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

The search for effective adjuncts to procedural revascularization for patients with coronary artery disease (CAD) has revealed, after several successful outcomes trials, the substantial potential of glucagon-like peptide 1 (GLP-1) analogs such as semaglutide. Because this potential has not been mechanistically illuminated in the setting of CAD and metabolic syndrome, we employed a large animal model to evaluate the cardiac consequences of GLP-1 receptor (GLP-1R) agonism. 16 Yorkshire swine, after provision of a high-fat diet for 5 weeks induce metabolic syndrome, underwent ameroid constrictor-mediated induction of focal CAD. Animals were then either randomized to receive semaglutide (SEM, n=8, 4 male, 4 female), or no drug (CON, n=8, 4 male, 4 female) for 5 weeks, followed by a terminal sternotomy for left ventricular pressure-volume catheterization, coronary collateral characterization, and myocardial resection and sectioning. Coronary arterioles from the peri-ischemic myocardium were mounted and suffused to assess vasoactivity, and molecular changes within the most ischemic territory were assayed using immunoblotting, immunofluorescence, and proteomics. Treated animals exhibited enhanced left ventricular filling, end diastolic volume, stroke volume, and cardiac index (all p<0.05); increased arteriolar density (p<0.001); improved microvascular endothelium-dependent vasodilation (p<0.01); and, as indicated by increases in fibroblast growth factor, angiostatin, endostatin, and endothelial nitric oxide synthase (all p<0.01), augmented vascular remodeling and endothelial function. In a large animal model that recapitulates the clinical comorbidities of CAD, improved left ventricular arteriolar density, vascular reactivity, and performance throughout the cardiac cycle position semaglutide as a highly promising addition to the adjunctive armamentarium against CAD.

Left ventricular (LV) flow state is associated with unfavorable outcome in patient with severe aortic stenosis. However, there is little information on its impact on long-term prognosis in a population without valvular disease. To examine the impact of LFS on all-cause mortality in multi-ethnic population we analyzed 4398 asymptomatic participants without clinical cardiovascular disease undergoing cardiac magnetic resonance (CMR) in the Multi-Ethnic Study of Atherosclerosis. LV stroke volume index (SVi), LVEF and myocardial contraction fraction (MCF) were measured. LV flow states were classified as normal flow state (NFS, SVi >35 ml/m²), low-flow state (LFS, 30-34 ml/m²) and very low-flow state (VLFS: SVi <30 ml/m²). Clinical data were collected at enrollment. Participants were followed up for a median of 14.2 years. All-cause and cardiovascular disease mortalities were used as primary endpoints. All-cause mortality was 16.2% and cardiovascular disease mortality 3.5%. VLFS and LFS groups had more cardiovascular risk factors and lower cardiac performance than NFS. The relationship between all-cause mortality and SVi was "L-shape with the "breakpoint" at 33.5ml/m2 for a statistical significance (p=0.009). All-cause mortality was significantly associated with LFS after adjusted for age, sex, LVEF, and LV mass index with hazard ratio (HR) 1.81, 95% CI: 1.31-2.49 for VLF and HR: 1.21, 95% CI: 0.95-1.54 for LFS with overall p value 0.001). The highest cardiovascular disease mortality was seen in VLFS.

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.

Women with a history of preeclampsia (hxPE) have elevated risk of cardiovascular disease, likely in part from reduced endothelial function. Preeclampsia is also associated with increased risk of depression. While evidence indicates that antidepressant pharmacotherapy may have vasculoprotective effects, it is unclear whether it preserves endothelial function in women with hxPE. We hypothesized that antidepressant-treated women with hxPE would have preserved endothelial function compared with unmedicated women with hxPE. Ten women with hxPE currently treated with an antidepressant (hxPE+AD), 10 not treated (hxPE-AD), and 10 unmedicated women with a history of uncomplicated pregnancy (HC) participated. Macrovascular endothelial function was measured via brachial artery flow-mediated dilation (FMD). Microvascular endothelial function and the nitric oxide (NO) component were assessed via cutaneous vascular conductance (CVC, %max) responses to graded infusions of acetylcholine (10^-10-10^-1M) alone or with 15mM N^G-nitro-L-arginine methyl ester [L-NAME; NO-synthase-inhibitor], respectively. Relative and absolute FMD in hxPE-AD were lower compared with HC (5.7±0.3% vs. 7.5±0.3%, P=0.02; 0.18±0.01mm vs. 0.23±0.01mm, P=0.02) and hxPE+AD (vs. 7.2±0.6% and 0.23±0.02mm, both P≤0.047). hxPE-AD had reduced microvascular endothelium-dependent vasodilation responses to acetylcholine compared with HC (10^-5 to 10^-2M, P=0.017). Peak CVC in hxPE-AD was lower than HC (82.0±2.9%max vs. 96.2±2.0%max, P<0.01) and hxPE+AD (vs. 92.3±3.4%max, P=0.04). L-NAME reduced microvascular dilation in all groups (P<0.001). NO-dependent dilation did not differ among groups (P=0.07). Collectively, macrovascular and microvascular endothelial function in hxPE+AD was greater than hxPE-AD and did not differ from HC, suggesting that antidepressant pharmacotherapy may preserve endothelial function in women with hxPE.

Preeclampsia induces adverse cardiovascular outcomes for both mother and offspring. We established a novel leptin-induced mouse model of preeclampsia that induces hypertension, endothelial dysfunction, and fetal growth restriction, which are collectively ablated by endothelial cell mineralocorticoid receptor (MR) deletion. However, literature lacks preclinical evidence to use MR antagonism for preeclamptic patients. We hypothesize eplerenone improves blood pressure, vascular function, and fetal outcomes in leptin-infused pregnant mice. We infused timed-pregnant Balb/c mice with saline (sham) or leptin via s.c. osmotic minipump and administered vehicle or eplerenone from gestation day (GD)11-18 and GD15-18. We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in 2^nd order mesenteric arteries by wire myography, and pup/placental weights on GD18. Eplerenone from GD11-18 ablated leptin-induced increases in BP but independently decreased fetal weight and placental efficiency. Eplerenone increased vascular contractility to phenylephrine and increased mRNA expression of NADPH oxidase (NOX) 1 and 2 in the placentas of pregnant mice in the GD11-18 cohort. We observed in our GD15-18 cohort that eplerenone no longer decreased fetal weight nor placental efficiency and there was no increase in contractility to phenylephrine. In conclusion, our data suggest that although eplerenone improves leptin-induced hypertension in pregnant mice, eplerenone reduces fetal weight when administered at mid-, but not late-, gestation in pregnant mice.

Wound healing after myocardial infarction (MI) is a dynamic and multifaceted process that links the molecular alterations induced by or in response to prolonged ischemia with structural and physiological changes to the damaged myocardium. Changes, at the tissue level, are driven by a complex intersection of cellular and molecular mechanisms that operate along a classic wound healing paradigm as an attempt to repair the damaged myocardium and restore cardiac physiology. Maladaptive healing prevents a return to the original homeostasis, rather yielding a myocardium reset to a new homeostatic status that can lead to heart failure due to compromised contractility, increased chamber dilation, and cardiac fibrosis or due to sudden cardiac death resulting from arrhythmias. This review summarizes our current knowledge of how key inflammatory drivers in the myocardium (cardiomyocytes, neutrophils, monocytes/macrophages, fibroblasts, and vascular endothelial cells) respond to molecular signals including cytokines, growth factors, and proteases to coordinate the wound healing process in the mouse model of MI. We also identify knowledge gaps that remain in our understanding of cardiac remodeling that are opportunities for future examinations.

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.

Mitochondrial respiration sustains the high energy demands of endurance exercise, yet the extent to which atrial, ventricular and skeletal muscle mitochondria adapt remains uncertain. At the same time, endurance athletes face an increased risk of atrial fibrillation (AF), but the role of cardiac metabolism in arrhythmia susceptibility is poorly understood. Here, we compared mitochondrial respiration in skeletal muscle and across all four cardiac chambers between trained and untrained racehorses (n=34) to investigate adaptations associated with long-term endurance exercise. We further examined whether cardiac metabolism was linked to AF propensity. All horses underwent treadmill performance testing, and mitochondrial respiration was assessed in permeabilised skeletal and cardiac muscle fibres. Cardiac RNA-sequencing and in vivo AF inducibility testing were performed in a subset of horses. Mitochondrial function varied by region: the left ventricle showed the greatest oxidative capacity, and the ventricles exceeded the atria in mitochondrial content. Trained horses showed improved skeletal complex I- and II-linked respiration, and skeletal muscle respiration correlated with aerobic performance. In contrast, cardiac mitochondrial content and mass-specific respiration were unchanged by endurance exercise, despite enrichment of mitochondrial complex I pathways on transcriptomic analysis. A greater cardiac capacity for fatty acid oxidation, but not mitochondrial respiration, was associated with protection against AF induction. These findings reveal tissue-specific mitochondrial adaptations to endurance exercise and implicate cardiac substrate preference, rather than respiratory capacity, as a potential determinant of AF vulnerability. This raises new questions about how different tissues adapt metabolically to exercise and the potential role of cardiac energetics in arrhythmogenesis.

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.