The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Abstract

19Cardiometabolic syndrome has become a global health issue. Heart failure is a common 20 comorbidity of cardiometabolic syndrome. Successful drug development to prevent 21 cardiometabolic syndrome and associated comorbidities requires preclinical models predictive 22 of human conditions. To characterize the heart failure component of cardiometabolic 2 23 syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean 24 ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular 25 gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human 26 cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and 27 cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, 28 and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-29 seq results demonstrated changes in left ventricular gene expression associated with fatty acid 30 and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart 31 failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly 32 decreased body weight, food intake, blood glucose, and triglycerides and improved exercise 33 capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly 34 lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model 35 for human cardiometabolic syndrome with established heart failure with preserved ejection 36 fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective 37 effect in obese ZSF1 rats.3 38 Introduction 39 Cardiometabolic syndrome (CMS)-a condition that encompasses impaired 40 metabolism (insulin resistance [IR], impaired glucose tolerance), dyslipidemia, hypertension, 41 renal dysfunction, central obesity, and heart failure (HF)-is now recognized as a disease by 42 the World Health Organization (WHO) and the American Society of Endocrinology [1]. 43 Obesity and diabetes mellitus comorbidities are associated with progressive left ventricular 44 (LV) remodeling and dysfunction. Also, these comorbidities are commonly observed in HF 45 with preserved ejection fraction (HFpEF) [2]. Results from a recent epidemiological study 46 (cohort of 3.5 million individuals) demonstrated an incremental increase in the hazard ratio 47 (HR) for HF; HRs were 1.8 in normal weight individuals with three metabolic abnormalities, 48 2.1 in overweight individuals with three metabolic abnormalities, and up to 3.9 in obese 49 individuals with three metabolic abnormalities. Incidence of HFpEF, which currently 50 represents approximately 50% of all HF cases, continues to rise and its prognosis fails to 51 improve partly due to the lack of therapies available to treat this disease [3]. 52 An important step in the development of novel therapeutic agents against CMS is the 53 establishment of a preclinical model that represents a cluster of cardiometabolic disturbances ...

Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation

“…As published previously, obese ZSF1 rats were obese, hyperglycaemic, and hyperlipidaemic and showed increased plasma DPP-4 levels compared to lean control ZSF1 at 20 weeks (Figure S1A-F). 22,23 Obese ZSF1 rats showed signs of MetS-induced diastolic dysfunction and left ventricular stiffening, as reflected by a significantly increased mitral valve deceleration time, E/deceleration time ratio and non-flow time (NFT), and a slightly, although non-significantly increased isovolumic relaxation time (IVRT), early mitral inflow peak velocity (E), and E/E' ratio (P = .06, .05, and .09, respectively) compared to lean ZSF1 rats ( Figure S1G-H and Table S1). In addition to signs of diastolic dysfunction, obese ZSF1 rats showed signs of cardiac remodelling, including increased total, perivascular, and interstitial fibrosis and cardiomyocyte hypertrophy ( Figure S2A-E), as published before.…”