Transthyretin cardiac amyloidosis: an evolving paradigm in recognition, diagnosis, and treatment

Transthyretin amyloid cardiomyopathy (ATTR-CM) has evolved from an underrecognized and largely untreatable infiltrative cardiomyopathy into a paradigm of precision cardiovascular medicine. The disease arises from transthyretin tetramer destabilization, protein misfolding, and progressive extracellular amyloid deposition, processes that ultimately shape its multisystem clinical phenotype. Importantly, the biology of ATTR-CM is often clinically apparent years before overt heart failure through extracardiac manifestations, including carpal tunnel syndrome, spinal stenosis, and tendon disease,. Recognition of this disease continuum has transformed diagnostic strategies, with contemporary evaluation integrating clinical red flags, multimodality imaging, exclusion of light-chain amyloidosis, radionuclide imaging, and genetic testing to establish ATTR subtype. Emerging artificial intelligence-enabled electrocardiographic and imaging approaches may further shift recognition toward earlier, pre-diagnostic disease recognition, although their clinical utility requires prospective validation. Management has undergone an equally profound transformation. Beyond physiology-guided treatment of heart failure, atrial fibrillation, and thromboembolic risk, disease-modifying therapies now directly target the amyloidogenic cascade through stabilization of circulating transthyretin or suppression of its hepatic synthesis. Cardiovascular outcome evidence for TTR silencers is currently agent-specific: vutrisiran demonstrated clinical benefit in HELIOS-B, whereas eplontersen did not significantly reduce the primary cardiovascular endpoint in CARDIO-TTRansform. The therapeutic frontier is expanding further toward monoclonal antibodies designed to promote clearance of established amyloid deposits, raising the possibility of moving from disease stabilization toward myocardial amyloid regression. This review integrates the molecular pathogenesis, clinical and imaging phenotype, contemporary diagnostic framework, emerging role of artificial intelligence, and rapidly evolving therapeutic landscape of ATTR-CM.