Atrial Fibrillation Burden Specifically Determines Human Ventricular Cellular Remodeling

• Published in: JACC. Clinical electrophysiology Vol. 8; no. 11; pp. 1357 - 1366
• Main Authors: Körtl, Thomas, Stehle, Thea, Riedl, Dominic, Trausel, Johanna, Rebs, Sabine, Pabel, Steffen, Paulus, Michael, Holzamer, Andreas, Marrouche, Nassir, Maier, Lars S., Sohns, Christian, Streckfuss-Bömeke, Katrin, Sossalla, Samuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2022
• Subjects: atrial fibrillation; Atrial Fibrillation - surgery; CASTLE-AF; Catheter Ablation - methods; Clinical Trials as Topic; heart failure; Heart Failure - etiology; Humans; Ventricular Dysfunction, Left; Ventricular Remodeling - physiology; heart failure; atrial fibrillation; iPSC-CM; AF; APD; iPSC; LVSD; CASTLE-AF; LV; AP; SR
• ISSN: 2405-500X; 2405-5018
• DOI: 10.1016/j.jacep.2022.07.016

Atrial fibrillation (AF) can either be a consequence or an underlying mechanism of left ventricular systolic dysfunction. Patients included in the CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial who suffered from AF and left ventricular systolic dysfunction benefited from an AF burden <50% after catheter ablation compared with those patients with an AF burden >50%. This analysis tried to explain the clinical findings of the CASTLE-AF trial regarding AF burden in a “back-to-bench” approach. To study the ventricular effects of different AF burdens, experiments were performed using human ventricular induced pluripotent stem cell–derived cardiomyocytes undergoing in vitro AF simulation. Epifluorescence microscopy, action potential measurements, and measurements of sarcomere regularity were conducted. Induced pluripotent stem cell–derived cardiomyocytes stimulated with AF burden of 60% or higher displayed typical hallmarks of heart failure. Ca2+ transient amplitude was significantly reduced indicating negative inotropic effects. Action potential duration was significantly prolonged, which represents a potential trigger for arrhythmias. A significant decrease of sarcomere regularity could explain impaired cardiac contractility in patients with high AF burden. These effects were more pronounced after 7 days of AF simulation compared with 48 hours. Significant functional and structural alterations occurred at the cellular level at a threshold of ∼50% AF burden as it was observed to be harmful in the CASTLE-AF trial. Therefore, these translational results may help to understand the findings of the CASTLE-AF trial. [Display omitted]