Background: Postoperative delirium (POD) is a severe complication following cardiac surgery and is associated with increased morbidity and mortality. The impact of intra- and early postoperative factors on the occurrence of POD following cardiac surgery remains controversial. To close this gap, we investigated intra- and early postoperative factors and their predictive values for POD. Methods: We performed a prospective observational study that aimed to FIND DElirium RIsk factors (FINDERI) for patients undergoing elective cardiac surgery. POD was assessed using the Confusion Assessment Method algorithm. Intra- and early postoperative factors were extracted from electronic medical records and reviewed by cardiac surgeons. To identify potential predictors of POD, we used univariate and multivariate logistic regression along with machine learning (ML) with ten-fold cross-validation. Results: In our study cohort of 490 patients, 106 screened positive for POD (21.6%). In the multivariate analysis, we found a positive association between POD occurrence and age (P < 0.001), duration of surgery (P = 0.027), combined (versus isolated) surgical procedures (P = 0.024), opening of the cardiac chambers (P = 0.046), and ventilation time (P < 0.001). The ML-based decision tree identified a two level-algorithm including ventilation time and aortic cross-clamping time, with an AUC of 0.7116 (P = 0.0002) in the validation set. In the ML-based LASSO regression analysis, we identified ventilation time, administration of erythrocyte concentrates (EC), and usage of cardiopulmonary bypass (CPB) as predictors of POD, with an AUC of 0.7407 (P < 0.0001) in the validation set. Conclusion: The results of this analysis highlight the associations between ventilation time, aortic cross-clamping time, administration of EC, and usage of CPB and POD. Additionally, they suggest that the optimization of surgical protocols has the potential to reduce POD risk in individuals undergoing cardiac surgery.

In heart failure and atrial fibrillation, a persistent Na⁺ current (I_NaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na_V1.8 contributes to arrhythmogenesis by inducing a I_NaL. Genome-wide association studies indicate that mutations in the SCN10A gene (Na_V1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na_V1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I_NaL and action potential duration. Ca²⁺ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca²⁺ leak. The I_NaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na_V1.8. No effects on atrial APD₉₀ were detected in any groups. Both SCN10A KO and specific blockers of Na_V1.8 led to decreased Ca²⁺ spark frequency and a significant reduction of arrhythmogenic Ca²⁺ waves. Our experiments demonstrate that Na_V1.8 contributes to I_NaL formation in human atrial CMs and that Na_V1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na_V1.8 could be a new target for antiarrhythmic strategies.

The sodium channel Na_V1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na_V1.8 contributes to arrhythmogenesis by inducing a persistent Na⁺ current (late Na⁺ current, I_NaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of Na_V1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that I_NaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of Na_V1.8. In contrast, we did not find any effects on ventricular APD₉₀. The frequency of spontaneous sarcoplasmic reticulum Ca²⁺ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of Na_V1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of Na_V1.8 in control cells. In conclusion, we show that Na_V1.8-induced I_NaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca²⁺ release. The inhibition or knockout of Na_V1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms Na_V1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.