Abstract
Treatment of acute myocardial infarct patients (AMI) includes rapid restoration of coronary blood flow and pharmacological therapy aimed to prevent pain and maintain vessel patency. Many interventions have been investigated to offer additional protection. One such intervention is remote ischaemic conditioning (RIC) involving short-episodes of ischaemia of the arm with a blood pressure cuff, followed by reperfusion to protect the heart organs from subsequent severe ischaemia. However, the recent CONDI2-ERIC-PPCI multicentre study of RIC in STEMI showed no benefit in clinical outcome in low risk patients. It could also be argued that these patients were already in a partially protected state, highlighting the disconnect between animal- and clinical-based outcome studies. To improve potential translatability, we developed an animal model using pharmacological agents similar to those given to patients presenting with an AMI, prior to PPCI. Rats underwent MI on a combined background of an opioid agonist, heparin and a platelet-inhibitor thereby allowing us to assess whether additional cardioprotective strategies had any effect over and above this “cocktail”. We demonstrated that the “background drugs” were protective in their own right, reducing MI from 57.5 ± 3.7% to 37.3 ± 2.9% (n = 11, p < 0.001). On this background of drugs, RIC did not add any further protection (38.0 ± 3.4%). However, using a caspase inhibitor, which acts via a different mechanistic pathway to RIC, we were able to demonstrate additional protection (20.6 ± 3.3%). This concept provides initial evidence to develop models which can be used to evaluate future animal-to-clinical translation in cardioprotective studies.
Highlights
Coronary heart disease is the leading cause of death worldwide
To improve the translatability of animal-to-clinical studies, we developed a small-animal model which attempts to narrow this divide. This consisted of an open-chest rat model, in which rats underwent myocardial ischaemia-reperfusion on a background of the three agents routinely used when patients present with an acute myocardial infarction (MI) i.e., an opioid agonist, heparin and an anti-platelet (P2Y12) inhibitor
We were able to demonstrate that agents routinely applied in the clinical setting to patients presenting with a STEMI, were able to protect the heart in their own right (Fig. 4)
Summary
Coronary heart disease is the leading cause of death worldwide. Returning coronary flow can, paradoxically, cause additional injury, known as ischaemia–reperfusion injury [19, 22]. Over the past few decades, we have witnessed a huge improvement in patient care, leading to a significant reduction in ischaemia–reperfusion injury and in the overall mortality of patients presenting with an acute myocardial infarction (MI) [41]. This improvement has been largely due to rapid intervention and ongoing therapy [41]. With regard to the latter, on hospital presentation, the majority of patients receive morphine, heparin and a P2Y12 inhibitor, each of which have been shown individually in preclinical studies to activate cardioprotective/pro-survival pathways [2, 7, 14, 17, 42]
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