3. The Preconditioning Phenomenon
The heart’s own self-preserving mechanism i.e. endogenous
protective mechanism.
Brief periods of ischemia (2-5 minutes) prior to a longer
duration of ischemia:
Reduce infarct size in most models
Reduce ventricular arrhythmias
If we can learn the mechanism of preconditioning, it may
lead to potentially important therapies.
4. Benefits of 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
Protection in Unstable angina
Protects against any activity that reproducibly cause
angina
Protecting donor organs before excision and
transport
Protecting other organs (brain, kidney) during
episodes of ischemia
7. ISCHAEMIC PRECONDITIONING
Important factors.
Duration of ischemia.
Number of cycles.
Duration of reperfusion.
Types.
Early, classic.
Late, second window of protection (Delayed).
Post Conditioning.
Remote.
8. TYPES
EARLY
Immediate
Lasts 2-3h.
LATE
12-24h.
Lasts 72h.
Dependent on:
Cardio protective
proteins.
Protects against
stunning
13. ISCHAEMIC PRECONTITIONG
C. END EFFECTORS
Protection of mitochondrial permeability
Increase in ATP stores
Local vasodilatation
Sympathetic inhibition
Inhibition of free radicals
17. DELAYED PRE-CONDITIONING
“MEDIATORS & END EFFECTORS”
Related to changes in protein activity
Heat shock proteins.
HSP – 72.
Antioxidant enzymes.
NOS (cox – 2)
Cytokine.
18. DELAYED PRE-CONDITIONING
Requires.
Myocardial protein synthesis.
Phosphorylation of transcription factors.
NOS.
SOD.
Heat shock protein.
Role of ROS.
Role of NO.
19.
20.
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. Postconditioning
Postconditioning is the phenomenon whereby
several brief coronary artery reperfusion/re-
occlusion 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
25. Vinten-Johansen J, Zhao ZQ, Zatta
AJ, Kin H, Halkos ME, Kerendi F.
Postconditioning--A new link in
nature's armor against myocardial
ischemia-reperfusion injury. Basic
Res Cardiol. 2005 Jul;100(4):295-
310.
26. Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F.
Postconditioning--A new link in nature's armor against myocardial
ischemia-reperfusion injury. Basic Res Cardiol. 2005 Jul;100(4):295-310.
27. Kloner RA, Dow J, Bhandari A. Postconditioning markedly
attenuates ventricular arrhythmias after ischemia-reperfusion. J
Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.
28. Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after
ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.
29. Ventricular Arrhythmias
with and without postconditioning
Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after
ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.
30. 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.
31. 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
33. Potential Mechanisms of Postconditioning
A. Triggers including:
1. Adenosine
2. Opioids
3. Erythropoietin
4. Endogenous nitric oxide
5. Reactive oxygen species
6. Acetylcholine
7. Tissue factors
8. Pro-inflammatory cytokines and bradykinin
9. Hydrogen sulfide
Kaur S, Singh N. Molecular aspects of ischaemic postconditioning.
Fundamental & Clinical Pharmacology 2009;23:521-536.
34. Potential Mechanisms of
Postconditioning
B. Mediators –Reperfusion injury salvage
kinase pathways including:
1. Phosphoinositide-3-kinase
2. Extra-cellular signal regulated kinase (1/2) pathways
3. Protein kinases G and C
C. End-effectors such as:
1. Mitochondrial permeability transition pore
2. Mitochondrial potassium ATP channel
35. Beneficial effects of Post conditioning : Clinical
evidence
Concordant improvements in coronary flow reserve
and ST-segment resolution during percutaneous
coronary intervention for acute myocardial
infarction: a benefit of post conditioning
36. Beneficial effects of Post conditioning : Clinical
evidence
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
37. 30 STEMI pts:
Control- Normal PPCI
IPost- 4x1 min
inflations/deflations
IPost reduced myocardial
injury by 36%.
Ischaemic Postconditioning in PPCI
Staat et al Circ 2005:112;2143.
38. 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 within 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
39. 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.
40. Remote Ischemic Preconditioning(RIPC)
or Ischemic Conditioning at a Distance
Ischemic conditioning of one vascular bed may
protect a remote vascular bed. This could occur
within the same organ or between different organs.
41. Remote Ischemic Preconditioning(RIPC) or
Ischemic Conditioning at a Distance
Regional ischemic preconditioning protects
remote virgin myocardium from subsequent
sustained coronary occlusion
Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic
'preconditioning' protects remote virgin myocardium from subsequent
sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9
Showed that “Brief episodes of ischemia in one vascular bed
protect remote, virgin myocardium from subsequent
sustained coronary artery occlusion in canine model.”
42. Remote Ischemic Preconditioning(RIPC) or
Ischemic Conditioning at a Distance
Reduction of myocardial infarct size by partial
reduction of blood supply combined with rapid
stimulation of the gastrocnemius muscle in rabbit.
Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance:
reduction of myocardial infarct size by partial reduction of blood supply
combined with rapid stimulation of the gastrocnemius muscle in the
rabbit. Circulation. 1997 Sep 2;96(5):1641-6.
Showed that remote ischemia of a skeletal muscle could
precondition the myocardium.
43. RIPC before hospital admission, as a complement to
angioplasty, and effect on myocardial salvage in
patients with AMI: 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.
44. 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.
45. Mechanism Of RIPC
Similar to delayed preconditioning
Involves translation of certain protective proteins in
response to ischemia
The mechanism of systemic spread of the protective
factors is not very well understood
But there is evidence of involvement of a humoral
factor in the systemic spread of these factors.
46.
47. RIPC in CABG surgery
Hausenloy et al Lancet 2007:370;575.
CK-MB/Trop release during
CABG surgery.
57 adult CABG patients:
RIPC- 3x5 min cuff inflation
Control- 30 min deflated cuff
RIPC reduced myocardial injury
by 43%.
Beneficial in CABG patients
receiving cardioplegia alone
(Venugopal et al Heart 2009).
Beneficial in congenital heart
disease and AAA surgery
(Cheung et al JACC 2006, Ali et al Circ 2007).
48. RIPC in elective PCI
Hoole et al Circ 2009:92;1821.
200 elective PCI
patients:
RIPC- 3x5 min cuff
inflation
Control- 30 min deflated
cuff
RIPC reduced median
trop I from 0.16 to 0.06
and increased number
of trop negative patients
from 24 to 42%.
49. -
RIPC in PPCI patients
Botker et al Lancet In Press Feb 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.
- Future studies should focus on specific
patients.
50. Rationale of Post Conditioning and RIPC
Post conditioning and RIPC mostly confer protection
against Ischemic Reperfusion Injury (IRI).
IRI has been well documented in all organ systems.
IRI has been defined as the composite of damage
accumulated during reduced perfusion and an add
on insult sustained during reperfusion
Several studies on cellular pathophysiology have
consistently shown that significant part of the
damage occurs not during the period of tissue
ischemia but during the period of reperfusion.
52. OTHER PRECONDITIONING STIMULI
(in addition to ischemia)
Oxidative (hyperoxia).
Mechanical (stretch).
Electrical (rapid pacing).
Thermal.
Chemical (hormonal).
Ionic (calcium).
Pharmacological.
53. Role Of Ischemic Pre Conditioning in Other
Organ systems
In humans, apart from the heart, the phenomenon of
IPC has been demonstrated in brain, skeletal muscle,
liver, kidney and spinal cord.
54. Ischemic Preconditiong of Brain
One of the many postulated neuroprotective agents
against cerebral ischemia
Early and late phase. Late phase has more robust
and long lasting neuro protective role
IPC promotes synaptic modification that may
preserve synaptic function and functional recovery
following cerebral ischemia
Found to be safe and well tolerated in critically ill
patients with SAH
Amelioration of oxidative stress might be the
mechanism
55. Role of Ischemic Preconditioning in Organ
preservation and transplantation
IPC found to provide additional protection than that
provided by hypothermia in organ preservation.
IRI sustained during Renal transplant contributes to
kidney damage and limits allograft.
REPAIR (REmote Preconditioning for Protection Against
Ischemia Reperfusion in Renal transplant) Trial
investigated whether RIPC improves kidney function and
other outcomes following living donor renal
transplantation.
Clinically meaningful improvement in kidney function
was noted
IPC has also been shown to be beneficial in lung
transplantation
56. Exercise and RIPC
Vigorous exercise has been shown to have cardio
vascular benefits similar to RIPC
The mechanisms of the beneficial effects have also
been found to be more or less similar
Cardiac rehabilitation programs are promoting
rigorous exercise in competent individuals
57. CONCLUSION
IPC harnesses a powerful innate protective mechansim.
It has shown much promise in recently published clinical
trials.
IPC beneficial in cardiac surgery, AAA surgery, elective PCI,
PPCI.
Potential benefit in cardiac arrest, cardiac transplantation,
stroke and other surgical settings.
Large adequately powered studies are required to fully
endorse the clinical use of IPC.
But its easy accessibility and lack of side effects make it a
useful option for use till other alternatives are available.
58. CONCLUSION
The perfect way to harness the protective effects of
IPC would be to develop a pharmacological agent
that can duplicate the effects of IPC and act as ‘The
Magic Bullet’ against the double onslaught of
ischemia and ischemia reperfusion injury.
