Course Of Pulmonary Arterial Hypertension Research Articles

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DISEASE: RATIONALE FOR MANAGEMENT ALGORITHM BASED ON A LITERATURE REVIEW

The substantial progress achieved in cardiology and paediatric cardiac surgery has led to a considerable increase of life expectancy of patients with congenital heart disease (CHD), and at the same time to growing number of adult patients developing pulmonary arterial hypertension (PAH) associated with congenital heart defects. Nowadays guidelines were developed and updated for PAH, but no expert recommendations exist for effective management of PAH associated with CHD. Thus, it is important to develop an algorithm for managing these patients, based on international standards and a comprehensive understanding of prognostic markers of worsening the course of pulmonary arterial hypertension (PAH), considering local cardiac tertiary hospitals' capabilities.
 The aim. To highlight the pathophysiology and clinical characteristics of PAH-CHD patients, identify prognostic markers for its onset and progression, and develop a management algorithm for patients.
 Results. The article presents the pathophysiology of PAH-CHD, the mechanisms of right ventricle adaptation to pressure overload, which determine the functional abilities of patients and prognosis, PAH formation, and progression after defects correction. The accurate identification of stages in PAH-CHD (volume overload, mixed, stage of pulmonary vascular disease) is essential for the timely determination of surgical intervention, selecting conservative treatment strategies, and predicting the outcomes of surgical defect correction. The type of defect, its size, and the volume of blood flow through the defect influence the onset and progression of PH-CHD. We review the pathophysiology and clinical features of PAH-CHD, as well as the reasons for the late diagnosis of heart failure at the stage of severe decompensation and irreversible remodelling of the lung vessels when diuretic therapy is not effective enough and inotropic support, circulatory mechanical support and heart / lung complex transplantation are required. The necessity of developing new scales for stratifying the risk of PAH-CHD is justified considering the particularities of the disease course and cardiac hemodynamic in different anatomical types of the defects. Based on this literature review, at the Municipal Enterprise «Dnipropetrovsk Regional Clinical Center for Diagnostics and Treatment» of the Dnipropetrovsk Regional Council» the algorithm for managing patients with PAH-CHD was devised and implemented into clinical practice.
 Conclusions. PAH is a common complication of CHD. The prevalence of PAH-CHD is substantial and it can manifest and progress even in patients with previously corrected heart defects. To effectively manage patients with PAH-CHD, an algorithm has been devised and implemented in clinical practice. It includes factors that have demonstrated associations with poor prognosis which are more than two hospitalizations for HF in the last year, pulmonary vascular resistance (PVR) (or index of PVR), mean pressure in the pulmonary artery, pulmonary capillary wedge pressure, left ventricular ejection fraction, heart failure with a reduced ejection fraction, right ventricle heart failure, NYHA FC, high risk of atrial fibrillation or flutter, 6-minute walking test distance, NTproBNP, highly sensitive C-reactive protein, B-lines on lung ultrasound, glomerular filtration rate, haemoglobin, platelet count, sodium, Model for End-Stage Liver Disease scale.

Long-term course of pulmonary arterial hypertension in adults with congenital heart disease under targeted therapy: a retrospective analysis of a single tertiary center.

Pulmonary arterial hypertension (PAH), a common complication in adults with congenital heart disease (CHD), leads to significant morbidity and mortality. Targeted PAH medication is available, but PAH-CHD patient data are limited. Several questions regarding indication, treatment escalation, and combination therapy remain unanswered. The aim of this study was therefore to evaluate PAH-specific treatment in adults with PAH-CHD to better understand PAH-specific therapy management. In this cross-sectional study we retrospectively examined clinical, demographic, and cardiac-catheterization data and medical management for PAH-CHD, and analyzed clinical course and midterm outcome. Over up to 14 years (median, 6.2 years), 103 PAH-CHD patients (66% female) receiving targeted PAH-therapy for pre-tricuspid-shunt (15.5%), post-tricuspid-shunt (32.0%), and complex CHD (52.4%) were followed. Based on modified clinical European Society of Cardiology (ESC) classification, patients were assigned to the following subgroups: Eisenmenger syndrome (ES) (45.6%), severe pulmonary vascular disease (PVD) in complex CHD (20.4%), post-repair patients (19.4%), prevalent systemic-to-pulmonary shunt (3.9%), coincidental/small defects (0%), and Fontan circulation (10.7%). Changes in targeted PAH therapy were observed 249 times, with up to 6 (median, 2) therapy changes over a median period of 1.3 years. Over the study course, the medical treatment strategy changed towards combination therapy (baseline, 13.6%; study-end, 41%), resulting mostly in stabilized functional class or even improvement in cases of prevalent systemic-to-pulmonary shunt, ES, and patients with repaired CHD. Functional class deterioration, however, was seen in patients with severe PVD due to complex CHD, and Fontan patients. Of the 103 patients in the study, 25 died (24.3%). Patients with repaired CHD and patients with systemic-to-pulmonary shunt or ES showed the best survival rates. Mortality was remarkably higher in patients with severe PVD in complex CHD and Fontan patients. Many patients with PAH-CHD benefited from targeted PAH therapy over a median period of 6.2 years. Treatment decisions after targeted PAH-medication initiation were based mainly on clinical assessment. To counteract disease progression, an escalation towards combination therapy was observed during the study course. We consider survival rates under targeted PAH medication to be favorable, particularly in the ES subgroup. Nevertheless, further research is needed to optimize the use of PAH medication, especially in patients with complex CHD.

Risk stratification in patients with pulmonary arterial hypertension at the time of listing for lung transplantation.

It is unknown whether pulmonary arterial hypertension (PAH) risk stratification instruments could be helpful to support the decision to list a patient for lung transplantation (LT). Our aim was to evaluate contemporary risk assessment tools in a cohort of PAH patients listed for LT. Consecutive PAH patients (without pulmonary veno-occlusive disease or unrepaired congenital heart disease) listed for LT at the French Pulmonary Hypertension Reference Center between January 2006 and December 2018 were included. At the time of listing, risk stratification was assessed using the ESC/ERS criteria, the REVEAL Lite 2 score and the COMPERA 2.0 method. The primary end point was overall survival after LT listing. Secondary outcome measures were mortality on waiting list and posttransplant survival. One hundred and two patients were enrolled (mean age 38 ± 13 years, 69% females). Overall survival after listing was 72%, 58% and 46% at 1, 3 and 5 years respectively. Survival after LT listing was lower in "high-risk" patients according to the ESC/ERS criteria (p=0.0001) and the REVEAL Lite 2 score (p=0.04). The COMPERA 2.0 method discriminated post-listing survival of patients at high-risk, intermediate-high and intermediate-low risk (p=0.04). The proportion of patients requiring urgent transplantation and extracorporeal life support as a bridge to transplantation was higher in the "high-risk" patients. Posttransplant survival was significantly lower in "high-risk" patients according to the ESC/ERS criteria (p=0.0004). High-risk PAH patients at the time of LT listing have poor outcomes, suggesting that LT should be considered earlier in the course of PAH remaining refractory to triple combination therapy with a parenteral prostacyclin.

Haemoptysis in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: Insights on Pathophysiology, Diagnosis and Management.

Haemoptysis represents one of the most severe major bleeding manifestations in the clinical course of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Accumulating evidence indicates that dysfunction of the pulmonary vascular bed in the setting of PAH predisposes patients to increased hemorrhagic diathesis, resulting in mild to massive and life-threatening episodes of haemoptysis. Despite major advances in PAH targeted treatment strategies, haemoptysis is still correlated with substantial morbidity and impaired quality of life, requiring a multidisciplinary approach by adult CHD experts in tertiary centres. Technological innovations in the field of diagnostic and interventional radiology enabled the application of bronchial artery embolization (BAE), a valuable tool to efficiently control haemoptysis in modern clinical practice. However, bleeding recurrences are still prevalent, implying that the optimum management of haemoptysis and its implications remain obscure. Moreover, regarding the use of oral anticoagulation in patients with haemoptysis, current guidelines do not provide a clear therapeutic strategy due to the lack of evidence. This review aims to discuss the main pathophysiological mechanisms of haemoptysis in PAH-CHD, present the clinical spectrum and the available diagnostic tools, summarize current therapeutic challenges, and propose directions for future research in this group of patients.

Compensatory roles of Protein Related to DAN and Cerberus (PRDC) decrease in pulmonary arterial hypertension.

Bone morphogenetic protein (BMP) signaling is commonly suppressed in patients with pulmonary arterial hypertension (PAH), but the compensatory mechanism of BMP signaling suppression is incompletely elucidated. This study aimed to investigate the role of PRDC, an antagonist of BMPs, in PAH and the underlying mechanism. Human lungs were collected and rat PAH was induced (monocrotaline, 60 mg/kg). BMP cascade and PRDC were detected in lungs and distal pulmonary artery smooth muscle cells (dPASMCs). In vitro cell experiments and in vivo supplementation of PRDC in hypertensive rats were subsequently performed. PRDC and BMP cascade all decreased in human and rat hypertensive lungs. Cell experiments confirmed that BMP2/4 inhibited dPASMCs proliferation by increasing cell cycle inhibitors (p21, p27), prevented dPASMCs migration by down-regulating MMP2/9 and up-regulating TIMP1/2 expression, and promoted dPASMCs apoptosis by up-regulating Bax, caspase3/9 and down-regulating Bcl-2 expression, as well as enhancing caspase3/7 activity, while, PRDC reversed the effects of BMP2/4 on dPASMCs proliferation, migration and apoptosis. In vivo trial found that PRDC supplementation deteriorated rat PAH in terms of pulmonary hemodynamics, vasculopathies and right ventricle hypertrophy. Taken together, compensatory decrease of PRDC in hypertensive lungs theoretically slow down the natural course of PAH, suggesting its therapeutic potential in PAH.

PATET ratio by Doppler echocardiography: noninvasive detection of pediatric pulmonary arterial hypertension.

Pulmonary artery acceleration time (PAT) and PAT: ejection time (PATET) ratio are echocardiographic measurements of pulmonary arterial hypertension (PAH). These non-invasive quantitative measurements are ideal to follow longitudinally through the clinical course of PAH, especially as it relates to need for and/or response to treatment. This review article focuses on the current literature of PATET measurement for infants and children as it relates to shortening of the PATET ratio in PAH. At the same time, further development of PATET as an outcome measure for PAH in pre-clinical models, particularly mice, such that the field can move forward to human clinical studies that are both safe and effective. Here we present what is known about PATET in infants and children and discuss what is known in pre-clinical models with particular emphasis on neonatal mouse models. In both animal models and human disease, PATET allows for longitudinal measurements in the same individual, leading to more precise determinations of disease/model progression and/or response to therapy.

Untargeted metabolomics towards understanding molecular mechanisms of pulmonary arterial hypertension

Abstract Background Pulmonary hypertension constitutes a rare disease characterized by a severe development and a high risk of premature death. One of its main clinical types is pulmonary arterial hypertension (PAH), in which the highest percentage of patients are affected by idiopathic PAH. The pathogenesis of this disease has not completely been discovered and elucidated so far, and non-specific clinical symptoms make the diagnosis of PAH a serious problem. Currently, PAH is confirmed with invasive examination based on right heart catheterization. Purpose The main aim of the study was to evaluate and compare both plasma and urine fingerprints of PAH patients and control group with the use of an untargeted metabolomics approach. The study also focused on correlation analysis between the observed metabolic changes and the clinical parameters to select specific indicators of PAH disease. Methods An untargeted metabolomics approach was applied to the plasma and urine samples with the use of gas chromatography coupled to triple quadrupole mass spectrometry (GC-QqQ/MS) and advanced statistical tests were applied to evaluate the potential metabolic indicators of PAH. The PAH patients (n=40) and healthy controls (n=39) were matched for age, sex, BMI and included in the study. The obtained raw datasets were properly processed (data deconvolution, signal correction using QCSVR method and PQN normalization) and subsequently subjected to uni- and multivariate statistical tests (Student's t-test, Welch's test, U Mann-Whitney test, PCA and OPLS-DA). The identification of the statistically significant metabolites was performed using universal libraries, such as: Fiehn's and NIST11. Results The statistically significant metabolites (n=10 and 11 for urine and plasma samples, respectively)originate from various biochemical pathways associated with the carbohydrate, amino acid, lipid, fatty acid and pyrimidine metabolism. The metabolic changes observed in the urine samples of PAH patients (compared to the control group) included different concentrations in: threonic acid, hippuric acid, acetic acid, sorbitol, butanoic acid and propionic acid. The metabolic alterations in the plasma samples covered changes in the levels of valine, leucine, lactic acid, hydroxybutanoic acid, nonanoic acid, cholesterol and octadecanoic acid. Metabolites representing the highest correlation with mean pulmonary arterial pressure include, for instance: propionic acid (r=0.85), valine (r=0.75) and lactic acid (r=0.63) Conclusions The observed metabolic changes are related to various biological processes that are disturbed in the course of PAH, namely: proliferation of pulmonary vascular cells or the functions of cardiomyocytes and the right ventricle of the heart. The obtained results confirmed the potential of a metabolomics approach to uncover and explain the underlying molecular mechanisms of PAH. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and High Education of Poland

TdTomato Transgenic Reporter Rat Reveals Endothelial‐Specific Changes in Progression of PAH

Background Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance and elevated pulmonary artery pressure, leading to right heart failure. Vasoconstriction and complex vascular remodeling contribute to progressive vasculopathy. The Sugen-hypoxia (SuHx) protocol generates arterial pathology in rats that recapitulates key features of PAH including vascular remodeling. Previously, a transgenic rat with endothelial cell-specific tdTomato expression was developed. This study aims to demonstrate the application of this transgenic rat as a novel tool for assessing the role of the pulmonary vascular endothelium in occlusive remodeling in PAH. Methods A cohort of CDH5-iCre/tdTomato reporter rats received an injection of the vascular endothelial growth factor receptor inhibitor Sugen5416, followed by 3 weeks of hypoxia, then 2-10 weeks of normoxia. Rats underwent echocardiography prior to tissue harvest, and the agarose/gel-infused lung preparation was used to evaluate tdTomato fluorescence, Hoechst nuclear dye, and autofluorescence. The pulmonary artery was cannulated through the right ventricle, and HBSS, NucBlue, then gelatin solution were perfused through the pulmonary circulation. Agarose solution was then infused through the trachea to inflate the lungs. Solidified lung tissue was cut into ~300 μm-thick serial lung slices for confocal imaging. Images were stitched together using the ImageJ Grid/Collection stitching plugin, generating up to 4.6 trillion-pixel high-content composite segments of tissue. Fulton Index measurements were obtained at 6 time points between weeks 5 and 13 of the SuHx protocol. Results Severe occlusive lesions were formed by week 5, consistent with the expected time course of SuHx in Sprague-Dawley rats. Plexiform lesions were observed by 9 weeks. TdTomato expression increased in grade II-IV lesions from 5 to 9 weeks, and abruptly decreased beyond 9 weeks. Echocardiography and Fulton Indices indicated right heart hypertrophy as PAH progressed from weeks 5 to 13. A peak RV/LV+S ratio of 0.68 was recorded at the 12-week time point, an approximate three-fold increase from normal values, before plateauing at 13 weeks. High-content images revealed marked differences in fluorescence intensity and visible lesion formation between early and late stage PAH. Conclusion Biphasic tdTomato endothelial fluorescence intensity at mid-late stages of PAH may indicate endothelial cell proliferation followed by cell death. Alternatively, time-dependent regulation of CDH5 may explain the time course of reporter expression, though further investigation is needed. In summary, the present study has demonstrated that the tdTomato transgenic reporter rat is a valuable tool for investigating endothelial cell dynamics, and high-content montage images offer a unique, comprehensive perspective of endothelial-specific remodeling over the progressive course of PAH.

Genetic Delivery and Gene Therapy in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive complex fatal disease of multiple etiologies. Hyperproliferation and resistance to apoptosis of vascular cells of intimal, medial, and adventitial layers of pulmonary vessels trigger excessive pulmonary vascular remodeling and vasoconstriction in the course of pulmonary arterial hypertension (PAH), a subgroup of PH. Multiple gene mutation/s or dysregulated gene expression contribute to the pathogenesis of PAH by endorsing the proliferation and promoting the resistance to apoptosis of pulmonary vascular cells. Given the vital role of these cells in PAH progression, the development of safe and efficient-gene therapeutic approaches that lead to restoration or down-regulation of gene expression, generally involved in the etiology of the disease is the need of the hour. Currently, none of the FDA-approved drugs provides a cure against PH, hence innovative tools may offer a novel treatment paradigm for this progressive and lethal disorder by silencing pathological genes, expressing therapeutic proteins, or through gene-editing applications. Here, we review the effectiveness and limitations of the presently available gene therapy approaches for PH. We provide a brief survey of commonly existing and currently applicable gene transfer methods for pulmonary vascular cells in vitro and describe some more recent developments for gene delivery existing in the field of PH in vivo.

Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats

ObjectiveA growing evidence demonstrates that inflammation is a major contributor to the pathogenesis of pulmonary arterial hypertension (PAH). However, blocking inflammation has only been shown to be of minor clinical benefit due to a lack of understanding of the precise inflammation present in PAH. Thus, the present study aimed to investigate characteristics of inflammatory process in PAH induced by monocrotaline (MCT) in rats. MethodsAdult male Sprague-Dawley rats received a single dose of MCT (50 mg/kg, ip), and the occurrence of PAH and inflammation biomarkers were measured at 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 days after MCT injection. ResultsFrom the 6th day after the injection of MCT, the mean pulmonary artery pressure gradually increased and doubled on the 30th day, accompanied by right ventricular hypertrophy and pulmonary arterial remodeling in a time-dependent manner. In the first 6 days after MCT treatment, only pro-inflammatory cytokines TNF-α, IL-1β increased, which was defined as acute inflammatory phase, after that, both pro-inflammatory factors TNF-α, IL-1β, IL-6, IL-12 and anti-inflammatory factors Arg1, IL-10, TGF-β increased, which was defined as chronic inflammatory phase. The M1/M2 macrophage ratios in lung and alveolar lavage fluid were elevated on the 6th and 30th day, moreover, which were higher on the 6th than 30th day, and the PI3K/Akt signaling pathway increased along with the progression of PAH and correlated with pro-inflammatory proteins, which revealed also to some extent the characteristics of inflammation of PAH induced by MCT. ConclusionThe course of PAH induced by MCT injection is progressive with persistent inflammation, which is defined as acute inflammatory phase within 6 days after MCT treatment, after that, is defined as chronic inflammatory phase.

Myocardial proteomic profile in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, fatal, and incurable disorder. Although advances in the understanding of the PAH pathobiology have been seen in recent years, molecular processes underlying heart remodelling over the course of PAH are still insufficiently understood. Therefore, the aim of this study was to investigate myocardial proteomic profile of rats at different stages of monocrotaline-induced PAH. Samples of left and right ventricle (LV and RV) free wall collected from 32 Wistar rats were subjected to proteomic analysis using an isobaric tag for relative quantitation method. Hemodynamic parameters indicated development of mild elevation of pulmonary artery pressure in the early PAH group (27.00 ± 4.93 mmHg) and severe elevation in the end-stage PAH group (50.50 ± 11.56 mmHg). In early PAH LV myocardium proteins that may be linked to an increase in inflammatory response, apoptosis, glycolytic process and decrease in myocardial structural proteins were differentially expressed compared to controls. During end-stage PAH an increase in proteins associated with apoptosis, fibrosis and cardiomyocyte Ca2+ currents as well as decrease in myocardial structural proteins were observed in LV. In RV during early PAH, especially proteins associated with myocardial structural components and fatty acid beta-oxidation pathway were upregulated. During end-stage PAH significant changes in RV proteins abundance related to the increased myocardial structural components, intensified fibrosis and glycolytic processes as well as decreased proteins related to cardiomyocyte Ca2+ currents were observed. At both PAH stages changes in RV proteins linked to apoptosis inhibition were observed. In conclusion, we identified changes of the levels of several proteins and thus of the metabolic pathways linked to the early and late remodelling of the left and right ventricle over the course of monocrotaline-induced PAH to delineate potential therapeutic targets for the treatment of this severe disease.

Changes in heart morphometric parameters over the course of a monocrotaline-induced pulmonary arterial hypertension rat model

BackgroundAim of this study was to assess changes in cardiac morphometric parameters at different stages of pulmonary arterial hypertension (PAH) using a monocrotaline-induced rat model.MethodsFour groups were distinguished: I–control, non-PAH (n = 18); II–early PAH (n = 12); III–end-stage PAH (n = 23); and IV–end-stage PAH with myocarditis (n = 7).ResultsPerformed over the course of PAH in vivo echocardiography showed significant thickening of the right ventricle free wall (end-diastolic dimension), tricuspid annular plane systolic excursion reduction and decrease in pulmonary artery acceleration time normalized to cycle length. No differences in end-diastolic left ventricle free wall thickness measured in echocardiography was observed between groups. Significant increase of right ventricle and decrease of left ventricle systolic pressure was observed over the development of PAH. Thickening and weight increase (241.2% increase) of the right ventricle free wall and significant dilatation of the right ventricle was observed over the course of PAH (p < 0.001). Reduction in the left ventricle free wall thickness was also observed in end-stage PAH (p < 0.001). Significant trend in the left ventricle free wall weight decrease was observed over the course of PAH (p < 0.001, 24.3% reduction). Calculated right/left ventricle free wall weight ratio gradually increased over PAH stages (p < 0.001). The reduction of left ventricle diameter was observed in rats with end-stage PAH both with and without myocarditis (p < 0.001).ConclusionsPAH leads to multidimensional changes in morphometric cardiac parameters. Right ventricle morphological and functional failure develop gradually from early stage of PAH, while left ventricle changes develop at the end stages of PAH.

3-Bromopyruvate ameliorates pulmonary arterial hypertension by improving mitochondrial metabolism

AimsAbnormal mitochondrial metabolism is an essential factor for excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which drives the pathological process of pulmonary arterial hypertension (PAH). 3-Bromopyruvate (3-BrPA) is an effective glycolytic inhibitor that improves mitochondrial metabolism, thereby repressing anomalous cell proliferation. Main methodsAn experimental PAH model was established by injection of monocrotaline (MCT) in male Sprague Dawley rats, following which rats were assigned to three groups: control, MCT, and 3-BrPA groups. Three days post injection of MCT, rats were treated with 3-BrPA or vehicle for 4 weeks. At the end of the study, hemodynamic data were measured to confirm PAH condition. Indicators of pulmonary arterial and right ventricular (RV) remodeling as well as the proliferative ability of PASMCs were assayed. Additionally, mitochondrial morphology and function, and antiglycolytic and antiproliferative pathways and genes were analyzed. Key findingsTreatment with 3-BrPA effectively improved pulmonary vascular remodeling and right ventricular function, inhibited PASMC proliferation, and preserved mitochondrial morphology and function. Besides, 3-BrPA treatment inhibited the PI3K/AKT/mTOR pathway and regulated the expression of antiproliferative genes in PASMCs. However, bloody ascites, bloating, and cirrhosis of organs were observed in some 3-BrPA treated rats. Significance3-BrPA acts as an important glycolytic inhibitor to improve energy metabolism and reverse the course of PAH. However, 3-BrPA is associated with side effects in MCT-induced rats, indicating that it should be caution in drug delivery dosage, and further studies are needed to evaluate this toxicological mechanism.

Blockade of JAK2 protects mice against hypoxia‐induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation

ObjectivesHypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH.MethodsSmooth muscle cell (SMC)‐specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre‐treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24‐hour hypoxic exposure.ResultsMice with hypoxia‐induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia‐induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia‐induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG‐101348, suppressed hypoxia‐induced human PASMC proliferation. Upon hypoxia‐induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation.ConclusionsOur studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.

Study Performed at Various Medical Centers to Learn More About Survival and Expected Course of Pulmonary Arterial Hypertension, a Type of High Blood Pressure in the Lungs Related to the Narrowing of the Small Blood Vessels in the Lungs

Study Performed at Various Medical Centers to Learn More About Survival and Expected Course of Pulmonary Arterial Hypertension, a Type of High Blood Pressure in the Lungs Related to the Narrowing of the Small Blood Vessels in the Lungs

Pulmonary hypertension in connective tissue disease

Pulmonary arterial hypertension (PAH) is amajor complication of systemic sclerosis (SSc) and screening is recommended for atimely initiation of disease-targeted drug therapy to modify disease progression. Patients with SSc-PAH have abetter prognosis when detected and treated early. The PAH can occur in all disease stages and subsets of SSc. Regular screening tests, which are indicative for PAH, e.g. echocardiography, diffusion capacity, brain natriuretic protein (BNP) and a6-min walking test, are recommended to enhance the suspicion, since clinical symptoms are unspecific and occur late in the course of PAH. In patients with suspected PAH, the diagnosis should be confirmed by right heart catheterization. Amultidisciplinary approach in expert centres including rheumatologists and respiratory physicians and cardiologists specialized in pulmonary hypertension is mandatory for management of patients with SSc at risk for or with manifest pulmonary arterial hypertension.

Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity.

Published data suggest that coexisting interstitial lung disease (ILD) has an impact on mortality in patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), but there is scarce knowledge if this is reflected by hemodynamics, exercise capacity, autoantibody profile, or pulmonary function. In this partially retrospective study, 27 SSc-PAH patients were compared to 24 SSc-PAH patients with coexisting ILD respecting to survival, pulmonary function, hemodynamics, exercise capacity, and laboratory parameters. Survival was significantly worse in SSc-PAH-ILD patients than in SSc patients with isolated PAH (1, 5, and 10-year survival rates 86, 54, and 54% versus 96, 92, and 82%, p=0.013). Compared to isolated SSc-PAH patients, patients with SSc-PAH-ILD revealed lower forced expiratory volume after 1s (FEV1) values at the time of PAH diagnosis as well as 1 and 2years later (p=0.002) without significant decrease in the PAH course in both groups. At PAH diagnosis, diffusion capacity for carbon monoxide (DLCO) values were lower in the ILD-PAH group. Coexisting ILD was not associated with lower exercise capacity, different FEV1/forced vital capacity (FVC) ratio, higher WHO functional class, or reduced hemodynamics. Higher levels of antibodies against angiotensin and endothelin receptors predict mortality in all SSc-PAH patients but could not differentiate between PAH patients with and without ILD. Our study confirmed an impact of ILD on mortality in SSc-PAH patients. Pulmonary function parameters can be used to distinguish PAH from PAH-ILD. The higher mortality rate cannot be explained by differences in hemodynamics, exercise capacity, or autoantibody levels. Mechanisms of mortality remain to be studied.

Hospitalization and Survival in Patients Using Epoprostenol for Injection in the PROSPECT Observational Study

BACKGROUND:Few studies have prospectively reported outcomes in patients with pulmonary arterial hypertension (PAH) treated with epoprostenol in the modern-day era of oral therapy and combination treatments. The Registry to Prospectively Describe Use of Epoprostenol for Injection (Veletri, prolonged room temperature stable-epoprostenol [RTS-Epo]) in Patients with Pulmonary Arterial Hypertension (PROSPECT) was established to prospectively describe the course of PAH in patients prescribed RTS-Epo.METHODS:PROSPECT is a multicenter, US-based drug registry of primarily group 1 patients with PAH treated with RTS-Epo who were parenteral-naive or parenteral-transitioned at enrollment. Patients were followed until discontinuation of RTS-Epo, withdrawal, loss to follow-up, death, or end of study (maximum 1 year). One-year freedom from hospitalization (FH) and survival estimates were summarized by prostacyclin history (parenteral-naive or parenteral-transitioned), sex, and chronic renal insufficiency (CRI).RESULTS:A total of 336 patients were included. The overall 1-year FH estimate was 51.0% ± 2.8% and was lower in parenteral-naive patients than parenteral-transitioned patients (42.8% ± 4.3% vs 57.1% ± 3.7%, respectively; P = .002). FH estimates were lower in male patients than female patients (38.3% ± 5.9% vs 54.6% ± 3.2%, respectively; P < .015) and in patients with CRI than patients without CRI (17.0% ± 8.4% vs 53.7% ± 2.9%, respectively; P < .001). The overall 1-year survival estimate was 84.0% ± 2.1%. Survival was poorer in parenteral-naive patients, male patients, and patients with CRI.CONCLUSIONS:Risk of hospitalization and mortality remain high in patients with PAH. In particular, patients who are parenteral-naive at initiation of RTS-Epo therapy, male patients, and patients with CRI require close monitoring and aggressive clinical management.

Abstract 15745: Tenascin-c Levels and Clinical Importance in Pulmonary Arterial Hypertension

Background: Prognostic markers are known to have an important value in guiding treatment of pulmonary arterial hypertension (PAH) which is associated with high mortality and morbidity. The prognostic importance of some biomarkers like BNP has been shown and used in the routine course of PAH. Tenacsin-C (TNC) is a glycoprotein located in the extracellular matrix which has an important role in PAH pathophysiology. However, the clinical relevance of PAH and TNC is unknown. In this study, we investigated the plasma levels of TNC in patients with PAH as a possible prognostic marker. Methods: Study population consisted of 45 PAH (29 women, mean age: 32±9 years, 34 with PAH associated with congenital heart disease, 9 idiopathic PAH and 2 chronic thromboembolic pulmonary hypertension) patients who were followed-up in our PAH centre. Twenty age-sex matched healthy subjects served as the control-group. Plasma TNC levels were measured using ELISA-method. All patients were evaluated with transthoracic echocardiography including assessment of right ventricle, six minute walk test, and NT-proBNP levels simultaneously, which are all known to have prognostic value in PAH. Data were comparatively evaluated using appropriate statistical analysis. Results: TNC levels in patients with PAH were significantly higher, compared to healthy controls (61.9±20.7 ng/mL versus 12.6±5.6 ng/mL, respectively, p&lt;0.0001). There was no significant relationship between age, gender, and TNC levels. There was a significant positive correlation between TNC levels in PAH group and functional class (rho=0.355, p=0.017) and NT-proBNP (rho=0.5, p=0.001) levels, whereas there was a significant negative correlation between TNC levels and fractional area change (FAC, rho=-0.33, p=0.035) and tricuspid annular plane systolic excursion (TAPSE, rho=-0.495, p=0.006). Conclusions: TNC levels are substantially increased in PAH. There is a significant association between TNC levels and parameters with proved prognostic value in PAH, such as functional class, TAPSE, FAC, and NT-proBNP levels. All of these data suggest that TNC levels in patients with PAH may be a new prognostic biomarker. Further prospective studies are needed to confirm this statement.

Carbon monoxide diffusing capacity and the complexity of diagnosis in pulmonary arterial hypertension

The increased interest in pulmonary arterial hypertension (PAH) witnessed during the last decades has dramatically changed our comprehension of the disease and its management, resulting in better functional capacity and haemodynamic profiles, and increased survival [1, 2]. The discovery of different pathophysiological pathways associated with PAH progression has allowed the development of targeted therapies that were responsible for such improvements [3]. Recently, more attention has been paid to the epidemiology and distinct phenotypes of PAH, not least by publication of several registries expanding our knowledge on the clinical and demographic characteristics of PAH patients [4–9] as well as on the burden that previously unrecognised forms of PAH might represent [10]. The pivotal study conducted by the US National Institutes of Health in the 1980s [11, 12] provided invaluable information about the natural course of PAH. The patients in that cohort were predominantly young females (mean age of 36 years) presenting with what was then called primary pulmonary hypertension, i.e. idiopathic, familial or appetite suppressant-associated PAH. The presence of comorbidities did not represent a significant issue at that time, …