[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.

Prognostic impact of follow-up pulmonary vascular resistance in pulmonary arterial hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH), caused by pulmonary artery remodelling and increased pulmonary vascular resistance (PVR) due to an unknown mechanism, is an intractable disease with a poor prognosis. The recent development of PAH-specific treatment medications may allow for higher PVR reduction than previously achieved. This study aimed to identify the prognostic significance of follow-up PVR levels achieved shortly after the initiation of targeted treatment in patients with idiopathic/heritable pulmonary arterial hypertension (I/H-PAH). METHODS: We analysed the data of all patients with I/H-PAH admitted to our hospital between 1998 and 2019. We collected data at baseline and during the first invasive haemodynamic evaluation. The primary outcome was death or lung transplantation. RESULTS: Of the 133 treatment-naïve patients enrolled in this study, 47 experienced adverse events during a median follow-up period of 6.4 (IQR 3.5-11.5) years. The median time interval to first follow-up from diagnosis was 162 (IQR 117-253) days. Incidence of the primary outcome was significantly lower in patients who achieved low PVR at follow-up. Of risk factors evaluated at follow-up, the multivariate Cox regression analysis revealed PVR as an independent predictor of the primary outcome (HR 1.103, 95% CI 1.029 to 1.183; p=0.006). The results were consistent across risk profiles according to the simplified risk stratification recommended by the European Society of Cardiology and European Respiratory Society guidelines. CONCLUSION: Follow-up PVR was an independent predictor of transplant-free survival in patients with I/H-PAH. Evaluation of haemodynamic status shortly after initiating treatment may help predict long-term prognosis.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

New prognostic markers in pulmonary arterial hypertension: CRP to albumin ratio and uric acid.

INTRODUCTION: Idiopathic pulmonary hypertension(IPAH) is a rare disease that causes severe morbidity and mortality despite advances in treatment management. Evaluating the prognosis of the disease is critical in determining therapeutic approaches. We aimed to evaluate the prognostic significance of C-reactive protein/albumin ratio (CAR) and uric acid, which is an easily applicable and inexpensive parameter in patients with IPAH. METHODS: Seventy-two IPAH patients and 99 consecutive non-IPAH patients as a control group were enrolled in the study retrospectively. Right heart catheterization(RHC), echocardiography, and laboratory parameters of the two groups and those who died and survived among the IPAH patients were compared. RESULTS: IPAH and control group were compared at the first stage and CAR (1.98(0.28-10.74), 0.75(0.22-4.7),respectively;p < 0.01) and uric acid (0.33(0.19-0.87), 0.3(0.11-0.48) mmol/L, respectively; p = 0.03) values were significantly higher in the pulmonary hypertension group compared to the control group. Compared with the surviving IPAH patients, CAR (4.60(1.39-10.74),1.54(0.28-6.74),respectively;p < 0.001) and uric acid levels (0.458(0.26-0.87), 0.315(0.19-0.56) mmol/L, respectively; p < 0.001) were significantly higher in the group of patients who died. In the multivariate Cox regression models uric acid(p < 0.001) and CAR(p < 0.001) were found to be associated with survival time. Receiver operating characteristic curves (ROC) analyses showed that > 1.54 CAR value (AUC = 0.81,Sens:85.7%,Spec:56.9%,p < 0.001) and > 5.85 mg/dL (>0.348 mmol/L) uric acid value (AUC = 0.864, Sens:85.7%, Spec:78.4%, p < 0.001) are strong predictors for mortality. CONCLUSION: In this study, we showed that simple markers such as CAR, which augment the inflammation marker feature of CRP, and uric acid can give prognostic information in PAH patients.

Inhibiting miR­1 attenuates pulmonary arterial hypertension in rats.

MicroRNAs (miRs) are reported to serve key roles in pulmonary arterial hypertension (PAH). miR­1 has been found in cardiovascular diseases. The present study aimed to determine whether the knockdown of miR­1 could inhibit right ventricle (RV) remodeling and thereby control PAH in model rats. PAH model rats were established by exposing rats to hypoxia, while cardiac fibroblasts (CFs) obtained from PAH model rats were treated with hypoxia to establish an in vitro model, and RV remodeling was evaluated by Masson staining and the levels of collagen I, collagen III, α­smooth muscle actin (α­SMA) and connective tissue growth factor (CTGF) evaluated by western blotting or reverse transcription­quantitative PCR. The results revealed that the expression levels of miR­1 were upregulated in the RV of PAH model rats induced with hypoxia and in the CFs treated with hypoxia. The mean pulmonary arterial pressure, RV systolic pressure, RV/(left ventricle + interventricular septum) and RV/tibia length were increased in PAH rats; however, the increases in all parameters were subsequently reversed by transfection with a miR­1 antagomiR in PAH model rats. The transfection with the miR­1 antagomiR inhibited the development of RV fibrosis and downregulated the mRNA expression levels of collagen I, collagen III, α­SMA and CTGF in the RV tissue of PAH model rats. The upregulation of collagen I, collagen III, α­SMA and CTGF expression levels in hypoxia­treated CFs was also subsequently reversed by miR­1 antagomiR transfection. The expression levels of collagen I, collagen III, α­SMA and CTGF were also upregulated in the CFs obtained from PAH model rats, and these increases were attenuated by miR­1 antagomiR transfection. The expression levels of phosphorylated (p)­PI3K and p­AKT were also upregulated in hypoxia­treated CFs, and these increases were also inhibited by transfection with miR­1 antagomiR. In conclusion, these results indicated that inhibiting miR­1 may attenuate RV hypertrophy and fibrosis in PAH model rats, a mechanism that may involve the PI3K/AKT signaling pathway.

Extracorporeal membrane oxygenation and lung transplantation: initial experience at a single brazilian center

OBJECTIVE: To report initial experience from the use of extracorporeal membrane oxygenation (ECMO) in patients who received lung transplantation. METHODS: Retrospective study of a single tertiary center in the Brazilian state of São Paulo, a national reference in lung transplantation, based on the prospective collection of data from electronic medical records. The period analyzed extended from January 2009 (beginning of the program) until December 2018. RESULTS: A total of 75 lung transplants were performed, with ECMO used in 8 (10.7%) cases. Of the patients, 4 (50%) were female. The mean age was 46.4±14.3 years. The causes of the end-stage lung disease that led to transplantation were pulmonary arterial hypertension in 3 (37.5%) patients, bronchiectasis in 2 (25%) patients, pulmonary fibrosis in 2 (25%) patients, and pulmonary emphysema in 1 (12.5%) patient. In our series, 7 (87.5%) cases were sequential bilateral transplantations. Prioritization was necessary in 4 (50%) patients, and in 1 patient, ECMO was used as a bridge to transplantation. The ECMO route was central in 4 (50%), peripheral venovenous in 2 (25%) and peripheral venoarterial in 2 (25%) patients. The mean length of the intensive care unit (ICU) stay was 14±7.5 days and of the hospital stay was 34.1±34.2 days. The mean ECMO duration was 9.3±6.6 days with a 50% decannulation rate. Three patients were discharged (37.5%). CONCLUSION: Lung transplantation requires complex treatment, and ECMO has allowed extending the indications for transplantation and provided adjuvant support in the clinical management of these patients.

Successful multimodality management of severe pulmonary arterial hypertension during pregnancy with VA-ECMO and atrial septostomy using stent.

A 30-year-old Thai woman (gravida 1, para 0) at 33 weeks gestation was referred to our hospital due to acute right ventricular failure. Pulmonary vasodilators were gradually administered before delivery. On the verge of sudden postpartum cardiac circulation collapse, she was resuscitated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Abdominal compartment syndrome was developed in the early period of the mechanical support. Knowledge of pathophysiology about pulmonary arterial hypertension during pregnancy was applied. Atrial septostomy was the effective procedure for discontinuing mechanical support (VA-ECMO) corresponding to the suitable timing for maximal effect of pulmonary vasodilators. The patient and her child were safe and discharged in 2 months after the admission.

Emergency caesarean section delivery and puerperium in a patient with severe idiopathic pulmonary arterial hypertension - a case report.

BACKGROUND: The aim of this paper is to describe the third pregnancy trimester, delivery and puerperium in patient with idiopathic pulmonary hypertension. CASE REPORT: a 30-year-old primigravida with idiopathic pulmonary hypertension was qualified for emergency Caesarean section. In the post partum period no improvement in managing pulmonary arterial hypertension was achieved. Because of progressive respiratory and circulatory failure as well as the pulmonary artery pressure exceeding the systemic pressure the AV ECMO was applied on postoperative day 6. During the ECMO period the emergency laparotomy due to bleeding was necessary. The further course of ICU treatment was uneventful. CONCLUSION: In described case things are left to chance or goodwill of specialists and final outcome depend on happy coincidences.

Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-ß) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.

Idiopathic pulmonary arterial hypertension with coexisting CHD.

Sinus venosus atrial septal defect can result in an increase in pulmonary blood flow and vascular resistance, leading to pulmonary hypertension. Rarely, the degree of pulmonary hypertension is out of proportion to the degree of intra-cardiac shunting. This case outlines the differences between pulmonary hypertension secondary to CHD and idiopathic pulmonary hypertension, and illustrates the investigation and management strategy used in a patient with features of both.

[Analysis of prognosis and associated risk factors in pediatric idiopathic pulmonary arterial hypertension].

Objective: To analyze the prognosis and associated risk factors of pediatric idiopathic pulmonary arterial hypertension. Methods: A total of 119 patients under 18 years of age diagnosed as idiopathic pulmonary arterial hypertension in the Pulmonary Arterial Hypertension Center in Beijing Anzhen Hospital between June 2007 and May 2017 were enrolled in this retrospective study. The clinical informations and follow-up data were collected. The endpoints of follow-up were defined as death or undergoing lung transplantation. Kaplan-Meier survival curve was used to assess the survival,and the COX risk regression model was used to analyze the prognostic risk factors. Results: The mean age at diagnosis was (5.9±4.2) years. For 92 (77.5%) patients, the main reason for visit was decreased activity with shortness of breath after exercise. Seventy patients (58.8%) were in baseline NYHA functional class Ⅲ-Ⅳ and 49 patients (41.2%) were in NYHA functional class Ⅰ-Ⅱ. The mean systolic pulmonary arterial pressure estimated by echocardiography was (90±23) mmHg (1 mmHg=0.133 kPa) . Right heart catheterization was performed in 50 patients. Hemodynamic parameters revealed that the mean pulmonary artery pressure was (66±19) mmHg. Mean right atrium pressure was (8.5±3.4) mmHg. Mean pulmonary vascular resistance index was (17±9) wood·m(2) and the mean cardiac index was (3.4±1.3)L/m(2); 100 patients (84.0%) received targeted therapy in which 55 patients (46.2%) were on monotherapy,40 patients (33.6%) were on dual therapy and 5 patients (4.2%) were on triple therapy. The mean time of follow-up was 22.0 months (0-108 months). During follow-up, 43 patients (36.1%) died and 1 patient received double-lung transplantation. Main causes of death including right heart failure, pulmonary hypertension crisis, asphyxia and massive hemoptysis. The mean survival time from diagnosis was 37.0 months,1-,2-,3-and 5-year survival rates were 86.3%, 72.2%, 51.4%and 37.8% respectively. Survival analysis showed that patients in baseline NYHA functional class Ⅰ-Ⅱ had better prognosis. COX regression analysis showed that NYHA function class, edema, increased total bilirubin and troponin concentration and the pulmonary artery and aorta diameter ratio measured by echocardiogram are risk factors of pediatric IPAH (HR=2.310, 2.723, 1.066, 1.696, 3.719, P=0.028, 0.005, 0.001, 0.024, 0.030) . While the existence of aterial septal defect or patent foramen ovale, using bosentan and phosphodiesterase inhibitors(,) dual or triple therapy were protective factors (HR=0.563, 0.559, 0.603, 0.682, 0.044, P=0.169, 0.076, 0.115, 0.258, 0.220) . In multivariate analysis only edema associated with decreased survival (HR=2.398, P=0.025) . Conclusion: Childhood idiopathic pulmonary arterial hypertension patients are seriously ill at visit. Worse cardiac function classification at visit associate with high mortality. Target therapy including using bosentan, dual or triple therapy can improve survival.

Management of Adults With Congenital Heart Disease and Pulmonary Arterial Hypertension in the UK: Survey of Current Practice, Unmet Needs and Expert Commentary.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a well-recognised complication of adult congenital heart disease (CHD). However, management is not currently standardised between centres and specific guidelines are lacking. In order to identify and understand the unmet needs related to PAH associated with CHD (PAH-CHD), a survey of physicians was performed. METHODS: An electronic survey was sent to two physician groups: (1) cardiologists registered in a UK cardiology directory; (2) specialist pulmonary hypertension (PH) physicians known to manage patients with adult PAH-CHD. The questions related to referral pathways, screening, therapy and palliative care. RESULTS: 821 surveys were distributed and 106 were returned. Respondents included a broad mix of specialist physicians with many patients along with general cardiologists managing only a small number of PAH-CHD patients. Although 97% of respondents have access to a specialist PH centre, patients are still being managed in non-specialist settings. Shared care arrangements are widespread but only 41% have formal shared care protocols. Palliative care services are limited and general cardiologists rarely perform 6-minute walk tests (6MWT) or quality of life assessments. People with PAH-CHD are often undertreated, with 39% of respondents reporting that fewer than 25% of these patients were receiving PAH-specific therapies. CONCLUSIONS: The survey revealed gaps and inconsistencies in the management of patients with PAH-CHD therefore patient-specific guidance is needed for many of these aspects.

Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.

Pulmonary arterial hypertension (PAH) is a rare but serious disease with a grave prognosis. Bone morphogenetic protein type 2 receptor (BMPR2) gene is a strong pathogenic factor for PAH. As a collaborative team from Kyorin University and Keio University in Japan, we have analyzed the BMPR2 gene in 356 probands and more than 50 family members, including secondary patients. Importantly, the study population is a racially, ethnically, and socially homogeneous population. In PAH patients, there is a high incidence of unique mutations in BMPR2, and several mutations are frequently observed in the Japanese population, suggesting that these common and recurring mutations may be highly pathogenic or have high penetrance, explaining why they are found frequently throughout the world. We have also mapped each breakpoint of exonic deletions/duplications and found that most break and rejoining points are in the Alu elements. Reviewing the distribution of the reported mutations on each exon of BMPR2 revealed that the number and frequency of mutations are imbalanced among exons. The penetrance of BMPR2 gene mutations was 3-fold higher in females than males. Full elucidation of BMPR2-mediated pathogenic mechanisms in PAH requires persistent efforts to achieve precision or individualized medicine as a therapeutic strategy for PAH.

Lung and heart-lung transplantation in pulmonary arterial hypertension.

BACKGROUND: Real use of lung (LT) and heart-lung (HLT) transplantation in pulmonary arterial hypertension (PAH) is unknown. The objectives were to describe the indication of these procedures on PAH treatment in a national cohort of PAH patients, and to analyze the potential improvement of its indication in severe patients. METHODS: Eligibility for LT/HLT was assessed for each deceased patient. Incident patients from REHAP diagnosed between January 2007 and March 2015 and considered eligible for LT/HLT were grouped as follows: those who finally underwent transplantation (LTP) and those who died (D-Non-LT). FINDINGS: Of 1391 patients included in REHAP, 36 (3%) were LTP and 375 (27%) died. Among those who died, 36 (3%) were D-Non-LT. LTP and D-Non-LT were equal in terms of age, gender, and clinical status. Ten percent of those who died were functional class I-II. Patients functional class IV were less likely to undergo LT (8.3% LTP vs. 30.6% D-Non-LT, p = 0.017). Patients with idiopathic and drug/toxin-associated PAH were more likely to undergo LT (44.4% LTP vs. 16.7% D-Non-LT, p = 0.011). CONCLUSIONS: The present results show that the use of LT/HLT could double for this indication. Relevant mortality in early functional class reflects the difficulties in establishing the risk of death in PAH.

Heritable pulmonary hypertension: from bench to bedside.

Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation.

Safety and Efficacy of Immunoadsorption as an Add-On to Medical Treatment in Patients with Severe Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: Despite optimized medical therapy, severe idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease with a poor outcome. Autoantibodies have been detected in IPAH that can contribute to worsening of the disease. OBJECTIVES: The objective of this prospective, open-label, single-arm, multicenter trial was to evaluate the safety and efficacy of immunoadsorption (IA) as an add-on to optimized medical treatment for patients with IPAH. METHODS: A total of 10 IPAH patients received IA over 5 days. Their clinical parameters, including hemodynamics measured by right heart catheter, were assessed at baseline and after 3 and 6 months. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included the change in 6-min walking distance, quality of life, safety, and plasma levels of IgG and autoantibodies. RESULTS: The evaluation of the 10 IPAH patients (75% female; 51 ± 12 years; 166 ± 10 cm; WHO functional class III; 53% on combination therapy) revealed that IA was a safe procedure that efficiently removed IgG and autoantibodies from the circulation. After 3 months, the mean PVR improved significantly by 13.2% (p = 0.03) and the cardiac index improved by 13.1%, but no significant changes were found in 6-min walking distance. The quality of life physical functioning subscale score significantly improved after 6 months. The serious adverse events in 3 patients were possibly related to IA and included pneumonia, temporary disturbance in attention, and thrombocytopenia. CONCLUSIONS: IA as an add-on to targeted medical treatment for IPAH is a safe procedure with beneficial effects on hemodynamics, especially in patients with high levels of autoantibodies. Larger-scale controlled studies are needed to assess its efficacy in IPAH and to identify responders.