remote ischemic conditioning: an update on mechanisms remote ischemic conditioning: an update on...

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.