Cardiology > Cardiac Amyloidosis

Background 

 Cardiac amyloidosis is a restrictive cardiomyopathy caused by the extracellular deposition of amyloid fibrils within the myocardium. These insoluble protein aggregates stiffen the ventricular walls, impair diastolic filling, and eventually lead to heart failure with preserved ejection fraction (HFpEF). The condition can mimic hypertrophic cardiomyopathy or heart failure and is frequently underdiagnosed. 

II) Classification/Types

By Amyloid Protein Type: 

• • AL (Light-chain) Amyloidosis: Associated with plasma cell dyscrasias such as multiple myeloma; tends to be aggressive with multiorgan involvement. 

• • ATTR (Transthyretin) Amyloidosis: 

• • Hereditary (mutant TTR): Caused by TTR gene mutations. 

• • Wild-type (senile systemic amyloidosis): Age-related deposition of wild-type TTR, primarily affecting the elderly. 

By Cardiac Involvement: 

• • Isolated cardiac involvement (common in wild-type ATTR) 

• • Multisystem involvement (common in AL amyloidosis) 

III) Pathophysiology 

Amyloid fibrils infiltrate the myocardial interstitium, leading to: 

• • Increased ventricular wall thickness without true hypertrophy 

• • Reduced myocardial compliance and restrictive filling pattern 

• • Conduction system involvement, causing arrhythmias 

• • Microvascular ischemia due to amyloid deposition in small coronary arteries 

IV) Epidemiology

• • Sex: Wild-type ATTR amyloidosis is more common in men. 

• • Age: Prevalence increases with age, especially >65 years. 

• • Ethnicity: Hereditary ATTR is more common in African Americans due to the V122I mutation. 

• • Comorbidities: Frequently coexists with carpal tunnel syndrome, spinal stenosis, or nephrotic syndrome. 

Etiology 

I) Causes

• • Plasma cell dyscrasias (e.g., multiple myeloma → AL amyloidosis) 

• • TTR gene mutations (hereditary ATTR) 

• • Age-related misfolding of wild-type TTR (wild-type ATTR) 

II) Risk Factors

• • Age >65 years 

• • Male sex (particularly for wild-type ATTR) 

• • Family history of amyloidosis 

• • Known monoclonal gammopathy or multiple myeloma 

Clinical Presentation 

I) History (Symptoms)

• • Progressive exertional dyspnea 

• • Fatigue and exercise intolerance 

• • Orthostatic hypotension 

• • Peripheral edema 

• • Palpitations or syncope (due to arrhythmias or conduction disease) 

• • Symptoms of other organ involvement (e.g., proteinuria, neuropathy) 

II) Physical Exam (Signs)

Vital Signs: 

• • Hypotension 

• • Low pulse pressure 

Cardiac Exam: 

• • Normal or soft S1 and S2 

• • S4 gallop may be absent due to stiff ventricles 

• • Possible murmurs of functional MR or TR due to annular dilation 

Pulmonary: 

• • Basilar crackles (if pulmonary congestion present) 

Peripheral: 

• • Jugular venous distension 

• • Hepatomegaly, ascites 

• • Lower extremity edema 

• • Carpal tunnel signs or purpura (especially in AL) 

Differential Diagnosis (DDx) 

• • Hypertrophic cardiomyopathy 

• • Restrictive cardiomyopathy (e.g., sarcoidosis, hemochromatosis) 

• • Heart failure with preserved ejection fraction (HFpEF) 

• • Constrictive pericarditis 

• • Infiltrative diseases (e.g., Fabry disease) 

Diagnostic Tests 

Initial Tests: 

• • Electrocardiogram (ECG): 

• • • Low-voltage QRS despite increased wall thickness 

• • • Pseudoinfarction pattern (Q waves) 

• • Chest X-ray: 

• • • Cardiomegaly, pulmonary congestion 

• • Echocardiogram (TTE): 

• • • Increased ventricular wall thickness 

• • • Diastolic dysfunction (restrictive filling) 

• • • Speckled or granular myocardial appearance 

• • Cardiac MRI: 

• • • Late gadolinium enhancement with global subendocardial pattern 

• • • T1 mapping and extracellular volume (ECV) expansion 

• • Serum/Urine Protein Electrophoresis and Free Light Chains: 

• • • To detect AL amyloidosis 

• • Bone Scintigraphy (99mTc-PYP scan): 

• • • Identifies ATTR amyloid if monoclonal proteins are absent 

• • Tissue Biopsy: 

• • • Congo red staining with apple-green birefringence under polarized light 

• • • Endomyocardial biopsy if diagnosis remains uncertain 

Basic Labs: 

• • Complete Blood Count (CBC): 
    May show anemia; helps rule out infection or hematologic malignancy. 

• • Comprehensive Metabolic Panel (CMP): 
    Assesses renal and hepatic function—important since amyloidosis can involve kidneys and liver. 

• • Elevated creatinine or BUN suggests renal involvement. 

• • Elevated alkaline phosphatase may indicate hepatic amyloid infiltration. 

• • Urinalysis: 
    To detect proteinuria (often nephrotic-range in AL amyloidosis). 

• • Serum and Urine Protein Electrophoresis (SPEP & UPEP) with Immunofixation: 
    Detects monoclonal protein (M-spike) in AL amyloidosis. 

• • Serum Free Light Chains (FLC): 
    Measures kappa/lambda ratio, often abnormal in AL amyloidosis. 

• • Cardiac Biomarkers: 

• • • Troponin T/I: Often mildly elevated due to myocardial injury. 

• • • NT-proBNP or BNP: Elevated due to diastolic dysfunction; highly sensitive to cardiac involvement. 

• • • Thyroid-Stimulating Hormone (TSH): 
      Hypothyroidism is more common in systemic amyloidosis. 

Treatment 

I) Medical Management

Heart Failure Management: 

• • • Diuretics for symptom relief 

• • • Caution with beta-blockers, ACE inhibitors (may worsen hypotension) 

• • • Avoid calcium channel blockers and digoxin (increased toxicity) 

AL Amyloidosis: 

• • • Chemotherapy (e.g., bortezomib, cyclophosphamide, dexamethasone) 

• • • Autologous stem cell transplantation in selected patients 

ATTR Amyloidosis: 

• • • Tafamidis (TTR stabilizer) 

• • • Patisiran or inotersen (TTR gene silencers for hereditary ATTR) 

II) Device Therapy

• • Pacemaker or ICD for conduction abnormalities or arrhythmias 

III) Advanced Therapies: 

• • Heart transplantation (careful patient selection) 

Patient Education, Screening, Vaccines 

• • Importance of recognizing red flag symptoms (e.g., syncope, neuropathy) 

• • Genetic counseling and testing in hereditary ATTR 

• • Routine monitoring of cardiac and renal function 

• • Sodium and fluid restriction if volume overload present 

Vaccinations: 

• • Annual influenza vaccine 

• • Pneumococcal vaccine 

• • COVID-19 vaccine 

Consults 

• • Cardiology: Evaluation and management of cardiac involvement 

• • Hematology/Oncology: For AL amyloidosis and chemotherapy planning 

• • Genetics: For hereditary ATTR amyloidosis 

• • Neurology: If peripheral/autonomic neuropathy present 

• • Nephrology: If renal involvement 

Follow-Up 

• • Serial Echocardiograms: Every 6–12 months to monitor function 

• • Biomarkers: NT-proBNP and troponin for disease progression 

• • Hematologic Response Monitoring: In AL amyloidosis 

• • Medication Tolerance: Assess for hypotension and renal function 

• • Reinforcement of Supportive Care: Diet, medication adherence, fall risk