Abstract 13549: GP130 Signaling Promotes Right Ventricular Dysfunction in Pulmonary Arterial Hypertension via Microtubules

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sasha Z Prisco ◽  
Lynn Hartweck ◽  
Lauren Rose ◽  
Thenappan Thenappan ◽  
Kurt W Prins
Keyword(s):  
Mass Spectrometry ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Disease ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Heart Catheterization ◽  
Pulmonary Arterial ◽  
The Relationship ◽  
Rv Function

Introduction: Pulmonary arterial hypertension (PAH) is a lethal pulmonary arterial vasculopathy that results in right ventricle dysfunction (RVD). We showed that microtubule-mediated junctophilin-2 (MT-JPH2 pathway) downregulation promotes t-tubule disruption and RVD; however, the upstream regulators of this pathway are unknown. GP130 signaling via its downstream mediator, STAT3 promotes microtubule remodeling in neonatal cardiomyocytes. However, the relationship between GP130 signaling and the MT-JPH2 pathway in RVD are unknown. Methods: Immunoblots of RV extracts were probed for the GP130 and the MT-JPH2 pathways in MCT rats treated with a GP130 antagonist (2 weeks after MCT injection). Quantitative mass spectrometry analyzed the microtubule associated protein (MAP) fraction of RV extracts. Echocardiography and invasive closed-chest right heart catheterization quantified RV function and pulmonary vascular disease. Pulmonary vasculature remodeling was assessed by H&E histology. Finally, the relationship between the GP130 agonist, interleukin (IL)-6, and RVD in PAH patients was examined. Results: GP130 antagonist treatment blunted RV STAT3 activation, normalized the MT-JPH2 pathway, and restored t-tubule architecture. Hierarchical cluster analysis and principal component analysis of 2842 proteins identified using mass spectrometry revealed normalization of the MAP-fraction with GP130 antagonist treatment. These molecular changes manifested as improved RV function, improved RV-pulmonary artery coupling, blunted RV hypertrophy, and improved survival despite no differences in pulmonary vascular disease severity. In PAH patients, higher IL-6 levels were associated with higher N-terminal pro-brain natriuretic peptide and lower RV fractional area change despite no differences in pulmonary vascular disease burden. Conclusions: Small molecular inhibition of GP130 enhances RV function, and improves survival in MCT PAH via modulation of the MT-JPH2 pathway.

Potential role of exercise echocardiography and right heart catheterization in the detection of early pulmonary vascular disease in patients with systemic sclerosis

2019 ◽  
Vol 4 (3) ◽  
pp. 219-224
Author(s):  
Gabor Kovacs ◽  
Horst Olschewski
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Disease ◽  
Right Heart Catheterization ◽  
Pulmonary Vascular Disease ◽  
Heart Catheterization ◽  
Right Heart ◽  
Pulmonary Hemodynamics ◽  
Pulmonary Arterial

Pulmonary vascular disease represents one of the most frequent complications in systemic sclerosis leading to increased mortality. The recognition and appropriate clinical management of early pulmonary vascular disease could significantly improve the prognosis of affected patients. Early pulmonary vascular disease is characterized by the histological signs of pulmonary vascular remodeling, mildly increased mean pulmonary arterial pressure (21–24 mmHg) at rest, abnormal pulmonary hemodynamics during exercise, decreased exercise capacity, and a high risk for development of pulmonary arterial hypertension. Pulmonary hemodynamics can be investigated during exercise by echocardiography or by right heart catheterization both representing important clinical tools for the screening and confirmation of early pulmonary vascular disease. Further studies are needed to better understand the clinical course of systemic sclerosis patients with early pulmonary vascular disease and to define the characteristics of patients that will or will not profit from pulmonary arterial hypertension treatment.

scholarly journals Telangiectases in Scleroderma: A Potential Clinical Marker of Pulmonary Arterial Hypertension

2009 ◽  
Vol 37 (1) ◽  
pp. 98-104 ◽  
Author(s):  
AMI A. SHAH ◽  
FREDRICK M. WIGLEY ◽  
LAURA K. HUMMERS
Keyword(s):  
Regression Analysis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Disease ◽  
Pulmonary Vascular Disease ◽  
Early Therapy ◽  
Clinical Marker ◽  
Point Increase ◽  
Pulmonary Arterial ◽  
The Mean

Objective.Clinical markers are needed to identify scleroderma patients at risk for pulmonary arterial hypertension (PAH) since early therapy may improve survival. We investigated whether increased numbers of telangiectases in scleroderma associate with measures of pulmonary vascular disease.Methods.One hundred forty-seven consecutive adult patients with scleroderma were enrolled in this cross-sectional study and scored for the presence of matted telangiectases on 11 body areas. Per body area, telangiectases were scored as 0 if none were present, 1 if there were fewer than 10 telangiectases, and 2 if 10 or more telangiectases were counted. Linear regression analysis was performed to assess the association between right ventricular systolic pressure (RVSP) and telangiectasia score, adjusted for age, race, smoking status, scleroderma subtype, disease duration, and autoantibody status. Logistic regression analysis was performed with PAH by right-heart catheterization (RHC) as the dependent variable.Results.The mean telangiectasia score was 6.0 (SD 4.5, range 0–20). RVSP and telangiectasia score were positively correlated (r = 0.271, p = 0.001). The mean RVSP increased by 10.9 mm Hg for every 10-point increase in telangiectasia score (95% CI 3.6–18.3 mm Hg, p = 0.004), adjusted for potential confounders. The adjusted relative odds of PAH by RHC were 12.4 for patients with a 10-point increase in telangiectasia score (95% CI 1.78–85.9, p = 0.01).Conclusion.Increased numbers of telangiectases strongly associate with the presence of pulmonary vascular disease. Telangiectases may be a clinical marker of more widespread aberrant microvascular disease in scleroderma.

Haemodynamic phenotypes and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial hypertension

2019 ◽  
Vol 79 (3) ◽  
pp. 370-378 ◽  
Author(s):  
Panagiota Xanthouli ◽  
Suzana Jordan ◽  
Nicklas Milde ◽  
Alberto Marra ◽  
Norbert Blank ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Disease ◽  
Walking Distance ◽  
Pulmonary Vascular Disease ◽  
Term Survival ◽  
Pulmonary Arterial ◽  
Definition Of ◽  
The Impact

BackgroundIn this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc).MethodsIn SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses.ResultsThe final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21–24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21–24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis.ConclusionThe data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.

scholarly journals Pulmonary Pulse Wave Transit Time is Associated with Right Ventricular–Pulmonary Artery Coupling in Pulmonary Arterial Hypertension

2016 ◽  
Vol 6 (4) ◽  
pp. 576-585 ◽  
Author(s):  
Kurt W. Prins ◽  
E. Kenneth Weir ◽  
Stephen L. Archer ◽  
Jeremy Markowitz ◽  
Lauren Rose ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Transit Time ◽  
Pulse Wave ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Pulse Wave Transit Time ◽  
Pulmonary Arterial

Pulmonary pulse wave transit time (pPTT), defined as the time for the systolic pressure pulse wave to travel from the pulmonary valve to the pulmonary veins, has been reported to be reduced in pulmonary arterial hypertension (PAH); however, the underlying mechanism of reduced pPTT is unknown. Here, we investigate the hypothesis that abbreviated pPTT in PAH results from impaired right ventricular–pulmonary artery (RV-PA) coupling. We quantified pPTT using pulsed-wave Doppler ultrasound from 10 healthy age- and sex-matched controls and 36 patients with PAH. pPTT was reduced in patients with PAH compared with controls. Univariate analysis revealed the following significant predictors of reduced pPTT: age, right ventricular fractional area change (RV FAC), tricuspid annular plane excursion (TAPSE), pulmonary arterial pressures (PAP), diastolic pulmonary gradient, transpulmonary gradient, pulmonary vascular resistance, and RV-PA coupling (defined as RV FAC/mean PAP or TAPSE/mean PAP). Although the correlations between pPTT and invasive markers of pulmonary vascular disease were modest, RV FAC ( r = 0.64, P < 0.0001), TAPSE ( r = 0.67, P < 0.0001), and RV-PA coupling (RV FAC/mean PAP: r = 0.72, P < 0.0001; TAPSE/mean PAP: r = 0.74, P < 0.0001) had the strongest relationships with pPTT. On multivariable analysis, only RV FAC, TAPSE, and RV-PA coupling were independent predictors of pPTT. We conclude that shortening of pPTT in patients with PAH results from altered RV-PA coupling, probably occurring as a result of reduced pulmonary arterial compliance. Thus, pPTT allows noninvasive determination of the status of both the pulmonary vasculature and the response of the RV in patients with PAH, thereby allowing monitoring of disease progression and regression.

scholarly journals 408 The relationship between right ventricle-arterial coupling and cardiac metabolism in pulmonary arterial hypertension - multimodal study

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R Kazimierczyk ◽  
P Szumowski ◽  
P Blaszczak ◽  
E Kazimierczyk ◽  
K Ptaszynska-Kopczynska ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Control Group ◽  
Hemodynamic Parameters ◽  
Metabolic Demand ◽  
Pulmonary Arterial ◽  
The Relationship ◽  
Rv Function ◽  
Worse Prognosis

Abstract Background Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). The concept of coupling mainly refers to the relationship between ventricular contractility and afterload. In advanced PAH, to maintain cardiac output, RV dilates and the uncoupling occurs with wall stress and increased metabolic demand. We previously confirmed that impaired RV function is associated with increased glucose uptake of RV myocytes estimated by PET, which marks patients with worse prognosis. Purpose Whether echocardiographic approach of coupling parameters in PAH patients has relationship with RV metabolic alterations. Methods Twenty-six stable PAH patients (mean age 49.92 ± 15.94 years) and sixteen healthy subjects (control group) were enrolled into the study. The TAPSE, reflecting RV contractility, was obtained by mono-dimensional echo in standard technique. The echo estimation of the sPAP was reflecting RV afterload. Ventricular-arterial coupling was evaluated by the ratio between those two parameters. All PAH patients had also right heart catheterization (RHC) and PET performed during baseline visit. Heart glucose metabolism was assessed with fluorodeoxyglucose (FDG) as a tracer in PET. Its uptake was quantified as mean standardized uptake value (SUV) for both left ventricle (LV) and RV. Mean follow-up time of this study was 16.6 ± 7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration. Results Most of enrolled patients were in the WHO functional Class III (61%, 16). There were significant correlations between echo-derived hemodynamic parameters and RHC-derived values e.g. emPAP vs mPAP (RHC), r = 0.86, p &lt; 0.001. Echo-estimated RV ventricular-arterial coupling parameter (TAPSE/sPAP) was 0.35 ± 0.20 in PAH group and 1.51 ± 0.22 in control group, p &lt; 0.001. Mean SUV RV/LV ratio was 1.03 ± 0.68 in PAH group and 0.19 ± 0.08 in controls, p &lt; 0.005. Echo-derived TAPSE/sPAP significantly correlated with hemodynamic parameters from RHC – cardiac output and pulmonary vascular resistance. Interestingly, we also observed significant correlations of TAPSE/sPAP with glucose uptake in PET - SUV RV as well as with SUV RV/LV (r=-0.63, p = 0.0006; r=-0.50, p = 0.0009), confirming higher metabolic demand in uncoupled heart in case of PAH. Furthermore, patients who reached CEP (n = 15, 57%) had a significantly lower TAPSE/esPAP ratio (0.29 ± 0.17 vs 0.43 ± 0.21, p = 0.04) and higher SUV RV/LV (1.39 ± 0.79 vs 0.55 ± 0.45, p = 0.01). ROC analysis revealed significant cut-off value of TAPSE/esPAP in predicting CEP (AUC 0.72 (95% CI 0.52-0.92), p = 0.03). Patients with TAPSE/esPAP lower than 0.25 mm/mmHg had worse prognosis, log-rank test, p = 0.001 (Figure 1). Conclusions Simple echocardiographic parameter reflecting RV coupling (TAPSE/esPAP) related to altered myocardium metabolism in PAH may predict outcome in patients with PAH. Abstract 408 Figure 1

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