This research letter investigates the cellular mechanisms by which atrial fibrillation (AF) exacerbates ventricular dysfunction in end-stage heart failure (HF), providing mechanistic context for the clinical benefits observed in the CASTLE-HTx trial. Using human ventricular trabeculae and patient-derived hiPSC cardiomyocytes, the authors demonstrate that AF simulation induces rapid contractile dysfunction and cellular remodelling specifically in failing myocardium, providing mechanistic insights into the CASTLE-HTx trial outcomes.
The study's primary strength lies in its robust translational approach, bridging clinical observations with molecular and cellular mechanisms.
The CASTLE-HTx trial demonstrated that catheter ablation improved prognosis in end-stage HF patients with AF, even in a population awaiting heart transplantation, with associated improvements in left ventricular systolic function. This benefit was attributed to a reduction in AF burden and restoration of rhythm control. However, the underlying cellular mechanisms remained elusive. This study elegantly addresses this knowledge gap by demonstrating that AF itself induces acute ventricular dysfunction in failing hearts using human tissue and patient-derived cardiomyocytes to replicate AF's effects in vitro.
In failing hiPSC cardiomyocytes, 48-hour AF simulation substantially reduced systolic calcium transient amplitude and impaired diastolic calcium elimination, associated with decreased SERCA2a activity, the primary calcium pump mediating sarcoplasmic reticulum uptake, and prolonged action potential duration. These alterations reflect hallmark features of HF-related electrical and contractile remodelling and were absent in healthy control cardiomyocytes after 48 hours of AF simulation, underscoring the particular vulnerability of failing myocardium to AF-induced stress.
In conclusion, this study convincingly bridges clinical and experimental cardiology by mechanistically substantiating the prognostic benefit of AF ablation observed in the CASTLE-HTx trial. It reinforces the concept that AF is not merely a bystander but a direct driver of ventricular dysfunction in end-stage HF, supporting early and aggressive rhythm control strategies in this high-risk population.
