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Acute Vasoreactivity and Genetic Polymorphisms in IPAH/FPAH Children and Adults

Erika Berman Rosenzweig


Jane Morse


M. Khan

B. Diamond

J. Knowles

Robyn Barst


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Conference: 2006 International PHA Conference and Scientific Sessions

Release Date: 06.23.2006

Presentation Type: Abstracts

Rosenzweig EB, Morse J, Khan M, Diamond B, Knowles J, Barst RJ.

Columbia University College of Physicians & Surgeons, New York, NY

BACKGROUNDMutations of Bone Morphogenetic Protein Receptor II gene (BMPR2) have been identified in patients with idiopathic pulmonary arterial hypertension (IPAH) and patients with familial pulmonary arterial hypertension (FPAH), however the impact of these mutations on disease severity and clinical course has yet to be determined. We analyzed whether BMPR2 mutations are associated with response to acute vasodilator testing (AVT) since AVT, has been used to predict: 1) acute pulmonary vascular bed "reactivity" as well as 2) response to long-term treatment with calcium channel blockade (CCB), i.e. patients who are responsive to AVT may be treated successfully with CCB.

METHODS:  BMPR2 mutations were determined by nucleic acid sequencing of all 13 exons and exon counting using MLPA kits. All comparisons were made using the Fisher’s exact test. Acute pulmonary vasoreactivity was defined and analyzed by two different criteria: #1) decrease in mean pulmonary arterial pressure (PAPm) > 20% without a decrease in cardiac output and the more recently described criteria #2) decrease of PAPm >10mmHg to PAPm < 40mmHg with a normal cardiac output.

RESULTSIn total, 163 patients, 114 patients (49 adult; 65 children) with IPAH and 49 patients (34 adult; 15 children) with FPAH were included in this analysis. 55 patients were acute responders, and 107 were non-responders, according to definition #1. According to definition #2, 46 patients were responders, and 116 were non-responders. 76% (n=124) of patients were BMPR2 negative and 24% (n=39) of patients were BMPR2 positive. We found that patients with BMPR2 mutations were less likely to have a positive response to AVT than BMPR2 negative patients (p<.0001). In addition, regardless of BMPR2 status, FPAH patients were less likely to respond to AVT than IPAH patients (p<0.0001). IPAH/FPAH children were also more likely to respond to AVT than IPAH/FPAH adults.

CONCLUSIONSPatients who are positive for BMPR2 mutations are less likely to respond to AVT than BMPR2 negative patients. In addition, previously not reported 1) regardless of BMPR2 status, FPAH patients are less likely than IPAH patients to respond to AVT, and 2) FPAH children were more likely to respond to AVT than adult FPAH patients. Furthermore, overall, children were more likely to respond to AVT than adults. While these data support the utility of determining BMPR2 mutation in identifying patients who are unlikely to respond to CCB therapy, identifying additional genetic polymorphisms that may predict efficacy with other targeted PAH therapeutic modalities are warranted.