Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF.

Background: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.

Methods: Eight-week-old male and female C57BL/6J mice received either N-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks.

Myeloid Cell Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction.

Background: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.

Methods: Eight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks.

Biomarker-specific differences between transpulmonary and peripheral arterial-venous blood sampling in patients with pulmonary hypertension.

: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial-venous ratio (PR) could substitute for the transpulmonary ratio (TPR). Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH ( = 18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH;  = 7) and isolated post-capillary PH (Ipc-PH;  = 9).

Combination therapy improves vascular volume in female rats with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model.

Adverse physiologic effects of Western diet on right ventricular structure and function: role of lipid accumulation and metabolic therapy.

Little is known about the impact of metabolic syndrome (MS) on right ventricular (RV) structure and function. We hypothesized that mice fed a Western diet (WD) would develop RV lipid accumulation and impaired RV function, which would be ameliorated with metformin. Male C57/Bl6 mice were fed a WD or standard rodent diet (SD) for eight weeks.

Inhibition of the -Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.

Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac late sodium current (I). Previous studies in mice implicate the PI3K- isoform in arrhythmia susceptibility. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on I and action potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO).

Low dose monocrotaline causes a selective pulmonary vascular lesion in male and female pneumonectomized rats.

Unlabelled: Purpose/Aim: Low doses (30-80 mg/kg) of monocrotaline are commonly used to create experimental models of pulmonary hypertension in rats. At these doses, monocrotaline causes pulmonary endothelial apoptosis and acute lung injury which ultimately results in pulmonary vascular disease. Higher doses of monocrotaline (300 mg/kg) are known to create severe liver injury, but previous investigations with lower doses have not reported histology in other organs to determine whether the vascular injury with monocrotaline is pulmonary-selective or generalized.

The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension.

Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH). Mechanisms underlying PH-LHD are incompletely understood, particularly for individuals with preserved left ventricular ejection fraction (LVEF). We hypothesized that transpulmonary concentrations of biomarkers representing signaling pathways with known effects on the pulmonary circulation could provide insight into the molecular etiology of PH-LHD in patients with preserved LVEF.

Endothelin-1 induces pulmonary but not aortic smooth muscle cell migration by activating ERK1/2 MAP kinase.

Endothelin 1 (ET-1) is an endogenous peptide that promotes vasoconstriction, endothelial and smooth muscle cell (SMC) proliferation, and fibrosis. ET-1 receptor antagonists are an important treatment strategy for pulmonary arterial hypertension, but less effective in systemic vascular disease. This observation suggests a special role for ET-1 in the pulmonary circulation.

Effects of adenosine and a selective A2A adenosine receptor agonist on hemodynamic and thallium-201 and technetium-99m-sestaMIBI biodistribution and kinetics.

Objectives: The purpose of this study was to compare a selective A(2A) adenosine receptor agonist (regadenoson) with adenosine in clinically relevant canine models with regard to effects on hemodynamics and thallium-201 ((201)Tl) and technetium-99m ((99m)Tc)-sestaMIBI biodistribution and kinetics.

Background: The clinical application of vasodilator stress for perfusion imaging requires consideration of the effects of these vasodilating agents on systemic hemodynamics, coronary flow, and radiotracer uptake and clearance kinetics.

Methods: Sequential imaging and arterial blood sampling was performed on control, anesthetized closed-chest canines (n = 7) to evaluate radiotracer biodistribution and kinetics after either a bolus administration of regadenoson (2.

Thrombin induces fibronectin-specific migration of pulmonary microvascular endothelial cells: requirement of calcium/calmodulin-dependent protein kinase II.

Pulmonary arterial hypertension (PAH) is a progressive disease of excess vasoconstriction and vascular cell proliferation that results in increased pulmonary vascular resistance and right heart failure. We have previously shown (66) that tissue factor expression is increased in the abnormal vessels of patients and rats with PAH. We hypothesized that tissue factor and its downstream mediator, thrombin, would promote migration of endothelial cells (EC) and the vascular pathology of PAH.

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction.

The alphavbeta3-integrin is expressed in angiogenic vessels in response to hypoxia and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of noninvasively tracking hypoxia-induced alphavbeta3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies.

Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension.

Severe pulmonary arterial hypertension (PAH) occurs in idiopathic form and in association with diverse diseases. The pathological hallmarks are distal smooth muscle hypertrophy, obliteration of small pulmonary arteriole lumens, and disorganized cellular proliferation in plexiform lesions. In situ thrombosis is also observed.

Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells.

Reactive oxygen species (ROS) contribute to the pathogenesis of atherosclerosis in part by promoting vascular smooth muscle cell (VSMC) growth. Previously we demonstrated that cyclophilin A (CyPA) is a secreted oxidative stress-induced factor (SOXF) that promotes inflammation, VSMC growth, and endothelial cell apoptosis. However, the mechanisms that regulate CyPA secretion are unknown.

Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction.

Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction.