Basic Mechanisms of Remote Ischemic Conditioning

Transcription

1 Basic Mechanisms of Remote Ischemic Conditioning Rajesh K Kharbanda Oxford, GB ESC From Bench to Practice: Bridging the gap Mechanisms and Clinical use of Ischaemic Conditioning

2 Disclosure Shareholder in CellAegis, a company developing IP directed towards automated preconditioning devices

3 What is remote conditioning? Initiating remote conditioning triggers Mediators of remote conditioning neuro-humoral Effectors of remote conditioning in target organ Why is it important to study mechanism?

4 What is ischemic conditioning? Brief ischemia induces protection (eg heart,brain) Ischemia Reperfusion Tissue death Ischemia Reperfusion Less Tissue death Local ischemic preconditioning

5 What is remote ischemic conditioning? Brief ischemia of an organ (eg limb) induces systemic protection (eg heart,brain) Ischemia Reperfusion Tissue death Ischemia Reperfusion Less Tissue death Remote ischemic Pre-conditioning Remote ischemic Per-conditioning Remote ischemic Post-conditioning

6 Inducing remote ischemic conditioning Cx preconditioning protects against LAD ischemia Przyklenk K et al. Circulation 1993;87:893-9 Can limb ischemia protect against human and porcine IR injury? Kharbanda R et al. Circulation 2002;106:2881-3

7 Trigger mediator - effector

8 Circulating factor(s) in remote conditioning Bioassay

9 Humoral mechanisms in ripc A. Rabbit and human ripc blood B. Fractionation of blood: Plasma/dialysate/C18 C. In vivo and Langendorff assay D. Isolated cells Opioid pathways Shimizu et al, Clinical Science, 2009; 117,

10 Humoral pathways, MAPKs, and PKC Plasma and dialysate of plasma transferred protection Protection of isolated cardiomyocytes inhibited by naloxone In vivo ripc upregulated MAPKs p42/p44 and induced PKC translocation

11 Triggers of circulating factor(s) in ripc FNS rabbits releases circulating cardioprotective humoral factor Sensory fibres can be activated by Capsaicin through TRVP-1 receptor Capsaicin also releases circulating cardioprotective humoral factor Redington K et al. Basic Res Cardiol 2012;107:241

12 Diabetic neuropathy inhibits release of humoral factor Diabetic neuropathy inhibits release of circulating cardioprotective humoral factor The factor released by patients with diabetes is biologically active Jensen R et al. Basic Res Cardiol 2012;107:285

13 Neural pathways in Pre-, Per- and Post-conditioning Capsaicin does not itself induce per- or post-conditioning Vagotomy abolished riprec protection but not per or post-conditioning Bassaly M et al. Exp Physiol 2012;107:241

14 Adenosine triggers of circulating factor release in animal and human ripc Steensrud et al. Am J Physiol 2010; 299: H1598 Arterial (but not intravenous) adenosine releases a circulating cardioprotective factor In humans arterial adenosine releases a circulating cardioprotective factor Contractor H, unpublished data

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16 What is/are the circulating factor(s) in ripc? Nature of the circulating factor(s) is not yet known not adenosine, CGRP Factor(s) are in plasma and in dialysate <14kDa Cross-species protection Is the circulating factor necessary to deliver ripc protection? What dose of circulating factor is effective? Does the factor work in the same way in different organs? How does the factor induce cardioprotection?

17 Non-humoral mediators of ripc Change of gene expression in distant tissue after ripc Konstantinov JTCVS 2005 Reduction of systemic neutrophil adhesion Shimizu J Surg Res 2009 Micro RNA effects in distant organs Li, unpublished data

18 Signaling Reperfusion injury Non-humoral mediators of ripc J Thomb &Hemost 2011; 9(2): Heart 2011;97:

19 Effector pathways in target tissue

20 ALDH-2 inhibition blocks ripc Contractor H, unpublished data

21 ALDH-2 pathway in human ripc Pharmacological Genetic Wild type Loss of function polymorphism Contractor H, unpublished data

22 Summary TRIGGER MEDIATOR EFFECTOR Ischemia initiates pathways Adenosine release Activation of C-fibres Local/systemic CGRP Cellular mediators Central and local reflex initiates systemic and target tissue release of factor(s) Small, hydrophilic substance <14kDa Unidentified cellular pathways Ligand activated, receptor mediated pathways similar to local IPC RISK/SAFE pathways Mitochondrial pathways also involved Delayed ripc effects

23 Why study the mechanism?

24 Signaling Why Peripheral study the mechanism? Increased sensitivity of GABA A R

25 Bench to Practice: Bridging the gap Understanding the mechanism of ripc will facilitate achieving the optimal results from future clinical studies - simple limb ischemia may not be powerful enough in all individuals (eg:neuropathy) - understanding pathways may identify why ripc is ineffective in certain situations - stimulating pathways pharmacologically may enhance protection above limb ischemia alone

26 Questions