No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission

Roubille, François; Mewton, Nathan; Elbaz, Meyer; Roth, O; Prunier, Fabrice; Cung, Thien Tri; Piot, Christophe; Roncalli, Jérôme; Rioufol, Gilles; Bonnefoy‐Cudraz, Eric; Wiedemann, Jean Yves; Furber, Alain; Jacquemin, L.; Willoteaux, S.; Abi-Khallil, W.; Sanchez, Ingrid; Finet, Gérard; Sibellas, Franck; Ranc, Sylvain; Boussaha, Inesse; Croisille, Pierre; Ovize, Michel

doi:10.1093/eurheartj/ehu054

Cited by 45 publications

(36 citation statements)

References 37 publications

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“…169,191 Most of the above studies have not taken age or the confounding risk factors and comorbidities into consideration, although some of them excluded patients with diabetes mellitus 144,148 or with an angiographically visible collateral circulation. 73,110,192 However, in a recent retrospective analysis for confounders, risk factors and diabetes mellitus did not interfere with protection by remote ischemic perconditioning in patients with AMI. 180 Apart from and in addition to comorbidities, medications are significant confounders of cardioprotection, either because they induce cardioprotection per se and leave less room for protection by a conditioning intervention or because they interfere with the signal transduction of a conditioning intervention.…”

Section: Lack Of Comorbidities and Comedications In Animal Experimentsmentioning

confidence: 91%

“…Several subsequent consensus papers 13,19,228 agreed that patients with a large area at risk, notably those with an anterior infarction, would have the greatest benefit from cardioprotection and that trials with clinical outcome as end point should, therefore, focus only on these patients. For effective cardioprotection by ischemic postconditioning to become apparent, the coronary blood flow at admission must be of TIMI (Thrombolysis in Myocardial Infarction) grade 0 to 1, whereas with some spontaneous thrombolysis (TIMI 2-3), no further infarct size reduction is achieved, 192 possibly as a result of preexisting protection by gentle reperfusion in both the placebo and the intervention groups. 229 For that same reason, that is, to avoid partial preexisting reperfusion before opening of the culprit coronary occlusion primary PCI, patients with angiographically visible collaterals were excluded in the proof-of-concept studies on ischemic postconditioning.…”

Section: Translation From Proof-of-concept Studies To Larger Trials Wmentioning

confidence: 99%

“…229 For that same reason, that is, to avoid partial preexisting reperfusion before opening of the culprit coronary occlusion primary PCI, patients with angiographically visible collaterals were excluded in the proof-of-concept studies on ischemic postconditioning. 73,110,192 Finally, for effective cardioprotection to become apparent and clinically meaningful, there must be sufficient salvageable myocardium left, and the time from symptom onset to interventional reperfusion should be no longer than 2 to 4 hours. 19,230,231 On the contrary, with a short duration of ischemia, all ischemic myocardium may be rescued by reperfusion per se, and an additional cardioprotection may be difficult to demonstrate.…”

Section: Translation From Proof-of-concept Studies To Larger Trials Wmentioning

confidence: 99%

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Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

176

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Abstract:The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of postmyocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-ofconcept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection. (Circ Res. 2016;119:676-695.

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Section: Lack Of Comorbidities and Comedications In Animal Experimentsmentioning

confidence: 91%

Section: Translation From Proof-of-concept Studies To Larger Trials Wmentioning

confidence: 99%

Section: Translation From Proof-of-concept Studies To Larger Trials Wmentioning

confidence: 99%

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Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

176

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“…Not all studies on POC were positive, and this may be related to lack of direct stenting with the consequence of coronary microembolization during the POC procedure 39,507 or to preexisting partial and gentle reperfusion. 508 For RIC, even an improved clinical outcome has been reported. 36 In contrast to the positive clinical studies with mechanical conditioning strategies, studies attempting to recruit cardioprotective signals pharmacologically have largely failed, including those on adenosine, [495][496][497][498] on PKCδ inhibition, 188 and on intravenous nitrite which is bio-converted to NO.…”

Section: Recruitment Of Cardioprotective Signaling In Patients With Amimentioning

confidence: 99%

Molecular Basis of Cardioprotection

Heusch

2015

Circulation Research

713

409

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Abstract:Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/ reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

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“…The time window for cardioprotection is restricted to the very first minutes of reperfusion, and conditioning only supposed to work in TIMI 0/1, because it will be applied at the time of reperfusion. This is confirmed in clinical studies since the effects of several cardioprotective strategies are lost in patients with pre-TIMI flow 2/3 17 23 27 28 43…”

Section: Determinants Of Reperfusion Injury In Patients With Stemimentioning

confidence: 64%

Targeting reperfusion injury in the era of primary percutaneous coronary intervention: hope or hype?

Lønborg

2015

Heart

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Introduction of reperfusion therapy by primary percutaneous coronary intervention (PCI) has resulted in improved outcomes for patients presenting with ST-segment elevation myocardial infarction. Despite the obvious advantages of primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion-a phenomenon known as reperfusion injury. Prevention of reperfusion injury may help to improve outcome following primary PCI. This review focuses on the clinical evidence of potential therapeutic cardioprotective methods as adjuvant to primary PCI. Despite overall disappointing, there exists some promising strategies, including ischaemic postconditioning, remote ischaemic conditioning, pharmacological conditioning with focus on adenosine, cyclosporine A, glucose-insulin-potassium, exenatide, atrial natriuretic peptide and metoprolol and cooling. But hitherto no large randomised study has demonstrated any effect on outcome, and ongoing studies that address this issue are underway. Moreover, this review will discuss important clinical predictors associated with reperfusion injury during primary PCI that may interfere with a potential protective effect (pre-PCI thrombolysis in myocardial infarction flow, preinfarction angina, collateral flow, duration of ischaemia and hyperglycaemia). This paper will also provide a short overview of the technical issues related to surrogate endpoints in phase II trials. Based upon these discussions, the paper will provide factors that should be taken into account when designing future clinical studies.

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No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission

Abstract: NCT01483755.

Cited by 45 publications

References 37 publications

Time to Give Up on Cardioprotection?

Time to Give Up on Cardioprotection?

Molecular Basis of Cardioprotection

Targeting reperfusion injury in the era of primary percutaneous coronary intervention: hope or hype?

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