Cardiac amyloidosis

Definition

In amyloidosis, misfolded, normally soluble proteins are deposited in tissue as insoluble fibrils (about 10 nm in diameter, beta-pleated sheet structure). In cardiac amyloidosis these deposits infiltrate the myocardium, producing a restrictive cardiomyopathy with diastolic dysfunction and heart failure.

Classification

• AL amyloidosis: overproduction of amyloidogenic monoclonal immunoglobulin light chains in a clonal plasma cell or other B-cell disorder; about 10–20 % of patients with multiple myeloma develop AL amyloidosis.
• ATTRv amyloidosis (hereditary): mutations in the transthyretin gene (TTR), more than 130 known mutations. V30M is common in Portugal, Sweden, Brazil and Japan; the V122I variant is present in about 4 % of American and Caribbean Black people. Clinically polyneuropathy, autonomic neuropathy, kidney disease and cardiomyopathy.
• ATTRwt amyloidosis (wild-type): deposition of non-mutated transthyretin, principally in the heart, increasingly recognized as a cause of infiltrative cardiomyopathy in older men.
• AA amyloidosis: deposition of serum amyloid A in chronic infections and inflammation; the heart is involved only late.

Occurrence & epidemiology

Transthyretin amyloid cardiomyopathy is found in about 16 % of patients with aortic stenosis undergoing transcatheter valve implantation and in about 13 % of patients admitted with heart failure with preserved ejection fraction. Monoclonal gammopathies are not uncommon from about 55 years of age, which is why typing of the amyloid is essential.

Aetiopathogenesis

Normally soluble wild-type or mutant proteins misfold, aggregate into oligomers and eventually into insoluble fibrils; failure of the normal clearance mechanisms for misfolded proteins probably also contributes. The deposits are metabolically inert but physically interfere with organ structure and function. Certain precursors (prefibrillar oligomers) are also directly toxic to cells. Transthyretin is produced mainly in the liver.

Clinical features

• Heart: restrictive cardiomyopathy with heart failure, heart block or arrhythmias; hypotension is common.
• Soft tissues: carpal tunnel syndrome, trigger finger, biceps tendon rupture and spinal stenosis often precede the cardiac manifestation of ATTRwt amyloidosis by years.
• Nerves: peripheral neuropathy with paraesthesia of toes and fingers (a common presenting manifestation in AL and ATTRv amyloidosis); autonomic neuropathy with orthostatic hypotension, erectile dysfunction, sweating abnormalities and motility disturbances.
• Typical of AL: macroglossia, periorbital bruising ("raccoon eyes"), nephrotic syndrome, hepatomegaly.

Extracardiac red flags

• Extracardiac in ATTR:
• carpal tunnel syndrome.
• Lumbar spinal stenosis.
• Distal biceps tendon rupture.
• Peripheral polyneuropathy.
• Autonomic dysfunction (orthostatic hypotension).
• Extracardiac in AL: macroglossia, periorbital purpura ('raccoon eyes'), nephrotic syndrome, hepatosplenomegaly, polyneuropathy.

Histology

Amyloid stains pink with hematoxylin and eosin and shows the characteristic apple-green birefringence under polarised light after Congo red staining; electron microscopy shows non-branching fibrils of about 10 nm. Aspiration of subcutaneous abdominal fat detects amyloid in about 80 % of AL but in less than 25 % of ATTRwt patients; heart and kidney biopsy have a sensitivity of nearly 100 % when the organ is involved. Typing is done by immunohistochemistry, by gene sequencing in hereditary forms and most accurately by mass spectrometry.

Diagnosis

Imaging and ECG

• Echocardiography: diffuse wall thickening of the left and often also the right ventricle; thickened interatrial septum and atrioventricular valves; granular sparkling myocardium; restrictive diastolic filling pattern, sometimes pericardial effusion; reduced longitudinal strain with relative sparing of the apex ("apical sparing").
• ECG: low voltage that does not match the wall thickness; pseudoinfarct pattern with Q waves and poor R-wave progression; AV delay or AV block.
• Cardiac MRI: diffuse subendocardial or transmural late gadolinium enhancement, markedly elevated native T1 values and increased extracellular volume (above 0.30).

Work-up

• Cardiac involvement: ECG (low voltage, arrhythmias), NT-proBNP or BNP and troponin; echocardiography with diastolic function, global longitudinal strain and biventricular wall thickening; cardiac MRI with subendocardial gadolinium enhancement.
• Bone scintigraphy (e.g. technetium pyrophosphate): Perugini grade 2 or 3 uptake together with consistent echocardiographic or MRI findings allows the diagnosis of ATTR cardiomyopathy without heart biopsy, provided a monoclonal protein has been excluded by laboratory tests.
• Search for a plasma cell disorder: serum free light chains, immunofixation of serum and urine (simple electrophoresis is insensitive), bone marrow biopsy; with more than 10 % clonal plasma cells evaluation for multiple myeloma.

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Further reading (open access)

1. MSD Manual Professional: Amyloidosis
2. StatPearls: Cardiac Amyloidosis
3. Transthyretin cardiac amyloidosis, Cardiovasc Res 2023
4. Cardiac Amyloidosis: A Review of Current Imaging Techniques, Front Cardiovasc Med 2021

Cross-references