Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction.

Isabel T N Nguyen,Ruben W A Van Drie,Marianne C Verhaar,Jens Van De Wouw,Maarten M Brandt,Daphne Merkus,Caroline Cheng,Dirk J Duncker,Jaap A Joles,Marian Wesseling,Saskia C A De Jager,Maarten J Cramer

doi:10.1371/journal.pone.0232399

Abstract

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Highlights

Heart failure (HF) is a growing global health problem, with high morbidity and mortality, and the leading cause for hospitalizations in patients above 65 years of age [1]
In the current study we investigated the development of early HF with a preserved ejection fraction (HFpEF) in the female obese ZSF1 rat, a model characterized by the presence of severe obesity, dyslipidemia and mild hypertension, and compared the longitudinal disease progression between male and female obese ZSF1 rats
Obesity in the ZSF1 rats was associated with increased left ventricular (LV) mass and diastolic dysfunction while ejection fraction was preserved

Summary

Introduction

Heart failure (HF) is a growing global health problem, with high morbidity and mortality, and the leading cause for hospitalizations in patients above 65 years of age [1]. HF can be divided into three types: HF with a preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced ejection fraction (HFrEF). Impaired LV filling, referred to as diastolic dysfunction, is observed in these patients [2]. Effective treatment options exist for HFrEF and HFmrEF, this is not true for HFpEF [6]. To better understand the underlying mechanisms and the effects of new therapies, animal models of early HFpEF are required. As it is not possible to mimic every detail of the disease in an animal model, the focus should be on specific pathophysiological aspects of early HFpEF in patients [11, 12]

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