Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF‐β cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice‐site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense‐mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell‐based systems. Disease‐causing mutation hot‐spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age‐ and sex‐dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated. Hum Mutat 27(2), 121–132, 2006.

Background— Right ventricular failure is a leading cause of death in patients with chronic pulmonary hypertension (PH). We checked whether detection of cardiac troponin T (cTnT), a specific marker of myocyte injury, could be useful in prognostic stratification of those patients. Methods and Results— Initial evaluation of 56 clinically stable patients (age 41±15 years) with pulmonary arterial (51 patients) or inoperable chronic thromboembolic (5 patients) PH (mean pulmonary arterial pressure 60±18 mm Hg) included cTnT test, allowing detection of its serum levels ≥0.01 ng/mL [cTnT(+)]. cTnT was detectable in 8 of 56 (14%) patients (mean±SD, 0.034±0.022; range, 0.010 to 0.077 ng/mL). Despite similar pulmonary hemodynamics, they had higher heart rate (92±15 versus 76±14 bpm, P =0.004), lower mixed venous oxygen saturation (50±10% versus 57±9%, P =0.04), and higher serum N-terminal pro-B–type natriuretic peptide (4528±3170 versus 2054±2168 pg/mL, P =0.03) and walked less during the 6-minute walk test (298±132 versus 396±101 m, P =0.02). Cumulative survival estimated by Kaplan-Meier curves was significantly worse at 24 months in cTnT(+) compared with cTnT(−) (29% versus 81%, respectively, log-rank test P =0.001). Multivariate analysis revealed cTnT status (hazard ratio, 4.89; 95% CI, 1.18 to 20.29; P =0.03), 6-minute walk test (hazard ratio, 0.93 for each 10 m; P =0.01), and pulmonary vascular resistance (hazard ratio, 1.13; P =0.01) as independent markers of mortality. All 3 cTnT(+) patients who survived the follow-up period converted to cTnT(−) during treatment. Conclusions— Detectable cTnT is a so-far ignored independent marker of increased mortality risk in patients with chronic precapillary PH, supporting the role of progressive myocyte injury in the vicious circle leading to hemodynamic destabilization.

Background— This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II ( BMPR2 ) gene. Methods and Results— TRV was estimated by Doppler echocardiography during supine bicycle exercise in normoxia and during 120 minutes of normobaric hypoxia (F io ₂ =12%; ≈4500 m) in 291 relatives of 109 PAH patients and in 191 age-matched control subjects. Mean maximal TRVs were significantly higher in PAH relatives during both exercise and hypoxia. During exercise, 10% of control subjects but 31.6% of relatives ( P <0.0001) exceeded the 90% quantile of mean maximal TRV seen in control subjects. Hypoxia revealed hypertensive TRV in 26% of relatives ( P =0.0029). Among control subjects, TRV at rest was not related to age, sex, body mass index, systemic blood pressure, smoking status, or heart rate. Within kindreds identified as harboring deleterious mutations of the BMPR2 gene, a hypertensive TRV response occurred significantly more often compared with those without detected mutations. Conclusions— Pulmonary hypertensive response to exercise and hypoxia in idiopathic/familial PAH relatives appears as a genetic trait with familial clustering, being correlated to but not caused by a BMPR2 mutation. The suitability of this trait to predict manifest PAH development should be addressed in long-term follow-up studies.