Transthyretin Cardiac Amyloidosis and Heart Failure: State-of-the-Art Review and Practice Guidance

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized and underdiagnosed cause of heart failure (HF), encompassing both preserved (HFpEF) and reduced (HFrEF) ejection fraction phenotypes. Once identifiable only following a biopsy, the advent of bone scintigraphy has dramatically improved noninvasive detection and detected a higher community prevalence, particularly among older patients with unexplained left ventricular hypertrophy. ATTR-CA arises from misfolding of transthyretin (TTR), leading to amyloid fibril deposition within the myocardium, which impairs cardiac compliance, conduction, and output. This review explores the evolving epidemiology of ATTR-CA in HF, mechanisms of disease progression, and key features for screening, emphasizing clinical red flags, biomarkers, and imaging features. This review also addresses the nuanced role of guideline-directed medical therapy in this population, where neurohormonal agents may offer limited benefit or be poorly tolerated due to restrictive physiology and autonomic dysfunction. Crucially, the emergence of amyloid-specific therapies, including TTR silencers, stabilizers, and degraders, has transformed the therapeutic landscape, offering mortality and morbidity benefits that were previously unavailable. Early diagnosis and individualized management, integrating conventional and amyloid-targeted approaches, are essential to improving outcomes in this complex and increasingly treatable cardiomyopathy.