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 2013 17. March 2013
Presenter Disclosure Information • The following relationships exist related to this presentation: • Shareholder in CellAegis a start-up company developing automated preconditioning devices
MI size prognostic determinant 60 • ” Traditional ” determinants Final infarct size (% of LV) 40 of MI size 20 0 • Area-at-risk (AAR) 0 20 40 60 Area-at-risk (% of LV Wavefront phenomenon • Ischemia duration • Residual perfusion of AAR (collaterals) • (Systemic hemodynamics)
Reperfusion injury Normoxic heart + 90 min ischemia + 1 min of reperfusion
Reperfusion injury Normoxic heart + 90 min ischemia + 1 min of reperfusion
The chain of infarct size reduction Myocardial infarction without reperfusion 2011; 32: 430-6 Reducing Infarct size (IS) referral 70 % delay Myocardial infarction with reperfusion Microcir- culation IS 30 % 2006;114:40-7 Myocardial infarction with reperfusion and Cardiopro- cardioprotection tection IS 5 % 2010;375:727-34
Cardioprotection by ischemic preconditioning Ischemia Reperfusion Tissue death Ischemia Modified Less tissue death reperfusion Experimental evidence Clinical translation 1990;82:2044 1993;342:276-7
Concept of remote preconditioning Ischemia Reperfusion Tissue death Ischemia Modified reperfusion Less tissue death Occlusion of CX Local Infarct size remote in LAD Przyklenk K et al . Circulation 1993;87:893-9 Three of four cycles of 5 minutes of limb Distant ischemia induced by remote blood pressure cuff inflation (200 mm Hg) Birnbaum Y et al. Circulation 1997;96:1641-6 Kharbanda R et al. Circulation 2002;106:2881-3
Translational studies – predictable ischemia Patient group Stimulus Outcome n Cardiac surgery TnT, inotropic score, airway resist Cheung Pediatric 4 x 5 min 37 TnT CABG ± valve (2006)Hausenloy 3 x 5 min 57 TnT (2007) CABG (cold-blood cardiopl) 3 x 5 min 45 TnT Venugopal (2009) CABG (crystaloid cardiopl) 3 x 5 min 53 TnI, defibrilation Thielman (2010) Valve replacement 3 x 5 min 81 No statistically significant TnI Li (2010) CABG (off-pump) 3 x 5 min 130 TnI; iNOS; eNOS Hong (2010) CABG (crystaloid+tramadol) 4 x 5 min 101 inotropic score Wagner (2010 Pediatric 3 x 5 min 60 kidney injury Zhou (2010) Cardiac with CP by-pass 3 x 5 min 120 Zimmerman (2011) CABG electiv + urgent 3 x 5 min No effect on TnT, inotropic, kidney, ECG 162 Rahman (2011) High risk CABG and valve 3 x 5 min No effect on TnT, inotropic, kidney 96 AUC TnI by isoflurane, No effect by Young (2012) CABG 3 x 5 min 72 Kottenberg (2012) propofol Non cardiac TnI, perioprative MI, kidney Ali (2007) Open AAA 2 x 10 min 82 Walsh (2009) EVAR 1 x 10 min No effect on renal funct and cardiac events 40 Walsh (2010) Open infrarenal AAA 1 x 10 min No effect on renal function 40 Walsh (2010) Carotid endarterectomy 1 x 10 min No effect on neurological + cardiac outcome 70 Elective PCI TnI, CKMB, CRP Iliodromitis Stent implantation 3 x 5 min 41 Hoole (2009) Elective PCI 3 x 5 min Reduced TnI; reduced MACCE 242
Predictable ischemia: PCI Distribution of 24-hour cTnI Kaplan-Meier graph of the MACCE rate in patients after PCI up to 6 years after elective PCI in 215 patients Hoole et al. Circulation 2009;119:820-827 Hoole et al. AHA Scientific Sessions 2012
Challenges in unpredictable ischemia Ischemia Reperfusion Tissue death Predictable: Local and Modified Less tissue death Ischemia remote pre- reperfusion Unpredictable: Pharmaco- Modified Less tissue death Ischemia logical- Drug reperfusion Modified Less tissue death Ischemia Post- reperfusion Modified Less tissue death Ischemia Remote- reperfusion Perconditioning
INTERMITTENT PERIPHERAL TISSUE ISCHEMIA DURING CORONARY ISCHEMIA REDUCES MYOCARDIAL INFARCTION THROUGH A K ATP DEPENDENT MECHANISM: FIRST DEMONSTRATION OF REMOTE ISCHEMIC PER CONDITIONING Percent myocardial infarction in area at risk Percent myocardial infarction in area at risk 100 100 p=0.004 p=0.004 75 75 50 50 25 25 0 0 Control Control Perconditioning Perconditioning Schmidt MR et al. Am J Physiol Heart Circ Physiol 2007;292:H1883-90.
Remote conditioning in the ambulance ECG Randomization Ambulance Patient
Translation into clinical practice: rIPerC during transportation to pPCI p=0.033 1 PCI only Salvage Index (median [IQR]) rIPerC 0.75 0.55 .5 Bøtker et al. Lancet 2010;373: 727-34 0 PCI only rIPerC
Influence of infarct location and vessel patency Infarct Location Vessel patency % of LV (median [IQR] 40 p=0.011 p=0.94 p=0.62 p=0.056 40 16 13 20 20 9 7 1 1 4 3 0 0 Occluded Non-occluded LAD Non-LAD TIMI 0-1 TIMI 2-3 PCI only rIPerC Bøtker et al. Lancet 2010; 373: 727-34
Relation between AAR and FIS 60 Final infarct size (% of LV) Difference in slope: 0.16 (0.05; 0.26), p = 0.003 • PCI only • rIPerC 40 20 0 Bøtker et al. Lancet 2010;373: 0 20 40 60 727-34 Area at risk (% of LV)
Translation into improvement of LV- function 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;3:656-662
Further clinical evidence Effect of rIPerC enhanced by morphine (n=96) Achieving full ST-resolution Controls rIPerC rIPerC+morphine Rentoukas et al. J Am Coll Cardiol Intv 2010;3:49-55
Translation into long term benefit Cumulative incidence of MACE p=0.016 Sloth et al. TCT 2012
Long term effect of rIPerC Sloth et al. TCT 2012
Long term follow-up after RIPC in CABG Thielman et al. AHA Annual meeting 2012
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.
rIPC in thrombolytically treated STEMI ?
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;42:2960-2962
Clinical results Patients with TIA or ischemic stroke (N=295) NIHSS on admission Penumbral salvage N=149 P = 0.016 ÷rPerC : 14.10 ml (1.60;79.82) + rPerC : 11.89 ml (0.53;63.39) Median (IQR) NIHSS = National Institutes of Health Stroke Scale Dupont et al. Int Stroke Conference, New Orleans 2012
Clinical perspectives: combination of stimuli Wei et al. Circ Res. 2011;108:1220-5
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;108:1220-5.
Underlying mechanisms Stimulus Effector Cell-signalling Protection Intracellular Receptor pathways Reduced IS – improved function Antiinflammatory effect Four cycles of Systemic 5 min limb release of ischemia and circulating 5 min conditioning Opening of mK ATP Prevents endothelial reperfusion substances Closure of MTPT dysfunction and platelet activation
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
Thank you! • • Torsten Toftegaard Nielsen Raj Kharbanda • Steen Buus Kristiansen • Andrew Reddington • Michael Rahbek Schmidt • Troels Martin Hansen • Morten Bøttcher • Sven Trautner • Christian J. Terkelsen • Jan Møller Nielsen • Keld E. Sørensen • Bo Løfgren • Niels Holmark Andersen • Nicolaj Støttrup • Steen H. Poulsen • • Kim Munk Henrik Wiggers • • Marie Mide Michelsen Leif Thuesen • • Aarhus Lars Krusell Christian Møller Pedersen • Jens Flensted Lassen • Rebekka Thomsen • Steen Dalby Kristensen • Jonas Riber Poulsen • Evald Høj Christiansen • Lars Ege Rasmussen • Henning Rud Andersen • Runa Poulsen • Anne Kaltoft • Jacob Johnsen • Søren Nielsen • Astrid Drivsholm Sloth • Michael Rehling
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