Cat eye syndrome: Clinical, cytogenetics and familial findings in a large cohort of 43 patients highlighting the importance of congenital heart disease and inherited cases.

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Risk assessment validation in patients with pulmonary arterial hypertension: Data from a Southern Brazil registry (RESPHIRAR study).

Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure and death. Registries are a valuable tool in the research of rare conditions such as PAH. Moreover, the risk assessment strategy has been validated in European and North American registries and has been reported to provide an accurate prediction of mortality and the clinical advantage of reaching low-risk status. However, there is no available data from Brazil. Thus, the aim of the present study was to describe the characteristics of a sample of PAH from Southern Brazil and to retrospectively validate the risk assessment at our population. The RESPHIRAR is a retrospective and multicentric registry on pulmonary hypertension. With a join collaboration from nine centers in Southern Brazil, demographics, clinical presentation, and hemodynamics data of PAH were collected between 2007 and 2017. Moreover, the REVEAL 2.0 and REVEAL 2.0 Lite risk assessments were validated in our population. Overall, 370 PAH patients were included in the present study. Patients were predominantly female (78.5%) and had a mean age of 41.8 ± 18.8 years. Most patients (33.4%) had idiopathic PAH, 30.2% had PAH associated with congenital heart disease, and 23.5% had PAH associated with connective tissue disease. The low-risk group showed significantly lower mortality than the intermediated- or high-risk group at diagnosis (p < 0.05). In conclusion, our data suggest that REVEAL 2.0 and REVEAL 2.0 Lite risk assessments can predict mortality risk in PAH patients in Southern Brazil.

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.

BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.

Soluble Guanylate Cyclase Stimulators (Riociguat) in Pulmonary Hypertension: Data from Real-Life Clinical Practice in a 3-Year Follow-Up. / Estimuladores de Guanilato Ciclase Solúvel (Riociguate) na Hipertensão Pulmonar: Dados da Prática Clínica Real em 3 Anos de Acompanhamento.

BACKGROUND: Pulmonary hypertension (PH) is a rare and complex disease with poor prognosis, which requires lifelong treatment. OBJECTIVE: To describe 3-year follow-up real-life data on treatment with soluble guanylate cyclase stimulators (Riociguat) of patients with PH, measuring current risk assessment parameters. METHODS: This study retrospectively collected clinical and epidemiological data of patients with PH of group 1 (pulmonary arterial hypertension) and group 4 (chronic thromboembolic PH). Non-invasive and invasive parameters corresponding to the risk assessment were analyzed at baseline and follow-up. Statistical analyses were performed using the SPSS 18.0 software, and p-values < 0.050 were considered statistically significant. RESULTS: In total, 41 patients receiving riociguat were included in the study. Of them, 31 had already completed 3 years of treatment and were selected for the following analysis. At baseline, 70.7% of patients were in WHO functional class III or IV. After 3 years of treatment, the WHO functional class significantly improved in all patients. In addition, the median of the 6-minute walk test (6MWT) significantly increased from 394 ± 91 m at baseline to 458 ± 100 m after 3 years of follow-up (p= 0.014). The three-year survival rate was 96.7%. CONCLUSION: In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially in the 6MWT, at 3 years of follow-up.

FUNDAMENTO: A hipertensão pulmonar (HP) é uma doença rara e complexa com prognóstico ruim, que exige tratamento pela vida toda. OBJETIVO: Descrever dados de 3 anos de acompanhamento da vida real sobre o tratamento com estimuladores de guanilato ciclase solúvel (Riociguate) de pacientes com HP, medindo parâmetros atuais de avaliação de risco. MÉTODOS: Coletamos dados clínicos e epidemiológicos retrospectivamente de pacientes com HP do grupo 1 (hipertensão arterial pulmonar) e do grupo 4 (HP tromboembólica crônica). Parâmetros não invasivos e invasivos correspondentes à avaliação de risco foram analisados na linha de base e no acompanhamento. Foram realizadas análises estatísticas usando o software SPSS 18.0, e os p-valores <0,050 foram considerados estatisticamente significativos. RESULTADOS: No total, 41 pacientes tratados com riociguate foram incluídos no estudo. Entre eles, 31 já concluíram 3 anos de tratamento e foram selecionados para a seguinte análise. Na linha de base, 70,7% dos pacientes estavam nas classes funcionais III ou IV da OMS. Depois de 3 anos de tratamento, a classe funcional da OMS melhorou significativamente em todos os pacientes. Além disso, a mediana do teste de caminhada de 6 minutos (TC6M) aumentou significativamente de 394 ± 91 m na linha de base para 458 ± 100 m após 3 anos de acompanhamento (p= 0,014). O índice de sobrevida após três anos foi de 96,7%. CONCLUSÃO: Em nossa coorte de vida real, a maioria dos pacientes com HP tratados com riociguate demonstraram parâmetros de risco estáveis ou melhores, especialmente no TC6M, aos 3 anos de acompanhamento.

Estimuladores de Guanilato Ciclase Solúvel (Riociguate) na Hipertensão Pulmonar: Dados da Prática Clínica Real em 3 Anos de Acompanhamento / Soluble Guanylate Cyclase Stimulators (Riociguat) in Pulmonary Hypertension: Data from Real-Life Clinical Practice in a 3-Year Follow-Up

Resumo Fundamento A hipertensão pulmonar (HP) é uma doença rara e complexa com prognóstico ruim, que exige tratamento pela vida toda. Objetivo Descrever dados de 3 anos de acompanhamento da vida real sobre o tratamento com estimuladores de guanilato ciclase solúvel (Riociguate) de pacientes com HP, medindo parâmetros atuais de avaliação de risco. Métodos Coletamos dados clínicos e epidemiológicos retrospectivamente de pacientes com HP do grupo 1 (hipertensão arterial pulmonar) e do grupo 4 (HP tromboembólica crônica). Parâmetros não invasivos e invasivos correspondentes à avaliação de risco foram analisados na linha de base e no acompanhamento. Foram realizadas análises estatísticas usando o software SPSS 18.0, e os p-valores <0,050 foram considerados estatisticamente significativos. Resultados No total, 41 pacientes tratados com riociguate foram incluídos no estudo. Entre eles, 31 já concluíram 3 anos de tratamento e foram selecionados para a seguinte análise. Na linha de base, 70,7% dos pacientes estavam nas classes funcionais III ou IV da OMS. Depois de 3 anos de tratamento, a classe funcional da OMS melhorou significativamente em todos os pacientes. Além disso, a mediana do teste de caminhada de 6 minutos (TC6M) aumentou significativamente de 394 ± 91 m na linha de base para 458 ± 100 m após 3 anos de acompanhamento (p= 0,014). O índice de sobrevida após três anos foi de 96,7%. Conclusão Em nossa coorte de vida real, a maioria dos pacientes com HP tratados com riociguate demonstraram parâmetros de risco estáveis ou melhores, especialmente no TC6M, aos 3 anos de acompanhamento.

Abstract Background Pulmonary hypertension (PH) is a rare and complex disease with poor prognosis, which requires lifelong treatment. Objective To describe 3-year follow-up real-life data on treatment with soluble guanylate cyclase stimulators (Riociguat) of patients with PH, measuring current risk assessment parameters. Methods This study retrospectively collected clinical and epidemiological data of patients with PH of group 1 (pulmonary arterial hypertension) and group 4 (chronic thromboembolic PH). Non-invasive and invasive parameters corresponding to the risk assessment were analyzed at baseline and follow-up. Statistical analyses were performed using the SPSS 18.0 software, and p-values < 0.050 were considered statistically significant. Results In total, 41 patients receiving riociguat were included in the study. Of them, 31 had already completed 3 years of treatment and were selected for the following analysis. At baseline, 70.7% of patients were in WHO functional class III or IV. After 3 years of treatment, the WHO functional class significantly improved in all patients. In addition, the median of the 6-minute walk test (6MWT) significantly increased from 394 ± 91 m at baseline to 458 ± 100 m after 3 years of follow-up (p= 0.014). The three-year survival rate was 96.7%. Conclusion In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially in the 6MWT, at 3 years of follow-up.

Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension.

Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient's current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy-weight: ≥40 kg; middle-weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six-minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2-17.9 years) and majority (71.4%, n = 25) of patients were in the heavy-weight cohort. Least square mean (standard error) changes from baseline in six-minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo-adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator's reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non-invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING: Bayer AG, Merck Sharp & Dohme.

Sotatercept for the Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).

Parasympathetic modulation withdrawal improves functional capacity in pulmonary arterial hypertension.

In 15 pulmonary arterial hypertension patients, the relation of functional capacity to their peripheral endothelial function and sympathaovagal modulation was studied by carrying out brachial artery ultrasound and electrocardiogram spectral analysis, respectively. The functional capacity was assessed by cardiopulmonary exercise testing and six-minute walking test. The sympathovagal modulation was correlated with the predicted peak oxygen consumption (peak VO2 %; r = 0.692, P < 0.05), peak O2 pulse (mL/beat; r = 0.661, P < 0.05), VE, minute ventilation, VCO2 carbon dioxide production (VE/VCO2 slope; r=-0.806, P < 0.01) and distance walked predicted (%6MWT; r = 0.694, P < 0.05). Moreover, there were negative correlations between parasympathetic modulation with peak VO2 (r = 0.755, P < 0.01), peak VO2% (r=-0.727, P < 0.01) and peak O2 pulse (r = 0.615, P < 0.05), %6MWT (r=-0.834, P < 0.01). Collectively these correlations indicate that parasympathetic withdrawal is crucial for improving functional capacity. This conclusion is supported by both positive and negative correlations of parasympathetic modulation with the functional capacity parameters. The sympathetic modulation predominance, although increases the cardiovascular risk, is probably crucial to facilitate the bronchodilation and the oxygen uptake.

Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Relationship between right atrium area and right ventricular ejection fraction on magnetic resonance imaging: comparison with other prognostic markers in patients with pulmonary arterial hypertension / Comparação da relação da área do átrio direito e fração de ejeção do ventrículo direito por ressonância magnética com outros marcadores prognósticos de pacientes com hipertensão arterial pulmonar

Abstract Objective: To compare the right atrium (RA) area and right ventricular ejection fraction (RVEF) with other known prognostic markers in patients with pulmonary arterial hypertension (PAH). Materials and Methods: This was a retrospective study of 74 patients diagnosed with PAH by right heart catheterization at a referral center between January 2018 and May 2018. All of the patients underwent cardiac magnetic resonance imaging (MRI) within 3 months of the right heart catheterization (RHC), as well as undergoing echocardiography, a 6-minute walk test, and determination of the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) within a month of the RHC. We attempted to determine whether the cardiac MRI-derived RA area correlated with ions between RVEF and RA area measured by that determined by echocardiography, as well as whether the cardiac MRI-derived RA area and RVEF correlated with the 6-minute walk distance and NT-proBNP level. Results: The MRI-derived RA area demonstrated a weak correlation with the pulmonary vascular resistance measured by RHC (r = 0.268; p = 0.055) and a moderate correlation with the NT-proBNP (r = 0.429; p = 0.003). All correlations between clinical characteristics and the RVEF were statistically significant. In the univariate linear analysis, the RVEF showed stronger correlations with the clinical characteristics than did the RA area. Conclusion: In patients with PAH, cardiac MRI-derived RVEF appears to correlate more strongly with other prognostic factors than does RA area.

Resumo Objetivo: Comparar a área do átrio direito (AD) e a fração de ejeção do ventrículo direito (FEVD) com outros marcadores prognósticos conhecidos em pacientes com hipertensão arterial pulmonar (HAP). Materiais e Métodos: Identificamos, retrospectivamente, 74 pacientes com diagnóstico de HAP por cateterismo cardíaco direito em um centro de referência, no período de 3 meses da ressonância magnética cardíaca (RMC), entre janeiro de 2018 e maio de 2018, que também realizaram ecocardiograma, teste de caminhada de 6 minutos e fração N-terminal do pró-peptídio natriurético tipo B (NT-proBNP) dentro de um mês. Foram realizadas correlações entre a FEVD e a área do AD avaliada por RMC com parâmetros como: ecocardiograma, teste de caminhada de 6 minutos e NT-proBNP. Resultados: A correlação entre a área do AD demonstrou correlação fraca com a resistência vascular pulmonar (r = 0,268; p = 0,055) e correlação moderada com NT-proBNP (r = 0,429; p = 0,003). Todas correlações entre parâmetros clínicos e a FEVD foram estatisticamente significantes. Na análise linear univariada, a FEVD apresentou maior correlação com as variáveis de desfecho clínico do que a área do AD. Conclusão: Ambos, FEVD e área AD por RMC, estão correlacionados com marcadores de prognóstico clínico; no entanto, a FEVD apresentou correlações mais fortes e significativas em relação à área do AD.

Relationship between right atrium area and right ventricular ejection fraction on magnetic resonance imaging: comparison with other prognostic markers in patients with pulmonary arterial hypertension.

OBJECTIVE: To compare the right atrium (RA) area and right ventricular ejection fraction (RVEF) with other known prognostic markers in patients with pulmonary arterial hypertension (PAH). MATERIALS AND METHODS: This was a retrospective study of 74 patients diagnosed with PAH by right heart catheterization at a referral center between January 2018 and May 2018. All of the patients underwent cardiac magnetic resonance imaging (MRI) within 3 months of the right heart catheterization (RHC), as well as undergoing echocardiography, a 6-minute walk test, and determination of the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) within a month of the RHC. We attempted to determine whether the cardiac MRI-derived RA area correlated with ions between RVEF and RA area measured by that determined by echocardiography, as well as whether the cardiac MRI-derived RA area and RVEF correlated with the 6-minute walk distance and NT-proBNP level. RESULTS: The MRI-derived RA area demonstrated a weak correlation with the pulmonary vascular resistance measured by RHC (r = 0.268; p = 0.055) and a moderate correlation with the NT-proBNP (r = 0.429; p = 0.003). All correlations between clinical characteristics and the RVEF were statistically significant. In the univariate linear analysis, the RVEF showed stronger correlations with the clinical characteristics than did the RA area. CONCLUSION: In patients with PAH, cardiac MRI-derived RVEF appears to correlate more strongly with other prognostic factors than does RA area.

Correction to: Multiparametric Magnetic Resonance Imaging in the Assessment of Pulmonary Hypertension: Initial Experience of a One-Stop Study.

The original version of this article unfortunately contained a mistake. There is a typo in the coauthor name, it should be Stephan Altmayer.

Multiparametric Magnetic Resonance Imaging in the Assessment of Pulmonary Hypertension: Initial Experience of a One-Stop Study.

INTRODUCTION: Our goal was to assess the diagnostic performance of magnetic resonance imaging (MRI) as a single method to diagnose pulmonary hypertension (PH) compared to right heart catheterization (RHC), computed tomography (CT), and ventilation/perfusion (V/Q) scintigraphy. METHODS: We identified 35 patients diagnosed with PH by RHC in our institution who have also undergone a CT, a scintigraphy, and an MRI within a month. All cases were discussed in multidisciplinary meetings. We performed correlations between the MRI-derived hemodynamic parameters and those from RHC. The sensitivity and specificity of MRI were determined to identify its diagnostic performance to identify chronic thromboembolic pulmonary hypertension (CTEPH) and interstitial lung disease PH. The gold standard reference for the diagnosis of CTEPH and ILD was based on a review of multimodality imaging (V/Q scintigraphy and CT scan) and clinical findings. RESULTS: Our results showed a good correlation between the hemodynamic parameters of cardiac MRI and RHC. Pulmonary vascular resistance had the best correlation between both methods (r = 0.923). The sensitivity and specificity of MRI to diagnose CTEPH was 100 and 96.8%, respectively. For the ILD-related PH, the MRI yielded a sensitivity of 60.0% and a specificity of 100%. Additionally, cardiac MRI was able to confirm all cases of PAH due to congenital heart disease initially detected by echocardiography. CONCLUSIONS: MRI represents a promising imaging modality as an initial, single-shot study, for patients with suspected PH with the advantages of being non-invasive and having no radiation exposure.

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension.

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated.In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event.

Hipertensão pulmonar devido à doença cardíaca esquerda / Pulmonary hypertension due to Heart Disease Left

A hipertensão pulmonar associada à doença cardíaca esquerda (HP-DCE) é a forma mais comum de hipertensão pulmonar encontrada na prática clínica atual. Embora freqüentemente alvo de terapia, a sua fisiopatologia permanece mal compreendida e seu tratamento permanece indefinido. Hipertensão pulmonar no contexto da doença cardíaca esquerda é um marcador de pior prognóstico e de gravidade da doença. Porém, desconhecemos se o seu tratamento primário é benéfico ou prejudicial. Um passo importante para o estudo futuro deste problema clínico será a padronização das definições e critérios diagnóstico...

Pulmonary hypertension associated with left heart disease (HP-ECD) is the most common form of pulmonary hypertension found in current clinical practice. Although often being target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of poor prognosis and severity of the disease. However, its primary treatment is not known to be beneficial or harmful. An important step for the future study of this clinical problem is the standardization of definitions and diagnostic criteria...

Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients.

BACKGROUND: The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study. METHODS: Exploratory efficacy outcomes included 6-minute walk distance (6 MWD) and WHO FC. Adverse events were recorded. Kaplan-Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. RESULTS: Median exposure to bosentan (n=173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations>3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6 MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. CONCLUSIONS: The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.