Cardiac amyloidosis: New insights into pathophysiology and therapeutic advances

Cardiac amyloidosis (CA) is a once underdiagnosed and often fatal condition that has evolved into a disease with expanding diagnostic and therapeutic possibilities. It is characterized by the extracellular deposition of misfolded amyloid proteins within the myocardium, leading to structural and functional impairment. Advances in understanding the pathophysiology encompassing the amyloid protein misfolding, aggregation and deposition in cardiac tissue as well as the role of genetic factors have been pivotal in driving progress in diagnosis and management. The deposition of amyloid proteins can lead to significant cardiac manifestations, including constrictive cardiomyopathy, heart failure (both preserved and reduced ejection fraction), and arrhythmias particularly atrial fibrillation, contributing to substantial morbidity and mortality. Diagnostic innovations, such as advanced imaging and novel biomarkers, have enabled early detection and precise subtype differentiation, underscoring the need for targeted therapies. Over the past decade, therapeutic advancements have introduced transformative medications that gained FDA approval for the management of transthyretin amyloidosis (ATTR) including transthyretin stabilizers and silencers. Promising strategies like gene editing, antisense oligonucleotides and monoclonal antibodies are currently under investigation. However, managing cardiac manifestations remains challenging, particularly in optimizing euvolemia and rate control in heart failure and atrial fibrillation with limitations in traditional medications. This review explores the evolving landscape of CA, from pathophysiologic insights to innovative therapies, and provides a comprehensive approach to the management of cardiac manifestations to address ongoing challenges this condition.