Genetic background of pulmonary (vascular) diseases - how much is written in the codes?

PURPOSE OF REVIEW: To provide a comprehensive overview of the underlying genetic defects of pulmonary (vascular) diseases and novel treatment avenues. RECENT FINDINGS: Pulmonary arterial hypertension (PAH) is the prime example of a pulmonary vascular disease, which can be caused by genetic mutations in some patients. Germline mutations in the BMPR2 gene and further genes lead to vessel remodelling, increase of pulmonary vascular resistance and onset of heritable PAH. The PAH genes with the highest evidence and strategies for genetic testing and counselling have been assessed and evaluated in 2023 by international expert consortia. Moreover, first treatment options have just arisen targeting the molecular basis of PAH. SUMMARY: Apart from PAH, this review touches on the underlying genetic causes of further lung diseases including alpha 1 antitrypsin deficiency, cystic fibrosis, familial pulmonary fibrosis and lymphangioleiomyomatosis. We point out the main disease genes, the underlying pathomechanisms and novel therapies trying not only to relieve symptoms but to treat the molecular causes of the diseases.

[Pulmonary hypertension in adults with congenital heart disease in light of the 2022-ESC-PAH guidelines - Part II: Supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management (shunt lesions, left ventricular disorders, univentricular hearts), interventions, intensive care, follow-up, future perspectives]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern im Lichte der 2022-ESC-PAH-Leitlinien.

The number of adults with congenital heart defects (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary hypertension (PH), which may develop early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart disease" is addressed only relatively superficial in these guidelines. Therefore, in the present article, this topic is commented in detail from the perspective of congenital cardiology.

Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. METHODS: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. RESULTS: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. CONCLUSION: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

The effect of exercise training and physiotherapy on left and right heart function in heart failure with preserved ejection fraction: a systematic literature review.

The impact of exercise training and physiotherapy on heart function and pulmonary circulation parameters in heart failure with preserved ejection fraction (HFpEF) patients is uncertain. Hence, we performed a systematic review of published trials studying physical training in HFpEF population, with a focus on exercise and physiotherapy effect on left ventricular (LV), right ventricular (RV) morphological, functional, and pulmonary circulation parameters. We searched Cochrane Library and MEDLINE/PubMed for trials that evaluated the effect of exercise training and/or physiotherapy in adult HFpEF patients (defined as LVEF ≥ 45%), including publications until March 2021. Our systematic review identified eighteen articles (n = 418 trained subjects, 4 to 52 weeks of training) and covered heterogeneous trials with various populations, designs, methodologies, and interventions. Five of twelve trials revealed a significant reduction of mitral E/e' ratio after the training (- 1.2 to - 4.9). Seven studies examined left atrial volume index; three of them showed its decrease (- 3.7 to - 8 ml/m2). Findings were inconsistent regarding improvement of cardiac output, E/A ratio, and E wave DecT and uncertain for RV function and pulmonary hypertension parameters. For now, no reliable evidence about rehabilitation effect on HFpEF cardiac mechanisms is available. There are some hypotheses generating findings on potential positive effects to parameters of LV filling pressure (E/e'), left atrium size, cardiac output, and RV function. This encourages a broader and more complex assessment of parameters reflecting cardiac function in future HFpEF exercise training studies.

Tolerability, safety and survival in patients with severe pulmonary arterial hypertension treated with intravenous epoprostenol (Veletri®): a prospective, 6-months, open label, observational, non-interventional study.

BACKGROUND: Epoprostenol AS (Veletri®), a thermostable epoprostenol formulation, provides better drug stability and improved clinical use compared to previous epoprostenol formulations. This study aims to expand clinical experience in the use of Veletri®, especially regarding tolerability, safety and survival. METHODS: Pulmonary arterial hypertension (PAH) patients at high risk despite pretreatment with at least double oral combination therapy and with clinical indication for epoprostenol (Veletri®) treatment were consecutively included in this prospective, open label, observational, non-interventional study. Clinical data were assessed at baseline, after 3 and 6 months. Adverse events (AEs) and serious adverse events (SAEs) were documented. Survival from initiation of Veletri® was assessed at last patient out. RESULTS: Fifteen patients (60 ± 13.7 years, WHO functional class III (n = 10) or IV (n = 5), severely impaired right ventricular function, mean pulmonary arterial pressure 54.8 ± 8.9 mmHg, mean pulmonary vascular resistance 4.4 ± 0.7 (median 3.8) Wood Units) were enrolled and treated with a mean dosage of 7.9 ± 3.9 (median 7.5) ng/kg/min. Eleven patients completed the study (treatment withdrawal n = 1, death n = 3). After a mean follow-up of 19.1 ± 13.5 (median 18.0) months, seven patients died and three were listed for lung transplantation. Seven AEs (nausea n = 3, diarrhea n = 1, flushing n = 2, headaches n = 1) and three SAEs (catheter infection n = 2, catheter occlusion n = 1) were related to Veletri®. The 1- and 2-year survival rates were 73.3% and 52.4%, respectively. CONCLUSIONS: The study showed that safety and tolerability of epoprostenol AS (Veletri®) was comparable to previous prostacyclin formulations and was feasible for most patients. The maximum tolerable dosage was lower than dosages reported in the literature. In future applications/trials the up-titration process should be pushing for higher dosages of epoprostenol in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients. Survival was as expected in these prevalent severely impaired patients. Trial registration The study was registered in the EUPAS registry (EUPAS32492).

Long-Term Safety, Outcome, and Clinical Effects of Subcutaneous and Intravenous Treprostinil Treatment in Patients with Severe Chronic Pulmonary Arterial Hypertension.

BACKGROUND: Current guidelines recommend treatment with parenteral prostacyclin analogs in patients with severe pulmonary arterial hypertension (PAH), who have insufficient response to treatment. Real-life data are sought to help physicians in treatment decisions and clinical care of patients. OBJECTIVE: This study analyzed safety, clinical effects, and long-term outcomes of subcutaneous (sc) and/or intravenous (iv) treprostinil via different pump systems in consecutive patients with PAH. METHODS: Thirty-seven patients with severe progressive PAH despite dual combination therapy (20 female, mean age: 52.3 ± 15 years, mean pulmonary vascular resistance: 12.1 ± 5.1 WU) were initiated with add-on treprostinil sc and were routinely clinically assessed. Changes in clinical parameters, adverse events, and outcome were analyzed retrospectively. RESULTS: In 24 of 37 patients, treprostinil administration was continued iv via implantation of LENUS Pro® pump after 3 ± 1.3 months, 6 patients continued with sc therapy, and 7 discontinued treatment. After 3, 6, 9, and 12 months of treprostinil treatment, patients showed a significant improvement in mean 6-min walk distance and tricuspid annular plane systolic excursion compared to baseline. In 8 of the 24 patients, iv pumps required surgical revision. During a mean follow-up of 2.82 ± 1.95 years, 12 patients died, four received lung transplantation. Transplant-free survival after 1, 2, and 3 years was 85.7%, 69.2%, and 65.3%, respectively. CONCLUSION: sc treprostinil as add-on to double combination treatment significantly improved exercise capacity and right heart function. In most patients, treprostinil could be continued via more tolerable iv administration approach (LENUS Pro® pump), showing reasonable overall survival with respect to the severity of PAH.

Genetics of High-Altitude Pulmonary Edema.

High-altitude pulmonary edema (HAPE) is the main cause of nontraumatic death at high altitude. HAPE development is not only related to the mode and speed of ascent and the maximum altitude reached, but also individual susceptibility plays an important role. In susceptible individuals, hypoxic pulmonary vasoconstriction leads to exaggerated elevated pulmonary arterial pressures and capillary leakage in the lungs. Thus, this review provides an overview of studies investigating the genetic background in HAPE susceptibles by focusing on specific variants, entire genes, genome-wide signatures, or family studies.

[New aspects in pediatric pulmonary hypertension - Commented 2022ERS/ESC-PH guidelines]. / Neue Aspekte bei der pulmonalen Hypertonie im Kindesalter ­ kommentierte 2022ERS/ESC-PH-Guidelines.

Pulmonary hypertension (PH) in childhood differs from that of adulthood particularly in the specific pathophysiology of congenital heart disease-associated pulmonary arterial hypertension, the presence of developmental lung disease, and the frequent association with chromosomal, genetic, and syndromal abnormalities. Treatment of children with PH requires a modified diagnostic algorithm tailored to childhood, as well as pathophysiologically oriented therapeutic strategies. In the current 2022 ERS/ESC-PH guidelines, the specific features of PH in children are highlighted in its own chapter and commented on by the authorship group in this article.

[Genetic diagnostics and molecular approaches in pulmonary arterial hypertension]. / Genetische Diagnostik und molekulare Ansätze bei pulmonalarterieller Hypertonie.

The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments.

[Pulmonary arterial hypertension in congenital heart disease - Part I]. / Pulmonale arterielle Hypertonie bei Erwachsenen mit angeborenen Herzfehlern ­ Teil I.

The number of adults with congenital heart disease (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary arterial hypertension (PAH), which may develop early in untreated CHD. Despite timely treatment of CHD, PAH often persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is addressed only relatively superficially in these guidelines. Therefore, this article addresses the perspective of congenital cardiology in greater depth.

Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.

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. These 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.

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

AIMS: This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group. CONCLUSION: This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.

Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension.

BACKGROUND: Iron deficiency affects up to 50% of patients with pulmonary arterial hypertension (PAH) but iron markers such as ferritin and serum iron are confounded by several non-disease related factors like acute inflammation and diet. The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients. METHODS: In this single-center, retrospective study we assessed indicators of iron status and clinical parameters specifying the time to clinical worsening (TTCW) and survival in PAH patients at time of initial diagnosis and at 1-year follow-up using univariable and multivariable analysis. RESULTS: In total, 150 patients were included with an invasively confirmed PAH and complete data on iron metabolism. The proportion of hypochromic erythrocytes > 2% at initial diagnosis was identified as an independent predictor for a shorter TTCW (p = 0.0001) and worse survival (p = 0.002) at initial diagnosis as well as worse survival (p = 0.016) at 1-year follow-up. Only a subset of these patients (64%) suffered from iron deficiency. Low ferritin or low serum iron neither correlated with TTCW nor survival. Severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001). CONCLUSIONS: The presence of hypochromic erythrocytes > 2% was a strong and independent predictor of mortality and shorter TTCW in this cohort of PAH patients. Thus, it can serve as a valuable indicator of iron homeostasis and prognosis even in patients without iron deficiency or anemia. Further studies are needed to confirm the results and to investigate therapeutic implications.

Effect of Supervised Training Therapy on Pulmonary Arterial Compliance and Stroke Volume in Severe Pulmonary Arterial Hypertension and Inoperable or Persistent Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Pulmonary arterial compliance (PAC) is a prognostic parameter in pulmonary arterial hypertension (PAH) reflecting the elasticity of the pulmonary vessels. OBJECTIVES: The objective of this post hoc analysis of a prospective randomized controlled trial (RCT) was to assess the effect of exercise training on PAC and stroke volume (SV) in patients with PAH and persistent/inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHOD: From the previous RCT, 43 out of 87 patients with severe PAH (n = 29) and CTEPH (n = 14) had complete haemodynamic examinations at baseline and after 15 weeks by right heart catheterization and were analysed (53% female, 79% World Health Organization functional class III/IV, 58% combination therapy, 42% on supplemental oxygen therapy, training group n = 24, and control group n = 19). Medication remained unchanged for all patients. RESULTS: Low-dose exercise training at 4-7 days/week significantly improved PAC (training group 0.33 ± 0.65 mL/mm Hg vs. control group -0.06 ± 1.10 mL/mm Hg; mean difference 0.39 mL/mm Hg, 95% confidence interval [CI] 0.15-0.94 mL/mm Hg; p = 0.004) and SV (training group 9.9 ± 13.4 mL/min vs. control group -4.2 ± 11.0 mL/min; mean difference 14.2 mL, 95% CI 6.5-21.8 mL; p < 0.001) in the training versus control group. Furthermore, exercise training significantly improved cardiac output and pulmonary vascular resistance at rest, peak oxygen consumption, and oxygen pulse. CONCLUSIONS: Our findings suggest that supervised exercise training may improve right ventricular function and PAC at the same time. Further prospective studies are needed to evaluate these findings.

The Experience, Prerequisites, and the Barriers in Organizing a Specialized Rehabilitation Program for Patients with Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a severe progressive disease, associated with reduced exercise capacity and poor quality of life. Although scientific evidence supports the incorporation of specialized training in the treatment of PH, it is only available in a few countries. OBJECTIVES AND METHODS: This article aims to share the experience of implementing a PH rehabilitation program, to summarize the barriers and prerequisites for launching this service, and to assess its early effect. We retrospectively analyzed our pathway in organizing this program, by singling out essential steps. RESULTS: The preparation phase took about 14 months. Establishing and running of a PH rehabilitation program required dedicated rehabilitation specialists to join the multidisciplinary PH expert team. Team members needed to gain special knowledge on exercise training in severely compromised patients; thus, supervision and education by experienced consultants was crucial. The main eligibility criteria for patients were stable status, optimal medical treatment, and motivation to undergo the training. The first results evaluating the effect of a specialized PH training program in 9 patients are promising. Seven of them improved their functional capacity over the period of 15 weeks. CONCLUSIONS: Despite a number of challenges and barriers, the implementation of a specialized rehabilitation program should be encouraged in a few dedicated PH expert centers per country, who are capable to fulfill all prerequisites and organizational aspects. Local PH experts, supervision by an experienced center, in-patient rehabilitation facilities, dedicated personnel, equipment, and patient motivation are essential.

Risk stratification and prognostic factors in patients with pulmonary arterial hypertension and comorbidities a cross-sectional cohort study with survival follow-up.

BACKGROUND: The objective of this study was to analyze prognostic factors and risk stratification in patients with pulmonary arterial hypertension (PAH) and comorbidities. METHODS: Patients with invasively diagnosed PAH were included in the analysis. Comorbidities were clinically diagnosed as proposed in the 6th World Symposium of pulmonary hypertension. Uni- and multivariate analysis were employed for identification of factors predicting survival and time to first clinical worsening (TTCW). Risk stratification was based on parameters from ESC/ERS-guidelines 2015. RESULTS: In total 142 patients were enrolled in the study, 90 of them were diagnosed as PAH without and 52 with comorbidities. All patients received targeted PAH therapy and were followed for 3.3 ± 2.4 years. In PAH patients without comorbidities survival and TTCW were significantly associated with reduced 6-min walking distance (6MWD), elevated N-terminal pro brain natriuretic peptide (NT-proBNP), WHO-functional class (WHO-FC) and right atrial (RA) area. In the multivariate analysis, 6MWD was an independent predictor for survival (p = 0.002) and WHO-FC for TTCW (p = 0.001). In patients with PAH and comorbidities these parameters had no significant association with survival and TTCW. Average risk score was significantly associated with survival (p = 0.001) and TTCW (p = 0.013) in PAH but not in PAH with comorbidities (both p > 0.05; figure 1). CONCLUSION: Risk stratification based on ESC/ERS-guidelines could only be confirmed in patients without comorbidities, but not in patients with PAH and comorbidities. The data of this study suggest, that a different risk stratification needs to be applied to PAH patients with comorbidities. Further studies are needed to confirm these results. TRIAL REGISTRATION: Not applicable, retrospective registry.

Supervised Exercise Training in Patients with Chronic Thromboembolic Pulmonary Hypertension as Early Follow-Up Treatment after Pulmonary Endarterectomy: A Prospective Cohort Study.

BACKGROUND: Data on exercise training in chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA) as well as data on clinical and haemodynamic changes shortly after PEA are lacking. OBJECTIVE: The objective of this prospective study was to analyse the safety, feasibility, and the effectiveness of combined supervised inpatient rehabilitation in patients with CTEPH directly after PEA. METHODS: CTEPH patients started a 19-week rehabilitation program (3 weeks as inpatients and continued at home for another 16 weeks) with supervised exercise training as follow-up treatment shortly after PEA. Haemodynamics were assessed by right heart catheterisation before PEA and 22 weeks after PEA. Non-invasive assessments as transthoracic echocardiography and 6-min walking distance (6MWD) were performed before PEA and after 3 (that is, beginning of rehabilitation), 6, and 22 weeks following PEA. Adverse events were recorded throughout the study. RESULTS: Forty-five CTEPH patients were included (49% female, 57.6 ± 12.4 years old, 60% WHO functional class III). Rehabilitation was started 3.3 ± 0.9 weeks after PEA. Exercise training was well tolerated in all patients without severe side effects. Haemodynamics measured by right heart catheterisation significantly improved from pre-PEA to 22 weeks post-PEA in cardiac output (+1.2 ± 1.5 L/min, 33.4%, p = 0.001) and mean pulmonary arterial pressure (-19 ± 13 mm Hg, -39.6%, p < 0.0001). Right heart size measured by echocardiography, 6MWD, quality of life, and oxygen saturation significantly improved not only within the first 3 weeks after PEA but also during the following 19 weeks of exercise training. CONCLUSIONS: Supervised exercise training was feasible as early follow-up treatment after PEA. Further controlled studies are needed to discriminate the effects of PEA and early follow-up rehabilitation. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov (NCT01393327) on July 13, 2011. The study start date was January 2010, and completion date was December 2013.

Myeloproliferative Diseases as Possible Risk Factor for Development of Chronic Thromboembolic Pulmonary Hypertension-A Genetic Study.

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.