Restrictive Infiltrative Cardiomyopathy

Restrictive infiltrative cardiomyopathy is a group of diseases in which deposition of abnormal material in the myocardium or interstitium produces stiff, non-dilated ventricles, biatrial enlargement, restrictive filling and heart failure with preserved or mildly reduced ejection fraction.

Amyloidosis is the commonest cause: AL (light chain), wild type transthyretin (ATTRwt) and variant transthyretin (ATTRv). Others are cardiac sarcoidosis, iron overload (haemochromatosis and transfusional), Fabry disease, and glycogen and lysosomal storage disorders such as Danon disease and Pompe disease.

ATTRwt affects mainly men over 60 years and is found in a substantial proportion of older patients with heart failure and increased wall thickness. The p.Val142Ile (V122I) TTR variant is carried by about 3 to 4% of African Americans, and its frequency in African populations is less well defined. AL amyloidosis arises from a clonal plasma cell disorder and is the form that kills fastest.

Endomyocardial fibrosis is a restrictive non-infiltrative disease that is relatively common in tropical Africa and belongs in the same differential.

Pathophysiology.

Deposits increase myocardial stiffness and wall thickness without increasing contractile mass. Diastolic filling is impaired and stroke volume falls, leaving the patient dependent on heart rate and preload.

AL light chains are directly cardiotoxic as well as forming fibrils, which explains rapid decline despite modest deposition. Troponin and NT-proBNP reflect this toxicity and define stage.

Conduction system infiltration causes atrioventricular block and bradyarrhythmia, and atrial infiltration causes atrial standstill and thrombus formation even in sinus rhythm.

Sarcoid granulomas cause patchy scar with ventricular tachycardia and heart block. Iron overload causes dilated or restrictive disease and arrhythmia through free iron toxicity.

Dyspnoea, exertional fatigue, oedema, ascites, early satiety, orthostatic hypotension, syncope, palpitations and intolerance of antihypertensive drugs. Right sided signs predominate: raised jugular venous pressure with a Kussmaul sign, hepatomegaly, ascites.

Extracardiac clues: bilateral carpal tunnel syndrome, lumbar spinal stenosis and biceps tendon rupture (ATTR), macroglossia, periorbital purpura, nephrotic syndrome and neuropathy (AL), bronze skin and diabetes (haemochromatosis), uveitis and skin lesions (sarcoidosis). Hypertension that has resolved on its own over time is a clue.

• ECG: low QRS voltage despite thick walls (not always present in ATTR), pseudo infarct Q waves, atrial fibrillation, conduction disease.
• Echocardiography: left ventricular wall thickness of 12 mm or more, granular sparkling, thick right ventricle and atrial septum, small pericardial effusion, restrictive filling (E/A over 2, deceleration time under 150 ms), and reduced longitudinal strain with relative apical sparing.
• Cardiac MRI: global subendocardial or transmural late gadolinium enhancement, abnormal myocardial nulling, raised native T1 and extracellular volume (over 0.40 in amyloid).
• NT-proBNP and high sensitivity troponin, which also stage disease.
• Amyloid workup: serum free light chains with serum and urine immunofixation together. If no monoclonal protein is found, bone avid tracer scintigraphy (technetium pyrophosphate, DPD or HMDP) with grade 2 or 3 uptake confirms ATTR without biopsy. If a monoclonal protein is present, tissue biopsy with Congo red staining and mass spectrometry typing is required. Do not give a diagnosis of ATTR on scintigraphy alone when a monoclonal protein is present. Test TTR genotype in all confirmed ATTR.
• Sarcoidosis: FDG-PET with perfusion imaging, MRI with patchy mid-wall enhancement, extracardiac biopsy.
• Iron overload: ferritin, transferrin saturation (over 45%), cardiac MRI T2* (under 20 ms indicates cardiac iron, under 10 ms severe), HFE genotype.
• Right heart catheterisation with simultaneous pressure traces where constriction is in question.

Differential diagnosis.

• Constrictive pericarditis (septal bounce, respirophasic septal shift, pericardial thickening, preserved annular e').
• Hypertrophic cardiomyopathy, hypertensive heart disease and aortic stenosis.
• Fabry disease and other storage disease.
• Endomyocardial fibrosis, Loeffler endocarditis, radiation heart disease and idiopathic restrictive cardiomyopathy.

Heart failure and arrhythmia (all causes).

• Loop diuretic: furosemide 20 to 80 mg orally daily, or torsemide 10 to 40 mg daily, or bumetanide 0.5 to 2 mg daily; titrate to dry weight and avoid over diuresis, which causes hypotension and renal failure; electrolytes and creatinine within 1 week of any change.
• Spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30; check at 1 week and 4 weeks).
• Avoid or use with great caution: beta blockers (fixed stroke volume, bradycardia), ACE inhibitors and ARBs (hypotension), non-dihydropyridine calcium channel blockers (verapamil and diltiazem contraindicated in amyloid), and digoxin (binds fibrils, toxicity at low levels).
• Orthostatic hypotension: midodrine 2.5 to 10 mg orally three times daily (last dose at least 4 hours before bed; maximum 40 mg daily; avoid supine hypertension).
• Atrial fibrillation: anticoagulate regardless of CHA2DS2-VASc score with apixaban 5 mg twice daily (2.5 mg twice daily if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over) or rivaroxaban 20 mg daily with food (15 mg if creatinine clearance 15 to 49 mL/min). Exclude atrial thrombus by transoesophageal echocardiography before cardioversion. Amiodarone 200 mg daily after loading for rhythm control.
• Pacemaker for symptomatic bradycardia or atrioventricular block. ICD for secondary prevention, and in cardiac sarcoidosis for ejection fraction 35% or under or sustained ventricular arrhythmia.

ATTR cardiomyopathy.

• Tafamidis meglumine 80 mg (four 20 mg capsules) orally once daily, or tafamidis free acid 61 mg once daily; long term; start early in functional class I to III; monitor NT-proBNP and echocardiography every 6 to 12 months; no renal or hepatic adjustment; avoid in pregnancy.
• Acoramidis 712 mg orally twice daily, long term; monitor creatinine; limited data when eGFR is under 15 mL/min/1.73 m2.
• Vutrisiran 25 mg subcutaneously every 3 months, long term; vitamin A at the daily reference intake while on therapy; licensing for cardiomyopathy varies by region.

AL amyloidosis (haematology led, urgent).

• Daratumumab 1800 mg (fixed dose subcutaneous formulation) weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, then every 4 weeks.
• With bortezomib 1.3 mg/m2 subcutaneously weekly, cyclophosphamide 300 mg/m2 (maximum 500 mg) weekly, and dexamethasone 20 to 40 mg weekly (20 mg or less with cardiac involvement or frailty), in 28-day cycles for up to 6 cycles.
• Monitor difference between involved and uninvolved free light chains, NT-proBNP and troponin each cycle; watch for fluid retention, orthostasis, neuropathy and infection.
• Selected patients with low cardiac stage may proceed to autologous stem cell transplantation.

Cardiac sarcoidosis.

• Prednisolone 0.5 mg/kg daily (usually 30 to 40 mg) for 4 weeks, then taper over 6 to 12 months to the lowest effective dose; repeat PET at 3 to 6 months; glucose, blood pressure, bone protection and co-trimoxazole 960 mg three times each week during prolonged high dose therapy.
• Methotrexate 10 to 20 mg orally once weekly with folic acid 5 mg weekly (not on the dose day) as a steroid sparing agent; full blood count, liver tests and creatinine every 2 weeks for 2 months, then every 3 months; reduce at eGFR 30 to 59 and avoid under 30.
• Infliximab 3 to 5 mg/kg intravenously at weeks 0, 2 and 6, then every 8 weeks, for refractory disease; exclude tuberculosis first and avoid in moderate to severe heart failure.
• ICD for ejection fraction of 35% or under, or with late gadolinium enhancement and inducible or documented ventricular tachycardia; pacing for atrioventricular block.

Iron overload.

• Hereditary haemochromatosis: venesection 450 to 500 mL weekly until ferritin is under 50 microgram/L, then maintenance every 2 to 4 months.
• Transfusional overload with cardiac involvement: deferoxamine 40 to 60 mg/kg daily subcutaneously over 8 to 12 hours for 5 to 7 days each week, or continuous intravenous 50 to 60 mg/kg daily for heart failure or arrhythmia; deferiprone 75 to 100 mg/kg daily orally in three divided doses (full blood count weekly, stop if neutrophils under 1.5 x 10^9/L); deferasirox film coated tablet 14 to 28 mg/kg once daily (creatinine and liver tests monthly, contraindicated at eGFR under 40 mL/min/1.73 m2). Combination of deferoxamine and deferiprone is used for severe cardiac iron.

Monitoring. Clinical review, NT-proBNP, troponin, and echocardiography every 3 to 6 months initially. Cardiac MRI or PET at intervals set by the cause. Device interrogation every 3 to 6 months.

Referral and escalation. Refer all suspected amyloidosis, sarcoidosis and storage disease to a specialist cardiomyopathy service.

Suspected AL amyloidosis with cardiac involvement (NT-proBNP over 332 ng/L with a monoclonal protein) needs haematology review within the same week, because untreated survival is measured in months.

Urgent cardiology review for syncope, high grade atrioventricular block, sustained ventricular tachycardia, atrial thrombus or rapidly progressive heart failure. Refer for transplantation assessment where advanced heart failure persists.

Special groups.

• Pregnancy: high risk; avoid tafamidis, acoramidis, methotrexate, deferasirox and deferiprone; specialist cardio obstetric care.
• Older adults: ATTRwt predominates; start diuretics and midodrine at the lowest dose.
• Kidney impairment: AL commonly involves the kidney; adjust diuretics, spironolactone, methotrexate and chelators by eGFR.
• Region specific: endomyocardial fibrosis and schistosomal disease should be considered in tropical Africa.