Remote Ischemic Conditioning:
An Update on Mechanisms
Karin Przyklenk PhD
Director, Cardiovascular Research Institute
Professor, Departments of Physiology & Emergency Medicine
Wayne State University School of Medicine
Detroit MI
ICT Focus Group Meeting: 17th November, 2013
Myocardial ‘Conditioning’
classic cardioprotective paradigms: ischemic preconditioning,
postconditioning
• protective stimuli (brief antecedent ischemia; stuttered
reflow) applied to the heart
remote ischemic conditioning (RIC): protective stimulus applied
at a remote site
first evidence: remote preconditioning (Przyklenk et al, 1993)
remote
ischemia
coronary occlusion
reperfusion
Remote Ischemic Conditioning: First Evidence
Infarct Size
25
(% of Risk Region)
20
15
p<0.05
10
Control
5
1 h LAD Occl
4.5 h
Reflow
0
Control
Cx PC
Circumflex (Cx) PC
1 h LAD Occl
4.5 h Reflow
Cx Occl
infarct size
(% of risk region)
Significant reduction of infarct size with
‘intra-cardiac’ remote ischemic
preconditioning
Przyklenk et al, Circulation 1993;87:893-99.
Developing the Concept . . .
intra-cardiac RIC
inter-organ RIC
‘Inter-organ’ RIC
•
•
•
model: isolated bufferperfused rabbit
PC stimulus: transfer of
coronary effluent
endpoint: infarct size
50
Donor: Control
30
40’ ischemia
1 h Reflow
Effluent
Acceptor: Control
Infarct Size
(% of Risk Region)
40
20
**
10
**
40’ ischemia
0
Donor: PC
40’ ischemia
Effluent
n
Do
Acceptor: PC
ntr
o
C
or-
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pto
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c
Ac
l
tro
n
o
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PC
PC
r
r
no
pto
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Do
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Ac
40’ ischemia
infarct size
**p<0.01 vs Donor-Control
Dickson et al, Am J Physiol 1999;277:H2451-57.
‘Inter-Organ’ RIC
•
•
•
model: anesthetized pig
PC stimulus: skeletal muscle
ischemia
endpoint: infarct size
Control
40’ LAD Occl
2 h Reflow
Hindlimb ischemia
40’ LAD Occl
infarct size
(% of risk region)
Kharbanda et al, Circulation 1997;106:2881-83.
Developing the Concept . . .
intra-cardiac RIC
inter-organ RIC
Phase II clinical trials
Phase III clinical trials
Developing the Concept . . .
characterize
(physiology)
understand
(mechanisms)
apply
Why is this important?
~25 published Phase II clinical trials
cardiac surgery; elective PCI; primary PCI in patients with STEMI
stimulus: multiple (3-4) 5 min episodes of limb ischemia
primary endpoint: infarct size or its surrogate
outcomes have been mixed . . .
. . . possibly a consequence of
gaps in our understanding of
the mechanisms of RPC
Ovize, Thibault & Przyklenk, Circulation Research 2013;113:439-50.
Mechanisms
For pre-, postconditioning:
trigger
receptor stimulation
signaling
effector
CARDIOPROTECTION
adenosine; bradykinin, opioids
G-protein coupled receptors
RISK, SAFE pathways
(ERK, PI3 kinase/Akt, JAK, STAT3)
mitochondria
(mPTP)
Mechanisms
For pre-, postconditioning:
trigger
receptor stimulation
signaling
effector
CARDIOPROTECTION
Mechanisms
For pre-, postconditioning:
For remote conditioning:
trigger
trigger
receptor stimulation
COMMUNICATION
signaling
effector
CARDIOPROTECTION
receptor stimulation
signaling
effector
CARDIOPROTECTION
Communication
In 1993:
trigger
COMMUNICATION
the infarct-sparing effect of remote
conditioning ‘. . . may be
mediated by factor(s) activated,
produced, or transported
throughout the heart during brief
ischemia-reperfusion.’
receptor stimulation
In 2013 . . .
signaling
effector
CARDIOPROTECTION
Communication: circulating humoral factor
Candidates:
adenosine, bradykinin, opiods
by HPLC: ‘small (<15 kDa) hydrophobic molecule’
from proteomic screens: Apo-A1
•
Hilbert et al, PLoS 2013;8:e77211
•
Hepponstall et al, PLoS 2012;7:e48284
‘educated guesses’: SDF1-α/CXCR4; microRNAs
•
Davidson et al, Basic Res Cardiol 2013;108:377
•
Duan et al, Cardiology 2012;122:36-43
SDF1-α/CXCR4 Signaling
Plasma SDF1- Concentration
(pg/mL)
1200
p<0.01
1000
800
Infarct Size
600
(% of Risk Region)
60
400
200
40
0
Control
• in vivo rat model
• plasma SDF1-α concentration
•
**
RIC
increased following RIC
CXCR4 inhibitor (AMD3100)
attenuated the infarct-sparing
effect of RIC
Davidson et al, Basic Res Cardiol 2013;108:377
20
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RIC
Communication: circulating humoral factor
Candidates:
adenosine, bradykinin, opiods
by HPLC: ‘small (<15 kDa) hydrophobic molecule’
from proteomic screens: Apo-A1
‘educated guesses’: SDF1-α/CXCR4; microRNAs
Source:
myocytes, endothelial cells?
Transported to heart via:
blood/perfusate
exosomes, microparticles/microvesicles
: neuronal pathways
Communication:
neuronal pathways
Source:
activation of sensory neurons
stimulation of
afferent neuronal pathways
CNS
Transported to heart via:
activation of efferent neuronal pathways
‘Remote Preconditioning Reflex’
Mastitskaya et al, Cardiovasc Res 2012;95:487-94.
Gourine & Gourine, Physiology 2013: in press.
Communication: neuronal pathways
Source:
activation of sensory neurons
stimulation of
afferent neuronal pathways
CNS
Transported to heart via:
activation of efferent neuronal pathways
Model-dependent?
In some models:
integrated (neurohumoral communication)?
redundant?
Summary
In 1993:
trigger
COMMUNICATION
the infarct-sparing effect of remote
conditioning ‘. . . may be
mediated by factor(s) activated,
produced, or transported
throughout the heart during brief
ischemia-reperfusion.’
receptor stimulation
In 2013 . . .
signaling
effector
CARDIOPROTECTION
observations, associations
. . . no integrated, unifying
hypothesis
Collaborators
Peter Whittaker, PhD
Joe Wider
Vishnu Undyala
Eric Dickson, MD
Michelle Maynard
Craig Smith, MD
Chad Darling, MD
Dale Greiner, PhD
Signaling
• myocardial biopsies obtained
•
from patients during coronary
artery bypass surgery
‘unique signaling signature of
RIPC’: increased STAT5
phosphorylation in patients
that received RIPC vs
Controls
Heusch et al, Circ Res 2012;110:111-15.