Author + information
- Derek M. Yellon, DSc∗ ( and )
- Xavier Rossello, MD
- ↵∗Address for correspondence:
Dr. Derek M. Yellon, The Hatter Cardiovascular Institute UCL, 67 Chenies Mews, London WC1E 6HX, United Kingdom.
- ischemia reperfusion injury
- out-of-hospital cardiac arrest
- perioperative myocardial injury
- reperfusion injury salvage kinase (RISK) cascade
- ST-segment elevation myocardial infarction
Targeting the myocardial injury that paradoxically occurs with acute reperfusion of ischemic myocardium remains 1 of the top 10 unmet clinical needs in cardiology (1). Although myocardial reperfusion is required to salvage viable myocardium in ST-segment elevation myocardial infarction (STEMI) patients, it comes at a price known as ischemia-reperfusion injury (IRI). Therapies aimed at protecting the heart against such injury, known as cardioprotective therapies, are required to further improve clinical outcomes (2), not only in STEMI patients but also in other patients experiencing acute global IRI, such as those undergoing coronary artery bypass graft surgery and survivors of cardiac arrest (3).
In this issue of the Journal, Arola et al. (4) report that, in comatose survivors of out-of-hospital cardiac arrest (OHCA), inhaled xenon combined with mild therapeutic hypothermia results in myocardial injury that is reduced compared to that achieved by hypothermia on its own; this reduction has been measured by the change of troponin release from baseline to 72 h after OHCA. After adjusting for independent covariates, the authors proposed xenon as an independent factor in attenuation of the severity of myocardial injury after OHCA.
Xenon is a noble gas that has been postulated to mediate pharmacological cardioprotection in previous experimental studies. Xenon’s cardioprotective conditioning effect has been linked to the up-regulation of prosurvival kinases recruited by the reperfusion injury salvage kinase (RISK) pathway, such as Akt and ERK, and has been reported to inhibit the mitochondrial permeability transition pore opening (5–7). Therefore, Arola et al. (4) have speculated in their clinical trial that xenon provides protective post-conditioning effect against an ongoing wave of reperfusion injury. Two big questions arise from this study; first, how could this gas protect through an acute conditioning-like phenomenon if the mean time from OHCA to initiation of xenon is more than 4 h; and, second, how could it be possible that despite propofol being a well-known cardioprotective agent (8), patients receiving xenon underwent less propofol administration and still presented with less myocardial injury? We suspect that the reason is because xenon, rather than acting through the well-known conditioning mechanisms may also act through a RISK-independent pathway. Indeed xenon targets reperfusion injury, as demonstrated by eliciting the protection against IRI when administered at the late phase of reperfusion in their study. It would be very interesting to test whether a pharmacological agent mimicking the conditioning effect exerts a synergistic effect when administered alongside xenon.
The use of troponin as a surrogate biomarker to predict prognosis and clinical benefits needs to be addressed separately. As far as we are aware, this biomarker has not been used regularly in the setting of OHCA. As such, it is crucial to delineate between myocardial infarct size and perioperative myocardial injury (PMI), both of which represent an increase of troponin levels in a completely different underlying pathophysiological setting. In STEMI patients, the rise of troponin levels correlates with myocardial infarct size, a well-defined prognostic factor (9), whereas the elevation of troponin levels following coronary revascularization by coronary artery bypass graft surgery is known as PMI. In the latter setting, it may not be a suitable biomarker for the effect of cardioprotective therapies, that is, remote ischemic preconditioning has demonstrated to reduce PMI in proof-of-concept studies (10) but has failed to translate this into clinical benefit in subsequent clinical outcome studies (11,12). Overall, the conclusions drawn by Arola et al. (4) about the efficacy of xenon are based on the assumption that reduction of post-cardiac arrest troponin release reflect its efficacy in protecting the heart against IRI. However, the troponin release originated by cardiac arrest is more likely to reflect the PMI resulting from an acute global insult than that of myocardial infarct size resulting from a prolonged insult, and caution should be taken when interpreting the reduction in troponin release by xenon. Taking into account the fact that transient increases in blood troponin concentrations are also observed in healthy individuals following extenuated exercise, asymptomatic patients and disease states other than acute coronary syndromes (13) make us ask how reliable troponin is as a biomarker?
Sudden cardiac death is a target for cardioprotection, and we welcome xenon as a “noble” member of the club aimed at protecting the heart against IRI in multiple settings, and we would encourage further investigation of this agent and its mechanistic potential.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Rossello has received support from the Sociedad Española de Cardiología (SEC) and Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) through the CARDIOJOVEN SEC-CNIC Program. Dr. Yellon has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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