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

Women threatening premature delivery receive synthetic glucocorticoids (sGC) to reduce offspring neonatal respiratory distress. Evidence linking prenatal sGC exposures to adverse cardiovascular outcomes is accumulating. We studied adult baboons, which had been exposed in utero to sGC equivalent to a human therapeutic dose, and compared to age-matched saline-exposed controls (CTR). Magnetic resonance imaging was performed in middle-aged male offspring (~10.5 y.) and in both sexes at old age (~16.5 y.) to assess heart structure, function, and paracardial adipose thickness (PAT). Postmortem left ventricular (LV) tissues were analyzed for mitochondrial electron transport chain complex activities and protein expression. In sGC vs CTR males, LV end-systolic (ESSI) and end-diastolic (EDSI) sphericity indexes increased with age (ESSI: p=0.0001, EDSI: p=0.002) being greater in elderly sGC group (ESSI: p=0.03, EDSI: p=0.0001 two-way ANOVA). In sGC-exposed males, global longitudinal strain (GLS) decreased with age versus CTR (p=0.03) and PAT was greater (p=0.03) than CTR males. In elderly sGC-exposed baboons, ejection fraction (p=0.04), ESSI (p=0.002), and PAT (p=0.002) were greater in males than females, while global radial strain (p=0.032) and GLS (p=0.014) were lower. EDSI was higher in both male and female sGC than in CTR (M: p=0.014, F: p=0.009). Mitochondrial analyses revealed reduced Complex I-linked respirations (p<0.05) with a negative correlation between PAT and MTCO1 mitochondrial protein in males (p=0.02), but not females. These results indicate that fetal sGC exposure impairs heart function and metabolism. Enhanced lifelong monitoring could improve understanding of the sex-specific mechanisms impacted by antenatal sGC.

Mitochondrial DNA (mtDNA) has emerged as a key signaling molecule, extending beyond its primary role in supporting energy production. Its replication, release, and degradation are tightly regulated, and their dysregulation can activate immune pathways, including TLR9, cGAS-STING, and inflammasomes. In this review, we summarize recent advances in understanding mtDNA biology, including mechanisms of replication and release, recognition by pattern recognition receptors, and its impact on disease. We highlight evidence linking mtDNA to cardiovascular disease, as well as the aging-related chronic kidney disease, lung disorders, and neurodegeneration, and discuss the utility of circulating mtDNA copy number as a biomarker. Finally, we outline therapeutic strategies to reduce mtDNA release, block its sensing, and enhance clearance via autophagy/mitophagy. These findings underscore mtDNA as both a driver of pathology and a promising target for diagnosis and therapy across multiple organ systems.

Background 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 months of medical treatment. Additionally, this study aimed to investigate the association between changes in endothelial function and the incidence of cardiovascular rehospitalizations or deaths. Methods 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 months. Patients were followed for 12 months. Results The mean age was 61.9 ± 10.2 years, with a sex ratio of 5:1. 42.5% of patients tend to experience endothelial dysfunction at baseline. After 3 months of optimal medical therapy (i.e., renin-angiotensin35 aldosterone system inhibitors, beta-blockers, the aldosterone antagonist spironolactone, and sodium- glucose co-transporter 2 inhibitors), EQI improved significantly (p<0.001), correlating with improved echography and hemodynamic parameters. Over 12 months, 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 (AUC = 0.82) and rehospitalization risk (AUC = 0.837). A ΔEQI ≥ 0.2 predicted a better prognosis (HR: 0.157, 95% CI: 0.054-0.454, p=0.001). Conclusion Patients with HFrEF exhibited endothelial dysfunction. The improvement in endothelial function after an optimized treatment is associated with an enhancement in echography and hemodynamic parameters. Additionally, endothelial function was a strong prognostic marker.

Hypertensive disorders of pregnancy (HDP), particularly early-onset preeclampsia (EOPE), are major causes of perinatal morbidity and mortality. While impaired placentation has long been recognized as a key mechanism, increasing evidence highlights the contribution of maternal cardiovascular dysfunction. However, how maternal haemodynamics influences neonatal circulatory transition remains poorly understood. In this prospective study, mother-infant pairs from pregnancies complicated by EOPE were enrolled if the mother had undergone echocardiographic assessment within three weeks prior to delivery and the neonate had received continuous hemodynamic monitoring by electrical cardiometry for at least 72 hours after birth. Associations between maternal and neonatal hemodynamic parameters were explored using correlation analysis and generalized linear mixed-effects models (GLMM) accounted for repeated neonatal measurements, neonatal exposure to dopamine or dobutamine and patent ductus arteriosus (PDA). Maternal systolic function indices (cardiac output (CO), Ejection fraction (EF), and ventricle tissue doppler s' velocities) inversely correlated with neonatal CO in fully adjusted GLMM models. EF was positively associated with neonatal systemic vascular resistances (SVR) when adjusted for inotropic support (p = 0.010), with attenuation after additional adjustment for PDA (p = 0.052). Overall, maternal systolic impairment in EOPE was associated with higher neonatal CO, indicating a compensatory increase in neonatal cardiac performance, while changes in neonatal vascular tone were minimal. These findings provide the first quantitative evidence of maternal-neonatal hemodynamic coupling and support the value of integrated cardiovascular assessment of both mother and newborn in hypertensive pregnancies.

Sex differences are evident in vascular mitochondrial function, however, the impact of sex on microvascular bioenergetics has never been studied. We investigated the bioenergetics of freshly isolated mouse brain microvessels (BMVs) from young mice (6-8 weeks). Oxygen consumption rate and extracellular acidification rates of BMVs were measured utilizing Agilent Seahorse XFe24 analyzer. The Real-Time ATP Rate assay showed reduced total ATP production with contributions from both glycolysis and oxidative phosphorylation (OxPhos) in BMVs from females compared with males. The Mitochondrial Stress test revealed lower basal respiration and ATP production in BMVs of females versus males. The Glycolytic Rate assay indicated reduced basal glycolysis and proton efflux rate (PER) in females, with no sex differences in basal PER and post-2-DG acidification. Mito Fuel Flex Test found no differences in fuel substrate utilization. Measurements utilizing homogenates of BMVs confirmed lower ATP levels in females, with no sex differences in citrate synthase activity or key mitochondrial protein/mRNA levels. Ex vivo oxygen-glucose deprivation followed by reoxygenation (OGD/R) of mouse BMVs displayed significantly reduced mitochondrial respiratory function as well as glycolytic activity in females versus males. However, OGD/R paradoxically increased lactate dehydrogenase release, a marker of cellular injury, from male BMVs but has no effect on female BMVs. Thus, female BMVs exhibited decreased mitochondrial respiratory and glycolytic function compared with males, despite similar substrate utilization for energy production. In young mice, the sex-dependent differences in OxPhos and glycolysis may increase the vulnerability of the microvasculature to OGD/R injury in males and vasoprotection in females.

Micro and nanoplastic (MNP) detection in human tissues demonstrates that exposure at any life stage is inevitable. We have previously demonstrated that pulmonary exposure to this emerging environmental contaminant impairs endothelial function in the uterine vasculature of nonpregnant and pregnant rats. However, neither the mechanism of this dysfunction nor the role of the endothelial-derived vasodilator, nitric oxide (NO), has been interrogated. Therefore, we assessed uterine macro- and microvascular reactivity in Sprague Dawley rats to determine the mechanistic role of NO signaling in endothelial dysfunction after repeated (gestational day 5-19) MNP inhalation during pregnancy. Results identified that MNP exposure reduced fetal growth and impaired endothelial-dependent dilation in the uterine microcirculation, which control placental perfusion and resource availability to the fetus. Levels of activated endothelial nitric oxide synthase (eNOS), phosphorylated on Ser¹¹⁷⁶, were substantially decreased (<50%) in uterine vessels from exposed rats. This suggests MNP inhalation limited NO production and bioavailability. Endothelial function was partially restored by supplementation of arterial segments with the eNOS cofactor tetrahydrobiopterin (BH₄), demonstrating that exposed vessels were BH₄-deficient. Partial restoration was also achieved by incubation with the reducing agent, dithiothreitol, suggesting that exposed vessels contained physiologically relevant levels of reactive oxygen and nitrogen species. Increased 3-nitrotyrosine residues and decreased thioredoxin protein expression further suggest MNP fosters nitrosative and oxidative stress in the uterine vasculature, impairing eNOS and endothelial-dependent dilation. These findings implicate eNOS uncoupling as a mechanistic basis for the vascular toxicity of MNPs and the adverse impact of MNPs on fetal development.NEW & NOTEWORTHY This study reveals that repeated micro and nanoplastic (MNP) inhalation throughout gestation blunts endothelial-dependent dilation in the uterine microcirculation, promoting fetal growth restriction. Exposure impaired endothelial nitric oxide signaling through deactivating endothelial nitric oxide synthase (eNOS), reducing the availability of the eNOS cofactor tetrahydrobiopterin, and producing a nitrosative and oxidative environment in uterine vascular tissue. These novel findings highlight the eNOS uncoupling as a key mechanism behind the fetal growth restriction induced by MNP.

Exercise training is known to improve the function of the heart in fish. However, at the cellular level, the mechanisms for improvements are still largely unknown. Therefore, we aimed to investigate the impact of exercise training on electric excitation of cardiac contraction in ventricular myocytes of rainbow trout (Oncorhynchus mykiss) through the investigation of sodium (I_Na), L-type calcium (I_CaL), delayed and inward rectifier potassium (I_Kr and I_K1) currents and action potential (AP) characteristics. The fish were divided into untrained (control) and trained groups. Control fish were kept in standard holding tanks with a water flow rate of 0.3 body lengths per second (bl s^-1), whereas trained fish experienced daily sessions of exercise for 6 h, 5 days a week, for a period of 4 wk, at a water flow rate of 0.9 bl s^-1. The patch-clamp technique was used to compare ion currents between groups. Trained fish exhibited higher whole cell capacitance, consistent with an increased membrane surface area of ventricular myocytes. Furthermore, exercise training led to reduced current densities of I_Na, I_CaL, and outward I_K1. These changes in currents were connected to marked alterations in AP morphology, including depolarized resting membrane potential (RMP), depolarized threshold potential (TP), and prolonged AP at 90% repolarization (APD₉₀). In summary, this study presents novel evidence that swimming exercise training can impact the ventricular ion currents, which leads to prolongation of the action potential, and that the cardiomyocytes of the rainbow trout are highly plastic, enabling them to respond to changes in the environment.NEW & NOTEWORTHY Exercise training modulates cardiac ion currents, enlarges cardiomyocytes, and prolongs action potentials, demonstrating notable electrophysiological adaptations linked to enhanced cardiac performance in rainbow trout.

Postinfarct myocardial remodeling is modulated by myeloid-derived cells; however, the precise mechanism remains to be fully elucidated. Here, by the targeted single-cell RNA sequence (scRNA-Seq) analysis, we newly identified a myeloid cell population that specifically expresses glycoprotein A repetition-predominant (GARP), a docking receptor and activator of latent transforming growth factor βs (TGF-βs). GARP-expressing myeloid (GEM) cells exhibited the gene expression profile characteristic of fibrocytes, fibroblast-like myeloid cells. Myeloid cell-specific GARP-null mice (GARP-CKO mice) showed ameliorated cardiac fibrosis and improved cardiac function after myocardial infarction (MI). Myeloid-specific GARP gene ablation resulted in the suppression of TGF-β signaling in cardiomyocytes and reduced the neutrophil infiltration into infarct myocardium, accompanied by decreased neutrophil chemotaxis cytokine production. In addition, cardiomyocyte apoptosis decreased in GARP-CKO mice, proposing that myeloid GARP/TGF-β axis is involved in cardiomyocyte loss. Comprehensive scRNA-Seq data, combined with the published dataset of healthy heart cells, revealed that GEM cells were derived from heart-resident fibrocytes. Finally, the Visium data of patients with MI suggested the existence of GARP⁺CD11b⁺ cells in postinfarct myocardium. Collectively, GARP-expressing fibrocytes deteriorate cardiac remodeling by regulating neutrophil infiltration and cardiomyocyte apoptosis. The blockade of the transition from fibrocytes to GEM cells could be a therapeutic strategy against postinfarct heart failure.NEW & NOTEWORTHY Myeloid cells are known to contribute to the progression of myocardial infarction. However, the precise roles of these cells have not been fully elucidated. Single-cell RNA sequencing analysis demonstrated a population of glycoprotein A repetition-predominant (GARP)-expressing myeloid cells (GEM cells) that were derived from heart-resident fibrocytes. GEM cells were found to regulate neutrophil infiltration and cardiomyocyte apoptosis, resulting in detrimental cardiac remodeling. Spatial transcriptomics suggests that GEM cells are also present in human infarcted myocardium.

Chronic kidney disease (CKD)-mediated oxidative stress, uremic toxicity, inflammation, and cardiovascular (CV) damage connect the kidney-heart-brain axis that contributes to cognitive impairment (CI) and progression to major neurological disorders. Although the sex disparity has a profound impact on CKD epidemiology, its role in the progression of CI needs to be elucidated in detail. The present study aims to unravel the sex-specific cross talk of the kidney-heart-brain axis in CKD. CKD and control subjects, equally represented by both sexes, were included in a cross-sectional study that involved a community-dwelling rural population. CV and CKD parameters, Mini-Mental State Examination (MMSE), markers of fibrosis and neurodegeneration were assessed. We elucidated the sex-specific associations among these factors through linear regression and structural equation modeling (SE), or Path, analyses. Patients with CKD have higher blood pressure versus controls, and men with CKD exhibited a decline in cardiac function versus sex- and age-matched controls. Both men and women with CKD had lower MMSE scores versus controls, although cognitive performance in women with CKD was significantly better than that of men with CKD. Path analysis revealed a direct association of the plasma phosphorylated Tau protein (pTau) and the ratio of amyloid β-42 to amyloid β-40 with MMSE scores in women only. Pro-brain natriuretic peptide and pTau were associated with short-term memory, a part of the MMSE assessment, also in women only. Our findings will broaden the current understanding and clinical consequences of the pathophysiological interactions between kidney and CV damage with brain function in a sex-dependent manner that could prompt innovative pharmacological interventions.NEW & NOTEWORTHY To our knowledge, the present study explored, for the first time, the direct sex-specific association of chronic kidney disease, cardiovascular disease, and cognitive function with a panel of fluid biomarkers of oxidative stress, inflammation, fibrosis, and neurodegeneration, including the novel profibrotic marker marinobufagenin. The study shows that dysregulated cardiac and neurodegeneration biomarkers, along with hypertension and cardiac remodeling, aggravate the progression of cognitive impairment in patients with chronic kidney disease (CKD) in a sex-specific manner.

This study compares myocardial injury responses in human donor hearts from donation after brain death (DBD) and donation after circulatory death (DCD), with a focus on myocardial membrane integrity, pyroptosis, and damage. Unlike DCD hearts, which are exposed to varying durations of functional warm ischemic time (fWIT), DBD hearts, which are never subjected to warm ischemia, served as controls. A total of 24 human hearts were procured, consisting of 6 from the DBD group and 18 from the DCD group. All procured hearts were placed in cold normal saline and stored for up to 6 h. Left ventricular biopsies were performed at 0, 2, 4, and 6 h to assess plasma membrane repair proteins (Annexin A1 and Dysferlin), pyroptosis markers [NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, and N-terminal fragment of gasdermin D (GSDMD-NT)], and to evaluate edema and injury scores. Data suggest that DBD hearts maintained stable levels of plasma membrane repair proteins and showed no evidence of pyroptosis activation or significant injury throughout cold storage. In contrast, DCD hearts exhibited profound Annexin A1 depletion, early and progressive pyroptosis, elevated edema, and worsening histopathological injury, directly correlated with fWITs. These findings underscore that warm ischemia is a critical determinant of pyroptotic damage in donor hearts, and highlight the relative resistance of DBD hearts to such injury during preservation. For DCD hearts, strategies to enhance membrane repair capacity and inhibit pyroptosis during the fWIT phase should be the focus to maintain donor heart quality and suitability for transplantation.NEW & NOTEWORTHY This study demonstrates that donor hearts procured after circulatory death (DCD) exhibit early Annexin A1 depletion and activation of the NLRP3/caspase-1/GSDMD-mediated pyroptosis pathway during cold storage-a phenomenon absent in brain-dead (DBD) donors. We establish a direct correlation between warm ischemia time and pyroptotic damage in DCD hearts. These findings highlight Annexin A1 as a crucial mediator of ischemic injury, offering a promising therapeutic target to enhance viability in DCD donor hearts.