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Update on Remote Ischemic Conditioning: Basic and Translational Perspectives

This webinar discusses remote ischemic conditioning, a technique that initiates the up-regulation of endogenous protective mechanisms in the heart to reduce ischemia-reperfusion injury and infarct size. It explores the development of the concept, inter-organ remote ischemic conditioning, and the current status of clinical trials. The webinar also highlights the gaps in our understanding of the characteristics and mechanisms of remote ischemic conditioning.

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Update on Remote Ischemic Conditioning: Basic and Translational Perspectives

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  1. Update on Remote Ischemic Conditioning: Basic and Translational Perspectives Karin Przyklenk PhD Director, Cardiovascular Research Institute Professor, Departments of Physiology & Emergency Medicine Wayne State University School of Medicine Detroit MI ICT Webinar: 3rd November, 2015 Disclosure: Scientific Advisor for LifeCuff, Inc.

  2. Ischemic ‘Conditioning’ • 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’

  3. Ischemic ‘Conditioning’ • classic cardioprotective paradigms: ischemic preconditioning, postconditioning • protective stimuli (brief antecedent ischemia; stuttered reflow) applied to the heart Control sustained ischemia sustained ischemia sustained ischemia Preconditioning Postconditioning infarct size

  4. Ischemic ‘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) sustained ischemia Remote preconditioning infarct size remote

  5. Circumflex (Cx) PC Cx Occl infarct size (% of risk region) Remote Ischemic Conditioning: First Evidence Control 1 h LAD Occl 1 h LAD Occl 4.5 h Reflow 4.5 h Reflow Significant reduction of infarct size with ‘intra-cardiac’ remote ischemic preconditioning Przyklenk et al, Circulation 1993;87:893-99.

  6. Developing the Concept . . . intra-cardiac RIC inter-organ RIC

  7. ‘Inter-organ’ RIC • model: isolated buffer-perfused rabbit • PC stimulus: transfer of coronary effluent • endpoint: infarct size Donor: Control Effluent Acceptor: Control Donor: PC Acceptor: PC Effluent **p<0.01 vs Donor-Control infarct size Dickson et al, Am J Physiol 1999;277:H2451-57. 40’ ischemia 40’ ischemia 40’ ischemia 40’ ischemia 1 h Reflow

  8. Hindlimb ischemia infarct size (% of risk region) ‘Inter-Organ’ RIC • model: anesthetized pig • PC stimulus: skeletal muscle ischemia • endpoint: infarct size Control 40’ LAD Occl 40’ LAD Occl 2 h Reflow Kharbanda et al, Circulation 1997;106:2881-83.

  9. Developing the Concept . . . intra-cardiac RIC inter-organ RIC Phase II clinical trials Phase III clinical trials

  10. Developing the Concept . . . characterize (physiology) understand (mechanisms) Why is this important? apply

  11. Ischemic ‘Conditioning’ • unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size • postconditioning, remote conditioning: poised for clinical translation . . .

  12. Ischemic ‘Conditioning’ • unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size • 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.

  13. Ischemic ‘Conditioning’ • unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size • 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

  14. Ischemic ‘Conditioning’ • unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size • however: • recent Phase III trials have been negative ERICCA Trial: Hausenloy DJ et al. N Engl J Med 2015;373:1408-17.

  15. Ischemic ‘Conditioning’ • unprecedented preclinical agreement: pre- post- and remote conditioning reduce infarct size • however: progress toward clinical translation ‘somewhere between frustrating and disappointing’ (Shevchuck & Laskey, Circulation Cardiovasc Interv 2013;6:484-492) . . . possibly a consequence of gaps in our understanding of the characteristics and mechanisms of RIC

  16. Characteristics sustained ischemia • 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) Remote preconditioning infarct size remote

  17. Characteristics sustained ischemia • “As for every drug and therapy, the principle of Paracelsus, dosis sola venenumfacit(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. Remote preconditioning infarct size remote

  18. Mechanisms For pre-, postconditioning: trigger adenosine; bradykinin, opioids receptor stimulation G-protein coupled receptors RISK, SAFE pathways (ERK, PI3 kinase/Akt, JAK, STAT) signaling mitochondria (mPTP) effector CARDIOPROTECTION

  19. Mechanisms For pre-, postconditioning: For remote conditioning: trigger trigger COMMUNICATION receptor stimulation receptor stimulation signaling signaling effector effector CARDIOPROTECTION CARDIOPROTECTION

  20. Communication In 1993: the infarct-sparing effect of remote conditioning ‘. . . may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia-reperfusion.’ In 2015 . . . trigger COMMUNICATION receptor stimulation signaling effector CARDIOPROTECTION

  21. Communication: neuronal and/or humoral Pickard et al., Basic Res Cardiol 2015; 110:453.

  22. Communication: neuronal • activation of sensory neurons stimulation of afferent pathways CNS • transported to heart via activation of efferent neuronal pathways Pickard et al., Basic Res Cardiol 2015; 110:453.

  23. Communication: humoral • as-yet unidentified ‘circulating protective factor’ • multiple candidates . . . Pickard et al., Basic Res Cardiol 2015; 110:453.

  24. Communication: humoral • 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

  25. Communication: humoral • 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.

  26. Communication • In 1993: • the infarct-sparing effect of remote conditioning ‘. . . may be • mediated by factor(s) activated, produced, or transported • throughout the heart during brief ischemia-reperfusion.’ • In 2015 . . . • observations, associations • no integrated, unifying hypothesis • in all likelihood: model-dependent trigger COMMUNICATION receptor stimulation signaling effector CARDIOPROTECTION

  27. Signaling trigger COMMUNICATION receptor stimulation role of STAT5 signaling effector CARDIOPROTECTION

  28. 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.

  29. Signaling • With propofol anesthesia: • RIPC failed to attenuate cTnI release • no evidence of STAT5 phosphorylation Kottenberg et al et al, J ThoracCardiovascSurg2014;147:376-82.

  30. Signaling • 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 ThoracCardiovascSurg2014;147:376-82.

  31. Ischemic ‘Conditioning’ From frustration and disappointment . . . characterize (physiology) understand (mechanisms) apply . . . to successful translation

  32. Collaborators • 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

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