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

Postmenopause is associated with increased adiposity, metabolic syndrome, and heightened cardiovascular disease (CVD) risk, yet the adipose-derived factors potentially contributing to vascular impairment remain poorly defined. Asprosin, a glucogenic adipokine secreted by white adipose tissue (WAT), is elevated in metabolic diseases; however, its association with postmenopausal vascular complications remains unknown. In this study, we investigated circulating and adipose tissue asprosin levels in a long-term ovariectomy (OVX) mouse model of postmenopause. Female mice underwent OVX or sham surgery and were followed for 20 weeks. OVX mice developed typical postmenopausal bone porosity, specifically in the lumbar vertebras, along with cardiometabolic disorders, including weight gain, increased adiposity, metabolic syndrome-like alterations, and significant arterial stiffness, an early vascular insult marker. Notably, these postmenopausal changes were associated with elevated circulating asprosin levels and increased asprosin expression in subcutaneous adipose tissue. Results from ex vivo wire myography studies demonstrated that asprosin directly potentiates vasoconstriction, implying that asprosin exerts a direct vascular effect. Together, these findings provide novel evidence of an association between elevated asprosin and postmenopausal vasculo-metabolic alterations. These observations support further investigation of asprosin as a potential biomarker of cardiometabolic and vascular changes and as a candidate for future.

Pregnancy and lactation increase cardiovascular demand and may unmask postpartum cardiac vulnerability under metabolic stress. We tested whether exposure to a high-fat/high-sucrose (HFHS) diet from pre-mating through lactation induces postpartum hemodynamic dysfunction with preserved ejection fraction (EF) and whether voluntary wheel running mitigates these alterations. Virgin C57BL/6J female mice were assigned to control sedentary (CS), HFHS sedentary (HS), or HFHS with voluntary wheel running (HE) across the reproductive window. Left ventricular (LV) pressure-volume (P-V) analysis was performed 6-9 days after weaning at baseline and during dobutamine challenge to assess β-adrenergic reserve. Despite preserved EF, HS dams exhibited reduced end-diastolic volume (EDV) and impaired forward performance (lower stroke volume [SV], cardiac output [CO], and stroke work [SW]) accompanied by higher filling pressure, increased diastolic stiffness (end-diastolic elastance, Eed), impaired ventricular-arterial coupling (Ees/Ea), and reduced load-independent contractility (end-systolic elastance [Ees]). Dobutamine increased chronotropic and inotropic indices across groups; however, HS remained lower than CS during dobutamine for SV and Ees, indicating limited capacity to augment performance under stress. In contrast, wheel running improved intrinsic contractility and maintained Ees/Ea at rest and during dobutamine without differences in body or heart weight. These findings indicate that HFHS exposure across pregnancy and lactation is associated with postpartum hemodynamic dysfunction characterized by preserved EF with impaired filling, increased diastolic stiffness, and reduced reserve; voluntary wheel running across this window mitigates key abnormalities in systolic mechanics and ventricular-arterial coupling.

Abdominal aortic aneurysm (AAA), a pathological dilatation of the abdominal aorta, is primarily driven by chronic inflammation of the aortic wall. While estrogen is known to exert protective anti-inflammatory effects in AAA, the role of endothelial estrogen receptor alpha (ERα) signaling in AAA pathogenesis remains unclear. We investigated the vasoprotective role of endothelial ERα using endothelial cell (EC)-specific ERα knockout (eERαKO) mice subjected to a β-aminopropionitrile (BAPN) plus angiotensin II (Ang II) model of AAA. eERα deficiency significantly accelerated AAA formation in male mice, evidenced by increased maximal aortic diameter, worsened medial elastin degradation, increased collagen deposition, and upregulated macrophage infiltration, whereas female mice were largely unaffected. Mechanistically, loss of endothelial ERα was associated with elevated endothelin-1 (ET-1) expression in aortic tissue. In vitro, pharmacological inhibition of ERα with methyl-piperidino-pyrazole increased endothelial ET-1 secretion and increased monocyte adhesion in EC-monocyte co-culture assays. Collectively, these findings reveal that endothelial ERα constrains AAA development in male mice, possibly by suppressing ET-1-mediated endothelial activation and macrophage recruitment. This work highlights a protective role of endothelial ERα signaling in maintaining aortic structural integrity and preventing aneurysmal disease.

Aims: Intracardiac mast cells (CMCs) have previously been shown to contribute to adverse remodelling and heart failure in animal models. As CMCs in human hearts remain unexplored, the aim of this study was to investigate the pathophysiological relevance of human CMCs through transcriptomic profiling. Methods and Results: Biopsies were collected from the four heart chambers of heart failure patients undergoing heart transplantation surgery (n = 9) as well as from deceased organ donors without chronic heart failure (n = 5). Using flow cytometry, C-kit+CD45+ CMCs and C-kit-CD45+ hematopoietic cells were identified in all failing and nonfailing hearts and were sorted for RNA sequencing analysis. In comparison to other hematopoietic C-kit-CD45+ cells and CMCs in nonfailing hearts, CMCs in failing hearts demonstrated significant activation of pathways involved in cardiac remodelling and heart failure, including fibrosis-associated and inflammatory pathways. Conclusion: Our results support a role for mast cells in human heart failure and constitute the first in-depth characterization of mast cells in the nonfailing and failing human heart.

Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic and vasodilatory effects via cyclic adenosine monophosphate-mediated signaling pathways. However, its comprehensive hemodynamic impact, particularly on venous return, remains incompletely characterized. Using the generalized circulatory equilibrium framework, we investigated the cardiovascular effects of milrinone in normal and heart failure (HF) canine models. Ten beagle dogs (five normal, five with acute left HF induced by left coronary microembolization) were studied under general anesthesia and open-chest conditions. Milrinone was administered intravenously at 0.5 µg·kg^-1·min^-1. From the circulatory equilibrium framework, we derived the effective stressed blood volume (SBV) and the logarithmic slope (SL) of left ventricular (LV) output curve, which indicates LV pumping capability. Milrinone infusion reduced SBV from 31.6 ± 1.3 to 26.5 ± 1.7 mL/kg in the normal model and from 35.7 ± 3.0 to 32.1 ± 3.6 mL/kg in the HF model, with a significant main effect of drug (P = 0.004) but no model × drug interaction in two-way ANOVA (P = 0.531). In the normal group, SL was unchanged [61.6 ± 1.6 to 62.2 ± 3.5 mL·min^-1·kg^-1], resulting in decreases in aortic pressure (AP) and cardiac output (CO). In contrast, in the HF group, milrinone increased SL [18.3 ± 3.1 to 30.2 ± 4.3 mL·min^-1·kg^-1], with a significant model × drug interaction (P = 0.044). As a result, AP and CO were preserved, while left atrial pressure was reduced. In conclusion, in the HF canine model, milrinone improves the circulatory equilibrium point by enhancing LV pumping function and reducing SBV.

Aortic stenosis (AS) induces complex alterations in ascending aortic flow, including increased turbulent kinetic energy (TKE), altered velocity profiles, and changes in flow organization, which can be quantified using 4D flow cardiovascular magnetic resonance (CMR). The physiological relevance of these flow-derived parameters with respect to left ventricular (LV) adaptation remains incompletely understood. We investigated the associations between 4D flow CMR-derived hemodynamic metrics and established markers of LV decompensation and remodeling in patients with AS. Fifty-nine patients with AS (70 ± 14 yrs.) underwent 4D flow CMR using a Bayesian multipoint phase-contrast sequence with k-t PCA acceleration and three velocity-encoding steps in each direction. Quantified parameters included peak TKE, stroke volume-normalized systolic TKE (Normalized TKE_sys), peak velocity, jet angle, relative flow displacement, and mean helicity. Associations with NT-proBNP and indexed LV mass were analyzed. Peak TKE, Normalized TKE_sys, and peak systolic velocity were significantly associated with both indexed LV mass and NT-proBNP, whereas mean helicity was associated with indexed LV mass only. In contrast, jet angle and flow displacement showed no relationship with either marker of LV decompensation and remodeling. During long-term follow-up, no 4D flow CMR parameter was associated with adverse clinical events, likely due to timely valve replacement in most patients. In conclusion, these findings indicate that flow energetics - particularly TKE and peak systolic velocity - most closely capture the hemodynamic burden imposed on the LV supporting their physiological relevance in AS. Isolated descriptors of flow geometry, in contrast, have not shown to reflect maladaptive LV remodeling.

Diet is a modifiable determinant of cardiovascular risk and may influence tolerance to cancer therapies. The mechanisms by which specific dietary components affect cardiac metabolism during anthracycline treatment remain poorly defined, limiting the incorporation of dietary recommendations into treatment guidelines. Here, we integrated heart proteomics data from patients treated with or without anthracyclines with a genome-scale reconstruction of human cardiac metabolism (CardioNet). Using constraint-based flux analysis, we conducted >30,000 in silico simulations of diet scenarios generated from chemical profiles of ~500 foods curated in the Periodic Table of Food Initiative. These simulations revealed that diets enriched in rapidly absorbable sugars and depleted of essential fatty acids impair cardiac metabolic efficiency, increasing reactive oxygen species production and the demand for purine salvage fluxes. These predicted metabolic patterns were consistent with plasma metabolomics from anthracycline-treated patients, validating our findings. Computational modeling of 39 recipes across six cuisines revealed cardiometabolic effects of omnivorous versus vegan diets in patients. Modeling of a healthy vegan diet increased cardiometabolic efficiency compared to a healthy omnivorous diet in patients treated with anthracyclines, independent of the culinary background. Our approach demonstrates that integrating the molecular composition of food with genome-scale metabolic models enables systematic analysis of diet patterns for translational testing. Ultimately, these in silico studies provide a framework for trials and may inform dietary recommendations for improving cardiometabolic health.

Background: Cardiosphere-derived cells (CDCs) and the non-steroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for HFpEF. While these interventions can improve diastolic properties, their direct effects on LV chamber stiffness have not been established. Accordingly, we examined their effect in swine with increased LV chamber stiffness and fibrosis from repetitive pressure overload (RPO). Methods: Swine (n=19) were subjected to daily (1-hour) episodes of RPO for 2-weeks using phenylephrine to transiently elevate LVEDP to ~30mmHg. After 2-weeks, RPO was discontinued and animals received intracoronary saline (n=6), allogeneic CDCs (30x106, n=7) or oral finerenone (20mg/day; n=6) and were followed for 4-weeks. LV end-diastolic pressure and end-diastolic volume index were measured at normal and elevated preload to assess LV chamber stiffness (ΔLVEDP/ΔLVEDVi) and post-mortem picrosirius red staining was performed to quantify interstitial fibrosis. Results: Four-weeks after cessation of RPO, saline-treated swine demonstrated sustained increases in LV chamber stiffness (1.7±0.3mmHg/mL/m² vs. 0.6±0.1mmHg/mL/m² in controls, p<0.01). This was associated with increased fibrosis (8.5±0.7% vs. 6.7±0.4% in controls, p<0.05) that decreased after treatment with CDCs (6.1±0.5%, p<0.05) and finerenone (5.4±0.6%, p<0.05). Despite these anti-fibrotic effects, LV chamber stiffness remained elevated after both agents (CDCs: 1.9±0.4mmHg/mL/m²; finerenone: 1.4±0.3mmHg/mL/m², both p<0.05 vs. normal controls). Conclusion: Although both CDCs and finerenone reduced fibrosis, these changes were not associated with reductions in LV chamber stiffness. Additional mechanisms likely underlie increased LV chamber stiffness in this model, which may have relevance to the therapeutic impact of these interventions on diastolic function in HFpEF.