Exenatide Treatment improves functional post-ischemic outcome in mice with diet induced obesity without infarct size reduction

Short title: Exenatide DIO AMI

Key words: DIO, AMI, Exenatide

Background: GLP1-RAs are well established therapeutic agents for patients with type 2 diabetes mellitus (TD2). The short acting GLP1 agonist Exenatide was shown to reduce infarct size in non-diabetic patients. However, the potency to improve post-ischemic recovery under diabetic conditions has not been investigated so far. In this study, we evaluated exenatide treatment in mice with diet-induced obesity (DIO) in-vivo and ex-vivo.

Methods: Mice were treated with high-fat diet (EF Bio-Serv #F1850 mod. 24% sucrose HF 35.85% lard) for 24 weeks. Exenatide (Exe) was injected for the last 8 weeks of diet duration every two days. After end of treatment, baseline echocardiographic assessment of cardiac function was conducted. In-vivo ischemia/reperfusion induced by transient ligation of the left-anterior descending artery for the duration of 30 minutes was conducted followed by 24h reperfusion with re-assessment of cardiac function. For ex-vivo ischemia, explanted hearts were transferred to Langendorff-perfusion with 40 minutes ischemia and 2h reperfusion. Infarct size and functional recovery in % from baseline [LV pressure gradient (dp), positive and negative derivate of pressure (+dP/dt and −dP/dt), LV end-diastolic (LVEDP) and end-systolic LV pressure (LVESP)] were assessed. Ratio paired t-test and unpaired t-test was conducted to compare groups, p<0.05 was considered significant.

Results: In-vivo infarct size did not differ between groups. However, post-ischemic dilatation was reduced in exenatide treated mice compared to non-treated controls (End-diastolic volume – DIO: 75.22 ± 11.26 µl vs. DIO+Exe: 58.18 ± 7.6 µl, p=0.0041). This was associated with improved ejection fraction [DIO: 33.05± 3.5% vs. DIO+Exe: 51.8±10.9%, p=0.0007). Moreover, contractility was improved shown by higher fractional shortening (DIO: 3.965 ± 1.39 % vs. DIO+Exe: 16.9 ± 7.1, p=0.0008). In line, maintenance of myocardial strain in remote area was better in exenatide treated mice (Circumferential strain rate in % from baseline – DIO: 48.46±32.5% vs. DIO+Exe: 89.45±32.73%, p=0.0330, radial displacement in % from baseline – DIO: 51.82±29% vs. DIO+Exe: 101.8±46.5%, p=0.0228). In ex-vivo ischemia, infarct size did not differ either. However, again myocardial recovery was improved shown by enhanced dp (DIO: 35.29±7.5% vs. DIO+Exe: 46.20±6.2%, p=0.0249), dpmin (DIO: 39.71±9.9% vs. DIO+Exe:54.40±9.04) and dpmax (DIO: 41.00±10.68% vs. DIO+Exe:54.60±7.4%, p=0.0348).

Conclusion: Long-term exenatide treatment prior to ischemia has the potency to improve post-ischemic dilatation and systolic function after in-vivo and ex-vivo ischemia. Infarct size was not affected. This indicates a protective effect by exenatide treatment on the non-infarcted areas of the myocardium. The results of this study empower a GLP1 agonists as promising targets in T2D patients with cardiovascular disease at risk for myocardial infarction.