Cardioprotection : Ischemic pre and post Conditioning

1. CARDIOPROTECTION
Dr Joura Vishal

2. Introduction
Coronary heart disease
• Leading cause of death worldwide
• 3.8 million men / 3.4 million women die of this disease /yr
Modalities of treatment Include
• Fibrinolysis
• PCI / CABG
• Medical treatment viz Antiplatelets ,ACEi /ARB etc.
• 90% of the patients experience fall in ejection fraction
post operatively

3. Introduction
Cardio protection : broad term that refers to all strategies
aimed at attenuation of injurious results of myocardial
ischemia and reperfusion
Injury consists of
• Arrhythmias : reversible / irreversible
• Impairment of cardiac contractile function / coronary blood
flow : reversible / irreversible
• Myocardial infarction – irreversible

4. Infarct size
Established with TTC assay :
Gold standard in experimental settings
Triphenylterazolium ( TPH ) Triphenyl fomazan (TPF)
Succinate
Dehydrog
enase

5. Determinants of Infarct size
 Area of myocardial ischemia :
the size of perfusion territory of the
coronary artery distal to the site of occlusion
 Duration of ischemia to which area at risk
 Amount of residual blood flow to the area at risk i.e the
collateral blood supply
Systemic hemodynamics notably the heart rate : minor
determinant

6. Reperfusion and reperfusion injury
Reduction in infarct size first reported by John Ross Jr and
his collaborates in 1972 by reperfusion
Reperfusion Injury :
First postulated in 1960 by Jennings et al as
• Cell swelling
• Contraction of myofibrils
• Disruption of sarcolemma
• Appearance of intramitochondrial calcium phosphate
particles

7. Reperfusion injury
Induced by
 Excess formation rOS
 Intracellular calcium overload
 Mitochondrial dysfunction
 Activation of intracellular proteolysis
 Uncoordinated excess activity

8. Clinical consequences of R.Injury
 Myocardial stunning
 No Reflow phenomenon
 Reperfusion arrhythmias
 Lethal reperfusion injury

9. Reperfusion injury
Myocardial stunning
• Best established manifestation
• Mechanical dysfunction that persists after reperfusion
despite absence of irreversible damage and despite
restoration of the normal or near normal coronary flow
• Lasts for several days to weeks

10. Reperfusion Injury
No reflow
 Inability to reperfuse a previously ischemic region
 Manifestation of severe micro vascular dysfunction
 Results from marked endothelial dysfunction resulting in
• vasoconstriction
• Platelet and PMN activation
• Free radical production

11. Reperfusion Injury
Reperfusion Arrythmias
• VPC
• Susutained or non sustained VT
• AIVR
• Atrial fibrillation
• Ventricular fibrillation
AIVR may be a manifestaion of early reperfusion or
continuing arterial patency

12. Reperfusion Injury
Lethal reperfusion injury
A form of myocardial death and necrosis with reperfusion of
severely injured myocardium
Contraction band necrosis : a severe disruptive necrosis
due to calcium reentry

13. Gentle reperfusion by slow restoration of coronary blood
flow or perfusion pressure in the first 20-30 min of
reperfusion after myocardial ischemia reduces infarct size
Heusch G J Am Coll Cardiol 2004

14. Types of Conditioning
 Ischemic preconditioning
 Ischemic postconditioning
 Remote ischemic preconditioning

15. Ischemic preconditioning
The heart’s own self-preserving mechanism
Cardioprotection by brief episode of ischemia and
reperfusion
Most consistent and the magnitude of protection is great
Reduce infarct size in most models
 Reduce ventricular arrhythmias
Discovered as a case of serendipity

17. Murry CE, et al. Circulation 1986

18. Time frames of ischemic preconditioning
Early or the “classical pre-conditioning” :Involves
• activation of existing signaling molecules
• wanes 1-2 hours after the ischemic insult
Late : the “second window” of protection (SWOP)related to
• Expression of signalling molecules
• Changes in gene expression
• Increased synthesis of cardioprotective stress proteins.
• begins 12-24 hours later and lasts for up to 72 hours
• More sustained but less powerful protection from infarction

20. A third window of protection observed 6hrs after coronary
microembolistaion
Skyschalluy A et al Circ Res 2007
Tolerance to pre-conditioning may occur where prolonged
hours of ischaemia can result in a loss of preconditioning
effect.
IPC can also be induced by other forms of stress like
• Hypoxia, stretch, heat shock and a1 receptor stimulation
Time frames of ischemic preconditioning

21. Clinical Evidence For Preconditioning
• Less chest pain, ST-segment elevation, lactate production with
subsequent compared to first angioplasty balloon inflation
• Reduction in infarct size, mortality and CHF in patients with
history of angina before acute MI
• Acute tolerance to angina (warm up phenomenon)
• Studies performed on human cardiac tissue:
• ATP levels during CABG
• In vitro studies on isolated human muscle
• In vitro studies on human myocytes

22. History of Any Angina - TIMI 4
No Angina Angina
TotalCKunits
0
100
120
140
160
Kloner, et al.
154
119
Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S,
Gibson M, Poole WK, Cannon CP, McCabe C, Braunwald E, for the TIMI 4
Investigators. Previous angina alters in-hospital outcome in TIMI 4. A clinical
correlate to preconditioning? Circulation 1995; 91:37-45.

23. History of Any Angina - TIMI 4
(%)
0
2
4
6
8
10
12
14
No Angina
Angina
8%
3%
7%
1%
12%
4%p = 0.03
p = 0.006
p = 0.004
In-Hospital
Death
Severe CHF/
Shock
Death
Severe CHF
Shock
Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S,
Gibson M, Poole WK, Cannon CP, McCabe C, Braunwald E, for the TIMI 4
Investigators. Previous angina alters in-hospital outcome in TIMI 4. A clinical
correlate to preconditioning? Circulation 1995; 91:37-45.

24. Conditioning protocol

25. Signal transduction in Cardioprotection
Three hierarchical levels
• Triggers
• Intracellular mediator cascade
• Effectors
Triggers : molecules released from various cell types
during ischemia and act on sarcolemmal membrane
receptors
This initiates an Intracellular cascade mostly protein
kinases that ultimately act on effectors – subcellular
elements viz mitochondria / cytoskeleton that stabilise the
jeopardized cardiomyocyte and prevent its death.

28. Signal transduction in Cardioprotection
Three parallel signaling pathways
• G protein coupled / natriuretic peptide receptors : centred on
Nitric oxide , NO synthase , cGMP, protein kinase G
• Reperfusion injury salvege kinase pathway : g protein coupled
/ growth factor receptors
• Survival activating factor enhancement pathway : TNF alpha /
JAK –STAT pathway

29. Limitations of ischemic preconditioning
NO reliable way to predict Myocardial infarction hence No
way to induce IPC or apply a stimulus
Aortic cross clamping / coronary artery cross clamping are
• Invasive
• Risk of coronary microembolization
• Risk of inducing infarction
• Risk of aortic embolization

30. Postconditioning
Postconditioning is the phenomenon whereby
several brief coronary artery
reperfusion/reocclusion cycles at the end of a
long coronary artery occlusion (stuttering
reperfusion) reduces infarct size
Zhao, Z-Q et al. Am J Physiol 2003;285:1574
Yang, X-M et al. JACC 2004;44:1103

31. Mechanism of postconditioning

32. Postconditioning
Primary PCI for STEMI
Repeat 30-60 sec balloon inflation at low pressure results
in:
• Greater attenuation of ST-segment elevation
• Improved distal coronary artery flow
• A significant reduction of 36% in infarct size
• 7% improvement in EF at one year

33. Post conditioning

34. Conditioning protocol

35. Results

36. Results

37. Results

38. Results

39. End points of post conditioning
 Decreased Infarct size
 Decreased tissue edema
 Decreased PMN accumulation
 Improved endothelial function
 Decreased endothelial response to Ach
 Decreased free radical production

40. Ischemic post conditioning
Vinten Johansen et al 2003

44. Remote ischemic preconditioning
Both IPC and post conditioning involve manipulation of the
culprit coronary artery : a risk of acute myocardial infarction

49. Experimental protocol
Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy
E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart.
Circulation. 2005 Oct 4;112(14):2143-8.

50. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy
E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart.
Circulation. 2005 Oct 4;112(14):2143-8.
Serum CK release over the first 72 hours of reperfusion

51. Copyright ©2005 American Heart Association
Blush grade and ST-segment shift during reperfusion
Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF,
Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the
human heart. Circulation. 2005 Oct 4;112(14):2143-8.

52. Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after
ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.

53. Concordant improvements in coronary flow reserve and ST-segment
resolution during percutaneous coronary intervention for acute
myocardial infarction:
a benefit of postconditioning
• 24 patients with evolving anterior STEMI were randomized to
ischemic postconditioning or usual care during PCI
• Postconditioned pts had a greater and more rapid resolution of ST
segment elevation (70% vs. 48%, p = 0.0002) by the end of the
procedure
• Postconditioned pts had greater hyperemic coronary vasodilator
reserve (2.2 vs. 1.5, p< 0.001)
• Peak serum creatine kinase was lower in postconditioned pts (1,524
vs. 1,862 IU/L in controls, p = 0.03)
• Conclusion: Postconditioning performed during PCI for STEMI
improved ST-segment resolution and coronary flow reserve,
measures of microcirculatory function, as well as reducing tissue
necrosis.
Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-
segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of
postconditioning. Catheter Cardiovasc Interv. 2008 Aug 1;72(2):212-20

54. Remote ischaemic conditioning before hospital admission, as a
complement to angioplasty, and effect on myocardial salvage in
patients with acute myocardial infarction: a randomised trial
• 333 patients with first AMI randomized to primary PCI with or
without remote conditioning (4 cycles of 5-minute brachial artery
cuff inflation & 5 minutes deflation)
• Median salvage index by myocardial perfusion imaging 0.75 in
remote conditioning group versus 0.55 in control group, p = 0.03
• Conclusion: Remote ischemic conditioning before hospital
admission increases myocardial salvage and is safe.
Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen
NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L,
Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning
before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in
patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727.

55. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen
NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L,
Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning
before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in
patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727.

56. RIPerC in PPCI patients
Botker et al Lancet 2010
• 246 STEMI patients
randomised in ambulance
to RIPC 4x5 min cuff on
arm or control.
- Myocardial salvage index improved at 30 days (0.56 to 0.76).
- Reduced myocardial infarct size at 30 days (SPECT P=0.05)
- No effect on Troponin-T, TIMI flow, LVEF, MACE at 30 days.
- All coronary territories, TIMI 2-3 flow and collaterals included.
-LAD infarcts greater reduction in infarct size.

57. Pharmacological strategies of
Myocardial salvage
 Inotropic stimulation of the reperfused stunned heart
 Antioxidants : major antioxidant being Glutathione
peroxidase and not superoxide dismutase
Vitamin E is required in prolonged and verly high oral
dosage to achieve therpeutic salvage concentration
 Sodium hydrogen antiport inhibition :
Cariporide a Na H exchange inhibitor at 120 mg dose for 6 -8
days periopertively reduced the rate of death and MI
undergoing CABG
GUARDIAN trial J Cardiac Surg 2003

58. Pharmacological strategies of
Myocardial salvage
Simulating endogenous cardioprotectants
• Adenosine via opening of mitochondrial K ATP channels
through interaction with A1 and A3 receptors
• Nitric oxide may serve to diminish reperfusion injury
through improved endothelial function , decreased platelet
and neutrophil activation , augmenting coronary flow
Vinten Johansen J Ann Thorac Surg 1999

59. Therapeutic applications of
preconditioning
Diabetes mellitus and preconditioning
• IPC is mediated at least in part by activation of the
KATP channel and this channel may be altered in the
diabetic heart;
• Certain oral hypoglycemic drugs (such as glibenclamide)
prevent IPC by blocking the KATP channel and has been
associated with an increase in early mortality in diabetics
following primary PCI for AMI

60. Therapeutic applications of
preconditioning
Role of nitroglycerin.
Four-hour infusion of nitroglycerin 24 to 48
hours before exercise stress testing with stable angina
showed an increase in workload during the test and
significant improvements in the (ECG) manifestations of
ischemia.

61. Pharmacological strategies of
Myocardial salvage
• Therapeutic hypothermia
• Magnesium therapy
• Pharmacological treatment of no reflow
1. Calcium antagonist : verapamil / diltiazem
reverse condition in 67% of cases
given as intracoronary infusion
2. Nicorandil given as intracoronary 2mg iv bolus
3. Sodium nitroprusside
4. GpIIb/IIIa inhibitors

62. Endovascular cooling
Endovascular coils and external cooling blankets are
used to bring the core temperature of a patient down to 33
degrees during PCI for acute myocardial infarction showed
reduction in infarct size in the subgroup of patients with an
anterior MI.

63. Nicorandil for NO reflow

73. End points of cardioprotection
Periprocedural myocardial injury during PCI / CABG as
estimated by trop I / Lv systolic dysfunction affect long term
survival
Estimation of infarct size by
• Thallium scan
• SPECT
• MRI

74. CONCLUSIONS
Ischemic Conditioning
• Reducing myocardial infarct size
• Reducing cardiac damage during PCI
• Protecting the myocardium during CABG and other
procedures requiring cardiopulmonary bypass
• Protecting the vasculature during vascular surgery
procedures

75. Ischemic Postconditioning in Surgery
Luo et al J Thorac Cardiovasc Surg 2007:133;1373.
• 24 children TOF surgery:
Control- Normal surgery
IPost- 2x30 sec aortic re-
clamping.
• Reduced trop-I by 50% and
CK-MB by 34%.
• Invasive treatment protocol.
• Other studies reporting
benefit in adult valve surgery.

76. 1. Improved myocardial perfusion and ST resolution 1,2
2. Reduced myocardial infarct size:
40% less CK-MB, 47% less trop I 4.
31% to 23% at 1 week (SPECT) 3.
20% to 12% at 6 mths (SPECT) 4.
63% to 51% (IS/AAR) at 3 months (N=86) 5.
3. Preserved LV ejection function by 7% (echo) at 1 year 4.
1. Staat et al Circ 2005
2. Ma et al J Interven Cardiol 2006
3. Yang et al J Interven Cardiol 2007
4. Thibault et al Circ 2008
5. Lonborg et al Circ Card Int 2010
Ischaemic Postconditioning in PPCI