Clinical meaning
Cardiac amyloidosis is a progressive and potentially fatal condition caused by the extracellular deposition of insoluble amyloid fibrils within the myocardium, resulting in increased wall thickness, diastolic dysfunction, and ultimately restrictive cardiomyopathy with heart failure. Amyloidosis encompasses a group of diseases characterized by the misfolding of normally soluble precursor proteins into insoluble beta-pleated sheet fibrillar aggregates that deposit in tissues and progressively disrupt organ architecture and function. In the heart, amyloid fibrils infiltrate the interstitial space between cardiomyocytes, the cardiac conduction system, cardiac valves, and coronary microvasculature, producing a characteristic pattern of disease. The two most common types of cardiac amyloidosis are AL (immunoglobulin light chain) amyloidosis and ATTR (transthyretin) amyloidosis, which differ fundamentally in their precursor protein, pathogenesis, prognosis, and treatment. AL amyloidosis (previously called primary amyloidosis) is caused by a clonal plasma cell dyscrasia (similar to multiple myeloma) in which a monoclonal population of plasma cells in the bone marrow produces excess immunoglobulin light chains (usually lambda light chains) that misfold into amyloid fibrils. These light chain-derived amyloid fibrils have direct cardiotoxic effects beyond their space-occupying properties: they activate oxidative stress pathways, induce cardiomyocyte apoptosis, and disrupt intracellular calcium handling, contributing to the rapid clinical deterioration seen in AL cardiac amyloidosis. AL amyloidosis is the more aggressive form, with median survival of only 6 months from the onset of heart failure symptoms if untreated, and approximately 5 years with modern chemotherapy. It typically presents in patients aged 55-70 and is a systemic disease that frequently involves the kidneys (nephrotic syndrome), liver (hepatomegaly), peripheral nerves (peripheral neuropathy, autonomic dysfunction), GI tract (malabsorption, bleeding), and soft tissues (macroglossia -- enlargement of the tongue; periorbital purpura -- raccoon eye bruising around the eyes, pathognomonic for AL amyloidosis). ATTR amyloidosis is caused by the deposition of misfolded transthyretin (TTR) protein. TTR is a transport protein primarily synthesized by the liver that carries thyroxine (T4) and retinol-binding protein (vitamin A) in the plasma. It normally circulates as a stable homotetramer, but destabilization of the tetramer into monomers promotes misfolding and aggregation into amyloid fibrils. ATTR amyloidosis exists in two forms: hereditary/variant ATTR (ATTRv), caused by autosomal dominant point mutations in the TTR gene (over 130 mutations identified; Val30Met and Val122Ile are among the most common) that destabilize the tetramer; and wild-type ATTR (ATTRwt, formerly senile cardiac amyloidosis), which occurs without TTR mutations and is caused by age-related destabilization of normal (wild-type) TTR protein. ATTRwt predominantly affects men over 70 and may be present in up to 13-25% of elderly patients hospitalized for heart failure with preserved ejection fraction (HFpEF), making it far more common than previously recognized. ATTR cardiac amyloidosis progresses more slowly than AL, with median survival of 2.5-3.5 years for ATTRv and 3.5-5 years for ATTRwt from diagnosis. The cardiac manifestations of amyloidosis result from the pathological effects of amyloid infiltration on myocardial structure and function. Progressive amyloid deposition causes increased ventricular wall thickness (which mimics left ventricular hypertrophy on echocardiography, but is caused by infiltration, not true myocyte hypertrophy -- this distinction is critical because treatments for hypertrophic cardiomyopathy such as beta-blockers and calcium channel blockers can worsen amyloid cardiomyopathy). The stiffened, non-compliant ventricles develop diastolic dysfunction (impaired relaxation and filling) that progresses to restrictive physiology (marked elevation of filling pressures with preserved or only mildly reduced systolic function until late stages). Clinically, this manifests as heart failure with relatively preserved ejection fraction but severely impaired cardiac output, presenting with dyspnea, exercise intolerance, peripheral edema, elevated JVP, ascites, and hepatomegaly. Low voltage on ECG (small QRS complexes) in the setting of increased wall thickness on echocardiography is a classic discordance that should immediately raise suspicion for cardiac amyloidosis -- true LVH typically shows HIGH voltage on ECG. Conduction system infiltration causes bradyarrhythmias (AV block, sick sinus syndrome often requiring pacemaker), and atrial amyloid deposition promotes atrial fibrillation (present in 40-70% of patients). Diagnosis has been revolutionized by technetium pyrophosphate (Tc-99m PYP) nuclear scintigraphy, which demonstrates intense myocardial uptake in ATTR cardiac amyloidosis (grade 2-3 uptake) with high sensitivity and specificity, potentially eliminating the need for endomyocardial biopsy in many cases. However, AL amyloidosis must be excluded by demonstrating absence of a monoclonal protein (serum free light chains, serum protein electrophoresis with immunofixation, urine protein electrophoresis with immunofixation) before a positive Tc-99m PYP scan can be attributed to ATTR. Endomyocardial biopsy with Congo red staining (demonstrating apple-green birefringence under polarized light) remains the gold standard for definitive diagnosis and amyloid typing. Treatment differs by type: AL amyloidosis requires chemotherapy targeting the clonal plasma cells (bortezomib-based regimens, autologous stem cell transplant in eligible patients, daratumumab); ATTR amyloidosis now has disease-modifying therapies including tafamidis (a TTR tetramer stabilizer that was shown in the ATTR-ACT trial to reduce mortality and hospitalizations by 30%) and in hereditary ATTR, patisiran or inotersen (TTR gene silencers that reduce hepatic TTR production by 80-90%). General heart failure management is challenging because many standard heart failure medications are poorly tolerated: beta-blockers reduce heart rate-dependent cardiac output in fixed stroke volume patients, ACE inhibitors/ARBs cause hypotension from autonomic neuropathy, and digoxin binds to amyloid fibrils causing toxicity at standard doses. Loop diuretics are the mainstay of symptom management.