What are the characteristics, diagnosis, and treatment of cardiac amyloidosis?

Cardiac Amyloidosis: Features, Diagnosis, and Treatment

Clinical Presentation

Cardiac amyloidosis primarily presents as heart failure with a restrictive cardiomyopathy phenotype, characterized by increased myocardial stiffness leading to diastolic dysfunction with initially preserved systolic function that progresses to systolic dysfunction in advanced stages. 1

Key Clinical Features

• Heart failure symptoms dominate the clinical picture, with median survival in AL amyloidosis of approximately 13 months, dropping dramatically to 4 months once heart failure symptoms develop 2, 3
• Orthopedic manifestations are critical red flags: bilateral carpal tunnel syndrome, biceps tendon rupture, and lumbar spinal stenosis should raise immediate suspicion for ATTR amyloidosis 1
• Peripheral neuropathy frequently accompanies hereditary ATTR amyloidosis and should prompt cardiac evaluation 1
• Conduction abnormalities occur due to infiltration of the conduction system, including atrioventricular block and atrial tachyarrhythmias 1
• Atrial fibrillation develops from both amyloid deposition in atrial walls and atrial dilation from elevated filling pressures 1

Electrocardiographic Features

• Low QRS voltage in limb leads occurs in approximately 50% of patients despite ventricular wall thickening on imaging—this voltage-mass discordance is a hallmark finding 1, 2
• Pseudoinfarct pattern in precordial leads mimics prior myocardial infarction 1, 2
• Atrioventricular conduction abnormalities are common 1

Diagnostic Approach

Initial Suspicion and Screening

When heart failure with preserved ejection fraction is present alongside increased left ventricular wall thickness, unexplained neuropathy, orthopedic manifestations (especially bilateral carpal tunnel syndrome), or family history of amyloidosis, cardiac amyloidosis must be actively excluded. 1

Echocardiographic Findings

• Increased ventricular wall thickness without chamber dilation, with hyperechogenic myocardial appearance 1
• Biatrial enlargement and thickening of valve leaflets and interatrial septum 1
• Thickened right ventricular free wall 1
• Small pericardial effusion is frequently present 1
• Restrictive filling pattern with markedly elevated E wave, reduced A wave, and decreased deceleration time 1
• Apical sparing pattern on longitudinal strain imaging—the "bulls-eye" appearance with preserved apical strain but significantly impaired mid-basal segment strain is highly characteristic 1

Biomarkers

Elevated BNP or NT-proBNP suggests cardiac involvement with 93% sensitivity and 90% specificity, and elevation can occur even before clinical heart failure develops. 1, 2

Advanced Imaging

Cardiac MRI demonstrates characteristic subendocardial or transmural late gadolinium enhancement globally, with elevated native T1 values and increased extracellular volume. 1

Nuclear Imaging for ATTR Diagnosis

Grade ≥2 myocardial uptake on bone scintigraphy (99mTc-PYP, DPD, or HMDP) combined with appropriate echocardiographic or cardiac MRI findings and absence of monoclonal light chain is diagnostic of ATTR cardiac amyloidosis without requiring endomyocardial biopsy. 1

This non-invasive diagnostic pathway represents a major advance, as technetium pyrophosphate scanning can distinguish AL from ATTR amyloidosis 1

Tissue Diagnosis

• Endomyocardial biopsy provides definitive diagnosis when Congo red staining shows apple-green birefringence under polarized microscopy 1, 4
• Non-cardiac tissue biopsy (abdominal fat pad, gingiva, rectum, bone marrow) can establish systemic amyloidosis diagnosis 1
• Mass spectrometry is the gold standard for amyloid typing 4

Determining Amyloid Type

After confirming cardiac amyloidosis, differentiation between AL and ATTR types is mandatory as treatment differs fundamentally. 1, 4

• For AL amyloidosis: Serum free light chain assay, serum and urine immunofixation electrophoresis demonstrate monoclonal gammopathy 1, 4
• For ATTR amyloidosis: Once ATTR is confirmed, genetic testing (DNA mutational analysis) must be performed to differentiate hereditary (ATTRm) from wild-type (ATTRwt) disease 1

Treatment Strategies

ATTR Cardiac Amyloidosis

Tafamidis is FDA-approved for treatment of ATTR cardiomyopathy (both wild-type and hereditary) to reduce cardiovascular mortality and cardiovascular-related hospitalization. 5

• Dosing: Either VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) orally once daily OR VYNDAMAX 61 mg (one 61-mg tafamidis capsule) orally once daily 5
• These formulations are not substitutable on a per mg basis 5
• Capsules must be swallowed whole, not crushed or cut 5

AL Cardiac Amyloidosis

For transplant-eligible patients, daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, dexamethasone) is first-line therapy, with high-dose melphalan followed by autologous stem cell transplantation as a treatment option. 4, 6

For transplant-ineligible patients, daratumumab-CyBorD is the preferred first-line option, with CyBorD as an alternative. 4

Close monitoring for cardiac decompensation during chemotherapy is essential, as AL amyloidosis patients are at higher risk for treatment-related toxicity 4

Heart Failure Management

Heart failure management in cardiac amyloidosis requires extreme caution with standard therapies due to the restrictive physiology. 1

• Diuretics: Judicious diuresis remains the mainstay, but use cautiously to avoid hypotension from underfilling a stiff ventricle 1
• ACE inhibitors/ARBs: Should be used with extreme caution or avoided due to hypotension risk 1
• Beta-blockers: Use cautiously if at all, as cardiac output is heart rate-dependent in severe restrictive physiology; probably should be avoided in AL amyloidosis 1
• Digoxin: Avoid—binds to amyloid fibrils causing toxicity even at normal serum levels 1
• Calcium channel blockers: Avoid—bind to amyloid fibrils causing exaggerated hypotensive and negative inotropic responses 1

Anticoagulation

Anticoagulation is indicated in patients with atrial fibrillation and should be strongly considered in those with history of embolic stroke, transient ischemic attacks, or demonstrable intracardiac thrombus, even in sinus rhythm. 1

The risk of intracardiac thrombus is elevated even in sinus rhythm due to atrial mechanical "standstill" from amyloid infiltration 1

Advanced Therapies

For end-stage disease, consider heart transplantation, heart-kidney transplantation, or (for hereditary ATTR) heart-liver transplantation 6

Critical Pitfalls to Avoid

• Do not dismiss low QRS voltage as "normal variant" when ventricular wall thickness is increased—this voltage-mass mismatch is pathognomonic 1, 2
• Do not use standard heart failure medications without extreme caution—digoxin and calcium channel blockers can cause severe toxicity 1
• Do not assume sinus rhythm protects against thromboembolism—atrial mechanical dysfunction occurs regardless of rhythm 1
• Do not delay genetic testing after ATTR diagnosis—distinguishing hereditary from wild-type disease affects family screening and prognosis 1
• Do not treat as typical heart failure with preserved ejection fraction—infiltrative cardiomyopathy requires specialized management 2, 3