What are the potential complications of cardiac amyloidosis in a patient over 60 with a history of plasma cell dyscrasias?

Complications of Cardiac Amyloidosis

Cardiac amyloidosis leads to progressive restrictive cardiomyopathy with high mortality risk, particularly from heart failure, arrhythmias, thromboembolism, and multiorgan dysfunction—with cardiac involvement being the primary driver of death in AL amyloidosis patients. 1

Cardiovascular Complications

Heart Failure and Hemodynamic Instability

• Progressive diastolic dysfunction evolves into restrictive cardiomyopathy with severe biventricular involvement, leading to refractory heart failure despite medical therapy 1, 2
• Persistent hypotension (systolic blood pressure <90 mm Hg) occurs frequently due to underfilling of the stiff, infiltrated heart and autonomic dysfunction 1
• Cardiac cachexia develops in advanced stages as a marker of end-stage disease 1
• Cardiac output becomes heart rate-dependent in severe restrictive physiology, making patients vulnerable to bradycardia 1

Arrhythmias and Conduction Abnormalities

• Atrial fibrillation is extremely common and carries high risk due to loss of atrial contribution to ventricular filling in the setting of severe diastolic dysfunction 1
• Recurrent ventricular arrhythmias and frequent implantable cardioverter-defibrillator shocks occur in advanced disease 1
• Conduction system disease may cause recurrent syncope requiring pacemaker implantation 1
• Sudden cardiac death from ventricular arrhythmias is a significant cause of mortality 1

Thromboembolic Complications

• Intracardiac thrombus formation occurs even in sinus rhythm due to atrial mechanical "standstill" from amyloid infiltration of atrial walls 1
• High left atrial pressures in heart failure contribute to atrial dysfunction and stasis 1
• Embolic stroke and transient ischemic attacks represent major morbidity 1
• The risk must be balanced against increased bleeding risk from amyloid angiopathy 1

Medication-Related Complications

Drug Toxicity and Intolerance

• Digoxin toxicity occurs even at normal serum levels because digoxin binds to amyloid fibrils, and should be avoided 1
• Calcium channel blockers bind to amyloid fibrils, resulting in exaggerated hypotensive and negative inotropic responses 1
• ACE inhibitors and angiotensin receptor blockers cause profound hypotension and should be used with extreme caution or avoided entirely 1
• Beta-blockers can precipitate low cardiac output states when severe restrictive physiology is present and should be avoided in AL amyloidosis 1

Treatment-Related Complications in AL Amyloidosis

• High-dose melphalan with stem cell transplantation carries 13% treatment-related mortality at 100 days, with 42% of deaths being cardiac deaths 1
• Significant hemodynamic fluctuations during hematopoietic cell transplantation increase morbidity and mortality in patients with cardiac involvement 1
• Plasma cell-directed therapies can cause cardiopulmonary toxicities, including grade 3/4 events in up to 36% of patients treated with carfilzomib 1

Extracardiac Complications

Autonomic Dysfunction

• Severe symptomatic orthostatic hypotension requiring midodrine and/or droxidopa develops frequently 1, 3
• Autonomic neuropathy severe enough to limit daily activities represents a contraindication to heart transplantation 1
• Orthostatic hypotension may be the presenting manifestation even without typical cardiac symptoms 3

Renal Complications

• Proteinuria ≥500 mg/day indicates significant renal involvement and represents a contraindication to heart transplantation 1
• Progressive kidney dysfunction occurs in approximately 70% of systemic AL amyloidosis patients 4
• Nephrotic syndrome with malnutrition compounds cardiac cachexia 1

Gastrointestinal and Nutritional Complications

• GI bleeding and malabsorption occur from amyloid infiltration of the GI tract 1
• Modified body mass index <600 kg/m² × g/L indicates severe malnutrition and contraindication to transplantation 1
• Severe weight loss and cardiac cachexia develop in advanced disease 1

Pulmonary Complications

• Symptomatic pulmonary involvement including pleural effusions, pleural involvement, and parenchymal nodules can occur 1
• These manifestations represent contraindications to heart transplantation 1

Peripheral Neuropathy

• Peripheral neuropathy severe enough to limit ambulation develops in many patients 1
• Bilateral carpal tunnel syndrome is a common early manifestation 5
• Neuropathic pain requires management with gabapentin or pregabalin 1

Advanced Disease Complications

Frailty and Functional Decline

• Fried frailty phenotype with ≥3 criteria (weakness, slowness, exhaustion, low physical activity, unintentional weight loss) develops and contraindicates transplantation 1
• Progressive functional decline limits candidacy for advanced therapies 1

Mechanical Circulatory Support Challenges

• Small left ventricular cavity makes LVAD cannula placement challenging with higher risk for suction events 1
• Biventricular dysfunction leads to right ventricular failure when LVADs are placed 1
• INTERMACS data show worse survival in cardiac amyloidosis patients with mechanical circulatory support compared to other cardiomyopathies, with high burden of early adverse events 1
• Infection risk is increased in AL amyloidosis patients receiving plasma cell-directed therapies 1

Transplantation Complications

• Cardiac transplantation for amyloidosis has poor prognosis with 5-year survival of only 20-30% due to progressive amyloid deposition in other organs 1
• Recurrence of amyloid deposition in the cardiac allograft occurs in AL amyloidosis 1
• Multiple extracardiac contraindications limit transplant candidacy 1

Prognostic Implications

Survival and Mortality

• Median survival is only 1.6 years in AL amyloidosis patients with cardiac involvement compared to 6.4 years without cardiac involvement 1
• Approximately 30% of patients die within the first year from diagnosis 1
• Cardiac involvement is the main driver of disease prognosis and mortality in AL amyloidosis 5
• Overall survival is poor once heart failure develops, with cardiac amyloidosis being the leading cause of death 2, 3

Disease Progression

• Persistent hyponatremia (serum sodium <134 mEq/L) indicates advanced disease and poor prognosis 1
• Elevated brain natriuretic peptide independently predicts mortality 6
• Late gadolinium enhancement on cardiac MRI has incremental prognostic value for mortality prediction 6