Experimental evidence, both in vitro and in vivo, has indicated cardioprotective effects of extracellular vesicles (EVs) derived from various cell types, including induced pluripotent stem cell-derived cardiomyocytes. The biological effects of EV secretion, particularly in the context of ischemia and cardiac electrophysiology, remain to be fully explored. Therefore, the goal of this study was to unveil the effects of exosome (EXO)-mediated cell–cell signaling during hypoxia by employing a simulated preconditioning approach on human-induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs). Electrophysiological activity of hIPSC-CMs was measured using a multielectrode array (MEA) system. A total of 16 h of hypoxic stress drastically increased the beat period. Moreover, hIPSC-CMs preconditioned with EXOs displayed significantly longer beat periods compared with non-treated cells after 16 h of hypoxia (+15.7%, p < 0.05). Furthermore, preconditioning with hypoxic EXOs resulted in faster excitation–contraction (EC) coupling compared with non-treated hIPSC-CMs after 16 h of hypoxia (−25.3%, p < 0.05). Additionally, microRNA (miR) sequencing and gene target prediction analysis of the non-treated and pre-conditioned hIPSC-CMs identified 10 differentially regulated miRs and 44 gene targets. These results shed light on the intricate involvement of miRs, emphasizing gene targets associated with cell survival, contraction, apoptosis, reactive oxygen species (ROS) regulation, and ion channel modulation. Overall, this study demonstrates that EXOs secreted by hIPSC-CM during hypoxia beneficially alter electrophysiological properties in recipient cells exposed to hypoxic stress, which could play a crucial role in the development of targeted interventions to improve outcomes in ischemic heart conditions.

Schizophrenia patients experience a 14·5-year life expectancy reduction, yet the link between cardiovascular risk prediction, ischaemic heart disease (IHD) diagnosis, and mortality remains fragmented. We synthesised evidence across the full continuum of IHD risk, morbidity, and mortality in schizophrenia patients to identify gaps in clinical recognition and prevention. This systematic review and meta-analysis searched PubMed, Embase, and Cochrane Library from database inception to June 17, 2026, for observational studies reporting IHD risk scores, incidence, prevalence, or mortality in schizophrenia populations. We pooled estimates with random-effects meta-analyses, using Robust Bayesian Meta-Analysis to assess bias. The study followed PRISMA and was registered with PROSPERO, CRD42023412510. We identified 62 studies (North America, Europe, Asia, and Oceania); 33 contributed to meta-analysis. Schizophrenia patients have elevated IHD mortality compared to general population (standardised mortality ratio [SMR] 2·26, 95 % CI 1·85-2·76; p < 0·001; I²=98·5 %). By contrast, IHD diagnostic incidence showed a weaker association across measures (hazard ratio 1·40, 95 % CI 1·00-1·97; p = 0·052), revealing an IHD diagnostic-mortality discordance. Elevated IHD mortality held in females (SMR 2·57, 2·00-3·29) and males (SMR 2·25, 1·84-2·75); within-study comparisons concentrated the relative IHD mortality burden in younger adults (<50 years) with conventionally low risk scores. The contrast between elevated IHD mortality and weak IHD diagnostic associations suggests systematic under-recognition of IHD in schizophrenia. Routine cardiovascular screening and low diagnostic thresholds for ischaemic symptoms are warranted for all schizophrenia patients, particularly younger adults and women, in whom conventional risk tools may underestimate risk. The Research Council of Norway FRIPRO, ID: 316,002.