In 1976, two researchers reported that the volatile anesthetic halothane reduced ST segment elevation in a canine model of brief coronary artery occlusion [1]. Given that ST segment elevation is highly associated with myocardial injury/infarction, left ventricular hypertrophy, acute pericarditis, and/or left bundle branch block [2], this finding was the first to suggest that volatile anesthesia offers some cardiac protection.
Since that first publication by Lowenstein et al., evidence has consistently confirmed this hypothesis. The same authors demonstrated that administering halothane prior to prolonged artery occlusion reduced myocardial infarct size and thus severity in canine models [3]. Other volatile agents – including enflurane [4], desflurane [4], and sevoflurane [5] – reduced myocardial damage following ischemic myocardial events in isolated hearts. Preconditioning with volatile anesthetics in animal models has been shown to protect myocardium during ischemic events [6], reduce myocardial damage [7], and preserve smooth muscle/endothelial viability after cytokine-induced injury [8], Interestingly, the anesthesia agent isoflurane has been shown to induce a “memory period” of cardiac protection even after it has been eliminated from the body [6], though the duration of this period appears to vary between volatile anesthetic agents [9].
Despite the ample evidence demonstrating that volatile anesthesia confers cardiac protection, far less is known about the mechanism underlying the phenomenon. Several key pathways appear to be implicated: adenosine type 1 receptors [10], protein kinase C [11], inhibitory guanine nucleotide binding Gi proteins [12], reactive oxygen and nitrogenous species [13], and KATP channels in both the mitochondria and sarcolemma [14,15]. However, the activation of some of these pathways appears to be drug specific [10]. Therefore, it is difficult to generalize the key mechanism underlying the cardioprotective effect of volatile anesthesia as a whole.
Though mechanism of action may differ by volatile agent, it is hypothesized that the end-effector – the final molecular mechanism which ultimately induces the cardioprotective effect – is shared. The current prevailing hypothesis is that mitochondrial and sarcolemmal KATP channels serve as end-effectors in the cardioprotective cascade [14,15]. This hypothesis arose from previous research on ischemic preconditioning, which occurs when a patient experiences brief vascular occlusion prior to an incident of prolonged cardiac ischemia to build up “resistance” to the event. Interestingly, preconditioning with volatile anesthesia has been shown to have similar effects as ischemic preconditioning: in both cases, preconditioned myocardial tissue appears to be better protected against ischemic insults than unconditioned controls [14]. Studies have indicated that both forms of preconditioning led to opening of KATP channels, an end-effector which is thought to ultimately lead to improved cellular protection against myocardial injury and ischemia [15]. Blockade of KATP channels has been shown to reverse the cardioprotective effect initiated by either ischemic precondition or anesthetic preconditioning [11,12], although these findings are somewhat controversial and seem to depend on experimental conditions [16] (in vivo versus in vitro) as well as the type of KATP channel antagonist [17]. Finally, preconditioning with both volatile anesthesia and temporary ischemia has been shown to have a synergistic effect [18].
Though much more remains to be discovered as to the mechanism of cardiac protection conferred by volatile anesthesia, the area of study has long been recognized as having ample potential. Moreover, the clinical implications of this research are both immediate and obvious: incorporating volatile anesthesia into the standard of care for patients with high risk of cardiac complications may lead to a decrease in procedure-related morbidity and mortality.
References
1 Bland, J. H., & Lowenstein, E. (1976). Halothane-induced decrease in experimental myocardial ischemia in the non-failing canine heart. Anesthesiology, 45(3), 287–293. https://doi.org/10.1097/00000542-197609000-00006
2 O’Keefe, J., Bybee, K., Layvie, C., & Hammil, S. (2012, July 1). ST-Segment Elevation: Defined by the Company It Keeps. Mayo Clinic Proceedings. Retrieved from https://www.mayoclinicproceedings.org/article/S0025-6196(12)00528-9/fulltext
3 Davis, R. F., DeBoer, L. W. V., Rude, R. E., Lowenstein, E., & Maroko, P. R. (1983). The effect of halothane anesthesia on myocardial necrosis,hemodynamic performance, and regional myocardial blood flow in dogs following coronary artery occlusion. Anesthesiology, 59(5), 402–411. https://doi.org/10.1097/00000542-198311000-00007
4 Coetzee, A., Skein, W., Genade, S., & Lochner, A. (1993). Enflurane and isoflurane reduce reperfusion dysfunction in the isolated rat heart. Anesthesia and analgesia, 76(3), 602–608. https://doi.org/10.1213/00000539-199303000-00027
5 Novalija, E., Fujita, S., Kampine, J. P., & Stowe, D. F. (1999). Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology, 91(3), 701–712. https://doi.org/10.1097/00000542-199909000-00023
6 Zaugg, M., Lucchinetti, E., Spahn, D. R., Pasch, T., & Schaub, M. C. (2002). Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways. Anesthesiology, 97(1), 4–14. https://doi.org/10.1097/00000542-200207000-00003
7 Tanaka, K., Ludwig, L. M., Krolikowski, J. G., Alcindor, D., Pratt, P. F., Kersten, J. R., Pagel, P. S., & Warltier, D. C. (2004). Isoflurane produces delayed preconditioning against myocardial ischemia and reperfusion injury: role of cyclooxygenase-2. Anesthesiology, 100(3), 525–531. https://doi.org/10.1097/00000542-200403000-00010
8 de Klaver, M. J., Buckingham, M. G., & Rich, G. F. (2003). Isoflurane pretreatment has immediate and delayed protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells. Anesthesiology, 99(4), 896–903. https://doi.org/10.1097/00000542-200310000-00023
9 Toller, W. G., Kersten, J. R., Pagel, P. S., Hettrick, D. A., & Warltier, D. C. (1999). Sevoflurane reduces myocardial infarct size and decreases the time threshold for ischemic preconditioning in dogs. Anesthesiology, 91(5), 1437–1446. https://doi.org/10.1097/00000542-199911000-00037
10 Roscoe, A. K., Christensen, J. D., & Lynch, C., 3rd (2000). Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology, 92(6), 1692–1701. https://doi.org/10.1097/00000542-200006000-00029
11 Toller, W. G., Kersten, J. R., Gross, E. R., Pagel, P. S., & Warltier, D. C. (2000). Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins. Anesthesiology, 92(5), 1400–1407. https://doi.org/10.1097/00000542-200005000-00031
12 Ludwig, L. M., Weihrauch, D., Kersten, J. R., Pagel, P. S., & Warltier, D. C. (2004). Protein kinase C translocation and Src protein tyrosine kinase activation mediate isoflurane-induced preconditioning in vivo: potential downstream targets of mitochondrial adenosine triphosphate-sensitive potassium channels and reactive oxygen species. Anesthesiology, 100(3), 532–539. https://doi.org/10.1097/00000542-200403000-00011
13 Novalija, E., Varadarajan, S. G., Camara, A. K., An, J., Chen, Q., Riess, M. L., Hogg, N., & Stowe, D. F. (2002). Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts. American journal of physiology. Heart and circulatory physiology, 283(1), H44–H52. https://doi.org/10.1152/ajpheart.01056.2001
14 Cason, B. A., Gamperl, A. K., Slocum, R. E., & Hickey, R. F. (1997). Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology, 87(5), 1182–1190. https://doi.org/10.1097/00000542-199711000-00023
15 Kersten, J. R., Gross, G. J., Pagel, P. S., & Warltier, D. C. (1998). Activation of adenosine triphosphate-regulated potassium channels: mediation of cellular and organ protection. Anesthesiology, 88(2), 495–513. https://doi.org/10.1097/00000542-199802000-00029
16 Hanouz, J. L., Yvon, A., Massetti, M., Lepage, O., Babatasi, G., Khayat, A., Bricard, H., & Gérard, J. L. (2002). Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro. Anesthesiology, 97(1), 33–41. https://doi.org/10.1097/00000542-200207000-00006
17 Zaugg, M., Lucchinetti, E., Spahn, D. R., Pasch, T., & Schaub, M. C. (2002). Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways. Anesthesiology, 97(1), 4–14. https://doi.org/10.1097/00000542-200207000-00003
18 Müllenheim, J., Ebel, D., Bauer, M., Otto, F., Heinen, A., Frässdorf, J., Preckel, B., & Schlack, W. (2003). Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits. Anesthesiology, 99(3), 624–631. https://doi.org/10.1097/00000542-200309000-00017
