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Abstract: Human induced pluripotent stem cells (hiPSC) and atrial hiPSC-derived cardiomyocytes (hiPSC-CM) have entered the arena of preclinical atrial fibrillation research. A central question is whether they reproduce the physiologic contribution of atrial selective potassium currents (such as the ultrarapid potassium current, I Kur ) to repolarization. Of note, 2 studies in single atrial hiPSC-CM reported prolongation of action potential duration by I Kur block indicating that I Kur might in fact represent a valuable target for the treatment of human atrial fibrillation. However, the results and interpretation are at odds with the literature on I Kur block in human atria and the results of clinical studies. We believe that the discrepancies indicate that experiments in single atrial CM (both adult atrial CM and atrial hiPSC-CM) might be misleading. Under particular experimental conditions, atrial hiPSC-CMs may not closely resemble the electrophysiology of the human atrium. Therefore, we recapitulate here methodological issues evaluating potential value of the I Kur as an antiarrhythmic target when investigated in animal models, in human atrial tissues, and finally in atrial hiPSC-CM., Competing Interests: C. Schulz and T. Christ have no conflict of interest. T. Eschenhagen is consultant and shareholder of Dinaqor AG., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Atrial fibrillation (AF) poses a significant therapeutic challenge with drug interventions showing only limited success. Phosphodiesterases (PDE) regulate cardiac electrical stability and may represent an interesting target. Recently, PDE8 inhibition was proposed as an antiarrhythmic intervention by increasing L-type Ca2+ current (ICa,L) and action potential duration (APD). However, the effect size of PDE8 inhibition on ICa,L and APD seems discrepant and effects on force are unknown. We investigated the impact of PDE8 inhibition on force using PF-04957325 in right atrial appendages, obtained from patients in sinus rhythm (SR) and with persistent AF (peAF) undergoing cardiac surgery. A computational model was employed to predict the effects of PDE8 inhibition on APD in SR and peAF. Results showed no increase in force after exposure to increasing concentrations of the PDE8 inhibitor PF-04957325 in either SR or peAF tissues. Furthermore, PDE8 inhibition did not affect the potency or efficacy of norepinephrine-induced inotropic effects in either group. Arrhythmic events triggered by norepinephrine were observed in both SR and peAF, but their frequency remained unaffected by PF-04957325 treatment. Computational modeling predicted that the reported increase in ICa,L induced by PDE8 inhibition would lead to substantial APD prolongation at all repolarization states, particularly in peAF. Our findings indicate that PDE8 inhibition does not significantly impact force or arrhythmogenicity in human atrial tissue., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in the human atrium. Data on the contribution of the slowly activating delayed rectifier currents (IKs) to repolarization are lacking for both human atrium and hiPSC-aCM., Methods and Results: Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model IKs contribution to action potential (AP) shape. Action potential was recorded by sharp microelectrodes. HMR-1556 (1 µM) was used to identify IKs and to estimate IKs contribution to repolarization. Less than 50% of hiPSC-aCM and aCM possessed IKs. Frequency of occurrence, current densities, activation/deactivation kinetics, and voltage dependency of IKs did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. β-Adrenoceptor stimulation with isoprenaline did not increase IKs neither in aCM nor in hiPSC-aCM. In tissue from SR, block of IKs with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultra-rapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031., Conclusion: I Ks exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), IKs does not appear to relevantly contribute to repolarization in hiPSC-aCM., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In times of physical stress, the body orchestrates a multisystemic regulatory response. The hormones epinephrine and norepinephrine play a role in the immediate regulation chain, while cortisol is involved in delayed regulation. The release of those stress hormones in response to exercise has previously been reported to elicit diverse immune reactions., Objective: The aim of this systematic review was to examine and present the acute effects of immediate pre- and mid-exercise carbohydrate ingestion on cortisol, epinephrine and norepinephrine levels in experienced endurance athletes., Methods: A systematic literature search was conducted using PubMed, Cochrane Library and Web of Science in accordance with PRISMA guidelines up to February 2023. Randomized controlled trials in English or German language were included if baseline and at least two follow-up measures of blood plasma or serum of chosen stress hormones (cortisol, epinephrine, norepinephrine) were collected in response to prolonged continuous endurance activity. Eligibility furthermore required an acute carbohydrate ingestion of at least 30 g of carbohydrates per hour no more than 30 min before start of the exercise, as well as a placebo-controlled study design., Results: Eleven studies of moderate to high quality were included in this review. Carbohydrate ingestion of at least 30 g per hour was able to attenuate rises in cortisol concentration in majority of the included studies. Epinephrine levels were considerably lower with ingestion of carbohydrates compared to placebo in all studies. Norepinephrine concentrations were largely unaffected by acute carbohydrate feeding., Conclusion: Pre- and mid-exercise ingestion of carbohydrates seems an effective dietary strategy to attenuate rises in cortisol and epinephrine levels and, thus, an effective countermeasure for endurance exercise-induced increases in stress hormone levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Christ, Ringleb, Haunhorst, Fennen, Jordan, Wagner and Puta.)