Simultaneous characterization of metabolic, cardiac, vascular and renal phenotypes of lean and obese SHHF rats.

Gina Youcef,Laurent Vallar Laurent Vallar,Anne Pizard,Rosa-Maria Rodriguez-Guéant,Simon Toupance,Damien Bergerot,Patrick Lacolley,Faiez Zannad,Frédéric Jaisser,Renaud Fay,Arnaud Olivier,Lina Tabcheh,Carlos Labat,Clément P J L'Huillier

doi:10.1371/journal.pone.0096452

Abstract

Individuals with metabolic syndrome (MetS) are prone to develop heart failure (HF). However, the deleterious effects of MetS on the continuum of events leading to cardiac remodeling and subsequently to HF are not fully understood. This study characterized simultaneously MetS and cardiac, vascular and renal phenotypes in aging Spontaneously Hypertensive Heart Failure lean (SHHF+/? regrouping +/+ and +/cp rats) and obese (SHHFcp/cp, “cp” defective mutant allele of the leptin receptor gene) rats. We aimed to refine the milestones and their onset during the progression from MetS to HF in this experimental model. We found that SHHFcp/cp but not SHHF+/? rats developed dyslipidemia, as early as 1.5 months of age. This early alteration in the lipidic profile was detectable concomitantly to impaired renal function (polyuria, proteinuria but no glycosuria) and reduced carotid distensibility as compared to SHHF+/? rats. By 3 months of age SHHFcp/cp animals developed severe obesity associated with dislipidemia and hypertension defining the onset of MetS. From 6 months of age, SHHF+/? rats developed concentric left ventricular hypertrophy (LVH) while SHHFcp/cp rats developed eccentric LVH apparent from progressive dilation of the LV dimensions. By 14 months of age only SHHFcp/cp rats showed significantly higher central systolic blood pressure and a reduced ejection fraction resulting in systolic dysfunction as compared to SHHF+/?. In summary, the metabolic and hemodynamic mechanisms participating in the faster decline of cardiac functions in SHHFcp/cp rats are established long before their physiological consequences are detectable. Our results suggest that the molecular mechanisms triggered within the first three months after birth of SHHFcp/cp rats should be targeted preferentially by therapeutic interventions in order to mitigate the later HF development.

Highlights

Chronic heart failure (HF) is of heterogeneous etiology but it usually occurs in the elderly [1] and unlike other cardiovascular problems its prevalence is increasing
Several studies demonstrated that patients affected by metabolic syndrome (MetS) -defined as the simultaneous occurrence of at least three of the five following risk factors: obesity, hypertension, dyslipidemia, type 2 diabetes and insulin resistance- have a higher risk of developing HF [2,3,4,5]
Metabolic disorders in SHHFcp/cp rats While no differences were observed at 1.5 months of age, SHHFcp/cp gained significantly more weight during the following 3 months than their SHHF+/? littermates as animals underwent a rapid growth phase (Figure 1A)

Summary

Introduction

Chronic heart failure (HF) is of heterogeneous etiology but it usually occurs in the elderly [1] and unlike other cardiovascular problems its prevalence is increasing. Several studies demonstrated that patients affected by metabolic syndrome (MetS) -defined as the simultaneous occurrence of at least three of the five following risk factors: obesity, hypertension, dyslipidemia, type 2 diabetes and insulin resistance- have a higher risk of developing HF [2,3,4,5]. Identifying and managing the patients at risk of HF prior to the onset of symptoms may be an effective approach to prolong active life by delaying or preventing the onset of HF in those patients [11] For this attractive preventive strategy to be effective, a deep understanding of the continuum of events underpinning the transition from obesity/ MetS to HF is required. A better characterization of risk factors for the transition to HF is likely to provide new preventive therapeutic opportunities

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Conclusion