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

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otTer advantages over isolated and cultured myocytes since these are more difficult to obtain, they do not retain the normal cell-to cell contact, ischemia is more difficult to accomplish and they can be maintained viable for short pefiods of time [42,3 151. A notable benefit derived from the prolonged stability of our preparation is that effects of reperfuslon can be examined for a period that extends beyond the first few hours that usually is not possible with in-vitro preparations. Limitations of the preparation: My study has several limitations which need to be mentioned. First, the preparation is superfused ("simulated ischaemia") as opposed to being artenally perfused. However, the removal of the vasculature as the natural pathway for the provision of substrate may also be advantageous by separating the confounding effects of the vascular changes and collateral flow induced by ischaernia and reperfusion. The present study used atrial tissue to characterize the effects of lschaemla and reperfusion in the human myocardium. However, atnal and ventricular myocardium possess characteristics of their own that may influence the susceptibility to ischaemia/reperfuslon injury and as a consequence results from one may not be applicable to the other. Thus, for example, the reported differences in the distribution of potassium channels [132], which contribute to the characteristic differences between atrial and ventricular action potentials, may determine a different response to ischaemia/reperfusion. Albeit, the fact that atfial tissue is generally stable and disease free, individual biological variation between patients may result in different susceptibility to ischaemia/reperfusion injury and this must be accounted for when interpreting results from any human study. 56
2.12 Conclusiow I have characterised a model of ischaernia and reoxygenation of human myocardium using right atrium appendage obtained from patients undergoing cardiac surgery. The tissue is readily available and the preparation is inexpensive. The preparation is stable for at least 24 hr and this permits the study of the early and delayed consequences of ischaemia and reperfusion. In addition, the extended stabilltv of the model may be potentially used for genetic manipulation to investigate the pathophysiological mechanisms underlying the injury sustained during Ischaemia and reperfusion, and to develop new therapeutical strategies to combat their undesirable effects. Once, the model was characterised, I will be able to use it to investigate the phenomenon of ischernic preconditioning in the human myocardium. The charactefisation of the early and delayed windows of protection has not been explored in full and is the subject of the third chapter 57
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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
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
Page 53 and 54: inexpensive. Briefly in this model,
Page 55 and 56: of each ischemic period, slices wer
Page 57 and 58: 30 nini FO linlin L 60 min 120 inin
Page 59 and 60: In Study 3 (see Figure 2.4), slices
Page 61 and 62: D. Metabolite analysis Samples were
Page 63 and 64: leakage is calculated as the net LD
Page 65 and 66: B. Effect of the severity of ischae
Page 67 and 68: 2.11 DISCUSSION: The present studie
Page 69 and 70: clearly insufficient to induce myoc
Page 71: The present model may facilitate th
Page 75 and 76: 3.5 3 V 2.5 3: m Je m Z0 z 2 1.5 0.
Page 77 and 78: (3 3 2.5 a 1.5 - -r T 0 2 0.5 0 I P
Page 79 and 80: Q oro . 21 . 0 'a IP 10 '. R -C3 A
Page 81 and 82: =3 0 h X CD 0 x CD :3 0 , 7, CD 0 0
Page 83 and 84: CHAPTER III PRECONDITIONING THE HUM
Page 85 and 86: 3.2 MATERIALS AND METHODS-. 3.2.1 E
Page 87 and 88: A117'reduction- At the end of the e
Page 89 and 90: -4 ýi r. () .1 a 0 1 tli n F5* - C
Page 91 and 92: v M. %; n C) .0 ý U ý ý - - - -2
Page 93 and 94: leakage resulting from precondition
Page 95 and 96: 3.5 DISCUSSION: The present studies
Page 97 and 98: during cardiac surgery totalling 10
Page 99 and 100: different. The cellular mechanisms
Page 101 and 102: cn Je 8 7 6 5 4 1 0 0.8 0.7 0.6 0.5
Page 103 and 104: 8 6 C) 2 0.7 0.6 Q) 0.5 0) E 25 0.4
Page 105 and 106: 6 5 CY) ,u3 CF) m -ýe m 2 1 0 -0.8
Page 107 and 108: CHAPTERIV THE ROLE OF THE KATPCHANN
Page 109 and 110: It has been reported that K.. %-I-p
Page 111 and 112: 0 a- I a 3 I cr =r Cl. 2 qQ 0'-ý 0
Page 113 and 114: Figure 4.7 shows that ischaemia alo
Page 115 and 116: Figure 4.2 Dosc-responsc experiment
Page 117 and 118: 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
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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).
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83. Downey JM, Liu GS and Thornton
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97. Ganote C, Armstrong S and Downe
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110. Grover GJ, D'Alonzo A, Hess T,
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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,
Page 229 and 230:
274. Schulz R, Post H, Valhaus C, e
Page 231 and 232:
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
Page 245 and 246:
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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