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Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2 , ATP13A3 , AQP1 and SOX17 .

The RV then uses a dimensional or \"heterometric\" adaptation (Starling's law of the heart) to maintain flow output in response to metabolic demand (3). Because of the major prognostic relevance of RV function, there is interest in an earlier and robust diagnosis of RV-arterial uncoupling and definition of critical Ees and Ees/Ea values associated with a risk for clinical deterioration. The diagnosis of PAH rested on a step-by-step approach to exclude pulmonary hypertension due to cardiac or pulmonary diseases and right heart catheterization showing mPAP >25 mm Hg and pulmonary vascular resistance >3 Wood units, in agreement with current recommendations (2). [...]mPAP cannot be a surrogate for RV ESP in the evaluation of RV contractility and RV-arterial coupling. Universities of Giessen and Marburg Lung Centre, member of the German Centre for Lung Research Giessen, Germany The study Is funded by the German Research Foundation, Bonn, Germany (Collaborative Research Center 1213, \"Pulmonary Hypertension and Cor Pulmonale\" and Excellence Cluster \"Cardio-Pulmonary System\").

Venous congestion has emerged as an important cause of renal dysfunction in patients with cardiorenal syndrome. However, only limited progress has been made in differentiating this haemodynamic phenotype of renal dysfunction, because of a significant overlap with pre‐existing renal impairment due to long‐term hypertension, diabetes, and renovascular disease. We propose congestive nephropathy (CN) as this neglected clinical entity. CN is a potentially reversible subtype of renal dysfunction associated with declining renal venous outflow and progressively increasing renal interstitial pressure. Venous congestion may lead to a vicious cycle of hormonal activation, increased intra‐abdominal pressure, excessive renal tubular sodium reabsorption, and volume overload, leading to further right ventricular (RV) stress. Ultimately, renal replacement therapy may be required to relieve diuretic‐resistant congestion. Effective decongestion could preserve or improve renal function. Congestive acute kidney injury may not be associated with cellular damage, and complete renal function restoration may be a confirmatory diagnostic criterion. In contrast, a persistently low renal perfusion pressure might induce renal dysfunction and histopathological lesions with time. Thus, urinary markers may differ. CN is mostly seen in biventricular heart failure but may also occur secondary to pulmonary arterial hypertension and elevated intra‐abdominal pressure. An increase in central venous pressure to >6 mmHg is associated with a steep decrease in glomerular filtration rate. However, the central venous pressure range that can provide an optimal balance of RV and renal function remains to be determined. We propose criteria to identify cardiorenal syndrome subgroups likely to benefit from decongestive or pulmonary hypertension‐specific therapies and suggest areas for future research.

Background Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTPEH). The objective of this study was to evaluate right heart size and function assessed by echocardiography during long term treatment with riociguat. Methods Patients who started riociguat treatment (1.0–2.5 mg tid) within the trials phase II, PATENT, PATENTplus, EAS, CHEST and continued treatment for 3–12 months were included in this study. Echocardiography was analysed off-line at baseline, after 3, 6 and 12 months by investigators who were blinded to clinical data. Last and baseline observation carried forward method (LOCF, BOCF) were performed as sensitivity analysis. Results Seventy-one patients (45% PAH, 55% CTEPH; 53.5% female; 60 ± 13 years, mean pulmonary arterial pressure 46 ± 10 mmHg, mean PVR 700 ± 282dynes·sec·cm-5) were included. After 6 months, RA and RV area, RV thickness tricuspid regurgitation velocity showed a significant reduction. After 12 months, patients receiving riociguat therapy showed a significant reduction in right atrial (− 2.6 ± 4.4 cm2, 95% CI -3.84, − 1.33; p  < 0.001, n  = 49) and right ventricular (RV) area (− 3.5 ± 5.2 cm2, 95% CI -5.1, − 1.9; p  < 0.001; n  = 44), RV thickness (− 0.76 ± 2.2 mm, 95% CI -1.55, 0.03; n  = 32), and a significant increase in TAPSE (2.95 ± 4.78 mm, 95% CI 1.52, 4.39; n  = 45) and RV fractional area change (8.12 ± 8.87 mm, 95% CI 4.61, 11.62; n  = 27). Both LOCF and BOCF showed similar results but lower effect sizes. Conclusion Patients under long-term treatment with riociguat show significantly reduced right heart size and improved RV function in PAH and CTEPH. Further controlled prospective studies are needed to confirm these results.

Background A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. T hese were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes’ discovery. Results A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients . Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Conclusions Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

With rising altitude the partial pressure of oxygen falls. This phenomenon leads to hypobaric hypoxia at high altitude. Since more than 140 million people permanently live at heights above 2500 m and more than 35 million travel to these heights each year, understanding the mechanisms resulting in acute or chronic maladaptation of the human body to these circumstances is crucial. This review summarizes current knowledge of the body’s acute response to these circumstances, possible complications and their treatment, and health care issues resulting from long-term exposure to high altitude. It furthermore describes the characteristic mechanisms of adaptation to life in hypobaric hypoxia expressed by the three major ethnic groups permanently dwelling at high altitude. We additionally summarize current knowledge regarding possible treatment options for hypoxia-induced pulmonary hypertension by reviewing in vitro, rodent, and human studies in this area of research.

Pulmonary hypertension is characterized by increased pulmonary artery pressure and carries an increased mortality. Population-based studies into pulmonary hypertension are scarce and little is known about its prevalence in the general population. We aimed to describe the distribution of echocardiographically-assessed pulmonary artery systolic pressure (ePASP) in the general population, to estimate the prevalence of pulmonary hypertension, and to identify associated factors. Participants (n = 3381, mean age 76.4 years, 59% women) from the Rotterdam Study, a population-based cohort, underwent echocardiography. Echocardiographic pulmonary hypertension was defined as ePASP>40 mmHg. Mean ePASP was 26.3 mmHg (SD 7.0). Prevalence of echocardiographic pulmonary hypertension was 2.6% (95%CI: 2.0; 3.2). Prevalence was higher in older participants compared to younger ones (8.3% in those over 85 years versus 0.8% in those between 65 and 70), and in those with underlying disorders versus those without (5.9% in subjects with COPD versus 2.3%; 9.2% in those with left ventricular systolic dysfunction versus 2.3%; 23.1% in stages 3 or 4 left ventricular diastolic dysfunction versus 1.9% in normal or stage 1). Factors independently associated with higher ePASP were older age, higher BMI, left ventricular diastolic dysfunction, COPD and systemic hypertension. In this large population-based study, we show that pulmonary hypertension as measured by echocardiography has a low prevalence in the overall general population in the Netherlands, but estimates may be higher in specific subgroups, especially in those with underlying diseases. Increased pulmonary arterial pressure is likely to gain importance in the near future due to population aging and the accompanying prevalences of underlying disorders.

BackgroundIn patients with pulmonary arterial hypertension, the 6-Minute Walk Test (6MWT) is recommended for risk stratification and follow-up by all guidelines. However, the prognostic value of the 6MWT has been discussed controversially. We sought to compare and validate all published 6MWT cut-off points.MethodsFrom the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)—registry we identified 2391 patients with pulmonary arterial hypertension who had at least one documented 6MWT measurement. A Medline search identified a total of 21 different threshold values for either single-point or change of 6MWT. All values were tested individually for prognostication of 1-year, 2-year and 3-year all-cause mortality.ResultsThe highest positive likelihood ratio was a cut-off value < 165 ms, whereas the best negative likelihood ratio was found to be a threshold of 440 ms. Furthermore, improvement in 6MWT had considerably less predictive value on mortality and survival than deterioration. Moreover, absolute single-point values outperformed change values for both improvement and worsening.ConclusionOur data confirmed the prognostic relevance of the 6MWT and support the cut-off values stated in most recent guidelines. Furthermore, these results explain why changes in 6MWT did not correlate consistently with prognosis in previous studies.

Background The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov). Methods PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration. Results All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses. Conclusions Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

The relevance of cor pulmonale in COPD and pulmonary hypertension due to COPD (PH-COPD) is incompletely understood. We aimed to investigate the relationship of right ventricular-pulmonary arterial (RV-PA) uncoupling with disease severity in COPD, and the relationship of RV-PA uncoupling and use of targeted PH therapies with mortality in PH-COPD. We retrospectively analyzed 231 patients with COPD without PH and 274 patients with PH-COPD. COPD was classified according to GOLD stages and the modified Medical Research Council dyspnoea scale. PH was categorized as mild-to-moderate or severe. RV-PA uncoupling was assessed as the echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. Of the cohort with COPD without PH, 21, 58, 54 and 92 were classified as GOLD I, II, III and IV, respectively. Patients in advanced GOLD stages and those with severe dyspnoea showed significantly decreased TAPSE/PASP.Of the PH-COPD cohort, 144 had mild-to-moderate PH and 130 had severe PH. During follow-up, 126 patients died. In univariate Cox regression, TAPSE/PASP and 6-min walk distance (6MWD; 10 m increments) predicted survival [hazard ratios (95% CI): 0.12 (0.03-0.57) and 0.95 (0.93-0.97), respectively]; notably, PH severity and simplified European Society of Cardiology/European Respiratory Society risk stratification did not. Among patients in the lowest or intermediate tertiles of TAPSE/PASP and 6MWD, those with targeted PH therapy had higher survival than those without (53 vs. 17% at 3 years). Cor pulmonale (decreased TAPSE/PASP and 6MWD) is associated with disease severity in COPD and predicts outcome in PH-COPD.