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In a family with pulmonary arterial hypertension, whole-exome sequencing led to identification of a mutation in the potassium-channel gene KCNK3 . Additional mutations resulting in loss of function of the channel were found in other families and in patients with idiopathic disease. Pulmonary arterial hypertension is a rare disease that is characterized by increased pulmonary-artery pressure in the absence of common causes of pulmonary hypertension, such as chronic heart, lung, or thromboembolic disease. 1 Before the advent of novel therapies, patients with idiopathic or familial pulmonary arterial hypertension had an estimated median survival of 2.8 years, with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34%, respectively. 2 However, despite progress in treatment, pulmonary arterial hypertension remains a progressive, fatal disease. The clinical presentation can be nonspecific, and patients often receive a diagnosis late in their clinical course. The cause of pulmonary . . .

Florent Soubrier and colleagues report a genome-wide association study of pulmonary arterial hypertension. They identify a susceptibility locus near CBLN2 associated with a twofold elevated risk of developing this life-threatening disease. Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases 1 , 2 , 3 . We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59–2.45; P = 7.47 × 10 −10 ). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.

The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.

There are limited data on the management of pulmonary arterial hypertension (PAH) in the elderly; therefore, this analysis compared the safety and efficacy of tadalafil between patients ≥65 and <65 years old. This was a post hoc analysis of the randomized, double-blind, placebo-controlled phase 3 Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST-1) study. Patients who completed the 16-week study or who discontinued because of clinical worsening and were not receiving tadalafil 40 mg were eligible for a long-term, open-label extension study. Adverse events (AEs) and efficacy outcomes were assessed in patients ≥65 versus <65 years old, and the dose dependency of common AEs was determined. Twenty-eight percent (112 of 405) of patients were ≥65 years of age (mean in this subset, 72 ± 5 years). Compared with younger patients, elderly patients were more likely to be World Health Organization functional class III/IV (75% vs. 65%, respectively) and to have lower exercise capacity as assessed by 6-minute walk distance (6MWD; mean, 299 vs. 366 m). Compared with placebo, tadalafil increased 6MWD by a mean of 35 and 43 m in patients ≥65 and <65 years, respectively. Common AEs (including headache, dyspepsia, and myalgia) were similar in both groups and tended to decrease in incidence with longer treatment duration. No differences in AEs were observed between elderly patients who received tadalafil 20 or 40 mg. In conclusion, the safety and efficacy of tadalafil for treatment of PAH are similar between elderly patients and patients <65 years old.

This review discusses biomarkers that are being researched for their usefulness to phenotype chronic inflammatory lung diseases that cause remodeling of the lung's architecture. The review focuses on asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension. Biomarkers of environmental exposure and specific classes of biomarkers (noncoding RNA, metabolism, vitamin, coagulation, and microbiome related) are also discussed. Examples of biomarkers that are in clinical use, biomarkers that are under development, and biomarkers that are still in the research phase are discussed. We chose to present examples of the research in biomarker development by diseases, because asthma, COPD, and pulmonary hypertension are distinct entities, although they clearly share processes of inflammation and remodeling.

The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial. We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥ 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥ 25 mm Hg was used. Among 572 subjects, 11.2% had TRV ≥ 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥ 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV ≥ 3.0 m/sec. At 24 months the cumulative survival was 83% with TRV ≥ 3.0 m/sec and 98% with TRV < 3.0 m/sec (p < 0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p < 0.0001) for TRV ≥ 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP ≥ 160 pg/mL, and 14.9 (5.5-39.9; p < 0.0001) for both TRV ≥ 3.0 m/sec and NT-proBNP ≥ 160 pg/mL. Age > 47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death. A TRV ≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.

The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.

Atrial septostomy has improved haemodynamics and clinical symptoms in selected patients with idiopathic pulmonary arterial hypertension. We found that, in 5 patients with idiopathic pulmonary arterial hypertension, septostomy resulted in decreased levels of brain-type natriuretic peptide, and improvement in symptoms of cardiac failure, suggesting that serial measurements of the peptide may have clinical utility.