The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction

Abstract

Aims Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods & Results Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF. Translational Perspective The failure of many treatment modalities for HFpEF may –at least in part– be explained by the lack of an adequate animal model. The diverse etiology of HFpEF is still largely neglected in pre-clinical research. In this study we developed a murine model that includes advanced age, female sex, in concert with co-morbidities: elevated blood pressure, obesity and T2DM. We demonstrate that this model recapitulates the human cardiometabolic HFpEF phenotype. We showed that contemporary glucose lowering drugs, liraglutide and dapagliflozin, which are both under study for HFpEF, have positive results. Our model may be useful to evaluate novel cardiometabolic, anti-fibrotic, and anti-inflammatory treatments for HFpEF.

SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis

“…The previously mentioned cardiometabolic effects of SGLT2 inhibitors, such as improvement in cardiomyocyte energetics and natriuresis, are desirable in patients with HPpEF. Treatment with dapagliflozin in a mouse model of HFpEF led to improvements in global longitudinal strain and cardiac fibrosis [54]. In our meta-analysis, the pooled results of 4 studies and 3738 patients with HFpEF found a 25% relative risk reduction in the composite outcome of cardiovascular death or HF hospitalizations/urgent visits among those randomized to SGLT2 inhibitors.…”

Dapagliflozin has No Protective Effect on Experimental Pulmonary Arterial Hypertension and Pulmonary Trunk Banding Rat Models

“…2) We just used one dose of dapagliflozin (1.5 mg/kg/day) for treatment. However, in recent preclinical studies on the cardiovascular protective effects of dapagliflozin, researchers also only used dose of 1.5 mg/kg/day for treatment ( Arow et al, 2020 ; Withaar et al, 2021 ). According to the manufacturer’s instructions and Obermeier’s study ( Obermeier et al, 2010 ), dose of 1.5 mg/kg/day in male rats is equivalent to about 9–19 times the human clinical dose of 10 mg/day calculated according to area under the concentration/time curve.…”

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

“…The factors contributing to HFpEF in contrast to HFrEF have been diverse, including endothelial dysfunction, changes in intrinsic cardiomyocyte stiffness with relaxation abnormalities, LV hypertrophy, and low-grade metabolic inflammation with variable extent of fibrosis and oxidative stress [44][45][46][47]. Moreover, both association and dissociation of Ang II and the NP system with markers of oxidative stress, blood pressure, maladaptive immune and inflammatory response, cardiac hypertrophy and fibrosis have all been reported in the context of preclinical DD and HF resulting from mechanical overload, genetic models of leptin resistance, and inappropriate activation of the RAAS [22,24,[48][49][50]. Cardiac fibrosis, intrinsic stiffness and hypertrophy have all been shown to be caused, in part, by enhanced ROS generation in the cardiovascular tissue [9,51,52].…”