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Basic Research in Cardiology

, Volume 104, Issue 5, pp 469–483 | Cite as

Ischemic postconditioning: experimental models and protocol algorithms

  • Andreas Skyschally
  • Patrick van Caster
  • Efstathios K. Iliodromitis
  • Rainer Schulz
  • Dimitrios T. Kremastinos
  • Gerd HeuschEmail author
Review

Abstract

Ischemic postconditioning, a simple mechanical maneuver at the onset of reperfusion, reduces infarct size after ischemia/reperfusion. After its first description in 2003 by Zhao et al. numerous experimental studies have investigated this protective phenomenon. Whereas the underlying mechanisms and signal transduction are not yet understood in detail, infarct size reduction by ischemic postconditioning was confirmed in all species tested so far, including man. We have now reviewed the literature with focus on experimental models and protocols to better understand the determinants of protection by ischemic postconditioning or lack of it. Only studies with infarct size as unequivocal endpoint were considered. In all species and models, the duration of index ischemia and the protective protocol algorithm impact on the outcome of ischemic postconditioning, and gender, age, and myocardial temperature contribute.

Keywords

Myocardial ischemia Reperfusion Postconditioning 

Introduction

Myocardium subjected to sustained ischemia without reperfusion is rendered to death. The ultimate amount of myocardial infarction critically depends on the severity and the duration of ischemia, and timely reperfusion is the only way to salvage the myocardium from irreversible damage. However, reperfusion is a double-edged sword which not only rescues from infarction but also induces irreversible damage [26]. In their original paper in 2003 Zhao et al. [92] reported that several brief cycles of ischemia/reperfusion at the onset of reperfusion reduced infarct size by 44% in anesthetized dogs. In retrospect, a first attempt of ischemic postconditioning was performed more than 10 years before [82]. However, the applied cycles of 5 min reperfusion interrupted by 5 min coronary re-occlusion failed to reduce infarct size, and this concept has therefore been abandoned until 2003. The attractiveness of ischemic postconditioning is that this protective stimulus is introduced at reperfusion, when it is clearly predictable and feasible in the clinical setting.

Since its first description, numerous experimental studies have been performed, and ischemic postconditioning was confirmed in mice, rats, and rabbits, both in vitro and in vivo, in dogs and pigs in vivo, and notably also in man (see Tables 1, 2, 3, 4, 5, 6). Also, some studies reported protocols which did not induce protection; however, since most studies reported only effective protocols, a systematic analysis of ineffective protocols is not possible. Whether or not postconditioning provides as powerful protection as preconditioning is unclear at present [1, 13, 56, 68, 74, 92]. Conceptually, preconditioning can protect against both ischemic and reperfusion injury and could therefore provide stronger protection, but since the reported protective algorithms have not been optimized such conclusion can not be firmly drawn. The underlying mechanisms and signal transduction of ischemic postconditioning are still not understood in detail [27]. Based on experiments in small rodents it was initially proposed that ischemic postconditioning activates so-called reperfusion injury salvage kinases (RISK) which then confer protection against infarction [4, 9, 77, 86, 87]. In one study in pigs postconditioning failed to protect from infarction, but activation of RISK was observed [68]. In a recent study, again in pigs, we have shown that RISK activation was not causal for postconditioning’s protection [72]. Clearly, species differences are an issue. Maintenance of myocardial acidosis during the first minutes of reperfusion was originally proposed as an underlying mechanism of postconditioning [26]. In fact, in isolated rabbit hearts, the normalization of tissue pH was delayed by a postconditioning maneuver and protection by postconditioning was lost with alkalosis during early reperfusion [7]. Also in pigs, acidic reperfusion can substitute for ischemic postconditioning and induce protection [65]. A potential end-effector of postconditioning is the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening was causally involved in postconditioning’s protection in several species [2, 21, 43]. In a recent study in man, the mPTP inhibitor cyclosporine A given at reperfusion induced protection [63], suggesting that mPTP opening is also a critical event in humans.
Table 1

Ischemic postconditioning in mice (infarct size determined by triphenyl tetrazolium chloride staining)

Index ischemia

Postconditioning protocol

Reperfusion

Area at risk

Infarct size

Anesthesia

Study population

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Duration (min)

Control (% of left ventricle)

PostCon (% of left ventricle)

Control (% of area at risk)

PostCon (% of area at risk)

Effect (% of control)

Age (weeks)

Gender

Isolated hearts (Langendorff mode; global ischemia)

 20

10

6

10/10

5

30

100

100

35

23

−34*

Pentobarbitala

 

m

Xi et al. [84]

 30

5

10

5/5

3

120

100

100

47

26

−44*

Pentobarbitala

 

m

Nishino et al. [54]

 30

5

10

5/5

3

120

100

100

61

42

−32*

Pentobarbitala

 

m

Nishino et al. [54]

 30

10

3

10/10

2

120

100

100

53

27

−49*

Pentobarbital

12–16

 

Przyklenk et al. [64]

 30

10

3

10/10

2

120

100

100

43

40

−7

Pentobarbital

80–96

 

Przyklenk et al. [64]

 30

10

6

10/10

3

120

100

100

53

29

−45*

Pentobarbital

12–16

 

Przyklenk et al. [64]

 30

10

6

10/10

3

120

100

100

43

41

−5

Pentobarbital

80–96

 

Przyklenk et al. [64]

 30

30

4

30/30

7

120

100

100

47

38

−19

Pentobarbital

 

m

Nishino et al. [54]

 45

5

3

5/5

1

45

100

100

40

30

−25*

Pentobarbital

 

m

Jin et al. [34]

 45

10

3

10/10

1

60

100

100

33

16

−52*

Pentobarbital

 

m

Kaljusto et al. [35]

In vivo hearts (regional ischemia)

 25

60

3

60/60

12

1,440

41

41

61

35

−43*

Fentanyl, midazolam

7–8

m

Gomez et al. [21]

 30

5

5

5/5

1

120

38

37

67

50

−26*

Pentobarbital

<12

f

Boengler et al. [3]

 30

5

5

5/5

1

120

37

38

60

47

−23*

Pentobarbital

>52

f

Boengler et al. [3]

 30

10

3

10/10

2

120

38

34

67

50

−25*

Pentobarbital

<12

f

Boengler et al. [3]

 30

10

3

10/10

2

120

37

38

60

66

10

Pentobarbital

>52

f

Boengler et al. [3]

 30

10

3

10/10

2

120

  

54

37

−31*

Pentobarbital

10–15

f

Heusch et al. [28]

 30

10

3

10/10

2

60

19

22

42

21

−50*

Pentobarbital

 

m

Kaljusto et al. [35]

 30

10

3

10/10

2

120

  

46

27

−42*

Ketamine, xylazine, atropine

8–10

m + f

Lim et al. [43]

 30

10

6

10/10

3

1,440

44

40

33

14

−58*

Pentobarbital

8–10

m

Bouhidel et al. [5]

 30

10

6

10/10

3

120

  

46

32

−31*

Ketamine, xylazine, atropine

8–10

m + f

Lim et al. [43]

 30

20

3

20/20

3

120

  

43

24

−44*

Pentobarbital

8–10

m

Tsutsumi et al. [78]

 60

60

3

60/60

5

1,440

35

35

58

39

−33*

Fentanyl, midazolam

8–10

m

Gomez et al. [20]

m/f male/female

* Significant effect

aUse of heparin

Table 2

Ischemic postconditioning in isolated rat heart preparations

Index ischemia

Postconditioning protocol

Reperfusion

Area at risk

Infarct size

Anesthesia

Study population

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Duration (min)

Control (% of left ventricle)

PostCon (% of left ventricle)

Method

Control (% of area at risk)

PostCon (% of area at risk)

Effect (% of control)

Age (weeks)

Gender

Langendorff mode, global ischemia

 10

10

5

10/10

8

120

100

100

NTB

11

12

9

Urethanea

20

m

Penna et al. [60]

 10

10

5

10/10

8

120

100

100

NTB

21

12

−43*

Urethanea

20

f

Penna et al. [60]

 30

10

3

10/10

2

90

100

100

TTC

35

35

0

Pentobarbitala

 

m

Kaljusto et al. [35]

 30

10

5

10/10

3

120

100

100

NTB

64

21

−67*

Urethanea

 

m

Penna et al. [59]

 30

10

5

10/10

3

120

100

100

NTB

65

22

−66*

Urethanea

 

m

Penna et al. [56]

 30

10

5

10/10

3

120

100

100

NTB

59

46

−22*

Urethanea

 

m

penna et al. [56]

 30

10

5

10/10

3

120

100

100

NTB

61

22

−64*

Urethanea

 

m

Penna et al. [57]

 30

10

5

10/10

3

120

100

100

NTB

64

28

−56*

Urethanea

 

m

Penna et al. [58]

 30

10

5

10/10

3

120

100

100

NTB

61

29

−52*

Urethanea

20

m

Penna et al. [60]

 30

10

5

10/10

3

120

100

100

NTB

52

40

−23*

Urethanea

20

f

Penna et al. [60]

 30

15

4

5–20/15–30

3

120

100

100

NTB

65

20

−69*

Urethanea

 

m

Penna et al. [56]

 30

15

4

5–20/15–30

3

120

100

100

NTB

59

45

−24*

Urethanea

 

m

Penna et al. [56]

 30

30

3

30/30

5

90

100

100

TTC

35

34

−3

Pentobarbitala

 

m

Kaljusto et al. [35]

 30

60

2

60/60

7

90

100

100

TTC

35

37

6

Pentobarbitala

 

m

Kaljusto et al. [35]

 40

5

12

5/5

3

60

100

100

TTC

50

32

−36*

Pentobarbital

 

m

Inserte et al. [32]

 40

10

6

10/10

3

60

100

100

TTC

50

44

−12

Pentobarbital

 

m

Inserte et al. [32]

 40

10

6

10/10

3

90

100

100

TTC

36

6

−83*

Decapitationa

14–15

m

Zhu et al. [93]

 40

30

2

30/30

3

60

100

100

TTC

34

17

−50*

Pentobarbitala

 

m

Ferrera et al. [17]

 40

30

2

30/30

3

120

100

100

TTC

35

17

−51*

Pentobarbitala

 

m

Ferrera et al. [17]

 90

10

3

20/10–20

1

40

100

100

TTC

60

22

−63*

Pentobarbital

  

Vessey et al. [81]

Working heart, regional ischemia

 35

10

6

10/10

3

40

48

52

TTC

36

18

−50*

Pentobarbital

 

m

van Vuuren et al. [79]

 35

10

6

10/10

3

40

49

49

TTC

28

27

−3

Pentobarbital

 

m

van Vuuren et al. [79]

Langendorff mode, regional ischemia

 30

10

6

10/10

3

120

  

TTC

30

12

−60*

Thiobarbitural

 

m

Jang et al. [33]

 30

10

6

10/10

3

120

37

49

TTC

48

18

−63*

Diethylethera

 

m

Kocsis et al. [38]

 35

10

6

10/10

3

120

  

TTC

51

32

−38*

Pentobarbitala

 

m

Tsang et al. [77]

 35

10

6

10/10

3

40

48

47

TTC

48

28

−42*

Pentobarbital

 

m

van Vuuren et al. [79]

 35

10

6

10/10

3

40

  

TTC

29

33

13

Pentobarbital

 

m

van Vuuren et al. [79]

 40

10

3

10/10

1

120

  

TTC

28

20

−29

Pentobarbitala

 

m

Kaljusto et al. [35]

TTC triphenyl tetrazolium chloride staining, NBT nitro blue tetrazolium staining, m/f male/female

* Significant effect

aUse of heparin

Table 3

Ischemic postconditioning in rats in vivo

Index ischemia

Postconditioning protocol

Reperfusion

Area at risk

Infarct size

Anesthesia

Study population

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Duration (min)

Control (% of left ventricle)

PostCon (% of left ventricle)

Method

Control (% of area at risk)

PostCon (% of area at risk)

Effect (% of control)

Age (weeks)

Gender

15

30

3

30/30

10

120

40

40

NTB

3

19

533*

Pentobarbital

 

m

Manintveld et al. [51]

30

5

3

5/5

1

120

40

40

NTB

36

45

25

Pentobarbital

 

m

Manintveld et al. [51]

30

10

3

10/10

2

180

32

31

TTC

52

40

−23*

Pentobarbital, isoflurane

 

m

Kin et al. [37]

30

10

3

10/10

2

180

32

30

TTC

53

40

−25*

Pentobarbital

 

m

Kin et al. [36]

30

10

3

10/10

2

180

39

41

TTC

53

39

−26*

Pentobarbitala

 

m

Zatta et al. [89]

30

10

3

10/10

2

180

31

29

TTC

57

42

−26*

Pentobarbitala

 

m

Zatta et al. [90]

30

10

3

10/10

2

120

33

32

TTC

48

24

−50*

Chloral hydrate

 

m

Fang et al. [15]

30

10

4

10/10

2

120

31

28

TTC

27

37

37

Ketamine, xylazine

 

f

Dow and Kloner [12]

30

10

4

10/10

2

120

27

30

TTC

31

27

−13

Pentobarbital, isoflurane

 

f

Dow and Kloner [12]

30

10

4

10/10

2

180

52

51

TTC

30

12

−60*

Pentobarbital

12–16

m

Yin et al. [88]

30

10

4

10/10

2

180

51

53

TTC

28

14

−50*

Pentobarbital

64–72

m

Yin et al. [88]

30

10

6

10/10

3

120

  

TTC

31

14

−54*

Thiobarbitural

 

m

Jang et al. [33]

30

10

6

10/10

3

180

32

30

TTC

52

40

−23*

Pentobarbital, isoflurane

 

m

Kin et al. [37]

30

10

6

10/10

3

1,440

63

64

TTC

65

41

−37*

Pentobarbital

14

m

Oikawa et al. [55]

30

10

6

10/10

3

1,440

27

30

TTC

54

36

−34*

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

30

10

20

10/10

11

120

31

33

TTC

27

50

85

Ketamine, xylazine

 

f

Dow and Kloner [12]

30

10

20

10/10

11

1,440

27

27

TTC

54

29

−47*

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

30

10

60

10/10

33

1,440

27

25

TTC

54

57

5

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

30

15

3

15/15

3

90

47

46

TTC

62

51

−23*

Pentobarbital

 

m

Kaljusto et al. [35]

30

15

3

15/15

3

120

40

40

NTB

36

53

47*

Pentobarbital

 

m

Manintveld et al. [51]

30

20

4

20/20

4

120

33

31

TTC

34

41

21

Pentobarbital, isoflurane

 

f

Dow and Kloner [12]

30

30

3

30/30

5

120

40

40

NTB

36

48

33*

Pentobarbital

 

m

Manintveld et al. [51]

30

30

3

30/30

5

30

  

PI

49

29

−41*

Pentobarbital

28

m

Wagner et al. [83]

30

30

6

30/30

10

1,440

27

29

TTC

54

56

3

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

30

30

8

30/30

13

120

31

34

TTC

27

42

56

Ketamine, xylazine

 

f

Dow and Kloner [12]

30

60

3

10/10

2

180

32

31

TTC

52

50

−4

Pentobarbital, isoflurane

 

m

Kin et al. [37]

40

10

3

10/10

1

180

40

35

TTC

33

24

−27

Isoflurane

 

m

Kaljusto et al. [35]

45

10

4

10/10

1

120

30

33

TTC

45

47

4

Ketamine, xylazine

 

f

Dow and Kloner [12]

45

10

20

10/10

7

1,440

27

29

TTC

65

57

−12*

Conscious

9–12

m

Sato et al. [66]

45

10

20

10/10

7

1,440

29

31

TTC

62

55

−11

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

45

20

4

20/20

3

120

38

33

TTC

43

47

9

Ketamine, xylazine

 

f

Dow and Kloner [12]

45

30

3

30/30

3

120

  

TTC

72

40

−45*

Pentobarbital

 

m

Liu et al. [44]

45

30

3

30/30

3

120

40

40

NTB

45

31

−31*

Pentobarbital

 

m

Manintveld et al. [51]

60

5

3

5/5

<1

120

40

40

NTB

60

53

−12

Pentobarbital

 

m

Manintveld et al. [51]

60

10

20

10/10

6

1,440

29

27

TTC

74

72

−3

Conscious

9–12

m

Sato et al. [66]

60

10

20

10/10

6

1,440

29

29

TTC

72

71

−1

Ketamine, xylazine, isoflurane

9–12

m

Tang et al. [74]

60

15

3

15/15

1

120

40

40

NTB

60

57

−5

Pentobarbital

 

m

Manintveld et al. [51]

60

30

3

30/30

3

120

40

40

NTB

60

47

−22*

Pentobarbital

 

m

Manintveld et al. [51]

90

30

3

30/30

2

120

40

40

NTB

65

52

−20

Pentobarbital

 

m

Manintveld et al. [51]

120

30

3

30/30

1

120

40

40

NTB

67

58

−13

Pentobarbital

 

m

Manintveld et al. [51]

TTC triphenyl tetrazolium chloride staining, NBT nitro blue tetrazolium staining, PI propidium iodide staining, m/f male/female

* Significant effect

aUse of heparin

Table 4

Ischemic postconditioning in rabbits (infarct size determined by triphenyl tetrazolium chloride staining)

Index ischemia

Postconditioning protocol

Reperfusion

Area at risk

Infarct size

Anesthesia

Study population

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Duration (min)

Control (% of left ventricle)

PostCon (% of left ventricle)

Control (% of area at risk)

PostCon (% of area at risk)

Effect (% of control)

Gender

Isolated hearts (Langendorff mode; global ischemia)

 30

30

2

30/30

3

120

100

100

17

5

−68*

Ketamine + xylazine

 

Donato et al. [11]

Isolated hearts (Langendorff mode; regional ischemia)

 30

10

3

10/10

2

120

  

34

38

10

Pentobarbital

 

Cohen et al. [7]

 30

10

6

10/10

3

120

  

33

10

−69*

Pentobarbital

m + f

Yang et al. [86]

 30

10

6

10/10

3

120

  

34

11

−69*

Pentobarbital

 

Cohen et al. [7]

 30

30

4

30/30

7

120

36

34

45

28

−38*

Ketamine, xylazine

 

Darling et al. [9]

 30

30

4

30/30

7

120

  

33

25

−26

Pentobarbital

m + f

Yang et al. [86]

In vivo hearts (regional ischemia)

 20

30

4

30/30

4

1,440

48

53

23

13

−43*

Ketamine, xylazine

m

Letienne et al. [40]

 25

30

4

30/30

4

1,440

52

43

51

34

−33*

Ketamine, xylazine

m

Letienne et al. [40]

 30

10

3

10/10

2

180

37

32

41

34

−17

Pentobarbitala

m

Chiari et al. [6]

 30

10

6

10/10

3

180

  

48

20

−58*

Thiopeptone

m

Iliodromitis et al. [31]

 30

20

3

20/20

3

180

37

36

41

20

−51*

Pentobarbitala

m

Chiari et al. [6]

 30

30

3

30/30

5

180

30

29

31

16

−49*

Pentobarbitala

m + f

Li et al. [42]

 30

30

4

30/30

7

180

  

40

16

−61*

Pentobarbital

m + f

Philipp et al. [62]

 30

30

4

30/30

7

180

  

35

20

−44*

Pentobarbital

m + f

Yang et al. [87]

 30

30

4

30/30

7

180

25

27

37

21

−43*

Pentobarbital, 2% isofluranea

m

Tessier-Vetzel et al. [75]

 30

30

4

30/30

7

180

26

26

49

37

−31*

Pentobarbital, 0.5% isofluranea

m

Tessier-Vetzel et al. [75]

 30

30

4

30/30

7

180

31

28

56

39

−30*

Pentobarbital

m

Couvreur et al. [8]

 30

30

4

30/30

7

180

28

28

55

39

−29*

Pentobarbitala

m

Tessier-Vetzel et al. [75]

 30

30

4

30/30

7

180

  

48

45

−6

Thiopeptone

m

Iliodromitis et al. [31]

 30

30

4

30/30

7

180

31

32

29

35

21

Ketamine, xylazine, pentobarbital

m

Hale et al. [24]

 30

30

4

60/60

13

180

31

31

42

45

7

Ketamine, xylazine, pentobarbital

m

Hale et al. [24]

 30

30

6

30/30

10

180

  

35

20

−44*

Pentobarbital

m + f

Yang et al. [87]

 30

60

4

60/60

13

240

  

59

28

−53*

Ketamine, xylazine

m

Argaud et al. [1]

 30

60

4

60/60

13

240

29

37

61

29

−52*

Ketamine, xylazine

m

Argaud et al. [2]

 30

60

4

60/60

13

180

  

47

33

−30*

Pentobarbitala

m

Gritsopoulos et al. [22]

 30

600

4

30/30

7

180

  

35

35

−3

Pentobarbital

m + f

Yang et al. [87]

 45

30

4

30/30

4

180

  

62

40

−36*

Pentobarbital

m + f

Yang et al. [87]

 45

30

4

30/30

4

1,440

55

52

70

61

−13

Ketamine, xylazine

m

Letienne et al. [40]

 60

30

4

30/30

4

1,440

57

54

81

80

−1

Ketamine, xylazine

m

Letienne et al. [40]

m/f male/female

* Significant effect

aUse of heparin

Table 5

Ischemic postconditioning in dogs, pigs and monkeys (infarct size determined by triphenyl tetrazolium chloride staining)

Index ischemia

Postconditioning protocol

Reperfusion (min)

Area at risk

Infarct size

Blood flow

Anesthesia

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Control (% of left ventricle)

PostCon (% of left ventricle)

Control (% of area at risk)

PostCon (% of area at risk)

Effect (% of control)

Control

PostCon

Isch. (% of baseline)

Rep. (% of baseline)

Isch. (% of baseline)

Rep. (% of baseline)

Dogs

 60

30

3

30/30

3

180

26

27

25

14

−44*

4

215

5

300

Morphine, isofluranea

Zhao et al. [92]

 60

30

3

30/30

3

180

22

22

24

10

−58*

4

100

5

72

Morphine, isofluranea

Halkos et al. [25]

 60

30

3

30/30

3

180

26

25

30

15

−50*

<10

 

<10

 

Acepromazine, pentobarbitala

Mykytenko et al. [52]

 60

30

3

30/30

3

1,440

29

31

39

27

−31*

6

 

<11

 

Acepromazine, pentobarbitala

Mykytenko et al. [53]

 60

30

3

30/30

3

1,440

27

30

39

27

−31*

<10

 

<11

 

Acepromazine, pentobarbitala

Mykytenko et al. [52]

 90

60

4

60/60

4

360

46

49

37

12

−68*

    

Pentobarbitala

Fujita et al. [18]

Pigs

 30

30

3

30/30

5

180

31

28

27

38

43

    

Ketamine, pentobarbital

Schwartz et al. [68]

 30

30

6

30/30

10

180

  

27

27

3

    

Ketamine, pentobarbital

Schwartz et al. [68]

 48

30

8

30/30

8

120

12

14

57

63

11

    

Thiopentala

Rodriguez-Sinovas et al. [65]

 60

30

8

30/30

7

120

15

15

76

57

−25*

    

Thiopentala

Rodriguez-Sinovas et al. [65]

 60

30

4

30/30

3

180

  

34

37

10

    

Ketamine, midazolam; propofol, pancuronium, fentanyl

Iliodromitis et al. [30]

 60

30

8

30/30

7

180

  

34

11

−69*

    

Ketamine, midazolam; propofol, pancuronium, fentanyl

Iliodromitis et al. [30]

 90

20

6

20/20

2

120

45

43

33

20

−39*

4

240

5

310

Ketamine, thiopental, enfluranea

Skyschally et al. [72]

 180

10

6

10/10

1

120

24

24

99

76

−23*

0

51

0

72

Azaperone, thiopental

Zhao et al. [91]

Monkeys

 90

30

6

30/30

3

480

  

44

28

−36*

    

Ketamine, pentobarbital

Downey and Cohen [13]

Blood flow expressed as % of baseline during ischemia and early (<15 min) reperfusion

m/f male/female

* Significant effect

aUse of heparin

Table 6

Ischemic postconditioning in patients undergoing percutaneous coronary interventions or cardiac surgery under cardioplegia (infarct size estimated by cardiac marker enzymes)

Index ischemia

Postconditioning protocol

Infarct size

Study population

References

Duration (min)

Delay (s)

Number of cycles

Ischemia/reperfusion per cycle (s)

Additive ischemia (% of index ischemia)

Method

Effect (% of control)

Age (years)

Gender

m/f (%)

Percutaneous coronary intervention

 198

30

Avg 6.1

25/25

1

CK peak

−27*

55

73/27

Darling et al. [10]

 225

180

2

90/180

1

CK peak

−18*

59

56/44

Laskey et al. [39]

 288

30

3

30/30

<1

cTi a.u.c.

−27*

61

74/26

Yang et al. [85]

 290

60

4

60/60

1

cTi a.u.c.

−47*

56

76/24

Thibault et al. [76]

 325

60

4

60/60

1

CK a.u.c.

−36*

58

56/44

Staat et al. [73]

 411

60

3

30/30

<1

CK-MB peak

−32*

64

68/32

Ma et al. [48]

Cardiac surgery under cardioplegia

 56

30

3

30/30

3

CK-MB 4 h post-OP

−21*

41

46/54

Luo et al. [45]

 62

30

2

30/30

2

cTi peak

−44*

5.6

68/32

Luo et al. [46]

 64

30

2/3

30/30

2

cTi 4 h post-OP

−50*

8

35/65

Li et al. [41]

 66

30

3

30/30

2

cTi peak

−50*

5.6

65/38

Luo et al. [47]

CK/CK-MB creatine kinase/creatine kinase isoenzyme B, cTi cardiac troponin I, peak peak release, a.u.c “aera under the curve”, cumulative release, m/f gender distribution

* Significant effect

We have now reviewed the literature on ischemic postconditioning with focus on species, models, and protocols.

Database search

A systematic search using the databases Pubmed, Web of Science and Scopus was performed without limitations for time and language and is current as of May 27, 2009. In addition to the search for the keyword “postconditioning” the reference lists of all retrieved articles were cross-checked. More than 400 peer-reviewed papers were evaluated. We focused only on studies which reported infarct size as the unequivocal endpoint. Data from experiments on pharmacological postconditioning, from experiments using genetically modified animals, from studies in which only functional or arrhythmic outcome was reported, and from studies which were solely published in non-English languages were excluded. Data from animals with co-morbidities (e.g. hypercholesteremia [31], hypertrophy) or co-treatments (e.g. statins) were also excluded [16].

The following parameters were condensed in Tables 1, 2, 3, 4, 5 and 6, grouped by species and model; sorting criteria within tables are (1) index ischemia, (2) postconditioning protocol, (3) reperfusion, (4) infarct size and (5) study population.

Index ischemia

Duration of the sustained ischemia initiating myocardial infarction (min).

Postconditioning protocol

Delay

Duration of the initial reperfusion period immediately after the index ischemia and before the postconditioning maneuver (s).

Number of cycles

Number of re-occlusions in the postconditioning maneuver.

Ischemia/reperfusion per cycle

Duration of each re-occlusion and each reperfusion separating two re-occlusions (s).

Additive ischemia

Cumulative duration of the re-occlusions relative to the duration of the index ischemia (%).

Reperfusion

Duration of reperfusion before infarct size determination (min); data not available for patients.

Infarct size

Area at risk

Data are given when area at risk was reported as percent of the left ventricle.

Method

Method of infarct size measurement is referred; in patient studies, infarct size was estimated from release of cardiac markers.

Control

Infarct size relative to the area at risk when immediate full reperfusion was established after the index ischemia (%); data not available for patient studies.

PostCon

Infarct size relative to the area at risk when reperfusion was initiated with a postconditioning maneuver (%); data not available for patient studies.

Effect

Impact of the postconditioning maneuver on infarct size, expressed as percent difference relative to controls (%); significant changes are indicated by asterisks.

Blood flow

Blood flow to the reperfused myocardium during ischemia and at early reperfusion (<15 min) expressed as % of baseline either determined by coronary inflow or regional myocardial blood flow.

Anesthesia

Type of anesthesia is referred; when the use of heparin was reported, the respective study is labeled with a +.

Study population

Age, gender

Data are given when reported in the respective study.

Algorithm of the postconditioning protocol

Duration of index ischemia

The index ischemia can be either too long or too short for ischemic postconditioning to reduce infarct size. During a more prolonged index ischemia, myocardial infarction progresses over time until it is almost complete, and there is no more room for salvage by ischemic postconditioning. In fact, in rats in vivo after an index ischemia of 60 min or longer infarct size reduction by ischemic postconditioning was largely attenuated: infarct size reduction ranged between 1 and 22% as compared to the respective control and was significant in only a single study. In contrast, studies using the same postconditioning algorithm after an index ischemia of 30 or 45 min revealed significant infarct size reductions between 23 and 47% as compared to the respective control.

Also, with too short duration of the index ischemia, postconditioning fails to reduce infarct size, as observed in rats [51, 60] and pigs [65, 68]. With shorter duration of ischemia, the total amount of infarction developing during ischemia and/or reperfusion decreases and there is little infarction to protect from. Simultaneously, the postconditioning maneuver largely increases the relative additive ischemia and thus offsets any potential protection. In this respect, infarct size reduction was attenuated or lost in 18 out of 35 studies, when the relative additive ischemia induced by the postconditioning algorithm exceeded 5% of the index ischemia, regardless of species.

In most species apart from rats and pigs, the duration of the index ischemia was not varied enough for a firm conclusion. Of note, in patients undergoing percutaneous coronary interventions for acute myocardial infarction, the duration of the index ischemia was much longer than in the experimental studies and of little importance for outcome: successful infarct size reduction was observed with index ischemia duration ranging from 198 to 411 min.

Postconditioning maneuver

The postconditioning algorithm consists of at least three factors: the delay after which the first re-occlusion is established, the duration and number of re-occlusions, the duration of the interspersed reperfusion. There appears to be a consensus that the delay up to the first re-occlusion can only be short, but the available data are surprisingly sparse. In rats in vivo, infarct size reduction by postconditioning was lost when the first re-occlusion was shifted from 10 to 60 s reperfusion [37]. In rabbits in vivo, protection was induced when the postconditioning maneuver was initiated at 30 s reperfusion but was lost at 60 s [61] or 10 min [87] reperfusion. However, in several studies in mice [20, 21], rabbits [1, 2], and dogs [18], and also in the available studies in patients [39, 48, 49, 50, 73, 76] ischemic postconditioning still reduced infarct size when the delay to the first re-occlusion ranged from 60 to 180 s. In the majority of studies, the postconditioning maneuvers were initiated within 60 s of reperfusion, and within this 60 s time frame no impact of a delay on infarct size reduction was noted. A delay of the postconditioning maneuver until 5 min of reperfusion was probably the major reason for the failure of the first postconditioning experiment [82].

The number of postconditioning cycles per se seems to have no impact on the outcome of ischemic postconditioning. Nevertheless, infarct size reduction by ischemic postconditioning clearly depends on “stimulus” strength. Too few cycles and/or too short duration of ischemia/reperfusion within each cycle fail to reduce infarct size. Increasing the number of postconditioning cycles in rats in vivo from 3 to 6 [51] and in pigs in vivo from 4 to 8 [30] was needed to establish protection. In rabbits in vivo, the prolongation of the ischemia/reperfusion cycle duration from 10 to 30 s also established protection [6].

Ischemic postconditioning with too many cycles and/or too long duration of ischemia/reperfusion within each cycle may also impair the outcome of postconditioning. As described above, additional ischemia relative to the duration of the index ischemia might limit the reduction of infarct size, and this may also have been one reason for failure in the first experiment with ischemic postconditioning using several cycles of 5 min reperfusion and 5 min coronary re-occlusion preceding complete reperfusion [82]. Rabbits appear to be more tolerant for the impact of additive ischemia than other species. Postconditioning was successful in 11 out of 16 studies in rabbits when additive ischemia was ≥7% of the index ischemia, whereas this was observed in only 6 out of 19 studies in all other species combined.

A technical problem which may result from repeated occlusion of the target vessel is the failure of complete reperfusion, and such failure of reperfusion may confound a potential protection. To exclude failure of full reperfusion, a flow measurement at early reperfusion is mandatory. Use of heparin may prevent thrombotic obstruction at the repetitively occluded target vessel. Since the duration of reperfusion has no impact on the outcome of postconditioning it is recommended that it is long enough to reliably demarcate infarcted tissue from viable tissue by standard staining methods, i.e. at least 60 min [17, 70].

Efficacy of ischemic postconditioning

Infarct size reduction by ischemic postconditioning is a robust phenomenon and was observed in 66% of the evaluated experimental studies, regardless of species, model, anesthesia, use of heparin, or duration of reperfusion before infarct size was determined. The postconditioning algorithm varied with the size of the animal under study and heart rate. Small animals with a higher heart rate such as mice and rats had shorter durations of ischemia/reperfusion as part of the postconditioning cycle whereas longer cycles were used in larger species with a lower heart rate such as dogs and pigs. There is no obvious reason for these differences but they may result from “trial and error” in designing the experimental setup and omitting the negative results in the finally published data. The number of postconditioning cycles was not different between species. All studies in humans revealed a significant reduction in infarct size with postconditioning algorithms similar to those used in large animal species.

Gender, age, temperature

In a single study [12] in rats in vivo, gender appeared to modify the protective effect of ischemic postconditioning. In comparable studies using male rats infarct size was reduced, whereas a similar postconditioning maneuver after a comparable duration of index ischemia failed to reduce and even increased infarct size in female rats. The reasons for this difference remain unclear. Under control conditions, infarct size per se was smaller in female than in male rats. Additive ischemia in these experiments did not exceed 4% of the index ischemia.

Age has a major impact on infarct size reduction by ischemic postconditioning in mice, but not in rats [88]. In isolated hearts from mice older than 80 weeks, postconditioning failed to reduce infarct size [64]. Postconditioning by three cycles of 10 s/10 s ischemia/reperfusion reduced infarct size in young (<12 weeks) mice in vivo but failed to do so in mice older than 52 weeks. However, changing the postconditioning algorithm to five cycles of 5 s/5 s ischemia/reperfusion in these mice fully reestablished the protection [3]. Interestingly, the biological age of these mice was similar to the biological age of patients in which postconditioning reduced infarct size considerably (Table 6).

In a single study, lowering the perfusate temperature by 0.5°C in isolated rat hearts largely attenuated infarct size reduction by ischemic postconditioning [79], possibly by attenuated generation/release of signaling molecules. This effect is contrary to the impact of temperature on infarct size per se which decreases when temperature decreases [14, 23, 69].

Species and models to study ischemic postconditioning

The goal of experimental studies on postconditioning is translation to humans. In this context, the temporal and spatial evolution of myocardial infarction is of critical importance. Myocardial infarction develops over time in close dependence on the residual collateral blood flow. Whereas in rodent hearts, myocardial infarction develops quickly and is almost complete within 30 min of coronary occlusion, the development of infarction in larger mammals is slower [67]. The available data in humans indicate that human infarct development is initially between that of cats and dogs and subsequently between that of pigs and dogs [19, 29, 80]. Intuitively, primates are closer to humans than other species. However, primates exhibit a surprising resistance against infarction. Baboons have only 2% infarction after 40 min coronary occlusion, whereas pigs have 46% after 40 min coronary occlusion [71]. Cynomolgus monkey have no infarct at all after 60 min coronary occlusion [13]. These differences are less pronounced with a longer duration of ischemia: after 90 min coronary occlusion infarct size was 17% in baboons [71], 44% in cynomolgus monkeys [13], and 53% in pigs [71]. Apart from and in addition to the temporal development of myocardial infarction, the spatial distribution of infarction should resemble that in humans, with preferentially subendocardial infarction, as seen in dogs, pigs, and primates. In mice, the inner layers are largely served by diffusion, and infarction occurs preferentially in the outer layers.

Mice

In the majority of studies, infarct size reduction by postconditioning was observed with 30 min index ischemia and a postconditioning maneuver with three to six cycles of 10 s re-occlusion separated by 10 s reperfusion. Additive ischemia remained below 5% of the index ischemia.

Rats

The majority of studies used an index ischemia of 30–40 min and a postconditioning maneuver with three to six cycles of 10 s re-occlusion separated by 10 s reperfusion. Additive ischemia remained below 5% of the index ischemia.

Rabbits

In all studies, index ischemia duration was 30 min. In the majority of studies, the postconditioning maneuver ranged from six cycles with 10 s re-occlusion separated by 10 s reperfusion to four cycles with 30 s re-occlusion separated by 30 s reperfusion. Additive ischemia of 7% of the index ischemia was tolerated by rabbits in vivo.

Dogs, pigs, monkeys

The duration of index ischemia for successful protection to occur was between 60 and 180 min. The postconditioning maneuver ranged from six cycles with 10 s re-occlusion separated by 10 s reperfusion to eight cycles with 60 s re-occlusion separated by 60 s reperfusion. Additive ischemia remained below 5% of the index ischemia.

Humans

In patients undergoing percutaneous coronary interventions for acute myocardial infarction, the duration of index ischemia was 198–411 min. In patients undergoing cardiac surgery the duration of ischemia was the period of cardiac arrest, ranging around 60 min, and was thus very different from the duration of ischemia with myocardial infarction. In most studies in humans, the postconditioning maneuver consisted of two to three cycles with 30 s re-occlusion separated by 30 s reperfusion. Additive ischemia remained below 3% of the index ischemia.

There are only limited data in humans so far, but the available data suggest that the postconditioning phenomenon in humans is very robust and less sensitive to differences in algorithm than the animal data; of note, also co-morbidities and co-medications appear to be less relevant in humans than in animals; finally, age and gender appear not to matter in the available human studies. However, the obvious robustness of the postconditioning phenomenon still leaves it as a potential “add-on” to timely reperfusion [26].

Summary

We could not identify an “ideal” postconditioning algorithm, but identified a number of factors, i.e. the duration of index ischemia, the algorithm of the postconditioning stimulus, gender, age, and temperature, which apparently contribute to the outcome of a postconditioning maneuver in experimental animal studies.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Andreas Skyschally
    • 1
  • Patrick van Caster
    • 1
  • Efstathios K. Iliodromitis
    • 2
  • Rainer Schulz
    • 1
  • Dimitrios T. Kremastinos
    • 2
  • Gerd Heusch
    • 1
    Email author
  1. 1.Institut für PathophysiologieUniversitätsklinikum EssenEssenGermany
  2. 2.2nd University Department of Cardiology Medical School, Attikon General HospitalUniversity of AthensAthensGreece

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