we are teleologically cardioprotected. we are already cardioprotected. nature has given us everything we need to be unbreakable.we just have to push the right buttons. please, pay heed to the turtles! they know best!

1. INHALATIONAL ANAESTHETICS
INDUCED CARDIOPROTECTION
Cosmin Balan

2. Assigning a definition
Cardioprotection is the limitation or prevention
of irreversible cellular injury in heart muscle
as a consequence of ischaemia/hypoxia/anoxia
and reperfusion.

3. Assigning a context
modulation of mitochondrial function to mimic
endogenous neuroprotective mechanisms found in
hypoxia-tolerant species confers protection against
otherwise lethal hypoxic stresses in hypoxia-intolerant
organs and organisms
lessons gleaned from the investigation of endogenous
mechanisms of hypoxia tolerance in hypoxia-tolerant
organisms may provide insight into clinical pathologies
related to low oxygen stress
Matthew E. Pamenter
Mitochondria: a multimodal hub of hypoxia tolerance
Canadian Journal of Zoology,2014,92(7):569-589

5. Learning from the best
Natural Born Survivors
Trachemys/Chrysemys Turtles
Near-suspended animation
Carassius Carassius (Crucian Carp)
Still active and responsive in the absence of O2
Natural Anoxia Tolerance

6. Facts about these two…
4-month survival advantage without O2
 outstrips a typical mammal by a factor of 1000
to 10,000.
CMRO2 turtle corrected for temp is smilar to that
of a typical mammal
 Half-lethal times of 45 h under anoxia at 50C
and 22h at 200C for their cousin, Car Auratus
 At room temperature,in anoxia, Car Car survives
for a few days
 During winter, Car Car tolerates anoxia several
months

7. They, too, get preconditioned

8. They lived to die another day
selection for hypoxia tolerance
O2 30%
SELECTION

9. Different timescales
similar outcome
The anoxic frog brain therefore experiences
the same sequence of degenerative changes
as the mammalian brain but on a greatly
extended time scale. The anoxic frog brain
dies very slowly.
Debra L. Knickerbocker and Peter L. Lutz
Slow ATP loss and the defense of ion homeostasis in the anoxic frog brain
The Journal of Experimental Biology 204, 3547–3551 (2001)

10. Key to their conundrum
Hochachka’s triad
EFFECTS
Slow alterations in H,lactate,Ca 2+
Slow ATP loss
Delayed apoptosis
REOXYGENATION
High Se-GPX
High G6PDH
High GSH
High SOD
REPAIR eg. Reptile neurogenesis
Modulation of ionic conductance and
pumps
Ion channel arrest
O2 conformers
Supply-demand balance
PKA,PKC,AMPK
Very low Pasteur effect
Fermentable substrate conservation
Arrest of protein synthesis
HYPOTHERMIA
METABOLIC SUPRESSION
METABOLIC
REENGINEERING
ION CHANNEL SUPPRESION

11. A link to human preconditioning
universal mechanism
mKATP
AR
mKATP
Ca 2+
ROS Vanden Hoeck et al,1998, J.Biol.Chem.273:18092-98
Pain et al,2000, Circ.Res. 87:460-66
Buck LT. 2004, Comp. Biochem. Physiol. B139:401-14
Buck LT. 2005, Comp.Biochem.Physiol. A142:50-57

12. Impossible to emulate

13. Impossible to emulate

14. Summary model of hypoxia tolerance
a second link to human preconditioning
Anaesthetic induced
early PC
Anaesthetic induced
late PC
Hochachka et al., Comparative Biochemistry and Physiology
Part B 130 (2001). 435-459

15. Chasing for the Holy Grail
hypoxia tolerance in humans
ISCHEMIC PRECONDITIONING
Charles E. Murry et al., Circulation 74, No. 5, 1124-1136, 1986
Preconditioning with ischemia: a delay of lethal cell
injury in ischemic myocardium

16. Murry’s paradigm
Circulation 1986
We postulated that multiple brief ischemic episodes might
actually protect the myocardium during a subsequent
sustained ischemic insult so that, in effect, we could
exploit ischemia to protect the heart from ischemic injury.
Strongest endogenous protective mechanism of the heart
Reduces infarct size
Improves recovery of function at reperfusion (reduced myocardial stunning)
Less reperfusion arrhytmias
Inherent to all tissues with high VO2
Has been described in the kidney, liver, small intestine, lung and brain
Universal mechanism
Endothelial and smooth muscle cells –they, too, get preconditioned
Lessens the endothelial cell damage leading to microvascular dysfunction
Two phase phenomenon-early (classic) and late (second window)

17. Two phases
Charles J. Lowenstein PNAS 1999;96:10953-10954
Acute memory phase Late memory phase

18. Chasing for the Holy Grail
hypoxia tolerance in humans
ISCHEMIC POSTCONDITIONING
Circulation,Laurent Argaud et al., INSERM E 0226, Université Claude Bernard Lyon
Postconditioning Inhibits Mitochondrial Permeability Transition, 2005
Postconditioning delays Ca2+-induced mPTP opening
Control: ischemia, no intervention
Sham: no ischemia
PreC: 1 episode of 5 minutes of ischemia
and 5 minutes of reperfusion before the prolonged
Ischemia
PostC: no intervention before the 30 minute
ischemia. After 1 minute of reflow after the release
of the 30-minute occlusion, we performed 4 episodes
of 1 minute of ischemia each separated by 1 minute
of reperfusion
NIM811: nonimmunosuppressive derivative of
cyclosporin A

19. Hormetic effect in ischemia protection in humans
living in the Goldilocks Zone
Ischemia-IPre/PostC
Hyperoxia
Mechanical-stretch
Electrical-rapid pacing
Thermal (hypothermia) /Chemical
Hormonal-remote IPreC
Pharmacological
ToxicityHormesis
Dose
DeteriorationImprovementEFFECT
Gems D. et al.,Cell Metabolism 7, March 2008
Stress-response Hormesis and Aging:
“That which does not kill us makes us stronger”
UCL
Sublethal exposure to stressors breeds stress resistance

20. Pharmacological armamentarium
engineered ischemia/anoxia protection
IPreC/IPostC mimetism
Inhalational anaesthetics
Opioids
H2S
Antioxidants
ACEI*
Cyclosporine(MPTP inh)
Nitroglycerine(Pre/PostC mim.)
Nicorandil(KATP)
Eniporide(Na+/H+inh)
ANP(PostC mimetic)
PDE5 inh. (Pre/PostC+MPTP)
VDR agonism(Olmesartan, D3)
Brain Sci. 2014, 4, 273-294
HORMETIC EFFECT

21. PROTECTION TOXICITY
engineered ischemia/anoxia protection
IPreC/IPostC mimetism

22. Pharmacological armamentarium
engineered ischemia/anoxia protection
INHALATIONAL ANAESTHETICS
SEVOFLURANE
PERIOPERATIVE CARDIOPROTECTION
► Flow-cond. demand-supply modulation
Negative inotropic & chronotropic action
Positive lusitropic action
Increased coronary bloodflow
V-A coupling modulation (ELV/EA)
Metabolic(oxidative substrate) modulation
•Oguchi , Br J Anaesthesia, 1995 May;74(5):569-75
•Pagel, Anesthesiology, 1996 Jul;85(1):112-20
•Takahata, Acta Anaesthesiologica Scandinavica,
Vol 39, Issue 4, , 449–456, May 1995
PROTECTION DURING CARDIOPLEGIC ARREST
PARADIGM SHIFT
IA induced preconditioning IA induced postconditioning
Kersten, Anesthesiology. 1997 Aug;87(2):361-70 Chen,Acta Pharmacol Sin. 2008 Aug;29(8):931-41
Mito demand-supply
modulation-CM survival pathway

23. SARCOLEMMA
AT1R M2R B2R P2YR
Gi Gi Gi Gi
NCX
NHE
Ca 2+
Na + Na +
H + H +
ENIPORIDE
LCa2+
Ca 2+
A1,A3
Gi
AgII Ach Bk ATP Ad
Redundancy
sK+
ATP
HMR-1098
PLC
e/iNOS
OPIOIDS
Gi
δ,κ
PKC
E
A
R
L
Y
P
R
E
C
O
N
D
I
T
I
O
N
I
N
G
DESFLURANE
SEVOFLURANE
ISOFLURANE
Gi
α,β
NE
ISCHEMIC BOUTS
ISCHEMIC BOUTS
PRAZOSIN
PROPRANOLOL
PTX
PTX
SPT
DPCPX
mK+
ATP
ROS
εδη
CALPHOSTIN C
STAUROSPORIN
CHELERYTHRINE
5HD
GLYBURIDE
DIAZOXID
NICORANDIL
NO
NITROGLYCERINE
SNAP
cPTIO L-NAME
L-NIL
PKG
GMPc
8-Br-cGMP
Ca 2+
RYR
IP3R
Ca 2+
SERCA
IP3
PIP2
DAG
Ca 2+
RISK PATHWAY
PI3K/AKT
MEK1/2
ERK1/2
RAS/RAF
P38 & JNK
TNFR
TNFα
JAK
JAK
STAT
TRANSCRIPTION FACTOR
UPREGULATION
AP-1
STAT
NF-kB
TNFR
JAK
JAK
STAT
JAK
JAK
TNFα
TNFR
MPTP
MnTBAP
MPG
iNOS
AlRed
Bcl-2
HSP27/70
COX-2
MnSOD
L
A
T
E
Mito restoration of Δψ
ATP production ↑
Prevention of apoptosis
Decrease of mito Ca 2+
SARCOLEMMA

24. Cytoprotective Mechanisms
sevoflurane emulates IPC
KATP
MPTP
KATP
MPTP
SMC-RC
SMC-RC
SMC-RC
KATP
MPTP
- - - - - - - - - - - - - -
++++++++++++++
- - - - - - - - - - - - - -
++++++++++++++
KATP
LCa2+
LCa2+
LCa2+
KATP
KATP
NCX
NHE
Ca 2+
Na + Na +
H + H +
Ca 2+
NCX
NHE
Ca 2+
Na +
Na +
H +
H +
Ca 2+
NCX
NHE
Ca 2+
Na + Na +
H + H +
Ca 2+
++++++++++++++
- - - - - - - - - - - - - -
ROS
ROS
ROS
ATPase
3Na +
2K +
ATPase
3Na +
2K +
Matrix volume dependent energy regulation
mKATP leads to depol. of the inner mito. mb.
Non linear dep. of Ca 2+ influx on mito. pot.
Mito. matrix contraction 30%
Intermembrane expansion
sKATP induced hyperpolarization
Dissociation of SMC
Modified ZAUGG, Br. J. Anaesth. (2003) 91 (4):551-565.

25. Myocyte Protection is Mediated by mKATP
A=control after 60 min of ischemia
5HD=5-hydroydecanoate (mKATPblocker)
HMR-1098=sKATPblocker
A=red myocytes are irreversibly damaged
Trypan blue-positive=red, damaged
ZAUGG,Anesthesiology 7 2002, Vol.97, 4-14

26. Sevoflurane Potentiates Diazoxide-Mediated Myocyte
Protection
ZAUGG,Anesthesiology 7 2002, Vol.97, 4-14
mKATP opener

27. Sevoflurane only primes mKATP
others open mKATP directly
ZAUGG,Anesthesiology 7 2002, Vol.97, 4-14
Flavoprotein Oxidation-Enhanced Autofluorescence in Myocytes
The redox state of flavoproteins(FAD) reflects mitoKATP activity
The redox state of flavoproteins(FAD) is reflected by their autofluorescence
Microscope, excitation at 480 nm and emission at 530 nm
Calibration of fluorescence:2,4 dinitrophenol uncouples OxF-marker 100%

28. Sevoflurane’s priming is mediated by PKC
ZAUGG,Anesthesiology 7 2002, Vol.97, 4-14
Flavoprotein Oxidation-Enhanced Autofluorescence in Myocytes
CHE = Chelerythrine (PKC inhibitor)

29. Takahiro Kamota, J Am Coll Cardiol, 2009;53:1814–22
Lucchinetti, Zaugg, Anesth Analg, 2009;109:1117–26
Mihaela Popescu, Bogdan Pavel, Leon Zagrean
Romanian Archives of Microbiology and Immunology
Vol 70 - No. 3 July - september 2011 - Dynamics of
endothelial progenitor cells following SEVOFLURANE
preconditioning
Sevoflurane-beyond the cardiomyocyte
The Recruitement of Bone Marrow Stem Cells into the Heart 1 Day after I/R Injury
J Am Coll Cardiol, 2009;53:1814–22

30. Perioperative Cardioprotection
cardiac preconditioning in Sevoflurane guided anaesthesia
Adenosine receptor agonists
Dipiridamol
KATP opener
Nicorandil,Diazoxid,Levosimendan,Minoxidil,
Bupivacaime,Ropivacaine
Opioid agonists
β1 receptor agonists
Isoproterenol,Norepinephrine,epinephrine
β1 blockers
carvedilol,nebivolol
α1 agonists
norepinephrine, phenylephrine
M2 receptor agonists
acetylcholine esterase inhibitors
Nitric oxide releasers
nitroglycerine, nitroprusside, L-arginine
Ca2+
B2-bradykinin receptor agonists
AECI-captopril,lisinopril,enalapril
 AT1 –receptor antagonists
Statins
PDE3 inhibitor
Amrinone, Milrinone
PDE5 inhibitor
Sildenafil
Adenosine receptor antagonists
teophylline, aminophylline
KATP blocker
Sulfonyl urea agents (antidiabetic agents and anti-
cancer drugs)
Opioid antagonists
β1 receptor antagonists
including reserpine
α1 antagonists
phentolamine
M2 receptor antagonists
atropine
Nitric oxide scavengers
vitamin E
Ca2+ channel blocker
Digoxin
Gadolinium
COX-2 inhibitors
PreCon ↑ PreCon ↓

31. Perioperative Cardioprotection
disease dependent cardioprotection efficacy
 Diabetes
 Increased age
 High plasma cholesterol
 Coronary artery disease
 Arterial hypertension
Healthy Systems Breed Highly Efficient PC
Factors/Diseases Ischemic PC Sevoflurane PC
 ↓ ↔ ↑
 ↓ ↔
 ↓
 ↓ ↔
 ↓↔
 ↓
 ?
 ?
 ?
 ?

32. Translating Experimental Studies
clinical confounders in IA based anaesthesia
Timing and mode of adminstration
Dose
Opioids
α,β agonists/antagonists
ACEI
Statins
PDE inhibitors
Sulfonylurea medication
Cardiac versus non-cardiac surgery
predictability of ischemia

33. Translating Experimental Studies
dichotomy
Ischemia Predictability
Non Cardiac SurgeryCardiac Surgery

34. Circulation. 2007;116:1971–1996
Randomized clinical trials in patients undergoing CABG surgery indicate that
volatile anesthetics decrease troponin release and enhance LV function compared
with propofol, midazolam, or balanced anesthesia techniques with opioids.
These data can likely be generalized to patients with CAD who are undergoing non
cardiac surgery.
Recommendations for Use of Volatile Anesthetic Agents
Class IIa
It can be beneficial to use volatile anesthetic agents during noncardiac
surgery for the maintenance of general anesthesia in hemodynamically
table patients at risk for myocardial ischemia. (Level of Evidence: B)

35. Landoni G, Fochi O, Bignami E, et al.
Cardiac protection by volatile anesthetics in non-cardiac surgery?
A meta-analysis of randomized controlled studies on clinically
relevant endpoints.
HSR Proc Intensive Care Cardiovasc Anesth. 2009;1:34–43.
Towards the 2014 Recommendations
No randomized study, among those which compared desflurane or sevoflurane to
intravenous anesthetics, has addressed major outcomes such as myocardial
infarction or mortality. Large, multicentre, randomized clinical trials including
patients undergoing high-risk non-cardiac surgery and reporting clinically
relevant outcomes such as myocardial infarction and mortality are needed.

36. Landoni G, Bignami E, Oliviero F, et al
Halogenated anaesthetics and cardiac protection in cardiac and
non-cardiac anaesthesia.
Ann Card Anaesth. 2009
Towards the 2014 Recommendations
This review supports the evidence that the choice of an anaesthetic regimen was
shown to have an impact on patients’ outcome following cardiac surgery.
Landoni G, Biondi-Zoccai GG et al.
Desflurane and sevoflurane in cardiac surgery: A meta-analysis of
randomized clinical trials.
J Cardiothorac Vasc Anesth 2007;21:502-11
Large, multicentre, randomised clinical trials including patients high-risk non-
cardiac surgery are needed to achieve a definitive demonstration of anaesthetic-
induced cardioprotection: this represents a difficult task because of the low
mortality rate in modern surgery and because of the number of interfering factors.

37. Giovanna A.L. Lurati Buse, MD; Philippe Schumacher, MD et al
Randomized Comparison of Sevoflurane Versus Propofol to
Reduce Perioperative Myocardial Ischemia in Patients Undergoing
Noncardiac Surgery
Circulation. 2012;126:2696-2704
Towards the 2014 Recommendations
Compared with propofol, sevoflurane did not reduce the incidence of myocardial
ischemia in high-risk patients undergoing major noncardiac surgery.
The sevoflurane and propofol groups did not differ in postoperative NT-proBNP
release, major adverse cardiac events at 1 year, or delirium.

38. Use of either a volatile anesthetic agent or total intravenous anesthesia is reasonable for
patients undergoing noncardiac surgery, and the choice is determined by factors other than
the prevention of myocardial ischemia and MI.
(Level of Evidence: A)
Although the benefit of using volatile anesthetic agents has been demonstrated in cardiac
surgery, a reduction in myocardial ischemia/MI has not been demonstrated in noncardiac
surgery.

39. Choosing the right thing
Complex non cardiac surgery, coronary artery disease,
advanced age, diabetes mellitus, chronic renal disease,
hypertension.
either/or
think like a turtle
there is no either/or
there is only SEVOFLURANE
think evidence-basedthink ACC-AHA