Pathophysiology and Comprehensive Pharmacological Management of ATTR Cardiac Amyloidosis: Knowledge Gaps, Ongoing Clinical Trials, and Future Research Directions

Abstract

The purpose of this review article is to discuss the current treatment modalities and ongoing clinical trials regarding cardiac amyloidosis (CA), specifically transthyretin cardiac amyloidosis (ATTR-CA). Amyloidosis refers to the extracellular deposition of insoluble amyloid fibrillar proteins. When these proteins are deposited in the heart’s myocardium, it is referred to as cardiac amyloidosis. CA can be divided into two main groups: light chain cardiac amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA), which can be further subdivided into wild-type transthyretin amyloidosis (ATTRwt) and hereditary transthyretin amyloidosis (ATTRv). ATTR-CA is an increasingly recognized cause of heart failure in the setting of progressive restrictive cardiomyopathy, particularly among older adults, males, and individuals of African descent, with remarkable advances in the therapeutic landscape. TTR stabilizers, including Tafamidis (approved in 2019) and Acoramidis (approved in 2024), have demonstrated significant reductions in mortality and cardiovascular hospitalizations. Gene silencing therapies, including Vutrisiran (approved in 2025), represent a new drug group that targets TTR production at the RNA level. Meanwhile, CRISPR-based gene editing with nexiguran ziclumeran (nex-z or NTLA-2001) and amyloid-depleting monoclonal antibodies offer the prospect of one-time curative treatments and active fibril clearance, respectively. However, despite these advances, substantial knowledge gaps persist: no head-to-head trials have compared stabilizers to silencers, optimal combination therapy regimens remain undefined, and the role of conventional guideline-directed medical therapy in ATTR-CA has only been supported by observational data.