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Early renal anomalies in experimental HFpEF associated with multiple comorbidities

par Sheikh Mohammad, Umair ;Hubesch, Geraldine ;Van Eycken, Marie ;Rorive, Sandrine ;Nortier, Joëlle ;El Fahsi, Bilal ;Singh, Sumeet Pal ;Vegh, Grégory ;Jespers, Pascale ;Hupkens, Emeline ;McEntee, Kathleen ;Vachiery, Jean-Luc ;Dewachter, Céline ;Dewachter, Laurence
Référence Belgian Society of Cardiology (BSC 2024)(9/02/2024: Brussels, Belgium)
Publication Non publié, 2024-02-09

Abstract de conférence

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Résumé :

Heart failure with preserved ejection fraction (HFpEF) is a growing cardiovascular epidemic, accounting for almost half of all prevalent heart failure cases worldwide. In HFpEF, renal dysfunction is frequent and associated with increased mortality. Pathomechanisms linking HFpEF and chronic kidney disease, which may present a bidirectionally causal relationship, remain largely unknown. In this context, we investigated the time course of renal abnormalities in an experimental rat model of HFpEF associated with multiple comorbidities. Obesity-prone (OP) and -resistant rats were respectively fed with a high-fat diet (HFD) or standard rat chow for 4 or 12 months (n=10 rats/group) and evaluated by echocardiography, cardiac catheterization, renal histological and pathobiological analyses. After 12-month HFD, OP rats developed HFpEF characterized by LV diastolic dysfunction assessed by increased left ventricular (LV) end-diastolic pressure associated to concentric LV hypertrophy and fibrosis, with preserved LV ejection fraction, whereas it was not observed after 4-month HFD. Serum levels of cystatin C and renal expression of the kidney injury molecule(KIM)-1 were both increased in HFpEF rats, indicating renal dysfunction. Histological analysis showed already in 4-month HFD-fed OP rats and even much more in HFpEF rats, glomerular enlargement and sclerosis, as well as inflammatory infiltrates in glomerular and tubular structures, associated with increased renal expression of inflammatory markers, including vascular and intercellular adhesion molecules and macrophage-specific marker CD68. Pro-inflammatory cytokines (interleukin-1β, -6 and tumor necrosis factor-alpha) were also upregulated in HFpEF kidneys. Renal apoptosis (assessed by increased pro-apoptotic Bax/Bcl2 ratio and TUNEL staining) was observed in HFpEF rats, as well as sustained fibrosis (assessed by PicroSirius Red and Mason's trichrome staining). This was associated with increased expression of matrix components (collagen-1a1, -3a1, and fibronectin1) and of pro-fibrotic factors (transforming growth factors-beta1 and 2).Renal pathological changes were objectivated prior the diagnosis of HFpEF in our experimental rat model of HFpEF.