pacing, with skeletal myofibrillar myopathy in most but not all; onset is typically in the 30s and CK is normal in a third; endomyocardial biopsy shows desmin-positive granulofilamentous aggregates. Restrictive physiology accounts for ~14% of DES cardiomyopathy overall^[3][4][5]
• Other: FLNC (3 of 32), LMNA (2), TCAP and LAMP2 (1 each)^[9]; BAG3, MYL2, MYL3 rarely - 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^[4][5].

Infiltrative/storage and other specific causes of restrictive physiology (several are themselves inherited, e.g. Fabry, Danon, hereditary ATTR, haemochromatosis):

• 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.

Prognosis varies substantially by underlying cause, severity, pulmonary pressures and whether disease-specific therapy exists. In idiopathic and genetic RCM, mortality without transplantation is high (older series quote a median survival of 2–5 years from diagnosis); treatable infiltrative causes such as ATTR amyloidosis, Fabry disease and haemochromatosis alter that trajectory.

Recommended baseline aetiology work-up (unless inappropriate given frailty or goals of care), RCM is a phenotype, so the underlying cause should 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 left and/or right ventricular physiology^[1]
• Normal or reduced diastolic volumes (of one or both ventricles) and normal or reduced systolic volumes^[1]
• Normal ventricular wall thickness^[1]
• Exclude constrictive pericarditis (key differential)

Biatrial enlargement is the usual presentation. Systolic function is often preserved, though rarely completely normal^[1].

Clinical Features:

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

ECG: low voltage (amyloidosis), AV block (DES, amyloidosis, sarcoidosis), AF, and P-wave abnormalities from atrial enlargement.^[1]

Echocardiography:^[1]

• Biatrial enlargement, non-dilated ventricles, preserved or near-preserved LVEF
• Restrictive filling: high E/A ratio, short deceleration time, reduced septal and lateral mitral annular e′, raised E/e′
• Estimated pulmonary artery pressure, RV function and IVC
• Wall thickness, valve and septal thickening, and pericardial effusion as clues to infiltration

Constriction versus restriction on echocardiography:^[6]

• Favouring constriction: respiration-related ventricular septal shift; preserved or increased medial e′ (≥9 cm/s), often exceeding lateral e′ ("annulus reversus"); expiratory diastolic flow reversal in the hepatic veins
• Favouring restriction: low medial and lateral e′, no septal shift, and hepatic vein flow reversal in inspiration

Cardiac MRI:^[1]

• Constriction: pericardial thickening and enhancement, with septal flattening or inversion in early inspiration on real-time free-breathing imaging
• Amyloidosis: diffuse subendocardial or transmural LGE, markedly raised native T1 and ECV
• Iron overload: myocardial T2* below 20 ms indicates iron loading and below 10 ms severe loading, which predicts heart failure^[7]
• Sarcoidosis: patchy mid-wall or subepicardial LGE, often involving the basal septum
• Endomyocardial fibrosis: apical obliteration with subendocardial LGE and overlying thrombus
• Fabry disease: low native T1

Cardiac catheterisation: simultaneous LV and RV pressure recording; both conditions show a dip-and-plateau pattern, but discordant respiratory variation in LV and RV systolic pressure favours constriction, while concordance favours restriction; also measures pulmonary vascular resistance before transplant listing.^[1]

Endomyocardial biopsy: if an infiltrative or storage cause is suspected and not confirmed non-invasively.^[1]

Exclude secondary causes:^[1]

• Serum free light chains plus serum AND urine immunofixation (amyloid; electrophoresis alone is not sufficient to exclude AL)
• Alpha-galactosidase levels (Fabry, males), genetic testing (females)
• Iron studies, ferritin (haemochromatosis)
• Eosinophil count (hypereosinophilic syndrome, endomyocardial fibrosis), CK (desminopathy)

Genetic testing: cardiomyopathy gene panel once infiltrative and storage causes have been excluded.^[1]

1. General measures:

• Active pursuit and treatment of the underlying cause where identifiable (e.g. venesection for HFE haemochromatosis, with chelation reserved for secondary iron overload or when venesection is not feasible, enzyme replacement for Fabry, disease-specific therapy for amyloidosis), since this dictates prognosis and treatment options
• Genetic counselling and family cascade testing where a genetic cause is confirmed, see the Genetic Testing page

2. Medical therapy:

• Diuretics for congestion (cautious - preload dependent)
• Anticoagulation if AF or high thromboembolic risk
• Avoid negative inotropes, which can worsen filling

3. Device therapy:

• Pacing or ICD may be indicated for conduction disease or arrhythmia, dependent on the underlying aetiology (see Complications)^[2]

4. Advanced heart failure and/or transplant referral:

• Heart transplantation is the definitive treatment for progressive idiopathic or genetic RCM without a treatable specific cause
• Consider early advanced-heart-failure/transplant referral given the generally poor prognosis of progressive RCM

• 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, particularly a rising pulmonary vascular resistance, which can preclude heart transplantation
• Refractory atrial arrhythmias
• Progressive deterioration despite therapy

Children: childhood-onset RCM carries a high risk of sudden death and pulmonary hypertension, and early referral for transplant assessment is usual.^[1]

Cause-specific risk tools: where a specific cause is found, its own staging applies, for example amyloid staging systems or myocardial T2* in iron overload.^[1][7]

Serial assessment: repeat echocardiography and, before listing, invasive haemodynamics to track pulmonary pressures and vascular resistance.^[1]

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]
• Consider early advanced-HF/transplant referral in progressive or idiopathic/genetic RCM; prognosis varies substantially by cause and by whether disease-specific therapy exists^[1]