© 2008 American Thoracic Society doi: 10.1164/rccm.200804-495ED
BMPR2 Mutation and Outcome in Pulmonary Arterial HypertensionClinical Relevance to Physicians and Patients
University of California, San Diego Despite major advances in the treatment of pulmonary arterial hypertension (PAH), the pathogenesis of this condition remains obscure. An array of cellular and molecular abnormalities develop in PAH that may cause or contribute to the angioproliferative phenotype characteristic of this condition (1); distinguishing those that are primary initiating events from those that are "second hits," or simply markers of vascular injury with little or no pathogenic role, constitutes a major challenge that will require collaboration between basic scientists and clinicians (2). The identification of mutations in the bone morphogenetic protein receptor 2 gene (BMPR2) in a substantial proportion of patients with a family history of PAH is one of the most significant advances in unraveling the pathogenesis of this disease (3, 4). This discovery has sparked a wealth of research that has led to a clearer understanding of how functional abnormalities in the BMPR2 pathway, either inherited or acquired, may lead to pulmonary vascular proliferation (5–7). Until recently, however, the clinical information derived from PAH population genotyping has been conflicting and provided limited insight. In this issue of the Journal (pp. 1377–1383), Sztrymf and colleagues (8) provide physicians and patients alike with a clearer understanding of the impact of BMPR2 mutations on the natural history of PAH. Among their important observations, Sztrymf and colleagues found that 20% of patients with no family history of PAH were found to have a mutation in BMPR2, suggesting that hereditable disease may be more common than currently appreciated. They also found that subjects with BMPR2 mutation, regardless of family history, had a more severe form of the disease, presenting at an earlier age and with more deranged hemodynamics as compared with those lacking the mutation. Although survival was comparable in both groups, patients with BMPR2 mutation were more likely to be treated with parenteral prostacyclin therapy or undergo transplantation. Taken together, their findings imply that, through mechanisms incompletely understood, the BMPR2 mutation induces a particularly aggressive form of PAH. The demonstration in this and in another recent study (9) that subjects with BMPR2 mutation are less likely to manifest acute vasoreactivity in response to testing with short-acting vasodilator agents such as nitric oxide or epoprostenol is consistent with the notion that vascular proliferation, rather than vasoconstriction, is the hallmark of PAH in this population, at least by the time their disease is clinically manifested. Although routine screening for BMPR2 mutations is neither widely available nor recommended in management guidelines for PAH (10), a number of international collaborative studies afford patients with PAH and their family members the capability to be tested. Such efforts may be important at two levels: for the medical community in their mission to both define the molecular basis of PAH and to identify other mutations that may contribute to the development of PAH, and for patients and their physicians in implementing a management strategy that is based, in part, on the unique features of their form of disease. Although PAH is classified as an orphan disease, it is perhaps more appropriately considered as a syndrome, characterized by elevations in pulmonary arterial pressure and manifested by symptoms due to right ventricular dysfunction, resulting from a variety of predispositions and external stimuli, which, in turn, may influence disease severity and natural history. The recognition that the natural history of subsets of PAH varies may have implications for future clinical trials in PAH: Although it may be impossible to include sufficient numbers of patients from each subset to allow a reliable assessment of treatment responses based on etiology, stratification for balance and subgroup analyses may provide some insight into the relative importance of specific pathogenic pathways in PAH subsets, generate strategies for targeting specific patient populations in future trials, and provide guidance to physicians regarding contemporary management of patients within subsets. The study by Sztrymf and colleagues reminds us that, despite how far we've come in our understanding of PAH and its management, we still have a long way to go. Although survival in their cohort was considerably better than that reported in the National Institutes of Health Registry (11) before the advent of medical and surgical treatments, median time to death or transplantation was, nevertheless, only about 10 years. Clinical trials addressing new therapeutic targets and strategies that optimize current therapies, including combination trials, are vitally important, but their implementation will be hampered by the limited patient pool. Accordingly, although therapies for PAH have evolved from invasive to simple, making the care of patients with PAH possible in the community, patients and physicians will be best served by referral to expert centers, where collaborative and translational efforts will further our understanding of this condition and lead to more effective treatments in the future. The study by Sztrymf and colleagues, representing such a collaborative effort at a national level, highlights the value of this approach. FOOTNOTES Conflict of Interest Statement: L.J.R. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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