Successful Tricuspid Valve Replacement in a Patient with Severe Pulmonary Arterial Hypertension and Preserved Right Ventricular Systolic Function

A 56-year-old patient with severe pulmonary hypertension developed severe tricuspid regurgitation, right-sided heart failure, and congestive hepatopathy. She was transferred for possible lung transplant and/or tricuspid valve surgery. Clinical and echocardiographic assessment provided confidence that acute tricuspid valve failure was responsible for the decompensation and that tricuspid valve replacement despite pulmonary hypertension could be performed

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

Background Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. Methods AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. Results This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. Conclusions Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe

Developing Pulmonary Vasculopathy in Systemic Sclerosis, Detected with Non-Invasive Cardiopulmonary Exercise Testing

BACKGROUND: Patients with systemic sclerosis (SSc) may develop exercise intolerance due to musculoskeletal involvement, restrictive lung disease, left ventricular dysfunction, or pulmonary vasculopathy (PV). The latter is particularly important since it may lead to lethal pulmonary arterial hypertension (PAH). We hypothesized that abnormalities during cardiopulmonary exercise testing (CPET) in patients with SSc can identify PV leading to overt PAH. METHODS: Thirty SSc patients from the Harbor-UCLA Rheumatology clinic, not clinically suspected of having significant pulmonary vascular disease, were referred for this prospective study. Resting pulmonary function and exercise gas exchange were assessed, including peakVO2, anaerobic threshold (AT), heart rate-VO2 relationship (O2-pulse), exercise breathing reserve and parameters of ventilation-perfusion mismatching, as evidenced by elevated ventilatory equivalent for CO2 (VE/VCO2) and reduced end-tidal pCO2 (PETCO2) at the AT. RESULTS: Gas exchange patterns were abnormal in 16 pts with specific cardiopulmonary disease physiology: Eleven patients had findings consistent with PV, while five had findings consistent with left-ventricular dysfunction (LVD). Although both groups had low peak VO2 and AT, a higher VE/VCO2 at AT and decreasing PETCO2 during early exercise distinguished PV from LVD. CONCLUSIONS: Previously undiagnosed exercise impairments due to LVD or PV were common in our SSc patients. Cardiopulmonary exercise testing may help to differentiate and detect these disorders early in patients with SSc

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)

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants

Une approche multidimensionnelle de l’optimisation de la radioprotection

Le principe d’optimisation de la radioprotection est souvent associé à la nécessité de prendre en compte la dimension collective du risque sanitaire. En réalité l’optimisation et l’approche collective de la radioprotection ne devraient pas être confondues. Il est en effet possible d’aborder l’optimisation en intégrant les multiples dimensions du détriment sanitaire. A titre d’illustration une méthode d’optimisation multicritère a été mise en œuvre dans le contexte de la détermination des niveaux «ALARA» pour le cycle du combustible PWR. Une telle méthode a permis de tenir compte simultanément du risque sanitaire et du risque associé aux groupes critiques. Les résultats obtenus montrent que l’optimisation ainsi conçue permet de réaliser une synthèse satisfaisante de l’approche traditionnelle dite individuelle et de l’approche collective. De façon générale, la crédibilité de la procédure d’optimisation dépendra pour une bonne part de la manière dont on aura su tenir compte de la multi- dimensionnalité inhérente à la plupart des choix de radioprotection

Quelques considérations sur l’évaluation technico-économique des choix de protection radiologique

Cet article propose une interprétation du principe d’optimisation dans une perspective pragmatique qui est celle de l’évaluation technico- économique des choix de protection radiologique. Ce processus comporte plusieurs étapes qui sont présentées brièvement et dont on discute ensuite l’importance relative, compte tenu de l’impact économique des choix de protection que l’on soumet à l’évaluation