Effects of atrial fibrillation on the human right ventricle

E. Kayser (Göttingen)¹, T. Körtl (Gießen)², J. Ruppert (Gießen)³, D. Riedl (Gießen)⁴, L. Stengel (Regensburg)⁵, R. Schramm (Bad Oeynhausen)⁶, J. Gummert (Bad Oeynhausen)⁶, H. Milting (Bad Oeynhausen)⁷, K. Streckfuß-Bömeke (Würzburg)⁸, S. T. Sossalla (Gießen)^2
1Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; ²Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; ³Justus-Liebig-Universität Giessen Gießen, Deutschland; ⁴Justus-Liebig-Universität Giessen Experimentelle Kardiologie Gießen, Deutschland; ⁵Universitätsklinikum Regensburg Klinik und Poliklinik für Innere Med. II, Kardiologie Regensburg, Deutschland; ⁶Herz- und Diabeteszentrum NRW Klinik für Thorax- und Kardiovaskularchirurgie Bad Oeynhausen, Deutschland; ⁷Herz- und Diabeteszentrum NRW E.& H. Klessmann-Institut f. kardiovask. Forschung Bad Oeynhausen, Deutschland; ⁸Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland

Background: Patients with pulmonary hypertension (PH) are more likely to suffer from worse cardiovascular outcome, when also they are simultaneously suffering from atrial fibrillation (AF). The influence of PH and AF on the right ventricle (RV) thereby remain unknown.

Methods: Experiments were performed using human right ventricular slices obtained from end-stage heart failure patients undergoing heart transplantation. slices were long-term cultivated and either stimulated regularly at 60 bpm (sinus rhythm simulation) or irregularly at 90 bpm (AF simulation).
Additionally, right ventricular human induced pluripotent stem cell cardiomyocytes (RV iPSC-CM) from healthy donors, expressing RV markers as ISl1, TBX1 and VCAN, were used for immunofluorescence staining. Cells were divided into a sinus rhythm group (regular stimulation with 60 bpm) and an AF group (irregular stimulation with 90 bpm). Both groups were stimulated for 48 h or 7 days. After 7 days, the stimulation of the AF group was switched to a sinus rhythm simulation, to represent an in vitro rhythm restoration.

Results: Compared to the beginning of the stimulation on day 0, after 7 days of AF stimulation, the contractile force significantly decreased. No significant change in contractile force was detected in the sinus rhythm group during the same period. Further, there was a tendency towards lower twitch amplitudes in the AF group compared to the SR group after 7 days (figure 1).
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Fig. 1: (A) Original representative twitch amplitudes. (B) Effects of SR and AF simulation on human contractile force. The total number of hearts analyzed is 5 with the total number of slices provided in each column. Data are presented with SEM, mixed-effects analysis was performed.

In RV iPSC-CM, AF simulation led to a decreased sarcomere regularity of alpha-actinin and titin after 7 days of AF stimulation, while no relevant differences were observed between the groups after 48 h. Interestingly, 5 days after the restoration of SR, a recovery in sarcomere organization was observed (figure 2).
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Fig. 2: Effects of sinus rhythm and AF simulation on sarcomere regularity for (A) alpha-actinin and (B) titin. Higher amplitude values directly correlate with higher sarcomere organization. In total, 3 RV iPSC-CM differentiations were used. The total number of analyzed cells is provided in each column. Data are presented with SEM, mixed-effects analysis was performed.

Conclusion: For the first time, we could demonstrate that AF simulation leads to impaired contractile force in human RV slices, which may at least in part can be explained by the irregular arrangement of alpha-actinin and titin in a RV iPSC-CM model. Subsequent investigations will specifically focus on patients with pulmonary hypertension (PH) and atrial fibrillation (AF) to examine the impact of this ‘double burden’ on the right ventricle (RV).