Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle
Background—The effect of a mutation in the bone morphogenetic protein receptor 2 gene (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension (PAH) is unknown. Therefore, we investigated RV function in PAH-patients with and without BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular (LV) tissue.
Methods and Results—In total, 95 idiopathic or familial PAH patients were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, 67 patients did not have a BMPR2 mutation. In vivo measurements were assessed using right heart catheterization (RHC) and cardiac magnetic resonance imaging. Despite a similar mean pulmonary artery pressure (non-carriers 54±15 vs. mutation carriers 55±9 mmHg) and pulmonary vascular resistance (755 (483-1043) vs. 931 (624-1311) dynes*s/cm5), mutation carriers presented with a more severely compromised RV function (RV ejection fraction: 37.6±12.8 vs. 29.0±9 %: p<0.05, cardiac index 2.7±0.9 vs. 2.2±0.4 l/min/m2). Differences continued to exist after treatment. To investigate the role of TGF-β and BMPRII signaling, human RV and LV tissue were studied in controls (n=6), mutation carriers (n=5) and non-carriers (n=11). However, TGF-β and BMPRII signaling, as well as hypertrophy, apoptosis, fibrosis, capillary density, inflammation and cardiac metabolism were similar between mutation carriers and non-carriers.
Conclusions—Despite a similar afterload, RV function is more severely affected in mutation carriers compared to non-carriers. However, these differences cannot be explained by a differential TGF-β, BMPRII signaling or cardiac adaptation.
- Received December 8, 2015.
- Revision received February 19, 2016.
- Accepted March 11, 2016.