Abstract-Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6 -mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3-miR-17/92-BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension. Key Words: pulmonary hypertension Ⅲ BMPR2 Ⅲ miR-17/92 Ⅲ interleukin-6 Ⅲ STAT3 P ulmonary hypertension is a devastating condition defined by the sustained elevation of pulmonary vascular resistance that leads rapidly to right heart failure and death when left untreated. 1 The pathogenesis of pulmonary hypertension is characterized by vascular remodeling and vasoconstriction. 2 Many chemotactic and inflammatory factors have been associated with these vascular changes including interleukin (IL)-6 and transforming growth factor (TGF)␤. [3][4][5] In familial pulmonary arterial hypertension, germline mutations in the gene encoding the type II receptor of the bone morphogenetic protein (BMPR2) comprise a genetic hallmark of the disease. 6 BMPR2 is a surface protein receptor that belongs to the transforming growth factor (TGF)␤ family. Its expression on endothelial and vascular smooth muscle cells mediates binding of bone morphogenetic proteins (BMPs) that have been identified as inhibitors of vascular smooth muscle cell proliferation while inducing cell death. 7 Thus, it was suggested that the downregulation of BMPR2 might lead to significant alterations in these signaling cascades and, ultimately, to remodeling of the pulmonary vascular bed. 8 Of interest, alterations in the surface expression of BMPR2 ha...

There is growing recognition of the clinical importance of pulmonary haemodynamics during exercise, but several questions remain to be elucidated. The goal of this statement is to assess the scientific evidence in this field in order to provide a basis for future recommendations.Right heart catheterisation is the gold standard method to assess pulmonary haemodynamics at rest and during exercise. Exercise echocardiography and cardiopulmonary exercise testing represent non-invasive tools with evolving clinical applications. The term "exercise pulmonary hypertension" may be the most adequate to describe an abnormal pulmonary haemodynamic response characterised by an excessive pulmonary arterial pressure (PAP) increase in relation to flow during exercise. Exercise pulmonary hypertension may be defined as the presence of resting mean PAP <25 mmHg and mean PAP >30 mmHg during exercise with total pulmonary resistance >3 Wood units. Exercise pulmonary hypertension represents the haemodynamic appearance of early pulmonary vascular disease, left heart disease, lung disease or a combination of these conditions. Exercise pulmonary hypertension is associated with the presence of a modest elevation of resting mean PAP and requires clinical follow-up, particularly if risk factors for pulmonary hypertension are present. There is a lack of robust clinical evidence on targeted medical therapy for exercise pulmonary hypertension.

AimsThe impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients.Methods and resultsEighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 ± 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was the change in peak VO2/kg. Secondary endpoints included changes in haemodynamics. For missing data, multiple imputation and responder analyses were performed. The study results showed a significant improvement of peak VO2/kg in the training group (difference from baseline to 15 weeks: training +3.1 ± 2.7 mL/min/kg equals +24.3% vs. control −0.2 ± 2.3 mL/min/kg equals +0.9%, P < 0.001). Cardiac index (CI) at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6 min walking distance, quality of life, and exercise capacity significantly improved by exercise training.ConclusionLow-dose exercise training at 4–7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that exercise training may improve the right ventricular function. Further, large multicentre trials are necessary to confirm these results.

Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions.

R ight ventricular (RV) pump function is of essential clinical and prognostic importance in a variety of heart and lung diseases and in pulmonary arterial hypertension (PAH). [1][2][3][4][5] Survival in pulmonary hypertension (PH) patients depends on the capability of the RV to adapt to chronically elevated pulmonary artery pressures. 6 Therefore, an accurate evaluation of RV pump function is crucial for screening, diagnosis, and follow-up assessment in PH. 7 However, it is difficult to assess RV function because of its complex geometry and load dependence and because of inadequate standardization of the assessment. 8 This is true for both noninvasive and invasive techniques.Evaluation of RV performance in PH patients has been recommended to be obtained at rest. 9 It is unknown whether assessment of RV function during exercise may be of additional benefit or even preferable. According to clinical experience, some PH patients with a severely enlarged right side of the heart and impaired RV pump function at rest do much better in their exercise capacity, World Health Organization functional class, and quality of life than others. They might differ in their RV reserve, defined as the ability of the ventricle to increase ejection fraction and stroke volume during exercise or pharmacological stress.10,11 RV and left ventricular (LV) contractileBackground-This study sought to analyze a new approach to assess exercise-induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure. Methods and Results-In this prospective study, patients with invasively diagnosed pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension and impaired right ventricular pump function despite a stable targeted pulmonary arterial hypertension medication underwent a broad panel of noninvasive assessments, including stress echocardiography and cardiopulmonary exercise testing. On the basis of the assumption that exerciseinduced PASP is a measure of right ventricular contractile reserve, patients were classified into 2 groups according to an exercise-induced PASP increase above or below the median. Patients were followed up for 3.0±1.8 years. Univariate and multivariate analyses were used for factors predicting survival. Of 124 patients, 66 were below the median exerciseinduced PASP increase of 30 mm Hg (low PASP), and 58 patients were above the median (high PASP). These groups were not significantly different in terms of medication and resting hemodynamics. Low PASP was associated with a significantly lower 6-minute walking distance, peak Vo 2 per kilogram, and 1-, 3-, and 4-year survival rates (92%, 69%, and 48%, respectively, versus 96%, 92%, and 89%). In the multivariate Cox model analysis adjusted for age and sex, PASP increase during exercise and peak Vo 2 per kilogram remained independent prognostic markers (hazard ratio, 2.56 for pea...