Leptin receptor deficient female mice as a mouse model of heart failure with preserve ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem and a major source of morbidity and mortality. However, to date, there are no therapies available to treat HFpEF mainly because of its poorly understood pathophysiology. The purpose of this study is to investigate whether Leptin receptor deficient (Leprdb/db) female mice can be used as an appropriate mouse model of HFpEF to investigate its pathophysiology. Notably, Leprdb/db female mice exhibit 3 risk factors for HFpEF i.e. diabetes, obesity and female gender. We assessed cardiac function, heart structure and heart microvessel phenotype in both leprdb/db female mice and their control Leprdb/+ littermates at 3, 6 and 12 months of age. From 3 months of age, Leprdb/db female mice present an elevated end-diastolic pressure (EDP) compared to their age-matched controls while their ejection fraction (EF) remain above 50% which indicate diastolic dysfunction with preserved EF. In addition, Leprdb/db mice have a significant cardiac hypertrophy characterized by an increased heart weight/tibia length ratio, increased left ventricular wall thickness and increased cardiomyocyte size. While both quantification of fibrosis after Picrosirius red staining and qPCR analysis and Col1a1 and Col3a1 mRNA expression did not reveal any significant changes is collagen amount, Lysyl oxidase mRNA was significantly increased in Leprdb/db female mice after 6 months of age indicating a probable increased collagen cross linking. The cardiac microvessel phenotype of these mice is characterized by an increased endothelium permeability (albumin extravasation) and activation (increased ICAM-1 and E-Selectin) while capillary density is not changed. This is associated with an increased macrophage infiltration. Leprdb/db mice recapitulate most features of HFpEF including increased EDP, unchanged EF, cardiac hypertrophy, EC activation and cardiac inflammation.