Atrial Fibrillation Aggravates Ventricular Dysfunction and Cellular Remodeling in Human Heart Failure

Background: Recent studies demonstrated the benefits of sinus rhythm restoration in patients with heart failure (HF) and atrial fibrillation (AF). Despite frequent coexistence of HF and AF, the cellular effects of AF in ventricular myocardium in pre-existing HF are largely unknown.

Methods: We performed contractility experiments using isolated ventricular trabeculae from end-stage HF patients after in vitro AF simulation by arrhythmic pacing for 8 h and at baseline. For healthy control, we performed respective experiments in human non-failing ventricular trabeculae. Fibrosis was quantified in ventricular tissue from HF patients with or without AF. Ventricular cardiomyocytes (CM) from end-stage HF patients with or without AF were isolated and subjected to intracellular Ca²⁺ imaging (epifluorescence microscopy with Fura-2 am) and patch-clamp evaluation of action potentials (AP). Furthermore, we used induced pluripotent stem-cell CM (iPSC-CM) from 2 patients with familial DCM and 1 healthy donor for 48 h AF simulation in culture and subsequently performed Ca²⁺ and AP measurements.

Results: Baseline contractile parameters of ventricular trabeculae (13/11 pat. SR/AF) and quantification of ventricular fibrosis (n = ⅚ pat.) showed no significant difference between end-stage HF patients with or without AF. 8 h of AF simulation in HF ventricular trabeculae led to a drastic deterioration of systolic and diastolic function with reduced force and slowed relaxation (n = 8 pat.). In contrast, AF simulation had no adverse effects on contractile parameters in non-failing trabeculae (n = 4 pat.). Patch-clamp experiments revealed a significant AP prolongation in isolated CM from HF patients with AF compared with SR (n = 15/6 pat.). Confirming those results, the AP duration after AF simulation was prolonged in DCM iPSC-CM (n = 9 diff.; 46/40 CM) but not in healthy iPSC-CM (n = 3 diff.; 15/15 CM). In healthy iPSC-CM (36/42 CM) 48 h of AF simulation had no effect on Ca²⁺ cycling, while in DCM iPSC-CM (110/82 CM) short-term AF simulation led to a 46% decrease of Ca²⁺-transient amplitude and slowed Ca²⁺ elimination compared with control. As a potential underlying mechanism, we found a significant reduction of SERCA activity by caffeine application.

Conclusion: Short-term AF simulation severely and rapidly compromised contractile function in human ventricular myocardium with end-stage HF. In DCM iPSC-CM 48 h of AF simulation adversely affected cellular Ca²⁺ handling and electrophysiology, but did not induce alterations in healthy CM. This study elucidates the detrimental mechanisms of AF-mediated aggravation of pre-existing heart failure and adds a mechanistic approach to clinical studies.

Publication History

Article published online:
11 February 2025