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Cardiovascular Science

3010 MSC

Ischemic Preconditioning

of the myocardium



Contents Page

1.0 Introduction

2.0 Methods and Materials

3.0 Results

4.0 iscussion

!.0 References

".0 #$$endi%



1.0 Introduction

#ccording to the &orld 'ealth (rgani)ation* ischemic heart disease is the

leading cause of death in +esterni)ed countries and is ty$ically

characterised ,y insufficient ,lood flo+ to regions of the myocardium*

+hich leads to myocardial infarction -o+ney* avis* Cohen* 200/

-&'(* 200. It is +ell recogni)ed that myocardial ischemia is a com$le%

$henomenon affecting the mechanical* electrical* structural and

,iochemical $ro$erties of the heart. es$ite this com$le%ity im$ressive

$rogress has ,een achieved in advancing our understanding and

a$$reciation of the cellular $rocesses and the mechanistic ,ases

underlying cardiac dysfunction* associated +ith ischemia and most

im$ortantly in a$$lying this no+ledge to develo$ thera$eutic

interventions -armay)an* 1".

5he myocardium is critically de$endent on its ,lood su$$ly* to fulfill its

$um$ing re6uirements. Interru$tion of coronary artery ,lood flo+* mostcommonly a result of atherosclerotic heart disease* can elicit ionic*

electro$hysiological and contractile distur,ances that im$ede or

ultimately su$$ress the hearts normal function resulting in myocardial

infarct -7aran8an* 7o,auira* Man8eet* #nton* 2003. (,viously the

hemodynamic determinants of o%ygen demand +ill also influence the

outcome of the ischemic insult and include heart rate* +all stress and

myocardial contractility -5he Mc9ra+:'ill Com$anies* 200.

uring acute myocardial infarction* the central area of necrosis is

generally surrounded ,y an area of in8ury* +hich in turn is surrounded ,y

an area of ischemia. 5hus* various stages of myocardial damage can

coe%ist. 5he distinction ,et+een ischemia and necrosis is +hether the

$henomenon is reversi,le -#'#* 200.

Ironically ischemia can e%ert $arado%ical effects on the heart* +hich are



$rimarily de$endent on the duration of the ischemic insult. 5he

myocardium is remara,ly sensitive to o%ygen de$rivation* thus

$rolonged $eriods of ischemia are visi,ly detrimental* resulting in the

genesis of lethal arrhythmias* contractile dysfunction and ultimatelynecrotic cell death -;evy Pa$$ano* 200/. <rief $eriods of ischemic

insults on the other hand actually invoe an intrinsic $rotective

mechanism* +hich renders the myocardium more resistant to su,se6uent

$otentially lethal ischemic e$isodes -eer* 1. 5his innate

$hysiological ada$tive $henomenon arose from the $ioneering +or of

Murry* =ennings and Reimer in 1"* +ho termed this conce$t ischemic

$reconditioning. Ischemic $reconditioning +as originally defined as the

enhancement of myocardial tolerance against infarction induced ,y a ,rief

su,lethal e$isode of ischemia in e%$erimental animals -Murry* =ennings*

Reimer* 1". Su,se6uently* the conce$t of ischemic $reconditioning +as

e%$anded and currently includes $rotection against myocardial stunning*

arrhythmia* and vascular dysfunction after ischemia>re$erfusion in8ury

-5etsu8i* 200".

Ischemic $reconditioning invoes a ,i$hasic $attern of $rotection in the

myocardium* an early or first +indo+ of $rotection and a delayed or

second +indo+ of $rotection -9hosh* 7g* 5al+ar* S6uire* 9alinanes*

2000 -figure 1. Murry and colleagues first descri,ed the acutely

manifested $hase of ada$tion. 5his first +indo+ of $rotection* no+

referred to as classical $reconditioning is manifested immediately

follo+ing ,rief su,lethal ischemia and confers a mared slo+ing in the

$rogression of irreversi,le ischemic in8ury during su,se6uent ischemic

e%$osure -7aran8an* 7o,auira* Man8eet* #nton* 2003. (ne of the most

distinctive features of classical $reconditioning is that the $rotection

afforded ,y antecedent ischemia +anes ra$idly. 7o $rotection against

either infarction or arrhythmias is o,served +hen the interval ,et+een

$reconditioning and the su,se6uent ischemic insult is e%tended ,eyond 2

hours -<a%tor* 1. 5he late $hase or second +indo+ of $rotection is

e%hi,ited a$$ro%imately 12 to /2 hours after the initial stimulus and is



characterised ,y ,oth infarct si)e reduction and an attenuation of $ost

ischemic contractile dysfunction -Pr)ylen* 2003 <oth $hases of

$reconditioning involve reduction of necrotic tissue mass -infarct si)e*

im$rovement of cardiac $erformance and reduction of arrhythmiasfollo+ing ischaemia and re$erfusion -Miller ?an &inle* 1 .

Figure 1: 5he ,i$hasic $hase of $rotection invoed ,y ischemic

$reconditioning.

5he underlying mechanisms of ischemic $reconditioning have ,een

e%tensively investigated* ho+ever the ,asis of such cardio$rotection is not

fully elucidated. Current evidence suggests that the cardio$rotective

mechanism $roduced as a result of ischemic $reconditioning is a multi:

factorial $rocess consisting of an early initial trigger* an intermediate

mediator and an end effector. -7aran8an* 7o,auira* Man8eet* #nton*

2003* -?iten:=ohansen* @hao* =iang* @atta* o,sen* 200/. 5he most

favoured current hy$othesis for the first +indo+ of $reconditioning

suggests that a variety of endogenous ligands such as adenosine*

,radyinin* catecholamines and o$ioids activate 9:$rotein cou$led

rece$tors lined to $rotein inase C -PC to initiate an intracellular

transduction $ath+ay -o+ney* avis* Cohen* 200/. It is thought PC

may activate a tyrosine inase* +hich in turn activates M#P inase leading

finally to the $hos$horlyation of effector $roteins* and $ossi,ly theactivation of mitochondrial #5P sensitive $otassium channels -mito A#5P



-Pr)ylen* 2003-9hosh* 7g* 5al+ar* S6uire* 9alinanes* 2000. #n

alternative candidate for initiating ischemic $reconditioning is a

$reischemic mild increase of the intracellular Ca2A concentration -BCa2A.

Short $eriods of ischemia and re$erfusion induce

a loss of Ca

2A

from thesarco$lasmic reticulum -SR and an accumulation of Ca2A in the cytosol

-&u Deher* 1!. Miya+ai and co:+orers inferred that a small

increase of BCa2A acts as a mediator of $reconditioning via activation of

PC -Miya+ai #shraf* 1/

5hese studies $rovide novel information to understand the underlyingmechanism of $rotection ,y $reconditioning of the myocardium and the

results have o,vious clinical im$ortance.

5he $ur$ose of this study is to investigate the degree to +hich ischemic

$reconditioning renders the myocardium more resistant to su,se6uent

su,lethal ischemic e$isodes* ,y measuring the return of function* of

systolic* diastolic and develo$ed $ressure as +ell as flo+ rate in$reconditioned hearts versus control hearts.



2.0 MethodsMouse Heart Perfusion Model

Preconditioned or genetically modified C!/><l" mice +ere anestheti)ed

+ith !0 mg>g of sodium $ento,ar,itone administered intra:$eritoneally. #

thoracotomy +as $erformed and hearts ra$idly e%cised into ice:cold re,s

,icar,onate ,uffer. 5he aorta +as then cannulated and hearts $erfused in

a ;angendorff mode at a $ressure of 0 mm'g* as outlined ,y us in detail

$reviously. 'earts +ere $erfused +ith a modified re,s ,icar,onate ,uffer

containing -in mME 7aCl* 11F 7a'C(3* 2!F Cl* 4./F '2P(4* 1.2F CaCl2*

2.!F MgS(4* 1.2F G5#* 0."F and +ith 11 mM glucose as e%ogenous

su,strates. 5he $erfusion fluid +as saturated +ith !H (2 and !H C(2 at

3/C -yielding a $' of /.4 and a P(2J!!0 mm'g at the aortic cannula*

and +as continuously filtered via a 0.4! K in:line filter. 5he left ventricle

+as vented +ith a $olyethylene drain to $revent fluid accumulation and an

intra:ventricular ,alloon introduced for assessment of contractile function*

as descri,ed $reviously. Coronary flo+ +as monitored via an ultrasonic

flo+:$ro,e in the aortic $erfusion line connected to a 510" flo+meter

-5ransonic Systems Inc* Ithaca* 7L* S#. Dunctional data +ere recorded at

1 ') on a 4 channel Mac;a, data ac6uisition system -#Instruments*

Castle 'ill* #ustralia. ?entricular $ressure +as digitally $rocessed to yield

systolic and diastolic $ressures and heart rate.

Ischemia-reperfusion protocol. #fter instrumentation all hearts +ere

introduced into a +ater:8aceted cham,er su$erfused +ith +armed

,uffer at 3/C* ensuring sta,le tem$erature throughout the

$rotocols. Dollo+ing a 20 min sta,ili)ation $eriod at intrinsic heart

rate hearts +ere s+itched to electrical $acing at 420 ,eats>min and

sta,ili)ed a further 10 min. 'earts +ere e%cluded from analysis at

this time if they met one of the follo+ing criteriaE i left ventricular

systolic $ressure N100 mm'gF ii coronary flo+ O! ml>minF iii



fluctuating -unsta,le contractile functionF or iv significant

arrhythmias. <aseline functional measurements +ere made ,efore

su,8ecting hearts to 20 min glo,al normothermic ischemia and 4!:

"0 min of re$erfusion.



3.0 Results

The early protective effect of ischemic preconditioning

and comparison of its efficacy ith control hearts! in the

first indo of preconditioning.

#s sho+n in figure 2* after 20 minutes of ischemia a mared increase in

diastolic $ressure +as o,served in the control hearts. 5he $reconditioned

hearts on the other hand sho+ed an initial rise in diastolic $ressure during

the ischemic $eriod* ho+ever once re$erfused the diastolic $ressure

dro$$ed ,ac do+n to ,aseline level. 5he tra8ectory of recovery of

diastolic $ressure is significantly im$roved in the $reconditioned hearts

relative to control PN0.0!.

Figure 2: emonstrates the effect of ischemic $reconditioning on the

time:course and the $ost ischemic recovery of diastolic

$ressure on adult mice hearts. 5he differences in diastolic$ressure ,et+een control and $reconditioned

P value Q



hearts +ere measured over a 20 minute $eriod of

ischemia* follo+ed su,se6uently ,y a "0 minute $eriod of

re$erfusion. Gach $oint re$resents a mean S.G.M for 4

hearts. 7ote that the tra8ectory of recovery of

diastolic $ressure is significantly im$roved ,y ischemic$reconditioning relative to control -P value Q 0.021012

#s sho+n in figure 3* after the 20 minute ischemic $eriod the recovery of

systolic $ressure im$roved +ith the $reconditioned hearts* ho+ever this

recovery does not sho+ a significant difference in com$arison to the

control hearts PJ0.0!.

Figure 3: emonstrates the effect of ischemic $reconditioning on the

time:course and the $ost ischemic recovery of systolic

$ressure on adult mice hearts. 5he differences in

systolic $ressure ,et+een control and $reconditioned

hearts +ere measured over a 20 minute $eriod of

P value Q



ischemia* follo+ed su,se6uently ,y a "0 minute $eriod of

re$erfusion. Gach $oint re$resents a mean S.G.M for 4

hearts. Gvidently the recovery of systolic $ressure after a $eriod

of ischemia is im$roved +ith ischemic $reconditioning*

ho+ever this recovery does not sho+ a significant difference incom$arison to the control hearts -P value Q 0.14/.



It is evident from figure 4* that ischemic $reconditioning has a $rofound

effect on the recovery of develo$ed $ressure follo+ing the 20 minute

ischemic $eriod. In com$aring control values +ith $reconditioned valuesthe recovery of develo$ed $ressure +as found to ,e significantly

increased +ith ischemic $reconditioning PN0.0!.

Figure ": emonstrates the effect of ischemic $reconditioning on the

time:course and the $ost ischemic recovery of develo$ed

$ressure on adult mice hearts. 5he differences in develo$ed

$ressure ,et+een control and $reconditioned hearts

+ere measured over a 20 minute $eriod of

ischemia* follo+ed su,se6uently ,y a "0 minute $eriod ofre$erfusion. Gach $oint re$resents a mean S.G.M for 4

hearts. 7oticea,ly the recovery of develo$ed $ressure after a

$eriod of ischemia im$roved considera,ly +ith ischemic

$reconditioning in com$arison to the control hearts.

-P value Q 0.01"4!.

P value Q



#s sho+n in figure ! ischemic $reconditioning a$$eared to have little

effect on the recovery of flo+ during the $ost the ischemic $eriod. 5he

difference in recovery ,et+een control and $reconditioned hearts +asfound to ,e insignificant PJ0.0!.

Figure #: emonstrates the effect of ischemic $reconditioning on the

time:course and the $ost ischemic recovery of flo+ rate in

adult mice hearts. 5he differences in flo+ rate ,et+een control

and $reconditioned hearts +ere measured over a 20 minute

$eriod of ischemia* follo+ed su,se6uently ,y a "0 minute

$eriod of re$erfusion. Gach $oint re$resents a mean S.G.Mfor 4 hearts. 5he recovery of flo+ rate after a $eriod of

ischemia +as actually lo+er +ith ischemic $reconditioning in

com$arison to the control hearts* ho+ever there +as no

significant difference -P value Q 0.13//0".

P value Q



".0 $iscussion

It has $reviously ,een demonstrated ,y Murry* =ennings and Reimer* that

a ,rief e$isode of ischemia slo+s the rate of #5P de$letion during

su,se6uent ischemic e$isodes -Murry* =ennings* Reimer* 1".

#dditionally* intermittent re$erfusion may ,e ,eneficial to the

myocardium ,y +ashing out cata,olites that have accumulated during

ischemia -<a%tor* 1. 5hus* it is $ro$osed that multi$le ,rief ischemic

e$isodes might actually render the heart more resistant to a su,se6uentsustained ischemic insult. 5o test this hy$othesis* the follo+ing

e%$eriment +as $erformed. (ne grou$ of adult mice -n Q 4 +ere

$reconditioned +ith three* 1 minute circumfle% occlusions* each se$arated

,y ! minutes of re$erfusion* follo+ed ,y a sustained 20 minute occlusion

and su,se6uently re$erfused for "0 minutes. 5he control grou$ -n Q 4

received a single 20 minute occlusion follo+ed su,se6uently ,y a "0

minute $eriod of re$erfusion. 5he diastolic $ressure* systolic $ressure*

develo$ed $ressure and flo+ rate of each of the hearts +ere measured

over the 0 minute ischemia> re$erfusion $eriod are $resented in

a$$endi% 1. 5he effects of ischemic $reconditioning +ere determined ,y

measuring $ost ischemic return of function as an end $oint.

%ffect of ischemic preconditioning on diastolic pressure

In the 0 minute study* $reconditioning +ith ischemia $arado%ically

reduced diastolic $ressure to 3.H of that seen in the control grou$. 5he

mean diastolic $ressure value at the end of the "0 minute re$erfusion

$eriod for the $reconditioned hearts +as 0.14mm'g* indicating a 100H

$ost ischemic return of function* "2.2H greater than that e%$erienced ,y

the control hearts. 5hese results returned a P value of 0.021012*

indicating a significant difference ,et+een the t+o grou$s in regards to

the return of function.

%ffect of ischemic preconditioning on systolic pressure



It can ,e seen from figure 3 that the recovery of systolic $ressure after a

$eriod of ischemia is marginally im$roved +ith ischemic $reconditioning.

5he e%tent to +hich ischemic $reconditioning increases $ost:ischemic

return of function is ho+ever limited* as the results of our e%$erimentindicate that the $reconditioned hearts e%hi,it only a 2H increase of $ost:

ischemic return of function over the control hearts. 5hese results returned

a P value of 0.14/* indicating that the $rotection conferred ,y ischemic

$reconditioning is relatively insignificant +ith regards to return of function

of systolic $ressure.

%ffect of ischemic preconditioning on developed pressure

#s sho+n in figure 4* the tra8ectory of recovery of develo$ed $ressure is

significantly im$roved ,y ischemic $reconditioning relative to the control

-P value Q 0.021012. 5he mean develo$ed $ressure value at the end of

the "0 minute re$erfusion $eriod for the $reconditioned hearts +as

10.11mm'g* indicating a "1.!H $ost:ischemic return of function* 14.2H

greater than that e%$erienced ,y the control hearts.

%ffects of ischemic preconditioning on flo rates

5he e%$erimental results o,tained for the effects of ischemic

$reconditioning on flo+ rates +ere some+hat une%$ected. (ne +ould

assume that ,ecause ischemic $reconditioning has resulted in an

increased $ost:ischemic return of function +ith all of the $revious end

$oint measures* similar results could ,e e%$ected +ith regard to flo+ rate.

5his ho+ever +as not the case as the results in figure ! sho+s that the

control hearts demonstrated a greater return of function then the

$reconditioned hearts. 5he mean flo+ rate value at the end of the "0

minute re$erfusion $eriod for the $reconditioned hearts +as

1.!1ml>min>g indicating a "1.!H $ost ischemic return of function* ".!H

lo+er than that e%$erienced ,y the control hearts. 5hese results are

contradictory to the results o,tained from several other studies* including

those done ,y Morris and co:+orers +ho re$orted an increased $ost:



ischemic return of function in $reconditioned hearts in com$arison to

control hearts -armay)an* 1".

5aen as a +hole the results from this study strongly suggest that

ischemic $reconditioning $rovides an e%tremely $otent endogenous

cardio$rotective mechanism* +hich renders the myocardium more

resistant to su,se6uent $otentially lethal $eriods of ischemia. 5he

mechanism ,y +hich ischemic $reconditioning confers $rotection still

remains under intense investigation* ho+ever studies done so far have

found that ischemic $reconditioning is multi:factorial $rocess consisting of

several ey initial triggers* +hich activate intermediate mediators +hich

su,se6uently converge u$on an end effector.

The mechanism of ischemic preconditioning

#lthough not fully elucidated the trigger mechanism of ischemic

$reconditioning has ,een found to involve a num,er of endogenously

released su,stances such as adenosine* ,radyinin and o$ioids* +hich are

released during ischemia and act in $arallel to trigger the $reconditioned

state through activation of multi$le 9:cou$led $rotein rece$tors -o+ney*

avis* Cohen* 200/. 5his multi$le trigger theory $ro$osed ,y 9oto and

colleagues re6uires that all triggers converge u$on a common target. It

+as found that $rotection afforded ,y all of the trigger su,stances could

,e ,loced ,y PC inhi,itors and thus PC is thought to ,e this common

target -9oto* ;iu* Lang* #rdell* M* o+ney* 1! -Mii* Cohen*

o+ney* 1. &hile adenosine cou$les directly to PC through

$hos$holi$ases* ,radyinin and o$ioids do so through a com$le% $ath+ay*

involving e$idermal gro+th factor rece$tors* $hos$hatidylinositol 3:

inase* #t* nitric o%ide synthase* guanylyl cyclise and P9 -Digure ".

Pain et al* $ro$osed that rece$tor stimulation led to the o$ening of

mitochondrial #5P sensitive $otassium channels* +hich results in an influ%

of $otassium that causes the mitochondria to s+ell +hich someho+ lead

to the $roduction of o%ygen ,ased free radicals* +hich in turn activate



PC -Pain* Lang* Crit)* 2000. PC is the central mediator of ischemic

$reconditioning* activating the survival inases #t and GR +hich are

thought to $hos$horylate 9S:3T* +hich in turn inhi,its the formation of

mitochondrial $ermea,ility transition $ores in early re$erfusion* thusconferring $rotection -o+ney* avis* Cohen* 200/.

Figure &: 5he $ro$osed mechanism ,y +hich ischemic $reconditioning

confers $rotection -o+ney* avis* Cohen* 200/.

#lthough there is currently no clinically $roven thera$ies that are +idely

used to enhance the myocardiumUs tolerance to ischemia and there,y

e%tend the time:+indo+ for tissue salvage ,y re$erfusion* thera$ies such

as ischemic $reconditioning +ould ,e e%$ected to ,e of value not only in

the management of acute myocardial infarction ,ut also in cardiac

surgery* +here the heart is often su,8ected to $eriods of glo,al ischemia

and re$erfusion. In the surgical setting* ischemic $reconditioning can ,e

used in con8unction +ith e%isting cardio$rotective strategies* such as

cardio$legic arrest or intermittent ventricular fi,rillation* to enhance $ost

ischemic myocardial via,ility and function.



#.0 References

AHA. -200* 03 0. Retrieved 0" 01* 200* from #merican 'eart #ssociationE

htt$E>>+++.americanheart.org>$resenter.8htmlVidentifierQ2!1

<a%tor* 9. a. -1. Delayed preconditioning and adaptative cardioprotection.

7e+ LorE S$ringer.

eer* ;. . -1. 5o+ard the heart of ischemic $reconditioning.

Cardiovascular research * 14:20.

o+ney* =. M.* avis* #. M.* Cohen* M. ?. -200/. Signaling $ath+ays in

ischemic $recondtioning. Heart Fail Rev * 11:1.

9hosh* S.* 7g* ;.* 5al+ar* S.* S6uire* I.* 9alinanes* M. -2000. Cardiotro$hin:1

$rotects the human myocardium from ischemic in8ury. Oxford ournals ! "# -3*

440:44/.

9oto* M.* ;iu* L.* Lang* W.* #rdell* =.* M* C.* o+ney* =. -1!. Role of ,radyinin

in $rotection of ischemic $reconditioning in ra,,it hearts. Circ res * "11:"21.

armay)an* M. -1". $yocardial ischemia% $echanisms! Reperfusion!

&rotection . <asel <erlin <ostonE <irhauser.

;evy* M. 7.* Pa$$ano* #. =. -200/. Cardiovascular &hysiology. Philadel$hiaE

Mos,y Glesvier.

Mii* 5.* Cohen* M.* o+ney* =. -1. ($oid rece$tors contri,utes to ischemic

$reconditioning through $rotein inase C activation in ra,,its. $ol Cell 'iochem *

3:12.

Miller* . ;.* ?an &inle* . M. -1. Ischemic $reconditioning limits infarct

si)e follo+ing regional. Cardiovascular Research * "0:"4.

Miya+ai* '.* #shraf* M. -1/. Ca2A as a mediator of ischemic

$reconditioning. Circ Res * /0:/.

Murry* C.* =ennings* <.* Reimer* #. -1". Preconditioning +ith ischemiaE a

delay of lethal in8ury in ischemic myocardium. Circulation * 1124:113".

7aran8an* .* 7o,auira* 5.* Man8eet* S.* #nton* ;. -2003. $yocardial Ischemia

and &reconditioning. 7e+ LorE S$ringer.

Pain* 5.* Lang* W.* Crit)* S. -2000. ($ening of mitochondrial #5P channels

triggers the $reconditioned state ,y generating free radicals. Circ Res * 4"0 :

4"".



Pr)ylen* . a. -2003. ;ate $reconditioning against myocardial stunning. oes

as$irin close the second +indo+ of endogenous cardio$rotectionV ournal of the

American College of Cardiology ! "( -/* 11!:11/.

Sato* 5.* (Roure* <.* Mar,an* G. -1. Modulation of mitochondrial #5P:

de$endent A channels ,y $rotein inase C. Circ Res * 110:114.

5etsu8i* M. -200". Myocardial res$onse to ischemic $reconditioningE is it a novel

$redictor of $rognosisV Am Coll Cardiol * 1004:100".

5he Mc9ra+:'ill Com$anies. -200. $echanisms of Reversi)le $yocardial

Ischemia. Retrieved =une 2* 200* from #ccess MedicineE

htt$E>>+++.accessmedicine.com>content.as$%VaIQ30!320

?iten:=ohansen* =.* @hao* @.:X.* =iang* R.* @atta* #. =.* o,sen* 9. P. -200/.

Preconditioning and $ostconditioningE innate cardio$rotection from ischemia:

re$erfusion in8ury. Appl &hysiol * 1441:144.

&'(. -200. Cardiovascular disease. Retrieved =une 1* 200* from &orld 'ealth

(rganisationE htt$E>>+++.+ho.int>to$ics>cardiovascularYdiseases>en>

&u* X. L.* Deher* =. =. -1!. Gffect of ischemia and ischemiaZre$erfusion on

ryanodine ,inding and Ca2A u$tae of cardiac sarco$lasmic reticulum. $ol Cell

Cardiol * 1"!:1/!.



Re$erfusion !0 30.1 0." !0.! 2.0

Re$erfusion !! 24.0 3.4 ".4 2/./

Re$erfusion "0 22." .! "!. 2/.3

Re$erfusion "! 21.2 0. "./ 2".

Re$erfusion 0 1.3 . /0." 2".!

4 7ormo%ia 0 1.0 13/.2 14".2 33.

Ischaemia ! /2.! 0.0 0.0 0.0

Ischaemia 10 4." 0.0 0.0 0.0

Ischaemia 1! /2.3 0.0 0.0 0.0

Ischaemia 20 "2.1 0.0 0.0 0.0

Re$erfusion 22 2!./ /!. !0.1 31.0

Re$erfusion 2! 30." !"./ 2".0 32.!

Re$erfusion 30 2.4 4!.3 1".0 31.

Re$erfusion 3! 34." !. 24.3 2.!

Re$erfusion 40 3. /2." 33. 2".4

Re$erfusion 4! 3." ".0 2.4 2".4

Re$erfusion !0 2/.3 /2. 4!.! 2/.3Re$erfusion !! 23. /4.4 !0.4 2/."

Re$erfusion "0 20.4 /." !.2 2/.0

Re$erfusion "! 1/.2 ". "." 2".3

Re$erfusion 0 1".3 /.1 /0. 2!.!Ischaemicreconditi

oning Conditions 5ime -min iastolic Systolic evelo$edDlo+

-ml>min>g

1 7ormo%ia 0 3.0 1"/. 1/2." 2".

Ischaemia ! :3.! 0.0 0.0 0.0

Ischaemia 10 4.1 0.0 0.0 0.0

Ischaemia 1! "!.2 0.0 0.0 0.0

Ischaemia 20 "1.0 0.0 0.0 0.0

Re$erfusion 22 11.1 123.2 112.1 2.0

Re$erfusion 2! !." 12!.2 11." 34.2

Re$erfusion 30 1./ 2.2 "2.! 30.

Re$erfusion 3! 13. /3.! !./ 21.

Re$erfusion 40 "./ /3.4 ""." 1.!

Re$erfusion 4! 3.0 2.2 /.3 1.0

Re$erfusion !0 0./ .! /. 1/.3

Re$erfusion !! :1.3 2./ 4.0 1".2

Re$erfusion "0 :3.1 100.1 103.1 1!.!

Re$erfusion "! :3. 101.3 10!.2 14.

Re$erfusion 0 :4.2 103.1 10/.4 14."

2 7ormo%ia 0 !.0 1!/.0 1"!.1 2".!

Ischaemia ! :3.4 0.0 0.0 0.0

Ischaemia 10 "4.4 0.0 0.0 0.0

Ischaemia 1! "4.1 0.0 0.0 0.0

Ischaemia 20 "0.4 0.0 0.0 0.0

Re$erfusion 22 .4 1!4.0 14!." 34.

Re$erfusion 2! .0 1!3.4 144.! 3!.2

Re$erfusion 30 14.1 //./ "3./ 33.

Re$erfusion 3! /.2 /1.0 "3. 24.4

Re$erfusion 40 2. /1.2 ".4 21.2

Re$erfusion 4! 0.3 //./ //.4 20.0

Re$erfusion !0 :2.0 4. ". 1.3



Re$erfusion !! :3.! ./ 2.2 1.1

Re$erfusion "0 :4." 1. ".4 1/./

Re$erfusion "! :4. . 4." 1".1

Re$erfusion 0 :!.1 0.1 !.1 1!.3

3 7ormo%ia 0 2.0 12./ 14.1 40./

Ischaemia ! 1.4 0.0 0.0 0.0

Ischaemia 10 . 0.0 0.0 0.0

Ischaemia 1! /./ 0.0 0.0 0.0

Ischaemia 20 /./ 0.0 0.0 0.0

Re$erfusion 22 2.2 1.3 "2.1 30.2

Re$erfusion 2! 34.0 /.4 4!.4 34.4

Re$erfusion 30 41.3 4.1 ". 2.

Re$erfusion 3! 31.2 !. !4./ 2."

Re$erfusion 40 24.0 10!./ 1." 2.1

Re$erfusion 4! 1. 11.0 .2 2.3

Re$erfusion !0 1.0 123./ 10!./ 2.2

Re$erfusion !! 1!. 12/./ 111. 2/./Re$erfusion "0 13.! 131. 11.! 2/.4

Re$erfusion "! 11.! 132./ 121.1 2".

Re$erfusion 0 10.! 133. 123.2 2"."

4 7ormo%ia 0 0.0 1".! 1//.3 2".2

Ischaemia ! :2. 0.0 0.0 0.0

Ischaemia 10 41. 0.0 0.0 0.0

Ischaemia 1! "!. 0.0 0.0 0.0

Ischaemia 20 "!.2 0.0 0.0 0.0

Re$erfusion 22 13.1 123. 110./ 3".0

Re$erfusion 2! 1.0 "!.1 4".1 3"./

Re$erfusion 30 21." "./ 4.1 33.2

Re$erfusion 3! 10.! .4 //. 22.

Re$erfusion 40 ".3 ./ 2.4 1.3

Re$erfusion 4! 2.! 100.1 /.! 1.1

Re$erfusion !0 0." 10".1 10!.! 1.

Re$erfusion !! 0. 103./ 102. 1.!

Re$erfusion "0 0.4 10/. 10/.4 1.2

Re$erfusion "! :0.1 10." 10. 1/.

Re$erfusion 0 :0./ 110.0 110./ 1/.!

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