What is cardiac amyloidosis?

What is Cardiac Amyloidosis?

Cardiac amyloidosis is an infiltrative restrictive cardiomyopathy caused by the accumulation of misfolded protein fragments (amyloid) in the cardiac extracellular space, leading to increased myocardial stiffness, diastolic dysfunction, and ultimately heart failure. 1, 2

Pathophysiology

The disease develops when abnormal proteins misfold and deposit as amyloid fibrils in the myocardial interstitium, disrupting normal cardiac architecture and function 2. These deposits cause several pathologic consequences:

• Increased myocardial stiffness results from amyloid infiltration between cardiac myocytes, impairing ventricular relaxation and causing diastolic dysfunction 1, 2
• Restrictive cardiomyopathy phenotype develops with increased ventricular wall thickness but reduced chamber size, leading to elevated filling pressures 1, 2
• Direct cellular toxicity occurs as misfolded proteins cause myocyte necrosis through oxidative stress, contributing to systolic dysfunction in advanced stages 2
• Initially preserved systolic function progresses to severe systolic dysfunction as the disease advances 1, 3

Main Types Affecting the Heart

Two primary forms account for nearly all cardiac amyloidosis cases:

AL (Light Chain) Amyloidosis

• Caused by misfolded immunoglobulin light chains produced by clonal plasma cells or B-cell disorders, with lambda light chain representing 75-80% of cases 2
• Affects up to 50% of patients with systemic AL amyloidosis 3
• Carries the worst prognosis with median survival of only 13 months, dropping to 4 months once heart failure symptoms develop 3, 2
• The circulating light chains deposit in cardiac tissue causing both architectural disruption and direct cytotoxicity to myocytes 2

ATTR (Transthyretin) Amyloidosis

• Results from accumulation of transthyretin protein (normally produced by the liver to transport thyroid hormones) that misfolds and deposits in tissues 4
• Two subtypes exist:
  • Wild-type ATTR (ATTRwt): Normal TTR protein misfolds due to aging-related processes, with median survival of 75 months 3, 2
  • Hereditary ATTR (ATTRv): Mutated TTR protein with variable cardiac involvement and median survival of 70 months 3

Clinical Presentation

Heart failure with restrictive physiology is the hallmark presentation 1, 3:

• Symptoms of congestion dominate the clinical picture, including dyspnea, peripheral edema, and exercise intolerance 3, 4
• Orthopedic manifestations such as bilateral carpal tunnel syndrome, biceps tendon rupture, and lumbar spinal stenosis should immediately raise suspicion for ATTR amyloidosis 1
• Peripheral neuropathy frequently accompanies hereditary ATTR and warrants cardiac evaluation 1
• Conduction abnormalities including atrioventricular block occur from infiltration of the conduction system 1
• Atrial fibrillation develops from both amyloid deposition in atrial walls and atrial dilation from elevated filling pressures 1

Key Diagnostic Features

Electrocardiographic Findings

• Low QRS voltage in limb leads despite ventricular wall thickening occurs in approximately 50% of patients—a paradoxical finding highly suggestive of amyloidosis 5, 3
• Pseudoinfarct pattern in precordial leads 3

Echocardiographic Characteristics

• Increased ventricular wall thickness without chamber dilation 1
• Biatrial enlargement 1
• Thickening of valve leaflets and interatrial septum 1
• Characteristic "apical sparing" pattern on strain imaging 5

Biomarkers

• Elevated BNP or NT-proBNP with 93% sensitivity and 90% specificity for cardiac involvement, often elevated before clinical heart failure develops 1

Advanced Imaging

• Cardiac MRI demonstrates characteristic subendocardial or transmural late gadolinium enhancement globally, with elevated native T1 values and increased extracellular volume 1
• Bone scintigraphy with grade ≥2 myocardial uptake combined with appropriate imaging findings and absence of monoclonal light chain is diagnostic of ATTR cardiac amyloidosis without requiring biopsy 1

Definitive Diagnosis

Endomyocardial biopsy identifying amyloid protein in cardiac tissue provides definitive diagnosis 5. However, in patients with noncardiac tissue-proven systemic amyloidosis, echocardiographic or cardiac MRI findings suggestive of infiltrative cardiomyopathy can support the diagnosis without biopsy 5.

Treatment Considerations

ATTR-Specific Therapy

• Tafamidis is FDA-approved for ATTR cardiomyopathy to reduce cardiovascular mortality and cardiovascular-related hospitalization 1, 6

AL-Specific Therapy

• Daratumumab-CyBorD as first-line therapy for transplant-eligible patients 1
• High-dose melphalan followed by autologous stem cell transplantation as a treatment option 1

Heart Failure Management Caveats

• Standard heart failure therapies require extreme caution due to restrictive physiology 5, 1
• Diuretics and vasodilators must be used cautiously due to risk of hypotension from underfilling a stiff heart 5
• Beta-blockers are usually avoided because cardiac output becomes heart rate-dependent in severe restrictive physiology 5
• Digoxin binds to amyloid fibrils and can cause toxicity even at normal serum levels 5
• Calcium antagonists bind to amyloid fibrils, resulting in exaggerated hypotensive and negative inotropic responses 5
• Judicious diuresis remains the mainstay of heart failure therapy 5

Anticoagulation

• Indicated in atrial fibrillation and should be strongly considered in patients with history of embolic stroke, transient ischemic attacks, or demonstrable intracardiac thrombus even in sinus rhythm 1