Abstract de conférence
Résumé : Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases and is expected to become even more prevalent in the coming years due to demographic shift towards an ageing population with an increasing prevalence of co-morbidities, including obesity and metabolic syndrome. In HFpEF, renal dysfunction is frequent and associated with increased mortality. However, pathomechanisms linking HFpEF and chronic kidney disease remain unknown. Here, we investigated the time course of renal abnormalities in an experimental rat model of HFpEF associated with metabolic syndrome.Obesity-prone (OP) and -resistant rats were respectively fed a high-fat diet (HFD) or standard rat chow for 4 and 12 months (n=10 rats/group) and evaluated by echocardiography, cardiac catheterization, renal histological, and pathobiological analyses. Standard show diet-fed OR rats were used as controls. After 4- and 12-month HFD, OP rats developed metabolic syndrome characterized by obesity, dyslipidemia, hypertension and glucose intolerance. After 12-month HFD, the metabolic syndrome led to HFpEF characterized by left ventricular (LV) diastolic dysfunction, concentric LV hypertrophy and fibrosis with preserved LV ejection fraction (Hubesch et al. Front Cardiovasc Med. 2022), as well as pulmonary hypertension and altered coupling between the right ventricle and pulmonary circulation (Hubesch et al. JAHA 2023). In HFpEF rats, plasma levels of cystatin C and creatinine were increased, indicating renal dysfunction. Histological analysis revealed glomerular enlargement and sclerosis, as well as inflammatory infiltrates in glomerular and tubular structures, after 4- and even more so after 12-month HFD. This was associated with increased renal expression of kidney injury (Kim-1) and inflammatory vascular and intercellular adhesion molecules, CD68, interleukins (IL)-1β and -6 and tumor necrosis factor-alpha markers. In the kidneys of HFpEF rats, activation of apoptotic processes, evaluated by an increased Bax-to-Bcl2 ratio and TUNEL staining, was observed. This was associated to sustained fibrosis, assessed using PicroSirius Red and Masson's trichrome stainings, together with increased renal expression of extracellular matrix components such as collagens 1a1 and 3a1, and fibronectin, as well as pro-fibrotic factors, such as transforming growth factors (TGF)-β1 and -β2. At systemic level, a pro-inflammatory phenotype was observed in HFpEF rats (already present after 4-month HFD in OP rats), with increased plasma levels of pro-inflammatory cytokines such as IL-1β, IL-6 and IL-13. In addition, plasma renin levels increased in 4-month HFD OP rats, while they decreased in HFpEF rats. Renal pathological functional, structural and biological changes were objectivated prior the diagnosis of cardiac dysfunction in our experimental rat model of HFpEF associated to metabolic syndrome.

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