The effect of sex and age on ex vivo cardiac electrophysiology: insight from a guinea pig model.

Highlighting the importance of sex as a biological variable, we recently reported sex differences in guinea pig in vivo electrocardiogram (ECG) measurements. However, substantial inconsistencies exist in this animal model, with conflicting reports of sex-specific differences in cardiac electrophysiology observed in vivo and in vitro. Herein, we evaluated whether sexual dimorphism persists in ex vivo preparations, using an isolated intact heart preparation. Pseudo-ECG recordings were collected in conjunction with dual optical mapping of transmembrane voltage and intracellular calcium from Langendorff-perfused hearts. In contrast to our in vivo results, we did not observe sex-specific differences in ECG parameters collected from isolated hearts. Furthermore, we observed significant age-specific differences in action potential duration (APD) and Ca2+ transient duration (CaD) during both normal sinus rhythm (NSR) and in response to dynamic pacing but only a modest sex-specific difference in CaD30. Similarly, the alternans fluctuation coefficient, conduction velocity during sinus rhythm or in response to pacing, and electrophysiology parameters (atrioventricular nodal effective refractory period, Wenckebach cycle length) were comparable between males and females. Results of our study suggest that the observed sex-specific differences in in vivo ECG parameters from guinea pigs are diminished in ex vivo isolated heart preparations, although age-specific patterns are prevalent. To assess sex as a biological variable in cardiac electrophysiology, a comprehensive approach may be necessary using both in vitro measurements from cardiomyocyte or intact heart preparations with secondary follow-up in vivo studies.NEW & NOTEWORTHY We evaluated whether the guinea pig heart has intrinsic sex-specific differences in cardiac electrophysiology. Although we observed sex-specific differences in in vivo ECGs, these differences did not persist ex vivo. Using a whole heart model, we observed similar APD, CaD, conduction velocity, and alternans susceptibility in males and females. We conclude that sex-specific differences in guinea pig cardiac electrophysiology are likely influenced by the in vivo environment and less dependent on the intrinsic electrical properties of the heart.

Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A.

Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA. This study aimed to examine the direct effects of BPA on cardiac electrophysiology compared with recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). Whole-cell voltage-clamp recordings were performed on cell lines transfected to express the voltage-gated sodium channel (Nav1.5), L-type voltage-gated calcium channel (Cav1.2), or the rapidly activating delayed rectifier potassium channel (hERG). Cardiac electrophysiology parameters were measured using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole rat heart preparations. BPA was the most potent inhibitor of fast/peak (INa-P) and late (INa-L) sodium channel (IC50 = 55.3, 23.6 µM, respectively), L-type calcium channel (IC50 = 30.8 µM), and hERG channel current (IC50 = 127 µM). Inhibitory effects on L-type calcium channels were supported by microelectrode array recordings, which revealed a shortening of the extracellular field potential (akin to QT interval). BPA and BPF exposures slowed atrioventricular (AV) conduction and increased AV node refractoriness in isolated rat heart preparations, in a dose-dependent manner (BPA: +9.2% 0.001 µM, +95.7% 100 µM; BPF: +20.7% 100 µM). BPS did not alter any of the cardiac electrophysiology parameters tested. Results of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, whereas BPS is markedly less potent. Additional studies are necessary to fully elucidate the safety profile of bisphenol analogs on the heart.