American Journal Of Physiology. Heart And Circulatory Physiology[JOURNAL]
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200 papers
Diet modulates cardiac metabolic stress during anthracycline treatment.
Kim K, Gao Y, Shankar T … +1 more , Karlstaedt A
Am J Physiol Heart Circ Physiol · 2026 May · PMID 41817306 · Publisher ↗
Diet is a modifiable determinant of cardiovascular risk and may influence tolerance to cancer therapies. The mechanisms by which specific dietary components affect cardiac metabolism during anthracycline treatment remain...
Diet is a modifiable determinant of cardiovascular risk and may influence tolerance to cancer therapies. The mechanisms by which specific dietary components affect cardiac metabolism during anthracycline treatment remain poorly defined, limiting the incorporation of dietary recommendations into treatment guidelines. Here, we integrated heart proteomics data from patients treated with or without anthracyclines with a genome-scale reconstruction of human cardiac metabolism (CardioNet). Using constraint-based flux analysis, we conducted >30,000 in silico simulations of diet scenarios generated from chemical profiles of ∼500 foods curated in the Periodic Table of Food Initiative. These simulations revealed that diets enriched in rapidly absorbable sugars and depleted of essential fatty acids impair cardiac metabolic efficiency, increasing reactive oxygen species production and the demand for purine salvage fluxes. These predicted metabolic patterns were consistent with plasma metabolomics from patients treated with anthracyclines, validating our findings. Computational modeling of 39 recipes across six cuisines revealed cardiometabolic effects of omnivorous versus vegan diets in patients. Modeling of a healthy vegan diet increased cardiometabolic efficiency compared with a healthy omnivorous diet in patients treated with anthracyclines, independent of the culinary background. Our approach demonstrates that integrating the molecular composition of food with genome-scale metabolic models enables systematic analysis of diet patterns for translational testing. Ultimately, these in silico studies provide a framework for trials and may inform dietary recommendations for improving cardiometabolic health. We developed a systems biology framework to predict how diet influences cardiac metabolism during cancer therapy. Across >30,000 in silico diet simulations, we identified nutrient patterns that either exacerbate or mitigate anthracycline-induced metabolic stress. These findings demonstrate how computational modeling can uncover diet-metabolism interactions driving cardiotoxicity and guide dietary interventions.
Blazing through a workout: cannabis and postexercise cardiovascular risk.
Greenlund IM, Migliaccio GCL, Gonzalez JE … +2 more , Xie K, Somers VK
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41811714 · Publisher ↗
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Cardiovascular disease, perceived stress, and physical activity: population-level associations relevant to cardiovascular physiology.
Mols RE, Bakos I, Madsen M … +3 more , Horváth-Puhó E, Sørensen HT, Bøtker HE
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41811713 · Publisher ↗
Medical advances have markedly improved survival among patients with cardiovascular disease (CVD). Psychosocial and behavioral factors, including stress and physical activity, are increasingly recognized as key determina...
Medical advances have markedly improved survival among patients with cardiovascular disease (CVD). Psychosocial and behavioral factors, including stress and physical activity, are increasingly recognized as key determinants of outcomes in this population. We investigated the association between existing CVD and perceived stress and examined how this association was modulated by physical activity levels in a Danish cohort, accounting for physiological and psychosocial conditions. We analyzed data on 102,650 Danish residents aged 50-65 yr by linking self-reported questionnaire data from the Better Health in Late Life cohort with national health registry data. CVD was identified using hospital discharge diagnoses. Stress was measured with the 10-item Perceived Stress Scale. Physical activity was assessed with a pilot-tested questionnaire. Seven percent of participants had CVD. Compared with those without CVD, they had a higher prevalence of moderate-to-high perceived stress (42% vs. 33%) and a slightly lower prevalence of meeting guideline-recommended physical activity (42% vs. 45%). High stress was associated with physical activity not meeting the recommended level in both groups; however, this association was stronger among those with versus without CVD {prevalence ratio 2.01 [95% confidence interval (CI): 1.89-2.14] vs. 1.52 (95% CI: 1.48-1.56)}. We observed similar associations between stress and cardiovascular risk factors, comorbidity, psychosocial factors, and socioeconomic status. The association between stress and low physical activity persisted after stratification by these conditions. In conclusion, high stress was most strongly associated with low physical activity among adults with CVD. The underlying mechanisms seem to extend beyond physiological pathways and need further investigation. In this population-based study of over 100,000 Danish adults, participants with cardiovascular disease reported higher perceived stress than those without. Elevated stress was associated with low physical activity across all participants, particularly among those with cardiovascular disease, but also with medical, psychosocial, and behavioral factors. These findings highlight the complex interplay between physiological and nonphysiological determinants of stress, underscoring the importance of integrating stress management and physical activity promotion into cardiovascular prevention and management strategies.
Modifying the structural substrate and progression of heart failure with preserved ejection fraction using a regular exercise regimen in pigs.
Samani SL, Barlow SC, Freeburg LA … +9 more , Catherwood GM, Churillo AM, Jones TL, Al-Soudi J, Ruiz R, Yigamawano FK, Shazly T, Zile MR, Spinale FG
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41811247 · Full text
Heart failure (HF) with a preserved ejection fraction (HFpEF) arises from a persistent left ventricular (LV) pressure overload (LVPO) ultimately causing increased LV myocardial stiffness (Km) and resistance to LV filling...
Heart failure (HF) with a preserved ejection fraction (HFpEF) arises from a persistent left ventricular (LV) pressure overload (LVPO) ultimately causing increased LV myocardial stiffness (Km) and resistance to LV filling resulting in increased pulmonary capillary wedge pressure (PCWP) and left atrial area (LAA). Increased LV collagen content (fibrosis) is a structural underpinning of this process. Although exercise programs have shown benefit in patients with HF, whether and to what degree an exercise program overlaid with progressive LVPO may alter HFpEF progression remains unclear. Pigs (25 kg) underwent progressive LVPO for 5 wk without ( = 8) or with daily exercise ( = 8, 10 degrees elevation, 2.5 mph, 10 min, 5 days/wk). Age-matched pigs with no LVPO served as controls ( = 8). In both LVPO groups, LV mass increased by approximately 55%, but in the LVPO exercise group, Km was reduced (19.30 ± 2.62 vs. 47.97 ± 8.63 kPa, < 0.05) as was PCWP (10.52 ± 0.35 vs. 11.88 ± 0.34 mmHg, < 0.05) and LAA (8.55 ± 0.43 ± vs. 9.83 ± 0.43 cm, < 0.05). LV collagen percent area was reduced in the LVPO exercise group compared with LVPO (5.96 ± 0.50 vs. 10.82 ± 0.39%, < 0.05). LV fibrillar collagen mRNA levels (collagen type 1a) increased by twofold with LVPO ( < 0.05) but returned to within referent normal values with LVPO and exercise. The unique and significant findings from this study were twofold. First, a concomitant exercise protocol overlayed with a progressive LVPO stimulus prevented the HFpEF phenotype, but did not alter the LV hypertrophic response. Second, the structural/molecular basis for this was likely reduced collagen content and expression. Thus, although clinical studies are required, these results suggest that a regular exercise protocol for patients at risk for HFpEF represents a potential preventive strategy. This is a translational research study that demonstrated that with left ventricular pressure overload, such as that which occurs with hypertension, that an exercise program can prevent changes in heart muscle function and structure, which in turn lead to heart failure.
When rescue becomes reprogramming: long-term cardiovascular outcomes in offspring following prenatal steroid exposure.
Tucker SM, Bradshaw JL
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41811198 · Full text
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Guidelines for evaluating endothelial function in vascular tissue.
McCarthy CG, Aalkjær C, Bagher P … +24 more , Beyer AM, Boedtkjer E, Bomfim GF, Breslin JW, Briones AM, Castorena-Gonzalez JA, Costa TJ, Dai Z, Davel AP, Earley S, Freed JK, Garland C, Isakson BE, Jepps TA, Kalucka J, Lavanderos B, Makino A, Norton CE, Segal SS, Tan W, Trask AJ, Wilson C, Zawieja SD, Wenceslau CF
Am J Physiol Heart Circ Physiol · 2026 May · PMID 41801061 · Full text
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...
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.
The metabolic balancing act between fatty acid and glucose substrate use for optimal myocardial function: key role for membrane substrate transporters.
Glatz JFC, Heather LC, Larsen TS … +2 more , Nabben M, Luiken JJFP
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41784153 · Publisher ↗
Cardiac contractile function is strictly dependent on proper metabolic energy provision. Long-chain fatty acids and glucose are the primary energy substrates and are also indispensable for serving additional cellular rol...
Cardiac contractile function is strictly dependent on proper metabolic energy provision. Long-chain fatty acids and glucose are the primary energy substrates and are also indispensable for serving additional cellular roles including synthesis of biosynthetic precursors and posttranslational modification of proteins. The balance between fatty acid and glucose utilization in the heart, and myocardial contractile function appear inextricably linked. A chronic shift toward a greater dependence on a single substrate, either fatty acids or glucose, results in a metabolic imbalance and is associated with impaired cardiac function. As a result, rebalancing fatty acid and glucose utilization is an effective approach to restore cardiac contractile performance. In this article, we discuss the significance of the fatty acid-to-glucose fuel balance for maintaining homeostatic control and show recent evidence that the membrane substrate transporters cluster of differentiation 36 (CD36; for fatty acid uptake) and glucose transporter 4 (GLUT4; for glucose uptake) are key targets to recover the myocardial substrate balance. In conclusion, the fatty acid-to-glucose substrate balance is both an effective target to treat heart failure and a useful parameter to monitor myocardial function in health and disease.
QT interval and cardiac restitution dynamics in racehorses: observations during maximal effort.
Avison A, Pyle WG, Sears W … +1 more , Physick-Sheard PW
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41784128 · Publisher ↗
Sudden cardiac death is a leading cause of athletic death in both humans and horses, making racehorses a potentially valuable model for investigating sudden cardiac death. Cardiac restitution ratio (QT/TQ interval) is us...
Sudden cardiac death is a leading cause of athletic death in both humans and horses, making racehorses a potentially valuable model for investigating sudden cardiac death. Cardiac restitution ratio (QT/TQ interval) is used to assess arrhythmia risk in humans, but investigations in athletes are scarce. The objective was to characterize the QT interval and cardiac restitution ratio in Thoroughbred racehorses during maximal effort. Automated restitution analysis was performed using 2,709 pairs of cardiac cycles from 30 Thoroughbred horses during races. Cardiac cycles were obtained during: prerace; acceleration out of the gate; race; immediate postrace; and recovery phases. Multivariable linear regression analyses were performed with both QT interval and cardiac restitution ratio as outcomes of interest. The QT/RR relationship varied by exercise period with cycles during maximal effort being distinct from those of prerace and recovery periods. Exercise period, RR interval, and their interaction were significantly associated with both QT interval and cardiac restitution ratio during maximal effort. QT intervals during the postrace period were relatively unresponsive to changes in RR interval compared with other exercise periods. QT intervals were longer, and cardiac restitution ratio were higher prerace than recovery at the same RR intervals. The QT/RR relationship is multifactorial, and variables associated with QT interval during maximal effort differ from other exercise periods. These changes suggest differences in intracellular mechanisms and/or extracellular controls (e.g., autonomic activity) between exercise periods that have biologically significant effects on myocardial electrophysiology and pathophysiology. Racehorses may be a useful model for studying cardiac function during exercise. ECG recordings obtained from racehorses during competition provide insight into the cardiac physiology of athletes and potentially pathophysiologic mechanisms that underlie the risk of exercise-associated arrhythmias. The QT/RR relationship is uniquely altered during maximal effort compared with other exercise periods, and the response of the QT interval to changes in heart rate (RR interval) is decreased immediately postrace.
Sympathetic neural control of blood pressure across the premenopausal lifespan.
Saboune J, Boyes NG, Limberg JK … +1 more , Usselman CW
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41779366 · Publisher ↗
The technique of microneurography has advanced our understanding of the sympathetic nervous system's role in the neurovascular control of blood pressure in humans, yet critical knowledge gaps remain, particularly across...
The technique of microneurography has advanced our understanding of the sympathetic nervous system's role in the neurovascular control of blood pressure in humans, yet critical knowledge gaps remain, particularly across the premenopausal female lifespan. Historically, premenopausal females have been considered relatively protected from cardiovascular diseases, leading to a disproportionate focus on postmenopausal populations in cardiovascular research. However, emerging evidence contradicts this assumption: premenopausal females with hypertension exhibit 15-20% higher mortality rates than age-matched males, and myocardial infarction deaths are rising fastest among females under the age of 45. This review addresses a major void in the literature by examining sympathetic regulation of blood pressure in premenopausal females and how it is modulated across unique reproductive health states, including menstrual cycling, hormonal contraceptive use, pregnancy, polycystic ovary syndrome, uterine fibroids, and endometriosis. Muscle sympathetic nerve activity fluctuates with some but not all hormonal changes, depending on the population and the conditions under which they are studied. Moreover, corresponding effects on blood pressure vary widely, suggesting a high degree of variability in how sympathetic outflow is transduced into blood pressure in females. Overall, our review highlights the need for longitudinal and mechanistic studies focused on hormonal transitions and specific premenopausal health states to better understand, and eventually mitigate, female-specific cardiovascular risk.
Hyaluronan in cardiac disease: implications for the extracellular matrix beyond collagen.
Ramalingam AR, Howard CM, Jones SP
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41778581 · Full text
The structure of the heart changes in response to physiological cues. Such intrinsic plasticity of the heart involves changes to the extracellular matrix (ECM) and supports the adaptation to physiologic excursions such a...
The structure of the heart changes in response to physiological cues. Such intrinsic plasticity of the heart involves changes to the extracellular matrix (ECM) and supports the adaptation to physiologic excursions such as athletic performance and pregnancy. Likewise, the ability of the ECM is critical for wound healing in the heart following myocardial infarction. Considering the involvement of the matrix in health and disease, it follows that a deep understanding of its composition and regulation would accelerate our pace of developing therapeutic interventions for the heart. Yet, we understand little of the composition of cardiac ECM and how its regulated. One such matrix component, hyaluronan (HA), has received scant attention in the heart despite its abundance rivaling that of collagen. This review addresses the biological origins of HA and its impact on the heart. HA production is linked to intermediary metabolism and is produced in response to injury. Much remains to be resolved regarding its production and degradation. And, although there are insights from other fields, the extent to which HA impacts the function of potential target cells is far from resolved. This review will also address techniques and tools available to assess cardiac HA and highlight areas of opportunity in the field along with some limitations in literature.
Cardiovascular scaling between humans and mice during postnatal development.
Martin RJ, Rego BV
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41778535 · Publisher ↗
Age selection in studies using mouse models is critical to aid translation of findings, but defining equivalent ages between humans and mice is difficult, particularly before maturity, because of tissue-specific variatio...
Age selection in studies using mouse models is critical to aid translation of findings, but defining equivalent ages between humans and mice is difficult, particularly before maturity, because of tissue-specific variation in developmental timelines across species. For cardiovascular research, such a mapping would provide a framework for the selection of appropriate ages in mouse studies of normal cardiovascular development and (pediatric) cardiovascular disease, including congenital defects. Toward this end, we compiled and mathematically modeled cardiovascular anatomical, functional, and biomechanical results from previous studies of postnatal development to assess whether a cardiovascular-specific age equivalence curve could be derived. For each variable, we determined optimal age scale factors that best align their time courses across humans and mice. The "overall optimal" age scale factor, taken as the mean of the optima across qualitatively similar variables, was 0.69 mouse weeks per human year, although individual optima ranged from 0.4 to 1.3 wk/yr, indicating that no universal scaling can fully align developmental time courses in humans and mice. Applying variable-specific age scale factors may therefore be more appropriate in studies that focus on specific tissues and their loading conditions. Some variables, including heart rate and related clinical metrics (e.g., rate pressure product) as well as aortic wall shear stress, exhibit qualitatively different time courses in humans and mice and cannot be aligned using any scale factor, further highlighting the limitations of this approach. Nevertheless, the optimal age scale factors identified here can help maximize translational relevance and interpretation of findings from cardiovascular developmental mouse studies. This study provides the first cardiovascular-specific, quantitative mapping of postnatal developmental time between humans and mice. By integrating anatomical, functional, and biomechanical data, we show that no single age scale factor can align cardiovascular maturation across species, although 0.69 mouse weeks per human year is the overall optimum. Variable-specific scaling better captures cross-species differences, particularly between structural growth and hemodynamic maturation. These results offer a practical framework to improve age selection and translational relevance in pediatric cardiovascular mouse studies.
Relative aortic valve stiffness: a new parameter quantifying aortic stenosis.
Buffle E, Papadis A, Blaser I … +9 more , Nozica N, Kassar M, Ludwig R, Berger D, Hänggi M, Mauri M, Obrist D, Seiler C, de Marchi SF
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41758062 · Full text
Aortic stenosis (AS) quantification relies on transvalvular gradients or aortic valve opening area (AVA), two measures that inherently depend on the instantaneous transvalvular flow rate (Q). We present a new quantificat...
Aortic stenosis (AS) quantification relies on transvalvular gradients or aortic valve opening area (AVA), two measures that inherently depend on the instantaneous transvalvular flow rate (Q). We present a new quantification method for AS based on new modeling where AVA saturates with increasing Q, contradicting the assumption of linear Q-AVA relation currently predominant in the literature. The objective of this study is the development of a new method for the quantification of AS. In 141 patient undergoing transesophageal echocardiography, AVA was obtained frame-by-frame over an entire systole from 3-D echocardiograms using multiplanar reconstruction. Q was retrieved by Doppler- and 3-D echocardiography of the left ventricular outflow tract. A sigmoid Q-AVA relation was fitted with a machine learning algorithm. The measured and the predicted AVA were compared between a parametrized linear and sigmoid Q-AVA relation model. A relative aortic valve stiffness (rAVS) was calculated, and an isostiffness nomogram was constructed. Cox proportional hazard modeling was used to look for predictors of rehospitalization-free survival. Compared with the linear model, the sigmoid model consistently better predicted measured AVA in all AS severity groups. Within severity groups, rAVS remained robust and constant, a property not shared by the linear model. A receiver operating characteristic (ROC)-analysis revealed a rAVS value of 1.51 as the best cut-off for distinguishing severe from nonsevere AS. Cox proportional hazard modeling showed its value as an independent predictor of rehospitalization-free survival. We present a new method for the quantification of AS that could help simplify the diagnosis of patients with low-flow, low-gradient AS. Aortic stenosis (AS) quantification relies on transvalvular gradients or aortic valve opening area (AVA). We present a new quantification method for AS based on new modeling of the aortic valve opening behavior. We fitted a sigmoid relation between flow rate and AVA and retrieved the "relative aortic valve stiffness" (rAVS). We could demonstrate its superior association with clinical endpoints compared with previous models in AS and provide a simple tool for its calculation using echocardiography.
Estimation of flow-induced deformation of glycocalyx layer on vascular endothelial cells: comparison of three methods.
Takahashi Y, Owaki Y, Maeda E … +2 more , Nagayama K, Matsumoto T
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41758026 · Publisher ↗
The endothelial glycocalyx layer plays a crucial role in mechanotransduction in response to fluid shear stress, yet its actual deformation under physiological fluid shear stress remains poorly understood. The present stu...
The endothelial glycocalyx layer plays a crucial role in mechanotransduction in response to fluid shear stress, yet its actual deformation under physiological fluid shear stress remains poorly understood. The present study aimed to quantify the shear-induced deformation of the glycocalyx on vascular endothelial cells using three independent experimental approaches. Mouse vascular endothelial cell line F-2 was cultured in a custom-made flow chamber and observed on a confocal laser scanning microscope while applying fluid shear stress. In , we analyzed changes in the fluorescence intensity profile of the region between photobleached and nonphotobleached regions in fluorescently labeled glycocalyx layer induced by application of fluid shear stress, to infer shear deformation. In , shear strain was estimated by measuring the reduction in layer thickness under oscillatory shear stress. In , horizontal displacements of the glycocalyx layer were directly measured using quantum dots attached to the glycocalyx surface and the cell membrane subjected to fluid shear stress. Across all methods, the glycocalyx layer exhibited consistent deformation with estimated shear strain values ranging from 3° to 10° per pascal of shear stress. From these findings, the Young's modulus of the glycocalyx layer was estimated to be 16-50 Pa, markedly lower than the modulus of the plasma membrane, suggesting high deformability. These results provide the first direct quantification of glycocalyx deformation under physiological-like shear conditions and offer critical insight into its mechanosensory function. Our findings support the concept that the endothelial glycocalyx layer actively contributes to flow-induced signaling and vascular function. Endothelial glycocalyx layer deformation under physiological fluid flow remains to be understood. This study provides the first direct quantification of shear-induced deformation of the endothelial glycocalyx layer using three distinct confocal microscopic approaches: photobleaching, thickness measurement, and quantum dots imaging. The observed shear strains from three approaches were consistent (3-10°/Pa), revealing that the glycocalyx is actually deformed in response to fluid shear stress and may serve as a key mechanosensor in vascular endothelial cells.
Pyelonephritis decreases serum cholesterol and mitigates atherosclerosis severity despite systemic inflammation.
Possenriede L, Sendtner GW, Falahat P … +5 more , Scheidt U, Miranda J, Schmitz J, Bräsen JH, von Vietinghoff S
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41740624 · Publisher ↗
Hypercholesterolemia and inflammation are main causes of cardiovascular disease. Urinary tract infections are common and frequently recur. We here tested how pyelonephritis affects atherosclerotic plaque development and...
Hypercholesterolemia and inflammation are main causes of cardiovascular disease. Urinary tract infections are common and frequently recur. We here tested how pyelonephritis affects atherosclerotic plaque development and lipid levels. LDL receptor-deficient () and wild-type mice were infected with uropathogenic . Renal and systemic inflammation, lipid levels, and atherosclerotic plaque development were assessed. Gene regulation was studied in pyelonephritis and in human cells in vitro. In patients admitted with urinary tract infections, serum lipids and disease severity were studied. Chronic pyelonephritis increased spleen weight, caused anemia, neutrophilia, and systemically elevated proatherogenic cytokines. Atherosclerotic aortic root lesion size in mice tended to be smaller. Decreased serum cholesterol positively associated with systemic neutrophil counts in wild-type and mice with chronic pyelonephritis and negatively with mice atherosclerotic lesion size. Cholesterol homeostasis and fatty acid metabolism related gene expression changes in the pyelonephritic kidney included known mediators of atherosclerosis, namely , , and downregulation and and upregulation. Magnitude of changes correlated with kidney neutrophil marker expression. Coincubation of human renal tubular epithelium or mononuclear cells with primary neutrophils under inflammatory conditions replicated and regulation. In patients admitted with urinary tract infections, leukocyte counts and inflammation markers C-reactive protein and procalcitonin negatively correlated with serum cholesterol. Our experiments demonstrate depression of serum cholesterol and relative protection against atherosclerotic lesion formation despite severe systemic inflammation in chronic bacterial kidney infection. They introduce regulation of renal cholesterol metabolism by neutrophils as an underlying mechanism. Bacterial infections are common, and a risk factor for acute cardiovascular events. Chronic inflammation promotes atherosclerosis. However, in mice with chronic pyelonephritis and systemic inflammation and neutrophilia, atherosclerotic lesions were not enlarged. Rather, lesion size correlated with cholesterol levels that decreased significantly. A similar decrease of serum cholesterol with inflammation was found in patients admitted for urinary tract infections. These data support a clinical relevance of proatherogenic lipid decrease in severe bacterial infection.
Examining oxidative stress as a mechanistic link between sleep irregularity and cardiovascular risk in young adults with chronic anxiety.
Richardson JW, Buck EA, Weggen JB … +4 more , Bakken BT, Fitzpatrick BJ, Campbell RG, Garten RS
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41740185 · Publisher ↗
Chronic anxiety is a highly prevalent condition in young adults that is often associated with irregular sleep patterns, potentially augmenting cardiovascular disease (CVD) risk. Sleep irregularity is significantly associ...
Chronic anxiety is a highly prevalent condition in young adults that is often associated with irregular sleep patterns, potentially augmenting cardiovascular disease (CVD) risk. Sleep irregularity is significantly associated with elevated oxidative stress and lower vascular function and blood pressure control in individuals with chronic anxiety. This study examined whether these impairments in vascular function and blood pressure control are driven by elevations in oxidative stress. Twenty-five young adults (24 ± 4 yr) with generalized anxiety disorder (GAD) or elevated GAD symptoms were assessed for total sleep time irregularity (TSTI) via wrist-worn accelerometry and separated into high TSTI and low TSTI groups via median split. Precursors to CVD development including oxidative stress (whole blood superoxide levels), vascular function (exercise-induced flow-mediated dilation), and blood pressure control (cardiovagal baroreflex sensitivity) were evaluated in both groups following both acute antioxidant (alpha-lipoic acid, vitamin C, and vitamin E) or placebo (microcrystalline cellulose) supplementation. The high TSTI group displayed significantly greater oxidative stress, significantly lower vascular function, and significantly lower blood pressure control. Following antioxidant supplementation, oxidative stress and blood pressure control were significantly improved in the high TSTI group, whereas vascular function was significantly improved independent of group. Antioxidant supplementation reduced oxidative stress and normalized blood pressure control differences between groups, implicating oxidative stress as a key mechanism linking sleep irregularity and CVD risk in young adults with chronic anxiety. This study is the first to identify oxidative stress as a mediator of early cardiovascular disease (CVD) risk associated with total sleep time irregularity (TSTI) in young adults with chronic anxiety. Antioxidant supplementation reduced oxidative stress and improved blood pressure regulation in the high TSTI group. These findings suggest that oxidative stress plays a central role in linking chronic anxiety, sleep irregularity, and elevated CVD risk.
Prognostic value of exercise blood pressure: role of fitness and exercise training.
Hoch JW, Domeier C, Silvestri P … +1 more , Watso JC
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41730298 · Full text
Abnormal blood pressure (BP) responses to exercise, both hypertensive and hypotensive, are strong independent predictors of cardiovascular morbidity and mortality across populations. Higher cardiorespiratory fitness is a...
Abnormal blood pressure (BP) responses to exercise, both hypertensive and hypotensive, are strong independent predictors of cardiovascular morbidity and mortality across populations. Higher cardiorespiratory fitness is associated with lower submaximal exercise BP across populations. Better vascular function and modulation of the autonomic nervous system likely drive this relation. Despite higher absolute BP values, athletes demonstrate lower BP responses relative to metabolic demand. These observations highlight a critical limitation of using absolute thresholds and support indexing exercise BP to metabolic or external workload for improved risk stratification. Furthermore, submaximal exercise BP is a superior target for risk assessment and intervention, as it provides unique prognostic value, predicting adverse events independent of resting BP and other risk factors, and consistently improves with exercise training, unlike the inconsistent response of maximal exercise BP. This review synthesizes the evidence on the prognostic value of exercise BP, its physiological relation with cardiorespiratory fitness, and its response to traditional and emerging exercise interventions. Ultimately, we propose a conceptual model for clinical consideration, designed to guide the integration of exercise BP assessment into practice as a modifiable cardiovascular disease risk factor.
Postnatal upregulation of cyclooxygenase-2 (COX-2) drives anatomical closure of the ductus arteriosus.
Noguchi T, Hidaka Y, Oka S … +8 more , Kemmotsu T, Takeuchi Y, Nakayama T, Yoshida K, Nakamura T, Uchida K, Miyagi E, Yokoyama U
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41730286 · Publisher ↗
Postnatal environmental changes markedly facilitate functional closure of the ductus arteriosus (DA). Vascular remodeling during both fetal and postnatal periods is essential for achieving permanent anatomical DA closure...
Postnatal environmental changes markedly facilitate functional closure of the ductus arteriosus (DA). Vascular remodeling during both fetal and postnatal periods is essential for achieving permanent anatomical DA closure; however, molecular mechanisms driving postnatal DA remodeling have yet to be fully elucidated. Single-cell RNA sequencing (scRNA-seq) revealed that postnatal mouse smooth muscle cells (SMCs) formed a transcriptionally distinct cluster compared with fetal ductus arteriosus smooth muscle cells (DASMCs), whereas other cell types remained in the same cluster after birth, highlighting a critical role for SMCs in postnatal DA remodeling. Transcriptome analysis identified genes differentially expressed in postnatal DASMCs compared with the adjacent arteries, among which cyclooxygenase-2 (COX-2) exhibited the most robust induction. Exposure to hydrogen peroxide, simulating oxidative stress encountered after birth, significantly increased COX-2 mRNA and protein expression in DASMCs. Given that platelet adhesion is a postnatal event in the DA and platelets are a major source of thromboxane A, we administered thromboxane A receptor agonist to DASMCs and found marked COX-2 upregulation. Lentiviral-based overexpression of COX-2 led to prostaglandin E (PGE) production. PGE stimulation increased expression of via PGE receptor EP4. silencing inhibited DASMC proliferation. To assess the in vivo relevance of COX-2, we maternally administered a selective COX-2 inhibitor, SC-236, and found impaired postnatal DA closure in mice. These data suggest that postnatal upregulation of COX-2 in DASMCs promotes anatomical closure, potentially involving ; inhibition of COX-2 at the very early postnatal period may interfere with DA closure. Postnatal environmental changes promote anatomical closure of the ductus arteriosus (DA). This study identifies cyclooxygenase-2 (COX-2) as a key driver of postnatal DA remodeling. DA smooth muscle cells (SMCs) undergo transcriptional changes after birth, with COX-2 markedly upregulated by oxidative stress and thromboxane A. COX-2-derived prostaglandin E enhanced SMC proliferation, potentially involving . In vivo COX-2 inhibition impaired DA closure, highlighting its essential role and potential vulnerability to early postnatal COX-2 suppression.
Sex differences in cardiovascular mechanisms underlying exercise intolerance in type 2 diabetes: the role of skeletal muscle microvasculature.
O'Gorman SA, Keske MA, Parker L … +4 more , Kaur G, Sacre JW, Terada T, Way KL
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41721830 · Publisher ↗
Type 2 diabetes (T2D) disproportionately increases cardiovascular disease risk and premature mortality in females compared with males. Exercise intolerance is a hallmark symptom of T2D and an early indicator of cardiovas...
Type 2 diabetes (T2D) disproportionately increases cardiovascular disease risk and premature mortality in females compared with males. Exercise intolerance is a hallmark symptom of T2D and an early indicator of cardiovascular dysfunction. Although both central (cardiac) and peripheral (vascular and skeletal muscle) factors contribute to exercise intolerance in T2D, skeletal muscle microvascular dysfunction is increasingly recognized as an early contributor and a key therapeutic target. However, the sex-specific cardiovascular mechanisms underlying exercise intolerance remain poorly understood. Females with T2D have lower exercise capacity and are less physically active than their male counterparts, which likely contributes to their heightened cardiovascular risk and worse clinical outcomes. Emerging evidence suggests that cardiac mechanisms may play a larger role in exercise intolerance in females, although sex differences in skeletal muscle microvascular function and dysfunction are poorly characterized. This narrative review synthesizes current research on the cardiovascular determinants of exercise intolerance in T2D, with a specific focus on the skeletal muscle microvasculature, and examines how sex differences in cardiovascular physiology and pathophysiology may affect exercise capacity. We highlight gaps in sex-specific research in healthy populations and individuals with T2D that limit insight into underlying disease mechanisms and effective therapies. Closing these gaps is essential for accurate risk assessment, timely diagnosis, and designing interventions that better address the cardiovascular needs of females with T2D.
Type 2 diabetes disrupts T-tubule and RyR2 organization in male but not in female rat ventricular muscle.
Rahmani M, Taberner AJ, Tran K … +2 more , Crossman DJ, Han JC
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41721828 · Publisher ↗
Females with diabetes often experience more severe cardiovascular outcomes than males with diabetes. It is unclear whether these sex-specific outcomes are rooted in distinct cellular alterations of key cardiac excitation...
Females with diabetes often experience more severe cardiovascular outcomes than males with diabetes. It is unclear whether these sex-specific outcomes are rooted in distinct cellular alterations of key cardiac excitation-contraction coupling (ECC) proteins, specifically transverse tubules (T-tubules), ryanodine receptors (RyR2), and filamentous actin (F-actin). This study investigated myocardial ECC structures in both sexes under type 2 diabetic conditions and measured cardiac functional outcomes at muscle level. Type 2 diabetes was induced in male and female Wistar rats using a high-fat diet and low-dose streptozotocin protocol. Left ventricular trabeculae were isolated and subjected to mechano-calorimetric experiments to quantify heat output and twitch force production. The same trabeculae were imaged using high-resolution stimulated emission depletion (STED) microscopy to assess structural organizations of the T-tubule, RyR2, and F-actin. Diabetic rats of both sexes developed hyperglycemia and glucose intolerance, without evidence of ventricular hypertrophy. Mechanoenergetic indices including activation heat, cross-bridge economy, and twitch-force kinetics were unaffected by diabetes in either sex. F-actin organization was not affected by diabetes. However, compared with their respective controls, diabetic males, but not diabetic females, exhibited structural differences in cardiac ECC proteins: reduced T-tubule area and skeleton length, and enlarged RyR2 clusters and calcium release units (CRUs) with increased RyR2 density. These results show that structural reorganization of cardiac RyR2 proteins occurred in diabetic males and not females, despite absence of ventricular hypertrophy and mechanoenergetic dysfunction in the muscles of these two groups. This study reveals sex-specific cardiac structural alterations of subcellular excitation-contraction coupling proteins in type 2 diabetic rats. Specifically, diabetic males showed evidence of reduced T-tubule area, enlarged RyR2 cluster, and increased calcium release unit density, but without macroscopic functional impairment. In contrast, diabetic females showed no such cardiac structural alterations, suggesting potential resilience mechanisms. These findings highlight that subcellular structural alterations precede functional decline and may underlie sex differences in diabetic cardiovascular outcomes.
There are no bad models, only bad questions: the tale of ex vivo vein culture systems.
Vazquez-Padron RI, Martinez L
Am J Physiol Heart Circ Physiol · 2026 Apr · PMID 41721801 · Publisher ↗
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