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

{"title":"β-Adrenergic receptors mediate sex differences in vasodilation but not sympathetic-mediated vasoconstriction during hypoxia.","authors":"Dain W Jacob, Brian Shariffi, Braden J Bond, Natasha G Boyes, Samuel A Martin, Anna M Gonsalves, Jennifer L Harper, Brian P Bostick, Jacqueline K Limberg","doi":"10.1152/ajpheart.00192.2025","DOIUrl":"10.1152/ajpheart.00192.2025","url":null,"abstract":"<p><p>β-Adrenergic receptors (ARs) mediate a portion of hypoxic vasodilation and blunt sympathetic vasoconstriction at rest. Vascular β-AR sensitivity may be greater in females relative to males; however, their sex-specific role during hypoxia has yet to be examined. We hypothesized β-AR blockade would blunt hypoxic vasodilation and augment sympathetic vasoconstriction during hypoxia, with effects greater in females relative to males. Ten female (26 ± 8 yr, 23 ± 3 kg/m²) and 13 male (28 ± 7 yr, 25 ± 2 kg/m²) adults completed two study visits randomized and blinded to oral placebo or propranolol (β-AR blockade; 1 mg/kg) (NCT05256069). Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed for 10-min normoxic rest, followed by 5 min of steady-state hypoxia (∼80% [Formula: see text]). Sympathetic activation was achieved via a cold pressor test (CPT) conducted during normoxia and steady-state hypoxia. FBF was normalized for mean BP (forearm vascular conductance, FVC). Absolute (Δ) and relative (%) changes in FVC in response to hypoxia and CPT were calculated. β-AR blockade significantly reduced hypoxic vasodilation in females but not in males (interaction of hypoxia and sex: ΔFVC <i>P</i> = 0.029, %FVC <i>P</i> = 0.030). Sympathetic vasoconstriction was attenuated during hypoxia in females compared with males (main effect of sex: ΔFVC <i>P</i> = 0.005, %FVC <i>P</i> = 0.015), but there was no effect of β-AR blockade in either sex (main effect of drug: ΔFVC <i>P</i> = 0.406; %FVC <i>P</i> = 0.238; interaction of drug and sex: ΔFVC <i>P</i> = 0.619, %FVC <i>P</i> = 0.390). β-Adrenergic receptors mediate hypoxic dilation in females but not in males and do not restrain sympathetic-mediated vasoconstriction during hypoxia in either sex.<b>NEW & NOTEWORTHY</b> β-Adrenergic receptors contribute to hypoxic vasodilation, attenuate sympathetic vasoconstriction at rest, and are more sensitive in females versus males. We hypothesized β-adrenergic receptor blockade would blunt hypoxic vasodilation and augment the sympathetic vasoconstriction during hypoxia, with effects greater in females relative to males. Present data demonstrate β-adrenergic receptors contribute to hypoxic vasodilation in females but do not restrain sympathetic-mediated vasoconstriction during hypoxia in either sex.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H233-H240"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224042","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":"The effect of transient sex hormone fluctuations on vascular endothelial function.","authors":"Casey G Turner, Jennifer J DuPont","doi":"10.1152/ajpheart.00174.2025","DOIUrl":"10.1152/ajpheart.00174.2025","url":null,"abstract":"<p><p>This review article summarizes the current literature investigating the effects of transient sex hormone fluctuations on large artery endothelial function, primarily concerning the menstrual cycle and the diurnal rhythm of testosterone secretion. Women and men experience acute fluctuations in circulating levels of sex hormones, and there is substantial variability in circulating levels of sex hormones in both sexes. These acute fluctuations in sex hormones generally coincide with alterations in endothelial cell function and in vivo endothelium-dependent vasodilation, and we see that the timing of these acute fluctuations matches the timing of cardiovascular events in both women and men. It is important to improve our understanding of how acute fluctuations in sex hormones affect endothelial function in women and men, as clinical cardiovascular complications coincide with these changes. This would allow for the identification of novel therapeutic targets and aid in the prevention and treatment of cardiovascular disease.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H217-H232"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214683","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":"Sex-specific modulation of cardiac fibrosis and lipid metabolism by B-vitamins in heart failure with reduced ejection fraction in mice.","authors":"Chloé David, Sonia Deschênes, Gabriel Ichkhan, Caroline Daneault, Isabelle Robillard Frayne, Bertrand Bouchard, Anik Forest, Yan Fen Shi, Marie-Ève Higgins, Martin G Sirois, Jean-Claude Tardif, Mathias Mericskay, Jérôme Piquereau, Matthieu Ruiz","doi":"10.1152/ajpheart.00841.2024","DOIUrl":"10.1152/ajpheart.00841.2024","url":null,"abstract":"<p><p>Despite significant advancements in therapies, heart failure (HF) remains a major health challenge. Women, who are underrepresented in HF research, are particularly in need of effective treatments. B-vitamins are a promising and cost-effective option for improving cardiac function. Our study aimed to investigate the sex-specific effects of B-vitamin supplementation on HF with reduced ejection fraction in mice. Male and female mice underwent transverse aortic constriction (TAC) to induce pressure overload. Four weeks post-TAC, mice were randomized to receive either a standard or a vitamin B-enriched (VitB) diet. We found that in females, but not in males, VitB <i>1</i>) extended survival, <i>2</i>) slowed down the decrease in ejection fraction (EF), and <i>3</i>) improved left ventricular morphology. The observed benefits in females were associated with evidence of improved cardiac and lung fibrosis and lower inflammation. In contrast, in males, VitB treatment did not reduce cardiac and lung fibrosis, whereas inflammation remained active in the myocardium. Regarding the circulating lipidome, disturbances were normalized in females with a specific enrichment in long-chain and polyunsaturated triglycerides (TGs) in response to VitB. Conversely, in males, lipidomic alterations remained under VitB treatment and were characterized by the accumulation of shorter and saturated TG in the circulation and myocardium. These data reveal a sex-specific response to VitB supplementation in HF in the context of pressure overload and point to a differential lipidomic remodeling that is only favorable in females.<b>NEW & NOTEWORTHY</b> This study explores the sex-specific effects of B-vitamin supplementation on heart failure with reduced ejection fraction in mice subjected to pressure overload. Our study found that B-vitamins improved survival rates, cardiac function, and reduced fibrosis in female mice, with favorable lipidomic remodeling characterized by an increase in polyunsaturated triglycerides. In contrast, male mice exhibited persistent inflammation, fibrosis, and unfavorable lipidome remodeling despite the B-vitamin supplementation. These findings underscore the sex-specific benefits of B-vitamins in heart failure, suggesting their potential therapeutic value for women, who remain underrepresented in cardiovascular research.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H69-H86"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960833","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":"Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.","authors":"Ana Vujic, Amy Koo, Guillaume Bidault, Jan Lj Miljkovic, Andrew M James, Andreas Dannhorn, Xiaowen Duan, Lucy M Davis, Jiro Abe, Joyce Valadares, Jordan J Lee, Alexis Diaz-Vegas, Keira Turner, Richard Goodwin, Daniel J Fazakerley, Antonio Vidal-Puig, Michael P Murphy, Thomas Krieg","doi":"10.1152/ajpheart.00482.2024","DOIUrl":"10.1152/ajpheart.00482.2024","url":null,"abstract":"<p><p>Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (<i>ND6 G13997A</i>), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in wild-type but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (<i>CD36</i>, <i>Cpt1b</i>, <i>Acly</i>, <i>Fas</i>, <i>Elovl6</i>, and <i>Scd1</i>) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 wk of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.<b>NEW & NOTEWORTHY</b> Loss of reverse electron transport (RET)-reactive oxygen species (ROS) impairs diastolic function and exercise capacity, which can be improved by long-term aerobic exercise. RET-ROS may act as a modulator of cardiac metabolism.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H154-H168"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962159","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":"Vagal impairment and cardiovascular risk in those with zero to low coronary artery calcification scores: the Multi-Ethnic Study of Atherosclerosis.","authors":"Madalena D Costa, Susan Redline, Roger B Davis, Murray Mittleman, Ary L Goldberger, Susan R Heckbert","doi":"10.1152/ajpheart.00295.2025","DOIUrl":"10.1152/ajpheart.00295.2025","url":null,"abstract":"<p><p>Coronary artery calcification (CAC) is the most reliable noninvasive predictor of major adverse cardiovascular events (MACEs). Individuals with no detectable or minimal CAC (Agatston score 1-100) are considered at the lowest risk. However, MACE does occur in these groups. This study evaluated whether quantification of cardiac vagal activity by heart rate fragmentation (HRF) improved MACE risk prediction beyond CAC imaging. Our study population is a cohort of the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression models were used to assess the association between HRF, derived from polysomnographic ECGs, and incident MACE in the overall cohort with concurrent polysomnographic ECG and CAC data, and three nonoverlapping subgroups: \"very-low-risk\" (CAC = 0), \"low-risk\" (0 < CAC < 100), and \"elevated-risk\" (CAC ≥ 100). Over a median (1st; 3rd quartiles) follow-up period of 8.9 (8.4; 9.4) yr, there were 164, 29, 47, and 88 incident MACEs in the overall cohort (<i>n</i> = 1,354), very-low-risk (<i>n</i> = 495), low-risk (<i>n</i> = 422), and higher-risk (<i>n</i> = 437) subgroups, respectively. A one standard deviation increment in HRF was associated with a 22% (3%-44%) and a 60% (16%-122%) increase in the rate of MACE in the overall cohort and those without detectable CAC, respectively. Neither the Framingham nor the MESA-CAC index was predictive of MACE in the lowest-risk subgroup until nearly a decade of follow-up. From a physiologic perspective, our results suggest that vagal dysfunction precedes the onset of overt cardiovascular disease (CVD). From a translational perspective, they indicate that HRF enhances risk stratification, especially in populations traditionally classified as very-low risk.<b>NEW & NOTEWORTHY</b> This study is the first to show that cardiac parasympathetic function, assessed via heart rate fragmentation (HRF), is independently associated with major adverse cardiovascular events (MACEs) in individuals traditionally considered low-risk due to nondetectable or minimal coronary artery calcification (CAC). HRF outperforms both the Framingham and MESA-CAC risk scores in the lowest-risk subgroup over the short term (<10 yr).</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H258-H266"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232990","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 PAD2 expression and myocardial citrullination decline with age in female mice independent of estrogen.","authors":"Samantha K Shorthill, Finley R Klinger, Aykhan Yusifov, Joshua P Thornburg, Marjie P Schmitt, Emma R Mehl, Sharanya S Bettadapura, Mason H Agor, Florence Teulé-Finley, Brian D Cherrington, Danielle R Bruns","doi":"10.1152/ajpheart.00023.2025","DOIUrl":"10.1152/ajpheart.00023.2025","url":null,"abstract":"<p><p>Cardiac aging is sexually dimorphic, with women more likely than men to develop diastolic dysfunction for which no therapies exist. Loss of estrogen (E2) during menopause increases the risk of diastolic dysfunction in women through unclear mechanisms. Citrullination, a posttranslational modification catalyzed by peptidylarginine deiminase 2 (PAD2), is positively regulated by E2, suggesting a novel mechanism linking PAD2, diastolic function, and E2 in the female heart. We hypothesized that PAD2 expression and citrullination are sexually dimorphic with aging such that as E2 levels decline, so does PAD2 expression and citrullination, contributing to diastolic dysfunction. PAD2 expression decreased with age in female mice but not in the aging male heart. Mass spectrometry detected citrullination of sarcomeric and metabolic proteins, with lower levels of citrullinated proteins in aged female hearts compared with young. To confirm direct regulation of PAD2 by E2, a cohort of young (2 mo) and aged (21 mo) mice underwent ovariectomy with or without E2 replacement. Contrary to our hypothesis, PAD2 expression was not regulated by E2 in the heart. To directly link PAD2 and diastolic function, we assessed cardiac function in middle-aged female global PAD2 knockout mice and found that loss of PAD2 resulted in diastolic dysfunction. Together, we establish that protein citrullination and PAD2 decline with age in the female heart, perhaps contributing to diastolic dysfunction. Elucidation of the mechanisms underlying PAD2 declines in the female heart remains to be determined and may benefit the development of therapies for diastolic dysfunction for aging women.<b>NEW & NOTEWORTHY</b> We tested peptidylarginine deiminase 2 (PAD2) as a novel regulator of diastolic dysfunction in the aging female heart. We found that PAD2 expression declines with age in the female heart and loss of PAD2 causes diastolic dysfunction. However, unlike in female reproductive tissue, PAD2 in the heart is not regulated by estrogen. Given the large burden of diastolic dysfunction in aging women, future work to understand the regulation of PAD2 and diastolic dysfunction is warranted.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H271-H281"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214682","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":"Reduced peak pressure gradient in patients with aortic stenosis and type 2 diabetes.","authors":"Kosuke Minai, Kazuo Ogawa, Toshikazu D Tanaka, Makoto Kawai, Jun Yoshida, Keisuke Shirasaki, Ryosuke Itakura, Seigo Yamashita, Tomohisa Nagoshi, Takayuki Ogawa, Michifumi Tokuda, Michihiro Yoshimura","doi":"10.1152/ajpheart.00255.2025","DOIUrl":"10.1152/ajpheart.00255.2025","url":null,"abstract":"<p><p>Diabetes impairs energy metabolism throughout the body, including the heart. However, the clinical effect of diabetes on left ventricular (LV) contractility remains unclear. To address this knowledge gap, we investigated the effect of diabetes on patients with aortic stenosis (AS), a model of increased LV afterload. We analyzed data from 276 consecutive patients with AS who underwent transthoracic surgery, echocardiography, cardiac catheterization, and fasting blood sampling. The peak aortic velocity was determined using continuous-wave Doppler echocardiography, and the peak pressure gradient (peak PG) was calculated using the simplified Bernoulli equation. The aortic valve area (AVA) determined using planimetry risk factors, including age, glycated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR) level, sex, hemoglobin level, hypertension, and dyslipidemia, that influenced the peak PG was examined using regression analysis. Structural equation modeling (SEM) was performed to identify the direct and indirect effects of these variables on the peak PG. SE revealed a significant association between the AVA and peak PG (<i>P</i> < 0.001). The peak PG significantly decreased with higher HbA1c (<i>P</i> < 0.001) and increased with age (<i>P</i> = 0.004). Other factors, including HOMA-IR, sex, hypertension, and dyslipidemia, had no significant effects. AVA decreased significantly with age (<i>P</i> = 0.007) and increased with sex (male) (<i>P</i> = 0.034). Diabetes reduces LV contractility, as evidenced in patients with AS. Insufficient glucose metabolism may contribute to LV dysfunction. Clinically, the severity of AS in patients with diabetes should not be underestimated based on the PG alone.<b>NEW & NOTEWORTHY</b> Diabetes may impair left ventricular (LV) contractility, but clear human evidence remains limited. This study investigated its impact in patients with aortic stenosis (AS), demonstrating that diabetes significantly reduces LV function. Clinically, our findings suggest that relying solely on pressure gradients may underestimate AS severity in patients with diabetes, highlighting the necessity for a more comprehensive assessment to ensure accurate evaluation and management of the disease.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H32-H38"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109401","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":"Bend it like BIN1: how a membrane-curving adaptor protein shapes cardiac physiology.","authors":"Heather C Spooner, Rose E Dixon","doi":"10.1152/ajpheart.00198.2025","DOIUrl":"10.1152/ajpheart.00198.2025","url":null,"abstract":"<p><p>Bridging integrator 1, initially named box-dependent myc-interacting protein-1 (BIN1), and also known as Amphiphysin 2 is a versatile N-BAR protein that plays essential roles in membrane remodeling, protein trafficking, and cellular organization across multiple tissues. Although extensively studied in cancer and Alzheimer's disease, BIN1's critical functions in cardiac physiology and pathology represent an emerging frontier with significant therapeutic implications. This review provides a synopsis of our current understanding of BIN1's structure-function relationships, with particular emphasis on cardiac-specific isoforms and their roles in heart function. We examine how BIN1's various domains-including the membrane-curvature forming and sensing BAR domain, phosphoinositide-binding motif, and SH3 protein-protein interaction domains-orchestrate its diverse cellular functions, from t-tubule growth, microfolding, and anchoring to directed protein trafficking and complex assembly. Recent discoveries highlight BIN1's involvement in cardiac aging and disease, where both deficiency and excess of BIN1 can lead to dysfunction. Notably, BIN1 levels are reduced in heart failure while increasing significantly during cardiac aging, suggesting a bidirectional pathophysiology where both insufficient and excessive BIN1 expression can impair cardiac function. We discuss emerging evidence regarding the role of BIN1 in cardiac pathologies, offering potential therapeutic targets. Understanding BIN1's membrane-shaping capabilities and its roles in organizing excitation-contraction coupling machinery could yield novel therapeutic strategies for addressing cardiac dysfunction in various disease contexts.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H94-H108"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109400","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":"Relative contribution of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction.","authors":"Emylie-Ann Labbé, Sara-Ève Thibodeau, Élisabeth Walsh-Wilkinson, Maude Chalifour, Pierre-Olivier Sirois, Juliette Leblanc, Audrey Morin-Grandmont, Marie Arsenault, Jacques Couet","doi":"10.1152/ajpheart.00092.2025","DOIUrl":"10.1152/ajpheart.00092.2025","url":null,"abstract":"<p><p>Using a two-hit murine model of heart failure with preserved ejection fraction (HFpEF), we studied cardiac reverse remodeling (RR) after stopping the causing stress [Angiotensin II (AngII) + high-fat diet (HFD); metabolic and hypertensive stress (MHS)] and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. This led to extensive left ventricle (LV) RR. We then studied the relative contribution to RR of only correcting the diet or allowing VE after stopping AngII. We next evaluated myocardial recovery after an extended period (12 wk instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Stopping AngII but continuing the HFD blocked RR in females, not males. Correcting the diet or implementing VE normalized most gene markers of LV hypertrophy or extracellular matrix remodeling, irrespective of sex. Twelve weeks of recovery were associated with normal LV morphology and function, except for several abnormal diastolic echocardiographic parameters. A second MHS after these 12 wk led to a loss of ejection fraction in males. The response of females was like that after the first MHS, suggesting a better myocardial recovery. The MHS likely changed myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity, which is responsible for pyruvate entry in the mitochondria, was reduced after MHS, and this was accompanied by an increase in PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining make males more sensitive to a second HFpEF-inducing stress.<b>NEW & NOTEWORTHY</b> Most new mouse models of heart failure with preserved ejection fraction (HFpEF) are based on the combination of hypertension and metabolic alterations. These models provide a better approximation of the complexity of the processes involved in human HFpEF. Here, we show that the extent of reverse remodeling and myocardial recovery after stopping the causal stress in a mouse model depends on the biological sex, recovery duration, and diet correction.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H51-H68"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148872","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":"Cellular and molecular mechanisms underlying hemodialysis arteriovenous fistula dysfunction and approaches to promote maturation: a vascular perspective.","authors":"Yan-Ting Shiu, Hannah Northrup, Yufeng Huang, Monique E Cho, Kanokwan Bunsawat","doi":"10.1152/ajpheart.00010.2025","DOIUrl":"10.1152/ajpheart.00010.2025","url":null,"abstract":"<p><p>Hemodialysis requires functional vascular access, which serves as the conduit for blood flow between the patient and the hemodialysis machine. The arteriovenous fistula (AVF), created by surgically connecting an artery to a nearby vein in the upper extremity, is the preferred form of vascular access for maintenance hemodialysis. Newly created AVFs must undergo a maturation process, during which the fistula vein enlarges and develops sufficient lumen size and blood flow to be used effectively for dialysis. However, since the invention of AVFs 60 years ago, rates of AVF maturation failure have remained high. Currently, no proven therapies exist to promote maturation or prevent maturation failure. This review examines the current understanding of the cellular and molecular mechanisms underlying AVF maturation failure, with particular focus on the impact of the chronic kidney disease (CKD) environment on the vascular system. In CKD, patients often have elevated levels of uremic toxins, increased oxidative stress, and chronic inflammation, all of which adversely affect the function of vascular wall cells (such as endothelial cells, vascular smooth muscle cells, and fibroblasts) and circulating cells (such as platelets and immune/inflammatory cells). The goal of this review is to explore the mechanisms influencing both native and AVF vasculature in the context of CKD. In addition, we will discuss current therapies aimed at improving native vasculature in patients with CKD, as well as investigational approaches to promote AVF maturation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H241-H257"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224041","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}