Pulmonary Vascular Function Research Articles

Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anemia

Exposure to high altitude worsens symptoms and crises in patients with sickle cell disease (SCD). However, it remains unclear if prolonged exposure to low barometric pressures exacerbates SCD etiologies or impairs quality of life. We tested the hypothesis that, relative to wild‐type (WT) mice, Berkley sickle cell mice (BERK‐SS) residing at sea level, mild (1609 m) and moderate (2438 m) altitude would have a higher rate of hemolysis, impaired cardiac function, and reduced exercise tolerance and that the level of altitude would worsen these decrements. Following 3 months of altitude exposure, right ventricular systolic pressures (RVSP) were measured (solid‐state transducer). In addition, the adaptive balance between pulmonary vascular endothelial nitric oxide synthase and endothelin was assessed in lung tissue to determine differences in pulmonary vascular adaptation and the speed/duration relationship (critical speed, CS) was used to evaluate treadmill exercise tolerance. At all altitudes, BERK‐SS mice had a significantly lower %Hct and higher total bilirubin and free hemoglobin concentration (P<0.05 for all). RVSPs in BERK‐SS were higher than WT at moderate altitude and when compared to BERK‐SS at sea level (P<0.05, for both). CS was significantly lower in BERK‐SS at mild and moderate altitude (P<0.05). BERK‐SS demonstrated exacerbated SCD complications and reduced exercise capacity associated with an increase in altitude. These results suggest that exposure to mild and moderate altitude enhances the progression of SCD in BERK‐SS mice compared to healthy WT cohorts and BERK‐SS mice at sea level and provides crucial information for the clinical counseling of SCD patients.Support or Funding InformationThis study was supported by the National Heart, Lung and Blood Institute Grants 1R01HL125642‐01A1 (Irwin DC), 1R01HL086680‐07 (Nozik‐Grayck E), 5P01HL014985‐38 (Stenmark KR), and T32‐HL007171 (Stenmark KR), Colorado Sickle Cell Treatment and Research Center (Hassell K and Nuss R).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Functional Capacity Improvement on Patent Ductus Arteriosus with Pulmonary Arterial Hypertension: A Case Report and Literature Review

Pulmonary artery hypertension (PAH) is a pathophysiological disorder involving a wide range of clinical conditions. This can be a condition of complications from heart disease and respiratory system. Pulmonary arterial hypertension is defined as an increase in mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest assessed by right heart catheterization. The cardiovascular rehabilitation program is a set of efforts to improve the underlying cause of cardiovascular disease such that it can maintain or restore the best conditions and secondary prevention. Cardiac rehabilitation and physical exercise programs have the benefit of improving pulmonary vascular endothelial function, physical activity capacity and quality of life parameters for PAH patients. A 6-minute walk test can be used to assess the functional capacity of PAH patients.

Effects of pharmacological inhibition of the hydrolase activity of soluble epoxide hydrolase in a murine model of pulmonary hypertension associated with cardiac insufficiency

We previously demonstrated that the inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory eicosanoids, displays protective effects against left ventricular dysfunction in a rat model of ischemic heart failure. However, its remains to be investigated the impact of sEH inhibition on pulmonary vascular and right heart dysfunctions that are known to aggravate the prognostic of left heart diseases. To study the impact of sEH inhibition on pulmonary vascular and right heart dysfunctions in left heart diseases. Ischemic heart failure was induced by definitive coronary artery ligation in Sprague–Dawley rats. Pulmonary vascular function (Mulvany), oedema (lung wet weight - dry weight), right ventricular function (cardiac MRI) and remodelling (right ventricular weight and fibrosis) were assessed in sham-operated rats and rats with HF treated or not by the sEH inhibitor TPPU (5 mg/L in drinking water) during 12 weeks. Rats with heart failure displayed a marked alteration in pulmonary smooth muscle constriction to norepinephrin and in pulmonary endothelial-dependent relaxation to acetylcholine, pulmonary edema, and an increase in right ventricular weight but not in fibrosis compared to sham-operated rats. TPPU did not modify these parameters in sham-operated rats but improved pulmonary relaxation to acetylcholine in rats with heart failure and reduced pulmonary edema without affecting right ventricular weight and fibrosis. Data obtained by cardiac MRI are currently being analysed. These preliminary results demonstrate that sEH inhibition improves pulmonary endothelial function in rats with heart failure, which could contribute to the beneficial effects of this new pharmacological class in the context of left heart diseases.

Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep

Chronic hypobaric hypoxia during fetal and neonatal life induces neonatal pulmonary hypertension. Hypoxia and oxidative stress are driving this condition, which implies an increase generation of reactive oxygen species (ROS) and/or decreased antioxidant capacity. Melatonin has antioxidant properties that decrease oxidative stress and improves pulmonary vascular function when administered postnatally. However, the effects of an antenatal treatment with melatonin in the neonatal pulmonary function and oxidative status are unknown. Therefore, we hypothesized that an antenatal therapy with melatonin improves the pulmonary arterial pressure and antioxidant status in high altitude pulmonary hypertensive neonates. Twelve ewes were bred at high altitude (3600 m); 6 of them were used as a control group (vehicle 1.4% ethanol) and 6 as a melatonin treated group (10 mg d-1 melatonin in vehicle). Treatments were given once daily during the last third of gestation (100–150 days). Lambs were born and raised with their mothers until 12 days old, and neonatal pulmonary arterial pressure and resistance, plasma antioxidant capacity and the lung oxidative status were determined. Furthermore, we measured the pulmonary expression and activity for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the oxidative stress markers 8-isoprostanes, 4HNE and nitrotyrosine. Finally, we assessed pulmonary pro-oxidant sources by the expression and function of NADPH oxidase, mitochondria and xanthine oxidase. Melatonin decreased the birth weight. However, melatonin enhanced the plasma antioxidant capacity and decreased the pulmonary antioxidant activity, associated with a diminished oxidative stress during postnatal life. Interestingly, melatonin also decreased ROS generation at the main pro-oxidant sources. Our findings suggest that antenatal administration of melatonin programs an enhanced antioxidant/pro-oxidant status, modulating ROS sources in the postnatal lung.

Analysis of pulmonary vascular injury and repair during Pseudomonas aeruginosa infection-induced pneumonia and acute respiratory distress syndrome.

Herein we describe lung vascular injury and repair using a rodent model of Pseudomonas aeruginosa pneumonia-induced acute respiratory distress syndrome (ARDS) during: 1) the exudative phase (48-hour survivors) and 2) the reparative/fibro-proliferative phase (1-week survivors). Pneumonia was induced by intratracheal instillation of P. aeruginosa strain PA103, and lung morphology and pulmonary vascular function were determined subsequently. Pulmonary vascular function was assessed in mechanically ventilated animals in vivo (air dead space, PaO2, and lung mechanics) and lung permeability was determined in isolated perfused lungs ex vivo (vascular filtration coefficient and extravascular lung water). At 48 hours post infection, histological analyses demonstrated capillary endothelial disruption, diffuse alveolar damage, perivascular cuffs, and neutrophil influx into lung parenchyma. Infected animals displayed clinical hallmarks of ARDS, including increased vascular permeability, increased dead space, impaired gas exchange, and decreased lung compliance. Overall, the animal infection model recapitulated the morphological and functional changes typically observed in lungs from patients during the exudative phase of ARDS. At 1 week post infection, there was lung histological and pulmonary vascular functional evidence of repair when compared with 48 hours post infection; however, some parameters were still impaired when compared with uninfected controls. Importantly, lungs displayed increased fibrosis and cellular hyperplasia reminiscent of lungs from patients during the fibro-proliferative phase of ARDS. Control, sham inoculated animals showed normal lung histology and function. These data represent the first comprehensive assessment of lung pathophysiology during the exudative and reparative/fibro-proliferative phases of P. aeruginosa pneumonia-induced ARDS, and position this pre-clinical model for use in interventional studies aimed at advancing clinical care.

Metabolism and Redox in Pulmonary Vascular Physiology and Pathophysiology.

Significance: This review considers how some systems controlling pulmonary vascular function are potentially regulated by redox processes to examine how and why conditions such as prolonged hypoxia, pathological mediators, and other factors promoting vascular remodeling contribute to the development of pulmonary hypertension (PH). Recent Advances and Critical Issues: Aspects of vascular remodeling induction mechanisms described are associated with shifts in glucose metabolism through the pentose phosphate pathway and increased cytosolic NADPH generation by glucose-6-phosphate dehydrogenase, increased glycolysis generation of cytosolic NADH and lactate, mitochondrial dysfunction associated with superoxide dismutase-2 depletion, changes in reactive oxygen species and iron metabolism, and redox signaling. Future Directions: The regulation and impact of hypoxia-inducible factor and the function of cGMP-dependent and redox regulation of protein kinase G are considered for their potential roles as key sensors and coordinators of redox and metabolic processes controlling the progression of vascular pathophysiology in PH, and how modulating aspects of metabolic and redox regulatory systems potentially function in beneficial therapeutic approaches.

Novel Role for PD-1:PD-L1 as Mediator of Pulmonary Vascular Endothelial Cell Functions in Pathogenesis of Indirect ARDS in Mice.

Deficiency of the co-inhibitory receptor, Programmed cell death receptor (PD)-1, provides a survival benefit in our murine shock/sepsis model for the development of indirect acute respiratory distress syndrome (iARDS). Further, of clinical significance, patients that develop ARDS express increased PD-1 on their blood leukocytes. While PD-1 expression and its regulatory role have been associated with mainly T-cell responses, the contribution of its primary ligand, PD-L1, broadly expressed on non-immune cells such as lung endothelial cells (ECs) as well as immune cells, is less well-understood. Here we show that a “priming insult” for iARDS, such as non-lethal hemorrhagic shock alone, produced a marked increase in lung EC PD-L1 as well as blood leukocyte PD-1 expression, and when combined with a subsequent “trigger event” (polymicrobial sepsis), not only induced marked iARDS but significant mortality. These sequelae were both attenuated in the absence of PD-L1. Interestingly, we found that gene deficiency of both PD-1 and PD-L1 improved EC barrier function, as measured by decreased bronchoalveolar lavage fluid protein (i.e., lung leak). However, PD-L1 deficiency, unlike PD-1, significantly decreased EC activation through the Angiopoietin/Tie2 pathway in our iARDS mice. Additionally, while PD-1 gene deficiency was associated with decreased neutrophil influx in our iARDS mice, EC monolayers derived from PD-L1 deficient mice showed increased expression of EC junction proteins in response to ex vivo TNF-α stimulation. Together, these data suggest that ligation of PD-1:PD-L1 may play a novel role(s) in the maintenance of pulmonary EC barrier regulation, beyond that of the classic regulation of the leukocyte tolerogenic immune response, which may account for its pathogenic actions in iARDS.

Right Ventricular and Pulmonary Vascular Function are Influenced by Age and Volume Expansion in Healthy Humans

Patients with heart failure (HF) often show signs of right ventricular (RV) dysfunction. The RV function of coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]/pulmonary arterial systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, but less is known about which factors influence this prognostic marker, and whether those factors can be modified. We sought to obtain normative values and discern the individual effects of age, sex, and fluid overload on RV function. Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest after a rapid saline solution infusion (10 mL/kg, 150 mL/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE/PASP and relevant variables. In healthy persons of all ages, the median (5th-95th percentiles) normative TASPE-PASP ratio was 1.25 (0.81-1.78) mm/mm Hg. The correlation between progressive age and declining TAPSE/PASP was significant (r = -0.35; P = .006). Sex did not influence TAPSE/PASP (P = .30). Rapid fluid expansion increased central venous pressure from 5 ± 2 mm Hg to 11 ± 4 mm Hg after fluid infusion (P < .0001). This resulted in a 32% decrease in the TAPSE-PASP ratio after fluid infusion, compared to baseline (P < .0001). The TAPSE-PASP ratio was affected by age, but not sex. TAPSE/PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status also dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients.

Right ventricular dysfunction and remodeling in diabetic cardiomyopathy.

The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health worldwide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, although the RV has a unique cellular origin and composition and unique biomechanical properties and is coupled to the lower-impedance pulmonary vascular bed. In this review, we discuss potential mechanisms responsible for RV dysfunction in DCM and review the imaging approaches useful for early detection, protection, and intervention strategies. Additional data are required from animal models and clinical trials to better identify the onset and features of altered RV and pulmonary vascular structure and function during the onset and progression of DCM and to determine the efficacy of early detection and treatment of RV dysfunction on clinical symptoms and outcomes.

Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease.

Neonatal pulmonary vascular disease (PVD) is increasingly recognized as a disease that complicates the cardiopulmonary adaptations after birth and predisposes to long‐term cardiopulmonary disease. There is growing evidence that PVD is associated with disruptions in the nitric oxide (NO)‐cGMP‐phosphodiesterase 5 (PDE5) pathway. Examination of the functionality of different parts of this pathway is required for better understanding of the pathogenesis of neonatal PVD. For this purpose, the role of the NO‐cGMP‐PDE5 pathway in regulation of pulmonary vascular function was investigated in vivo, both at rest and during exercise, and in isolated pulmonary small arteries in vitro, in a neonatal swine model with hypoxia‐induced PVD. Endothelium‐dependent vasodilatation was impaired in piglets with hypoxia‐induced PVD both in vivo at rest and in vitro. Moreover, the responsiveness to the NO‐donor SNP was reduced in hypoxia‐exposed piglets in vivo, while the relaxation to SNP and 8‐bromo‐cyclicGMP in vitro were unaltered. Finally, PDE5 inhibition‐induced pulmonary vasodilatation was impaired in hypoxia‐exposed piglets both in vitro and in vivo at rest. During exercise, however, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in hypoxia‐exposed as compared to normoxia‐exposed piglets. In conclusion, the impaired endothelium‐dependent vasodilatation in piglets with hypoxia‐induced PVD was accompanied by reduced responsiveness to NO, potentially caused by altered sensitivity and/or activity of soluble guanylyl cyclase (sGC), resulting in an impaired cGMP production. Our findings in a newborn animal model for neonatal PVD suggests that sGC stimulators/activators may be a novel treatment strategy to alleviate neonatal PVD.

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3−/− mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

Venous congestion and pulmonary vascular function in Fontan circulation: Implications for prognosis and treatment

BackgroundElevation in central venous pressure (CVP) plays a fundamental pathophysiologic role in Fontan circulation. Because there is no sub-pulmonary ventricle in this system, CVP also provides the driving force for pulmonary blood flow. We hypothesized that this would make Fontan patients more susceptible to even low-level elevation in pulmonary vascular resistance index (PVRI), resulting in greater systemic venous congestion and adverse outcomes. MethodsAdult Fontan patients and controls without congenital heart disease undergoing clinical evaluation that included cardiac catheterization and echocardiography were examined retrospectively. Outcomes including all-cause mortality and the development of Fontan associated diseases (FAD, defined as protein losing enteropathy, cirrhosis, heart failure hospitalization, arrhythmia, or thromboembolism) were assessed from longitudinal assessment. ResultsAs compared to controls (n = 82), Fontan patients (n = 164) were younger (36 vs 45 years, p < 0.001), more likely to be on anticoagulation or antiplatelet therapy, and more likely to have atrial arrhythmia or cirrhosis. There was a strong correlation between CVP and PVRI in the Fontan group (r = 0.79, p < 0.001), but there was no such relationship in controls. Elevated PVRI identified patients at increased risk for FAD (HR 1.92, 95% CI 1.39–2.41, p = 0.01), and composite endpoint of FAD and/or death (HR 1.89, 95% CI 1.32–2.53, p = 0.01) per 1 WU∗m2 increment. ConclusionsSystemic venous congestion, which is the primary factor in the pathogenesis of FAD and death, is related to even low-level abnormalities in pulmonary vascular function. Multicenter studies are needed to determine whether interventions targeting pulmonary vascular structure and function can improve outcomes in the Fontan population.

Impaired Cardiac Reserve and Abnormal Vascular Load Limit Exercise Capacity in Chronic Thromboembolic Disease

ObjectivesThis study was a comprehensive evaluation of cardiopulmonary function in patients with chronic thromboembolic (pulmonary vascular) disease (CTED) during exercise. BackgroundExertional dyspnea is frequent following pulmonary embolism, but only a minority of patients eventually develops chronic thromboembolic pulmonary hypertension (CTEPH). Better understanding of the factors that limit exercise capacity in patients with persistent pulmonary artery obstruction could help to further define the entity of CTED. MethodsFifty-two subjects (13 healthy control subjects, 14 CTED patients, and 25 CTEPH patients) underwent cardiopulmonary exercise testing and exercise cardiac magnetic resonance with simultaneous invasive pressure registration. Pulmonary vascular function and right ventricular contractile reserve were assessed through combined invasive pressure measurements and magnetic resonance imaging volume measures. ResultsExercise capacity was reduced by 29% and 57% in patients with CTED and CTEPH respectively, compared with control subjects. Both CTED (3.48 [interquartile range: 2.24 to 4.36] mm Hg × l−1 × min−1) and CTEPH patients (8.85 [interquartile range: 7.18 to 10.4] mm Hg × l−1 × min−1) had abnormal total pulmonary vascular resistance. Right ventricular contractile reserve was reduced in CTED patients compared with control subjects (2.23 ± 0.55 vs. 3.72 ± 0.94), but was still higher than that in CTEPH patients (1.34 ± 0.24; p < 0.001). As opposed to patients with CTEPH in whom right ventricular ejection fraction declined with exercise, right ventricular ejection fraction still increased in patients with CTED, albeit to a lesser extent than in healthy control subjects (interaction p < 0.001), which illustrated the distinct patterns of ventricular−arterial coupling. ConclusionsCTED represents an intermediate clinical phenotype. Exercise imaging unmasks cardiovascular dysfunction not evident at rest and identifies hemodynamically significant disease that results from reduced contractile reserve or increased vascular load.

Pulmonary vascular dysfunction in metabolic syndrome

Metabolic syndrome is a critically important precursor to the onset of many diseases, such as cardiovascular disease, and cardiovascular disease is the leading cause of death worldwide. The primary risk factors of metabolic syndrome include hyperglycaemia, abdominal obesity, dyslipidaemia, and high blood pressure. It has been well documented that metabolic syndrome alters vascular endothelial and smooth muscle cell functions in the heart, brain, kidney and peripheral vessels. However, there is less information available regarding how metabolic syndrome can affect pulmonary vascular function and ultimately increase an individual's risk of developing various pulmonary vascular diseases, such as pulmonary hypertension. Here, we review in detail how metabolic syndrome affects pulmonary vascular function.

Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anaemia.

Sickle cell disease (SCD) results in cardiopulmonary dysfunction, which may be exacerbated by prolonged exposure to environmental hypoxia. It is currently unknown whether exposure to mild and moderate altitude exacerbates SCD associated cardiopulmonary and systemic complications. Three months of exposure to mild (1609m) and moderate (2438m) altitude increased rates of haemolysis and right ventricular systolic pressures in mice with SCD compared to healthy wild-type cohorts and SCD mice at sea level. The haemodynamic changes in SCD mice that had lived at mild and moderate altitude were accompanied by changes in the balance between pulmonary vascular endothelial nitric oxide synthase and endothelin receptor expression and impaired exercise tolerance. These data demonstrate that chronic altitude exposure exacerbates the complications associated with SCD and provides pertinent information for the clinical counselling of SCD patients. Exposure to high altitude worsens symptoms and crises in patients with sickle cell disease (SCD). However, it remains unclear whether prolonged exposure to low barometric pressures exacerbates SCD aetiologies or impairs quality of life. We tested the hypothesis that, relative to wild-type (WT) mice, Berkley sickle cell mice (BERK-SS) residing at sea level, mild (1609m) and moderate (2438m) altitude would have a higher rate of haemolysis, impaired cardiac function and reduced exercise tolerance, and that the level of altitude would worsen these decrements. Following 3months of altitude exposure, right ventricular systolic pressure was measured (solid-state transducer). In addition, the adaptive balance between pulmonary vascular endothelial nitric oxide synthase and endothelin was assessed in lung tissue to determine differences in pulmonary vascular adaptation and the speed/duration relationship (critical speed) was used to evaluate treadmill exercise tolerance. At all altitudes, BERK-SS mice had a significantly lower percentage haemocrit and higher total bilirubin and free haemoglobin concentration (P<0.05 for all). right ventricular systolic pressures in BERK-SS were higher than WT at moderate altitude and also compared to BERK-SS at sea level (P<0.05, for both). Critical speed was significantly lower in BERK-SS at mild and moderate altitude (P<0.05). BERK-SS demonstrated exacerbated SCD complications and reduced exercise capacity associated with an increase in altitude. These results suggest that exposure to mild and moderate altitude enhances the progression of SCD in BERK-SS mice compared to healthy WT cohorts and BERK-SS mice at sea level and provides crucial information for the clinical counselling of SCD patients.

The β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure with Preserved Ejection Fraction: A Randomized Controlled Trial

Background Heart failure with preserved ejection fraction (HFpEF) is associated with pulmonary vascular dysfunction, particularly during exercise. Pulmonary vasodilators may favorably reduce pulmonary artery (PA) tone in HFpEF, but this could theoretically worsen left atrial hypertension and pulmonary congestion. Objective To evaluate whether the inhaled β-adrenergic agonist albuterol would improve PA vascular function during exercise in HFpEF. Methods We performed a randomized double blind placebo controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in HFpEF using high fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance (PVR) during exercise. Results Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo, followed by repeat assessment of rest and exercise hemodynamics. Albuterol improved the primary endpoint of exercise PVR as compared to placebo (−0.6±0.5 vs +0.1±0.7 Wood units, p=0.003). As compared to placebo, albuterol enhanced PA compliance with exercise, improved cardiac output reserve and RV-PA coupling, reduced right atrial and pulmonary artery pressures, and enhanced left ventricular transmural distending pressure during exercise (all p Conclusions Albuterol improves pulmonary vascular function and cardiac hemodynamics with exercise in patients with HFpEF. Further study is warranted to evaluate the chronic efficacy of β-agonists and other pulmonary vasoactive medicines in this population. Clinical Trial Registration: Inhaled Beta-adrenergic agonists to Treat Pulmonary Vascular Disease in Heart Failure with Preserved Ejection Fraction (BEAT HFpEF) - NCT02885636. https://clinicaltrials.gov/ct2/show/NCT02885636

P1614Right ventricular and pulmonary vascular function indices for risk stratification of patients with pulmonary regurgitation

P1614Right ventricular and pulmonary vascular function indices for risk stratification of patients with pulmonary regurgitation

Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia.

During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas Tie2 blockade by angiopoietin-2 increases, inflammation and permeability during sepsis. The role of angiopoietin-1/-2 in pneumonia remains unidentified. To investigate the prognostic and pathogenic impact of angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia. Serum angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n = 148, n = 395). Human postmortem lung tissue, pneumolysin- or angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated. In patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment, and length of hospital stay if combined with angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial angiopoietin-2 release, angiopoietin-2 increased endothelial permeability, and angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with angiopoietin-2 knockdown showed reduced permeability on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus pneumoniae-infected mice. Finally, angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia. These data suggest a central role of angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased angiopoietin-2 serum levels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.

NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

BackgroundPulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH.MethodsIn this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs.ResultsResults demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-β), which in turn led pulmonary arteriolar remodeling in COPD lungs.ConclusionThese results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling.

Dose and timing of normal saline resuscitation on endothelial glycocalyx in early septic shock

To observe the effect of different doses and timing of normal saline (NS) resuscitation combined with norepinephrine (NE) on endothelial glycocalyx in rabbits with early septic shock. Thirty New Zealand male rabbits were randomly divided into sham group, model group, 30 mL and 60 mL timely resuscitation groups (30 mL and 60 mL timely group), and 30 mL delayed resuscitation group (30 mL delayed group) with 6 rabbits in each group. The rabbit model of septic shock was reproduced by cecal ligation and puncture (CLP). The rabbits in sham group were only received abdominal cavity open without cecal and ligation. The rabbits in 30 mL and 60 mL timely groups and 30 mL delayed group were intravenous infused with 30 mL/kg or 60 mL/kg NS immediately or 1 hour after model reproduction for 1 hour, and the mean arterial pressure (MAP) was maintained over 75 mmHg (1 mmHg = 0.133 kPa) compared with intravenous pumping of 0.02-0.05 μg×kg-1×min-1 NE followed by 5 mL/h NS infusion till the end of the experiment. The rabbits in sham and model groups were only given 5 mL/h NS. The changes in arterial blood gas before and immediately after resuscitation were observed in three fluid resuscitation groups. The internal jugular vein blood was collected at 0, 3, 6 hours after model reproduction. The levels of syndecan-1 (polysaccharide envelope marker) in plasma were determined by enzyme linked immunosorbent assay (ELISA). The rabbits were sacrificed at 6 hours after model reproduction, and the lung tissue was harvested. Western Blot was used to determine the protein expressions of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase 2 (MMP-2) and syndecan-1. The positive expression of syndecan-1 in lung tissue was observed by immunohistochemical method. (1) Blood gas analysis: compared with the results before resuscitation, the levels of lactic acid (Lac) after resuscitation in three fluid resuscitation groups were significantly decreased, especially in 30 mL timely group; the central venous blood oxygen saturation (ScvO2) was significantly increased, especially in 30 mL delayed group. Oxygenation index (PaO2/FiO2) was improved in 30 mL timely and 30 mL delayed resuscitation groups, which was decreased in 60 mL delayed group. (2) Plasma marker: compared with sham group, plasma syndecan-1 level in model group was significantly increased with a time-dependent manner. Plasma syndecan-1 levels at 3 hours in 30 mL timely and 30 mL delayed groups were significantly decreased as compared with those of model group (ng/L: 138.0±2.4, 139.7±15.7 vs. 161.5±4.1, both P < 0.05), but it was significantly increased at 6 hours in 30 mL delayed group (ng/L: 213.1±19.4 vs. 206.4±15.5, P < 0.05). The plasma syndecan-1 levels at 3 hours and 6 hours in 60 mL timely group were significantly higher than those in model group (ng/L: 233.0±28.9 vs. 161.5±4.1, 252.3±27.2 vs. 206.4±15.5, both P < 0.05). (3) Protein expression in lung tissue: compared with sham group, the protein expressions of ICAM-1 and MMP-2 in lung tissue of model group were significantly increased, and syndecan-1 protein expression was significantly decreased. After 30 mL timely or 30 mL delayed resuscitation, the protein expressions of ICAM-1 and MMP-2 in lung tissue were significantly decreased, and syndecan-1 protein expression was significantly increased, especially in 30 mL timely group, which showed statistical differences as compared with those of model group (ICAM-1 protein: 0.56±0.09 vs. 1.04±0.05, MMP-2 protein: 0.83±0.15 vs. 1.06±0.06, syndecan-1 protein: 2.09±0.08 vs. 0.99±0.03, all P < 0.05). The change tendency of protein expressions in 60 mL timely group was opposite to the other two resuscitation groups. (4) Immunohistochemistry: the positive expression of syndecan-1 in lung tissues was significant in the sham group, and it was lowered in model group. The positive expression of syndecan-1 was increased after 30 mL timely or 30 mL delayed resuscitation, but further weakened in 60 mL timely group. The dose and timing of resuscitation with NS in septic shock can affect pulmonary vascular endothelial glycocalyx function. The timely resuscitation with 30 mL NS in combination with NE plays a protective effect on endothelial cell and glycocalyx. However, NS resuscitation which was not timely or excessive infusion can make the glycocalyx degradation more obvious, resulting in increased endothelial permeability, microcirculation damaged, thus aggravate lung injury.