Characterization of renal alterations in an experimental model of HFpEF associated with metabolic syndrome in rats

Abstract

Introduction

Heart failure with preserved ejection fraction (HFpEF), which now accounts for more than half of all cases of heart failure, is considered to be a major public health problem rising in prevalence due to the ageing of the population and the growing incidence of associated co-morbidities. In patients with HFpEF, renal dysfunction is highly prevalent (up to 50% of patients) and is associated with significant mortality.

Objective

To characterize the progression of renal abnormalities in an original experimental model of HFpEF associated with metabolic syndrome in rats.

Method

Obesity-prone (OP) and obesity-resistant (OR) rats were fed with a high-fat diet (HFD) or standard chow for 4 and 12 months respectively (10 rats/group). Cardiac function and structure were assessed by echocardiography and heart catheterization, while the kidneys were analyzed at histological and molecular levels. OR rats were used as controls.

Results

After 4 and 12 months on a HFD, OP rats developed a metabolic syndrome, which led after 12 months to HFpEF, characterized by left ventricular (LV) diastolic dysfunction, concentric hypertrophy and fibrosis, elevated plasma levels of the cardiac biomarker soluble ST2, together with preserved LV ejection fraction. Renal dysfunction in HFpEF rats was evidenced by increased plasma creatinine and cystatin C levels. Histological analysis showed progressive glomerular enlargement, sclerosis, and tubular inflammation (assessed by MPO staining) at 4 months and worsening at 12 months of HFD. These abnormalities were associated with increased renal expression of kidney injury molecule (Kim)-1 and inflammatory markers, such as intercellular (ICAM) and vascular cell adhesion molecules (VCAM), macrophage marker CD68, and TNF-α, observed at both 4 and 12 months of HFD. Apoptosis (assessed by TUNEL staining) associated with sustained fibrosis (assessed by PicroSirius Red and Masson's trichrome stainings) were observed at both 4 and 12 months of HFD. Circulating pro-inflammatory cytokines, including interleukin (IL)-1β, -6, and -13, were elevated in HFpEF rats.

Conclusion

Our results show that renal pathological changes precede the diagnosis of HFpEF. This highlights the complex interplay between cardiac and renal dysfunction in HFpEF, suggesting the need for early clinical intervention targeting both organs.