Background: Pulmonary hypertension (PH) and atrial fibrillation (AF) frequently coexist and mutually worsen clinical outcome. Despite the high prevalence of both conditions, the impact of PH on right ventricular (RV) function in the presence of AF and the underlying cellular mechanisms remain largely unexplored.
Methods: Human RV tissue was obtained from explanted hearts of patients with end-stage heart failure undergoing heart transplantation and further processed into myocardial slices. These slices were cultivated for 7 days and divided into 4 groups: (1) sinus rhythm (SR), (2) SR + PH, (3) AF and (4) AF + PH. While SR slices were stimulated regularly with 60 bpm, AF was simulated with 90 bpm and 30% beat-to-beat variability. A PH simulation model was designed by inducing hypoxia through adding 100 M cobalt chloride (CoCl2) to the medium and by applying increased diastolic tension to mimic elevated wall stress. During cultivation, contractility parameters were continuously recorded. In addition, RV cardiomyocytes derived from human induced pluripotent stem cells (RV-hiPSC-CM) were divided into the same 4 groups and after 7 days of stimulation, intracellular calcium homeostasis was analyzed by epifluorescence microscopy.
Results: In total, 34 RV slices from 6 patients were analyzed. After 7 days, AF-stimulation significantly impaired twitch amplitude in all groups compared to SR. The strongest decline was observed in slices exposed to AF and CoCl₂, indicating a combined detrimental effect of AF and PH simulation on RV contractile function (p<0.0001). No significant intergroup differences were detected when diastolic tension, relaxation time 80% (RT80%), time-to-peak, post rest ratio or force frequency relationship were analyzed. To further investigate the underlying mechanism, we used a RV-hiPSC-CM model. At the end of the 7-day period, the calcium transient amplitude was significantly reduced in the AF (p<0.007), PH (p<0.0001) and AF + PH groups (p<0.0001) compared to the SR group. Conversely, diastolic calcium levels and RT80% showed no significant alterations. The findings of this study demonstrate consistent contractile impairment under AF and PH stimulation in both models.
Conclusion: This study demonstrates that the coexistence of pulmonary hypertension and atrial fibrillation synergistically impairs right ventricular function. As almost half of patients with pulmonary hypertension develop atrial fibrillation, our findings provide a mechanistic basis for the poor prognosis observed in this population and may guide the development of targeted therapeutic strategies.
