Remote ischemic conditioning in the STEMI and stroke: are we ready for clinical implementation?

Transcription

1 Remote ischemic conditioning in the STEMI and stroke: are we ready for clinical implementation? Hans Erik Bøtker, MD, Ph.D. Aarhus University Hospital Skejby Denmark ACC Rockies March 2013

2 Presenter Disclosure Information The following relationships exist related to this presentation: Shareholder in CellAegis a start-up company developing automated preconditioning devices

3 Final infarct size (% of LV) MI size prognostic determinant Traditional determinants of MI size Area-at-risk (AAR) Ischemia duration Area-at-risk (% of LV Wavefront phenomenon Residual perfusion of AAR (collaterals) (Systemic hemodynamics)

4 Reperfusion injury Normoxic heart + 90 min ischemia + 1 min of reperfusion

5 Reperfusion injury Normoxic heart + 90 min ischemia + 1 min of reperfusion

6 The chain of infarct size reduction Myocardial infarction without reperfusion 2011; 32: Infarct size (IS) 70 % Reducing referral delay IS 30 % Myocardial infarction with reperfusion 2006;114:40-7 IS 5 % Myocardial infarction with reperfusion and cardioprotection Microcirculation Cardioprotection 2010;375:727-34

7 Cardioprotection by ischemic preconditioning Ischemia Reperfusion Tissue death Ischemia Modified reperfusion Less tissue death Experimental evidence Clinical translation 1990;82: ;342:276-7

8 Concept of remote preconditioning Ischemia Reperfusion Tissue death Ischemia Modified reperfusion Less tissue death Local remote Occlusion of CX Infarct size in LAD Przyklenk K et al. Circulation 1993;87:893-9 Distant remote Three of four cycles of 5 minutes of limb ischemia induced by blood pressure cuff inflation (200 mm Hg) Birnbaum Y et al. Circulation 1997;96: Kharbanda R et al. Circulation 2002;106:2881-3

9 Translational studies predictable ischemia Cardiac surgery Patient group Stimulus Outcome n Cheung (2006)Hausenloy (2007) Venugopal (2009) Thielman (2010) Li (2010) Hong (2010) Wagner (2010 Zhou (2010) Zimmerman (2011) Rahman (2011) Young (2012) Kottenberg (2012) Pediatric CABG ± valve CABG (cold-blood cardiopl) CABG (crystaloid cardiopl) Valve replacement CABG (off-pump) CABG (crystaloid+tramadol) Pediatric Cardiac with CP by-pass CABG electiv + urgent High risk CABG and valve CABG 4 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min 4 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min 3 x 5 min TnT, inotropic score, airway resist TnT TnT TnT TnI, defibrilation No statistically significant TnI TnI; inos; enos inotropic score kidney injury No effect on TnT, inotropic, kidney, ECG No effect on TnT, inotropic, kidney AUC TnI by isoflurane, No effect by propofol Non cardiac Ali (2007) Walsh (2009) Walsh (2010) Walsh (2010) Open AAA EVAR Open infrarenal AAA Carotid endarterectomy 2 x 10 min 1 x 10 min 1 x 10 min 1 x 10 min TnI, perioprative MI, kidney No effect on renal funct and cardiac events No effect on renal function No effect on neurological + cardiac outcome Elective PCI Iliodromitis Hoole (2009) Stent implantation Elective PCI 3 x 5 min 3 x 5 min TnI, CKMB, CRP Reduced TnI; reduced MACCE

10 Predictable ischemia: PCI Distribution of 24-hour ctni in patients after PCI Kaplan-Meier graph of the MACCE rate up to 6 years after elective PCI in 215 patients Hoole et al. Circulation 2009;119: Hoole et al. AHA Scientific Sessions 2012

11 Challenges in unpredictable ischemia Predictable: Unpredictable: Ischemia Reperfusion Tissue death Ischemia Ischemia Drug Modified reperfusion Modified reperfusion Less tissue death Less tissue death Local and remote pre- Pharmaco- logical- Ischemia Modified reperfusion Less tissue death Post- Ischemia Modified reperfusion Less tissue death Remote- Perconditioning

12 INTERMITTENT PERIPHERAL TISSUE ISCHEMIA DURING CORONARY ISCHEMIA REDUCES MYOCARDIAL INFARCTION THROUGH A K ATP DEPENDENT MECHANISM: FIRST DEMONSTRATION OF REMOTE ISCHEMIC PERCONDITIONING Percent myocardial infarction in area at risk p= Control Pe rconditioning Figure 6: Effect of RIperC on infarct size Schmidt MR et al. Am J Physiol Heart Circ Physiol 2007;292:H

13 Remote conditioning in the ambulance ECG Randomization Patient Ambulance

14 Translation into clinical practice: riperc during transportation to ppci Salvage Index (median [IQR]) p= PCI only riperc 0 PCI only riperc Bøtker et al. Lancet 2010;373:

15 % of LV (median [IQR] Influence of infarct location and vessel patency Infarct Location Vessel patency 40 p=0.011 p= p=0.056 p= LAD Non-LAD Occluded Non-occluded TIMI 0-1 TIMI 2-3 PCI only riperc Bøtker et al. Lancet 2010; 373: hjkg hjkg

16 Final infarct size (% of LV) Relation between AAR and FIS Difference in slope: 0.16 (0.05; 0.26), p = PCI only riperc Area at risk (% of LV) Bøtker et al. Lancet 2010;373:

17 Translation into improvement of LVfunction in most severely affected patients Patients with LAD STEMI: 30-day EF by echo and gated SPECT Munk K et al. Circ Cardiovasc Imaging 2010;3:

18 Achieving full ST-resolution Further clinical evidence Effect of riperc enhanced by morphine (n=96) Controls riperc riperc+morphine Rentoukas et al. J Am Coll Cardiol Intv 2010;3:49-55

19 Translation into long term benefit Cumulative incidence of MACE p=0.016 Sloth et al. TCT 2012

20 Long term effect of riperc Sloth et al. TCT 2012

21 Long term follow-up after RIPC in CABG Thielman et al. AHA Annual meeting 2012

22 Challenges in translation From healthy experimental animals to patients with risk factors and comorbidity Clinical heterogeneity Reperfusion through residual stenosis Microembolization Area-at-risk Timing of reperfusion Age Medication Medication Loss of cardioprotective signalling anti-dm (metformin, SU) β-blockers, statins, Comorbidity opioids, ACEI, AT1-blockers, NTG, DM, hypertension, cholesterol adenosine a.o.

23 ripc in thrombolytically treated STEMI?

24 Experimental results (rats): Remote ischemic perconditioning in evolving stroke Focal cerebral ischemia: Transiet middle cerebral artery occlusion 120 min Reperfusion: 24 hours Pre-conditioning: 40 min before ischemia Remote Per-conditioning: 40 min before reperfusion Protection by both IPC and riperc (p<0.001) riperc > local IPC Hahn CD et al. Stroke 2011;42:

25 Clinical results Patients with TIA or ischemic stroke (N=295) Penumbral salvage N=149 patient: 408 NIHSS on admission P = rperc: ml (1.60;79.82) + rperc: ml (0.53;63.39) Median (IQR) NIHSS = National Institutes of Health Stroke Scale Dupont et al. Int Stroke Conference, New Orleans 2012

26 Clinical perspectives: combination of stimuli Wei et al. Circ Res. 2011;108:1220-5

27 Perspectives: efficacy of combination Repeated ripostc improves survival in a rat model of myocardial infarction despite absence of further reduction of infarct size compared to riperc alone Wei et al. Circ Res. 2011;108:

28 Underlying mechanisms Stimulus Effector Cell-signalling Protection Receptor Intracellular pathways Reduced IS improved function Four cycles of 5 min limb ischemia and 5 min reperfusion Systemic release of circulating conditioning substances Opening of mk ATP Closure of MTPT Antiinflammatory effect Prevents endothelial dysfunction and platelet activation

29 Conclusion Reperfusion injury is a true treatment target riperc activates endogenous cardioprotection riperc can be translated into a clinical context, but true clinical benefit awaits larger multicenter trials Challenges in the translation of riperc in thrombolytically treated stroke

30 Thank you! Torsten Toftegaard Nielsen Steen Buus Kristiansen Michael Rahbek Schmidt Morten Bøttcher Christian J. Terkelsen Keld E. Sørensen Niels Holmark Andersen Steen H. Poulsen Henrik Wiggers Leif Thuesen Lars Krusell Jens Flensted Lassen Steen Dalby Kristensen Evald Høj Christiansen Henning Rud Andersen Anne Kaltoft Søren Nielsen Michael Rehling Raj Kharbanda Andrew Reddington Troels Martin Hansen Sven Trautner Jan Møller Nielsen Bo Løfgren Nicolaj Støttrup Kim Munk Marie Mide Michelsen Christian Aarhus Møller Pedersen Rebekka Thomsen Jonas Riber Poulsen Lars Ege Rasmussen Runa Poulsen Jacob Johnsen Astrid Drivsholm Sloth