remote ischemic conditioning: an update on mechanisms remote ischemic conditioning: an update on...
TRANSCRIPT
Remote Ischemic Conditioning:An Update on Mechanisms
Remote Ischemic Conditioning:An Update on Mechanisms
Karin Przyklenk PhD
Director, Cardiovascular Research InstituteProfessor, Departments of Physiology & Emergency Medicine
Wayne State University School of MedicineDetroit MI
ICT Focus Group Meeting: 17th November, 2013
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)
Myocardial ‘Conditioning’Myocardial ‘Conditioning’
coronary occlusion reperfusion
remoteischemia
Przyklenk et al, Circulation 1993;87:893-99.
Remote Ischemic Conditioning: First EvidenceRemote Ischemic Conditioning: First Evidence
Infarct Size(% of Risk Region)
Control Cx PC0
5
10
15
20
25
p<0.05
1 h LAD Occl4.5 h
Reflow
Control
Cx Occl
1 h LAD Occl4.5 h Reflow
Circumflex (Cx) PC
infarct size(% of risk region)
Significant reduction of infarct size with ‘intra-cardiac’ remote ischemic preconditioning
Developing the Concept . . . Developing the Concept . . .
intra-cardiac RIC
inter-organ RIC
‘Inter-organ’ RIC‘Inter-organ’ RIC
Dickson et al, Am J Physiol 1999;277:H2451-57.
40’ ischemia1 h Reflow
Donor: Control
40’ ischemia
Donor: PC
infarct size
40’ ischemia
Acceptor: Control
40’ ischemia
Acceptor: PC
Effluent
Effluent
Infarct Size(% of Risk Region)
Donor-Contro
l
Acceptor-Contro
l
Donor-PC
Acceptor-PC
0
10
20
30
40
50
** **
**p<0.01 vs Donor-Control
• model: isolated buffer-perfused rabbit
• PC stimulus: transfer of coronary effluent
• endpoint: infarct size
Kharbanda et al, Circulation 1997;106:2881-83.
• model: anesthetized pig
• PC stimulus: skeletal muscle ischemia
• endpoint: infarct size
40’ LAD Occl2 h Reflow
Control
40’ LAD Occl
Hindlimb ischemia
infarct size(% of risk region)
‘Inter-Organ’ RIC‘Inter-Organ’ RIC
intra-cardiac RIC
inter-organ RIC
Phase II clinical trials
Phase III clinical trials
Developing the Concept . . . Developing the Concept . . .
Developing the Concept . . . 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.
MechanismsMechanisms
For pre-, postconditioning:
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
adenosine; bradykinin, opioids
G-protein coupled receptors
RISK, SAFE pathways(ERK, PI3 kinase/Akt, JAK, STAT3)
mitochondria(mPTP)
MechanismsMechanisms
For pre-, postconditioning:
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
MechanismsMechanisms
For remote conditioning:
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
COMMUNICATION
For pre-, postconditioning:
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
CommunicationCommunication
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
COMMUNICATION
In 1993:
the infarct-sparing effect of remote conditioning ‘. . . may bemediated by factor(s) activated, produced, or transportedthroughout the heart during brief ischemia-reperfusion.’
In 2013 . . .
Communication: circulating humoral factorCommunication: 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
Davidson et al, Basic Res Cardiol 2013;108:377
Plasma SDF1- Concentration(pg/mL)
Control RIC0
200
400
600
800
1000
1200
p<0.01
Infarct Size(% of Risk Region)
Control
RIC
Control +
Inhibito
r
RIC + Inhibito
r0
20
40
60
**
SDF1-α/CXCR4 Signaling
• in vivo rat model
• plasma SDF1-α concentration increased following RIC
• CXCR4 inhibitor (AMD3100) attenuated the infarct-sparing effect of RIC
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
Communication: circulating humoral factorCommunication: circulating humoral factor
: neuronal pathways: 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 pathwaysCommunication: 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?
Communication: neuronal pathwaysCommunication: neuronal pathways
SummarySummary
signaling
receptor stimulation
trigger
effector
CARDIOPROTECTION
COMMUNICATION
In 1993:
the infarct-sparing effect of remote conditioning ‘. . . may bemediated by factor(s) activated, produced, or transportedthroughout the heart during brief ischemia-reperfusion.’
In 2013 . . .
observations, associations
. . . no integrated, unifying hypothesis
CollaboratorsCollaborators
Peter Whittaker, PhD
Joe Wider
Vishnu Undyala
Eric Dickson, MD
Michelle Maynard
Craig Smith, MD
Chad Darling, MD
Dale Greiner, PhD
SignalingSignaling
• 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.