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IntroductionBased on data that outcome in patients with acute myocardial infarction is predicted by final infarct size (IS), reducing IS is of paramount importance. Recent experimental studies have demonstrated a strong infarct-sparing effect of SGLT2 inhibitors – a class of drugs which have proved to be safe and beneficial in patients with heart failure. Repurposing SGLT2 inhibitors for the benefit of patients presenting with acute myocardial infarction should be preceded by investigation of the underlying mechanisms of this infarct limitation. Experimental and clinical data indicate a potential role for autonomic modulation in these mechanisms, specifically sympatho-inhibition. The aim of this study was to investigate the role of the parasympathetic mechanism in the infarct-limiting effect of SGLT2 inhibition.MethodsFortyeight Sprague Dawley male rats were fed with a standard diet containing either the SGLT2 inhibitor ertugliflozin or vehicle, for 5-7 days. Myocardial ischaemia/reperfusion injury was initiated by a 40-min occlusion of the left anterior descending coronary artery followed by a 2hr period of reperfusion under isoflurane anaesthesia. Bilateral cervical vagotomy was performed 10min prior to myocardial ischaemia. Alternatively, muscarinic receptors were blocked systemically with the non-selective blocker atropine sulphate (2 mg/kg bolus, then 1 mg/kg/h) or the M3-selective blocker 4-DAMP (2 mg/kg bolus).ResultsPre-treatment with ertugliflozin reduced IS in comparison with the vehicle-treated controls (pvs. Ertu for vagotomy, Pvs. Ertu for both atropine sulphate and 4-DAMP).ConclusionThese results suggest that the Infarct-limiting effect of the SGLT2 inhibitor ertugliflozin, may be mediated via activation of the vagus nerve and M3-cholinoreceptors.

Purpose A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide. Methods A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion. Results Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39). Conclusion Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Introduction As long-term outcome in patients with acute myocardial infarction (MI) is predicted by final infarct size (IS), reducing IS is of paramount importance. Recent experimental studies have demonstrated a strong infarct-sparing effect of SGLT2 inhibitors – a class of drugs which have proved to be safe and beneficial in patients with heart failure. Repurposing SGLT2 inhibitors for the benefit of patients presenting with an acute MI should be preceded by investigation of the underlying mechanisms of infarct limitation. Experimental and clinical data indicate a potential role for autonomic modulation in these mechanisms, specifically sympatho-inhibition. The aim of this study was to evaluate the role of parasympathetic tone in the infarct-sparing effect of SGLT2 inhibitors. Methods Twenty seven Sprague Dawley rats were fed with the diet containing the SGLT2 inhibitor Ertugliflozin or vehicle for 3 days. Myocardial ischaemia/reperfusion injury was caused by a 40-min left anterior descending coronary artery occlusion followed by 2 hours of reperfusion under isoflurane anaesthesia (4% for induction and 1.5-2% for maintenance). Two groups of animals, pre-treated with Ertugliflozin, were subjected to parasympathetic denervation prior to myocardial ischaemia, either with the muscarinic receptor antagonist, atropine sulfate i.v. (2 mg/kg bolus, then 1 mg/kg/h), or bilateral cervical vagotomy (figure 1). Results Pre-treatment with Ertugliflozin reduced IS by 63% (p 0.05 vs. vehicle, p Conclusion These results suggest that the Infarct-limiting effect of SGLT2 inhibitor Ertugliflozin may be mediated via M-cholinoreceptors. Conflict of Interest No

Background and Purpose: Currently, reperfusion is the only existing treatment strategy for patients with acute ischemic stroke. However, reperfusion may cause further brain damage. One of the feasible therapies targeting reperfusion injury is remote ischemic conditioning (RIC). The main objective of this study was to test the neuroprotective effects of RIC in a rat model of acute ischemic stroke in a randomized and blinded two-centre MRI study with a priori sample size calculation . Methods: Eighty male Sprague Dawley rats underwent 90-min middle cerebral artery occlusion. Multiparametric MRI was performed per-occlusion to ascertain focal cerebral ischemia (inclusion criteria) and to control interindividual variability in the analysis. RIC was started 10 min before reperfusion, and consisted of 4 cycles of 5-min left hind limb ischemia. The primary endpoint of the study was infarct size measured on T2-weighted MRI at 24h, corrected for edema, and expressed as percentage of the area-at-risk of infarction . Secondary endpoints were hemispheric space-modifying edema, infarct growth between per-occlusion and 24h MRI, and neurofunctional outcome measured by neuroscores. Results: Two animals died in each group. In total, 47 rats were included in the analysis after applying the pre-defined inclusion criteria (23 in control group and 24 in RIC group). Infarct size was significantly reduced in the RIC group (mean, interquartile range: 19% [8% ; 32%] vs control: 40% [17% ; 59%], p=0.028). This infarct-limiting effect was still statistically significant after adjustment for apparent diffusion coefficient (ADC) lesion size in multivariate analysis. In the subgroup of rats with ADC lesion > 100 mm3, infarct size reduced from 58% [40%; 66%] to 32% [27%; 40%], p=0.004. In line with this result, RIC significantly improved neuroscores (6 [3 ; 8] vs control: 9 [7 ; 11], p=0.032). The other secondary endpoints were not statistically different between groups. Conclusions: RIC in the setting of acute stroke in rats is safe, reduces infarct size and improves functional recovery in a two-centre international study using translational imaging endpoints.

Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.

Currently, ischemic stroke remains one of the most costly and devastating clinical syndromes, accounting for 9% of all deaths and being the second leading cause of death in the world (Davidson et al., 2018). Approximately 20% of strokes are caused by intracerebral hemorrhage, while the other ~80% are classified as ischemic. With the discovery of thrombolysis, reperfusion therapy became an option for the treatment of ischemic stroke. More recently, endovascular recanalization with mechanical thrombectomy has brought about a paradigm shift in the optimal management of patients with large vessel occlusion. Importantly, early reperfusion is the only therapy that is proven to limit infarct size in patients with acute ischemic stroke. However, despite a successful recanalization being achieved in more than 70% of patients treated with mechanical thrombectomy +/– intravenous tissue recombinant plasminogen activator, functional independence (modified Rankin score 0–2 at 3 months after ischemic stroke) is obtained only in ~45% of cases. This reveals the further need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy.

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury. NIHR Biomedical Research Council (SD) and the British Heart Foundation PG/18/44/33790, PG/16/85/32471 (SD, DY). German Research Foundation SFB 1116 B08 (GH, PK). This work has been supported by the OPeRa program (ANR-10-IBHU-0004 OPeRa) and completed within the framework of the RHU MARVELOUS (ANR-16-RHUS-0009) (MO). Sí