The Role of the BMPR2 pathway in Group-II Pulmonary Hypertension Secondary to Valve Heart Disease

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Abstract BMPR2 is widely known to be key in the pathobiology of pulmonary arterial hypertension. Recently, data regarding pulmonary hypertension (PH) secondary to left-heart disease (LHD) have focused on inflammatory and proliferative pathways rather than classic hemodynamic scope but BMPR2 role is yet to be determined. In the current study, we assessed BMPR2 and its regulatory factor, SRSF2, in patients with PH due to valvular heart disease (VHD). Blood samples from patients included in the Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) clinical trial were analysed. The study involved PH-VHD patients with combined pre-and postcapillary PH, isolated postcapillary PH, control patients without PH and healthy subjects. We sequenced the BMPR2 exons, measured BMPR2 A-isoform expression and analysed SRSF2 gene expression levels in blood samples. Our results demonstrate that BMPR2 A-isoform levels are reduced in patients with PH-VHD compared to controls and, even more, healthy subjects. Furthermore, BMPR2 A-isoform expression showed meaningful prognostic value among PH-VHD patients. Notably, whereas pathogenic gene variants were ruled out, SRSF2 was indeed associated with BMPR2 A-isoform differential expression. To the best of our knowledge, this is the first study demonstrating the involvement of BMPR2 gene expression in PH-LHD patients, supports BMPR2 A-isoform as a potential prognosis biomarker and this pathway as a therapeutic target.

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