cardiac metabolism, as well, were similar between mutation carriers and noncarriers. Conclusions-Despite a similar afterload, RV function is more severely affected in mutation carriers than in noncarriers. However, these differences cannot be explained by a differential transforming growth factor β, bone morphogenetic protein receptor II signaling, or cardiac adaptation. response to rather than the amount of pressure overload determines the fate of the RV in PAH patients. Patients with PAH may have an underlying genetic predisposition, in particular, a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene.5-11 BMPR2 mutations are an autosomal dominant cause of PAH with reduced penetrance (14% in men, 42% in women) clinically characterized by a younger age and a more severe hemodynamic compromise at presentation in comparison with patients who have idiopathic PAH. 10,[12][13][14][15] The bone morphogenetic protein (BMP) receptor II encoded by the BMPR2 gene belongs to the transforming growth factor β (TGF-β) superfamily and mutations have been shown to result in a disturbed BMP/TGF-β balance. [16][17][18] Decreased BMP receptor II activity leads to an overactivated TGF-β signaling, which stimulates vasculogenesis, intimal hyperplasia, and medial smooth muscle growth in the pulmonary vasculature. 19,20 In addition, growing evidence suggests a key role for TGF-β signaling in the response to pressure overload of the heart. 21-23Although TGF-β signaling is necessary to protect the heart against uncontrolled matrix degradation and dilatation, excessive TGF-β signaling might be detrimental because of maladapted hypertrophy and myocardial dysfunction, as previously described in left heart failure. [21][22][23] Furthermore, a recent study by Hemnes et al 24 showed that the RV hypertrophic response was disturbed in pulmonary hypertensive mice carrying a BMPR2 mutation. However, whether RV function and adaptation in PAH patients carrying a BMPR2 mutation differs from PAH patients without an identified BMPR2 mutation remains currently elusive. Therefore, the aim of this study was 2-fold: (1) to determine the effects of a BMPR2 mutation on RV function in PAH patients and (2) to compare the histological and morphological characteristics of RV tissue samples from PAH patients with and without a BMPR2 mutation. Methods Study Population Clinical StudyWe retrospectively reviewed patients with pulmonary hypertension seen at the VU University Medical Center (Amsterdam, the Netherlands) between March 1995 and October 2014. Patients were eligible for this study when the results from BMPR2 mutation analysis were available. In total, 123 PAH patients were genetically screened for the presence of a BMPR2 mutation. After the exclusion of 28 patients, 95 patients were included in this study. Twenty-eight patients were carriers of a BMPR2 mutation (mutation carriers), and no BMPR2 mutation was identified in 67 sporadic PAH patients (noncarriers). Patients with a family history of PAH with no evidence of a BMPR2 mutation ...

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