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

Abdominal aortic aneurysm (AAA) is a common, progressive, and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic patients with AAA. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of patients with AAA from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (∼30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and patients with AAA. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic smooth muscle cells (SMCs) but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth-inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rates in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.NEW & NOTEWORTHY AAA grows slower in patients affected by diabetes. This growth inhibition is lost when the enzyme lysyl oxidase (LOX) is blocked in diabetic mice. The predominant arterial isoform of LOX, LOX-like 2 (LOXL2), overlaps with type IV collagen in the outer media of murine aneurysm tissue. Circulating LOXL2 correlates inversely with AAA growth in patients. Type IV collagen cross-linking by LOXL2 may play a role in the AAA growth inhibition associated with diabetes.

The endothelin-B receptor (ET_BR) mediates vasodilation in young women, an effect that is absent in postmenopausal women. We have previously demonstrated that ET_BR-mediated vasodilation is regulated by estradiol (E₂) in young women; however, the impact of E₂ on ET_BR function in postmenopausal women remains unknown. Accordingly, the objective of this study was to test the hypothesis that E₂ exposure restores ET_BR-mediated dilation in postmenopausal women. Ten healthy postmenopausal women (55 ± 2 yr of age, 5 ± 3 years since menopause) completed the study. E₂ was administered by transdermal patch for 7 days (0.1 mg/day, Vivelle-Dot patch). Vasodilation in the cutaneous microcirculation (microvascular endothelial function) was measured via local heating (42°C) using laser Doppler flowmetry combined with intradermal microdialysis perfusions of lactated Ringer's (control) and ET_BR antagonist (BQ-788, 300 nM) at baseline and after E₂ administration. There was no effect of E₂ on ET_BR function [hormone × site, F(1,9) = 0.77, P = 0.40]. These data demonstrate that in contrast to findings in premenopausal women, E₂ administration does not restore ET_BR function in postmenopausal women.NEW & NOTEWORTHY The vascular endothelial endothelin-B receptor (ET_BR) mediates vasodilation in premenopausal women, an effect modulated by estradiol. ET_BR-mediated vasodilation is lost in postmenopausal women, but the effect of exogenous estradiol administration on ET_BR function in postmenopausal women is not known. During estradiol administration, ET_BR blockade did not affect cutaneous microvascular vasodilatory response to local heating. We demonstrate that exogenous estradiol administration does not restore ET_BR-mediated vasodilation in postmenopausal women.

Lower body negative pressure (LBNP) has been used for decades in humans to model arterial baroreceptor unloading and represents a powerful tool for evaluating cardiovascular responses to orthostatic challenges. However, LBNP studies in animals have been limited to conditions of anesthesia or sedation, where cardiovascular reflexes are altered. Given the consequent uncertainties, the usefulness of LBNP studies in these preclinical models has been severely hampered. Here, we developed an approach using a novel system to study LBNP responses in awake rats instrumented for telemetric blood pressure (BP) measurement. BP responses to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by measurements under various treatments. In awake untreated rats, BP was well maintained up to -15 mmHg LBNP and there was a robust baroreceptor response in heart rate (HR). Under anesthesia with 3% isoflurane, BP was not maintained at LBNP below -3 mmHg and baroreceptor responses in HR were completely blocked, confirming the limited usefulness of this method under anesthesia. Interrogation of the autonomic pathways involved in the response revealed that muscarinic (atropine) and β₁-adrenergic (atenolol) blockade, separately or together, blocked the HR responses, but BP remained well maintained. α₁-adrenergic blockade (prazosin) severely blunted the ability to maintain BP in response to LBNP. These data are consistent with findings in human subjects in that the vascular component of the orthostatic reflex predominates in preserving BP. Validation of this novel method provides a valuable tool for investigating orthostatic (in)tolerance in a facile preclinical model.NEW & NOTEWORTHY Orthostatic hypotension or intolerance is a common but often underappreciated disorder that is associated with a variety of neurological comorbidities. LBNP studies provide a valuable tool to study these conditions, but heretofore could only be used in human subjects, since animal subjects needed to be anesthetized or sedated, which blunts or eliminates neurocardiovascular reflexes. This novel method allowing LBNP studies in awake rats will provide a valuable preclinical model for studying these disorders.

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3^OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3^FL) and LPP3^OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 wk, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3^OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared with LPP3^FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3^OE mice were protected from increased plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared with LPP3^FL mice. Female LPP3^OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.NEW & NOTEWORTHY Lipid phosphate phosphatase 3 (LPP3) hydrolyzes bioactive lipids including lysophosphatidic acid (LPA), elevated levels of which are implicated in obesity-induced metabolic and cardiac dysfunction. We show that cardiac-specific overexpression of LPP3 lowers plasma LPA levels, blunts LPA signaling in cardiomyocytes, and increases pyruvate-linked mitochondrial respiration in the heart at baseline in both male and female mice. In female mice, LPP3 overexpression also protects from high-fat diet-induced obesity, insulin resistance, and cardiac dysfunction.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for the treatment of type 2 diabetes but have recently been approved for chronic weight management and reducing cardiovascular risk in individuals with overweight and obesity. Despite this approval, significant heterogeneity in the cardioprotective benefits and less desirable increases in resting heart rate (RHR) with GLP-1 RAs have been reported. To better understand cardiovascular responses to GLP-1 RAs and the potential role of health behaviors in influencing these responses, we leveraged wearable technology and causal inference analysis. We tracked RHR, heart rate variability (HRV), physical activity, and sleep in 66 individuals (42 ± 9 yr, body mass index: 30.0 ± 7 kg/m²) from the week before to 12 wk following the initiation of GLP-1 RA medication. Propensity score matching on a larger sample of wearable users identified a control group with similar anthropometric and cardiovascular characteristics (Ps > 0.26). After the 12-wk study period, GLP-1 users showed significant (Ps < 0.05) weight loss (-10.0%, 95% CI: -11.2% to -8.5%) and changes in RHR (3.2 ± 0.8 beats/min) that were mediated (P < 0.01) by changes in HRV (-6.2 ± 1.4 ms) compared with control. Trends (Ps < 0.10) suggested that increases in weekly physical activity were associated with GLP-1 RA medication (31.5 ± 13.2 min) and that higher physical activity levels accompanied an attenuation of RHR increases. Our real-world findings align with clinical trial data in showing rapid and significant weight loss with GLP-1 RAs, coinciding with increases in RHR that are mediated by changes in autonomic function (i.e., HRV). Physical activity may help to offset RHR increases, but further research is needed to confirm these effects.NEW & NOTEWORTHY These findings are among the first to provide daily insights into cardiovascular and behavioral responses following GLP-1 RA initiation. Substantial weight loss and significant increases in resting heart rate mediated by reductions in heart rate variability during the initial 12 wk of GLP-1 RA therapy were observed. In addition, trends suggest an increase in physical activity with GLP-1 therapy, and that physical activity may help to temper GLP-1 RA-associated increases in resting heart rate.

The promise of injection of extracellular matrix (ECM) from animal hearts as a treatment of myocardial ischemia has been limited by immune reactions and harsh ECM-damaging extraction procedures. We developed a novel method to produce lab-grown human three-dimensional (3-D) acellular ECM particles from human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM architecture. We hypothesized that intramyocardial injection (I/M) of this novel ECM (dia ∼ 200 microns) would improve cardiac function in a postmyocardial infarction (MI) murine model. WT mice aged 8-10 wk underwent ligation of the left anterior descending coronary (LAD) artery and I/M injection of 10 μL ECM or normal saline (n = 10/group). Compared with control, ECM-treated hearts showed significant reduction in infarct size (P = 0.04), increased capillary density in ischemic myocardium (P = 0.01), and increased fractional shortening (FS) (P < 0.05) on postoperative days (POD) 14, 21, and 28 by echocardiography. There were no significant differences in immunogenic response as determined by TNFα, IL6, CD86, or CD163 levels (P > 0.05 for all) in the hearts. Biodistribution of fluorophore-conjugated ECM demonstrated localized epifluorescence in the heart after I/M injection, without significant peripheral end organ epifluorescence. Proteomic analysis of ischemic and perfused myocardium from control and ECM-treated hearts using LC-MS/MS (n = 3/group) detected significant changes in proteins involved in cardiomyocyte contractility and fatty acid metabolism. These findings suggest that 3-D ECM particles induce recovery of ischemic myocardium, by upregulating protein networks involved in cellular contractility and metabolism. Taken together, 3-D ECM particles represent a promising therapy for MI and warrant confirmatory studies in a high-fidelity large animal model.NEW & NOTEWORTHY Our novel lab-grown, human 3-D extracellular matrix (ECM) represents a novel therapeutic approach to prevent pathological remodeling and heart failure in an animal model of heart attack. This novel finding may help develop nonsurgical therapeutic modalities aimed at reducing the global burden of cardiovascular disease.

Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine (n = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, P = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, P = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, P < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, P = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, P = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, P = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.NEW & NOTEWORTHY Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.

An increasing number of procedures over the past two decades for aortic stenosis (AS) reflects the combination of an aging population and less invasive transcatheter options. As a result, the hemodynamics of the aortic valve (AV) have gained renewed interest to understand its behavior and to optimize patient selection. We studied the hemodynamic relationship between pressure loss (ΔP) and transvalvular flow (Q) of the normal AV as well as the impact of a variable supravalvular stenosis. Our mechanistic study included 11 healthy swine monitored during dobutamine stress and followed by acute aortic banding to simulate AS. Hemodynamics were continuously recorded, and transvalvular ΔP versus Q were analyzed using proportional and linear models. During dobutamine infusion, normal valves exhibited a highly linear relationship between ΔP and Q (median R² of 0.93). Progressive aortic banding eventually displayed a highly linear relationship between an increasing ΔP and the decreasing Q, characterized by a constant systemic circulatory resistance (median R² of 0.91). Consequently, a normal AV can be described by a single parameter: its resistance, median 0.37 Wood units (WU) in swine. During dobutamine stress and aortic banding, the systemic bed behaves like a constant and stable resistance, median of 11.9 WU in swine. These findings carry significant implications for quantifying normal and diseased AV behavior and potentially might improve patient selection and treatment outcomes.NEW & NOTEWORTHY This study demonstrates that the normal aortic valve functions like a resistor with a proportional pressure loss ΔP versus transvalvular flow Q relationship. During dobutamine stress and progressive aortic banding, a "load line" of constant resistance characterizes the systemic circulation. Consequently, during stress conditions, the relative pressure loss over a stenotic aortic valve (the stress aortic valve index, SAVI) quantifies the relative reduction in maximal flow. Potentially, SAVI might optimize patient selection for procedures to treat aortic stenosis.

Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency (ESAM^-/-) exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that ESAM^-/- mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized ESAM^-/- mice and employed isolated, ventilated, and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in ESAM^-/- mice compared with WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in ESAM^-/- mice, whereas SNP-induced responses were similar in wild-type (WT) and ESAM^-/- mice. Inhibition of NO synthase with N(ω)-nitro-l-arginine methyl ester increased agonist-induced PVR in WT but not in ESAM^-/- mice. Pulmonary arteries isolated from ESAM^-/- mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, and NO-mediated maintenance of PVR in mice.NEW & NOTEWORTHY Our study reveals a novel role for ESAM in contributing to the maintenance of pulmonary vascular resistance under normal physiological conditions. Employing mice with global genetic deficiency of ESAM and using isolated whole lung preparation, we show significant impairments in nitric oxide-mediated pulmonary artery function. In vitro cell culture studies demonstrate impaired fluid shear stress-induced cell alignment in human lung endothelial cells after siRNA-mediated ESAM knockdown.