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

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journal of the American College of Cardiology Vol. 37, No. 3,2001 0 2001 by die American Collep of Cardiology ISSN 0735-1097/0132D. 00 Published by EIsevier Sck= Inc. PH S0735-1097(00)01161-X ]Failure to Precondition Pathological Human Myocardium Sudip Ghosh, FRCS, * Nicholas B. Standen, PHD, t Manuel Galifianes, MD, PHD* Leicester, United Kingdom ONECTIMS We investigated the effects of ischernic preconditioning (PC) on diabetic and fiiifing human myocardium and the role of mitochondrial KATP channels on the response in these diseased tissues. BXIýID Ilere is conflicting evidence to suggest that PC is a healthy heart phenomenon. NEFIVIDS Right atrial appendages were obtained from seven diffierent groups of patients: nondiabetics, diet-controlled diabetics, noninsulin-dependent diabetics (NIDD) receiving KATp channel blockers, insulin-dependent diabetics (IDD), and patients with left ventricular ejection fraction (LVEF) >5096, LVEF between 3096 and 5096 and LVEF
712 0" et &L h wcomMe geg in Obwa»d Hý OSwardkm AMweviafiom and Acrosqmw CK = creatine, Idnase DCD = diet-controlled diabetes IDD = insulin-dependent diabetes K, Tp = AT? -dependent potassium channels LVEF = left ventricular ejection firaction MIT = 3-[4,5-dim&thyIthiazol-2-yI1-2,5 diphenyltetrazolium. bromide NIDD = noninsulin-dependent diabetes PC = preconditioning PKC =protein kinase C earlier shown, also in the rat heart, that myocardial infarc- tion is reduced in diabetes and that PC fin-ther increases the protection of these hearts. Ilere are very few studies in human diabetic tissue. Cleveland et al. (16) used a func- tional isolated atrial ft-abeculae model and showed that PC did not confer any protection of the myocardium on patients taking long-term oral hypoglycemic agents. They hypothesized that long-term inhibition of KA-rp channels with these agents may be responsible for the excess cardiovascular mortality associated with diabetes. Heart failure is common in all forms of heart disease. Mechanical dysfunction of the failing heart is due to many factors, including neurohormonal disturbance, accumulation of extr; icellular matrix, alteration of excitation-contraction coupling and maladaptation of myocardial energetics (17). Very few studies have investigated the effects of the PC response in the failing myocardiurn in light of alterations in the cellular metabolic and biochemical pathways associated with heart failure. Cleveland et al. (3) showed in isolated ventricular tr-Abeculae from patients requiring heart trans- plantation that PC conferred protection. However, more recently Dekker et al. (18) have studied perfused papillary muscles from rabbits in which cardiac failure has been induced by a combination of pressure and volume overload- TaMe L Patient Characteristics JACC Vol. 37, No. 3,2001 March 1,2001: 711-8 ing. The end points used to assess responses to ischemia namely the time to onset of a rise in the intracellula concentration of Ca" (cellular uncoupling) and of ischerni contracture, were delayed by PC in normal myocardiurn but were exaggerated by PC in the fiding myocardium. The aims of the present study were 1) to investigate the effiects of PC on the diabetic and failing human myocar dium, and 2) to investigate the role of mitochondrial. KAjT channels in the responses of these pathological conditions These studies were carried out in an in vitro model of human right atrial myocardium of simulated ischemia and reoxygenation. MATERUNLS MD METHODS preparation. The right atrial appendage of patients undergoing elective coronary artery surgery or aortic valve replacement was obtained. Patients were ex- cluded if they hýd enlarged right atriums, atrial arrhythmia or right ventricular failure, or were taking opioid analgesia Patient characteristics are detailed in Table 1. Local ethica committee approval was obtained for the harvesting tech- nique, and the investigation conforms to the principles outlined in the Declaration of Helsinki. The specimen were collected in oxygenated HEPES buffered solution at 4' to 5*C and immediately sectioned and prepared for study Briefly, the appendage was mounted onto a ground glass plate with the epicardial surface face down and was then sliced with surgical skin graft blades (Shwann-Morton Sheffield, United Kingdom) to a thickness of between 300 and 500 jAm. 'Me specimen and the slide were kept moist throughout the procedure. Then 30 to 50 mg of muscle were transferred to conical flasks (25 ml ErIenmeyer flasks Duran, Astell Scientific, Kent, United Kingdom) containing 10 ml of oxygenated buffered solution. Following this, the flasks were placed in a shaking water bath maintained at Noudiabetics DCD NIDD IDD LVEF >50% LVEF = 30%-50% LVEF
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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
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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).
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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)
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.
Page 223 and 224: 233. Okazaki Y, Kodama K, Sato H, K
Page 225 and 226: 248. Pryzlenk K, Li G, Whittaker P
Page 227 and 228: 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
Page 233 and 234: 300. Tani M, Suganuma Y, Hasegawa H
Page 235 and 236: 312. Tosaki A, Engelman DT, Engelma
Page 237 and 238: 324. Walker D, Marber M, Walker J a
Page 239 and 240: 337. Yamashita N, Nishida M, Hoshid
Page 241 and 242: 351. Zhang JG, Lindup WE. (1993). R
Page 243 and 244: 444 J. -G. Zhang and others are dif
Page 245 and 246: 446 J. -G. Zhang and others Assessm
Page 247 and 248: 448 J. -G. Zhang and others 0.9 0.8
Page 249 and 250: 450 J. -G. Zhang and others C E 07
Page 251 and 252: 4S2 J. -G. Zhang and othen effects
Page 253 and 254: ELSEVIER Abstract Cardiovascular Re
Page 255 and 256: 936 S. Ghosh et al. / Cardiovascula
Page 257 and 258: 938 S. Ghosh et al. / Cardiovascula
Page 259: 940 S. Ghosh et al. [41 Goto M, Liu
Page 263 and 264: 714 Gbosb ot aL hmoo dmoWmbDbsnedH
Page 265 and 266: 716 chmä et aL Pi unamOso äu In O
Page 267: 718 ehe* et &L ditioning in the hum
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