Targeted Immune and Growth Factor Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension Reveals a Potential Role of the Hepatic Growth Factor

Pulmonary arterial hypertension (PAH) is characterized by an insult in the pulmonary vasculature, with subsequent right ventricular (RV) adaptation to the increased afterload that ultimately leads to RV failure. The awareness of the importance of RV function in PAH has increased considerably because right heart failure is the predominant cause of death in PAH patients. Given its wide availability and reduced cost, echocardiography is of paramount importance in the evaluation of the right heart in PAH. Several echocardiographic parameters have been shown to have prognostic implications in PAH; however, the role of echocardiography in the risk assessment of the PAH patient is limited under the current guidelines. This review discusses the echocardiographic evaluation of the RV in PAH and during therapy, and its prognostic implications, as well as the potential significant role of repeated echocardiographic assessment in the follow-up of patients with PAH.

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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

European Respiratory Journal ◽

10.1183/13993003.02428-2020 ◽

2020 ◽

pp. 2002428

Author(s):

Myriam Amsallem ◽

Andrew J. Sweatt ◽

Jennifer Arthur Ataam ◽

Julien Guihaire ◽

Florence Lecerf ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Validation Cohort ◽

Nyha Class ◽

Severe Disease ◽

Added Value ◽

Right Heart ◽

Expression Levels ◽

Pulmonary Arterial

No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort) and 76 patients (validation cohort). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, New York Heart Association NYHA class and NT-proBNP] and Stanford score [RV end-systolic remodelling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Biomarkers expressions were measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant, or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk for heart failure who warrant closer follow-up and intensified therapy.

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Left ventricular dysfunction in patients with suspected pulmonary arterial hypertension

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132014000600004 ◽

2014 ◽

Vol 40 (6) ◽

pp. 609-616 ◽

Cited By ~ 11

Author(s):

Francisca Gavilanes ◽

José Leonidas Alves Jr ◽

Caio Fernandes ◽

Luis Felipe Lopes Prada ◽

Carlos Viana Poyares Jardim ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cardiac Catheterization ◽

Ventricular Dysfunction ◽

Right Heart Catheterization ◽

Left Ventricular ◽

Heart Catheterization ◽

Right Heart ◽

Pulmonary Arterial

OBJECTIVE: To evaluate the role of right heart catheterization in the diagnosis of pulmonary arterial hypertension (PAH). METHODS: We evaluated clinical, functional, and hemodynamic data from all patients who underwent right heart catheterization because of diagnostic suspicion of PAH-in the absence of severe left ventricular dysfunction (LVD), significant changes in pulmonary function tests, and ventilation/perfusion lung scintigraphy findings consistent with chronic pulmonary thromboembolism-between 2008 and 2013 at our facility. RESULTS: During the study period, 384 patients underwent diagnostic cardiac catheterization at our facility. Pulmonary hypertension (PH) was confirmed in 302 patients (78.6%). The mean age of those patients was 48.7 years. The patients without PH showed better hemodynamic profiles and lower levels of B-type natriuretic peptide. Nevertheless, 13.8% of the patients without PH were categorized as New York Heart Association functional class III or IV. Of the 218 patients who met the inclusion criteria, 40 (18.3%) and 178 (81.7%) were diagnosed with PH associated with LVD (PH-LVD) and with PAH, respectively. The patients in the HP-LVD group were significantly older than were those in the PAH group (p < 0.0001). CONCLUSIONS: The proportional difference between the PAH and PH-LVD groups was quite significant, considering the absence of echocardiographic signs suggestive of severe LVD during the pre-catheterization investigation. Our results highlight the fundamental role of cardiac catheterization in the diagnosis of PAH, especially in older patients, in whom the prevalence of LVD that has gone undiagnosed by non-invasive tests is particularly relevant.

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Endothelial PHD2 Deficiency Induces Nitrative Stress via Suppression of Caveolin-1 in Pulmonary Arterial Hypertension

10.1101/2021.09.24.461744 ◽

2021 ◽

Author(s):

Bin Liu ◽

Dan Yi ◽

Jingbo Dai ◽

Yi Peng ◽

Rebecca Vanderpool ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Right Heart ◽

Caveolin 1 ◽

Nitrative Stress ◽

Ros Scavenger ◽

Pulmonary Arterial ◽

Cav1 Expression

Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 [PHD2]) with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. ROS scavenger manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) treatment inhibited obliterative pulmonary vascular remodeling and suppressed severe PAH in Egln1Tie2Cre mice. Genetic restoration of endothelial Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PAH and improved right heart function. These data suggest that suppression of endothelial Cav1 expression secondary to PHD2 deficiency augments nitrative stress, which contributes to obliterative vascular remodeling and severe PAH. Thus, ROS scavenger might have great therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.

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Selection of Infusion Prostacyclin Therapy in Pulmonary Arterial Hypertension: Not Just a Last Resort

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-16.1.14 ◽

2017 ◽

Vol 16 (1) ◽

pp. 14-19

Author(s):

Robert Schilz ◽

Myung Park

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Heart Failure ◽

Survival Advantage ◽

Right Heart ◽

Apparent Paradox ◽

Early Evidence ◽

Pulmonary Arterial ◽

Selection Of

Pulmonary arterial hypertension (PAH) is a progressive, fatal vasculopathy that clinically manifests as increased pulmonary vascular resistance and elevation of pulmonary arterial pressures, ultimately leading to right heart failure and death. Median untreated survival period is 2.8 years, with a survival rate of 34% at 5 years before the availability of epoprostenol.1 Parenteral prostacyclin therapy is arguably the most effective and longest Food and Drug Administration-approved class of drugs for PAH and has been included in guidelines for treatment of PAH for almost 20 years. Intravenous epoprostenol as Flolan® remains the only drug that has demonstrated a survival advantage (Figure 1).2 Despite this demonstration of survival advantage and early evidence in its ability to improve a majority (70%) of patients to a point where they no longer required active listing for lung transplantation,3 epoprostenol or other infusion agents have consistently been shown to be withheld or underutilized in patients with advanced PAH.45 This apparent paradox as well as significant successful prostacyclin therapy in a variety of PAH patients6–8 forms the basis of our discussion on the role of infusion prostacyclins in modern management of PAH.

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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

10.1101/2020.06.19.20136028 ◽

2020 ◽

Author(s):

Myriam Amsallem ◽

Andrew J. Sweatt ◽

Jennifer Arthur Ataam ◽

Julien Guihaire ◽

Florence Lecerf ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Heart ◽

Online Data ◽

Expression Levels ◽

Screening Study ◽

Remodeling Index ◽

Pulmonary Arterial ◽

The Right

ABSTRACTRationaleNo prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH).ObjectivesTo identify the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.MethodsPlasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort from 2008-2011) and 76 (validation cohort from 2012-2014). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, NYHA and NT-proBNP] and Stanford score [RV end-systolic remodeling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Expression levels of biomarkers were measured in RV samples from PAH patients undergoing transplant and controls, and mice subjected to pulmonary artery banding (PAB).Measurements and Main ResultsHigh levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were significantly associated with worse Mayo and Stanford scores but not with pulmonary vascular resistance or pressure in both discovery and validation cohorts (this latter had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added incremental value to the REVEAL score in the prediction of death, transplant, or hospitalization at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.ConclusionHigh plasma HGF levels are associated with a RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH.At a Glance CommentaryScientific Knowledge on the SubjectRight heart maladaptation is the main cause of death in patients with pulmonary arterial hypertension (PAH). Recent non-invasive imaging studies have improved right heart adaptive phenotyping in PAH, identifying right ventricular (RV) free-wall longitudinal strain and the RV end-systolic remodeling index as markers of right heart maladaptive phenotypes (RHMP). Emerging evidence suggests a link between inflammation and RV failure in PAH patients and experimental disease models, yet no prior proteomic screening study has centered on the right heart.What This Study Adds to the FieldThis targeted proteomics screening study identifies 4 plasma biomarkers of RHMP in two clinical cohorts of patients with PAH. Among them, hepatic growth factor is shown to be prognostic and incremental to the REVEAL risk score for prediction of 3-year death, lung transplant and readmission. HGF and its receptor c-Met are overexpressed in RV tissue samples from PAH patients undergoing transplant as compared to controls, and mice subjected to pulmonary artery banding (PAB), warranting further exploration as a potential right ventricular-specific therapeutic target.Online data supplementsThis article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org.

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