01 March 2017 by Benoit Ranchoux

Role of metabolic syndrome in pulmonary hypertension associated with left heart disease

Rationale

Heart failure with preserved ejection fraction (HFpEF) affects over 50% patients with heart failure. Over 50% of HFpEF patients develop pulmonary hypertension (WHO2-PH) with pulmonary vascular remodeling which leads to worst prognosis. Interestingly, 94% of patients with PH due to hearth diseases and 34.3% of patients with idiopathic pulmonary arterial hypertension display at least 2 characteristics of metabolic syndrome (MS) suggesting its implication in pathogenesis.

Hypothesis

MS and associated adipose tissue inflammation may act as a trigger in clinical complication of HFpEF into PH by exacerbating aberrant pulmonary vascular remodeling and right and left ventricles dysfunction.

Methods

We developed a new model of WHO2-PH due to HFpEF and MS using Wistar rats. HFpEF is induced by supra-coronary aortic banding (SAB). Chronic MS is induced by high fat diet (HF) and/or olanzapine (4mg/kg/2 days) for 9 weeks.

Results

Only SAB rats with HF+olanzapine develop PH (≤25 mmHg). Increased visceral and mediastinal fat accumulation (CT scan) is associated with increased plasmatic level of leptin and increased pulmonary levels of leptin, leptin receptor, p-STAT3, IL-6 and CD68 and down-expression of PPARdelta which strongly correlates with PH severity. Olanzapine exposure on preadipocytes in vitro leads to obese adipocyte differentiation and leptin over-expression. Leptin exposure on macrophages leads to PPARdelta down-regulation and M1 inflammatory response. Leptin-exposed macrophages supernatants increased pulmonary smooth muscle cells proliferation which is implicated aberrant pulmonary vascular remodeling.

Conclusion

HFpEF is not sufficient to induce PH. Chronic MS lead to adipose tissue inflammation which worsen PH development in case of HFpEF.

Key Contributors

Benoît Ranchoux1, François Potus1, Eve Tremblay BSc1, Steeve Provencher1 and Sébastien Bonnet1. 1Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Canada.


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