Infiltrative Cardiomyopathy: Amyloid, Sarcoid & Iron

Clinical meaning

Infiltrative cardiomyopathies are a group of myocardial diseases characterized by the abnormal deposition of substances within the cardiac interstitium, leading to progressive ventricular stiffness, diastolic dysfunction, and ultimately heart failure with preserved or mildly reduced ejection fraction (HFpEF). The three major subtypes — cardiac amyloidosis, cardiac sarcoidosis, and hemochromatosis (iron overload cardiomyopathy) — share a common hemodynamic phenotype of restrictive physiology but differ fundamentally in their pathogenesis and treatment.

Cardiac Amyloidosis: Amyloidosis results from the extracellular deposition of insoluble fibrillar proteins (amyloid) in a cross-beta-pleated sheet configuration that is resistant to proteolytic degradation. Two types predominantly affect the heart. AL (light-chain) amyloidosis occurs when clonal plasma cells in the bone marrow produce immunoglobulin light chains that misfold and deposit as amyloid fibrils in multiple organs including the heart, kidneys, liver, and peripheral nerves. It is associated with multiple myeloma and other plasma cell dyscrasias. ATTR (transthyretin) amyloidosis involves the deposition of transthyretin protein, normally produced by the liver for thyroid hormone and retinol transport. Wild-type ATTR (wtATTR, formerly senile cardiac amyloidosis) is increasingly recognized in elderly patients (predominantly men >65) and may account for up to 13% of HFpEF in the elderly. Hereditary ATTR (hATTR) results from mutations in the TTR gene, with over 130 identified mutations, the most common being V122I (found in 3-4% of African Americans). Amyloid fibrils infiltrate the myocardial interstitium, separating and encasing individual cardiomyocytes, causing progressive wall thickening without true myocyte hypertrophy (pseudo-hypertrophy). This infiltration impairs diastolic relaxation and increases ventricular stiffness, raising filling pressures while chamber size remains normal or small. The conduction system is frequently involved, leading to heart block and arrhythmias.

Diagnosis & workup

Diagnostics & workup: - Echocardiography: increased wall thickness (>12 mm) with normal or small LV cavity, diastolic dysfunction (grade II-III), biatrial enlargement, granular sparkling myocardial texture (amyloid), pericardial effusion; strain imaging shows apical sparing pattern (cherry on top) pathognomonic for cardiac amyloidosis - Cardiac MRI with gadolinium: diffuse subendocardial or transmural late gadolinium enhancement (LGE), elevated native T1 mapping and expanded extracellular volume (ECV) — highly sensitive for amyloid infiltration; patchy LGE in basal septum for sarcoidosis; T2* mapping <20 ms diagnostic for iron overload - Technetium-99m pyrophosphate (Tc-99m PYP) bone scintigraphy: Grade 2-3 uptake with absent monoclonal protein on serum and urine studies is diagnostic for ATTR cardiac amyloidosis without need for biopsy — highly sensitive and specific - Serum and urine immunofixation electrophoresis with free light chains: essential to exclude AL amyloidosis before diagnosing ATTR; AL requires different treatment (chemotherapy) and has worse cardiac prognosis - BNP/NT-proBNP and troponin: markedly elevated and used for staging in amyloidosis (Mayo staging system); persistent troponin elevation reflects ongoing myocyte injury from amyloid infiltration - Endomyocardial biopsy: definitive diagnosis showing Congo red staining with apple-green birefringence under polarized light (amyloid), non-caseating granulomas (sarcoidosis), or Prussian blue staining for iron (hemochromatosis) - Serum ferritin and transferrin saturation: ferritin >300 ng/mL in men or >200 ng/mL in women with transferrin saturation >45% suggests iron overload; HFE gene testing for hereditary hemochromatosis - ECG: low voltage (amyloid — despite thick walls, creating voltage-mass mismatch), pseudo-infarct pattern (Q waves without CAD), AV conduction abnormalities (sarcoidosis), atrial fibrillation - FDG-PET scan: active inflammation in cardiac sarcoidosis (requires special preparation with high-fat, low-carbohydrate diet to suppress normal myocardial glucose uptake); guides immunosuppressive therapy initiation and monitors treatment response

Risk factors: - Age >65 years (wild-type ATTR amyloidosis is markedly age-dependent; up to 25% of elderly patients with HFpEF may have undiagnosed wtATTR) - African American ancestry (V122I TTR mutation present in 3-4%, causing hereditary ATTR cardiomyopathy) - Plasma cell dyscrasia or multiple myeloma (AL amyloidosis) - Family history of TTR mutation (hereditary ATTR — autosomal dominant with variable penetrance) - Systemic sarcoidosis (25-30% have subclinical cardiac involvement) - Hereditary hemochromatosis (C282Y homozygosity — Northern European descent) - Chronic transfusion dependence: thalassemia major, sickle cell disease, myelodysplastic syndromes (secondary iron overload) - Bilateral carpal tunnel syndrome (early sign of ATTR amyloid deposition in transverse carpal ligament, often preceding cardiac symptoms by 5-10 years) - Lumbar spinal stenosis (ATTR amyloid deposition in ligamentum flavum)

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