What is cardiac amyloidosis?

What is Cardiac Amyloidosis?

Cardiac amyloidosis is a disease caused by the deposition of misfolded amyloid proteins in the heart tissue, leading to a restrictive cardiomyopathy characterized by increased myocardial stiffness, diastolic dysfunction, and progressive heart failure. 1, 2

Pathophysiology

The disease process involves several key mechanisms:

• Amyloid protein deposits accumulate in the myocardial interstitium, disrupting normal myocyte function and causing progressive stiffening of the heart muscle 3, 2
• In early stages, the heart maintains normal size with preserved systolic function but develops significant diastolic dysfunction due to increased ventricular rigidity and elevated filling pressures 3, 4
• As disease progresses, amyloid deposits cause myocyte necrosis through oxidative stress, eventually leading to systolic dysfunction in advanced stages 3
• The restrictive physiology creates a characteristic dip-and-plateau pattern in early diastolic left ventricular pressure 4

Types of Cardiac Amyloidosis

Several distinct forms exist, each with different prognosis and treatment:

• AL (light chain) amyloidosis: Affects up to 50% of patients with systemic AL disease, with median survival of only 13 months that drops to 4 months once heart failure symptoms develop 3, 4
• ATTR (transthyretin) amyloidosis - wild-type (senile): Common cardiac involvement with median survival of 75 months 3
• ATTR (transthyretin) amyloidosis - hereditary (mutant): Variable cardiac involvement with median survival of 70 months 3
• AA (reactive) amyloidosis: Rarely affects the heart (less than 10% of cases), primarily involves liver, spleen, and kidneys 1, 3
• Isolated atrial amyloidosis: Limited to cardiac tissue only 3

Clinical Presentation

The disease manifests through several characteristic features:

• Primary presentation is heart failure with symptoms of congestion in the setting of restrictive cardiomyopathy 3, 2
• Orthopedic manifestations including bilateral carpal tunnel syndrome, biceps tendon rupture, and lumbar spinal stenosis should immediately raise suspicion for ATTR amyloidosis 2
• Peripheral neuropathy frequently accompanies hereditary ATTR amyloidosis and warrants cardiac evaluation 2
• Conduction abnormalities develop from infiltration of the conduction system, including atrioventricular block and atrial tachyarrhythmias 2
• Atrial fibrillation occurs due to both direct amyloid deposition in atrial walls and atrial dilation from chronically elevated filling pressures 2

Diagnostic Features

Electrocardiographic Findings

• Low QRS voltage in limb leads despite ventricular wall thickening (present in approximately 50% of patients) - a classic paradoxical finding 1, 3
• Pseudoinfarct pattern in precordial leads 3

Echocardiographic Findings

• Increased ventricular wall thickness without chamber dilation 2, 5
• Biatrial enlargement 2, 5
• Thickening of valve leaflets and interatrial septum 2
• Increased myocardial echogenicity ("granular sparkling" appearance) 5
• In advanced disease: E/A ratio >2.5, deceleration time <150 msec, and markedly elevated left atrial volume index (>50 mL/m²) 4

Biomarkers

• Elevated BNP or NT-proBNP suggests cardiac involvement with 93% sensitivity and 90% specificity, and can be elevated even before clinical heart failure develops 3, 2
• Presence of serum or urine monoclonal gammopathy suggests AL amyloidosis but does not establish the diagnosis 1

Advanced Imaging

• Cardiac MRI demonstrates characteristic subendocardial or transmural late gadolinium enhancement globally, with elevated native T1 values and increased extracellular volume 2, 6
• Abnormal myocardial nulling pattern on T1 scout images (myocardium nulls before blood pool) 6
• Nuclear imaging with technetium-99m pyrophosphate: Grade ≥2 myocardial uptake combined with appropriate echocardiographic/MRI findings and absence of monoclonal light chain is diagnostic of ATTR cardiac amyloidosis without need for biopsy 1, 2

Definitive Diagnosis

• Endomyocardial biopsy identifying amyloid protein in cardiac tissue provides definitive diagnosis of cardiac amyloidosis 1
• Histologic confirmation from biopsies of abdominal fat pad, gingiva, rectum, bone marrow, or other affected organs showing amorphous pink deposits on light microscopy and apple-green birefringence with Congo red staining under polarized microscopy 1
• In patients with noncardiac tissue-proven systemic amyloidosis, echocardiographic or cardiac MRI findings suggestive of infiltrative cardiomyopathy can support the diagnosis without endomyocardial biopsy 1
• Once amyloidosis is confirmed, immunohistochemistry with antibodies against amyloid A, κ- and λ-light chains, and TTR amyloid is essential to determine the specific type, as this dictates treatment strategy and prognosis 1
• If TTR amyloid is detected, DNA mutational analysis must be performed to differentiate between wild-type (senile) and hereditary variants 1, 3

Treatment Considerations

ATTR Cardiac Amyloidosis

• Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved for treatment of ATTR cardiomyopathy to reduce cardiovascular mortality and cardiovascular-related hospitalization 7

AL Cardiac Amyloidosis

• Daratumumab-CyBorD is recommended as first-line therapy for transplant-eligible patients 2
• High-dose melphalan followed by autologous stem cell transplantation is a treatment option, though treatment-related mortality remains substantial 2, 5

Heart Failure Management

• Judicious diuresis remains the mainstay of heart failure therapy 1
• Diuretics and vasodilators must be used cautiously due to risk of hypotension from underfilling of a stiff heart 1
• β-blockers should be used with extreme caution or avoided entirely, as cardiac output is heart rate-dependent in severe restrictive physiology; they are usually avoided in AL amyloidosis 1
• ACE inhibitors and ARBs should be used with caution and probably avoided due to hypotension risk 1
• Digoxin should be avoided as it binds to amyloid fibrils and can cause toxicity even at normal serum levels 1
• Calcium channel blockers should be avoided as they bind to amyloid fibrils, resulting in 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, 2
• Thrombus formation can occur even in sinus rhythm when atria develop mechanical "standstill" from amyloid infiltration of atrial walls 1