Rationale: Pulmonary hypertension (PH) associated with heart failure (HF) with preserved ejection fraction (PH-HFpEF) affects over 50% of all patients with HFpEF and confers poor prognosis. Pathological mechanisms that lead to PH-HFpEF are unclear. Given that metabolic syndrome (MetS) is associated with PH (pulmonary venous hypertension (94.1%); pulmonary arterial hypertension (34.3%)) and HFpEF (35%), we hypothesized that MetS might be implicated in PH-HFpEF pathogenesis.
Methods/Results: Using supra-coronary aortic banding (SAB), we first induced HFpEF in Wistar rats, characterized by left ventricular (LV) hypertrophy and elevated LV systolic and end-diastolic pressure in a nondilated LV with normal EF, 10 weeks post-surgery (n=8; p<0,001). MetS was then induced by high fat diet (HF) and olanzapine (4mg/kg/2d). Establishment of MS was confirmed by significant increase in the fat/lean body mass (minispec Brucker lf90), visceral fat accumulation (CT Scan), systemic hypertension and hepatic triglyceride accumulation. 10 weeks after surgery, hemodynamic parameters were analysed by both echocardiography and right and left heart catheterization. Interestingly only SAB+MetS rats developed PH characterized by a significant decreased in pulmonary acceleration time and tricuspid annular plane excursion (PAAT; TAPSE; echocardiography; P <0.001) and increased mean pulmonary arterial pressure and right ventricular systolic pressure (mPAP, RVSP; P<0.001). PH development in SAB+MetS was associated with an increased level of leptin in the plasma, that leads to pulmonary arteries smooth muscle cells (PASMC) proliferation through Leptin/Stat3 axis and macrophages mediated inflammation. Metformin treatment both in vivo (300mg/kg; 3-weeks) and in vitro reversed all these abnormalities and significantly improved PH-HFpEF. Using human samples (n=5 PH-HFpEF and matched controls) we demonstrated similarities in leptin receptor overexpression and STAT3 activation in PASMC.
Conclusion: We have developed a valid murine model of PH-HFpEF. We confirm that MetS is a trigger of PH-HFpEF. Leptin axis contributes to MetS induced PH-HFpEF. Therefore, metformin might have therapeutic potential in this condition.