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

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6 m, v, finherfor his unslinling academic jqfluenve and to mY ivýfe and their love and sup1m)rl. daughier. for
ABSTRACT Ischaemic preconditioning (PC) describes the increased resistance to myocardial infarction that follows short sublethal periods of ischaernia. It has been shown to exist in all mammalian species investigated to date. In the early 90's, some evidence started to evolve which reported that this powerful card ioprotect 1 ve phenomenon exists in man. After ischaernia that triggers preconditioning, there are 2 phases of protection: an early phase (short-lived) termed early of classic preconditioning and a late (more prolonged) phase termed a second window of protection. The evidence for this has primarily come from work on the rabbit and rat isolated hearts. There is no information related to the characteristics of this preconditioning phenomenon in humans. The study commenced with the development of an itt Wiro model of human myocardium to study the effects of ischaernia and reperfusion injury. The data provided evidence that the in t4fro incubation of human atrial tissue is stable and slices are viable for at least 24 hr and that this permits the study of early and delayed consequences of ischaemia and reperfusion in the human myocardium. This model was also used to study the preconditioning phenomenon fully. There were some unanswered questions pertaining to the characteristics of the PC phenomenon. The results showed that maximal protection can be achieved with 4-6 min of ischaernic stimulus/5min reperfusion and beyond that, protection was abolished. It also reported that this early phase was protective for only 2 hours after the tfigger and that in the atnum, a second window of protection existed although much less potent. iii
Page 1: ISCHAEMIC PRECONDITIONING OF THE HU
Page 5 and 6: andomised clinical study with the f
Page 7 and 8: CHAPTERI Introduction 35 Matefials
Page 9 and 10: Discussion 151 CHAPTER Vill Conclus
Page 11 and 12: 44 CK leakage and MTT reduction on
Page 13 and 14: The Wellcome Trust and The British
Page 15 and 16: Presentations International "The Ef
Page 17 and 18: Abbreviations An attempt has been m
Page 19 and 20: 1.1 Introduction Ischaernic heart d
Page 21 and 22: 1.2 Myocardial Ischaemia Myocardial
Page 23 and 24: hours up to several days to complet
Page 25 and 26: phosphates and its influence on hyd
Page 27 and 28: 1.4 Myocardial Protection This refe
Page 29 and 30: performed. This process is repeated
Page 31 and 32: 1.6 Possible Mechanisms of Ischaemi
Page 33 and 34: kilodalton stress proteins. These p
Page 35 and 36: and these proteins have been sugges
Page 37 and 38: K vi-1, channels were initially fou
Page 39 and 40: tissues the K.. %,.,, channels are
Page 41 and 42: Subsequently, Jaburek et al 1145] i
Page 43 and 44: venous capacitance vessels. At ther
Page 45 and 46: preconditioning to be investigated
Page 47 and 48: In the angioplasty model, Tomai et
Page 49 and 50: patients were randomized into two g
Page 51 and 52: 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
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Figure 4.6 Dosc-response experiment
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1 0.9 -ý 0.8 0.7 E 0.6 0.5 0.4 0.2
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activity, and showed that diazoxide
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Furthermore, Van den Hoek et al [3
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mechanism by which the opening of m
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5.1 INTRODUCTION: Within the enormo
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5.2 MATERIALS AND METHODS: 5.2.1 Ex
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M77'rechiction: At the end of the e
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oc 0 0 cr F; * 10 eb I ý; o I 5 0
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Pages missing original in the
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esulted in a decrease of CK leakage
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are on long-term hypoglycaernics or
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absence of uniformity of expeniment
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5.7 Conclusion Preconditioning is a
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0.9 0.8 07 m 0.6 E -0 0t 4 0.3 02 0
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-0 1.2 1 &8 0.6 04 0.2 o Aerobic Is
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6.1 INTRODUCIFION' Life expectancv
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(MI-T) to blue t'()rmazan product C
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The demonstration that ischaemic in
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Table 61 Patients' demographic and
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Nure 6,1: Creatine Kinase (CK) leak
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CHAPTER VII IN VIVO STUDIES ON T"E
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The apparent discrepancy bet,.,,, e
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In the off-pump group, coronary byp
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eduction as described in section 3.
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7.4.2 In vitro studies Figures 7.3A
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preconditioning stimulus in man is
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myocardium. Several investigators [
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Table 7.2 - Patients haemod-v-namic
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(0 -I 3 CD CD CD 1 3 0 :3 0 0 =r w
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0 co t X 3 co 0 0 Cumulative Releas
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-& a) c) UT 0 =r w CD 3 CD 0 1ý (a
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When ischaernic preconditioning was
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evidence tbr the involvement ot'PKC
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institution o fcardiopu Imo nary by
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Biblioqraphv 1. Abete P, Ferrara N,
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14. Auchampach J, Cavero, I and Gro
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27. Becker LB, Van den Hoek TLV, Sh
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41. Bums PG, Krunkenkamp IB, Calder
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55. Cohen G, Shirai T, Weisel RD, e
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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)
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137. Hu H, Sato T, Seharaseyon J, L
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151. Jennings R, Steenbergen C, Kin
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164. Kelpzig H, Kobert G, Mafter C,
Page 215 and 216:
178. Lamping K, Christensen C, Pelc
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192. Liu GS, Thornton J, Van Winkle
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206. Maulik N, Yoshida T, Das DK. (
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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,
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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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