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

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.

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.

The heart rate variability coefficient of variation (HRV-CV) is an index of day-to-day cardiac autonomic fluctuation that may serve as a scalable digital biomarker for behavioral monitoring and health risk stratification. We investigated how many nights of sleep-derived HRV were needed to reliably estimate 7-day HRV-CV, and examined associations with behavioral and demographic characteristics linked to health. We analyzed ∼2 million nocturnal HRV readings from >21,000 wearable device users, stratified by age and sex. Seven-day HRV-CV was calculated, and a simulation determined the minimum nights required for reliable estimates. Associations with alcohol, physical activity, sleep, and variability of these behaviors were evaluated. Additional models examined associations between HRV-CV with age, biological sex, and body mass index (BMI). At least five of seven nights were required to achieve acceptable agreement with full-week HRV-CV values (intraclass correlation coefficient ≥ 0.80). Higher HRV-CV was associated with greater alcohol consumption, lower physical activity, shorter and less consistent sleep, and greater behavioral variability (Ps < 0.001), with stronger associations for alcohol and sleep compared with HRV. HRV-CV increased with age in males after ∼40 yr and showed a U-shaped pattern in females, declining through midlife and rising after ∼50 yr. HRV-CV increased with BMI in both sexes (Ps < 0.01). HRV-CV measured during nocturnal sleep can be reliably estimated from at least five nights of data, with higher values associating with less favorable behavioral profiles, older age, and higher BMI. These findings support the use of HRV-CV as a scalable, behavior-sensitive digital biomarker with potential applications in personalized health monitoring and risk stratification.NEW & NOTEWORTHY We identify HRV-CV measured during sleep as a scalable measure of day-to-day HRV fluctuation. Analyzing nearly 2 million HRV readings from >21,000 individuals, we document that five nights are sufficient for reliable 7-day estimates. Higher HRV-CV is associated with greater alcohol consumption, lower activity, shorter and less consistent sleep, older age, and higher BMI. These findings provide the first large-scale characterization of HRV-CV and support its potential as a biomarker for behavioral monitoring and risk stratification.

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.

Small extracellular vesicles (EVs) have become essential mediators of intercellular and interorgan communication in vivo, with significant therapeutic potential and prognostic value in cardiovascular diseases. Despite extensive research on exosomal cargoes and their biological effects, the in vivo dynamics and systemic distribution of cardiac-derived small EVs under pathological conditions remain poorly understood. This study used cardiac small EVs-tracking mice to profile the distribution and production of cardiomyocyte-derived small EVs following myocardial infarction (MI). We observed distinct temporal dynamics in cardiac small EVs uptake between males and females. In the heart, uptake increased markedly during the acute injury phase and declined during the healing phase in males, whereas it gradually declined in females, with both sexes showing preferential uptake by endothelial cells and leukocytes. The distribution of cardiac-derived small EVs in peripheral organs gradually decreased over time in male mice but followed different patterns in females. Females exhibited higher circulating levels of cardiac-derived small EVs and a more dynamic uptake into peripheral organs than males. Meanwhile, cardiac small EVs biogenesis tended to increase on day 3 but significantly decreased by day 14 in male MI hearts, whereas it increased in females as MI progressed. These findings provide the first comprehensive in vivo spatial and temporal map of endogenous cardiac small EVs dynamics after MI and its sexual dimorphism, laying a crucial foundation for future mechanistic studies.NEW & NOTEWORTHY Although extracellular vesicle (EV) contents and cargoes have attracted significant interest for their roles in intercellular and interorgan communication after myocardial infarction (MI), the endogenous dynamics and biogenesis of cardiac small EVs following MI, and their sexual differences, remain largely unknown. Here, we present the first in vivo characterization of cardiomyocyte-derived small EVs dynamics and sexual dimorphism in response to MI injury, establishing a framework and offering crucial mechanistic insights for future studies.

Adverse conditions within the embryonic environment can alter embryogenesis, programing systemic physiological changes that may manifest as disease states in adult life. The process of developmental programing represents an important factor underlying cardiometabolic diseases, many of which are leading causes of death globally. Importantly, there is evidence that males are less tolerant to certain environmental perturbations during embryogenesis, mirrored by sex differences in the incidence of certain cardiometabolic diseases. Understanding sex differences in programed responses in mammalian models is complicated by maternal compensation and placental factors. Avian models offer a valuable comparable system in which such effects are not present. Here, we investigate the influence of developmental hypoxia and hypothermia in programing cardiovascular structure and function in the domestic chicken (Gallus gallus domesticus). In agreement with mammalian studies, adult males but not females show pathological mitochondrial morphology and respiratory capacity, ventricular hypertrophy, and reduced body weight programed by embryonic hypothermia and hypoxia. Notably, adult males but not females incubated under combined hypoxia and hypothermia display reduced left ventricle size, more spherical mitochondria, and a reduction in mitochondrial complex IV activity in cardiomyocytes. Adult females incubated under hypothermic conditions show higher protein levels of mitochondrial complex V and do not display the same level of telomere shortening in comparison with males incubated under identical conditions. These data not only represent novel findings in birds but also demonstrate the utility of the avian model for understanding sex differences in developmental stress responses, revealing common responses among endothermic amniotes.NEW & NOTEWORTHY How does stress before birth shape lifelong heart health? We show that chickens exposed to low oxygen or cold during development grow into adults with long-lasting, sex-specific heart changes. Males developed smaller bodies, altered heart structure, mitochondrial dysfunction, and faster telomere shortening, whereas females showed enlarged hearts but preserved mitochondrial function. Our findings reveal how early environmental stress programs cardiovascular health differently in males and females, with broad relevance for understanding heart disease risk.

Acute myocardial ischemia triggers electrophysiological changes, including altered cardiac action potential and conduction slowing. Optical mapping is widely used to study these changes, but most experiments use excitation-contraction uncouplers to suppress contractile motion and motion artifacts. We hypothesized that contraction suppression with these uncouplers masks ischemic effects, leading to misleading results. We compared Langendorff-perfused, noncontracting hearts treated with blebbistatin to contracting hearts under acute ischemic conditions. Optical mapping with emission ratiometry and motion-tracking postprocessing minimized motion artifacts, whereas ischemia was induced by ligating the obtuse marginal branch of the left circumflex coronary artery. Contracting hearts exhibited faster and more pronounced reductions in action potential duration (APD) and action potential triangulation (2 min vs. 14 min), along with an increased incidence of spatially discordant alternans (SDA). They also displayed steeper APD restitution slopes, whereas these slopes were flattened in noncontracting hearts. These differences may stem from reduced metabolic demands and the absence of mechanoelectric feedback in noncontracting hearts. In contrast, contracting hearts, with higher metabolic activity and mechanical feedback, experienced more severe ischemic changes. These findings highlight the limitations of using blebbistatin-treated, noncontracting hearts in electrophysiological research, as critical ischemic effects may be underestimated. This study underscores the need to integrate mechanical and electrical dynamics in preclinical models to accurately replicate ischemic conditions, enhancing the translational relevance of experimental cardiac research.NEW & NOTEWORTHY This study highlights key differences in acute ischemic responses between contracting and blebbistatin-treated noncontracting rabbit hearts. Contracting hearts showed faster, more severe action potential duration reductions, increased spatially discordant alternans, and steeper restitution slopes, emphasizing the role of mechanoelectric feedback and higher metabolic demands. These findings challenge reliance on noncontracting models in electrophysiological research, underscoring the need for models integrating mechanical and electrical dynamics to improve the translational relevance of ischemic studies.