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

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.

The dynamic nature of a myocardial bridge (MB) makes invasive hemodynamic assessment more complex than atherosclerotic coronary artery disease (CAD), and the influence of blood pressure (BP) on these measurements remains unclear. We investigated whether BP affects the hemodynamic significance of myocardial bridges (MBs), and compared this with CAD and normal vessels as a reference. We included 63 patients with an MB who underwent dobutamine resting full-cycle ratio (RFR) measurements, and compared them against reference groups of 85 patients with CAD and 45 patients with normal coronaries who underwent RFR and adenosine fractional flow reserve (FFR). Regression analyses were used to assess the relation between BP parameters and hemodynamic measurements. Higher systolic BP was associated with higher RFR values (i.e., less functionally significant lesions) in patients with an MB (0.03 RFR increase per 20 mmHg systolic blood pressure rise; P < 0.05) and in patients with CAD (0.01 RFR increase per 20 mmHg systolic blood pressure rise; P < 0.05). Pulse pressure showed the strongest association, with a 20 mmHg higher pulse pressure associated with a 0.05 higher dobutamine RFR in MBs and a 0.02 higher RFR in CAD (both P < 0.05). In patients with an MB, this relation was only present with low maximal MB compression (≤36%), and no relation was observed with more severe MB compression (P_interaction < 0.05). Higher procedural BP is associated with higher hemodynamic index values (i.e., less functionally significant lesions) in myocardial bridging, suggesting BP should be considered when interpreting measurements near treatment thresholds.NEW & NOTEWORTHY Higher procedural blood pressure (BP) is associated with less significant hemodynamic measures in myocardial bridging, suggesting BP should be considered when interpreting borderline hemodynamic measurements.

Postural orthostatic tachycardia syndrome (POTS) is a debilitating disorder characterized by excessive increases in heart rate upon standing and poor orthostatic tolerance. Impairments in large artery, endothelial, and venous function may collectively, or individually, result in excessive blood pooling and impaired venous return, or other inadequate vascular response to standing, thus contributing to POTS. Herein, we tested the hypothesis that patients with POTS would exhibit reduced large artery stiffness, enhanced endothelial function, and greater lower limb venous pooling while standing, compared with healthy controls. Fourteen participants with a clinical diagnosis of POTS and 15 age-matched controls (all females; median age [interquartile range]; 21 [19-37] yr, P = 0.769) were recruited. Central arterial stiffness was determined using carotid-femoral pulse wave velocity (cfPWV; SphygmoCor). Endothelial function was assessed using brachial artery flow-mediated dilation (FMD) following a 5-min forearm occlusion at 200 mmHg. Functional measures of calf venous volume and filling time (90% maximal venous filling) were acquired (air plethysmography) while standing. cfPWV was increased in people with POTS [(means ± SD) 5.5 ± 0.9 vs. 4.8 ± 0.4, P = 0.031], whereas FMD was not different between groups (P = 0.854). During standing, calf venous volume was 29% greater in people with POTS (P = 0.048), and venous filling time was almost twice as long (404 ± 199 vs. 207 ± 99 s; P = 0.003). These findings indicate that people with POTS exhibit increased central arterial stiffness, preserved endothelial function, and increased calf venous filling during standing. Such differences in lower limb venous filling dynamics on standing likely contribute to the orthostatic intolerance that characterizes POTS.NEW & NOTEWORTHY Females with POTS and age-matched healthy controls underwent assessments of central arterial stiffness, endothelial function, and calf distensibility. Pulse wave velocity was higher in people with POTS, but brachial artery flow-mediated dilatation was not different between groups. Standing calf volume was greater in people with POTS, and maximal filling times were twice as long, suggesting altered venous and/or microvascular function. Augmented venous pooling in patients with POTS may impair venous return and orthostatic tolerance.

Vasodilation and vasoconstriction of small resistance vessels in the coronary microcirculation are key mechanisms for regulating coronary blood flow. This dynamic regulation acts as a reserve system that ensures adequate perfusion under varying physiological conditions and metabolic demands. In the presence of coronary artery stenosis, part of this vasodilatory reserve may already be used, triggered by pressure-flow autoregulation mechanisms that maintain normal blood flow at rest. Fractional flow reserve (FFR), measured during pharmacologically induced maximum vasodilation/hyperemia (typically with adenosine), remains the gold standard for diagnosing coronary artery disease. Computed tomography-derived FFR (CT-FFR) provides noninvasive FFR estimates and is increasingly recommended as a gatekeeper to invasive evaluation. Most current CT-FFR models assume a fixed microvascular response to adenosine, treating vasodilation capacity as constant and optimal for all patients and lesions. Using intracoronary pressure measurements, we quantified how stenosis severity affects the microcirculatory response to adenosine. Based on these findings, we developed a CT-FFR algorithm that incorporates autoregulation. In comparison across 280 lesions, the autoregulation-based model reduced prediction variability (SD = 0.1006 vs. 0.1167, P value = 0.013) and improved the coefficient of determination (R² = 0.398 vs. 0.179) relative to a fixed-response model, using invasive FFR as reference. However, the area under the curve (AUC) remained unchanged. Sensitivity analyses showed that autoregulation effects were minor in lesions with CT-FFR > 0.7. Feature analysis showed that vessel location, patient sex, and heart rate are associated with the microvascular response to adenosine, emphasizing the need to consider these factors in the combined assessment of epicardial and microvascular disease.NEW & NOTEWORTHY We present a novel autoregulation-aware model of microvascular resistance for CT-FFR computations. The model improves prediction accuracy compared with conventional approaches for modeling the hyperemic state. Integration of CCTA-derived anatomy and invasive pressures reveals sex- and territory-dependent microvascular responses to adenosine, highlighting the diagnostic role of combined assessment of epicardial and microvascular disease.