American journal of physiology. Heart and circulatory physiology最新文献

{"title":"Gender minority stress, testosterone, and blood pressure responses to stress in transgender and nonbinary adults.","authors":"Keila Turino Miranda, Shannon I Delage, Kit Chokly, Vic Gort, Jody L Greaney, Carl G Streed, Jesse D Moreira-Bouchard, Charlotte W Usselman","doi":"10.1152/ajpheart.00548.2026","DOIUrl":"10.1152/ajpheart.00548.2026","url":null,"abstract":"<p><p>Trans and nonbinary adults assigned female at birth (TNBF) are at elevated cardiovascular risk, an effect proposed to occur secondary to testosterone use. However, gender minority (GM) stress may also contribute to cardiovascular risk. Therefore, we examined the relative association of GM stress and testosterone with blood pressure (BP) and its regulation in TNBF adults. In 24 TNBF adults (12 not using and 12 using testosterone), GM stress was derived from a standardized composite score of seven psychosocial scales, and total testosterone was measured via radioimmunoassay. BP was assessed at rest and during acute physical (cold pressor test; CPT) and psychological (Stroop color word test; SCWT) stress. Resting systolic (SBP; 115 ± 7 vs. 115 ± 13 mmHg; <i>P</i> = 0.978) and diastolic BP (DBP; 68 ± 6 vs. 68 ± 11 mmHg; <i>P</i> = 0.995) did not differ between testosterone nonusers and users. Backward elimination linear regression indicated that GM stress was negatively associated (SBP: β: -0.589, <i>P</i> = 0.002; DBP: β: -0.492, <i>P</i> = 0.006) and total testosterone was positively associated (SBP: β: 0.301, <i>P</i> = 0.079; DBP: β: 0.422, <i>P</i> = 0.013) with BP responses to the SCWT (SBP: R² = 0.430, <i>P</i> = 0.003; DBP: R² = 0.553, <i>P</i> = 0.001), but not resting BP or BP responses to the CPT. Our findings suggest that greater GM stress exposure blunts BP responses to psychological, but not physical, stress, whereas higher total testosterone levels are associated with greater BP responses to psychological stress among TNBF adults. Given established links between BP, its regulation, and cardiovascular risk, these data highlight the importance of integrating both physiological and psychological factors when examining cardiovascular risk in TNBF adults.<b>NEW & NOTEWORTHY</b> Our study illuminates the relation of gender minority stress, alongside total testosterone levels, to measures of cardiovascular risk in trans and nonbinary adults. Our findings suggest that cardiovascular risk in trans and nonbinary adults likely reflects interacting psychosocial and hormonal factors, highlighting psychological stress pathways as potential targets for prevention and intervention.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1267-H1276"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148904843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiomyocyte-specific expression of HIF-1α mediates the cardioprotective effects of growth hormone-releasing hormone.","authors":"Rosemeire M Kanashiro-Takeuchi, Lauro M Takeuchi, Wayne Balkan, Karina Dutra Asensi, Raul A Dulce, Amarylis C B A Wanschel, Konstantinos E Hatzistergos, Shathiyah Kulandavelu, Russell G Saltzman, Lina A Shehadeh, Wei Sha, Andrew V Schally, Stefan Kurtenbach, Joshua M Hare","doi":"10.1152/ajpheart.00118.2026","DOIUrl":"10.1152/ajpheart.00118.2026","url":null,"abstract":"<p><p>Heart failure (HF) with preserved ejection fraction (HFpEF) carries a high mortality and remains a major therapeutic challenge. Effective targeted therapies capable of reversing HFpEF pathophysiology are urgently needed. We previously demonstrated that activation of the cardiac growth hormone-releasing hormone (GHRH) pathway using high potency synthetic agonists of GHRH (GHRH-agonists) improves the HFpEF phenotype in both large and small animal models, including in a murine model of cardiometabolic HFpEF [high-fat diet + <i>N</i>^ω-nitro-l-arginine methyl ester (l-NAME)]. Here we sought to define the downstream signaling pathways responsible for this effect. A transcriptomic screen in human inducible-pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CMs) identified the hypoxia-induced factor (HIF-1α) pathway as being activated by GHRH receptor (GHRHR) signaling, revealing an oxygen-independent mechanism of HIF-1α activation. Based on this finding, we investigated the interaction between the cardioprotective effects of the GHRH-agonist MR-356 and HIF-1α pathway activation in the murine HFD + l-NAME model of cardiometabolic HFpEF. We generated a cardiomyocyte-specific HIF-1α knockout (HIF-1α^CMKO) mouse line and demonstrated that our previously reported beneficial effects of GHRH-agonist administration were completely abolished in HIF-1α^CMKO mice. Together, these findings establish the GHRHR-HIF-1α axis as a putative integrative pathway coupling metabolic and contractile remodeling, suggesting that therapeutic targeting of this axis represents a novel disease-modifying approach to treating cardiometabolic HFpEF.<b>NEW & NOTEWORTHY</b> Heart failure with preserved ejection fraction (HFpEF) lacks effective disease-modifying therapies. This study identifies a novel cardioprotective mechanism in which growth hormone-releasing hormone activates hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes under normoxic conditions. Using human iPSC-derived cardiomyocytes and a cardiometabolic HFpEF mouse model, the authors show that cardiomyocyte HIF-1α is required for GHRH-mediated improvements in diastolic function, myocardial mechanics, and exercise capacity, revealing a previously unrecognized therapeutic axis for HFpEF.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1199-H1211"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective effects of CDP-choline in ischemia/reperfusion injury using a swine model of acute myocardial infarction.","authors":"Héctor González-Pacheco, Felipe Massó, Luis M Amezcua-Guerra, Francisco J Molina-Méndez, Juan Villegas-Juache, Arturo Abundes-Velasco, Regina de la Mora-Cervantes, Mary C Herrera-Zarza, Laura V Torres-Araujo, Jorge A Ortega-Hernández, Cecilia Zazueta, Wylly R García-Niño, Francisco Correa, Alberto Aranda-Fraustro, Jesús Vargas-Barron, Jorge L Vargas-Estrada, Alexandra Arias-Mendoza, Julio Sandoval-Zárate","doi":"10.1152/ajpheart.90128.2026","DOIUrl":"https://doi.org/10.1152/ajpheart.90128.2026","url":null,"abstract":"<p><p>Myocardial ischemia/reperfusion (I/R) injury remains a major determinant of final infarct size and adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Following our previous demonstration of CDP-choline-mediated cardioprotection in cultured cardiomyocytes and rodent models, the present study evaluated its efficacy in a clinically relevant closed-chest porcine model of myocardial I/R injury. Sixteen Yorkshire pigs underwent 60 min of left anterior descending coronary artery occlusion followed by reperfusion and were randomized to intravenous CDP-choline (n = 8) or placebo (n = 8). CDP-choline (1,000 mg) was administered 30 min after coronary occlusion, followed by 500 mg every 12 h. The primary endpoint was infarct size assessed 24 h after reperfusion by cardiac magnetic resonance. Area at risk was quantified by T2-weighted imaging, whereas infarct size and myocardial salvage were assessed by late gadolinium enhancement. Baseline characteristics and area at risk were comparable between groups. CDP-choline significantly reduced absolute infarct mass (10.34 ± 6.45 vs. 21.09 ± 10.36 g; P=0.026), increased myocardial salvage index (65.86 ± 18.72% vs. 40.42 ± 17.62%; P<0.05), and decreased histological infarct size (8.31 ± 10.9% vs. 17.41 ± 12.5%; P = 0.015). CDP-choline also reduced cumulative troponin release (AUC₀-₉₆ h, P=0.001), demonstrated a significant treatment-by-time interaction (P=0.012), and attenuated myocardial oxidative stress. In this proof-of-concept study, CDP-choline reduced infarct size, enhanced myocardial salvage, and attenuated myocardial injury in a clinically relevant porcine model of myocardial I/R. These findings support further mechanistic investigation and provide a rationale for future translational evaluation of CDP-choline as an adjunctive cardioprotective strategy during reperfusion in STEMI.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cross-sectional analysis of vascular geometry in adults: associations of age and biological sex with iliofemoral arterial and venous tortuosity.","authors":"Pauline M Berens, Benjamin C Liu, Arash Fereydooni, Ryan S Belkin, Johan Bondesson, Benjamin K Wang, Shipra Arya, Christopher P Cheng","doi":"10.1152/ajpheart.00301.2026","DOIUrl":"10.1152/ajpheart.00301.2026","url":null,"abstract":"<p><p>Iliofemoral vascular tortuosity may reflect vascular aging, yet natural anatomic variation remains poorly characterized at scale. In this single-center retrospective study, we quantified arterial and venous iliofemoral tortuosity in a large cohort of adults with contrast-enhanced abdominopelvic computed tomography (CT) scans. Using an nnU-Net-based deep learning pipeline, iliofemoral arteries and veins were segmented from CT images. Representative centerlines were extracted and mean centerline curvature was computed to quantify tortuosity. Primary analyses explored associations of arterial and venous tortuosity with core covariates: age, biological sex, race, body mass index, height, and smoking status. Secondary analyses evaluated associations with clinical comorbidities and medication exposures. Complete-case analytic cohorts included 725 patients for arterial analyses and 718 for venous analyses. After adjustment for core covariates, age was positively associated with both arterial and venous tortuosity, with a stronger association for arteries than veins (+15% vs. +6% per decade). Tortuosity variability among the cohort was higher for arteries than veins (2.2-fold higher residual variance). Female sex was associated with lower arterial and venous tortuosity. Traditional atherosclerotic risk factors, including hypertension, hyperlipidemia, and diabetes, were not associated with iliofemoral tortuosity. After adjustment for co-occurring conditions, end-stage renal disease was associated with lower arterial and venous tortuosity, and congestive heart failure was associated with lower venous tortuosity. Connective tissue disease was associated with higher venous tortuosity. These findings demonstrate distinct arterial, venous, age-related, and sex-related patterns of iliofemoral tortuosity. In addition, they provide morphometric context for studies evaluating large-vessel geometry and vascular stiffness, hemodynamics, and disease-specific procedural outcomes.<b>NEW & NOTEWORTHY</b> Using an automated CT-based approach, this study quantified iliofemoral arterial and venous tortuosity in a large, adult cross-sectional cohort. Age had a strong positive association with arterial and venous tortuosity. Males had higher arterial and venous tortuosity than females. These findings support differential remodeling of arteries and veins with age and provide a framework for future studies of large-vessel geometry and mechanics.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1093-H1104"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary UDP-sugars provide actionable prediction of acute kidney injury in cardiac surgery patients.","authors":"Christine Légaré, Patrick Caron, Mohammad M Al-Bataineh, Aisha Ford, David R Emlet, Jessica Deslauriers, Dennis Brown, Chantal Guillemette, Siamak Mohammadi, Sylvie Breton","doi":"10.1152/ajpheart.00233.2026","DOIUrl":"10.1152/ajpheart.00233.2026","url":null,"abstract":"<p><p>Acute kidney injury (AKI) affects up to 50% of patients undergoing cardiopulmonary bypass, yet early diagnostic biomarkers and targeted therapies remain limited. Although AKI is attributed to bypass-induced renal ischemia, the underlying molecular mechanisms are poorly understood. This study characterizes renal inflammatory dynamics in cardiac surgery patients, beginning intraoperatively. One hundred adults undergoing cardiopulmonary bypass were enrolled at the Quebec Heart and Lung Institute in Canada (July 2021-April 2024). Urine and plasma samples were collected before and up to 5 days post bypass. Proinflammatory P2Y14 receptor ligands (UDP-sugars) were quantified by LC-ESI-MS/MS, and kidney injury marker-1 (KIM-1) and inflammatory mediators were measured by multiplex immunoassays. AKI was defined using modified KDIGO criteria: serum creatinine increase ≥ 0.3 mg/dL or urine output ≤ 0.5 mL/kg/h for 24 h postoperatively. Urinary UDP-sugars increased significantly within 0-4 h post bypass in patients with AKI, whereas plasma levels remained unchanged. Urinary UDP-sugars correlated with KIM-1 at 4 h and preceded proinflammatory cytokines (CXCL1, CCL2, and IL-18), which peaked at 12 h. Immunofluorescence localized P2Y14 to collecting duct apical membranes, and detected CD45⁺/myeloperoxidase (MPO)⁺ neutrophils in ischemic human kidneys. Patients with elevated UDP-sugars showed significantly higher inflammatory markers compared with those with low levels. In conclusion, UDP-sugars released by damaged renal tubules trigger inflammatory cytokine secretion in patients with AKI. The UDP-sugar/P2Y14 axis represents a novel early predictor and therapeutic target for cardiac surgery-associated AKI. The robust expression of P2Y14 and the presence of proinflammatory immune cells in human ischemic kidneys further support the potential of this therapeutic strategy.<b>NEW & NOTEWORTHY</b> Acute kidney injury (AKI) is common in patients with open-heart surgery, but early diagnostics and therapies are limited. This study identifies a proinflammatory pathway activated during cardiopulmonary bypass. UDP-sugars are ligands of the P2Y14 receptor that appear during surgery in the urine of patients with AKI, predicting its onset. Patients with elevated UDP-sugars exhibited higher urinary inflammatory markers. Thus, the UDP-sugar/P2Y14 axis may serve as an early predictor and therapeutic target for cardiac surgery-related AKI.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1105-H1121"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13600465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formate reduces cardiac ischemia-reperfusion injury in murine ex vivo and in vitro models.","authors":"Haley Garbus, Raihan Kabir, Obialunanma V Ebenebe, Priyanka Patel, Deepthi Ashok, Diego Quiroga, Samarjit Das, Brian O'Rourke, Mark J Crabtree, Mark J Kohr","doi":"10.1152/ajpheart.00348.2026","DOIUrl":"10.1152/ajpheart.00348.2026","url":null,"abstract":"<p><p>Ischemic heart disease is a leading cause of death in the United States. We and others have demonstrated that nitric oxide (NO) signaling and associated protein <i>S</i>-nitrosation (SNO) play a key role in reducing ischemic injury in the heart. We also find that although females typically exhibit endogenous protection from ischemic injury, this protection is abrogated with the loss of the formate-generating enzyme alcohol dehydrogenase 5 (ADH5), but formate supplementation provided a rescue. Here, we investigate the cardioprotective efficacy of formate in male hearts. Hearts were Langendorff-perfused and subjected to ischemia-reperfusion (IR) injury with and without formate. Formate-mediated protection was also examined using an in vitro model of coverslip-induced ischemic injury to identify cardiomyocyte-specific effects. We found that formate increases postischemic protein SNO levels and yields protection from IR injury in both ex vivo and in vitro models. However, NO synthase inhibition blocked the formate-mediated increase in protein SNO in vitro and attenuated protection from IR injury ex vivo. Furthermore, postischemic levels of tetrahydrobiopterin (BH₄), a cofactor necessary for NO synthase (NOS) function, were preserved in formate-treated hearts. Collectively, our findings suggest that formate is a potent cardioprotective agent that preserves postischemic BH₄ levels and enhances protein SNO levels through a NOS-dependent mechanism. These findings have significant implications for the clinical prevention and treatment of ischemic heart disease in males.<b>NEW & NOTEWORTHY</b> Formate perfusion before ischemia improved functional recovery and dramatically reduced infarct size following ischemia-reperfusion injury in male hearts. Mechanistically, formate-mediated protection was associated with preserved postischemic tetrahydrobiopterin levels and increased protein <i>S</i>-nitrosation levels. These findings represent an important step toward the treatment of ischemic heart disease in males.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1122-H1132"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-of-day variation in complement activation and endothelial glycocalyx nanomechanics in ST-elevation myocardial infarction.","authors":"Isaiah Joseph Ting, Benedikt Fels, Kristina Kusche, Carl Vahldieck","doi":"10.1152/ajpheart.00515.2026","DOIUrl":"10.1152/ajpheart.00515.2026","url":null,"abstract":"<p><p>Time-of-day variation in myocardial infarction onset and ischemia-reperfusion injury is well established, but whether complement activation and the endothelial glycocalyx in ST-elevation myocardial infarction (STEMI) show temporal organization remains unclear. This study evaluated whether complement activation and endothelial glycocalyx nanomechanics in STEMI exhibit time-of-day structure and relate to short-term clinical outcomes. Endothelial glycocalyx height and stiffness and cortical stiffness were quantified in vitro using nanoindentation of human umbilical vein endothelial cells incubated with patient serum, not measured directly in patients. These measures, together with syndecan-1, C3a, C5a, left ventricular ejection fraction (LVEF), and discharge duration, were analyzed by blood sampling time in 63 first-onset patients with STEMI undergoing emergency percutaneous coronary intervention, using 6-h bins, 24-h cosinor modeling, and multivariable analysis. Morning sampling (0600 to <1200 h) showed higher cortical stiffness, syndecan 1, C3a, and C5a, and lower in vitro glycocalyx height and stiffness versus afternoon and evening; LVEF did not differ between bins. Cosinor analysis identified early-morning acrophases for cortical stiffness, syndecan 1, C3a, and C5a, with opposing evening acrophases for in vitro glycocalyx height and stiffness; troponin and C-reactive protein showed no time-of-day pattern. Principal component analysis identified a dominant component along which in vitro glycocalyx disruption and complement activation aligned with prolonged hospitalization, whereas preserved in vitro glycocalyx nanomechanics aligned with higher LVEF. Complement activation and endothelial glycocalyx nanomechanics in STEMI are structured across the 24-h day, reflecting time-of-day variation. Clock time is thus a physiologically relevant variable for interpreting endothelial vulnerability in acute myocardial infarction, generating hypotheses for glycocalyx-preserving and complement-modulating strategies.<b>NEW & NOTEWORTHY</b> Endothelial glycocalyx nanomechanics and complement activation in STEMI, assessed via serum-driven nanoindentation of cultured endothelial cells and circulating biomarkers, are structured across the 24-h day. Morning sampling during emergency PCI was associated with a glycocalyx-injury phenotype, characterized by reduced glycocalyx height and stiffness, elevated cortical stiffness, syndecan 1, C3a, and C5a, with opposing acrophases. This is the first evidence that the complement-glycocalyx injury pattern in STEMI shows temporal organization, identifying clock-time as relevant for endothelial biomarker interpretation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1341-H1350"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A biphasic effect of alcohol on endothelial plasticity through regulation of endothelial-to-mesenchymal transition.","authors":"Weimin Liu, Yusof Gusti, Fathima Athar, Naresh K Rajendran, Paul A Cahill, Eileen M Redmond","doi":"10.1152/ajpheart.00310.2026","DOIUrl":"10.1152/ajpheart.00310.2026","url":null,"abstract":"<p><p>Alcohol influences cardiovascular disease, but whether it does so by affecting endothelial plasticity is unknown. We tested whether alcohol regulates endothelial-to-mesenchymal transition (EndMT) to influence arterial pathology. Human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC) were exposed to inflammatory cytokines or hypoxia in the absence or presence of ethanol (5-100 mM). In vivo, carotid ligation was performed in mice gavaged with/without either daily moderate ethanol (2 drinks equivalent/day) or episodic binge exposure (7 drinks equivalent, 2 days/wk) and myoendothelial cells assessed. Cytokines and hypoxia induced EndMT in vitro characterized by loss of endothelial markers, increased mesenchymal markers, and enhanced migratory capacity. Low-to-moderate-dose ethanol (5-25 mM) attenuated marker changes, preserving endothelial phenotype, whereas high-dose ethanol (50-100 mM) either had no effect or exacerbated EndMT. The inhibitory effect of moderate-dose ethanol on cytokine- and hypoxia-induced changes in α-smooth muscle actin (αSMA) and cadherin-5 (<i>Cdh5</i>) expression was abrogated by γ-secretase inhibition, consistent with involvement of Notch signaling. Carotid ligation induced neointimal formation and accumulation of myoendothelial cells indicative of EndMT. Daily moderate-dose ethanol significantly attenuated neointimal hyperplasia and diminished the myoendothelial cell population, whereas in contrast, episodic binge ethanol exposure increased pathologic remodeling and myoendothelial cell abundance. Alcohol modulates endothelial transdifferentiation in a biphasic manner. Low-to-moderate-dose alcohol exposure suppresses EndMT and limits pathological remodeling, whereas higher level binge exposure promotes these processes. These findings identify regulation of endothelial plasticity as a potential novel mechanism linking alcohol consumption patterns to vascular disease risk.<b>NEW & NOTEWORTHY</b> We identify a previously unrecognized biphasic effect of alcohol on endothelial phenotypic plasticity. Low-to-moderate-dose alcohol suppresses endothelial-to-mesenchymal transition (EndMT), whereas high-level (binge) exposure promotes this proatherogenic process. Given the central role of EndMT in vascular remodeling and atherosclerosis, these findings provide a mechanistic framework linking alcohol consumption and cardiovascular disease risk - potentially explaining both the protective effect at low-to-moderate levels, and the detrimental impact of heavy alcohol use.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1363-H1376"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variable expressivity in long QT syndrome type 2 rabbits defines a low threshold for therapeutic <i>I</i>_Kr restoration.","authors":"Nilufer N Turan, Allison Welton, Yichun Lu, Tae Yun Kim, Karim Roder, Elif Sengun, Anatoli Y Kabakov, Peter Bronk, Rebecca Martinez-Moreno, Brett Baggett, Dennis Tai, Derrick Kang, Matthew Killeen, Anne Merley, Susanna Kurnick, Lara Helwig, Katja E Odening, Bum-Rak Choi, Gideon Koren","doi":"10.1152/ajpheart.00154.2026","DOIUrl":"10.1152/ajpheart.00154.2026","url":null,"abstract":"<p><p>Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in the human <i>ether-a-go-go</i>-related gene (hERG) potassium channel, resulting in QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death. We previously developed a transgenic LQT2 rabbit model that recapitulates the human disease and segregates into two phenotypically distinct lines, LQT2A and LQT2G. Using optical mapping and cardiomyocyte patch clamp, we investigated the electrophysiological basis of variable disease expressivity and its potential future implications for gene therapy. LQT2G hearts were highly arrhythmogenic, with isoproterenol inducing frequent premature ventricular contractions and pVT, whereas LQT2A hearts required additional rapid component of the delayed rectifier potassium current (<i>I</i>_Kr) blockade to reliably trigger arrhythmias. Patch-clamp recordings revealed <i>I</i>_Kr expression in 21% of LQT2A cardiomyocytes at near-wild-type current density, compared with only 5.5% of LQT2G cells exhibiting low <i>I</i>_Kr. Computer simulations demonstrated that restoration of <i>I</i>_Kr in >23% of cardiomyocytes fully suppressed early afterdepolarizations through electrotonic coupling. To assess achievable transgene expression, we designed a novel minimally invasive gene delivery method for rabbits. To this end, neonatal wild-type rabbits received three different doses of adeno-associated virus 9 (AAV9) encoding the red-fluorescent reporter mKate2 via jugular vein injection, resulting in viral load-dependent, regionally distributed mosaic cardiac expression reaching approximately 20%. However, high-dose intravenous AAV9 delivery was associated with dose-dependent hindlimb weakness and dorsal root ganglia pathology, indicating that this administration route is not suitable in rabbits despite achieving biologically sufficient levels of cardiac transduction. Our experimental observations and computational modeling identify ∼20% as a plausible range for effective <i>I</i>_Kr restoration, generating a testable therapeutic hypothesis.<b>NEW & NOTEWORTHY</b> In a transgenic rabbit model of long QT syndrome type 2 exhibiting variable phenotypic expressivity, we show that partial <i>I</i>_Kr restoration is associated with reduced ventricular arrhythmias. Combined electrophysiological mapping, single-cell recordings, and computational modeling identify a low range of <i>I</i>_Kr restoration that may reduce arrhythmogenicity, whereas AAV9 studies demonstrate that mosaic cardiac gene expression approaching this range is achievable, highlighting the translational relevance of partial <i>I</i>_Kr restoration and challenges of safe in vivo gene delivery.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1402-H1418"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestry-Based Disparities in Cardiovascular Outcomes and Polygenic Risk Among Adults with Congenital Heart Disease in the All of Us Research Program.","authors":"Tobias K Fuchs, Anthony Collura, Ramu Anandakrishnan","doi":"10.1152/ajpheart.90019.2026","DOIUrl":"https://doi.org/10.1152/ajpheart.90019.2026","url":null,"abstract":"<p><p>Most individuals born with congenital heart disease now survive to adulthood, producing a growing population at risk for major adverse cardiovascular events (MACE). Ancestry-based disparities are incompletely characterized and polygenic risk has not been related to outcomes. We analyzed 6,771 adult ACHD participants in All of Us (White n=5,065, Hispanic n=882, Black n=824) and computed five polygenic scores: one for coronary artery disease and four for heart failure trained on African, European, Hispanic or Latin American, and multi-ancestry data. MACE was present in 51.0% and differed by ancestry (Black 56.3%, White 50.7%, Hispanic 47.5%; P=0.001). Black participants developed heart failure 11 years earlier (median 54 vs. 65 years). The pooled disparity attenuated to the null after comorbidity adjustment, with chronic kidney disease accounting for 58.6% of the age- and sex-adjusted effect, but age-specific estimates opposed one another (adjusted OR 1.78 at 40, 0.66 at 80; interaction P<0.001); survivor selection may contribute at older ages. No score improved discrimination or explained the disparity (area under the curve change ≤0.0047). The African-ancestry score was associated with heart failure alone (OR 1.09 per SD, q=0.022); the European and multi-ancestry scores with heart failure, arrhythmia, and MACE alike. Performance did not track training-population ancestry. The coronary and African-ancestry scores ordered the same participants in opposite directions (r=-0.198), indicating between-group offsets reflect allele frequency rather than genomic risk. Black participants underwent fewer structural cardiac reinterventions (8.6% vs. 16.4%; adjusted OR 0.47, P<0.001) despite comparable adjusted ACE inhibitor or angiotensin receptor blocker prescription.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}