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Early renal alterations in metabolic syndrome-associated heart failure with preserved ejection fraction (HFpEF) in rats

par Sheikh Mohammad, Umair ;Hubesch, Geraldine ;Van Eycken, Marie ;Vegh, Grégory ;Hupkens, Emeline ;Jespers, Pascale ;Singh, Sumeet Pal ;McEntee, Kathleen ;Vachiéry, Jean-Luc;Rorive, Sandrine ;Dewachter, Céline ;Dewachter, Laurence
Référence BRC Belgian Working Group on Basic Research in Cardiology(9-12-2024: Auditorium Léon Frédéricq – GIGA Research Insitute University of Liège (Campus Sart-Tilman))
Publication Non publié, 2024-12-09

Abstract de conférence

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Résumé :

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is expected to become more prevalent as the population ages and the incidence of co-morbidities increases over the coming years. In HFpEF patients, renal dysfunction is frequently observed and contributes to increased mortality. This study aims to investigate the evolution of renal abnormalities in a rat model of HFpEF associated with metabolic syndrome. Obesity-prone (OP) and -resistant (OR) rats were fed a high-fat diet (HFD) and standard chow respectively, for 4 and 12 months (10 rats/group). Cardiac structure and function were assessed using echocardiography and catheterization, while kidneys were analyzed at histological and pathobiological levels. OR rats were used as controls. After 4 and 12 months on HFD, OP rats developed metabolic syndrome, which subsequently led (after 12-month) to HFpEF, characterized by left ventricular (LV) diastolic dysfunction, concentric LV hypertrophy and fibrosis, with preserved LV ejection fraction. In HFpEF rats, elevated plasma creatinine and cystatin C levels indicated renal dysfunction. Histological analysis revealed progressive glomerular enlargement and sclerosis, and tubular inflammation already present after 4- and more after 12-month HFD. This was associated with increased expression of kidney injury (Kim)-1 and inflammatory markers. Apoptosis (assessed by TUNEL staining) was identified in the kidneys after 4- and 12-month HFD. In HFpEF rats, sustained renal fibrosis was confirmed by PicroSirius Red and Masson’s trichrome stainings, along with increased expression of extracellular matrix components. At circulating level, HFpEF rats exhibited a pro-inflammatory phenotype with elevated levels of cytokines, including IL-1β, -6, and -13, which was already present after 4-month HFD. To conclude, renal pathological abnormalities precede the diagnosis of HFpEF in our experimental rat model, highlighting the complex intertricated pathogenesis of renal and cardiac dysfunction in this disease.