ischaemic preconditioning of the human heart. - Leicester Research ...

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the primary end-point and instead surrogate end-points have to be used Because of this the demonstration of this phenomenon in the setting of cardiac surgery has been controversial Yellon et al [3461 were the first examine the effect of two I-minute ischaernic episodes, where each was followed by 2-minute reperfusion on myocardial high energy phosphate content in patients undergoing coronary artery bypass graft surgery using cardiopulmonary bypass. They claimed that the human mvocardium showed the typical biochemical features of preconditioning observed by Murry and colleagues 12241 in their classic canine model of ischaemic preconditioning and thus could be preconditioned. Following that, there have been some recent studies [294,3341 which also highlight the potential benefits of preconditioning in the cardiac surgery setting. However, Perrault et al [2421 failed to show a beneficial effect of ischaemic preconditioning when this was induced with 3-minute aortic cross- clamping followed by 2-minute reperfusion before the administration of warm blood cardioplegia Similar findings have been reported by other investigators 165,1011 questioning the ability of preconditioning to protect the human heart The dispute on the occurrence or not of card ioprotect ion by preconditioning during cardiac surgery is further fuelled by a more recent study by Yellon and colleagues 131 using a protocol identical to the one used in their first study, they showed a reduction of TnT release at 72 hrs in patients exposed to preconditioning but not at 24 or 48 hrs Interestingly, in contrast with their first study, the same authors reported an absence of protection on myocardial high energy phosphates. These opposed results are puzzling and contrast with the overwhelming evidence that preconditioning is card ioprotect i ve during coronary angioplasty [781 and in in vitro experimental conditions using atnial trabeculae [2821 or isolated myocytes [521. My finding that CPB can act as a 152
preconditioning stimulus in man is supported by another study in sheep 1401 and sheds light on the above controversy. During cardiac surgery, there may be pre- and intraoperative factors such as oploid agonist [275] and anaesthetic agents [631 that may numic the protection of preconditioning. These include the use of oplo'd agon'sts, aprotonin and importantly cardiopulmonary bypass itself Anaesthetic agents did not play a significant role in this study because ischaemic preconditioning exerted protection in all the patients operated on without CPB (le off-pump) and the atrial myocardium harvested prior to the institution of CPB was protected by ischaernic preconditioning in all instances Hypothermla is another cardioprotective factor [1201 that may influence the card toprotection of preconditioning. Recently, Takeshima et al 12961 have also demonstrated that preconditioning is not protective with deep hypothermia, however moderate hypothermia alone, as used in the present studies, does not inhibit the preconditioning response. Mechanism ofpreconditioning by cartUopulmonary bypavs Although the precise mechanism of ischaernic preconditioning still remains unclear, recent investigations have clearly identified a number of factors that are essential to achieve protection. CPB induces a systemic inflammatory reaction and it is possible that some elements of this reaction may be responsible for the observed protection In this connection, Yamashita and co workers [3381 have recently reported that II. - I and TNF-a, production of which is increased by CPB, causes an elevation in tissue Mn- SOD, as has been shown to occur when brief sub-lethal ischaernia or anoxic inSLIltS are induced [337]. However, this thesis in unlikely since the production of cytokines is a late event in response to CPB that requires more than 10 min 153
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ISCHAEMIC PRECONDITIONING OF THE HU
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ABSTRACT Ischaemic preconditioning
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andomised clinical study with the f
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CHAPTERI Introduction 35 Matefials
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Discussion 151 CHAPTER Vill Conclus
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44 CK leakage and MTT reduction on
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The Wellcome Trust and The British
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Presentations International "The Ef
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Abbreviations An attempt has been m
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1.1 Introduction Ischaernic heart d
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1.2 Myocardial Ischaemia Myocardial
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hours up to several days to complet
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phosphates and its influence on hyd
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1.4 Myocardial Protection This refe
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performed. This process is repeated
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1.6 Possible Mechanisms of Ischaemi
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kilodalton stress proteins. These p
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and these proteins have been sugges
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K vi-1, channels were initially fou
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tissues the K.. %,.,, channels are
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Subsequently, Jaburek et al 1145] i
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venous capacitance vessels. At ther
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preconditioning to be investigated
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In the angioplasty model, Tomai et
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patients were randomized into two g
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CHAPTER 11 THE HUMAN RIGHT ATRIAL T
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inexpensive. Briefly in this model,
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of each ischemic period, slices wer
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30 nini FO linlin L 60 min 120 inin
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In Study 3 (see Figure 2.4), slices
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D. Metabolite analysis Samples were
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leakage is calculated as the net LD
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B. Effect of the severity of ischae
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2.11 DISCUSSION: The present studie
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clearly insufficient to induce myoc
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The present model may facilitate th
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2.12 Conclusiow I have characterise
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3.5 3 V 2.5 3: m Je m Z0 z 2 1.5 0.
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(3 3 2.5 a 1.5 - -r T 0 2 0.5 0 I P
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Q oro . 21 . 0 'a IP 10 '. R -C3 A
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=3 0 h X CD 0 x CD :3 0 , 7, CD 0 0
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CHAPTER III PRECONDITIONING THE HUM
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3.2 MATERIALS AND METHODS-. 3.2.1 E
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A117'reduction- At the end of the e
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-4 ýi r. () .1 a 0 1 tli n F5* - C
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v M. %; n C) .0 ý U ý ý - - - -2
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leakage resulting from precondition
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3.5 DISCUSSION: The present studies
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during cardiac surgery totalling 10
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different. The cellular mechanisms
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cn Je 8 7 6 5 4 1 0 0.8 0.7 0.6 0.5
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8 6 C) 2 0.7 0.6 Q) 0.5 0) E 25 0.4
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6 5 CY) ,u3 CF) m -ýe m 2 1 0 -0.8
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CHAPTERIV THE ROLE OF THE KATPCHANN
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It has been reported that K.. %-I-p
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0 a- I a 3 I cr =r Cl. 2 qQ 0'-ý 0
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Figure 4.7 shows that ischaemia alo
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Figure 4.2 Dosc-responsc experiment
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Figure 4.4 Dose-response experiment
Page 119 and 120: Figure 4.6 Dosc-response experiment
Page 121 and 122: 1 0.9 -ý 0.8 0.7 E 0.6 0.5 0.4 0.2
Page 123 and 124: activity, and showed that diazoxide
Page 125 and 126: Furthermore, Van den Hoek et al [3
Page 127 and 128: mechanism by which the opening of m
Page 129 and 130: 5.1 INTRODUCTION: Within the enormo
Page 131 and 132: 5.2 MATERIALS AND METHODS: 5.2.1 Ex
Page 133 and 134: M77'rechiction: At the end of the e
Page 135 and 136: oc 0 0 cr F; * 10 eb I ý; o I 5 0
Page 137 and 138: Pages missing original in the
Page 139 and 140: esulted in a decrease of CK leakage
Page 141 and 142: are on long-term hypoglycaernics or
Page 143 and 144: absence of uniformity of expeniment
Page 145 and 146: 5.7 Conclusion Preconditioning is a
Page 147 and 148: 0.9 0.8 07 m 0.6 E -0 0t 4 0.3 02 0
Page 149 and 150: -0 1.2 1 &8 0.6 04 0.2 o Aerobic Is
Page 151 and 152: 6.1 INTRODUCIFION' Life expectancv
Page 153 and 154: (MI-T) to blue t'()rmazan product C
Page 155 and 156: The demonstration that ischaemic in
Page 157 and 158: Table 61 Patients' demographic and
Page 159 and 160: Nure 6,1: Creatine Kinase (CK) leak
Page 161 and 162: CHAPTER VII IN VIVO STUDIES ON T"E
Page 163 and 164: The apparent discrepancy bet,.,,, e
Page 165 and 166: In the off-pump group, coronary byp
Page 167 and 168: eduction as described in section 3.
Page 169: 7.4.2 In vitro studies Figures 7.3A
Page 173 and 174: myocardium. Several investigators [
Page 175 and 176: Table 7.2 - Patients haemod-v-namic
Page 177 and 178: (0 -I 3 CD CD CD 1 3 0 :3 0 0 =r w
Page 179 and 180: 0 co t X 3 co 0 0 Cumulative Releas
Page 181 and 182: -& a) c) UT 0 =r w CD 3 CD 0 1ý (a
Page 183 and 184: When ischaernic preconditioning was
Page 185 and 186: evidence tbr the involvement ot'PKC
Page 187 and 188: institution o fcardiopu Imo nary by
Page 189 and 190: Biblioqraphv 1. Abete P, Ferrara N,
Page 191 and 192: 14. Auchampach J, Cavero, I and Gro
Page 193 and 194: 27. Becker LB, Van den Hoek TLV, Sh
Page 195 and 196: 41. Bums PG, Krunkenkamp IB, Calder
Page 197 and 198: 55. Cohen G, Shirai T, Weisel RD, e
Page 199 and 200: 69. Currie RW and White FP (1983).
Page 201 and 202: 83. Downey JM, Liu GS and Thornton
Page 203 and 204: 97. Ganote C, Armstrong S and Downe
Page 205 and 206: 110. Grover GJ, D'Alonzo A, Hess T,
Page 207 and 208: 122. Hamilton T and Weston A (1989)
Page 209 and 210: 137. Hu H, Sato T, Seharaseyon J, L
Page 211 and 212: 151. Jennings R, Steenbergen C, Kin
Page 213 and 214: 164. Kelpzig H, Kobert G, Mafter C,
Page 215 and 216: 178. Lamping K, Christensen C, Pelc
Page 217 and 218: 192. Liu GS, Thornton J, Van Winkle
Page 219 and 220: 206. Maulik N, Yoshida T, Das DK. (
Page 221 and 222:
219. Miyawaki H, Zhou X, Ashraf, M.
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233. Okazaki Y, Kodama K, Sato H, K
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248. Pryzlenk K, Li G, Whittaker P
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260. Saito S, Tamura Y, Moriuchi M,
Page 229 and 230:
274. Schulz R, Post H, Valhaus C, e
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288. Stewart JR, Blackwell WH, Crut
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300. Tani M, Suganuma Y, Hasegawa H
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312. Tosaki A, Engelman DT, Engelma
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324. Walker D, Marber M, Walker J a
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337. Yamashita N, Nishida M, Hoshid
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351. Zhang JG, Lindup WE. (1993). R
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444 J. -G. Zhang and others are dif
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446 J. -G. Zhang and others Assessm
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448 J. -G. Zhang and others 0.9 0.8
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450 J. -G. Zhang and others C E 07
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4S2 J. -G. Zhang and othen effects
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ELSEVIER Abstract Cardiovascular Re
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936 S. Ghosh et al. / Cardiovascula
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938 S. Ghosh et al. / Cardiovascula
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940 S. Ghosh et al. [41 Goto M, Liu
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712 0" et &L h wcomMe geg in Obwa»
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714 Gbosb ot aL hmoo dmoWmbDbsnedH
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716 chmä et aL Pi unamOso äu In O
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718 ehe* et &L ditioning in the hum
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