Transthyretin Amyloid Cardiomyopathy: A Review of Approved Pharmacotherapies.

Abstract

Transthyretin (TTR) amyloidosis (ATTR) occurs due to misfolding and aggregation of TTR protein in numerous organs and tissues, resulting in various clinical presentations including cardiomyopathy and polyneuropathy. The pathophysiology of ATTR cardiomyopathy is characterized by TTR deposition in the interstitial space between cardiac myocytes, contributing to microvascular dysfunction and cardiac myocyte injury and necrosis. As the misfolded TTR protein accumulates in cardiac tissue, it results in impaired diastolic function, progressive ventricular wall thickening, and impaired longitudinal systolic function. Understanding the pathophysiology of ATTR cardiomyopathy has allowed for the development of pharmacotherapies that target the disease process, including the identification of a stabilizing TTR gene mutation, threonine119methionine (T119M), that confers resistance towards amyloidogenesis. In 2019, the Food and Drug Administration approved tafamidis for the treatment of ATTR cardiomyopathy due to its ability to stabilize the TTR tetramer and prevent dissociation into monomers that subsequently cause amyloidosis. In 2024, acoramidis was approved for ATTR cardiomyopathy as a novel TTR stabilizer structurally designed to mimic the stabilizing effects of the T119M mutation by binding selectively and with high affinity to TTR, preventing the dissociation of TTR tetramer into monomers and aggregation into amyloid fibrils. In 2025, vutrisiran, a small interfering ribonucleic acid that cleaves TTR messenger RNA and decreases the production of TTR protein, was approved for use in ATTR cardiomyopathy. In their clinical trials, these approved therapies demonstrated significant mortality and morbidity benefits in patients with ATTR cardiomyopathy, including a decrease in cardiovascular events, hospitalizations, and functional status.