Arrhythmias in patients with transthyretin cardiac amyloidosis and the impact of contemporary disease-modifying therapies.

Abstract

Transthyretin cardiac amyloidosis (ATTR-CM) is an increasingly recognized infiltrative cardiomyopathy characterized by extracellular deposition of misfolded transthyretin fibrils, leading to progressive myocardial stiffening, electrical remodeling, and conduction-system disease. These pathophysiological changes create a complex arrhythmic substrate, resulting in a high burden of atrial, bradyarrhythmia, and ventricular arrhythmias that significantly contribute to morbidity and mortality. Despite advances in disease recognition, the optimal management of arrhythmias in ATTR-CM remains challenging, with limited evidence guiding antiarrhythmic strategies and device therapy. In particular, the prognostic significance of ventricular arrhythmias and the role of implantable cardioverter-defibrillators (ICDs) remain controversial. Recent disease-modifying therapies (DMTs), including transthyretin stabilizers (tafamidis, diflunisal) and gene-silencing agents (patisiran, vutrisiran), have transformed the therapeutic landscape and may modify disease progression and arrhythmic burden, although their direct antiarrhythmic impact is not yet fully defined. This narrative review provides a structured overview of the mechanisms, epidemiology, and clinical management of arrhythmias in ATTR-CM, with a focus on clinically relevant decision-making and the potential influence of contemporary DMTs. Finally, it highlights key unresolved questions and areas requiring further prospective research.