Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction- a substudy of the CONDI-2/ERIC4 PPCI randomised controlled trial

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear. Methods and Results: In a pre-specified substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomised to immediate RIC consisting of an automated autoRICTM cuff on the upper arm inflated to 200mmHg for 5 minutes and deflated for 5 minutes for 4 cycles (n=53) or sham (n=47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography (TEG). Baseline thrombotic status was similar in the 2 groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454±105s vs. 403±105s; mean difference 50.1s; 95% confidence interval [CI] 93.7- 6.4, P=0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time-point. Conclusion: RIC may reduce platelet reactivity in the first 48h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity.Peer reviewedFinal Accepted Versio

Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man

AIMS: Ischaemia-reperfusion (IR) injury causes endothelium-dependent vasomotor dysfunction that can be prevented by ischaemic preconditioning. The effects of IR injury and preconditioning on endothelium-dependent tissue plasminogen activator (t-PA) release, an important mediator of endogenous fibrinolysis, remain unknown. METHODS AND RESULTS: Ischaemia-reperfusion injury (limb occlusion at 200 mmHg for 20 min) was induced in 22 healthy subjects. In 12 subjects, IR injury was preceded by local or remote ischaemic preconditioning (three 5 min episodes of ipsilateral or contralateral limb occlusion, respectively) or sham in a randomized, cross-over trial. Forearm blood flow (FBF) and endothelial t-PA release were assessed using venous occlusion plethysmography and venous blood sampling during intra-arterial infusion of acetylcholine (5-20 µg/min) or substance P (2-8 pmol/min). Acetylcholine and substance P caused dose-dependent increases in FBF (P<0.05 for all). Substance P caused a dose-dependent increase in t-PA release (P<0.05 for all). Acetylcholine and substanceP-mediated vasodilatation and substanceP-mediated t-PA release were impaired following IR injury (P<0.05 for all). Neither local nor remote ischaemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release. CONCLUSION: Ischaemia-reperfusion injury induced substanceP-mediated, endothelium-dependent vasomotor and fibrinolytic dysfunction in man that could not be prevented by ischaemic preconditioning. CLINICAL TRIAL REGISTRATION INFORMATION: Reference number: NCT00789243, URL: http://clinicaltrials.gov/ct2/show/NCT00789243?term=NCT00789243andrank=1

Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation: The clopidogrel-statin interaction

To examine whether CYP3A4-metabolizing statin use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation, using time-varying drug exposure ascertainment

Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury

Aim: Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. Methods: Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5–20 μg min–1; n = 11) or sodium nitroprusside (2–8 mg min–1; n = 10) before and after intra-arterial infusion of placebo or rotigaptide, and again following IRI. Results: Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/AAR[%]: 18.7 ± 4.1 [rotigaptide] vs. 43.6 ± 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or rotigaptide (P = NS). Conclusions: Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction

ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies

Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia–reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes