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doi: 10.1097/ALN.0b013e31824234c5
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Translating Volatile Anesthetic-induced Cardioprotection into Systems Biology

Lotz, Christopher M.D.*; Kehl, Franz M.D., Ph.D., D.E.A.A.

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FOR more than a decade, cardioprotection by volatile anesthetics has fueled hopes of preventing myocardial damage in the perioperative setting. Discoveries established in the laboratory largely facilitated the use of volatile anesthetics in cardiac anesthesia, and guidelines of the American College of Cardiology-American Heart Association recommend volatile anesthesia for noncardiac surgery in patients with increased risk of myocardial ischemia.1 Analogous to this powerful arm, remote ischemic preconditioning (RIPC) salvages the heart from a distance (e.g., muscle ischemia via repetitive blood pressure cuff inflations leads to myocardial protection). The ostensible effortless practicability of this technique has made it promising for daily clinical use, a fact corroborated by the results of encouraging first clinical trials.2
Nevertheless, the translation of basic research into an effective daily therapeutic regimen remains challenging. New light is shed by a recent study of Lucchinetti et al.,3 who investigated additional protective effects of RIPC when combined with isoflurane-based general anesthesia for on-pump coronary artery bypass graft surgery.
The study offers a number of intriguing findings, as well as a seminal approach guiding the future of cardioprotective research. The authors used limb RIPC as a second preconditioning stimulus on top of isoflurane-based anesthesia, providing a true translational design by subsequently connecting studies of clinical outcome with microarray analyses.
“Lucchinetti et al. need to be congratulated for their breakthrough translational study design, integrating clinical studies with a global scale signaling pathway analysis.”
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It may not actually surprise that the combined application of isoflurane and RIPC did not offer additional clinical benefits because all preconditioning strategies are believed to share common signaling end effectors. Indeed, animal studies indicate that anesthetic preconditioning follows a threshold phenomenon, whereas concentrations of 0.25 minimum alveolar concentration suffice to salvage a maximum of myocardial tissue.4 Nevertheless, the continuous application of isoflurane does not follow a pure preconditioning or postconditioning protocol, but rather fulfills its “classic duties” as a hypnotic agent. This raises the question of whether the “protocol issue” actually may be purely academic. Previous studies indicated a fully blossomed cardioprotective response after continuous application once the threshold is surpassed.5 Can one now assume anesthetic preconditioning and postconditioning as a phenomenon of every volatile-driven anesthesia? Is anesthetic preconditioning and postconditioning already successfully integrated into the clinical routine? The jury is still out; each specific clinical setting needs to be taken into account, and large-scale prospective investigations are needed to comprehensively answer these questions. Furthermore, on a cautionary note, it has to be stated that the study by Lucchinetti et al. was not designed to prove the cardioprotective efficacy of isoflurane versus a nonvolatile-driven anesthesia because none of the groups was “isoflurane free.”
However, at this point the true strength of the translational study design comes into play, because the concomitantly conducted microarray analysis clearly depicted signaling changes correlated with an ameliorated clinical outcome. The specific pathways induced by isoflurane (i.e., fatty acid oxidation and DNA-damage signaling) emphasize the cardioprotective response because, in particular, the mitochondrion is the putative final stage of preconditioning and postconditioning.6 No correlation between signaling changes elicited by RIPC and clinical biomarkers could be established. Thus, the study provides a direct molecular feedback of cellular signaling changes within the heart and clinical outcome parameters.
Moreover, global scale transcriptional analysis, as conducted via microarray analysis, represents a tool to demonstrate changes on a multipathway scale. This is clearly superior to the traditional single pathway investigation. One can be assured that isoflurane-induced and RIPC-induced signaling were comprehensively investigated, indicating DNA and mitochondrial signaling as a putative differentiating signaling entities. Obviously, the study by Lucchinetti et al. can be only the beginning of a long journey; many years of research efforts have taught the field that cardioprotection is a multipathway, multisystems phenomenon. This includes genetic reprogramming, altered protein expression, posttranslational modifications, and metabolic remodeling. Therefore, future insight needs to be gained in all of these areas.7 These efforts will not always be rewarded by positive results because translation into the clinics is tedious and sometimes disappointing. The current study provides a good example; superior cardioprotection by using RIPC in addition to isoflurane would have been desirable. Nevertheless, the importance of the study is not hampered by its “negative result,” and RIPC may well prove its place in the clinics through future, large-scale investigations.
Lucchinetti et al. need to be congratulated for their breakthrough translational study design, integrating clinical studies with a global scale signaling pathway analysis. This pioneering concept is a much-needed step in cardioprotective research. And not to be forgotten: the study conclusively answers a clinically relevant research question. The results should excite all anesthesiologists because they corroborate the all-day-everyday cardioprotective properties of volatile anesthetics.
Christopher Lotz, M.D., * Franz Kehl, M.D., Ph.D., D.E.A.A.† *Department of Anesthesiology, Bayerische Julius-Maximilians-Universität, Würzburg, Germany. †Department of Anesthesiology and Critical Care Medicine, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany. kehl@klinikum-karlsruhe.de
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References

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3. Lucchinetti E, Bestmann L, Feng J, Freidank H, Clanachan AS, Finegan BA, Zaugg M: Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: Lack of synergy or evidence of antagonism in cardioprotection? ANESTHESIOLOGY 2012; 116:296–310

4. Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR: Is isoflurane-induced preconditioning dose related? ANESTHESIOLOGY 2002; 96:675–80

5. Lange M, Redel A, Smul TM, Lotz C, Nefzger T, Stumpner J, Blomeyer C, Gao F, Roewer N, Kehl F: Desflurane-induced preconditioning has a threshold that is lowered by repetitive application and is mediated by beta 2-adrenergic receptors. J Cardiothorac Vasc Anesth 2009; 23:607–13

6. Murphy E, Steenbergen C: Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008; 88:581–609

7. Lotz C, Liem D, Ping P: New frontiers in myocardial protection: A systems biology approach. J Cardiovasc Pharmacol Ther 2011; 16:285–9

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