The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

Abstract

We previously reported on the development of left ventricular (LV) structural and functional changes in an aged, female rat model where the effects of ovariectomy and excess weight (stimulated by fructose in water) were also explored. Ovariectomy and/or excess weight led to a prolongation of active relaxation, loss of cardiac output, and LV fibrosis in the setting of preserved ejection fraction. In this follow-up study, we wished to characterize the possible role of LV inflammation, oxidative stress (OS), and cell death in inducing such changes. Four experimental groups were studied: young (3 months old), aged (18 months old), aged + ovariectomy (OVX), and aged + ovariectomy + 10% fructose (OVF). Using conventional histology and immunohistochemistry of myocardium as well as biochemical assays of plasma samples, we document the presence of inflammatory cell aggregates in LV myocardium which are associated to high levels of plasma inflammatory cytokines (IL-1β, TNF-α, IFN-γ, TGF-β1) and OS (carbonyl proteins) in aged, OVX, and OVF vs. young animals. In the inflammatory areas, normal cardiac tissue was substituted by replacement and interstitial fibrosis and M1 macrophages, (as per by CD68 immunostaining) as we all as by co-localization with TGF-β1. We also document increases in plasma troponin I levels, loss of capillary density, cardiomyocyte hypertrophy, and death. Select changes were further aggravated by ovariectomy and/or excess weight. In conclusion, aging in the female rat heart, when compounded with estrogen depletion and excess weight promotes the development of greater levels inflammation, OS, fibrosis, capillary rarefaction, cardiomyocyte hypertrophy, and injury/death. These factors likely play an important role in the development of LV remodeling that leads to the development of a “pre-HFpEF” phenotype. Impact statement: The incidence of HFpEF continues to increase and ∼2/3 of the patient population are post-menopausal women. Unfortunately, most studies focus on the use of male animal models of remodeling. In this study, however, using female rats to set a model of pre-HFpEF, we provide insights to possible mechanisms that contribute to HFpEF development in humans that will lead us to a better understanding of the underlying pathophysiology of HFpEF.