Author's personal copy Postconditioning with curaglutide, a novel GLP-1 analog, protects against heart ischemia-reperfusion injury in an isolated rat heart

Aim: GLP-1(7-36)amide (GLP-1) is an intestinal hormone with effects on glucose metabolism and feeding behavior, including insulinotropic, insulinomimetic, glucagonostatic and anorectic actions. In experimental settings, GLP-1 has also been shown to diminish infarct size following heart ischemia-reperfusion. GLP-1 analogs with extended half-lives are continuously being developed against type 2 diabetes mellitus. Of these, only exendin-4 (exenatide, registered as Byetta) has been shown to mimic the infarct size-limiting effect of GLP-1 in a clinically relevant application as a postconditioning agent. The aim of this work was to test, in a postconditioning mode, a novel, proteolysis-resistant GLP-1 analog N-Ac-GLP-1(7-34)amide, herein termed curaglutide, for its cardioprotective ability. Method: Global ischemia (35 min)-reperfusion (120 min) was applied in isolated, retrogradely perfused rat hearts. Peptides were present for 15 min at the onset of reperfusion. Cardiac function parameters (beats per minute, left ventricle developed and diastolic pressures, rate-pressure product) were measured. Infarct size was determined by 2,3,5-tripehyltetrazolium chloride staining and planimetry. Results: Curaglutide did not affect any of the functional heart parameters when administered without preceding ischemia. Curaglutide 0.3 nM diminished significantly the postischemic hypercontracture, with no significant effect on the left ventricle developed pressure or rate-pressure product. Infarct size was reduced by curaglutide postconditioning from 24.8% (SEM 2.8, N = 14) to 11.4% (SEM 3.2, N = 8; P b 0.05). These effects of curaglutide on postischemic hypercontracture and infarct size were similar in magnitude to corresponding effects of GLP-1 receptor agonist exendin-4. The cardioprotective effects of both agents were abolished in the presence of a GLP-1 receptor antagonist exendin(9-39). Conclusion: Curaglutide is a new, proteolysis-resistant GLP-1 analog with a beneficial effect on reperfusion-injury in an isolated rat heart. Curaglutide was here shown to act through GLP-1 receptors. Based on the present results, more extensive experimental studies in vivo, comparing dose-response characteristics and efficacy of curaglutide and exendin-4 appear warranted

Multi-material additive manufacturing of low sintering temperature Bi2Mo2O9 ceramics with Ag floating electrodes by selective laser burnout

Additive manufacturing (AM) of co-fired low temperature ceramics offers a unique route for fabrication of novel 3D radio frequency (RF) and microwave communication components, embedded electronics and sensors. This paper describes the first-ever direct 3D printing of low temperature co-fired ceramics/floating electrode 3D structures. Slurry-based AM and selective laser burnout (SLB) were used to fabricate bulk dielectric, Bi2Mo2O9 (BMO, sintering temperature = 620–650°C, εr = 38) with silver (Ag) internal floating electrodes. A printable BMO slurry was developed and the SLB optimised to improve edge definition and burn out the binder without damaging the ceramic. The SLB increased the green strength needed for shape retention, produced crack-free parts and prevented Ag leaching into the ceramic during co-firing. The green parts were sintered after SLB in a conventional furnace at 645°C for 4 h and achieved 94.5% density, compressive strength of 4097 MPa, a relative permittivity (εr) of 33.8 and a loss tangent (tan δ) of 0.0004 (8 GHz) for BMO. The feasibility of using SLB followed by a post-printing sintering step to create BMO/Ag 3D structures was thus demonstrated

Clinical outcomes after treatment of multiple lesions with zotarolimus-eluting versus sirolimus-eluting coronary stents (a SORT OUT III substudy)

<p>Abstract</p> <p>Background</p> <p>Data on clinical outcomes among patients treated with the zotarolimus-eluting Endeavor™ stent versus the sirolimus-eluting Cypher™ stent favor the sirolimus-eluting stent. However, a separate comparison of clinical outcome among patients treated for multiple lesions with these stents is lacking. We performed this comparison within the SORT OUT III trial data set.</p> <p>Methods</p> <p>Among 2332 patients randomized in SORT OUT III, 695 were treated for multiple lesions with zotarolimus-eluting (n = 350) or sirolimus-eluting (n = 345) stents and followed for 18 months. Major adverse cardiac events (MACE); composite of cardiac death, myocardial infarction, or target vessel revascularization (TVR); was the primary endpoint.</p> <p>Results</p> <p>Zotarolimus-eluting compared to sirolimus-eluting stent treatment was associated with increased MACE rate (13.2% vs. 2.6%; hazard ratio 5.29 with 95% confidence interval: 2.59-10.8). All secondary endpoints; all cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization, in-stent restenosis, and definite stent thrombosis; were observed more frequently among zotarolimus-eluting stent treated patients. For all endpoints, hazard ratios were 1.6 to 4.6 times higher than in the overall results of the SORT OUT III trial.</p> <p>Conclusions</p> <p>We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent.</p

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy.

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1-17.1)% of LV mass; control: 11.1 (7.0-17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial

The Compare-Acute trial of fractional flow reserve-guided multivessel angioplasty in myocardial infarction

The Compare-Acute trial demonstrates the relative safety and utility of performing multivessel FFR to examine the significance of non-culprit lesions during primary PCI. Patients who had an FFR-guided PCI strategy for non-culprit lesions during the index hospitalisation had fewer adverse cardiovascular events, essentially unplanned revascularisations, as compared to patients who were treated for the infarct-related artery only