Ischemic Conditioning and

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• Ischemic Conditioning and
• Endothelial Function
• Todd Anderson
• Libin Cardiovascular Institute
• University of Calgary

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Disclosures

• Department of Cardiac Sciences and Libin
  Cardiovascular Institute U of Calgary
• Grant support by Alberta Innovates
• Merck, Amgen, Abbott

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Flow-Mediated Vasodilation
FMD 10.5
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Microvasculature
Philpott et al. ATVB 2007272065
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Flow-Mediated Vasodilation- Velocity
Baseline Doppler (VTI19.1cm)
Hyperemic Doppler (VTI60.5 cm)
Co variance 17
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Shear stress, hyperemic velocity and Risk Factors
Unadjusted (univariate) Coefficient p value Adjusted Coefficient
Age -1.633 lt0.001 -1.004
Systolic BP -0.894 lt0.001 -0.489
Fasting Glucose -10.774 lt0.001 -3.889
LDL -8.211 lt0.001 -6.201
HDL 21.187 lt0.001 13.667
Current Smoking -2.869 0.514 ----
CRP -1.712 lt0.001 -0.915
BMI -3.898 lt0.001 -1.930
FATE n1477 , Overall R2 for hyperemic velocity
0.171
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Coronary Intervention and Endothelial Function
FMD is NO-dependent
8 subjects A-mode Echo and RH
Joannides et al. Circ 95911314
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Coronary Blood Flow - Metabolic Vasodilation
Resistance Vessels - Adenosine

• Adenosine probably plays a role at low perfusion
  pressures alone and in combination with K ATP
  channels blockade
• Ischemia may shift control to small resistance
  vessels which are metabolically controlled
  (adenosine)
• May act through A receptors, inhibit NE release
  or via K ATP channels blockade
• Important in debt repayment in reactive hyperemia

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Endothelial Function and Hypercholesterolemia
Dietary Correction in previously cholesterol-fed
rabbits normalizes superoxide radicals and
improves endothelium-dependent dilation.
Ohara Y et al. Circulation 199592898-903.
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Endthelial Function and Risk Factors
Brachial FMD
Celermajer et al. Lancet 923401111
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Ischemic Conditioning

• Ischemia-reperfusion injury
• Kloner JCI 1974541496 No reflow in dogs
• Reimer et al. Circulation 1977 56786
  wavefront of ischemic death
• Braunwald and Kloner. JCI 1985761713 double
  edged sword and concept of stunned myocardium
  Circulation 1982
• Ischemic conditioning
• Murry et al. Circulation 1986 741174 IPC

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Ischemic Conditioning
Significant parallelism between pre and
post-conditioning
Vinten-Johansen JAP 20071031441
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Ischemic Conditioning and Endothelial Function

• Ischemia-reperfusion injury causes injury and
  acute conduit and NO dependent micro-vessel
  endothelial dysfunction
• Pre and post-conditioning with IPC bouts of
  transient ischemia attenuate this abnormality
• Pharmacological conditioning prevents IR
  endothelial dysfunction acutely but less reliably
  chronically
• IPC improves LV function during acute myocardial
  infarction in some but not all studies
• Remote IPC also results in variable outcomes
• IPC may also have favorable effects on other
  outcomes including blood pressure

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Ischemic Conditioning
Kharbanda Circ 2001 1031624
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Ischemic Conditioning
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
Kharbanda Circ 2001 1031624
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Remote Ischemic Conditioning
20 minutes of ischemia with and without 3 cycles
of 5 minutes of IPC on the contra-lateral arm
Kharbanda Circ 2002 1062881
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Remote Ischemic Post-Conditioning
19 healthy subjects RIPC and RPostC 20 minutes of
ischemia With and without glibenclamide to assess
K ATP channels Both prevented the ? FMD with IR
(PostC in leg but not arm) and this was blocked
by glibenclamide
Loukogeorgakis et al. Circulation 20071161386
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Ischemia-Reperfusion Injury
45 normal subjects with 15 minutes of
ischemia Attenuation of FMD but no change in
hyperemic stimulus or PAT-index IR doesnt
impair microvascular function
Alhejily et al. Microcirculation 2013
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Pharmacologic Conditioning - Statins
Liuni et al. Clin Hemorheol 201045161
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Ischemic Conditioning
30 healthy subjects IR alone vs 1 day IPC vs 7 d
IPC protocol 3 cycles of 5 min of ischemia and
reperfusion Celecoxib did not change
results. Both 1 and 7 days of IPC attenuated IR
decrease in FMD
Luca et al. JAHA 20132(1)
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Ischemic Conditioning
30 healthy subjects IR alone vs 1 day IPC vs 7 d
IPC protocol 3 cycles of 5 min of ischemia and
reperfusion Celecoxib did not change
results. Both 1 and 7 days of IPC attenuated IR
decrease in FMD
Luca et al. JAHA 20132(1)
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Ischemic Post-Conditioning
30 patients with primary PCI Randomized to 4
cycles of 1 min inflation/deflation prior to
PCI AUC CK rise post MI
Staat et al. Circ 20051122143
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Ischemic Post-Conditioning
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
Dwyer et al. J Interventional Cardiol
201326482.
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Ischemic Conditioning
Hausenloy Nature Reviews Cardiology 20118619
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Ischemic Conditioning and Endothelial Function

• Effect of acute or repeated episodes of IPC in
  patients with endothelial dysfunction is unknown
• Acute and 7 days of IPC can ameliorate the
  IR-induced decreases in FMD with no effect on
  measures of microvascular response (hyperemic
  velocity or PAT)
• Pre-conditioning may be more effective than
  post-conditioning in the forearm acute
  endothelial dysfunction model (and studies are
  mixed with AMI)
• Further studies are needed to assess the effects
  of longer term IPC on endothelial function and
  cardiovascular pathophysiology