T ing cardioplegia for open heart operations [l-31, and. Efflux of Adenosine and Its Catabolites During Cold Blood Cardioplegia

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1 Efflu of Adenoine nd t tbolite During old Blood rdioplegi Ju iinen, MD, M. J. Pekk Rtikinen, MD, Ki Krlqit, MD, nd Keijo J. Peukurinen, MD, PD Deprtent of rdiotori Surgery, Aneteiology, nd nternl Mediine, Oulu Unierity entrl Hopitl, nd Deprtent of Medil Bioeitry, Oulu Unierity, Oulu, Finlnd Leel of yordil igenergy popte deree during rdioplegi for open ert opertion, wit ubequent inree in te leel of denoine nd it etbolite. t been deontrted in eperientl odel tt te effluent onentrtion of purine n be ued eure of te erge yordil energy tte. et denylte lo nd yordil energy tte were eluted ere by deterining ortoronry inu differene in leel of denoine tbolite in 17 ptient during old blood rdioplegi for eletie oronry rtery byp grfting. Repeted blood ple were tken before rolping of te ort, wen rdioplegi olute w infued into te orti root nd grft fter fie ditl ntooe, nd fter delping of te ort. Te ortoronry inu differene in leel of totl purine inreed.7, 7., 7.1, 7., nd 1.fold (fro te prelp leel of pol/l; p <.1) for grft one troug fie ntooed t n erge of 1,,, 6, nd 76 inute fter te orti rolp, repetiely. Hypontine nd ntine were preent in te iget onentrtion. Vodiltory denoine onentrtion of 1 to polll were obered in te oronry inu wile te ort w rolped. Tere w liner poitie orreltion between te ortoronry inu purine differene nd orreponding rolp tie (r =.6; p <.1). Te etbolite differene ettled t ore negtie leel fter delping of te ort tn tt preiling before pleent of te rolp, uggeting ontinuou wout of denoine nd it tbolite during te inute potlp obertion period. We onlude tt oniderble net efflu of purine our een during old blood rdioplegi, te reltie nge in effluent onentrtion being gretet t te ery beginning nd towrd te end of te rolp tie. Te net lo of igenergy popte y be of oe linil ignifine in te deelopent of potopertie yordil tunning, epeilly wit prolonged orti rolp tie. On te oter nd, onitoring efflu of denoine nd it tbolite into te oronry inu during nd fter orti rolping ould be ued for opring different rdioplegi etod. ( 1;:16) e leel of tiue denine nuleotide deree dur T ing rdioplegi for open ert opertion [l1, nd ti i tougt to be one of te eni of te prolonged potiei entriulr dyfuntion [61. onoitntly wit te deree in leel of denine nuleotide, leel of denoine nd it degrdtion produt inree wit ubequent wout fro te reperfued yordiu [l, 7, 1. Aordingly, to enne te potiei reoery of denoine tripopte, ue been de of te preention of denoine tboli or te upply of denoine or oter preuror of denine nuleotide lge ptwy [7, 1]. n eperientl odel enou onentrtion of denoine nd it etbolite e been own to orrelte negtiely wit te yordil tiue energy tte [ 1, 11, nd eureent of ortoronry inu (AoS) differene in tee etbolite lo been ued to etite nge in yordil energy tte in linil Aepted for publition Ot 7, 1. Addre reprint rquet to Dr Peukurinen, Diiion of rdiology, Deprtent of nternl Mediine, Oulu Unierity entrl Hopitl, Kjnintie, Oulu, Finlnd. etting, u tril ping [1, 161 nd perutneou trnluinl oronry ngioplty [17, 11. A net relee of nuleoide into te S blood lo been deontrted ieditely fter potiuindued iei rret during rdi opertion [1]. Te purpoe of te preent work w to deterine te tiedependent nge in te AoS differene of denoine nd it tbolite during interittent old blood rdioplegi nd fter delping of te ort, nd tu to etbli etod for elution of nge in yordil energeti during oronry byp opertion. Te ppro introdued ere ould be ued wen opring different rdioplegi ondition. Mteril nd Metod Ptient Seenteen ptient, ditted to te opitl for eletie oronry byp opertion, were inluded in te erie. Mot of te d treeeel diee douented by preopertie oronry ngiogrpy, nd ot of te d uffered fro preiou yordil infrtion. Only of te d n ejetion frtion le tn., te 1 by Te Soiety of Tori Surgeon OO:7//$6.

2 1;:16 SSE ET AL 17 Tble 1. linil nfortion Vrible o. of Ptient Age (Y) Se (le/fele) Preiou infrtion (nterior/inferopoterior/lotion unknown) Angin petori (YHA //V) Ejetion frtion LVEDP ( Hg) Dieed eel (1///LMA) Blood rdioplegi (ntegrde/ntegrde retrogrde) rdiopulonry byp tie (in) Aorti rolp tie (in) Byp grft (//6/7/) Byp grft per ptient Endrteretoy (1//) Periopertie infrtion Low output yndroe 1 <. L. in. ntrrteril blloon puping Potperirdiotoy yndroe (ildkeere) Potopertie rryti (tril fibrilltion) Potopertie ondution diturbne (prtil RBBB) Vlue 17 6 f (167) 1/ /1/ /1/1/ //1/ ()J. 1 (71) /6/6/1/ /1/ Vlue in prentee re rnge. Four d ejetion frtion <.. = rdi inde; LMA = left in oronry rtery; LVEDP = left entriulr endditoli preure; YHA = ew York Hert Aoition; RBBB = rigt bundlebrn blok. erge being.6?.11 (tndrd deition). Te preopertie rteriti of te ptient nd teir periopertie nd potopertie oure re preented in Tble 1. Te protool w epted by te intitutionl reiew bord, nd te ptient ge teir infored onent for te reer before te opertion. Protool All edition eept pirin w llowed until te dy of te opertion. Apirin w witdrwn week before te opertion. Adinitrtion of dipyridole (1 g tree tie dily), on te oter nd, w trted dy before, te lt doe being gien on te orning of te opertion. All te ptient were operted on by te e ief tori urgeon. After edin ternotoy te left internl tori rtery w dieted nd te ptient w eprinied. Te ending ort nd bot e were nnulted. Before rdiopulonry byp or on prtil rdiopulonry byp, wit te ert till beting, elfinflted blloon teter w introdued into te S i te rigt triu uing plption tenique. Te left 1 entrile w ented wit nnul introdued i te rigt upper pulonry ein. Full rdiopulonry byp w initited nd intined wit pillry oygentor (Dideo optflow D7; Dideo, Mirndol, tly) nd roller pup (Stokert APS; Stokert ntruente, Muni, Gerny). Wr igpotiu rdioplegi w trted, being repled by old blood rdioplegi wit le potiu fter rdi rret, wereupon te ert w ooled. Te ditl ntooe were opleted in te order of iportne, deided on te bi of finding in oronry ngiogrpy, eept tt te left internl tori rtery nd te left nterior deending oronry rtery (LAD) were lwy ntooed lt. After e ditl ntooi old blood rdioplegi w deliered into te orti root nd ein grft onneted to te nifold of te orti rdioplegi line t rte of 1 Win for pproitely inute. Additionl retrogrde perfuion i te S teter w ued in ptient. After te lt ditl ntooi te ert w wred wit ypolei nd yperklei blood (> ). All te proil ntooe were opleted wit te id of tngentil lp fter reol of te rolp. Blood olleting nd Proeing Blood w olleted iultneouly fro te orti root nd S (1) one before (1. 1. inute) rolping of te ort, () during te rolp period fter fie ditl ntooe, wen rdioplegi olution w deliered into orti root nd grft (1. 1.,.?.7,.., 6.., nd 7.6. inute fro rolping), nd () fter delping of te ort (,, 1, nd inute), but witout te proil ntooe onneted. Fro preliinry dt it w eident tt efflu of denoine tbolite into te S did not lwy tke ple in ontnt fion. Terefore, during te inute deliery of interittent rdioplegi, tree or ore repeted blood ple were tken fro te S, nd n erge of te eured pl onentrtion w ued in ubequent lultion. Te blood w witdrwn into yringe in eond t pproitely 1inute interl. A typil eple of te AoS differene in leel of purine in four repeted blood ple during interittent rdioplegi fter four ditl ntooe in 1 ptient i own in Figure 1. To orten te rolp tie, blood w olleted fter fie ntooe t te ot. Adenoine i rpidly tken up nd etbolied by red blood ell, nd it lflife in un pl reently been etited to be of te order of.6 to 1. eond, depending on te denoine onentrtion []. Ontyd nd Srder [1] introdued n elegnt etod for denoine deterintion in un pl inoling blood pling into yringe ontining dipyridole, nd it w eentilly ti etod tt w ued ere. To gurntee blood onentrtion of dipyridole uffiient to preent te uptke of denoine into red blood ell, te ptient were gien 1 g of dipyridole orlly tree tie dily for dy before te opertion, te lt

3 1 SSE ET AL 1;: 16 L i 1 1 Anlyi of Adenoine nd t Metbolite A fully utoted igpreure liquid rotogrpy yte w ued to nlye denoine nd it degrdtion produt. Te ple were injeted into n RP S reeredpe olun (Brownlee) nd eluted wit 1 oyl oniu popte, ph./% etnol (oy ol). Te erge retention tie for ypontine, ntine, inoine, nd denoine were.,.1,.7, nd.1 inute, repetiely. Beue ypontine nd ntine were oetie oeluted, te u of tee etbolite w lulted. Aborbne of te eluent t 6 n w onitored, nd eternl tndrd were ued for pek identifition nd quntifition. Te pek in oe of te ple were lo identified by enyti ift nlyi deribed erlier [1, Sple nuber 1 Fig. An eple of irtqoron y inu onentrtion differene in denoine nd it trtbolite during infuion of old blood rdioplegi olution to te orti root nd ein grft in 1 ptient. Four repeted blood ple were witdrwn (in eond) t 1inute interl fro te oronry inu during te inute deliey of old blood rdioplegi fter te opletion of e ditl ntooi. fopen irle = left irufle rtery; loed irle = digoril brn of te left nterior deending rtery; open tringle = left oblique rginl rtery; loed tringle = left nterior deending rtery.) doe being gien our before te trt of te opertion. n ddition, te L blood ple were witdrwn into yringe prefilled wit 1.O L of dipyridole olution in finl onentrtion of. ol/l. Tee ple were ieditely injeted into eprinied tube on ie nd entrifuged. Two illiliter of pl w idified wit 6% perlori id, te etrt were neutrlied wit ovl KOH/. olll trietnoline ydroloride, nd te neutrlied etrt were ued for te nlyi of denoine, inoine, ypontine, nd ntine ontent. Preliinry tet wit rdiotie denoine, inoine, nd ypontine owed tt dipyridole effetiely preented te uptke of denoine nd inoine into te red blood ell. Hypontine, on te oter nd, w ditributed eenly in blood [M. Beue dipyridole i not n effiient inibitor of denoine deintion nd furter etboli in te pl nnot be preented totlly, te leel of inoine nd te leel of ypontine plu ntine were lo deterined. Sttitil Anlyi Onewy nlyi of rine w ued to tet te tiedependent nge in leel of denoine or it etbolite. Te ttitilly ignifint nge (p <.) were loted by Dunn' ultiple rnge t tet. Te differene between denoine, inoine, nd ypontine plu ntine were teted wit twowy nlyi of rine. Te orreltion between ArS differene in leel of purine nd te orti rol.p tie were nlyed wit regreion nlyi. Reult Wout Kineti of Adenoine nd t Metbolite ei led to degrdtion of igenergy popte wit uultion of teir brekdown produt, nd wout of tee etbolite ten tke ple upon reperfuion. Ti wout w tudied during te inute infuion of rdioplegi olute into te orti root nd grft fter e opleted ditl ntooi. To tudy te pttern of etbolite efflu, repeted blood ple were tken fro te S during te deliery of old blood rdioplegi. A typil eple of te AoS onentrtion differene of purine in 1 ptient i own in Figure 1. Metbolite wout took ple t reltiely tedy rte fter te firt two eel were byped, in ti e te irufle rtery nd te digonl brn of te LAD. After opletion of te fourt nd epeilly te fift ditl ntooi, rpid inree in te AoS purine differene were obered upon initition of infuion of te rdioplegi olution, fter wi te rte of wout dereed. Ti kind of wout pttern w often een fter te LAD w byped, uggeting uultion of brekdown produt of igenergy popte during prolonged iei nd ubequent rpid wout upon reperfuion. On te oter nd, te obered rition in te efflu kineti y be n inditor of uneen yordil protetion during rdioplegi. Beue of te obered rition in te etbolite efflu kineti during interittent rdioplegi, erge pl onentrtion for ll te repeted S blood ple were ued wen lulting te etbolite rterioenou differene during te rolping period.

4 1;:1& SSE ET AL 1 Aorforon y Sinu onentrtion Differene in Adenoine Metbolite Te onentrtion of denoine, inoine, nd ypontine plu ntine re preented in Tble nd toe of totl purine in Figure. Adenoine w lwy preent t te lowet onentrtion nd ypontine plu ntine t te iget onentrtion ( p <.1 by twowy nlyi of rine) (ee Tble ). Te S onentrtion of te etbolite lwy eeeded toe eured in te orti root. Tere w tiedependent inree in te AoS onentrtion differene in denoine nd it degrdtion produt fter rolping of te ort, te differene in denoine, inoine, nd ypontine plu ntine inreing 7.,., nd 1.fold, repetiely ( p =.7, p <.1, p <.1) (ee Tble ). Te denoine onentrtion in te S pl inreed ore tn 1 pol/l. Te reltie inree in te efflu of purine w gretet t te ery beginning of te rolping nd gin fter n erge of 6 inute, wen te fourt ple were olleted (ee Fig ). Tere w liner orreltion between te rolp tie nd te orreponding AoS differene in leel of purine (r =.6; p <.1) (Fig ). Te purine efflu dereed ieditely fter te relee of te rolp, but in pite of te inute reperfuion upon byp, te AoS purine leel differene did not re tt obered before rolping of te ort in ny of te ptient, due to te reltiely ig ypontine plu ntine onentrtion in te S (ee Tble ; Fig ). oent Any deree in te yordil energy tte been own to orrelte negtiely wit inreed enou onentrtion of denoine nd it tbolite. Ti been deontrted in iei nd lo during inreed ert ule worklod [ 1, ]. Myordil biopy peien e own tt denoine tripopte onentrtion deree during old blood rdioplegi nd wout of denine nuleotide degrdtion produt our upon reperfuion 11, 11. t w deontrted ere tt AoS onentrtion differene in purine leel inreed towrd te end of te rolping period. Te reult owed tt te AoS differene in leel of purine were tiedependent nd orrelted wit te durtion of iei, tu uggeting tt te erge yordil energy tte w dereed during te orti rolp in pite of te protetie old blood rdioplegi. Te gretet reltie nge in te AoS etbolite differene were obered between te prelping ple nd te firt ple during rolping of te ort nd between te fourt nd fift ple, tken fter n erge of 6 inute of rolping. t n be ypoteied tt te ert i epeilly ulnerble t te beginning of te orti rolp period beue of inuffiient ulrition nd protetion. After te firt grft re finied te deliery of old blood rdioplegi y beoe ore oogeneou, nd te protetion of te yordiu on te wole y be iproed wit dereed rte of denine nuleotide degrdtion. Soe "preonditioning" of yordiu y lo our [6]. Wit prolonged rolping nd oerll durtion of iei te energy tte woren gin in pite of totl reulrition nd te potentil "preonditioning" effet (ee Fig ). t ould be noted tt uing our tenique te yordiu upplied by te ntie LAD i lwy reulried lt troug te internl tori rtery wen te rolp i releed. Tu te region beind te LAD were probbly let proteted during te opertion. n ot e te fift, ie, te lt ple were olleted fter ntooi of te LAD. Suboptil protetion of yordil region upplied by te LAD leding to n uultion of denoine etbolite during rolping of te Ao i lo uggeted by te oewt different etbolite wout kineti fter ntooi of te LAD (ee Fig 1). Te efflu of purine w quntittiely iilr in te ptient reeiing ntegrde or ntegrde plu retrogrde rdioplegi during teir opertion. or did te efflu orrelte wit preopertie ejetion frtion, degree of oronry rtery diee, or potopertie outoe, but te ptient popultion tudied w reltiely ll. Te AoS differene in leel of purine ettled t ore negtie leel fter delping of te ort tn tt preiling before pleent of te rolp (ee Fig ). One poible reon for ti w tt te proil ntooe were opleted beind ide lp witout oplete reulrition. Ti i lo onitent wit erlier reult owing tt during oronry byp opertion wout of denoine tbolite tke ple fter relee of te orti rolp [l]. Soe etite of net denine nuleotide loe during te orti rolp period n be done, if te AoS onentrtion differene in teir tbolite nd te rte of interittent infuion of rdioplegi olution re known. Su lultion, bed on te dt of erge AoS onentrtion differene in te purine opound (ee Tble ) nd te erge ount of rdioplegi olution deliered to te orti root nd ein grft fter opletion of e ditl ntooi (1 uin nd inute), ow tt pproitely 1 pol of denine nuleotide would be lot during te orti rolping. Wen doing ti lultion, one to ue tt ll te infute end up in te S, oweer. Te leel of denoine tripopte in te un yordiu re reported to be of te order of 1 to ol/kg of dry ule [l1. f wetldry weigt rtio of 7.7 [7] i pplied to ert of g, n etite of pproitely pol i obtined for te denoine tripopte ontent of te yordiu. Weiel nd oite [l] eured n inree of.7 poyg of freeedried yordiu in biopied tiue denoine plu inoine plu ypontine onentrtion during orti rolp in oronry byp opertion. f one ue tt te etboli nge re eenly ditributed, ti equl pol in te wole ert. Tking ti

5 1 SS" ET AL 1;1& k k ; w. L" M & M ;; G =. : d: n p! M 'B! w p: n n " w ; n n ; W M dr E W i n? $ n 1 % d: 1 6 ;F: P ' 1! p: r '7. : n. g 1. p? r;? d ' rj rj ;F: n Y Y. ; E? & rj p! n M B

6 1;:1& SSE ET AL 11 MYOARDAL EERGETS DURG ARDOPLEGLA 1._ : r : e 1 $ "; 1 L.% 1 y A T,,,OO ot o?& ' l \ T '7' oronry rtery perfuion. Tey etited wout of purine nd be of ovkg dry ule equling pproitely 1 pol in te wole ert during old potiu blood rdioplegi of 1 to inute. Te reult of Weiel nd oite [l] owed tt during interittent rdioplegi for oronry byp opertion of te denylte degrdtion produt re wed out wen te orti rolp i releed, o tt fter inute of reperfuion te leel of igenergy popte nd preuror dereed fro 1. to 1.7 FoUg of freeedried yordiu, uggeting wout of 1. " ". '. '. ' pol of denylte for te wole ert. 1 L U y ' eied dipyridole or not. n onluion, we deontrte ere etod for etition of tiedependent purine efflu nd yordil energy tte during interittent rdioplegi for oronry byp opertion. t i eident tt efflu of denine nuleotide degrdtion produt our wen te rdioplegi olution i deliered to te orti root nd grft, te erge AoS differene in purine onentrtion orrelting wit te durtion of rolping nd tu totl iei. Te reltie nge in te yordil energeti, etited by en of te tbolite AoS onentrtion differene, were gretet t te beginning

7 1 SSE ET AL 1;1.& Ti tudy w upported by te Po uri Foundtion, te Finni Angiology Soiety, te Finni Foundtion for rdioulr Reer, nd te Medil ounil of te Adey of Finlnd. Referene Weiel RD, Mikle DAG, Finkle D, Tuiti L, Mdonik MM, no J. Delyed yordil etboli reoery fter blood rdioplegi. 1;7. Kijer L, Jnon E, Sidt W, Bofi V. Myordil energy depletion during profound ypoteri rdioplegi for rdi opertion. J Tor rdio Surg 1:: 6. Sollei A, Sidt W, Jnon E, Bofi V, Kijer L. Adenine nuleotide degrdtion in un yordiu during rdioplegi. rdio Re 17;1:61. Brunwld E, Kloner RA. Te tunned yordiu: prolonged, potiei entriulr dyfuntion. irultion 1;66: 116. Elli SG, Henke, Sndor T, Wynne J, Brunwld E, Kloner RA. Tie oure of funtionl nd bioeil reoery of yordiu lged by reperfuion. J A oll rdiol 1;1:17. Bolli R. Meni of yordil tunning. irultion 1;:7. Foker JE, Einig S, Wng T. Adenoine etboli nd yordil preertion. J Tor rdio Surg 1; 616. Peukurinen KJ, Tkl TES, uutinen EM, Hinen E. Trirboyli id yle etbolite during iei in iolted perfued rt ert. A J Pyiol 1;:H1. Huprey SM, Seelye R. proed funtionl reoery of iei yordiu by uppreion of denoine tboli. J Tor rdio Surg 1;:16. Muer M, Hoffeiter HM, ienber, Sper W. nfluene of riboe, denoine, nd ir on te rte of yordil denoine tripopte yntei during reperfuion fter oronry rtery oluion in te dog. ir Re 1;6:. Bolling SF, Bie LE, Gllger KP, Boe EL. Enned yordil protetion wit denoine. 1;71. De Jong JW, n der Meer P, n Loon H, Owen P, Opie LH. Adenoine djunt to potiu rdioplegi: effet on funtion, energy etboli, nd eletropyiology. J Tor rdio Surg 1;1:. Kiiluo KT, Peukurinen KJ, Hinen E. Role of ellulr energy tte nd denoine in te regultion of oronry flow during rition in ontrtion frequeny in n iolted perfued rt ert. J Mol ell rdiol 16;1:11. Kiiluo KT, Peukurinen KJ, Hinen E. Aette in dued nge in rdi energy etboli in te rt. Bi Re rdiol 1;:1. 1, Ree wj, de Jong Jw, Verdouw PD. Effet of pingindued yordil iei on ypontine efflu fro te un ert. A J rdiol 177;: Ree WJ, n den Berg R, Mnter M, et l. Teporl reltion of nge in regionl oronry flow nd yordil ltte nd nuleoide etboli during pingindued iei. A 1 rdiol 16:: Serruy PW, Suryprn.t H, Piione F, et l. lyordil relee of ypontine nd ltte during perutneou trnluinl oronry ngioplty. A J rdiol 1;6: 1E. 1. Peukurinen K, keio M, Airkinen J, Huikuri H, Linnluoto M, Tkkunen J. nge in yordil energy etboli in eletie oronry ngioplty. rdio Re 11;: Fo A, Reed GE, Meiln H, Silk BB. Relee of nuleoide fro nine nd un ert n inde of prior iei. A J rdiol 17;:.. Moer GH, Srder J, Deuen A. Turnoer of denoine in pl of un nd dog blood. A J Pyiol 1;6: Ontyd J, Srder J. Meureent of denoine, inoine nd ypontine in un pl. J rotogr 1;7.. Mnfredi JP, Sprk HV. Adenoine role in oronry odiltion indued by tril ping nd norepineprine. A J Pyiol 1;:H6.. Bunger R. Terodyni tte of ytooli denylte in guine pig yordiu. Energylinked dptie nge in free denylte nd purine nuleoide relee. n: Gerl E, Beker BF, ed. Topi nd perpetie in denoine reer. Berlin: SpringerVerlg, 17.. Rtikinen MJP, Peukurinen KJ, Hinen E. ellulr oure nd role of denoine in ioproterenolindued oronry odilttion. J lol ell rdiol 11;:117.. Uui PA, Peukurinen KJ, Vuolteeno, Rukoo H, Hinen E. Role of yordil redo nd energy tte in ieitiulted relee of tril ntriureti peptide. J Mol ell rdiol 1;: Murry E, Jenning RB, Reier KA. Preonditioning wit iei: dely of letl ell injury in iei yordiu. irultion 16;7: Kinnul VL, Hinen. Effet of ypoi on itoondri1 nd ytoroe onentrtion in rt ert nd lier during potntl deelopent. At Pyiol Snd 177;: 66.. Rotn MT, Bi DS, Sipon JB, Hon D. oronry eodyni during perutneou trnluinl oronry ngioplty. A J rdiol 1;: Kubler W, Spiekern PG, Bretneider H. nfluene of dipyridole on yordil denoine etboli. J Mol ell rdiol 17;1:.