Clinical Implications of Determining BMPR2 Mutation Status in a Large Cohort of Children and Adults With Pulmonary Arterial Hypertension Erika B. Rosenzweig, MD, a Jane H. Morse, MD, a James A. Knowles, MD, PhD, a Kiran K. Chada, PhD, b Amar M. Khan, MD, a Kari E. Roberts, MD, a Jude J. McElroy, AB, a Nicole K. Juskiw, a Nicole C. Mallory, a Stuart Rich, MD, c Beverly Diamond, MD, a and Robyn J. Barst, MD a Background: Bone morphogenetic protein receptor type 2 (BMPR2) mutations occur in idiopathic and familial pulmonary arterial hypertension (IPAH, FPAH); however, the impact of these mutations on clinical assessment and disease severity remains unclear. We investigated the role of BMPR2 mutations on acute vasoreactivity and disease severity in IPAH/FPAH children and adults. Methods: BMPR2 mutation types were determined in 147 IPAH/FPAH patients. Hemodynamics were obtained at baseline and with acute vasodilator testing. Results: Of 147 patients (69 adults, 78 children; 114 with IPAH, 33 with FPAH), 124 (84%) were BMPR2 mutation-negative, and 23 (16%) were mutation-positive. BMPR2 mutation-positive patients were less likely to respond to acute vasodilator testing than mutation-negative patients (4% vs 33%; p  0.003; n = 147). BMPR2 mutation-positive children also appeared less likely to respond to acute vasodilator testing than mutation-negative children. BMPR2-positive patients had lower mixed venous saturation (57  9% vs 62  10%; p  0.05) and cardiac index (CI; 2.0  1.1 vs 2.4  1.5 liters/min; p  0.05) than BMPR2-negative patients. Conclusions: Patients with BMPR2 mutations are less likely to respond to acute vasodilator testing than mutation-negative patients and appear to have more severe disease at diagnosis. Determination of BMPR2 mutations appears to help identify IPAH/FPAH children and adults who are unlikely to respond to acute vasodilator testing and, thus, unlikely to benefit from calcium channel blockade (CCB) treatment. J Heart Lung Transplant 2008;27:668 –74. Copyright © 2008 by the International Society for Heart and Lung Transplantation. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by right ventricular failure and death if untreated. Bone morphogenetic protein type 2 (BMPR2) mutations have been identified in idiopathic pulmonary arterial hypertension (IPAH) and familial pulmonary arterial hypertension (FPAH). 1–4 Although there have been significant advances in the treatment of PAH with disease-specific targeted therapies, there is still no cure. Furthermore, choice of “optimal” medical treatment remains challenging due to our inability to predict which agent will be most efficacious for a given patient. 5,6 To date, the only method to predict whether a patient will respond favorably to a given treatment is by determining their response to acute vasodilator testing during right heart cardiac catheterization. 7–9 Patients with a robust response to acute vasodilator testing, with no change or an increase in cardiac output, may benefit from long-term oral calcium chan- nel blockade (CCB). 10 These patients, with appropriate treatment, also appear to have a slower disease progres- sion than those without a significant acute vasodilator testing response. 7,9 Elliot et al 11 reported that IPAH and FPAH adult patients with BMPR2 mutations are less likely to respond to acute vasodilator testing than BMPR2 mutation-negative patients. However, the signif- icance of BMPR2 mutations in IPAH and FPAH children has not yet been described. Furthermore, the impact of BMPR2 mutations and mutation type on disease severity and/or clinical course remains unclear. The objectives of our study were to determine: (1) whether BMPR2 mutations are associated with From the a Department of Pediatric Cardiology, Columbia University College of Physicians & Surgeons, New York, New York; b University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey; and c Section of Cardiology, University of Chicago, Chicago, Illinois. Submitted December 12, 2007; revised February 8, 2008; accepted February 17, 2008. Supported by Grant No. HL-060056 from the NIH-NHLBI (to J.H.M.). Reprint requests: Erika Berman Rosenzweig, MD, Department of Pediatric Cardiology, Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 255, New York, NY 10032. Telephone: 212-305-4436. Fax: 212-342-1443. E-mail: esb14@columbia.edu Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.02.009 668 PULMONARY HYPERTENSION