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

Dilated cardiomyopathy (DCM), characterized by left ventricular dilation and systolic dysfunction, remains a major cause of heart failure, necessitating improved diagnostic strategies. Conventional imaging techniques such as echocardiography and MRI, along with classical cardiovascular markers like NT-proBNP and cTnT, demonstrate limited sensitivity for DCM-specific phenotypes. Given the critical role of lipids and proteins in cardiac physiology, their alteration may provide disease-specific diagnostic insights. To address the scarcity of comprehensive lipidomic studies and validated protein biomarkers in DCM, we used a high-resolution mass spectrometry-based integrative omics approach coupled with machine learning. Plasma samples from 360 participants, including patients with DCM and controls, were analyzed to identify specific proteolipidomic alterations. We detected 125 significantly altered lipids (0.8 ≥ FC ≥ 1.2; P_adj < 0.05) and 10 proteins, of which 39 lipids and 10 proteins were identified as primary discriminators using a Boruta-based ML approach. ELISA validation confirmed β2-microglobulin [β2micoglobulin (B2M); 6.85 ± 2.86 μg/mL vs. 4.26 ± 1.25 μg/mL; P < 0.0001] and tetranectin (CLEC3B; 1.99 ± 0.88 μg/mL vs. 2.49 ± 0.90 μg/mL; P = 0.0006) as significant protein biomarkers. Single-cell transcriptomic data from DCM myocardium supported these trends, showing cell type-specific alterations in B2M and CLEC3B expression. CLEC3B was positively correlated with phosphatidic acid (PA) (18:1/20:1), whereas oxidative stress marker 8-OHdG was markedly elevated in DCM plasma. Integrative receiver operating characteristic (ROC) analysis combining top lipid discriminators with B2M and CLEC3B achieved an area under the curve (AUC) of 0.99, surpassing NT-proBNP (0.96). Overall, this study delineates the first comprehensive proteolipidomic signature of DCM and proposes a robust multiparametric biomarker panel with enhanced diagnostic precision.NEW & NOTEWORTHY First study of global proteolipidomic changes in dilated cardiomyopathy (DCM). A machine-learning-guided biomarker pipeline identified 39 lipids and 10 proteins distinguishing DCM. We propose that PE (14:0/22:4), phosphatidic acid (PA) (18:1/20:1), and tetranectin (CLEC3B) may link oxidative stress, apoptosis, and ECM remodeling in DCM. A panel combining the top 8 lipid markers along with β2micoglobulin (B2M) and CLEC3B achieved an area under the curve (AUC) of 0.99, outperforming NT-proBNP and offering superior diagnostic accuracy.

Arterial pulse wave velocity (PWV), defined as the speed at which a blood pressure pulse propagates along the arterial tree, is the gold standard for assessment of arterial stiffness and can serve as an independent predictor of cardiovascular events, such as myocardial infarction, stroke, and heart failure. However, recent animal data suggest that pulse wave velocity measurements may not only assess arterial stiffness but also highly dynamic changes in local homeostasis and the delicate artery whole body interplay. This narrative review summarizes the major contributing factors to changes in pulse wave velocity and proposes novel classification into these factors as being either intrinsic or extrinsic to the vasculature. Intrinsic factors known to modulate pulse wave velocity include the elastin, collagen and calcium content of the arterial wall, smooth muscle tone, and endothelial cell function. In contrast, extrinsic factors include variables such as sex, and others that can fluctuate such as blood pressure, heart rate, metabolic health, and age. We highlight how increases in pulse wave velocity may be variable and oversimplified depictions of aortic stiffness and suggest that they are holistic measurements of vascular hemodynamic stress that also include the cumulative impact of mechanical forces, biochemical alterations, and structural and/or functional changes to the vasculature.

The capacity of the endothelium to release tissue-type plasminogen activator (t-PA) is markedly impaired in adults with obesity, underlying their increased thrombotic risk. Circulating endothelial cell-derived microvesicles (EMVs) are systemic modulators of vascular health and disease, and are elevated with obesity. The experimental aim of this study was to determine whether circulating EMVs are associated with obesity-related endothelial fibrinolytic dysfunction. Twenty-eight sedentary, midlife and older adults (45-71 yr) were studied: 14 normal-weight (7 M/7 F; age: 55 ± 4 yr; body mass index: 23.1 ± 1.6 kg/m²) adults and 14 adults with obesity (7 M/7 F; 57 ± 8 yr; 31.9 ± 2.9 kg/m²). EMV identification (CD144⁺) and concentration in peripheral blood were determined by flow cytometry. Endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2.0-8.0 µg/min). Circulating EMV levels were ∼170% higher (P < 0.001) in adults with obesity (183 ± 58 EMV/µL) compared with normal-weight (68 ± 12 EMV/µL) adults. Endothelial t-PA release in response to BK was significantly lower (∼30%) in the adults with obesity (from 0.7 ± 3.6 to 35.9 ± 15.1 ng/100 mL tissue/min) versus normal-weight adults (-0.5 ± 2.3 to 68.4 ± 21.1 ng/100 mL tissue/min). Consequently, total t-PA release (area under the BK curve) was lower (∼35%; P = 0.007) in the adults with obesity (205 ± 118 ng/100 mL tissue vs. 325 ± 97 ng/100 mL tissue). Circulating EMVs were significantly and inversely associated with both peak t-PA release (r = -0.67; P = 0.0001) and total t-PA release to BK (r = -0.53; P = 0.004). In summary, obesity-related increase in circulating EMVs is associated with diminished endothelial t-PA release. Circulating EMVs may serve as a biomarker of fibrinolytic dysfunction in adults with obesity.NEW & NOTEWORTHY Obesity is associated with profound impairment in the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA), the primary mechanism underlying endogenous thrombolysis. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. This study demonstrates that circulating EMVs are elevated in adults with obesity and are associated with reduced endothelial t-PA release. Circulating EMVs represent a novel systemic biomarker of obesity-related endothelial fibrinolytic dysfunction and, in turn, thrombotic risk.

Sigma receptor agonists are suspected to modulate blood pressure in humans. We investigated how modulation of sigma receptors impacts phenylephrine (PE)-induced contraction in human mesenteric arterial rings obtained from human organ donors. This study also explored the relationship between sigma receptor activation, PE-induced arterial contraction, and the history of the organ donor's alcohol use. The concentration responsiveness of PE-induced arterial contraction was tested using wire myography in the absence and presence of the sigma receptor agonist PRE-084, and the sigma receptor antagonists BD-1047 and SM-21. Sigma receptor-1 expression in the arteries was also investigated using an automated capillary electrophoresis system. The results show that PRE-084 elicited a downward shift in the PE concentration-response curve. Notably, this trend only occurred in arteries from donors with histories of non-/light drinking or moderate drinking (P < 0.05) but not with arteries obtained from donors with histories of heavy or binge drinking. The sigma receptor-1 antagonist BD-1047 elicited an upward shift in the PE concentration-response curve in arteries from non-/light and moderate drinkers but not from heavy drinkers. Interestingly, the sigma receptor-2 antagonist caused an upward shift in the PE concentration-response curve in arteries from all three groups of donors. Notably, sigma receptor-1 protein levels were decreased in arteries from heavy drinkers compared with the other groups. Collectively, the findings suggest that sigma receptors in human arteries may promote relaxation. However, heavy alcohol consumption reduces arterial sigma receptor-1 expression and impairs its ability to modulate contraction.NEW & NOTEWORTHY Activation or inhibition of sigma receptor-1 was found to modulate phenylephrine-induced contraction of isolated mesenteric arteries from human organ donors. However, this effect was impaired in arteries from donors who were heavy alcohol consumers, because the arteries from these individuals had relatively low protein expression of sigma receptor-1. These findings reveal a potential new role of sigma receptor-1 in the control of arterial tone in humans that is modulated by alcohol use.

Obesity in pregnant women increases offspring cardiovascular risk and causes fetal cardiac dysfunction. The underpinning mechanisms remain unclear. We hypothesized that circulating factors in serum from fetuses of women with obesity induce pathological cardiomyocyte hypertrophy. Pregnant women with obesity or healthy weight were recruited at term and provided umbilical cord serum and placentas, which were used for isolation of primary trophoblast cells. Primary cardiomyocytes were isolated from neonatal rats. Compared with cord serum from healthy weight women, cord serum from women with obesity upregulated cardiomyocyte mRNA expression of atrial natriuretic factor (Anf) and brain natriuretic peptide (Bnp) and increased the ratio of β-to α-myosin heavy chain expression (Myh7:Myh6), when it was supplemented into the culture medium. This effect was prevented by treating the cord serum with heat-freeze cycling and DNase or RNase digestion. Separately, conditioned medium from trophoblast cells from women with obesity increased cardiomyocyte Anf expression without altering Bnp or Myh7:Myh6. MicroRNAs miR-142 and miR-17, which are associated with cardiac function, were increased in abundance in extracellular vesicles isolated from cord serum from women with obesity. However, miR-142-3p, miR-142-5p, and miR-17-5p did not increase Anf, Bnp, or Myh7:Myh6 expression when they were transfected into cardiomyocytes. Neither cord serum nor the upregulated microRNAs from women with obesity altered cardiomyocyte size. The results show that human fetal circulating and placenta-derived factors induce gene expression hallmarks of pathological hypertrophy in cardiomyocytes and may mediate cardiac dysfunction in children of women with obesity.NEW & NOTEWORTHY Obesity in pregnant women increases risk for heart problems in their children. This study treated heart cells growing in a dish with blood plasma from the umbilical cords of newborn babies. Plasma from babies of women with obesity activated genes linked to heart failure. This means we could design treatments targeting plasma molecules, like microRNAs, or the way the placenta releases them. This could improve children's heart health if the mother has obesity.

Fetal growth restriction (FGR) secondary to placental insufficiency often leads to morbidity and mortality in the perinatal period. Fetal adaptations such as "brain sparing" blood flow redistribution offer some protection, but predicting whether a fetus in this state will survive is challenging. The goal of this research was to identify vascular responses predictive of stillbirth or hypoxia based on serial Doppler ultrasound measurement in a mouse model of FGR. We performed serial Doppler ultrasound observations of fetal blood flow redistribution in a murine model of FGR, where prolongation of pregnancy was induced pharmacologically with progesterone in 56 CD-1 mice. Observations were made at E18.5 (physiologic term), E19.5 (term +1), and E20.5 (term +2). Flow velocity waveforms were obtained from the middle cerebral artery (MCA), ductus arteriosus (DA), main pulmonary artery (MPA), ductus venosus (DV), umbilical artery (UA), and umbilical vein (UV). Following euthanasia, pimonidazole immunohistochemistry quantified tissue hypoxia. Among 56 pregnancies, the strongest predictor of stillbirth was low DA peak systolic velocity at E19.5 (<217 mm/s, P = 0.021, R² = 0.52). Among survivors, cerebral hypoxia was predicted by elevated MCA peak systolic (>26.6 mm/s, P = 0.022, R² = 0.59) and end-diastolic velocity (>10.1 mm/s, P = 0.043, R² = 0.53, whereas high MPA flow (>0.73 mL/min, P = 0.029, R² = 0.51) predicted hepatic hypoxia. Overall, fetuses with a weaker pulmonary blood flow redistribution response were found to have worse outcomes, despite cerebral vasodilation. This minimally invasive murine model offers valuable insights into this pathophysiology of FGR-related stillbirth and highlights the prognostic potential of assessing fetal brain flow and pulmonary perfusion in tandem during sonographic surveillance of high-risk pregnancies.NEW & NOTEWORTHY Fetal growth restriction, often caused by placental disease, is an important cause of fetal injury and stillbirth. Understanding how the fetus adapts under these conditions is key to predicting survival. Here we report physiological adaptations in a mouse of model of fetal growth restriction that predict the risk of stillbirth.

The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy (OVX) surgeries were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.NEW & NOTEWORTHY Obesity induces hypertension in females through the leptin-aldosterone-mineralocorticoid axis; however, the origin of this sex-specific mechanism remains unknown. Utilizing obese female mice, ovariectomy did not significantly impair blood pressure (BP), vascular function, or aldosterone synthase, whereas leptin receptor blockade lowered BP and restored vascular reactivity. In human cells and tissues, sex hormones did not alter aldosterone synthase expression. These data indicate that sex hormones do not drive the sex difference in the mechanism of obesity-associated hypertension.