Journal of molecular and cellular cardiology plus最新文献

{"title":"YAP/TAZ deletion in vascular smooth muscle cells mirrors atherosclerosis-associated transcriptional programs","authors":"Fatima Daoud ,&nbsp;Johan Holmberg ,&nbsp;Hanna Winter ,&nbsp;Nadja Sachs ,&nbsp;Lars Maegdefessel ,&nbsp;Sebastian Albinsson","doi":"10.1016/j.jmccpl.2025.100487","DOIUrl":"10.1016/j.jmccpl.2025.100487","url":null,"abstract":"<div><div>The transcriptional co-activators YAP (<em>YAP1</em>) and TAZ (<em>WWTR1</em>) are central regulators of vascular smooth muscle cell (VSMC) phenotype and vascular homeostasis. This study investigates the consequences of VSMC-specific YAP/TAZ deletion and its relevance to atherosclerosis. Using bulk and single-cell RNA sequencing data, we demonstrate that gene expression changes following two (2-week YT) and eight weeks (8-week YT) of YAP/TAZ deletion recapitulate key features of murine and human atherosclerosis. Transcriptomic comparisons revealed substantial overlap and concordance between YAP/TAZ-deficient VSMCs and different stages of plaque development, with 8-week YT displaying stronger resemblance to atherosclerotic lesions. Shared differentially expressed genes were enriched for inflammatory mediators, extracellular matrix remodeling factors, and chondrogenic markers. Gene ontology and Reactome pathway enrichment analyses highlighted upregulation of immune-related pathways, extracellular matrix remodeling, and chondrogenic differentiation, accompanied by the downregulation of muscle contractile programs. Integration of ChIP-seq data and promoter motif analyses identified 19 conserved YAP–TEAD target genes that were consistently repressed at both 2-week and 8-week YT. Several of these target genes were also downregulated in atherosclerotic plaques, such as genes involved in cytoskeletal integrity (e.g., <em>SRF, NEXN</em>). Notably, loss of YAP/TAZ induced a phenotypic shift in VSMCs toward chondromyocyte-like and fibromyocyte-like states, analogous to those seen in murine and human atherosclerosis. These findings suggest that YAP/TAZ safeguard VSMC identity by directly repressing pro-inflammatory and osteochondrogenic programs, and that their disruption may contribute to atherogenesis. This positions YAP/TAZ–TEAD axis as a key guardian of vascular homeostasis and a potential therapeutic target for limiting plaque progression.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100487"},"PeriodicalIF":2.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of morphological, functional, and biochemical features of H9c2 rat cardiomyoblast retinoic acid differentiation","authors":"Nicole S. York ,&nbsp;Joel E. Rivera ,&nbsp;Mohammadreza Rahmani Manesh ,&nbsp;K’sana Wood Lynes-Ford ,&nbsp;Rory Smith ,&nbsp;Leigh E. Wicki-Stordeur ,&nbsp;Laura T. Arbour ,&nbsp;Leigh Anne Swayne","doi":"10.1016/j.jmccpl.2025.100486","DOIUrl":"10.1016/j.jmccpl.2025.100486","url":null,"abstract":"<div><div>Cell culture models enable advancement in our understanding of heart development and heart disease. The H9c2 rat ventricular cardiomyoblast cell line can be differentiated with retinoic acid and low serum, leading to morphological, molecular, and functional changes that partially resemble aspects of cardiomyoblast-to-cardiomyocyte differentiation. However, morphological, functional, and biochemical changes are rarely investigated in parallel, thereby limiting fulsome understanding of how these processes are interlinked, and to what extent these model cardiomyoblasts can be differentiated. To provide a parallel analysis as a resource for future studies, we therefore characterized H9c2 cell morphology, Ca²⁺ handling, and gene expression after five days (5 days<em>-in-vitro</em>, DIV5), and fourteen days (DIV14) of exposure to differentiation stimuli, consisting of retinoic acid and low serum. We observed statistically significant morphological changes during differentiation. We saw changes consistent with those already described in the context of cardiomyoblast differentiation. However, some of these were previously limited to qualitative observations, for example increased cell length. Notably, several of our morphological observations are completely novel, such as increases in eccentricity, perimeter length (aka cell boundary length), and in the density of actin clusters, were investigated de novo. Differentiation also resulted in the onset of spontaneous Ca²⁺ transients – this is the first instance, to our knowledge, that this has been characterized in the absence of pharmacological stimulation. The mean frequency and synchronicity of Ca²⁺ transients in differentiated H9c2 cells were much lower than those observed in primary cardiomyocytes, underscoring their relatively immature differentiation state from a functional perspective. Additionally, key cardiomyocyte cytoskeletal proteins and ion channel transcript and protein expression levels changed significantly with differentiation, including at early timepoints (DIV5 h and DIV3) which had not yet been investigated by others, in alignment with changes normally observed in cardiomyocyte development. Overall, our findings position differentiated H9c2 cells as a relatively high-throughput model for studying cardiomyoblast differentiation, while also clarifying their limitations in recapitulating fully mature cardiomyocyte phenotypes, and highlight reliable markers (e.g., <em>Cacna1c, Myom2</em>, cTnT, VCL, and <em>Gja5</em>) for experimental readouts.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100486"},"PeriodicalIF":2.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt/β-catenin signaling regulates cardiac Cx43 in a metabolic substrate-dependent manner","authors":"Omar Kayyem ,&nbsp;Ruonan Gu ,&nbsp;Ying Xia ,&nbsp;Jerry Wang ,&nbsp;Aizhu Lu ,&nbsp;Hongwei Wang ,&nbsp;Darryl R. Davis ,&nbsp;Peter Liu ,&nbsp;Wenbin Liang","doi":"10.1016/j.jmccpl.2025.100488","DOIUrl":"10.1016/j.jmccpl.2025.100488","url":null,"abstract":"<div><h3>Background</h3><div>Both Na_v1.5 and Cx43 are critical for the fast electrical impulse conduction in the myocardium and their reductions create the arrhythmogenic substrate. Wnt/β-catenin signaling is activated in arrhythmogenic myocardium, and although this signaling is known to downregulate cardiac Na_v1.5, its regulation of Cx43 is unclear as conflicting results have been reported. The present study investigated how Wnt/β-catenin signaling regulates Cx43 in rat and human cardiomyocytes and if it is dependent on the sex of the cells or the metabolic substrates.</div></div><div><h3>Methods</h3><div>Male and female neonatal rat ventricular myocytes (NRVMs) were treated with CHIR-99021 (CHIR) or Wnt3a protein, two different activators of the Wnt/β-catenin signaling, either in a medium rich in glucose (a preferred metabolic substrate in heart failure) or in a medium rich in lipid (∼150 μM fatty acid, a preferred substrate in healthy hearts). Both healthy and Brugada Syndrome human iPSC-derived cardiomyocytes (iPSC-CMs) were used to confirm observations in NRVMs.</div></div><div><h3>Results</h3><div>When maintained in a glucose-rich medium, <em>Gja1</em> mRNA (encoding Cx43) was reduced by a low concentration of CHIR (1 μM) in female NRVMs but only at a high concentration of CHIR (10 μM) in male NRVMs. However, reductions in Cx43 protein were observed at 1 μM CHIR in both male and female NRVMs, suggesting the involvement of both transcriptional and post-transcriptional mechanisms. When maintained in a lipid-rich medium, neither <em>Gja1</em> mRNA nor Cx43 protein was altered by CHIR at 1 or 3 μM. In contrast, CHIR-induced reductions in <em>Scn5a</em> mRNA and Na_v1.5 protein were observed in both glucose-rich and lipid-rich media, with no significant sex-specific differences detected. Consistent with studies using CHIR, which is a Wnt receptor-independent activator, Wnt3a protein also reduced both <em>Gja1</em> mRNA and Cx43 protein in NRVMs in the glucose-rich medium but not in the lipid-rich medium. In human iPSC-CMs from two healthy volunteers and one Brugada Syndrome patient, Wnt/β-catenin signaling activation reduced <em>GJA1</em> mRNA and Cx43 protein in a standard, glucose-containing medium.</div></div><div><h3>Conclusions</h3><div>These data demonstrate that metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes, with reductions in Cx43 mRNA and protein only observed when glucose is the primary metabolic substrate, which occurs in arrhythmogenic conditions such as cardiac hypertrophy and heart failure.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100488"},"PeriodicalIF":2.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ac-SDKP and eplerenone confer additive cardioprotection against angiotensin II-induced cardiac injury in C57BL/6J mice","authors":"Suhail Hamid ,&nbsp;Sarah Sarkar ,&nbsp;Hongmei Peng ,&nbsp;Matrougui Khalid ,&nbsp;Pablo A. Ortiz ,&nbsp;Jiang Xu ,&nbsp;Tang-Dong Liao ,&nbsp;Robert A. Knight ,&nbsp;Nour-Eddine Rhaleb","doi":"10.1016/j.jmccpl.2025.100485","DOIUrl":"10.1016/j.jmccpl.2025.100485","url":null,"abstract":"<div><div>Eplerenone, a mineralocorticoid receptor antagonist, is an anti-hypertensive and cardioprotective drug. We showed that N-Acetyl-Seryl-Aspartyl-Proline (Ac-SDKP) exerts beneficial effects on the heart. Whether Ac-SDKP provides additional cardioprotective effects if combined with eplerenone in angiotensin II (Ang II)-induced hypertension remains unknown. Male C57BL/6J mice were treated with either sham, Ang II (2.9 mg/kg/day, s.c.), Ang II + Ac-SDKP (1.6 mg/kg/day, s.c.), Ang II + Eplerenone (150 mg/kg/day in mouse chow), or Ang II + Ac-SDKP + Eplerenone. Treatment lasted for eight weeks. Systolic blood pressure (SBP) measurements were taken weekly. Echocardiography (Echo) and magnetic resonance imaging (MRI) were performed at the end of the experiment. SBP was increased in all mice with Ang II and was not affected by any treatment. Posterior wall thickness (PWT) and left ventricular (LV) mass were increased in Ang II–treated groups. LV mass was not significantly affected by treatment, but PWT was reduced by both monotherapies and showed the greatest reduction with combined Ac-SDKP and eplerenone. Ejection fraction (EF) decreased in the Ang II group compared to the sham group. EF increased with all treatments (MRI), and there was a further significant increase in EF for mice treated with Ac-SDKP + Eplerenone compared to those receiving a single treatment (Echo). Our data indicate that treatment with Ac-SDKP or Eplerenone improves cardiac function in Ang II-induced hypertension, and supplying Ac-SDKP to Eplerenone provides additive, not synergistic, cardioprotective effects. These beneficial effects were associated with decreased myocardial collagen accumulation, CD68-positive macrophage infiltration, and the expression of CHOP, an endoplasmic reticulum stress mediator. Ac-SDKP could be an effective supplementary treatment alongside Eplerenone for managing hypertension-associated cardiac damage and dysfunction.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100485"},"PeriodicalIF":2.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145121059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell dynamics reveal a stress-induced decision between hypertrophy and apoptosis in neonatal rat cardiomyocytes","authors":"Bryan Chun ,&nbsp;Lavie Ngo ,&nbsp;Jeffrey J. Saucerman","doi":"10.1016/j.jmccpl.2025.100484","DOIUrl":"10.1016/j.jmccpl.2025.100484","url":null,"abstract":"<div><div>Cardiomyocyte hypertrophy and apoptosis underlie cardiomyopathies and heart failure. While previous studies have reported both hypertrophy and apoptosis at the population level, how individual cells commit to these distinct analog and digital fates is unclear. To elucidate how individual cells decide to grow and/or die, we developed a high-content microscopy approach to track single-cell dynamics of neonatal rat cardiomyocytes. Even untreated cells exhibited substantial single-cell variability in growth and death. Uniform treatments of staurosporine or phenylephrine induced distinctive morphological programs resulting in apoptosis and hypertrophy, respectively, but only in cell subpopulations. Increasing concentrations of the β-adrenergic receptor agonist isoproterenol caused a population-level biphasic induction of hypertrophy and then apoptosis, consistent with either apoptosis in the most hypertrophic cells (a grow-and-die model) or an early decision between hypertrophy and delayed apoptosis (a grow-or-die model). By tracking single-cell fates, we found that when stressed with either isoproterenol or phenylephrine, individual cells that hypertrophy are protected from later apoptosis. Further, caspase 3 inhibition shifted the single-cell probability from apoptosis to hypertrophy fates. Machine learning models found that a cell's initial size and DNA content or condensation could predict a cell's bias for hypertrophy or apoptosis. Together, these data support a grow-or-die conceptual model for cardiomyocyte decisions. This single-cell profiling method for tracking joint analog-digital cell decisions reveals that despite hypertrophy and apoptosis co-occurring at the population level, individual cardiomyocytes decide early whether to grow or die.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100484"},"PeriodicalIF":2.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic administration of analgesic buprenorphine, but not carprofen, affects cardiomyocyte contractility in rodents","authors":"Inez Duursma ,&nbsp;Valentijn Jansen ,&nbsp;Nicole Zaat ,&nbsp;Tyler J. Kirby ,&nbsp;Jolanda van der Velden ,&nbsp;Diederik W.D. Kuster","doi":"10.1016/j.jmccpl.2025.100482","DOIUrl":"10.1016/j.jmccpl.2025.100482","url":null,"abstract":"<div><div>Rodents are often used in cardiac research, where they undergo a wide variety of procedures. To ensure animal welfare, the rodents are often analgesized before, during and/or after a procedure. Contractility measurements in isolated murine cardiomyocytes are an often used method to assess function; however, little is known about the effects of analgesia on this. Therefore, we investigated the effect of systemic injection of a non-steroidal anti-inflammatory drug, carprofen (<em>N</em> = 3 mice, <em>n</em> = 273 CMs; N = 3 rats, <em>n</em> = 241 CMs) and an opioid, buprenorphine (<em>N</em> = 4 mice, <em>n</em> = 326 CMs; N = 4 rats, <em>n</em> = 308 CMs) on isolated cardiomyocytes using unloaded contractility measurements. We found that buprenorphine prolongs the relaxation of cardiomyocytes, an effect confound to the first 3 h post-isolation, whereas carprofen does not affect contractility. As analgesia might influence the stress response, we assessed the influence of carprofen and buprenorphine on the β-adrenergic receptor (AR) response. The response of cardiomyocytes to both a β-AR agonist and antagonist was not affected by carprofen or buprenorphine. <em>In vitro</em> addition of the analgesics to rat cardiomyocytes (<em>N</em> = 3 rats, <em>n</em> = 197 CMs saline, <em>n</em> = 214 CMs carprofen, <em>n</em> = 211 CMs buprenorphine) revealed that the effect of buprenorphine on contractility is caused by a systemic response rather than a direct response of cardiomyocytes specifically. Collectively, our results suggest that carprofen and buprenorphine do not affect isolated cardiomyocyte contractility if measurements are performed at least 4 h post-isolation.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100482"},"PeriodicalIF":2.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145160042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Med13 and Med13L: Critical redundant players in basal cardiac function and gene expression","authors":"Kayla M. Henry ,&nbsp;Richard N. Gardner ,&nbsp;Alexis M. Oppman ,&nbsp;Nastaran Daneshgar ,&nbsp;Mariela Rosales ,&nbsp;Ines Martins ,&nbsp;Kedryn K. Baskin ,&nbsp;Chad E. Grueter","doi":"10.1016/j.jmccpl.2025.100481","DOIUrl":"10.1016/j.jmccpl.2025.100481","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have linked mutations in the Mediator complex, specifically Mediator 13 (Med13) and Mediator 13-like (Med13L), with both congenital heart defects and cardiovascular diseases. Med13 and Med13L are mutually exclusive paralogs within the kinase submodule of the Mediator complex that have been shown to have partially redundant functions in embryonic development and transcription, but their combined roles have not been investigated in the adult heart. We investigated the critical yet redundant roles of Med13 and Med13L in adult murine cardiomyocytes for basal cardiac function.</div></div><div><h3>Methods</h3><div>We generated an inducible Med13 and Med13L cardiomyocyte-specific knockout mouse model to investigate Med13 and Med13L regulation of cardiac function and transcription. We performed RNAseq on mice four weeks after the start of tamoxifen to identify changes in gene expression. Differentially expressed genes were compared across cardiac knockouts of Med13/13L, Med13, Med12, Med1, and Med30 elucidating similar mechanisms of cardiac dysfunction.</div></div><div><h3>Results</h3><div>Med13/13L knockout resulted in decreased cardiac function leading to lethal heart failure in a median timeframe of 6 weeks from the start of tamoxifen. There is significant gene dysregulation after Med13/13L knockout with similar gene dysregulation of fibrotic pathways and calcium handling across Mediator cardiac knockouts.</div></div><div><h3>Conclusions</h3><div>Med13 and Med13L function partially redundantly within the heart to maintain basal cardiac function and transcription, as well as redundancies within cardiac phenotypes related to mediator complex disruptions.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100481"},"PeriodicalIF":2.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JMCC plus receives first impact factor","authors":"Davor Pavlovic ,&nbsp;Rebekah Gundry","doi":"10.1016/j.jmccpl.2025.100480","DOIUrl":"10.1016/j.jmccpl.2025.100480","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100480"},"PeriodicalIF":2.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cocaine and the heart – bad news for risk/reward","authors":"Jules C. Hancox,&nbsp;Andrew F. James","doi":"10.1016/j.jmccpl.2025.100477","DOIUrl":"10.1016/j.jmccpl.2025.100477","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100477"},"PeriodicalIF":2.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific human electromechanical multiscale in-silico models for virtual therapy evaluation","authors":"Maxx Holmes ,&nbsp;Zhinuo Jenny Wang ,&nbsp;Ruben Doste ,&nbsp;Julia Camps ,&nbsp;Hector Martinez-Navarro ,&nbsp;Hannah Smith ,&nbsp;Jakub Tomek ,&nbsp;Blanca Rodriguez","doi":"10.1016/j.jmccpl.2025.100479","DOIUrl":"10.1016/j.jmccpl.2025.100479","url":null,"abstract":"<div><h3>Background</h3><div>Women are under-represented in cardiovascular research, leading to poorer outcomes. Investigating sex-differences in electromechanical function is essential for improving therapy evaluation. This study presents sex-specific human cellular and biventricular electromechanical models for mechanistic investigation of sex-differences in therapeutic response.</div></div><div><h3>Methods</h3><div>Protein genomic expression data from healthy human myocytes calibrated sex-specific electrophysiological models, integrated into biventricular models with male and female anatomies. Multi-scale validation utilised sex-specific clinical and experimental datasets, including responses to drug action. Ionic mechanisms underlying sex-differences in drug response were explored.</div></div><div><h3>Results</h3><div>Simulations showed agreement with clinical ECGs, including QTc intervals (Male: 312 ms; Female: 339 ms), and T-wave amplitude (6–9 % difference). Mechanical biomarkers (LVEF, Female: 68 %; Male: 50 %) matched sex-stratified UK Biobank data (<em>n</em> = 806; 46 % Male). ECG sex-characteristics were driven by ionic differences, while mechanical differences stemmed from anatomical and ionic differences. Simulations predicted exacerbated QTc prolongation under Dofetilide in women (54–78 % higher than males) and T-wave amplitude reduction in men (max: −0.25 mV). Verapamil increased T-wave amplitude in females and decreased it in males, without affecting QTc. Simulations demonstrated reduced repolarisation reserve and increased QTc susceptibility in women via hERG inhibition, while enhanced calcium buffering protected against T-wave amplitude loss. LVEF changes in response to calcium block were more sensitive to anatomical differences between male and female than to ionic sex phenotypes.</div></div><div><h3>Conclusion</h3><div>Sex differences in repolarisation reserve, calcium handling, and anatomy are key factors underpinning ECG and LVEF responses to drugs. Specifically, under calcium block, females showed more preserved LVEF, while under hERG block, females showed more QTc prolongation.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100479"},"PeriodicalIF":2.2,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}