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Ischemic Conditioning
Todd Anderson
Libin Cardiovascular Institute
University of Calgary
Disclosures
• Department of Cardiac Sciences and Libin
Cardiovascular Institute – U of Calgary
• Grant support by Alberta Innovates
– Merck, Amgen, Abbott
Ischemic Conditioning
• Ischemia-reperfusion injury
• Ischemic conditioning
• Endothelial function
• PCI
• CABG
• Myocardial infarction
• Others
• Remote ischemic conditioning
Ischemic Conditioning
• Ischemia-reperfusion injury
– Kloner JCI 1974:54:1496 – No reflow in dogs
– Reimer et al. Circulation 1977; 56:786 – wavefront of ischemic death
– Braunwald and Kloner. JCI 1985;76:1713 – double edged sword and
concept of stunned myocardium Circulation 1982
• Ischemic conditioning
– Murry et al. Circulation 1986; 74:1174 – IPC
– Series of 3-4 cycles of reperfusion and occlusion (minimum of 30 s in
duration)
– Longer cycles have been used for remote conditioning
Ischemia-reperfusion injury
Mozaffari et al. Am J CV Disease 2013;3:180
Endothelial
Dysfunction
No reflow
Myocardial
stunning
Ischemic Conditioning
Mozaffari et al. Am J CV Disease 2013;3:180
Ischemic Conditioning
Vinten-Johansen JAP 2007;103:1441
Significant parallelism
between pre and post-
conditioning
End effector is closing
of the mitochondrial
permeability transfer
pore
Ischemic Conditioning
Murry et al. Circ 1986;74:1124
Canine studies
with either 40
minutes or 3
hours of
ischemia
4x5min cycles
prior
Ischemic Conditioning
Hausenloy Nature Reviews Cardiology 2011;8:619
Ischemic Conditioning
Kharbanda Circ 2001; 103:1624
BASELINE
(3.65 mm) REACTIVE HYPEREMIA
(4.08 mm)
Flow-Mediated Vasodilation
FMD = 10.5 %
Ischemic Conditioning
Kharbanda Circ 2001; 103:1624
Attenuation of NO dependent increases in
FBF post IR injury with activation of
neutrophils as well
Attenuation of FMD with pre-conditioning
attenuating this abnormality
Remote Ischemic Conditioning
Kharbanda Circ 2002; 106:2881
20 minutes of ischemia with
and without 3 cycles of 5
minutes of IPC on the
contra-lateral arm
Ischemic Conditioning in PCI
Crisp et al. Circ 2009;188:820
242 elective PCI
patients
Normal TnI pre
Remote IPC with 3 5
min cycles upper arm
Primary EP was TnI
at 24 h as was lower in
IPC group (p=0.04)
Remote Ischemic Conditioning in PCI
Yetgin Circ J 2012;76:2392
Meta-analysis
4 PCI (2 STEMI)
13 CABG
Remote IPC
Biomarkers EP
Ischemic Post-Conditioning in STEMI
Frohlich EHJ 2013;34:1714
No reflow, microvascular dysfunction and hemorrhage,
stunning, arrhythmias
Ischemic Post-Conditioning
Staat et al. Circ 2005;112:2143
30 patients with
primary PCI
Randomized to 4
cycles of 1 min
inflation/deflation
prior to PCI
AUC CK rise post MI
Ischemic Conditioning in STEMI
Schevchuck Circ CV Interventions 2013, 6:484
Ischemic Conditioning in STEMI
Schevchuck Circ CV Interventions 2013, 6:484
Biomarker
reduction
Ischemic Conditioning in STEMI
Schevchuck Circ CV Interventions 2013, 6:484
Infarct size by CMR
Ischemic Conditioning in STEMI – time effect?
Schevchuck Circ CV Interventions 2013, 6:484
Ischemic Post-Conditioning
Dwyer et al. J Interventional Cardiol; 2013;26:482.
102 patients with
primary PCI
Randomized to 4
cycles of 1 min
inflation/deflation
prior to PCI
CMR EP of Area at
Risk
No change in EF or
microvascular
obstruction
Remote Ischemic Conditioning in STEMI
• 1st STEMI n=242 pts , Upper limb RIPC
• 4 x 5 min cycles
• Primary – LV function by echo and perfusion
• Overall no change in EF but there was improvement in large MI
Munk et al. Circ CV Imaging 2010;3:656
Remote Ischemic Conditioning in STEMI
• Anterior STEMI
• Lower limb RIPC
• 3 x 5 min cycles
• 100 pts
• Primary – CK-MB
• Secondary – CMR no
difference in infarct
size at 3-5 days or 4
months
Crimi et al. JACC CV Inter 2013; 6:1055
P=0.043
Ischemic Conditioning and renal function
• 225 pts with NSTEMI
and PCI
• 3 cycles of coronary
IPC
• AKI endpoint
• Baseline creat 88 µM
• Trend for decrease in
30 day outcomes as
well
• Previous trial by Er
Circ 2012
Defteros JACC 2013;61:1949
Ischemic Conditioning
• Other possible indications
• Blood pressure reduction
• Exercise capacity improvement
• Neurosurgery
• Bowel surgery
Ischemic Conditioning - Summary
• Attractive, safe and inexpensive approach with rich
basic science rationale
• Significant heterogeneity in the result so far for
IPC in PCI, CABG and STEMI
• Similar ambiguity exists for remote IPC
• Several large randomized trials are underway
• Large definitive trial needed with clinical end-
points to determine utility of the approach