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

Endothelial function, a key determinant of prognosis in heart failure with reduced ejection fraction (HFrEF), is still frequently under-assessed in clinical practice. The present study aimed to assess endothelial function in patients with HFrEF and investigate its association with echocardiography and hemodynamics over 3 mo of medical treatment. In addition, this study aimed to investigate the association between changes in endothelial function and the incidence of cardiovascular rehospitalizations or deaths. This prospective longitudinal study included 120 patients with HFrEF. Hemodynamic parameters were assessed using impedance cardiography. Endothelial function was evaluated using digital thermal monitoring to calculate the endothelial quality index (EQI) at baseline and after 3 mo. Patients were followed for 12 mo. The mean age was 61.9 ± 10.2 yr, with a sex ratio of 5:1. A total of 42.5% of patients tend to experience endothelial dysfunction at baseline. After 3 mo of optimal medical therapy (i.e., renin-angiotensin-aldosterone system inhibitors, β-blockers, the aldosterone antagonist spironolactone, and sodium-glucose cotransporter 2 inhibitors), EQI improved significantly (P < 0.001), correlating with improved echocardiographic and hemodynamic parameters. Over 12 mo, there were 5 deaths (4.16%) and 44 heart failure rehospitalizations (36.6%), predominantly among those with severe endothelial dysfunction (P = 0.008). Improved EQI was associated with reduced mortality [area under the curve (AUC) = 0.82] and rehospitalization risk (AUC = 0.837). A ΔEQI ≥ 0.2 predicted a better prognosis, with a reduced risk of 1-year rehospitalization for acute heart failure.NEW & NOTEWORTHY Endothelial dysfunction is highly prevalent in patients with heart failure, with significant improvements observed after medical optimization. Importantly, changes in endothelial function strongly correlated with echocardiographic and hemodynamic improvements and independently predicted mortality and rehospitalization risk. Notably, an improvement in endothelial function emerged as a valuable prognostic marker.

There are numerous differences in arrhythmia propensity and cardiac electrophysiology between women and men. One proposed reason is differences in the autonomic nervous system (ANS) influence. We therefore compared the sympathetic and parasympathetic influence (sympathovagal balance) on the sinoatrial node (SAN) at rest in healthy young women (n = 15) and men (n = 15) with a mean age of 24 yr. Pharmacological blockade of the ANS influence on the SAN was induced by sequential bolus injections of atropine (0.04 mg/kg body wt) and propranolol (0.2 mg/kg body wt) during continuous electrocardiographic recordings. The heart rate (HR) at baseline, after atropine, and the intrinsic heart rate (IHR) after adding propranolol were used to calculate the accelerator "m," which is ≥1.00, and decelerator "n," which is ≤1.00 according to the Rosenblueth and Simeone concept and equation: HR = m × n × IHR. On the group level, IHR was median [interquartile range (IQR)] 93.3 (88.4-98.8) beats/min, m was 1.16 (1.13-1.22), n was 0.58 (0.55-0.64), and the sympathovagal balance m × n was 0.70 (0.65-0.76), confirming dominant parasympathetic influence at rest. There were no significant differences between women and men in any of these measures, and thus no fundamental difference in the ANS influence on the main impulse generator of the heart at rest. This result contrasts with the significant differences in electrophysiological measures at rest and their responses to stress tests, as well as to the differences in arrhythmia propensity between women and men on both the atrial and ventricular level of the heart.NEW & NOTEWORTHY Differences in the autonomic nervous system (ANS) activity is one potential explanation for differences in cardiac electrophysiology between women and men. We therefore compared the ANS influence on the sinoatrial node (SAN; main cardiac impulse generator), between women and men at rest. Atropine and propranolol were used to sequentially block the two ANS limbs. There were no statistically significant differences between women and men in the ANS influence on the SAN at rest.

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.

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.NEW & NOTEWORTHY 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.

Periostin (Postn) is a matricellular protein that plays a crucial role in cardiac fibrosis following myocardial infarction (MI). However, the role of Postn in infarct healing to date has been derived from experiments conducted exclusively on male animals, leaving its sex-specific functions unaddressed. Thus, we investigated the sex-specific role of Postn in acute wound healing and extracellular matrix (ECM) remodeling post-MI using a Postn knockout (KO) mouse model. Survival analysis revealed increased mortality in male Postn KO mice compared with that of females post-MI. qPCR analysis of the infarct scar showed that Postn was required for the increased expression of structural collagen (Col1a1 and Col3a1), collagen fibrillogenesis (Fmod), collagen stabilization (Lox), collagen synthesis (Plod2), and alpha-smooth muscle actin (Acta2) genes in males, whereas in females, the regulation of these genes occurred independently of Postn post-MI. We note that fibromodulin protein levels were higher in female Postn KO mice than in males, suggesting a putative protective role. Transcriptomic analysis revealed distinct gene expression patterns between sexes and phenotypes, with male Postn KO infarct scars showing the greatest dysregulation of genes, characterized by increased expression of ECM-related genes and suppressed mitochondrial-related gene expression, whereas female Postn KO infarct scars exhibited increased mitochondrial-related gene expression and reduced expression of fibrosis-associated genes. These findings emphasize sex as a biological variable in Postn actions in heart and highlight distinct molecular mechanisms underlying male and female infarct healing.NEW & NOTEWORTHY We determined that cardiac wound healing following MI is periostin (Postn) dependent in male mice but Postn independent in female mice. To date, previous Postn knockout (KO) studies have exclusively used male animals. The current experimental design includes both sexes and reveals that the underlying mechanism of action to be sex dependent. Specifically, changes in the expression of collagen synthesis and cross-linking genes in the infarct scar are dependent on Postn expression in males only.

Doxorubicin (DOX), an effective chemotherapy, exhibits a narrow therapeutic index and detrimental adverse effects involving muscle atrophy and dysfunction. The precise mechanisms underlying DOX-mediated myopathy are not fully understood. Although the contribution of inflammation is well appreciated, the mechanisms by which inflammatory cells mediate muscular pathologies remain to be identified. In this study, we characterized the dynamics of neutrophil responses during DOX treatment. DOX administration induced expansion of neutrophils in the heart, spleen, and muscle of mice. Depletion of these cells with anti-Ly6G antibodies ameliorated DOX-mediated cardioskeletal atrophy and dysfunction, including ejection fraction, stroke volume, and cardiac output. DOX-expanded neutrophils demonstrated constitutive production of reactive oxygen species (ROS), and elimination of the ROS-producing enzyme NOX2, but not myeloperoxidase, prevented DOX-induced cardioskeletal myopathy. Our findings underscore the pivotal role of neutrophil-derived ROS in driving DOX-induced cardiotoxicity and skeletal myopathy.NEW & NOTEWORTHY DOX is a commonly used cancer treatment, but its severe side effects, limit its clinical use. This research highlights neutrophil-derived reactive oxygen species (ROS) production through the NOX2 complex as a key contributor to this myopathy, offering a potential therapeutic to protect against cardiotoxicity without compromising DOX's anticancer benefits. These insights open new avenues for safer, more effective cancer treatments.

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 (Ldlr^-/-) and wild-type mice were infected with uropathogenic Escherichia coli. 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 Ldlr^-/- mice tended to be smaller. Decreased serum cholesterol positively associated with systemic neutrophil counts in wild-type and Ldlr^-/- mice with chronic pyelonephritis and negatively with Ldlr^-/- mice atherosclerotic lesion size. Cholesterol homeostasis and fatty acid metabolism related gene expression changes in the pyelonephritic kidney included known mediators of atherosclerosis, namely Pcsk9, Lipa, and Stab2 downregulation and Abca1 and Msr1 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 LIPA and MSR1 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.NEW & NOTEWORTHY 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.

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 approach I, 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 approach II, shear strain was estimated by measuring the reduction in layer thickness under oscillatory shear stress. In approach III, 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.NEW & NOTEWORTHY 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.

Evolution of gas exchange during intact cord resuscitation (ICR) remains unexplored. We aimed to investigate changes in placental hemodynamics and gas exchange during ICR in lambs with and without congenital diaphragmatic hernia (CDH). Eight CDH lambs (4.2 kg, 4 females) and nine controls (3.9 kg, 3 females) underwent ICR. At 80 days gestation (term = 142 days), CDH was induced by diaphragmatic incision. After c-section at term, mean arterial pressure (MAP) was monitored via an aortic catheter. Umbilico-placental blood flow (Qup) was assessed with a flow transducer on the umbilical artery. Umbilical venous pressure was recorded, and blood gases from the aorta and umbilical vein were analyzed to evaluate placental oxygen transfer. ICR was performed for 60 min, followed by cord clamping (CC). Qup and umbilical venous Po₂ were similar and stable in both groups up to 50 min. MAP was 20% lower in normal lambs compared with CDH lambs (P < 0.05) but equalized after CC. In CDH lambs, placental oxygen transfer was maintained during ICR (2.7 [2.2-3.3] mL/kg/min). [Formula: see text] was unchanged during ICR (53 [50-58] mmHg) and abruptly increased after CC (83 [60-101] mmHg) (P < 0.05). For control lambs, placental oxygen transfer dropped to 0 [-0.3 to 0.2] mL/kg/min within 20 min of starting resuscitation, coinciding with an significant increase in [Formula: see text] (minute 0 = 16 [12; 18] mmHg; minute 20 = 50 [48-105] mmHg and minute 75 [50; 110] mmHg after CC). ICR may support oxygenation and carbon dioxide removal in CDH newborns through placental gas exchange.NEW & NOTEWORTHY Maternal anesthesia with halogenated gas sustains placental circulation for 1 h postbirth. Intact cord resuscitation supports oxygenation (placental oxygen transfer ∼2.7 mL/kg/min) for 1 h in the congenital diaphragmatic hernia (CDH) lamb model. Maintaining feto-placental circulation during delivery room resuscitation in the context of CDH ensures continuous oxygenation and carbon dioxide clearance for up to 1 h.

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.NEW & NOTEWORTHY 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.