In this episode of Hospital Medicine Unplugged, we unpack cardiac amyloidosis—recognize the red flags hiding inside “routine HFpEF,” diagnose ATTR noninvasively, and start disease-modifying therapy before restrictive physiology becomes irreversible.

ATTR cardiac amyloidosis is far more common than previously recognized, especially in older adults with HFpEF and increased LV wall thickness. Key clues include voltage-mass discordance—thick ventricles on echo with surprisingly low ECG voltage—and extracardiac findings like carpal tunnel syndrome, lumbar spinal stenosis, trigger finger, or biceps tendon rupture that may precede diagnosis by years.

Echo pearls: • Increased wall thickness with preserved EF • Restrictive filling pattern • Biatrial enlargement • Classic “apical sparing” strain pattern

The modern diagnostic breakthrough is nuclear imaging: • Grade 2–3 uptake on technetium-PYP scan + negative monoclonal protein testing = essentially diagnostic for ATTR-CM without biopsy.

Never skip monoclonal protein screening: • Serum free light chains • Serum immunofixation • Urine immunofixation

This distinction matters because AL amyloidosis is a hematologic emergency requiring plasma-cell–directed therapy.

Treatment changed dramatically with tafamidis: • Reduces mortality • Lowers cardiovascular hospitalizations • Works best when started early

Acoramidis joined the field in 2024 as another TTR stabilizer with similar benefits.

Heart failure management is different here: • Loop diuretics are the backbone • ACE inhibitors, ARBs, and beta-blockers are often poorly tolerated • Avoid digoxin and non-dihydropyridine calcium channel blockers

Key pearl: anticoagulate atrial fibrillation regardless of CHA₂DS₂-VASc score due to extreme thromboembolic risk.

We close with the system moves: when HFpEF doesn’t quite fit—especially with unexplained LVH, neuropathy, orthopedic history, or voltage-mass discordance—think amyloid early, order monoclonal protein studies plus PYP scanning, and start disease-modifying therapy before fibrosis and restrictive failure dominate the trajectory.

Not all HFpEF is hypertensive heart disease—sometimes the diagnosis is hiding in the carpal tunnel scar.