Characterization and progression of heart failure with preserved ejection fraction in SDT fatty rats

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex clinical phenotype associated with the presence of multiple comorbidities including diabetes, obesity, and metabolic syndrome. A major challenge in the search of new therapies for HFpEF is the development of relevant animal models. The Spontaneously Diabetic Torii (SDT) fatty rat is a well-established type2 diabetic model with multiple diabetes-related comorbidities such as nephropathy, neuropathy, and retinopathy. However, the onset and spontaneous progression of cardiac dysfunction is not yet reported in this model. Purpose To validate the SDT fatty rat as a type2 diabetes related HFpEF model, we assessed the natural evolution, i.e., without any diet or surgical intervention, of cardiac function in SDT fatty at different ages starting at 7-week of age. Methods The cardiovascular phenotyping of male SDT fatty rats was assessed by echocardiography at 7, 12 and 17-week of age and invasive left intraventricular and blood pressure measurements at 17-week of age. Vascular function of isolated thoracic aortas was also evaluated at 17-week of age. Renal function was investigated by measuring the Glomerular Filtration Rate (GFR) and urine parameters at 7, 12 and 17-week of age. A group of Sprague Dawley (SD) rats was included as a negative control. Results Compared to SD rats, echocardiography in SDT fatty showed cardiac remodeling starting at 7 weeks and persistent with age. Systolic function and ejection fraction were preserved, while diastolic function was impaired as early as 7-week of age and worsened with time. E/A was comparable in SDT fatty and SD rats at 7-week of age and then increased with age to reach 1.8±0.1 vs 1.2±0.05 in SD (p<0.001) at 17 weeks, while E’/A’ was already inverted at 7 weeks (0.9± 0.02 vs 1.3±0.03 in SD, p<0.001), and lasted with age which is a sign of relaxation default and suggestive of a restrictive filling pattern. E/E’ was significantly higher at 7-week of age (16.1± 0.9 vs 12.1±0.6 in SD, p<0.01) and further increased at 17 weeks (23.1± 0.8 vs 12.1±0.8 in SD, p<0.001) indicating higher filling pressure. Intraventricular and arterial pressure were also increased (p<0.05). As well, SDT fatty rats showed altered endothelium vasodilating properties. As expected, SDT fatty rats were hyperglycemic and showed renal impairment expressed by higher proteinuria, urine albumin/creatinine ratio, KIM-1 and cystatin-C levels and a hyperfiltration state (80% higher GFR, p<0.05). Conclusions The present data demonstrate that the SDT fatty rats developed diastolic dysfunction characterized by a restrictive profile combining compliance and relaxation impairments as well as higher filling pressure along with hypertension. This type2 diabetic model seems as a very promising model to translate the hypertension/kidney dysfunction and cardiometabolic clinical HFpEF phenogroups and is consequently a relevant model to evaluate drugs targeting HFpEF.