Technology is moving in the direction where one day there may be a ‘preconditioning gene panel’ that is run on every patient preoperatively to customize choice of anesthetic regimen for surgery.

Image: ©Thinkstock.

Image: ©Thinkstock.

In 2007, the American College of Cardiology/American Heart Association guidelines first recommended perioperative volatile anesthetic use in patients at risk for myocardial ischemia.1  Numerous animal studies from canines to nematodes provided evidence for volatile anesthetic protection against myocardial ischemia–reperfusion injury.2,3  Several clinical trials conducted in patients undergoing coronary artery bypass grafting suggested the experimental study results translated into clinically relevant cardioprotection.4  However, almost a decade later, the primary molecular mechanisms mediating volatile anesthetic–induced cardioprotection still remain to be identified. In this month’s issue of Anesthesiology, Wojtovich et al.5  aim to provide novel insight into this limitation by deciphering the identity of a cardiac myocyte mitochondrial potassium channel that mediates volatile anesthetic–induced preconditioning. By using a genetic knock-out approach in mice, the authors identify the Slo2 gene family encoded potassium channel subtype Slo2.1 in cardiac myocyte mitochondria as a key determinant of volatile anesthetic–induced preconditioning from myocardial ischemia–reperfusion injury.5 

Both Slo2.1 (Kcnt2/’Slick’) and Slo2.2 (Kcnt1/’Slack’) are potassium channels activated by increased intracellular sodium levels and belong to the “big” conductance K+ channel (BK) family. The newly identified localization of Slick in cardiac myocyte mitochondria may add another piece to the puzzle of mitochondrial ion channels apparently involved in the complex response of cardiomyocytes to ischemia–reperfusion injury, including the mitochondrial ATP-sensitive K+ channel, the mitochondrial permeability transitional pore, and other BK channels that are long recognized in mediating volatile anesthetic–induced preconditioning via regulation of mitochondrial function.6  Although initial reports suggested that a Ca2+-activated BK channel (likely Slo1) was responsible for anesthetic preconditioning,7–9  the fact that Slo1−/− mice can still be preconditioned by isoflurane,10  coupled with the results of the study by Wojtovich et al., suggest reevaluation of these early findings.

In their present study, Wojtovich et al. report for the first time evidence that volatile anesthetic–induced K+ flux is abolished in cardiac myocyte mitochondria isolated from mice lacking Slick (Slo2.1−/−). Subsequently, isoflurane-induced preconditioning effects were absent in Slo2.1−/− mice but not in Slo2.2−/− mice subjected to myocardial ischemia–reperfusion injury. By demonstrating Slo2.1-mediated protective effects of volatile anesthetics that are independent of ischemia or pharmacologic K+ channel openers, the authors provide specificity for a novel molecular target for volatile anesthetic specific effects.

Thus, in the era of precision medicine, this study may provide us with more extensive knowledge to which patients undergoing cardiac surgery will benefit from receiving volatile anesthetics to reduce ischemia–reperfusion injury. The recommendations of the 2007 American College of Cardiology/American Heart Association guidelines have been continuously modified to downplay the powerful effects that volatile anesthetics have in reducing myocardial injury in preclinical models. In 2011, the recommendations for patients undergoing coronary artery bypass graft surgery were changed to only recommend the use of volatile anesthetics to facilitate extubation in cardiac patients.11  Further, the 2014 guidelines for patients undergoing noncardiac surgery recommend similarly the use of either volatile or intravenous agents.12  Primary endpoints such as a reduction in postoperative troponin levels or improved cardiac function were often met only in elective and highly selective cardiac patient populations4  and remained nonevident or controversial in patient populations undergoing noncardiac surgery.13,14  Numerous reasons may explain the clear lack of translation from experimental models to heterogeneous patient populations. Conditions such as diabetes likely attenuate the ability to precondition the myocardium and medications such as ATP-sensitive K+ channel channel inhibitors, used clinically to manage diabetes, may further block the effects of volatile anesthetics.14  Intravenous agents including opioids may also synergistically act with volatile anesthetics to reduce myocardial injury.15 

Advances in patient care are urgently needed to reduce perioperative myocardial reperfusion injury. Numerous preclinical studies provide a wealth of promising data on how volatile anesthetics or strategies like remote ischemic preconditioning effectively exert myocardial protection. Although the latter involves different mechanisms and requires additional molecular mediators,16  recently published results from two large studies show that remote ischemic conditioning strategies fail in providing benefit to patients.17,18  These data add to the litany of agents and interventions proposed to limit reperfusion injury that have failed in the clinic, including even cyclosporine A.19  The controversial data from clinical trials, however, must bring us back to better understand underlying molecular and cellular mechanisms in the basic science laboratory. Technology is moving in the direction where one day there may be a “preconditioning gene panel” that is run on every patient preoperatively to customize choice of anesthetic regimen for surgery. Candidate genes specific to volatile anesthetics, as that identified in the current manuscript, move us one step closer to identifying novel mechanisms to address the shortcomings of failed clinical translation.

Competing Interests

The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.

References

1.
Fleisher
LA
,
Beckman
JA
,
Brown
KA
,
Calkins
H
,
Chaikof
E
,
Fleischmann
KE
,
Freeman
WK
,
Froehlich
JB
,
Kasper
EK
,
Kersten
JR
,
Riegel
B
,
Robb
JF
,
Smith
SC
Jr
,
Jacobs
AK
,
Adams
CD
,
Anderson
JL
,
Antman
EM
,
Buller
CE
,
Creager
MA
,
Ettinger
SM
,
Faxon
DP
,
Fuster
V
,
Halperin
JL
,
Hiratzka
LF
,
Hunt
SA
,
Lytle
BW
,
Nishimura
R
,
Ornato
JP
,
Page
RL
,
Tarkington
LG
,
Yancy
CW
;
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery); American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society for Vascular Surgery
:
ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): Developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery.
Circulation
2007
;
116
:
e418
99
2.
Toller
WG
,
Gross
ER
,
Kersten
JR
,
Pagel
PS
,
Gross
GJ
,
Warltier
DC
:
Sarcolemmal and mitochondrial adenosine triphosphate- dependent potassium channels: Mechanism of desflurane-induced cardioprotection.
Anesthesiology
2000
;
92
:
1731
9
3.
van Swinderen
B
,
Galifianakis
A
,
Crowder
M
:
Common genetic determinants of halothane and isoflurane potencies in Caenorhabditis elegans.
Anesthesiology
1998
;
89
:
1509
17
4.
De Hert
SG
:
Cardioprotection in anesthesia.
Minerva Anestesiol
2008
;
74
:
259
70
5.
Wojtovich
AP
,
Smith
CO
,
Urciuoli
WR
,
Wang
YT
,
Xia
X-M
,
Brookes
PS
,
Nehrke
K
:
Cardiac Slo2.1 is required for volatile anesthetic stimulation of K+ transport and anesthetic preconditioning.
Anesthesiology
2016
;
124
:
1065
76
6.
Agarwal
B
,
Stowe
DF
,
Dash
RK
,
Bosnjak
ZJ
,
Camara
AK
:
Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury.
Front Physiol
2014
;
5
:
341
7.
Bentzen
BH
,
Osadchii
O
,
Jespersen
T
,
Hansen
RS
,
Olesen
SP
,
Grunnet
M
:
Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury.
Pflugers Arch
2009
;
457
:
979
88
8.
Redel
A
,
Lange
M
,
Jazbutyte
V
,
Lotz
C
,
Smul
TM
,
Roewer
N
,
Kehl
F
:
Activation of mitochondrial large-conductance calcium-activated K+ channels via protein kinase A mediates desflurane-induced preconditioning.
Anesth Analg
2008
;
106
:
384
91
9.
Xu
W
,
Liu
Y
,
Wang
S
,
McDonald
T
,
Van Eyk
JE
,
Sidor
A
,
O’Rourke
B
:
Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane.
Science
2002
;
298
:
1029
33
10.
Wojtovich
AP
,
Sherman
TA
,
Nadtochiy
SM
,
Urciuoli
WR
,
Brookes
PS
,
Nehrke
K
:
SLO-2 is cytoprotective and contributes to mitochondrial potassium transport.
PLoS One
2011
;
6
:
e28287
11.
Hillis
LD
,
Smith
PK
,
Anderson
JL
,
Bittl
JA
,
Bridges
CR
,
Byrne
JG
,
Cigarroa
JE
,
Disesa
VJ
,
Hiratzka
LF
,
Hutter
AM
Jr
,
Jessen
ME
,
Keeley
EC
,
Lahey
SJ
,
Lange
RA
,
London
MJ
,
Mack
MJ
,
Patel
MR
,
Puskas
JD
,
Sabik
JF
,
Selnes
O
,
Shahian
DM
,
Trost
JC
,
Winniford
MD
:
2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Circulation
2011
;
124
:
e652
735
12.
Fleisher
LA
,
Fleischmann
KE
,
Auerbach
AD
,
Barnason
SA
,
Beckman
JA
,
Bozkurt
B
,
Davila-Roman
VG
,
Gerhard-Herman
MD
,
Holly
TA
,
Kane
GC
,
Marine
JE
,
Nelson
MT
,
Spencer
CC
,
Thompson
A
,
Ting
HH
,
Uretsky
BF
,
Wijeysundera
DN
:
American College of Cardiology; American Heart Association: 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.
J Am Coll Cardiol
2014
;
64
:
e77
137
13.
Lindholm
EE
,
Aune
E
,
Norén
CB
,
Seljeflot
I
,
Hayes
T
,
Otterstad
JE
,
Kirkeboen
KA
:
The anesthesia in abdominal aortic surgery (ABSENT) study: A prospective, randomized, controlled trial comparing troponin T release with fentanyl-sevoflurane and propofol-remifentanil anesthesia in major vascular surgery.
Anesthesiology
2013
;
119
:
802
12
14.
Zaugg
M
,
Lucchinetti
E
,
Behmanesh
S
,
Clanachan
AS
:
Anesthetic cardioprotection in clinical practice from proof-of-concept to clinical applications.
Curr Pharm Des
2014
;
20
:
5706
26
15.
Ludwig
LM
,
Patel
HH
,
Gross
GJ
,
Kersten
JR
,
Pagel
PS
,
Warltier
DC
:
Morphine enhances pharmacological preconditioning by isoflurane: Role of mitochondrial K(ATP) channels and opioid receptors.
Anesthesiology
2003
;
98
:
705
11
16.
Gross
ER
,
Hsu
AK
,
Urban
TJ
,
Mochly-Rosen
D
,
Gross
GJ
:
Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C.
Basic Res Cardiol
2013
;
108
:
381
17.
Hausenloy
DJ
,
Candilio
L
,
Evans
R
,
Ariti
C
,
Jenkins
DP
,
Kolvekar
S
,
Knight
R
,
Kunst
G
,
Laing
C
,
Nicholas
J
,
Pepper
J
,
Robertson
S
,
Xenou
M
,
Clayton
T
,
Yellon
DM
;
ERICCA Trial Investigators
:
Remote ischemic preconditioning and outcomes of cardiac surgery.
N Engl J Med
2015
;
373
:
1408
17
18.
Meybohm
P
,
Bein
B
,
Brosteanu
O
,
Cremer
J
,
Gruenewald
M
,
Stoppe
C
,
Coburn
M
,
Schaelte
G
,
Böning
A
,
Niemann
B
,
Roesner
J
,
Kletzin
F
,
Strouhal
U
,
Reyher
C
,
Laufenberg-Feldmann
R
,
Ferner
M
,
Brandes
IF
,
Bauer
M
,
Stehr
SN
,
Kortgen
A
,
Wittmann
M
,
Baumgarten
G
,
Meyer-Treschan
T
,
Kienbaum
P
,
Heringlake
M
,
Schön
J
,
Sander
M
,
Treskatsch
S
,
Smul
T
,
Wolwender
E
,
Schilling
T
,
Fuernau
G
,
Hasenclever
D
,
Zacharowski
K
;
RIPHeart Study Collaborators
:
A multicenter trial of remote ischemic preconditioning for heart surgery.
N Engl J Med
2015
;
373
:
1397
407
19.
Cung
TT
,
Morel
O
,
Cayla
G
,
Rioufol
G
,
Garcia-Dorado
D
,
Angoulvant
D
,
Bonnefoy-Cudraz
E
,
Guérin
P
,
Elbaz
M
,
Delarche
N
,
Coste
P
,
Vanzetto
G
,
Metge
M
,
Aupetit
JF
,
Jouve
B
,
Motreff
P
,
Tron
C
,
Labeque
JN
,
Steg
PG
,
Cottin
Y
,
Range
G
,
Clerc
J
,
Claeys
MJ
,
Coussement
P
,
Prunier
F
,
Moulin
F
,
Roth
O
,
Belle
L
,
Dubois
P
,
Barragan
P
,
Gilard
M
,
Piot
C
,
Colin
P
,
De Poli
F
,
Morice
MC
,
Ider
O
,
Dubois-Randé
JL
,
Unterseeh
T
,
Le Breton
H
,
Béard
T
,
Blanchard
D
,
Grollier
G
,
Malquarti
V
,
Staat
P
,
Sudre
A
,
Elmer
E
,
Hansson
MJ
,
Bergerot
C
,
Boussaha
I
,
Jossan
C
,
Derumeaux
G
,
Mewton
N
,
Ovize
M
:
Cyclosporine before PCI in patients with acute myocardial infarction.
N Engl J Med
2015
;
373
:
1021
31