Advances in the treatment of transthyretin cardiac amyloidosis: Current and emerging therapies

Transthyretin cardiac amyloidosis (ATTR-CA) has been recognized as an underdiagnosed and undertreated cause of heart failure with often unrecognized multiorgan involvement. Guideline development and the establishment of nonbiopsy criteria for diagnosis of ATTR-CA have led to an increased rate of diagnosis and hence patients referred for therapies. ATTR is a protein misfolding disorder where the TTR tetramer disassociates into monomers which form insoluble amyloid depositions in organs, including the heart. ATTR-CA can be due to autosomal dominant transmitted gene mutation or due to misfolding of wild-type TTR. Prior to 2019, there were no FDA-approved pharmacological treatments for ATTR-CA. Understanding of ATTR-CA pathogenesis has enabled development of targeted strategies with novel disease-modifying therapies. Current and emerging therapies for ATTR-CA include (1) TTR gene silencing (siRNA, ASO, CRISPR/Cas9), (2) TTR tetramer stabilization, and (3) TTR amyloid fibril degradation. This review focuses on the pathophysiology of ATTR-CA, diagnostic criteria, and addresses current and emerging treatments for this diverse disorder.