update on remote ischemic conditioning: basic and translational perspectives update on remote...

Update on Remote Ischemic Conditioning:

Basic and Translational Perspectives

Update on Remote Ischemic Conditioning:

Basic and Translational Perspectives

Karin Przyklenk PhD

Director, Cardiovascular Research InstituteProfessor, Departments of Physiology & Emergency Medicine

Wayne State University School of MedicineDetroit MI

ICT Webinar: 3rd November, 2015

Disclosure: Scientific Advisor for LifeCuff, Inc.

preconditioning

postconditioning

remote conditioning

initiate the up-regulation of endogenous protective mechanisms that render the heart resistant to ischemia-reperfusion injury; reduce infarct size

Control ‘Conditioned’

Ischemic ‘Conditioning’Ischemic ‘Conditioning’

classic cardioprotective paradigms: ischemic preconditioning, postconditioning

• protective stimuli (brief antecedent ischemia; stuttered reflow) applied to the heart

Control

Postconditioning

Preconditioning sustained ischemia

sustained ischemia

infarct size

sustained ischemia


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)

Remotepreconditioning

sustained ischemia

remote infarct size


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



characterize(physiology)

understand(mechanisms)

apply

Why is this important?

unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size

postconditioning, remote conditioning: poised for clinical translation . . .



however, results of Phase II trials have been mixed

• i.e., remote conditioning: outcomes have ranged from positive to neutral to deleterious

Ovize, Thibault & Przyklenk, Circulation Research 2013;113:439-50.



however:

• results of Phase II trials have been mixed

• remote conditioning: outcomes have ranged from positive to neutral to deleterious

• recent meta-analyses: outcomes have been mixed

• results of recent Phase III trials have been negative

• remote conditioning: ERICCA, RIPHeart




however:

• recent Phase III trials have been negative

ERICCA Trial: Hausenloy DJ et al. N Engl J Med 2015;373:1408-17.


however: progress toward clinical translation ‘somewhere between frustrating and disappointing’ (Shevchuck & Laskey, Circulation Cardiovasc Interv 2013;6:484-492)

. . . possibly a consequenceof gaps in our understanding of the

characteristics and mechanismsof RIC


CharacteristicsCharacteristics

site of remote ischemia?

number and duration of remote ischemic episodes?

timing of stimulus relative to onset of sustained ischemia?

threshold required to evoke myocardial protection?

‘dose response’ and possibility of ‘hyperconditioning’? (Whittaker & Przyklenk, Dose Response 2014;12:650-63)


sustained ischemia

remote infarct size

CharacteristicsCharacteristics

“As for every drug and therapy, the principle of Paracelsus, dosis sola venenum facit (the dose alone makes the poison), applies to remote ischemic preconditioning. Unfortunately, we do not know the right dose of ischemia to deliver.”

Zaugg & Lucchinetti, N Engl J Med 2015;373;1470-72.


sustained ischemia

remote infarct size

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, STAT)

mitochondria(mPTP)

MechanismsMechanisms

For remote conditioning:

signaling


trigger

effector

CARDIOPROTECTION

COMMUNICATION

For pre-, postconditioning:

signaling


trigger

effector

CARDIOPROTECTION

CommunicationCommunication

signaling


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 2015 . . .

Pickard et al., Basic Res Cardiol 2015; 110:453.

Communication: neuronal and/or

humoral


Communication: neuronalCommunication: neuronal

activation of sensory neurons stimulation of afferent pathways CNS

transported to heart via activation of efferent neuronal pathways

activation of sensory neurons stimulation of afferent pathways CNS

transported to heart via activation of efferent neuronal pathways


Communication: humoralCommunication: humoral

as-yet unidentified ‘circulating protective factor’

multiple candidates . . .

as-yet unidentified ‘circulating protective factor’

multiple candidates . . .

Candidates include:

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

targeted hypotheses: SDF (stromal cell derived factor)1-α/ CXCR4; one or more miRNAs; exosomes• Davidson et al, Basic Res Cardiol 2013;108:377

• Duan et al, Cardiology 2012;122:36-43

• Slagsvold et al, Circ Res 2014;114:851-9

• Li et al, Basic Res Cardiol 2014;109:423

• Giricz et al, JMCC 2014;68:75-8



• isolated buffer-perfused rat hearts

• exosomes detected in effluent from preconditioned hearts

• transfer of effluent from preconditioned hearts to naïve acceptors: cardioprotective

• depletion of exosomes: loss of ‘transferred’ protection

Giricz et al, JMCC 2014;68:75-8.

CommunicationCommunication

signaling


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 2015 . . .

observations, associations

no integrated, unifying hypothesis

in all likelihood: model-dependent

SignalingSignaling

signaling


trigger

effector

CARDIOPROTECTION

COMMUNICATION

role of STAT5

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.

SignalingSignaling

With propofol anesthesia:

•RIPC failed to attenuate cTnI release

•no evidence of STAT5 phosphorylation

Kottenberg et al et al, J Thorac Cardiovasc Surg 2014;147:376-82.

SignalingSignaling

With propofol anesthesia:

•RIPC failed to attenuate cTnI release

•no evidence of STAT5 phosphorylation

Propofol anesthesia was used in >90% of patients in ERICCA, 100% of patients in RIPHeart

Kottenberg et al et al, J Thorac Cardiovasc Surg 2014;147:376-82.

characterize(physiology)

understand(mechanisms)

apply


From frustration and disappointment . . .

. . . to successful translation

Collaborators

Peter Whittaker, PhD

Michelle Maynard

Eric W. Dickson, MD

Chad E. Darling, MD

Craig Smith, MD

Dale Greiner, PhD

Peter Whittaker, PhD

Michelle Maynard

Eric W. Dickson, MD

Chad E. Darling, MD

Craig Smith, MD

Dale Greiner, PhD

Thomas Sanderson, PhD

Rita Kumar, PhD

Yi Dong, MBBS PhD

Christian Reynolds, PhD

Joe Wider

Andrew Kulek

Vishnu Undyala, MS

Thomas Sanderson, PhD

Rita Kumar, PhD

Yi Dong, MBBS PhD

Christian Reynolds, PhD

Joe Wider

Andrew Kulek

Vishnu Undyala, MS

update on remote ischemic conditioning: basic and translational perspectives update on remote...

Documents

signature of ripc

remote conditioning

ripc vs controlsheusch

infarct sizehowever

disappointing shevchuck

clinical translation

circulation cardiovasc

opiodsby hplc