scholarly journals Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension

Heart ◽  
2020 ◽  
Vol 106 (17) ◽  
pp. 1332-1341 ◽  
Author(s):  
Philippe Chouvarine ◽  
Martin Giera ◽  
Gabi Kastenmüller ◽  
Anna Artati ◽  
Jerzy Adamski ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Vena Cava ◽  
Dicarboxylic Acids ◽  
P Value ◽  
Blood Collection ◽  
Lipid Species ◽  
Metabolite Concentrations ◽  
Pulmonary Arterial

ObjectiveWhile metabolic dysfunction occurs in several pulmonary arterial hypertension (PAH) animal models, its role in the human hypertensive right ventricle (RV) and lung is not well characterised. We investigated whether circulating metabolite concentrations differ across the hypertensive RV and/or the pulmonary circulation, and correlate with invasive haemodynamic/echocardiographic variables in patients with PAH.MethodsProspective EDTA blood collection during cardiac catheterisation from the superior vena cava (SVC), pulmonary artery (PA) and ascending aorta (AAO) in children with PAH (no shunt) and non-PAH controls (Con), followed by unbiased screens of 427 metabolites and 836 lipid species and fatty acids (FAs) in blood plasma (Metabolon and Lipidyzer platforms). Metabolite concentrations were correlated with echocardiographic and invasive haemodynamic variables.ResultsMetabolomics/lipidomics analysis of differential concentrations (false discovery rate<0.15) revealed several metabolite gradients in the trans-RV (PA vs SVC) setting. Notably, dicarboxylic acids (eg, octadecanedioate: fold change (FC)_Control=0.77, FC_PAH=1.09, p value=0.044) and acylcarnitines (eg, stearoylcarnitine: FC_Control=0.74, FC_PAH=1.21, p value=0.058). Differentially regulated metabolites were also found in the transpulmonary (AAO vs PA) setting and between-group comparisons, that is, in the SVC (PAH-SVC vs Con-SVC), PA and AAO. Importantly, the differential PAH-metabolite concentrations correlated with numerous outcome-relevant variables (e.g., tricuspid annular plane systolic excursion, pulmonary vascular resistance).ConclusionsIn PAH, trans-RV and transpulmonary metabolite gradients exist and correlate with haemodynamic determinants of clinical outcome. The most pronounced differential trans-RV gradients are known to be involved in lipid metabolism/lipotoxicity, that is, accumulation of long chain FAs. The identified accumulation of dicarboxylic acids and acylcarnitines likely indicates impaired β-oxidation in the hypertensive RV and represents emerging biomarkers and therapeutic targets in PAH.

scholarly journals Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

2018 ◽  
Vol 96 (3) ◽  
pp. 295-303 ◽  
Author(s):  
Rafaela Siqueira ◽  
Rafael Colombo ◽  
Adriana Conzatti ◽  
Alexandre Luz de Castro ◽  
Cristina Campos Carraro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Protein Expression ◽  
Arterial Hypertension ◽  
Female Rats ◽  
Antioxidant Defenses ◽  
Thioredoxin 1 ◽  
Pulmonary Arterial ◽  
The Right

The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into 4 groups (n = 6 per group): sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM). MCT (60 mg·kg−1 i.p.) was injected 1 week after ovariectomy or sham surgery. Three weeks later, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through Western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared with SM, being accompanied by an elevation in the estrogen receptor β (ER-β). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling.

scholarly journals The striated muscles in pulmonary arterial hypertension: adaptations beyond the right ventricle

2015 ◽  
Vol 46 (3) ◽  
pp. 832-842 ◽  
Author(s):  
Emmy Manders ◽  
Silvia Rain ◽  
Harm-Jan Bogaard ◽  
M. Louis Handoko ◽  
Ger J.M. Stienen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Exercise Intolerance ◽  
Muscle Dysfunction ◽  
Striated Muscles ◽  
Pulmonary Arterial ◽  
The Right ◽  
The Impact

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterised by progressive remodelling of the small pulmonary vessels. The daily-life activities of patients with PAH are severely limited by exertional fatigue and dyspnoea. Typically, these symptoms have been explained by right heart failure. However, an increasing number of studies reveal that the impact of the PAH reaches further than the pulmonary circulation. Striated muscles other than the right ventricle are affected in PAH, such as the left ventricle, the diaphragm and peripheral skeletal muscles. Alterations in these striated muscles are associated with exercise intolerance and reduced quality of life. In this Back to Basics article on striated muscle function in PAH, we provide insight into the pathophysiological mechanisms causing muscle dysfunction in PAH and discuss potential new therapeutic strategies to restore muscle dysfunction.

scholarly journals Repetitive and Brief Occlusion of Total Right Atrium Venous Blood Flow Improves Experimental Pulmonary Arterial Hypertension: a novel potential therapeutic strategy

2020 ◽  
Author(s):  
Nan Liu ◽  
Ying Xing ◽  
Chen Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Superior Vena ◽  
Venous Blood ◽  
Vena Cava ◽  
Vegf Receptor ◽  
Venous Blood Flow ◽  
History Of ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a vascular disorder associated with significant morbidity and mortality. The pathophysiology of PAH remains controversial, but the only currently available therapies for PAH are pharmacological pulmonary artery vasodilation, decreasing right ventricular (RV) afterload, and relieving symptoms. By now, there is no therapy being able to minimize vascular remodeling processes and thus to reverse or delay the natural history of the disease. It has been generally thought that reduction of RV preload was detrimental, which deteriorated the systemic hemodynamics. In the present study, however, we repetitively and briefly occluded (RBO) both superior vena cava and inferior vena cava by ligation (occlusion for less than 5 seconds then re-open for 30 seconds and repeated 5 cycles as one sequence, 1 sequence every 6 hours) to intermittently restrict RV preload, for continuous 24 hours, total 5 sequences, in the Sugen 5416 (VEGF receptor blocker) and hypoxia induced PAH rat models and we found this strategy was beneficial for lowering pulmonary vascular resistance (PVR).

P4688Additional role of unmodifiable risk factors in pulmonary arterial hypertension risk stratification according to current ESC/ERS guidelines

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Zuffa ◽  
F Dardi ◽  
M Palazzini ◽  
E Gotti ◽  
A Rinaldi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pulmonary Arterial Hypertension ◽  
High Risk ◽  
Risk Stratification ◽  
Arterial Hypertension ◽  
Specific Treatment ◽  
Low Risk ◽  
P Value ◽  
Pulmonary Arterial

Abstract Background Current pulmonary hypertension (PH) guidelines stratify the risk of patients with pulmonary arterial hypertension (PAH) using a multiparametric approach. Anyway, the role of unmodifiable risk factors is not taken into account. Purpose The aim of this study was to evaluate the role of unmodifiable risk factors (age, gender, PAH aetiology) in PAH risk stratification using the recently proposed simplified risk table and to test if these factors influence the response to PAH-specific treatment. Methods All patients with PAH referred to a single centre were included from 2003 to 2017. We applied a simplified risk assessment strategy using the following criteria: WHO functional class, 6-min walking distance, right atrial pressure or brain natriuretic peptide plasma levels and cardiac index (CI) or mixed venous oxygen saturation (SvO2). The last 2 criteria were based on which parameter was available; if both were available the worst was chosen. Risk strata were defined as: Low risk= at least 3 low risk and no high-risk criteria; High risk= at least 2 high risk criteria including CI or SvO2; Intermediate risk= definitions of low or high risk not fulfilled. Then we performed multivariate Cox analysis to evaluate what are the independent predictors of survival (age, gender, PAH aetiology together with the recently proposed simplified PAH risk table) and we tested if these factors influence the response to PAH specific therapy comparing the % improvement of hemodynamic parameters from baseline to 3–4 months after starting treatment. Wilcoxon-Mann-Whitney test was used for comparisons. Results Six hundreds and twenty-one treatment-naïve patients were enrolled. Age [HR (95% CI) = 1.022 (1.014–1.030); p-value <0.001], male gender [HR (95% CI) = 1.881 (1.479–2.392); p-value <0.001] and connective tissue disease (CTD)-PAH aetiology [HR (95% CI)= 2.278 (1.733–2.995); p-value <0.001] were all independent predictors of prognosis in patients with PAH together with the recently validated simplified PAH risk table [HR (95% CI) = 2.161 (1.783–2.618); p-value <0.001] but they didn't significantly influence the response to PAH specific treatment as shown in the Figure. Figure 1 Conclusions Age, gender and CTD-PAH aetiology significantly influence prognosis together with the recently validated simplified PAH risk table but don't significantly influence the response to PAH-specific treatment. Acknowledgement/Funding None

scholarly journals Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401988977 ◽  
Author(s):  
Edda Spiekerkoetter ◽  
Elena A. Goncharova ◽  
Christophe Guignabert ◽  
Kurt Stenmark ◽  
Grazyna Kwapiszewska ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systemic Disease ◽  
Right Ventricular Failure ◽  
Lung Pathology ◽  
Ventricular Failure ◽  
Disease Pathogenesis ◽  
Pulmonary Arterial

In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.

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