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ObjectivesPulmonary arterial hypertension (PAH) is a devastating disease with limited survival and occurs as a frequent complication in patients with systemic sclerosis (SSc). A definite diagnosis of PAH is obtained by right heart catheterisation (RHC); however, the initial suspicion is raised by non-invasive methods. We assessed the diagnostic accuracy of key parameters derived from cardiopulmonary exercise testing (CPET) for detecting and ruling out SSc-associated PAH.MethodsIn a multicentre setting, we prospectively evaluated 173 consecutive patients with SSc without known PAH, but with clinical suspicion of PAH. Each patient underwent CPET and RHC.ResultsRHC identified PAH in 48 patients (27.8%), postcapillary pulmonary hypertension (PH) in 10 patients (5.8%) and ruled out PH in 115 patients (66.5%). CPET parameters correlated significantly with pulmonary haemodynamics. PeakVO2 and VE/VCO2 showed highest correlations with pulmonary arterial pressure, transpulmonary pressure gradient and pulmonary vascular resistance. Several parameters showed high sensitivity and specificity for PAH detection by receiver operating characteristic analysis. However, peakVO2 showed highest diagnostic accuracy (sensitivity 87.5%, specificity 74.8% at a threshold level of 13.8 mL/min/kg). A peakVO2 of >18.7 mL/kg/min was reached by 38/173 patients (22%) and excluded PAH in our cohort (negative predictive value 1.0). A nadir VE/VCO2 ratio of >45.5 showed a positive predictive value of 1.0. Diagnostic accuracy was highest in patients with low pulmonary arterial wedge pressure (<12 mm Hg). There were no study-related serious adverse events.ConclusionsCPET is a safe and valuable method in the non-invasive detection of SSc-associated PAH. It may be particularly beneficial for reducing unnecessary RHC procedures.

Aim of this prospective study was to evaluate the effects of exercise training in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH). Thirty-five consecutive patients with invasively confirmed inoperable or residual CTEPH (16 women;19 men; mean age 61±15 years, mean pulmonary artery pressure, 63±20 mmHg; primary inoperable n = 33, persisting pulmonary hypertension after pulmonary endarterectomy n = 2) on stable disease-targeted medication received exercise training in-hospital for 3 weeks and continued at home for 15 weeks. Medication remained unchanged during the study period. Efficacy parameters have been evaluated at baseline, after 3 and 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of median 36.4 months (interquartile range 26.6-46.6 months). All patients tolerated exercise training without severe adverse events. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 61±54 meters after 3 weeks (p<0.001) and by 71±70 meters after 15 weeks (p = 0.001), as well as scores of quality-of-life questionnaire, peak oxygen consumption and maximal workload. NT-proBNP improved significantly after 3 weeks of exercise training (p = 0.046). The 1-year survival rate was 97%, 2-year survival rate was 94% and the 3-year-survival 86% respectively. Training as add-on to medical therapy may be effective in patients with CTEPH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further multicentric randomized controlled studies are needed to confirm these promising results. ClinicalTrials.gov NCT01398345.

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.

Background Systemic sclerosis (SSc) is a severe rheumatic disease of the interstitial tissue, in which heart and lung involvement can lead to disease-specific mortality. Our study tests the hypothesis that in addition to established prognostic factors, cardiopulmonary exercise testing (CPET) parameters, particularly peak oxygen uptake (peakVO 2 ) and ventilation/carbon dioxide (VE/VCO 2 )-slope, can predict survival in patients with SSc. Subjects and methods We retrospectively assessed 210 patients (80.9% female) in 6 centres over 10 years with pulmonary testing and CPET. Survival was analysed with Cox regression analysis (adjusted for age and gender) by age, comorbidity (Charlson-Index), body weight, body-mass index, extensive interstitial lung disease, pulmonary artery pressure (measured by echocardiography and invasively), and haemodynamic, pulmonary and CPET parameters. Results Five- and ten-year survival of SSc patients was 93.8 and 86.9%, respectively. There was no difference in survival between patients with diffuse (dcSSc) and limited cutaneous manifestation (lcSSc; p  = 0.3). Pulmonary and CPET parameters were significantly impaired. Prognosis was worst for patients with pulmonary hypertension ( p  = 0.007), 6-min walking distance < 413 m ( p  = 0.003), peakVO 2  < 15.6 mL∙kg − 1 ∙min − 1 , and VE/VCO 2 -slope > 35. Age (hazard ratio HR = 1.23; 95% confidence interval CI: 1.14;1.41), VE/VCO 2 -slope (HR = 0.9; CI 0.82;0.98), diffusion capacity (Krogh factor, HR = 0.92; CI 0.86;0.98), forced vital capacity (FVC, HR = 0.91; CI 0.86;0.96), and peakVO 2 (HR = 0.87; CI 0.81;0.94) were significantly linked to survival in multivariate analyses (Harrell’s C = 0.95). Summary This is the first large study with SSc patients that demonstrates the prognostic value of peakVO 2  < 15.6 mL∙kg − 1 ∙min − 1 (< 64.5% of predicted peakVO 2 ) and VE/VCO 2 -slope > 35.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected (p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients.

Exercise capacity and survival of patients with IPF is potentially impaired by pulmonary hypertension. This study aims to investigate diagnostic and prognostic properties of gas exchange during exercise and lung function in IPF patients with or without pulmonary hypertension. In a multicentre setting, patients with IPF underwent right heart catheterization, cardiopulmonary exercise and lung function testing during their initial evaluation. Mortality follow up was evaluated. Seventy-three of 135 patients [82 males; median age of 64 (56; 72 years)] with IPF had pulmonary hypertension as assessed by right heart catheterization [median mean pulmonary arterial pressure 34 (27; 43) mmHg]. The presence of pulmonary hypertension was best predicted by gas exchange efficiency for carbon dioxide (cut off ≥152% predicted; area under the curve 0.94) and peak oxygen uptake (≤56% predicted; 0.83), followed by diffusing capacity. Resting lung volumes did not predict pulmonary hypertension. Survival was best predicted by the presence of pulmonary hypertension, followed by peak oxygen uptake [HR 0.96 (0.93; 0.98)]. Pulmonary hypertension in IPF patients is best predicted by gas exchange efficiency during exercise and peak oxygen uptake. In addition to invasively measured pulmonary arterial pressure, oxygen uptake at peak exercise predicts survival in this patient population.

Background Although combination therapy is the gold standard for patients with pulmonary arterial hypertension (PAH), some of these patients are still being treated with monotherapy. Methods We conducted a retrospective analysis at four German PH centres to describe the prevalence and characteristics of patients receiving monotherapy. Results We identified 131 incident PAH patients, with a mean age of 64 ± 13.8 years and a varying prevalence of comorbidities, cardiovascular risk factors and targeted therapy. As in other studies, the extent of prescribed PAH therapy varied with age and coexisting diseases, and younger, so-called “typical” PAH patients were more commonly treated early with combination therapy (48% at 4–8 months). In contrast, patients with multiple comorbidities or cardiovascular risk factors were more often treated with monotherapy (69% at 4–8 months). Survival at 12 months was not significantly associated with the number of PAH drugs used (single, dual, triple therapy) and was not different between “atypical” and “typical” PAH patients (89% vs. 85%). Conclusion Although “atypical” PAH patients with comorbidities or a more advanced age are less aggressively treated with respect to combination therapy, the outcome of monotherapy in these patients appears to be comparable to that of dual or triple therapy in “typical” PAH patients.

Background Nasal high-flow oxygen therapy (HFOT) is a novel treatment option for patients suffering from acute or chronic respiratory failure. Aim of our study was to compare safety and efficacy of HFOT with those of conventional oxygen treatment (COT) in normo- and hypercapnic COPD patients. Methods A single cohort of 77 clinically stable hypoxemic patients with an indication for long-term oxygen treatment (LTOT) with or without hypercapnia successively received COT and HFOT for 60 min each, including oxygen adaption and separated by a 30 min washout phase. Results HFOT was well-tolerated in all patients. A significant decrease in PaCO 2 was observed during oxygen adaption of HFOT, and increased PaO 2 coincided with significantly increased SpO 2 and decreased AaDO 2 during both treatment phases. Even at a flow rate of 15 L/min, oxygen requirement delivered as air mixture by HFOT tended to be lower than that of COT (2.2 L/min). Not only was no increase in static or dynamic lung volumes observed during HFOT, but even was a significant reduction of residual lung volume measured in 36 patients (28%). Conclusions Thus, short-term use of HFOT is safe in both normocapnic and hypercapnic COPD patients. Lower oxygen levels were effective in correcting hypoxemic respiratory failure and reducing hypercapnia, leading to a reduced amount of oxygen consumption. Long-term studies are needed to assess safety, tolerability, and clinical efficacy of HFOT. Trial registration ClinicalTrials.gov NCT01686893 13.09.2012 retrospectively registered (STIT-1) and NCT01693146 14.09.2012 retrospectively registered (STIT-2). Studies were approved by the local ethics committee (Ethikkommission der Medizinischen Universität Innsbruck, Studienkennzahl UN3547, Sitzungsnummer 274/4.19).

Aims Pulmonary arterial hypertension (PAH) is often diagnosed in elderly patients with comorbidities. Although initial monotherapy is recommended for these patients, the value of combination therapy remains unclear. Here, we compare the efficacy of initial monotherapy and combination therapy in PAH patients with cardiovascular comorbidities. Methods and results Data from adult patients with incident pre‐capillary PAH and cardiovascular comorbidities from the COMPERA database (European registry for PH) were analysed. A matched‐pair analysis of patients treated with monotherapy versus combination therapy based on age, sex, WHO functional class (FC) and 4‐strata risk at baseline was performed. The matching strategy identified 216 pairs of PAH patients with cardiovascular comorbidities, who differed considerably from the enrolled patient population (n = 1871), especially in terms of mean age (mono: matched pairs 62.9 ± 13.5 years vs. 70.6 ± 11.4 years, combination: matched pairs 62.0 ± 13.6 years vs. 60.5 ± 14.9 years). In the matched‐pair analysis, the initial combination therapy group showed more pronounced improvements in WHO‐FC, N‐terminal pro–B‐type natriuretic peptide (BNP/NT‐proBNP) and risk status than patients treated with initial monotherapy, with no significant differences in 6‐min walk distance (6MWD), PAH‐related hospitalisations, survival and drug discontinuation. Conclusions This analysis suggests that PAH patients with comorbidities may benefit more pronounced from combination therapy regarding WHO‐FC, BNP/NT‐pro‐BNP and risk status without a significant difference in survival. Good tolerability is indicated. However, given the relatively younger patient matched subgroup, these findings may not necessarily apply to older patients with a wider range of comorbidities. AIM This analysis provides a comparison of the efficacy of initial mono and combination therapy in patients with PAH and cardiovascular comorbidities or with risk factors of HFpEF (heart failure with preserved ejection fractioin).METHOD Data from the European COMPERA registry were used for a matched pair analysis. Changes in clinical parameters, risk status and PAH‐related hospitalizations, survival and continuation of PAH treatment from baseline to follow‐up were assessed.FINDINGS 216 matched pairs of patients were identified. This cohort differed from the original one, especially in terms of age. At follow‐up patients with initial combination therapy showed greater improvements e.g. in risk status (fig.). No significant differences in survival were observed.Figure: Risk stratification at first follow‐up among patients with at least one cardiovascular comorbidity.