Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction

Abstract

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

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

“…A recent study comparing males to females found that 26-week-old obese ZSF1 female rats exhibit evidence of impaired cardiac function that is largely comparable to age-matched males [9]. Our examination of 19-to 21-week-old obese ZSF1 females was generally consistent with their observations.…”

“…Although both lean and obese ZSF1 rats, by inheritance of a hypertensive gene, showed elevated blood pressure [4], only 20-week-old obese ZSF1 males demonstrated LV hypertrophy, left atrial (LA) dilation, and increased myocardial stiffness due to myofilament changes [8]. In a recent study it was shown that, at 26 weeks of age, both ZSF1 males and females exhibited comparable impaired cardiac function and diastolic dysfunction [9].…”

Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation

“…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 G‐H and Table ). 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 A‐E), as published before 9,22 . As such, the obese ZSF1 rats could be used as a model of MetS‐induced cardiac diastolic dysfunction and remodelling.…”

SARS-CoV-2 infection leads to cardiac pericyte loss, fibrosis, cardiomyocyte hypertrophy, and diastolic dysfunction

“…4a-b). This is the a slightly smaller range of hypertrophy reported for animal HFpEF models, where increases between 35% and 45% have been reported 25,26 . Other viral myocarditis models, such as CVB3 infection in mice, show approximately 15% increases in cardiomyocyte size after five weeks 27 , further highlighting the unique nature of this cardiac hypertrophy.…”