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

{"title":"Omega-6/omega-3 oxylipin imbalance and altered 15-LOX and sEH pathways in Fontan physiology.","authors":"Stephanie P B Caligiuri, Amir Ravandi, Harold M Aukema, Ashish H Shah","doi":"10.1152/ajpheart.00901.2025","DOIUrl":"10.1152/ajpheart.00901.2025","url":null,"abstract":"<p><p>The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation often develop progressive multisystem dysfunction, the biochemical underpinnings of which remain poorly understood. Oxylipins are bioactive lipid mediators implicated in cardiovascular disease and represent targetable pathways that may contribute to the pathophysiology of the Fontan state. The study aims to quantify plasma oxylipins in individuals with Fontan circulation, compared with matched controls, and assess correlations with hemodynamic function and exercise capacity. A total of 20 adult patients with Fontan circulation and 20 matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. Compared with controls, Fontan participants exhibited significantly increased (34%) total plasma oxylipin concentrations, with a 42% elevation in ω-6 fatty acid-derived oxylipins. Among these, metabolites generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%. In addition, product-to-substrate ratios reflecting putative soluble epoxide hydrolase (sEH) activity for ω-6 fatty acids were nearly threefold higher in the Fontan group. Several oxylipins derived from ω-3 and ω-6 fatty acids, including those generated by 15-LOX and sEH pathways, demonstrated significant correlations with key clinical parameters, including resting and exercise hemodynamics, ventilatory efficiency, and peak oxygen consumption (V̇o₂). Individuals with Fontan circulation exhibit marked alterations in circulating oxylipins, particularly those involving ω-6 fatty acid metabolism via 15-LOX and sEH. These findings offer mechanistic insights and identify potentially modifiable targets.<b>NEW & NOTEWORTHY</b> Fontan patients exhibit a distinct oxylipin signature characterized by markedly elevated total and ω-6-derived oxylipins, including increased 15-LOX activity and higher sEH product-to-substrate ratios, alongside reduced ω-3 species such as 20-hydroxydocosahexanoic acid (20-HDoHE) and 17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated ω-6 oxylipins correlated with poorer exercise capacity, greater frailty, and impaired hemodynamics, whereas ω-3 oxylipins showed the opposite trend. These findings identify oxylipin dysregulation as a central metabolic hallmark and potential therapeutic target in Fontan circulation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1466-H1478"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519715","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":"DIA-PINN: A physics-informed machine learning method to estimate global intrinsic diastolic chamber properties of the left ventricle from pressure-volume data.","authors":"Javier Fernández-Topham, Manuel Guerrero-Hurtado, Juan Carlos Del Álamo, Javier Bermejo, Pablo Martinez-Legazpi","doi":"10.1152/ajpheart.00109.2026","DOIUrl":"10.1152/ajpheart.00109.2026","url":null,"abstract":"<p><p>Pressure-volume (PV) loop analysis remains the gold standard for assessing the intrinsic global diastolic properties of the left ventricle (LV). Traditional fitting techniques rely on local, phase-constrained fittings and are limited due to their sensitivity to noise, landmark selection, violation of assumptions, and nonconvergence. We aimed to develop and validate DIA-, a physics-informed neural network (PINN) framework capable of calculating intrinsic diastolic properties of the LV from measured instantaneous PV data, combining mechanistic interpretability with machine learning flexibility. Instantaneous LV diastolic pressure was modeled as the sum of <i>1</i>) time-dependent relaxation-related pressure and <i>2</i>) volume-dependent recoil and stiffness-related pressures. DIA-PINN was trained using time, LV pressure, and LV volume as inputs, enforcing data fidelity, model consistency, and physiological plausibility within the loss function. Performance was evaluated in 4,000 Monte Carlo simulations of LV PV-loops, and in clinical data from 59 patients who underwent catheterization (39 with heart failure and normal ejection fraction and 20 controls). DIA-PINN-derived indices were compared with those obtained from a previously validated global optimization method (GOM). On the simulation data, DIA-PINN accurately recovered all constitutive indices (intraclass correlation coefficients near unity) and improved GOM performance. On the clinical data, diastolic indices derived using DIA-PINN strongly correlated with GOM estimates (<i>R</i> > 0.90, <i>P</i> < 0.001) but were insensitive to initialization. DIA-PINN performed best under vena cava occlusion, as varying preload improved parameter identifiability. When applied to instantaneous pressure-volume data, a generalizable PINN framework, DIA-PINN, provides an improved method for assessing global intrinsic diastolic properties of cardiac chambers.<b>NEW & NOTEWORTHY</b> Our work introduces DIA-PINN, a physics-informed neural network framework to process instantaneous ventricular pressure-volume data, solving a mechanistic model of diastole with machine learning techniques. Compared with current conventional or optimization-based approaches, the PINN provides the most reliable estimates of diastolic stiffness, relaxation, and elastic recoil, insensitive to initialization. By embedding physiological constraints into network training, this approach achieves robust, interpretable, and clinically applicable quantification of gold-standard metrics of intrinsic global diastolic chamber properties.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1590-H1599"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643634","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":"Cardiac metabolic remodeling drives dicarbonyl stress-induced mitochondrial dysfunction in experimental heart failure with preserved ejection fraction.","authors":"Ankit Aryal, Parnia Mobasheran, Luther Bishop, Sabyasachi Chatterjee, Scott Jennings, Huijing Xia, Eric Lazartigues, Qinglin Yang","doi":"10.1152/ajpheart.00029.2026","DOIUrl":"10.1152/ajpheart.00029.2026","url":null,"abstract":"<p><p>Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin II (1.5 μg/g/day) and phenylephrine (50 μg/g/day) in 8- to 10-wk-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by an ∼20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by sevenfold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and antiglycation strategies as promising therapeutic avenues.<b>NEW & NOTEWORTHY</b> Recent studies increasingly highlight profound metabolic remodeling within the HFpEF heart; however, it remains unclear if this is an intrinsic or systemic phenomenon. In the present study, we identify dicarbonyl and glycative stress as key drivers of mitochondrial dysfunction in an ANGII/PE mouse model with HFpEF phenotype independent of systemic metabolic disease. These findings reveal a previously unrecognized metabolic-mitochondrial axis and suggest dicarbonyl detoxification and mitochondrial antiglycation as potential therapeutic targets.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1689-H1701"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760025","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":"Drug repurposing using transcriptomics: principles and unmet needs in cardiovascular disease.","authors":"Samuel Leung, Clint L Miller, Amrit Singh, Ying Wang","doi":"10.1152/ajpheart.00899.2025","DOIUrl":"10.1152/ajpheart.00899.2025","url":null,"abstract":"<p><p>Although cardiovascular disease is the leading cause of death globally, therapeutic development in this field is slow. Given the high cost of developing new drugs and running clinical trials for cardiovascular disease, repurposing of drugs with approved safety profiles is an attractive strategy for therapeutic development that can significantly reduce the time and cost investment before phase II clinical trials. In the era of \"Omics,\" various new methods and several large databases have been developed to enable the use of transcriptomics data for drug repurposing. This review summarizes the principles and workflow of signature mapping, which forms the foundation of statistical models used for transcriptome-based drug repurposing. We highlight the features of different analysis pipelines and databases that have been developed for signature mapping. These analysis pipelines prioritize genes that are statistically important, an approach that fundamentally differs from the pharmacological approach of identifying disease-driving and therapeutically targetable pathways. Outcomes of signature mapping pipelines are sensitive to the quality of input data, and results are not always reproducible. Moreover, all widely used RNA-seq databases are derived from cancer research and lack high-quality molecular data for cardiovascular disease. These unmet needs call for interdisciplinary collaboration and large networks of cardiovascular research-oriented biobanks to create the databases needed for transcriptomic-based signature mapping for drug repurposing efforts.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1508-H1521"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572031","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":"Guidelines for evaluating endothelial function in vascular tissue.","authors":"Cameron G McCarthy, Christian Aalkjær, Pooneh Bagher, Andreas M Beyer, Ebbe Boedtkjer, Gisele F Bomfim, Jerome W Breslin, Ana M Briones, Jorge A Castorena-Gonzalez, Tiago J Costa, Zhiyu Dai, Ana P Davel, Scott Earley, Julie K Freed, Christopher Garland, Brant E Isackson, Thomas A Jepps, Joanna Kalucka, Boris Lavanderos, Ayako Makino, Charles E Norton, Steven S Segal, Wenbin Tan, Aaron J Trask, Calum Wilson, Scott D Zawieja, Camilla F Wenceslau","doi":"10.1152/ajpheart.00656.2025","DOIUrl":"10.1152/ajpheart.00656.2025","url":null,"abstract":"<p><p>The endothelium plays a central role in maintaining vascular homeostasis by orchestrating vascular tone, inflammation, healing, permeability, and thrombosis. Assessing endothelial function in vascular tissue is essential for understanding the cellular and molecular mechanisms underlying cardiovascular physiology and pathology. Traditional approaches, such as wire and pressure myography, have been instrumental in defining endothelium-dependent responses and identifying key pharmacological targets. However, the complexity and heterogeneity of endothelial cells across vascular beds and their dynamic phenotypic changes in health and disease necessitate the incorporation of new investigative strategies. Emerging methodologies, including bulk and single-cell transcriptomics, proteomics, and advanced imaging, now provide unprecedented insights into endothelial cell diversity and function. A team of leading experts in the field, who collectively reached a consensus on the most widely used techniques to evaluate endothelial function, developed these guidelines. The document establishes best practices for assessing endothelial function, from endothelial cell cultures to isolated vascular tissues, integrating conventional functional assays with modern molecular approaches. By fostering methodological consistency and embracing innovation, our goal is to enhance rigor, reproducibility, understanding, and discovery in endothelial biology.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1600-H1672"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13085230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375826","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":"When pregnancy tests the heart: voluntary wheel running attenuates HFHS-associated postpartum hemodynamic dysfunction.","authors":"Eunhee Chung, Yun-Ju Fang, Filip Konecny","doi":"10.1152/ajpheart.00018.2026","DOIUrl":"10.1152/ajpheart.00018.2026","url":null,"abstract":"<p><p>Pregnancy and lactation increase cardiovascular demand and may unmask postpartum cardiac vulnerability under metabolic stress. We tested whether exposure to a high-fat/high-sucrose (HFHS) diet from premating through lactation induces postpartum hemodynamic dysfunction with preserved ejection fraction (EF) and whether voluntary wheel running mitigates these alterations. Virgin C57BL/6J female mice were assigned to control sedentary (CS), HFHS sedentary (HS), or HFHS with voluntary wheel running across the reproductive window. Left ventricular (LV) pressure-volume (P-V) analysis was performed 6-9 days after weaning at baseline and during dobutamine challenge to assess β-adrenergic reserve. Despite preserved EF, HS dams exhibited reduced end-diastolic volume (EDV) and impaired forward performance [lower stroke volume (SV), cardiac output, and stroke work] accompanied by higher filling pressure, increased diastolic stiffness (end-diastolic elastance, <i>E</i>_ed), impaired ventricular-arterial coupling (<i>E</i>_es/<i>E</i>_a), and reduced load-independent contractility [end-systolic elastance (<i>E</i>_es)]. Dobutamine increased chronotropic and inotropic indices across groups; however, HS remained lower than CS during dobutamine for SV and <i>E</i>_es, indicating limited capacity to augment performance under stress. In contrast, wheel running improved intrinsic contractility and maintained <i>E</i>_es<i>/E</i>_a at rest and during dobutamine without differences in body or heart weight. These findings indicate that HFHS exposure across pregnancy and lactation is associated with postpartum hemodynamic dysfunction characterized by preserved EF with impaired filling, increased diastolic stiffness, and reduced reserve; voluntary wheel running across this window mitigates key abnormalities in systolic mechanics and ventricular-arterial coupling.<b>NEW & NOTEWORTHY</b> HFHS exposure across pregnancy and lactation produces postpartum hemodynamic dysfunction with preserved EF, marked by higher filling pressure, increased diastolic stiffness, and impaired ventricular-arterial coupling and β-adrenergic reserve. Voluntary wheel running from premating through lactation improves intrinsic contractility and preserves coupling during dobutamine challenge.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1361-H1367"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472385","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":"RNAi-mediated p38δ silencing mitigates anthracycline cardiotoxicity in female mice.","authors":"Katy A Trampel, Katherine Y Gross, Daniel O'Reilly, Altynai Melisova, Batool Salman, Sophie Green, Sharon A George, Anastasia Khvorova, Igor R Efimov, Tatiana Efimova","doi":"10.1152/ajpheart.00944.2025","DOIUrl":"10.1152/ajpheart.00944.2025","url":null,"abstract":"<p><p>The anthracycline antibiotic doxorubicin (DOX) is a potent chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity. We previously reported that genetic deletion of p38δ protects female mice from DOX-induced cardiotoxicity (DIC), suggesting that inhibiting this kinase could be an effective treatment. Here, we developed a fully chemically stabilized small interfering RNA (siRNA) that effectively silences p38δ. In an acute DIC model, silencing p38δ reduced mortality and morbidity, preserved heart structure and function, and decreased fibrosis in female mice. It also alleviated DOX-induced electrophysiological remodeling and decreased cardiac inflammation and senescence-associated secretory phenotype (SASP). Transcriptomic analysis of DOX-treated p38δ-deficient hearts revealed the downregulation of genes associated with inflammation, ion transport, and impulse generation, and the upregulation of genes involved in oxidative stress management, autophagy, and immune signaling. These findings support silencing p38δ as a promising approach to protect against DIC, highlighting the potential of siRNA-based therapies to mitigate anthracycline cardiotoxicity.<b>NEW & NOTEWORTHY</b> This study presents the first isoform-specific inhibition of p38δ using a docosanoic (DCA)-conjugated, fully chemically stabilized siRNA. Our lead compound, si644, achieves potent, durable, and well-tolerated p38δ silencing in vivo in mouse hearts and ex vivo in human cardiac organotypic slices. si644-mediated p38δ silencing protects female mice from DIC by mitigating DOX-induced structural, electrophysiological, fibrotic, and inflammatory remodeling. These findings establish p38δ inhibition as a promising therapeutic strategy for preventing anthracycline cardiotoxicity.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1522-H1539"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502792","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":"From transplant rejection to coronary no-reflow: an immune-ischemic framework for antibody-mediated microvascular dysfunction.","authors":"Francesco Tona, Giovanni Civieri, Giacomo Bernava, Emanuele Cozzi","doi":"10.1152/ajpheart.00906.2025","DOIUrl":"10.1152/ajpheart.00906.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1545-H1552"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643586","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":"Reductions in myocardial interstitial fibrosis are dissociated from LV chamber stiffness in swine with repetitive pressure overload.","authors":"Emily Hudson, Alexandra Gilligan, John M Canty, Brian R Weil","doi":"10.1152/ajpheart.00082.2026","DOIUrl":"10.1152/ajpheart.00082.2026","url":null,"abstract":"<p><p>Cardiosphere-derived cells (CDCs) and the nonsteroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for heart failure with preserved ejection fraction (HFpEF). Although these interventions can improve diastolic properties, their direct effects on left ventricular (LV) chamber stiffness have not been established. Accordingly, we examined their effect in swine with increased LV chamber stiffness and fibrosis from repetitive pressure overload (RPO). Swine (<i>n</i> = 19) were subjected to daily (1 h) episodes of RPO for 2 wk using phenylephrine to transiently elevate left ventricular end-diastolic volume (LVEDP) to ∼30 mmHg. After 2 wk, RPO was discontinued, and animals received intracoronary saline (<i>n</i> = 6), allogeneic CDCs (30 × 10⁶, <i>n</i> = 7), or oral finerenone (20 mg/day; <i>n</i> = 6) and were followed for 4 wk. LV end-diastolic pressure and end-diastolic volume index were measured at normal and elevated preload to assess LV chamber stiffness (ΔLVEDP/ΔLVEDVi), and postmortem picrosirius red staining was performed to quantify interstitial fibrosis. Four weeks after cessation of RPO, saline-treated swine demonstrated sustained increases in LV chamber stiffness (1.7 ± 0.3 mmHg/mL/m² vs. 0.6 ± 0.1 mmHg/mL/m² in controls, <i>P</i> < 0.01). This was associated with increased fibrosis (8.5 ± 0.7% vs. 6.7 ± 0.4% in controls, <i>P</i> < 0.05) that decreased after treatment with CDCs (6.1 ± 0.5%, <i>P</i> < 0.05) and finerenone (5.4 ± 0.6%, <i>P</i> < 0.05). Despite these antifibrotic effects, LV chamber stiffness remained elevated after both agents (CDCs: 1.9 ± 0.4 mmHg/mL/m²; finerenone: 1.4 ± 0.3 mmHg/mL/m², both <i>P</i> < 0.05 vs. normal controls). Although both CDCs and finerenone reduced fibrosis, these changes were not associated with reductions in LV chamber stiffness. Additional mechanisms likely underlie increased LV chamber stiffness in this model, which may have relevance to the therapeutic impact of these interventions on diastolic function in HFpEF.<b>NEW & NOTEWORTHY</b> Swine with increased left ventricular (LV) chamber stiffness and fibrosis from 2 wk of repetitive pressure overload demonstrated discordant effects following two disparate antifibrotic interventions. A single infusion of intracoronary allogeneic cardiosphere-derived cells and 4 wk of oral finerenone each effectively reduced myocardial interstitial fibrosis. Despite reversal of fibrosis, LV chamber stiffness did not improve with either intervention, suggesting that myocyte-dependent mechanisms may play an important role in diastolic dysfunction from intermittent hemodynamic overload.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1394-H1404"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13055569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442303","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":"Associations of urinary isoprostanes with structural and load-dependent arterial stiffness: the Multi-Ethnic Study of Atherosclerosis.","authors":"Theodore M DeConne, Petra Buzkova, Ryan Pewowaruk, Bruce M Psaty, Adam D Gepner, Joseph A Delaney, Timothy M Hughes, Nels C Olson","doi":"10.1152/ajpheart.00971.2025","DOIUrl":"10.1152/ajpheart.00971.2025","url":null,"abstract":"<p><p>Total carotid pulse wave velocity (T-PWV), a measure of arterial stiffness, is caused by structural (S) remodeling and elevated blood pressure exerting a pressure-load on the arterial wall. Isoprostanes are oxidative stress biomarkers that have been associated with arterial stiffness. We sought to investigate the cross-sectional and longitudinal associations of urinary 8-isoprostane (iPF2α-III) and its metabolite (iPF2α-III-M), measured at a single timepoint at baseline, with carotid T-PWV, S-PWV, and load-dependent (LD)-PWV in a subset (<i>n</i> = 744) of participants enrolled in the Multi-Ethnic Study of Atherosclerosis. We hypothesized that higher iPF2α-III and iPF2α-III-M concentrations would be associated with higher T-PWV, S-PWV, and LD-PWV. These relationships were evaluated using multivariable linear regression models adjusted for potential confounders in the entire analytical sample and in analyses stratified by hypertension medication class and race/ethnicity. In cross-sectional analyses of the entire analytic sample, there were no associations of acute iPF2α-III or iPF2α-III-M with carotid T-PWV, S-PWV, or LD-PWV after adjusting for risk factors. In adults taking angiotensin-II acting antihypertensive medications, higher iPF2α-III was associated with higher S-PWV, whereas higher iPF2α-III-M was associated with higher T-PWV and S-PWV. In the entire analytic sample, baseline isoprostanes were not associated with carotid PWV measured nearly a decade later. However, in analyses stratified by race/ethnicity, higher baseline iPF2α-III was associated with higher S-PWV nearly a decade later among self-identified White participants. These results suggest that single-timepoint measures of urinary 8-isoprostane are not a robust biomarker of arterial stiffness but may be associated with structural remodeling in select populations.<b>NEW & NOTEWORTHY</b> We examined cross-sectional and longitudinal associations of urinary isoprostanes with carotid T-PWV, and its associated mechanisms (S-PWV and LD-PWV), in a multiethnic cohort of adults. Higher isoprostanes were cross-sectionally associated with carotid artery stiffness driven by structural remodeling in adults who self-reported taking angiotensin-II acting medications or self-identified as White. No associations were observed with isoprostanes and carotid stiffness a decade later in the entire analytic sample. Oxidative stress may augment the risk of structural remodeling in select populations.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1481-H1490"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519660","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}