Modeling heart failure risk in diabetes and kidney disease: limitations and potential applications of transverse aortic constriction in high-fat-fed mice

Abstract

There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson's trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.

Sotagliflozin, a dual SGLT1/2 inhibitor, improves cardiac outcomes in a mouse model of early heart failure without diabetes

“…The functional role of myocardial SGLT1 remains largely unclear. Accordingly, we aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in a mouse model of cardiac pressure overload in the presence and absence of type 2 DM (15).…”

“…week into the dietary protocol, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (15). Here, mice were anesthetized with a mixture of ketamine and…”

“…An oral glucose tolerance test (OGTT) was performed following a 5-6 h fast between 08:00-14:00 h using 50% w/v D-glucose solution (2 g/kg body weight) and a SensoCard glucometer (15). Body fat content was measured in conscious mice using nuclear magnetic resonance (Bruker's Minispec MQ10, Houston, USA).…”

“…Transthoracic echocardiography (M-mode) was performed in a blinded fashion by an experienced veterinarian (M.F.) using a Philips iE33 ultrasound machine with a 15 MHz linear transducer (Philips, Amsterdam, Netherlands) under 1.8% inhaled isoflurane anesthesia, as previously described (15). All data are the average of at least three consecutive beats.…”

“…Mice were weighed and placed individually into metabolic cages for 24 h urine collection (15). Mice were acclimatized to the metabolic cages by housing for a short period of daylight prior to the 24 h collection.…”