Late Breaking Abstract - Inflammation and metabolic syndrome exacerbate pulmonary hypertension associated with left heart disease

Background: Pulmonary hypertension (PH) due to left heart disease (PH-LHD) or Group2 PH is the most prevalent form of PH worldwide. PH-LHD is a deleterious complication of diastolic dysfunction and often associated with metabolic syndrome (MetS). The mechanisms remain unknown; PH-targeted therapies for this group are non-existent and the development of a new preclinical model is crucial. Inflammation plays a role in MetS, PH and adverse vascular remodeling. We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in Group2 PH. Methods and results: In rats, we induced diastolic dysfunction by supra-coronary aortic banding (SAB) surgery and MetS, by the combination of a high-fat diet (HFD) and olanzapine. Only SAB+MetS rats developed precapillary PH (echocardiography and right/left heart catheterization). Lungs from Group2-PH patients and SAB+MetS rats displayed macrophage and IL-6 accumulation, STAT3 activation and increased proliferation of pulmonary artery smooth muscle cells (PASMC), which contributes to adverse remodeling of distal PA. In vitro, IL-6 activates STAT3 and induces pulmonary arterial smooth muscle cell proliferation. Metformin treatment decreased inflammation and IL-6 levels, and STAT3 activation and PASMC proliferation both. In vivo, targeting IL-6 by either anti-IL-6 antibody or metformin treatment reversed pulmonary vascular remodeling and improve PH-LHD. Conclusions: We developed a new preclinical model of Group 2 PH and showed that MetS exacerbates SAB-induced PH-LHD. We displayed that IL-6 promotes SAB-induced pulmonary vascular remodeling and PH-LHD. We proposed IL-6 as a therapeutic target in Groups 2 PH