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

Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF cases, yet evidence-based therapies remain lacking due to limited understanding of its underlying pathological mechanisms. Our study aimed to uncover early pathological mechanisms in HFpEF by exposing mice to dietary conditions resembling a Western diet-rich in fats, salt, and low in fiber-alongside excess mineralocorticoids to replicate significant aspects of human HFpEF. Echocardiography was performed at both 3-week and 6-week intervals post-challenge, revealing cardiac alterations as early as 3-weeks. While ejection fraction remained preserved, mice exhibited signs of diastolic dysfunction, reduced stroke volume, and left atrial enlargement. Additionally, changes in pulmonary flow velocities were noted by the 3-week mark, suggesting elevated pulmonary pressure. Extracardiac comorbidities included organ congestion, increased adiposity, impaired glucose tolerance, and hypercholesterolemia. Molecular analyses unveiled evidence of low-grade inflammation, oxidative stress, and impaired NO-cGMP-PKG signaling, contributing to the observed decrease in titin phosphorylation, thereby impacting myocardial stiffness. Additionally, impaired NO signaling might have influenced the alterations observed in coronary flow reserve. Moreover, dysregulation of calcium signaling in cardiomyocytes and reduced SR load were observed. Interestingly, elevated phosphorylation of cMyBP-C was linked to preserved ejection fraction despite reduced SR load. We also observed intestinal atrophy, possibly due to low dietary fiber intake and diminished gut perfusion, potentially contributing to systemic low-grade inflammation. These findings reveal how excess mineralocorticoids-salt-induced hypertension, and dietary factors, like high-fat and low-fiber intake, contribute to cardiac dysfunction and metabolic disturbances, offering insights into early HFpEF pathology in this model.

Systemic inflammation is reported in normal-weight obesity (NWO) and metabolically healthy obesity (MHO), which may be linked to their increased cardiovascular disease (CVD) risk. Yet, drivers of this inflammation remain unclear. We characterized factors known to influence inflammatory status (i.e., intestinal permeability, adipose tissue, diet quality, microbiota), and their relationships with measured inflammation, in NWO and MHO, healthy control subjects (CON), and metabolically unhealthy obesity (MUO; N = 80; n = 20/group). Serum indicators of intestinal permeability and inflammation were assessed by ELISA and/or multiplex. Total, visceral, and percent body fat were measured with dual-energy X-ray absorptiometry (DXA). Fecal microbiota composition was assessed via 16S rRNA sequencing (n = 9-10/group). For C-reactive protein (CRP), MUO > NWO > CON (P < 0.0001). In MHO, CRP was intermediate and similar to both MUO and NWO. Lipopolysaccharide binding protein (LBP) and the ratio of LBP to soluble CD14 (sCD14) were higher in MHO and MUO vs. CON/NWO (P < 0.0001). Across correlation and regression analyses, LBP consistently displayed the strongest relationships with CRP in the entire sample (r = 0.78; β = 0.57; P < 0.0001) and in MHO (r = 0.74; P < 0.01) but not NWO (r = 0.37; P = 0.11). Shannon index was higher in CON compared with MUO (P < 0.05) and inversely correlated with CRP in the full sample (r = -0.37; P < 0.05). These data are consistent with the notion that intestinal permeability is associated with low-grade inflammation in MHO, which could be implicated in this population's reported CVD risk.NEW & NOTEWORTHY This is the first study to our knowledge to examine biomarkers of intestinal permeability in normal-weight obesity and one of few assessing microbiota compositions in this population. Additionally, we report that individuals with metabolically healthy obesity and metabolically unhealthy obesity displayed similar evidence of intestinal permeability, which was more strongly associated with systemic inflammation than total and visceral adipose tissue mass.

Mitochondrial dysfunction contributes significantly to the development of atrial fibrillation (AF). Conflicting data regarding the atrial pacing and the risk of AF existed, and the impact of atrial pacing on mitochondrial function remains unknown. Therefore, we sought to examine the association between atrial pacing percentage and mitochondrial function in patients with cardiovascular implantable electronic devices (CIEDs) with atrial pacing capability. This is a cross-sectional study involving 183 patients with CIEDs with atrial pacing capability. The oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Among 183 patients, 55.7% had permanent pacemakers, 7.7% had defibrillators, and 36.6% had cardiac resynchronization therapy. Mean age was 67.5 ± 14.7 yr with 51% being male. Mean left ventricular ejection fraction (LVEF) was 53.9 ± 16.8%. We demonstrated that the presence of atrial pacing above 50% correlated with higher levels of mitochondrial spared respiratory capacity (P = 0.043) and coupling efficiency (P = 0.045). After adjusting with multiple linear regression for age, sex, LVEF, history of AF, sick sinus syndrome, comorbidities, estimated glomerular filtration rate (eGFR), cardiac resynchronization therapy (CRT), and percentage of ventricular pacing, our findings revealed a statistically significant association between a higher percentage of atrial pacing and increased spared respiratory capacity (β, 0.217, P = 0.046), lower nonmitochondrial respiration (β, -0.230; P = 0.023), and proton leak (β, -0.247; P = 0.022). We demonstrated that atrial pacing enhances mitochondrial performance in PBMCs and left ventricular contractile performance in patients with CIEDs. This observation may serve as an additional support for the preventive effect of atrial pacing in the prevention of atrial arrhythmia.NEW & NOTEWORTHY Atrial pacing enhances mitochondrial spare respiratory capacity and reduces proton leak. This finding may provide further evidence supporting the preventive role of atrial pacing in reducing the risk of atrial fibrillation in patients with cardiac implantable electronic devices.

Rheumatoid arthritis (RA) is characterized by deteriorated vascular health and increased cardiovascular risk. Physical activity (PA) is recommended for cardiovascular management in RA, but evidence on the associations between objectively-measured PA and vascular health markers in RA is limited. In this cross-sectional study, eighty-two post-menopausal women with RA (62±7 years) undertook ultrasound assessments of vascular function and structure, including brachial and superficial femoral artery (BA and SFA) flow-mediated dilation; baseline and post-hyperemia peak diameters; and carotid intima-media thickness. Participants also performed a 7-day accelerometer-based assessment of PA and sedentary behavior (SB). Fitted regression models controlled for age, body mass index and disease activity were conducted to examine associations between vascular and PA outcomes. Regression analyses revealed that prolonged SB (bouts>60min) and total sedentary time were inversely associated with both baseline and peak BA diameters, with each additional hour of SB resulting in decreases of 0.08-0.1mm in these diameters (p≤0.01). Total sedentary time also showed similar negative associations with peak SFA diameters (β=-0.14[-0.24-0.05], p<0.01). Conversely, light-intensity PA and stepping time were positively associated with both baseline and peak BA diameters, with each additional hour increasing these diameters by 0.10-0.24mm (p≤0.02). Finally, standing time was positively associated with SFA peak diameter (β=0.11[0.01-0.20], p=0.02). No associations were found between moderate-to-vigorous PA and vascular outcomes. In conclusion, in patients with RA, SB was negatively, while light PA was positively, associated with BA and SFA diameters. These findings suggest that reducing SB and increasing PA, even at light intensities, may improve vascular health in RA.

The accuracy of femoral artery blood flow measurements via Doppler ultrasound hinges on assumptions of laminar flow upstream of the femoral bifurcation. Existing scanning guidelines recommend a minimum proximity of 2-3cm distal to the flow divider for avoiding multi-directional blood flow yet lack experimental evidence to support this recommendation. This study aimed to determine the minimum distance required to avoid multi-directional flow contamination near the femoral bifurcation and to assess the reliability of vector flow imaging (VFI) in these measurements. Twenty healthy adults (10 females, 25±4yrs) participated in this study. Ultrasound VFI was employed to visualize blood flow patterns, quantify flow uniformity via vector concentration coefficient (VCC), and multi-directional flow length was quantified at rest in triplicate (n=20), post-isometric contraction (n=20), and during thigh cuffing (n=10). At rest, the mean multi-directional flow length was 3.12±0.59cm, which decreased to 2.80±0.66cm post-contraction (P=0.02). Thigh cuffing (80mmHg) resulted in a multi-directional flow length of 2.75±0.64cm, not significantly different from rest (P=0.69). Males exhibited a shorter multi-directional flow length compared to females (mean difference: 0.31±0.71cm, P=0.05). The VCC increased from 0.39±0.08 at rest to 0.57±0.15 post-contraction (P<0.01), indicating increased flow uniformity. Reliability metrics demonstrated good-to-excellent reproducibility at rest, with ICC(3,1)=0.85 and 0.84 and CV%=7.1±6.2% and 7.5±4.5% for multi-directional flow length and VCC, respectively. Our data suggest a minimum scanning proximity of 3.5cm to the femoral bifurcation to ensure blood flow assessments are free of multi-directional flow, and invite further study in different body positions and arteries of interest to increase rigour in this area.