Genetic Profiling of Combined Post-Capillary and Pre-Capillary Pulmonary Hypertension in Left Heart Diseases

Purpose Pulmonary hypertension (PH) in left heart diseases (LHD) has been redefined as isolated post-capillary PH (IpcPH) and combined post-capillary and pre-capillary PH (CpcPH). CpcPH's pathophysiology is not well understood. Predisposing constitutional factors may play a role in CpcPH development, as suggested by the variability in the adaptation of the pulmonary circulation to the elevation of pulmonary artery wedge pressure (PAWP). We sought to determine whether a genetic predisposition to CpcPH could be identified, suggesting a common pathway with pulmonary arterial hypertension (PAH). Methods Based on Erasme's hospital right heart catheterization database from January 2007 to January 2015, we selected PH-LHD patients to further identify CpcPH patients. Clinical and hemodynamic variables were used to compare IpcPH to CpcPH patients. A small cohort of CpcPH patients underwent genetic testing for genes predisposing to heritable PAH using a gene panel approach and MLPA analysis. Results 93 patients presented with PH-LHD, of which 32% met the definition of CpcPH. Clinical data was similar in both IpcPH and CpcPH groups except for higher morphometric features in CpcPH patients. Missense variations of the BMPR2 gene (c.1749C>A, p.Asn583Lys) and of the ENG gene (c.1316A>C, p.Lys439Thr) were identified in one CpcPH patient presenting with heart failure due to dilated cardiomyopathy. Based on current knowledge, both variants were classified as variants of unknown significance (VUS). Conclusion Our study uncovered genomic variations in the BMPR2 and ENG genes of a CpcPH patient, which may support the concept that a predisposing genetic background could modulate the precapillary component in CpcPH, potentially suggesting common genetic pathways between CpcPH and PAH, although this has to be further confirmed by functional testing, studies in bigger cohorts and with IpcPH control populations.