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

{"title":"Multiomic and electrophysiologic analyses reveal that an inherited MRC2 variant causes fibroblast dysfunction and increased atrial fibrillation susceptibility.","authors":"Kevin S Ho, Joshua A Keefe, Shuai Zhao, Mohit M Hulsurkar, Sung Yun Jung, Md Abul Hassan Samee, Xander H T Wehrens","doi":"10.1152/ajpheart.00452.2025","DOIUrl":"10.1152/ajpheart.00452.2025","url":null,"abstract":"<p><p>A recent study identified a rare variant in the mannose receptor C type 2 (<i>MRC2</i>) gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) electrocardiogram pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and <i>MRC2</i> was recently proposed as a protective gene for AF. We determined whether the E990G-heterozygous (het) loss-of-function variant in <i>Mrc2</i> increases AF susceptibility and identified aberrant cellular mechanisms resulting from <i>Mrc2</i> deficiency in atrial cardiofibroblasts (ACFs) and atrial tissue in mice that may promote AF. Programmed electrical stimulation was performed to determine AF susceptibility in <i>Mrc2</i> E990G-het mice and wild-type (WT) controls. ACFs were isolated from these mice and cultured, and transcriptomic profiling by RNA sequencing and secretomic/proteomic profiling by mass spectrometry were performed on ACFs and whole atrial tissue. E990G-het mice exhibited increased susceptibility to pacing-induced AF and had decreased atrioventricular effective refractory periods compared with WT controls. Transcriptomic, secretomic, and proteomic profiling of cultured ACFs and whole atrial tissue revealed differential expression of several fibrotic regulators in E990G-het versus WT mice, including decreased ACF expression of matrix metalloproteinase 13, which degrades collagen types I, II, and III; decreased ACF expression and secretion of matrix metalloproteinase 12, which degrades collagen types I, III, IV, elastin, and fibronectin; and increased tissue levels of cellular communication network factor 2/connective tissue growth factor, a profibrotic regulator. In conclusion, <i>Mrc2</i> E990G-het mice exhibit increased AF susceptibility and differentially regulated fibrotic genes and proteins.<b>NEW & NOTEWORTHY</b> Our study reveals a rare MRC2 gene variant (E990G) linked to familial supraventricular tachycardia and Wolff-Parkinson-White syndrome increases atrial fibrillation (AF) susceptibility in mice. The E990G-heterozygous variant disrupts atrial cardiofibroblast function, reducing protective matrix metalloproteinases (MMP-12 and MMP-13) and elevating profibrotic CCN2/CTGF levels, as shown through transcriptomic and proteomic profiling. This suggests that MRC2 deficiency promotes AF by altering fibrotic regulation in atrial tissue.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1055-H1071"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124099","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":"On the measurement of the vortex formation time in the left ventricle.","authors":"Coskun Bilgi, Ben A Lin, Gary F Mitchell, Niema M Pahlevan","doi":"10.1152/ajpheart.00623.2025","DOIUrl":"10.1152/ajpheart.00623.2025","url":null,"abstract":"<p><p>Vortex formation during left ventricular (LV) diastole plays a crucial role in cardiac filling. Vortex formation time (VFT), originally developed for piston-cylinder systems, has been adapted for cardiac studies as a potential LV performance metric; however, discrepancies in the literature remain regarding its measurement and clinical utility. This study evaluates these inconsistencies and introduces a new VFT formulation grounded in fluid dynamics, by conceptualizing the diastolic motion of the atrioventricular plane as a piston-cylinder mechanism. Alongside the proposed approach, four existing VFT variations were examined, each incorporating different cardiac parameters. The clinical relevance of these formulations was assessed using cardiac MRI data from 86 participants (32 females), including both healthy individuals and patients with heart failure. Correlations between VFTs and six diastolic function metrics, as well as the sensitivity of each method in distinguishing between health and disease, were evaluated. None of the VFT formulations consistently correlated with all diastolic metrics, though each showed a significant relationship with at least one. Notably, only the introduced piston-based VFT correlated significantly with mitral e' velocity (<i>P</i> < 0.0001) and atrial contraction duration (<i>P</i> < 0.05), suggesting it captures unique aspects of LV mechanics. All VFT formulations yielded lower values in the heart-failure group, with three of the four reliably distinguishing between clinical groups. These findings indicate that while each VFT formulation reflects distinct LV mechanisms and may provide complementary insights into diastolic function, none appear sensitive enough to serve as a standalone, comprehensive diastolic metric.<b>NEW & NOTEWORTHY</b> This study addresses discrepancies in the literature regarding the measurement of vortex formation time (VFT) as an index of diastolic function. We evaluate the clinical relevance of three existing VFT formulations and introduce a novel, fluid dynamics-based method (VFT_piston) that models the left ventricular base as a moving piston. Using healthy and heart-failure participants, we demonstrate that each VFT formulation captures distinct aspects of ventricular mechanics and VFT_piston offers physiologically meaningful correlations with diastolic metrics.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1094-H1103"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181857","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":"Wave intensity analysis with exercise identifies impairments in pulmonary hypertension.","authors":"Christopher G Lechuga, Farhan Raza, Mitchel J Colebank, Claudia E Korcarz, Jens C Eickhoff, Naomi C Chesler","doi":"10.1152/ajpheart.00194.2025","DOIUrl":"10.1152/ajpheart.00194.2025","url":null,"abstract":"<p><p>Wave intensity analysis provides a novel approach to understanding the dynamic interactions between the right ventricle and pulmonary vasculature, particularly in pulmonary hypertension, a condition characterized by elevated pulmonary arterial pressures and vascular remodeling. This prospective study used wave intensity analysis to evaluate right ventricular and pulmonary vascular mechanics in 22 participants with pulmonary hypertension (including precapillary, isolated postcapillary, and combined pre/postcapillary pulmonary hypertension), and three without pulmonary hypertension. Forward and backward compression and decompression waves were quantified at rest and during incremental exercise (25, 50, and 75 W). Relationships between metrics of wave intensity analysis, hemodynamics, right ventricular function, and oxygen consumption were analyzed using linear mixed-effects modeling. Wave intensity patterns highlighting vessel-specific pulmonary vascular and right ventricular pathobiology were observed in different phenotypes. Precapillary pulmonary hypertension exhibited highest forward compression waves, which correlated with right ventricular contractility (<i>P</i> < 0.01). Backward compression waves correlated strongly with characteristic impedance (<i>P</i> = 0.002) in combined pre/postcapillary pulmonary hypertension and inversely with pulmonary arterial compliance (<i>P</i> = 0.003) in precapillary pulmonary hypertension. The ratio of backward to forward compression (systolic) waves decreased in isolated postcapillary pulmonary hypertension during exercise (<i>P</i> < 0.001), suggesting right ventricular reserve capacity that improves vascular-ventricular coupling. Wave intensity metrics demonstrated strong correlations with oxygen consumption in participants without pulmonary hypertension, indicating sensitivity to exercise-induced changes in cardiopulmonary status. Wave intensity analysis with exercise suggests vessel-specific pulmonary vascular and right ventricular characteristics unique to pulmonary hypertension phenotypes. These findings highlight wave intensity analysis as a promising tool for advancing understanding of cardiopulmonary pathobiology in pulmonary hypertension.<b>NEW & NOTEWORTHY</b> Wave intensity analysis (WIA) during exercise reveals distinct ventricle-/vessel-specific impairments across PH phenotypes. Cpc-PH exhibited highest forward and backward compression waves, reflecting elevated RV energy expenditure and pulmonary vascular stiffness, respectively. Precapillary PH demonstrated higher forward and backward decompression waves, suggesting differences in RV and pulmonary vascular mechanics. The compression reflection index decreased in Ipc-PH with exercise, indicating RV reserve capacity. These findings highlight WIA's potential for phenotyping PH and advancing cardiopulmonary pathophysiology assessment.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1017-H1030"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12534041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051656","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":"Dysregulated smooth muscle cell proliferation and gene expression underlie <i>ACTA2</i> variant-associated aortopathy.","authors":"Mark E Pepin, Richard N Mitchell, Rajat M Gupta","doi":"10.1152/ajpheart.00579.2025","DOIUrl":"10.1152/ajpheart.00579.2025","url":null,"abstract":"<p><p>Pathogenic variants affecting alpha-2 smooth muscle actin (<i>ACTA2</i>) account for approximately 20% of nonsyndromic familial thoracic aortic aneurysms (TAA) and confer a high risk of dissection; however, the cell type-specific transcriptional mechanisms underlying <i>ACTA2</i>-associated TAA remain poorly defined, particularly for variants of uncertain significance. In this study, we investigated the transcriptional and cellular effects of a novel <i>ACTA2</i> p.Met49Thr mutation identified in a young male in his early twenties, who developed a dissected ascending aortic aneurysm without traditional risk factors. Using clinically archived formalin-fixed paraffin-embedded (FFPE) aortic tissue, we isolated intact nuclei and performed single-nucleus RNA sequencing (snRNA-Seq) to generate 17,938 transcriptomes. Relative to a nongenetic hypertensive TAA control, <i>ACTA2</i>-p.Met49Thr aortic tissue displayed marked expansion of vascular smooth muscle cells (VSMCs) (70.6% vs. 39.7%), accompanied by upregulation of proliferation-associated transcripts including <i>FOSB</i>, <i>FOS</i>, <i>JUN</i>, and <i>DEPP1</i>. Lineage tracing via trajectory analysis revealed transcriptional progression from quiescent to pro-proliferative VSMC states, enriching for human loci associated with aortic strain and diameter. Histological evaluation corroborated these findings, demonstrating medial hypercellularity, elastic fiber fragmentation, and adventitial fibrosis enriched within the <i>ACTA2</i>-p.Met49Thr specimen. Taken together, these findings implicate a novel pathogenic <i>ACTA2</i> variant that drives transcriptional reprogramming and proliferative VSMC remodeling, supporting that <i>ACTA2</i>-associated aortopathy progression occurs via functional cell state transitions. In addition, this work demonstrates the feasibility of FFPE-compatible snRNA-Seq for clinical variant annotation.<b>NEW & NOTEWORTHY</b> This study uncovers how a novel <i>ACTA2</i> variant (p.Met49Thr) likely drives thoracic aortic aneurysm through a pro-proliferative shift in vascular smooth muscle cell states. Using FFPE-compatible single-nucleus RNA-sequencing (snRNA-seq), this study links transcriptomic profiling of the human aorta to vascular traits, highlighting a pathologic cell state transition in <i>ACTA2</i>-mutant aortopathy. More broadly, it also serves as a proof-of-concept to leverage snRNA-seq technology using archived human tissue for clinical phenotype-to-variant characterization.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1072-H1079"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190678","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":"Twelve-week nitrate-rich beetroot extract supplementation improves lower limb vascular function and serum angiogenic potential in postmenopausal women.","authors":"Thiago Silveira Alvares, Vivian Pinheiro, David N Proctor, Carlos Adam Conte Junior, Rogerio Nogueira Soares","doi":"10.1152/ajpheart.00592.2025","DOIUrl":"10.1152/ajpheart.00592.2025","url":null,"abstract":"<p><p>Postmenopausal women have reduced nitric oxide (NO) bioavailability and impairments within the microcirculation and lower limb conduit arteries, key factors contributing to cardiovascular disease (CVD) development and mortality. Dietary nitrate supplementation has shown promise in improving vascular function, yet most studies are limited to short-term interventions and upper-limb conduit artery function assessment. We investigated whether a 12-wk nitrate-rich beetroot extract supplementation improves lower-limb conduit artery and skeletal muscle microvascular function, alongside serum angiogenic potential, in postmenopausal women. Postmenopausal women (60-85 yr) were randomized to consume nitrate-rich (8.8 mmol nitrate, <i>n</i> = 8) or nitrate-depleted beetroot extract (0.7 mmol nitrate, <i>n</i> = 8) daily for 12 wk. Femoral artery endothelial function was assessed via flow-mediated dilation (FMD), whereas tibialis anterior muscle microvascular reactivity was evaluated by near-infrared spectroscopy-derived reperfusion slope (StO₂ <i>slope 2</i>) every 4 wk. Serum angiogenic potential was evaluated through endothelial tube formation assays using human umbilical vein endothelial cells. Serum nitrate increased significantly at <i>weeks 4</i>, <i>8</i>, and <i>12</i> in the nitrate-rich group (<i>P</i> < 0.05), with no changes in controls. Femoral artery FMD improved significantly after 12 wk (<i>P</i> < 0.05), whereas tibialis anterior microvascular reactivity increased after 8 and 12 wk (<i>P</i> < 0.05). Serum from nitrate-supplemented participants at <i>week 12</i> induced a 1.8-fold increase in vitro tube formation compared with baseline (<i>P</i> < 0.05). Collectively, the current findings suggest nitrate-rich beetroot extract as a potential dietary strategy to attenuate the vascular detrimental effects of menopause and reduce CVD risk in older women.<b>NEW & NOTEWORTHY</b> Postmenopausal women exhibit impaired lower limb vascular function and reduced angiogenic capacity, increasing cardiovascular risk. This study demonstrates that 12 wk of nitrate-rich beetroot extract supplementation enhances femoral artery endothelial function, skeletal muscle microvascular reactivity, and serum angiogenic potential, offering a promising dietary strategy to improve vascular health in this population.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1047-H1054"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051609","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":"Arrhythpy: an automated tool to quantify and classify arrhythmias in Ca²⁺ transients of iPSC-cardiomyocytes.","authors":"Karim Ajmail, Charlotte Brand, Thomas Borchert, Benjamin Meder, Sabine Rebs, Katrin Streckfuss-Bömeke","doi":"10.1152/ajpheart.00414.2025","DOIUrl":"10.1152/ajpheart.00414.2025","url":null,"abstract":"<p><p>Arrhythmias constitute an intricate and clinically significant phenomenon of great importance in various research areas. Calcium (Ca²⁺) homeostasis plays a pivotal role in forming rhythmic contractions in the heart, and its dysregulation has emerged as a critical component in the development of arrhythmias. However, the quantification of arrhythmias has been limited to indirect measurements via Ca²⁺ sparks, electrophysiological parameters, or manual classification, which can lead to human bias. We aimed to develop an analysis platform that automatically analyzes arrhythmias in human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Here, we present Arrhythpy, a robust and automated open-source program that quantifies and classifies confocal microscopy-based Fluo-4 Ca²⁺ transients to generate a measure of arrhythmia. In contrast to other automated and semiautomated analysis tools, which measure established parameters such as time-to-peak, Arrhythpy directly analyzes the degree of arrhythmia in a Ca²⁺ transient. We demonstrate its utility in monitoring Ca²⁺ transient-based arrhythmias in atrial and ventricular iPSC-CMs from healthy individuals and patients with cardiac disease, including dilated cardiomyopathy (DCM) and Takotsubo syndrome (TTS). Arrhythpy analysis of iPSC-CMs of patients with TTS recapitulated TTS phenotypes, including atrial arrhythmia that could be normalized with β-blocker treatment. The program's adaptable framework enables the analysis of arrhythmic patterns in various cell types using periodic dye-based line scan measurement techniques, applicable to both single cells and layered cultures.<b>NEW & NOTEWORTHY</b> Arrhythmias in calcium transients are easy to detect by human perception. However, quantifying these arrhythmias in a computer-readable manner remains challenging. To address this, we developed Arrhythpy, an automated tool that measures arrhythmias in iPSC-derived cardiomyocytes by analyzing Ca²⁺ transients. Unlike other tools, Arrhythpy directly evaluates arrhythmia levels. It effectively monitors arrhythmias in healthy and diseased iPSC-CMs, including dilated cardiomyopathy and Takotsubo syndrome. Arrhythpy's flexible framework suits varied cell types and measurement techniques.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1110-H1125"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068800","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":"MitoQ reduces senescence burden in doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage.","authors":"Hossein Abdeahad, Denisse G Moreno, Samuel I Bloom, Lucas Norman, Lisa A Lesniewski, Anthony J Donato","doi":"10.1152/ajpheart.00568.2025","DOIUrl":"10.1152/ajpheart.00568.2025","url":null,"abstract":"<p><p>Cardiovascular toxicity is one of the adverse consequences of chemotherapy, limiting its therapeutic application. Chemotherapeutics, such as doxorubicin (DOXO), induce endothelial dysfunction via genotoxic effects, and reactive oxygen species (ROS) and mitochondrial ROS (mtROS) generation. These mechanisms can induce cellular senescence, a persistent cell cycle arrest promoting inflammation, which elevates future cardiovascular disease risk. The adverse impact of DOXO on endothelial function can be mitigated by the mitochondria-targeted antioxidant, mitoquinol (MitoQ); however, its precise protective mechanism in endothelial cells (ECs) remains unclear. The present study hypothesizes that cotreating ECs with MitoQ and DOXO attenuates DOXO-induced mtROS, thereby reducing DNA damage, senescence, and inflammation. Mitochondrial superoxide levels, mitochondrial mass, DNA damage, and cellular senescence were assessed in human umbilical vein ECs (HUVECs) 48 h after DOXO and/or MitoQ treatment. DOXO treatment increased mtROS production and reduced mitochondrial mass compared with the vehicle group. Cotreatment with MitoQ decreased mtROS production and preserved mitochondrial mass compared with DOXO alone. MitoQ Cotreatment prevented senescence induction in DOXO-treated HUVECs, evidenced by preventing increased mRNA expression for senescence markers and senescence-associated β-galactosidase activity, alongside higher cell proliferation (bromodeoxyuridine incorporation). In addition, MitoQ cotreatment reduced DNA damage and telomere dysfunction (DNA damage signaling at telomeres) compared with DOXO alone. Collectively, these data suggest mtROS drives cellular senescence in ECs through increased DNA damage and telomere dysfunction. These findings provide insight into mechanisms underlying DOXO-induced endothelial dysfunction and support mitochondrial-targeted antioxidant treatment as a potential therapeutic to mitigate chemotherapy-induced cardiovascular toxicity.<b>NEW & NOTEWORTHY</b> Doxorubicin (DOXO) is a widely used chemotherapy drug that can damage blood vessels and promote cardiovascular disease. This study shows that MitoQ, a mitochondria-targeted antioxidant, protects endothelial cells from DOXO-induced oxidative stress, DNA damage, and senescence. By preserving mitochondrial health, MitoQ may prevent vascular toxicity in cancer patients receiving DOXO, offering a potential strategy to improve cardiovascular outcomes in survivorship.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1154-H1161"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197919","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":"Yin and Yang: opposing faces of metabolism in physiological and pathological cardiac remodeling.","authors":"Thomas G Martin","doi":"10.1152/ajpheart.00750.2025","DOIUrl":"10.1152/ajpheart.00750.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1104-H1106"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224745","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":"Pregnancy-dependent cardioprotection via GPER activation in Dahl salt-sensitive rats with superimposed preeclampsia.","authors":"Allan K N Alencar, Kenneth F Swan, Mistina M Manoharan, Christopher A Natale, Sarah H Lindsey, Gabriella C Pridjian, Michael R Garrett, Carolyn L Bayer","doi":"10.1152/ajpheart.00262.2025","DOIUrl":"10.1152/ajpheart.00262.2025","url":null,"abstract":"<p><p>Preeclampsia is a hypertensive disorder of pregnancy that affects multiple organs, increasing cardiovascular risks for both the mother and offspring. This study investigated LNS8801, a selective and orally bioavailable G protein-coupled estrogen receptor (GPER) agonist, to improve cardiac function in virgin and pregnant Dahl salt-sensitive (SS/Jr) rats, a model of superimposed preeclampsia with exacerbated cardiac and renal dysfunction during pregnancy. Female Dahl SS/Jr rats bred at 18-20 wk were randomized into four groups: Virgin + Vehicle, Virgin + LNS8801, Pregnant + Vehicle, and Pregnant + LNS8801. LNS8801 was orally administered in pregnant rats from <i>gestational day</i> (GD) <i>9</i> to <i>20</i> and an equivalent period in virgin controls. Cardiac function was assessed via echocardiography. LNS8801 improved cardiac function in pregnant Dahl SS/Jr rats, enhancing global longitudinal, circumferential, and radial strain, as well as increasing systolic function compared with the vehicle-treated controls. In addition, LNS8801 enhanced diastolic function, improving left ventricular compliance (E/A ratio) and early mitral annular velocity (e'), while reducing left ventricular filling pressures (E/e' ratio) in comparison to pregnant rats treated with vehicle. In contrast, LNS8801 had no significant effects on cardiac function and blood pressure in virgin Dahl SS/Jr rats, suggesting that pregnancy-related adaptations may enhance GPER-mediated cardioprotection. LNS8801 treatment significantly reduced proteinuria in both virgin and pregnant rats, indicating a pregnancy-independent renal protective effect. This study highlights the importance of pregnancy-specific adaptations on the cardiovascular effects of GPER activation. Although LNS8801 demonstrated cardioprotective and antihypertensive benefits in pregnant Dahl SS/Jr rats, its effects were absent in virgin animals.<b>NEW & NOTEWORTHY</b> In this work, GPER (G protein-coupled estrogen receptor) was investigated as a novel therapeutic target for managing cardiovascular complications in preeclampsia. Activation of GPER by the selective agonist LNS8801 significantly improved cardiac function during pregnancy, with no effect on virgin animals, suggesting a pregnancy-specific impact. It also reduced blood pressure in pregnant Dahl SS/Jr rats with superimposed preeclampsia.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1080-H1093"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172367","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":"Mechanisms of exercise limitation in heart failure with preserved ejection fraction and obesity: a case of engine-chassis mismatch.","authors":"Stephen J Foulkes, Sara Moura-Ferreira, Mauricio Milani, Youri Bekhuis, Maarten Falter, Boris Delpire, Rik Pauwels, Sarah Stroobants, Siddharth Jogani, Simon Vanhentenrijk, Sibel Altintas, Ruta Jasaityte, Jan Stassen, Lieven Herbots, Guido Claessen, Mark J Haykowsky, Jan Verwerft","doi":"10.1152/ajpheart.00587.2025","DOIUrl":"10.1152/ajpheart.00587.2025","url":null,"abstract":"<p><p>Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), but its impact on limitations in peak oxygen uptake (V̇o_2peak) and its Fick determinants remains unclear. We assessed these factors in patients with obesity and patients without obesity with HFpEF, and non-HFpEF controls. Patients with HFpEF were subgrouped by body mass index [body mass index (BMI) ≥ 30 or < 30 kg/m²] into HFpEF with (HFpEF_Obese, <i>n</i> = 139) or without obesity (HFpEF_Nonobese, <i>n</i> = 317), and non-HFpEF controls (CON, <i>n</i> = 270). Cardiopulmonary exercise testing with simultaneous echocardiography assessed V̇o_2peak, cardiac output (CO), stroke volume (SV), heart rate (HR), mean pulmonary artery pressure (mPAP) dynamics, and arterio-venous oxygen difference (a-vO₂diff). HFpEF_Obese tended to have higher absolute V̇o_2peak (+7%, <i>P</i> = 0.069), and significantly higher peak exercise CO and SV, with no differences in HR or a-vO₂diff. Resting and exercise mPAP and mPAP/CO slopes did not differ between HFpEF obesity phenotypes. In contrast, bodyweight-indexed V̇o_2peak was markedly lower in HFpEF_Obese (-23%) despite comparable indexed peak CO and SV. Regardless of HFpEF subgroup, V̇o_2peak, central (CO, HR, mPAP) and peripheral factors (a-vO₂diff) were markedly impaired in HFpEF versus CON (<i>P</i> < 0.05 for all). Therefore, although patients with HFpEF_Obese have preserved absolute V̇o_2peak and cardiac reserve, bodyweight-indexing reveals that these adaptations are insufficient for the heightened metabolic and functional demands induced by obesity. Alternatively, several physiological HFpEF features are not exacerbated by obesity. This highlights the importance of incorporating weight loss alongside multicomponent therapeutic strategies to address exercise intolerance in HFpEF.<b>NEW & NOTEWORTHY</b> Patients with obesity with heart failure with preserved ejection fraction (HFpEF) have larger hearts and preserved cardiac reserve, but this was insufficient to maintain bodyweight-indexed V̇o_2peak at comparable levels to patients without obesity. Obesity did not exacerbate other HFpEF impairments, such as decreased oxygen extraction or elevated pulmonary pressures. This suggests weight loss may help to improve exercise intolerance in obese patients with HFpEF, but should be combined with other treatments to target all of the features that contribute to exercise intolerance in HFpEF.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1126-H1136"},"PeriodicalIF":4.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197947","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}