Tian Zou

Aims: The prevalence of atrial fibrillation (AF), particularly age-related AF, is increasing rapidly with global aging. Cellular senescence is a key contributing factor to AF, yet the underlying mechanisms driving atrial cardiomyocyte senescence remain elusive. Although MAPK15 has recently been implicated in regulating epithelial cell senescence, its potential role in the heart remains unclear. Therefore, this study aims to investigate the role of MAPK15 in atrial cardiomyocyte senescence and AF, and to elucidate the underlying mechanisms. Methods and Results: We investigated the role and underlying mechanisms of MAPK15 in atrial cardiomyocyte senescence and AF by cardiac-specific overexpression or knockdown of MAPK15, as well as treatment with small-molecule inhibitors. A combination of transcriptomic and metabolomic profiling, co-immunoprecipitation with mass spectrometry, site-directed mutagenesis, patch-clamp recording, optical mapping and intracardiac electrophysiology was employed both in vitro and in vivo. Findings were further validated using human atrial appendage specimens. Results showed that MAPK15 was closely associated with atrial cardiomyocyte senescence and AF. Overexpression of MAPK15 aggravated senescence and promoted AF. Mechanistically, MAPK15 induced palmitoylation of mitochondrial calcium uniporter dominant negative subunit b (Mcub) at C91, causing its dissociation from the mitochondrial Mcu complex and translocation to the cytoplasm. This impaired inhibition of mitochondrial calcium uptake, leading to calcium overload, ROS overproduction, and cellular senescence. C91S mutation or palmitoylation inhibition (2-BP) reversed these effects. Subsequently, senescent cardiomyocytes showed increased triggered activity, fibrosis, and altered connexin43 distribution, facilitating AF onset. And serological analysis suggested that IL-17a may act as an upstream regulator of MAPK15. Conclusion: Our findings identify MAPK15 as a novel regulator of atrial cardiomyocyte senescence and AF. MAPK15 promotes mitochondrial calcium overload through palmitoylation of Mcub at C91, highlighting a new mechanistic axis linking mitochondrial dysfunction, cellular senescence, and arrhythmogenesis. Translational Perspective: Age-related atrial fibrillation is highly prevalent and frequently associated with adverse cardio- and cerebrovascular events, constituting a significant global public health burden. In this study, we demonstrated at both in vivo and in vitro levels that the MAPK15-Mcub axis promotes atrial cardiomyocyte senescence and senescence-associated AF, which was further validated in atrial appendage tissues from clinical patients, enhancing the clinical translational relevance of our findings. Moreover, we identified circulating IL-17a as a potential upstream activator associated with MAPK15 signaling, suggesting its potential utility in preclinical screening and as an insightful clue for future immunomodulatory strategies. The development of small-molecule agents specially targeting MAPK15 or Mcub in cardiomyocytes may represent a novel therapeutic strategy for treating atrial myocyte senescence and AF.

Introduction: Cardiogenic shock (CS) carries high morbidity and mortality. However, evidence for mechanical circulatory support (MCS) in non‐ischemic CS remains limited, as prior trials have focused on infarct‐related shock. Methods: We performed a retrospective cross‐sectional study using the Nationwide Inpatient Sample (2017–2019), identifying hospitalizations with a principal diagnosis of CS and excluding acute myocardial infarction. Patients were categorized into mutually exclusive groups: no MCS, intra‐aortic balloon pump (IABP) only, Impella only, or extracorporeal membrane oxygenation (ECMO) only. Primary outcomes were in‐hospital mortality, length of stay (LOS), and total hospital cost. Survey‐weighted multivariable models adjusted for demographics, hospital characteristics, and comorbidity burden using Elixhauser and Charlson indices. Results: Among 104 045 hospitalizations, 6040 received MCS. IABP was most common, followed by Impella and ECMO. Among patients receiving a single MCS strategy, overall in‐hospital mortality was 29.5%., with lower mortality in the IABP group (19.9%) compared with Impella (37.4%) and ECMO (44.3%). After adjustment, IABP was associated with lower observed in‐hospital mortality versus no MCS (aOR 0.58, 95% CI 0.53–0.64; p < 0.01), whereas Impella and ECMO showed increased aOR. IABP and ECMO were associated with longer LOS, while Impella was not. All MCS strategies were associated with higher costs, with ECMO showing the greatest increase (cost ratio 3.30, 95% CI 3.12–3.50). Conclusion: In non‐ischemic CS, MCS strategies demonstrate distinct profiles of mortality and resource utilization. IABP was associated with lower observed in‐hospital mortality, whereas all MCS were linked to higher costs, highlighting heterogeneity in outcomes and the need for further research.