Abstract
INTRODUCTION: Chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF) are more prevalent in the elderly. There is a lack of large animal models that allow the study of the impact of age on CKD and HFpEF in a translational fashion. This manuscript reports the first large preclinical model of CKD-HFpEF and metabolic derangements in naturally aged swine. METHODS: CKD-HFpEF was induced in naturally aged (6-9 years old) and young (3 months old) pigs, followed for 14 weeks, and compared to normal young and old controls (n = 5/group). Renal and cardiac hemodynamics were quantified in vivo by multidetector-CT, echocardiography, and pressure-volume relationship studies. Renal and cardiac microvascular (MV) architecture (3D-micro-CT) and morphometric analysis (staining) were investigated ex vivo. RESULTS: Both young and old pigs developed CKD-HFpEF, but the renal, cardiac, and metabolic phenotype was accentuated in aging animals. Aging and CKD-HFpEF influenced fasting insulin levels and insulin resistance, glomerular filtration rate, cortical MV density, glomerulosclerosis, perivascular fibrosis, and tubular injury. Tubule-interstitial fibrosis and peritubular capillary density were influenced by aging, CKD-HFpEF, and their interaction (2-way ANOVA). Similarly, cardiac MV density, perivascular fibrosis, and myocardial remodeling were influenced by aging and CKD-HFpEF, and E/A by their interaction. Notably, renal and cardiac MV density correlated with renal and cardiac functional and structural changes. CONCLUSION: Our study establishes the first large animal model of aging CKD-HFpEF, allowing the investigation of age as a biological variable in cardiorenal and metabolic diseases. This new platform could foster new age-related research toward developing therapeutic interventions in CKD-HFpEF.