INHALATIONAL ANAESTHETICS

INDUCED CARDIOPROTECTION

Cosmin Balan

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.

Assigning a context

modulation of mitochondrial function to mimicendogenous neuroprotective mechanisms found inhypoxia-tolerant species confers protection againstotherwise lethal hypoxic stresses in hypoxia-intolerantorgans and organisms

lessons gleaned from the investigation of endogenousmechanisms of hypoxia tolerance in hypoxia-tolerantorganisms may provide insight into clinical pathologiesrelated to low oxygen stress

Matthew E. PamenterMitochondria: a multimodal hub of hypoxia toleranceCanadian Journal of Zoology,2014,92(7):569-589

Learning from the bestNatural Born Survivors

Trachemys/Chrysemys TurtlesNear-suspended animation

Carassius Carassius (Crucian Carp)Still active and responsive in the absence of O2

Natural Anoxia Tolerance

Facts about these two…

4-month survival advantage without O2

outstrips a typical mammal by a factor of 1000to 10,000.

CMRO2 turtle corrected for temp is smilar to thatof a typical mammal

Half-lethal times of 45 h under anoxia at 50Cand 22h at 200C for their cousin, Car Auratus At room temperature,in anoxia, Car Car survivesfor a few days During winter, Car Car tolerates anoxia severalmonths

They, too, get preconditioned

They lived to die another dayselection for hypoxia tolerance

O2 30%

SELECTION

Different timescalessimilar outcome

The anoxic frog brain therefore experiencesthe 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. LutzSlow ATP loss and the defense of ion homeostasis in the anoxic frog brainThe Journal of Experimental Biology 204, 3547–3551 (2001)

Key to their conundrumHochachka’s triad

EFFECTS

Slow alterations in H,lactate,Ca 2+

Slow ATP lossDelayed apoptosis

REOXYGENATION

High Se-GPXHigh G6PDHHigh GSHHigh SOD

REPAIR eg. Reptile neurogenesis

Modulation of ionic conductance and pumpsIon channel arrest

O2 conformersSupply-demand balancePKA,PKC,AMPKVery low Pasteur effectFermentable substrate conservationArrest of protein synthesisHYPOTHERMIA

METABOLIC SUPRESSION

METABOLICREENGINEERING

ION CHANNEL SUPPRESION

A link to human preconditioninguniversal 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

Impossible to emulate

Impossible to emulate

Summary model of hypoxia tolerancea 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

Chasing for the Holy Grailhypoxia tolerance in humans

ISCHEMIC PRECONDITIONING

Charles E. Murry et al., Circulation 74, No. 5, 1124-1136, 1986Preconditioning with ischemia: a delay of lethal cellinjury in ischemic myocardium

Murry’s paradigmCirculation 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 heartReduces 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)

Two phases

Charles J. Lowenstein PNAS 1999;96:10953-10954

Acute memory phase Late memory phase

Chasing for the Holy Grailhypoxia tolerance in humans

ISCHEMIC POSTCONDITIONING

Circulation,Laurent Argaud et al., INSERM E 0226, Université Claude Bernard LyonPostconditioning 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 ischemiaand 5 minutes of reperfusion before the prolongedIschemia

PostC: no intervention before the 30 minuteischemia. After 1 minute of reflow after the releaseof the 30-minute occlusion, we performed 4 episodesof 1 minute of ischemia each separated by 1 minuteof reperfusion

NIM811: nonimmunosuppressive derivative ofcyclosporin A

Hormetic effect in ischemia protection in humansliving in the Goldilocks Zone

Ischemia-IPre/PostC

Hyperoxia

Mechanical-stretch

Electrical-rapid pacing

Thermal (hypothermia) /Chemical

Hormonal-remote IPreC

Pharmacological

ToxicityHormesis

DoseDet

erio

rati

on

Imp

rov

emen

tE

FF

EC

T

Gems D. et al.,Cell Metabolism 7, March 2008Stress-response Hormesis and Aging:

“That which does not kill us makes us stronger”UCL

Sublethal exposure to stressors breeds stress resistance

Pharmacological armamentariumengineered 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

PROTECTION TOXICITY

engineered ischemia/anoxia protectionIPreC/IPostC mimetism

Pharmacological armamentariumengineered ischemia/anoxia protection

INHALATIONAL ANAESTHETICSSEVOFLURANE

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

SA

RC

OL

EM

MA

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

EARLY

PR

ECONDIT

IONING

DESFLURANE

SEVOFLURANE

ISOFLURANE

Gi

α,β

NE

ISCHEMIC BOUTS

ISCHEMIC BOUTS

PRAZOSIN

PROPRANOLOL

PTX

PTXSPT

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

TN

FR

TNFαJAK

JAKSTAT

TRANSCRIPTION FACTOR

UPREGULATION

AP-1

STAT

NF-kB

TN

FR JAK

JAK

STATJAK

JAKTNFα

TN

FR

MPTP

MnTBAP

MPG

iNOS

AlRed

Bcl-2

HSP27/70

COX-2

MnSOD

LATE

Mito restoration of Δψ

ATP production ↑

Prevention of apoptosis

Decrease of mito Ca 2+

SARCOLEMMA

Cytoprotective Mechanismssevoflurane 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

ATPase3Na +

2K +

ATPase3Na +

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.

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

Sevoflurane Potentiates Diazoxide-Mediated Myocyte Protection

ZAUGG,Anesthesiology 7 2002, Vol.97, 4-14

mKATP opener

Sevoflurane only primes mKATPothers 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%

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)

Takahiro Kamota, J Am Coll Cardiol, 2009;53:1814–22

Lucchinetti, Zaugg, Anesth Analg, 2009;109:1117–26

Mihaela Popescu, Bogdan Pavel, Leon ZagreanRomanian Archives of Microbiology and ImmunologyVol 70 - No. 3 July - september 2011 - Dynamics ofendothelial progenitor cells following SEVOFLURANEpreconditioning

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

Perioperative Cardioprotectioncardiac preconditioning in Sevoflurane guided anaesthesia

Adenosine receptor agonistsDipiridamol

KATP openerNicorandil,Diazoxid,Levosimendan,Minoxidil,

Bupivacaime,Ropivacaine

Opioid agonistsβ1 receptor agonists

Isoproterenol,Norepinephrine,epinephrine

β1 blockerscarvedilol,nebivolol

α1 agonistsnorepinephrine, phenylephrine

M2 receptor agonistsacetylcholine esterase inhibitors

Nitric oxide releasersnitroglycerine, nitroprusside, L-arginine

Ca2+

B2-bradykinin receptor agonistsAECI-captopril,lisinopril,enalapril

AT1 –receptor antagonistsStatinsPDE3 inhibitor

Amrinone, Milrinone

PDE5 inhibitor Sildenafil

Adenosine receptor antagoniststeophylline, aminophylline

KATP blockerSulfonyl urea agents (antidiabetic agents and anti-

cancer drugs)

Opioid antagonists

β1 receptor antagonistsincluding reserpine

α1 antagonistsphentolamine

M2 receptor antagonistsatropine

Nitric oxide scavengersvitamin E

Ca2+ channel blocker

Digoxin

Gadolinium

COX-2 inhibitors

PreCon ↑ PreCon ↓

Perioperative Cardioprotectiondisease 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

↓ ↔ ↑

↓ ↔

↓

↓ ↔

↓↔

↓

?

?

?

?

Translating Experimental Studiesclinical 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 surgerypredictability of ischemia

Translating Experimental Studiesdichotomy

Ischemia Predictability

Non Cardiac SurgeryCardiac Surgery

Circulation. 2007;116:1971–1996

Randomized clinical trials in patients undergoing CABG surgery indicate thatvolatile anesthetics decrease troponin release and enhance LV function comparedwith propofol, midazolam, or balanced anesthesia techniques with opioids.These data can likely be generalized to patients with CAD who are undergoing noncardiac surgery.

Recommendations for Use of Volatile Anesthetic AgentsClass IIa

It can be beneficial to use volatile anesthetic agents during noncardiacsurgery for the maintenance of general anesthesia in hemodynamicallytable patients at risk for myocardial ischemia. (Level of Evidence: B)

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 clinicallyrelevant 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 tointravenous anesthetics, has addressed major outcomes such as myocardialinfarction or mortality. Large, multicentre, randomized clinical trials includingpatients undergoing high-risk non-cardiac surgery and reporting clinicallyrelevant outcomes such as myocardial infarction and mortality are needed.

Landoni G, Bignami E, Oliviero F, et alHalogenated 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 wasshown 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 ofrandomized 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.

Giovanna A.L. Lurati Buse, MD; Philippe Schumacher, MD et alRandomized Comparison of Sevoflurane Versus Propofol toReduce Perioperative Myocardial Ischemia in Patients UndergoingNoncardiac Surgery

Circulation. 2012;126:2696-2704

Towards the 2014 Recommendations

Compared with propofol, sevoflurane did not reduce the incidence of myocardialischemia in high-risk patients undergoing major noncardiac surgery.The sevoflurane and propofol groups did not differ in postoperative NT-proBNPrelease, major adverse cardiac events at 1 year, or delirium.

Use of either a volatile anesthetic agent or total intravenous anesthesia is reasonable forpatients undergoing noncardiac surgery, and the choice is determined by factors other thanthe prevention of myocardial ischemia and MI.

(Level of Evidence: A)

Although the benefit of using volatile anesthetic agents has been demonstrated in cardiacsurgery, a reduction in myocardial ischemia/MI has not been demonstrated in noncardiacsurgery.

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