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Postconditioning signalling in the heart: mechanisms and translatability

Bice, Justin S. and Baxter, Gary Francis 2015. Postconditioning signalling in the heart: mechanisms and translatability. British Journal of Pharmacology 172 (8) , pp. 1933-1946. 10.1111/bph.12976

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Abstract

The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 0007-1188
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 5 October 2014
Last Modified: 28 Dec 2017 03:58
URI: http://orca-mwe.cf.ac.uk/id/eprint/72281

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