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

{"title":"Warm-ischemia and cold storage induced modulation of ferroptosis observed in human hearts donated after circulatory death and brain death.","authors":"Shiyi Li, Katherine V Nordick, Abdussalam E Elsenousi, Rishav Bhattacharya, Randall P Kirby, Adel M Hassan, Camila Hochman-Mendez, Todd K Rosengart, Kenneth K Liao, Nandan K Mondal","doi":"10.1152/ajpheart.00806.2024","DOIUrl":"10.1152/ajpheart.00806.2024","url":null,"abstract":"<p><p>We investigated ferroptosis, a type of programmed cell death mechanism, in human hearts donated after brain death (DBD) and those donated after circulatory death (DCD), focusing on warm ischemia time (WIT) and cold storage. A total of 24 hearts were procured, with six from the DBD group and 18 from the DCD group. The DCD group was divided into three subgroups, each containing six hearts, based on different WITs of 20, 40, and 60 min. All procured hearts were placed in cold storage for up to 6 h. Left ventricular biopsies were performed at 0, 2, 4, and 6 h. We measured ferroptosis regulators [glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and transferrin receptor], iron content (Fe²⁺ and Fe³⁺), and lipid peroxidation (malondialdehyde, MDA) in the cardiac tissue. Modulation of ferroptosis was observed in both DBD and DCD hearts. Warm ischemia injury increased myocardial vulnerability to ferroptotic cell death. For DBD hearts, up to 6 h of cold storage increases cardiac levels of MDA, iron content, and ACSL4, thereby increasing vulnerability to ferroptotic cell death. In contrast, for DCD hearts with a WIT of 40 min or more, warm ischemia injury was identified as the primary factor contributing to increased myocardial susceptibility to ferroptotic cell death. Ferroptosis may serve as a promising target to optimize cold preservation for DBD hearts. For DCD hearts, strategies to inhibit ferroptosis should focus on the early warm ischemia phase to assess donor heart quality and suitability for transplantation.<b>NEW & NOTEWORTHY</b> The first human heart research explored the effects of ischemia on the myocardial ferroptotic cell death mechanism. Prolonged cold storage increases the susceptibility of DBD hearts to ferroptotic cell death. In contrast, warm ischemic injury appears to be the main factor leading to the vulnerability of DCD heart ferroptosis. Targeting ferroptosis could be beneficial in optimizing cold preservation for DBD hearts. However, for DCD hearts, interventions should focus on the early phase of warm ischemia.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H923-H936"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584163","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":"Exploring the mechanisms of sex-specific proarrhythmia in long QT syndrome through computational modeling.","authors":"Isabella Doherty, Roshni Shetty, Haibo Ni, Stefano Morotti, Eleonora Grandi","doi":"10.1152/ajpheart.00792.2024","DOIUrl":"10.1152/ajpheart.00792.2024","url":null,"abstract":"<p><p>Females exhibit longer QT intervals and a higher risk of long QT syndrome (LQTS) associated arrhythmogenesis compared with males. Although several studies suggest these sex disparities result from the effect of sex hormones on cardiac ion channels, the underlying mechanisms remain incompletely understood. This research investigates the arrhythmogenic effects, sex-specific risk, and mechanisms associated with LQTS linked to either to loss-of-function of the rapidly activating delayed rectifier K⁺ current (<i>I</i>_Kr), or gain-of-function of the L-type Ca²⁺ current (<i>I</i>_CaL). We primarily used the Tomek-Rodriguez (ToR-ORd) model of human ventricular cardiomyocytes and incorporated sex-specific parameterizations based on previous studies. The O'Hara-Rudy and Grandi-Bers models were used to demonstrate model-independence of the findings. We used a populations-of-models approach to assess early afterdepolarization (EAD) susceptibility in control and LQTS male and female groups. All female models had consistently longer action potentials and were more prone to EADs than male models. In the ToR-ORd model, <i>I</i>_Kr loss-of-function led to EADs in 65.8% of females versus 22.8% of males. <i>I</i>_CaL gain-of-function led to EADs in 66.2% of females but only 3.6% of males. Using logistic regression analysis, we identified key ionic predictors of EAD susceptibility, with maximal conductance of the L-type Ca²⁺ current (<i>G</i>_CaL) and maximal transport rate of the Na⁺/Ca²⁺ exchanger (<i>G</i>_NCX) consistently emerging as positively and maximal conductance of the rapidly activating delayed rectifier K⁺ current (<i>G</i>_Kr) as negatively associated to EADs across both sexes and LQTS types. Notably, higher <i>G</i>_NCX but lower <i>G</i>_Kr in female versus male cardiomyocytes could explain heightened female EAD risk. Our studies explore the ionic traits that favor (or confer resilience against) EADs with potential implications for personalized treatments. <b>NEW & NOTEWORTHY</b> We explored sex disparities in long QT syndrome (LQTS) using sex-specific human ventricular cardiomyocyte models. We showed that females exhibit greater susceptibility to early afterdepolarizations (EADs) than males, and identified key ionic predictors of EAD risk, including increases in the voltage-gated L-type Ca²⁺ current and electrogenic Na⁺/Ca²⁺ exchanger, and downregulation of the rapidly activating delayed rectifier K⁺ current. These findings offer new insights into sex-specific mechanisms underlying arrhythmogenesis in LQTS, with potential implications for personalized treatments.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H963-H972"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623108","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":"Aortic aneurysm and dissection: complement and precision medicine in aortic disease.","authors":"Leonie Dreher, Malte B Kuehl, Ulrich O Wenzel, Dominik Kylies","doi":"10.1152/ajpheart.00853.2024","DOIUrl":"10.1152/ajpheart.00853.2024","url":null,"abstract":"<p><p>Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix-metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering proinflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H814-H829"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527825","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":"Elevated frame rates during exercise echocardiography improve speckle-tracking success rate and augment deformation values.","authors":"Fabian Spahiu, Michelle Ottlik, Lars C Helbig, Eric J Stöhr","doi":"10.1152/ajpheart.00817.2024","DOIUrl":"10.1152/ajpheart.00817.2024","url":null,"abstract":"<p><p>Although two-dimensional (2-D) speckle-tracking echocardiography (STE) is important for the clinical quantification of myocardial function, it remains unknown whether increased frame rates during exercise STE augment tracking success and absolute deformation values. Overall, 19 participants (15 males and 4 females; aged 26.7 ± 4.8) underwent stepwise exercise testing on a recumbent bicycle. Exercise started at 50 W, increasing by 30 W every 3 min until a target heart rate (HR) of 130-140 beats/min was reached. During the last 90 s of each exercise stage, echocardiographic sequences for offline quantification of longitudinal strain (LS), peak twist, untwisting velocity, basal rotation, and apical rotation were acquired with high [high frames per second (HFPS)], medium [medium frames per second (MFPS)], and low-frames per second (LFPS)]. Differences in tracking success were determined by using Chi-square test, and the impact of different frame rates on absolute deformation values was compared by using mixed-model analysis. Utilization of HFPS significantly improved tracking success for parasternal short-axis images. LS acquired at HFPS was the highest at baseline and across all the exercise stages. Similar trends were observed for twist, peak untwisting velocity, and apical rotation, whereas basal rotation showed no differences. Mixed-model analysis revealed a significant impact of frame rate setting on LS (<i>P</i> < 0.05) and untwisting velocity (<i>P</i> < 0.05). In contrast to recommendations by leading organizations advocating for frame rates between 40 and 80 frames per second (fps) during resting conditions, with a proportional increase as heart rate rises, our findings suggest that consistently maintaining the frame rate at the highest feasible level is preferable for achieving optimal-tracking success and accuracy in STE.<b>NEW & NOTEWORTHY</b> This study demonstrates the benefits of high frame per second (HFPS) rate settings in speckle-tracking echocardiography, achieving superior-tracking success and higher deformation values, including longitudinal strain and untwisting velocity, compared with lower frame rates. These advantages, particularly evident at elevated heart rates, highlight the importance of high temporal resolution for accurate cardiac imaging under stress conditions. The findings support prioritizing HFPS in clinical and research settings to improve tracking reliability and data accuracy.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H752-H760"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063093","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":"Endothelial dysfunction promotes age-related reorganization of collagen fibers and alters aortic biomechanics in mice.","authors":"Liya Du, Jeffrey Rodgers, Nazli Gharraee, Olivia Gary, Tarek Shazly, John F Eberth, Susan M Lessner","doi":"10.1152/ajpheart.00056.2023","DOIUrl":"10.1152/ajpheart.00056.2023","url":null,"abstract":"<p><p>Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide (NO), is a risk factor for the occurrence and progression of various vascular diseases. This study investigates the effect of endothelial dysfunction on age-related changes in aortic extracellular matrix (ECM) microstructure and the relationship between microstructural adaptation and the mechanical response. Here, we used groups of NOS3 knockout (KO), NOS3 heterozygotes (Het), and wild-type (WT) B6 mice (controls) to study changes in hemodynamic parameters, collagen fiber organization, and both active and passive aortic mechanics using biaxial pressure myography over a time course from 1.5 to 12 mo. Our results show that homeostatic levels of passive circumferential stress and stretch were preserved in KO mice by remodeling adventitial collagen fibers toward a more predominantly circumferential direction with age, rather than by increased fibrosis, in response to hypertension induced by endothelial dysfunction. However, passive aortic stiffness in KO mice was significantly increased owing to geometrical changes, including significant increases in wall thickness and decreases in inner diameter, and by ECM microstructural reorganization, during this maladaptive vascular remodeling. Furthermore, long-term NO deficiency significantly increased smooth muscle cell (SMC) contractility initially, but this effect was attenuated with age. These findings improve our understanding of microstructural and mechanical changes during the maladaptive vascular remodeling process, demonstrating a role for adventitial collagen fiber reorientation in the response to hypertension.<b>NEW & NOTEWORTHY</b> Endothelial dysfunction facilitates the reorganization of collagen fibers toward a more predominantly circumferential orientation with age, consequently promoting homeostatic normalization of passive circumferential stress and stretch in the vessel subjected to hypertension.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H900-H914"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584401","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":"Retinoic acid signaling and metabolism in heart failure.","authors":"Lauren E Parker, Kyriakos N Papanicolaou, Stephanie Zalesak-Kravec, Eva M Weinberger, Maureen A Kane, D Brian Foster","doi":"10.1152/ajpheart.00871.2024","DOIUrl":"10.1152/ajpheart.00871.2024","url":null,"abstract":"<p><p>Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL)-deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all<i>-</i>trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the vitamin A metabolites, or retinoids, in adult heart physiology and heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H792-H813"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397789","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":"Prognostic circulatory signature metabolites of stable versus unstable angina: an application of NMR spectroscopy.","authors":"Ashish Gupta, Shiridhar Kashyap, Deepak Kumar, Khushbhu Meena, Anupam Kumar, Ankit Kumar Sahu, Sudeep Kumar, Aditya Kapoor","doi":"10.1152/ajpheart.00707.2024","DOIUrl":"10.1152/ajpheart.00707.2024","url":null,"abstract":"<p><p>In spite of the ongoing efforts to probe the metabolic signatures of stable (SA) from unstable (UA) angina, it is concerning that to date there are no clinically validated circulatory biochemical signatures against the intrinsic anatomical changes that are screened by invasive coronary angiography. Hence, the aim of this study is to generate precise biochemical fingerprints using filtered serum-based metabolomics and high-throughput nuclear magnetic resonance (NMR) spectroscopy to accurately distinguish the metabolic signatures of patients suffering with SA or UA angina. The study includes 118 filtered serum samples from patients suffering from UA (<i>n</i> = 50) and SA (<i>n</i> = 68). High-resolution NMR spectroscopy was used to assess the metabolic remodeling in these cohorts. Subsequently, principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), and artificial neural network (ANN) analysis were adapted to engender a precise prediction model. Analysis of the receiver operating characteristic (ROC) curve was conducted to determine the clinical usefulness of metabolic markers. The outcome revealed that the metabolic profile for the underlying disease is characterized by altered metabolite levels in UA relative to SA. Creatinine, 3-OH butyrate, and aspartate level could differentiate 100% of UA from SA with 100% sensitivity and specificity. To monitor and determine UA from patients with SA, ¹H NMR-based filtered serum metabolic profiling seems to be a promising, less invasive, and faster investigative approach.<b>NEW & NOTEWORTHY</b> There are no metabolic signatures present to identify unstable from stable angina. Coronary angiography identifies anatomical changes after the event of unstable angina, but NMR-based metabolomics identifies unstable from stable angina within 4 h. Creatinine, 3-OH butyrate, and aspartate were able to segregate unstable from stable angina.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H761-H773"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490384","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":"Effect of 12-wk dietary nitrate supplementation on carotid arterial stiffness in postmenopausal females.","authors":"Vivian Dos Santos Pinheiro, David N Proctor, Rogerio Nogueira Soares, Thiago Silveira Alvares","doi":"10.1152/ajpheart.00065.2025","DOIUrl":"10.1152/ajpheart.00065.2025","url":null,"abstract":"<p><p>Menopause is associated with reduced nitric oxide (NO) bioavailability, a key contributor to increased arterial stiffness and, consequently, greater risk of cardiovascular disease-related mortality in postmenopausal females. Even though dietary nitrate has been shown to increase NO bioavailability in postmenopausal females acutely, previous studies showed no impact of dietary nitrate supplementation on arterial stiffness in postmenopausal females. Their findings were likely limited by the acute and/or short-term design. Thus, this study aimed to determine whether 12 wk of dietary nitrate supplementation via beetroot extract improves carotid artery stiffness in postmenopausal females. A randomized, double-blind, placebo-controlled, and parallel-design trial was conducted with 20 postmenopausal females (60-85 yr). Participants received nitrate-rich (NR-BEETx, 8.8 mmol/day) or nitrate-depleted (ND-BEETx) beetroot extract. Carotid stiffness parameters-pulse wave velocity (PWVβ), β stiffness, pressure-strain elastic modulus, augmentation index (AIx), and arterial compliance-were measured at baseline and <i>weeks 4</i>, <i>8</i>, and <i>12</i>. Serum nitrate and nitrite concentrations and blood pressure were also assessed. Compared with ND-BEETx, NR-BEETx supplementation significantly reduced PWVβ, β stiffness, elastic modulus, and AIx at <i>weeks 4</i>, <i>8</i>, and <i>12</i>, whereas arterial compliance increased by <i>week 12</i>. Serum nitrate and nitrite concentrations were elevated five- to sixfold and 1.5- to 2-fold, respectively, in the NR-BEETx group, with peak concentrations occurring at <i>week 8</i> and showing a plateau or slight decrease at <i>week 12</i>. Blood pressure remained unchanged in both groups. Twelve weeks of nitrate-rich beetroot extract supplementation improved carotid artery stiffness and increased NO bioavailability without altering blood pressure. These findings suggest that beetroot extract supplementation can be recommended as an alternative nutritional strategy to mitigate carotid artery stiffening in postmenopausal females.<b>NEW & NOTEWORTHY</b> Postmenopausal females experience reduced nitric oxide (NO) bioavailability and elevated carotid artery stiffness, a well-established independent risk factor for end-organ damage and all-cause mortality. In this study, we demonstrate that 12 wk of dietary nitrate supplementation through beetroot extract significantly increased NO bioavailability and improved carotid artery stiffness in postmenopausal females.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H937-H944"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603554","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":"Tissue elasticity modulates cardiac pacemaker cell automaticity.","authors":"Young Hwan Choi, Jing Leng, Jinqi Fan, Rafael J Ramirez, Hee Cheol Cho","doi":"10.1152/ajpheart.00813.2024","DOIUrl":"10.1152/ajpheart.00813.2024","url":null,"abstract":"<p><p>Tissue elasticity is essential to a broad spectrum of cell biology and organ function including the heart. Routine cell culture models on rigid polystyrene dishes are limited in studying the impact of tissue elasticity in distinct regions of the myocardium such as the cardiac conduction system. Gelatin, a derivative of collagen, is a simple and tunable platform for modeling tissue elasticity. We sought to study the effects of increasing tissue stiffness on cardiac pacemaker cell function by using transcription factor-reprogrammed pacemaker cells cultured on gelatin hydrogels with specific elasticity. Our data indicate that automaticity of the pacemaker cells, measured in rhythmic contractions and oscillating intracellular Ca²⁺ transients, was enhanced when cultured on a stiffer matrix of 14 kPa. This was accompanied by increased expression of cardiac pacemaker ion channel, Hcn4, and a reciprocal decrease in Cx43 expression compared with control conditions. Propagation of Ca²⁺ transients was slower in the pacemaker cell monolayers compared with control, which recapitulates a hallmark feature in the native pacemaker tissue. Ca²⁺ transient propagation of pacemaker cell monolayer was slower on stiffer than on softer hydrogel, and this was dependent on enhanced proliferation of cardiac fibroblasts rather than differences in gap junctional coupling. Culturing the pacemaker cells on rigid plastic plates led to irregular or loss of synchronous contractions as well as unusually long Ca²⁺ transient durations. Taken together, our data demonstrate that automaticity of pacemaker cells is augmented by stiffer extracellular matrix substrates within the elasticity range of the healthy myocardium. This simple approach presents a physiological in vitro model to study mechanoelectric feedback of cardiomyocytes including the conduction system cells.<b>NEW & NOTEWORTHY</b> The major achievement of this work is development of a robust and straightforward approach to model cardiac conduction system cells with a range of cardiac tissue elasticity with a goal to understand the impact of tissue stiffness on cardiac pacing. Our data provide a framework for further investigation of the heart rhythm in health and disease in the context of fibrosis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H978-H990"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623109","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":"Leveraging circulating DNase I activity to detect silent coronary artery disease among hypertensive diabetes individuals.","authors":"Amit Babu, Chinnappa A Uthaiah, Preetam Narayan Wasnik, Neha Rani Verma, Matam Vijay-Kumar, Jessy Abraham","doi":"10.1152/ajpheart.00088.2025","DOIUrl":"10.1152/ajpheart.00088.2025","url":null,"abstract":"<p><p>In individuals with diabetic hypertension, silent coronary artery disease (CAD) is common due to underlying chronic inflammation, but there is no biomarker to monitor this high-risk group of individuals before noticeable symptoms emerge clinically. cfDNA from dying endothelial cells triggers chronic inflammation, leading us to hypothesize that enzymes that degrade cfDNA, DNase I and/or II, could serve as more sensitive biomarkers for silent CAD. To test this, we conducted a study with 30 hypertensive diabetic patients with clinical symptoms of CAD (CAD-HTN-DM) and 30 controls without CAD (HTN-DM). Negligible serum DNase II activity was detected in both groups. Student's <i>t</i> test was used to compare cfDNA, DNase I activity, and groups. We observed elevated serum DNase I activity in the CAD-HTN-DM group (1.71 ± 0.1 U/mL) compared with the HTN-DM group (1.12 ± 0.1 U/mL) (<i>P</i> < 0.0001). Among the CAD-HTN-DM group, DNase I activity was significantly higher in patients with all three coronary arteries blocked, even though the cfDNA levels were similar in both groups. Elevated DNase I activity was associated with a 1.5-fold increased risk of major adverse cardiac events despite ongoing treatment with statins, antihypertensive medications, and antidiabetic therapies. Surprisingly, serum DNase I activity was lower in patients who suffered a myocardial infarction. By leveraging our observations, we hope that regular monitoring of serum DNase I activity will identify individuals at high risk for the clinical onset of CAD, enabling early intervention to mitigate its adverse effects and slow its progression.<b>NEW & NOTEWORTHY</b> Our observation suggests that the progression of cardiac disease among hypertensive patients with diabetes is associated with elevated DNase I activity that maintains optimal cfDNA levels, thereby reducing its inflammatory potential and worsening of cardiac dysfunction. Thus, DNase I activity may be both a protective factor early on and a potential biomarker for cardiac health among hypertensive patients with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H973-H977"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603567","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}