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Remote ischemic conditioning in the STEMI and stroke: are we ready for clinical implementation? Hans Erik Btker, MD, Ph.D. Aarhus University Hospital Skejby Denmark ACC Rockies 2013 17. March 2013 Presenter Disclosure Information The

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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
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Presenter Disclosure Information

  • The following relationships exist

related to this presentation:

  • Shareholder in CellAegis

a start-up company developing automated preconditioning devices

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MI size prognostic determinant

  • ”Traditional” determinants
  • f MI size
  • Area-at-risk (AAR)
  • Ischemia duration
  • Residual perfusion of AAR

(collaterals)

  • (Systemic hemodynamics)

20 40 60 20 40 60

Area-at-risk (% of LV

Final infarct size (% of LV) Wavefront phenomenon

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Reperfusion injury

Normoxic heart + 90 min ischemia + 1 min of reperfusion

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Reperfusion injury

Normoxic heart + 90 min ischemia + 1 min of reperfusion

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The chain of infarct size reduction

Myocardial infarction without reperfusion Myocardial infarction with reperfusion Myocardial infarction with reperfusion and cardioprotection

Reducing referral delay Infarct size (IS) 70 % IS 30 % IS 5 %

2011; 32: 430-6

2006;114:40-7

2010;375:727-34

Microcir- culation Cardiopro- tection

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Cardioprotection by ischemic preconditioning

Tissue death Ischemia

Modified reperfusion

Less tissue death Ischemia Reperfusion Experimental evidence Clinical translation

1993;342:276-7 1990;82:2044

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Concept of remote preconditioning

Przyklenk K et al. Circulation 1993;87:893-9

Three of four cycles of 5 minutes of limb ischemia induced by blood pressure cuff inflation (200 mm Hg) Occlusion of CX Infarct size in LAD

Birnbaum Y et al. Circulation 1997;96:1641-6 Kharbanda R et al. Circulation 2002;106:2881-3

Distant remote Local remote

Tissue death Ischemia Modified reperfusion Less tissue death Ischemia Reperfusion

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Translational studies – predictable ischemia

Patient group Stimulus Outcome n

Cardiac surgery

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 37 57 45 53 81 130 101 60 120 162 96 72

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 82 40 40 70

Elective PCI

Iliodromitis Hoole (2009) Stent implantation Elective PCI 3 x 5 min 3 x 5 min  TnI,  CKMB,  CRP Reduced TnI; reduced MACCE 41 242

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Predictable ischemia: PCI

Hoole et al. Circulation 2009;119:820-827 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. AHA Scientific Sessions 2012

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Challenges in unpredictable ischemia

Ischemia Reperfusion Tissue death

Local and remote pre- Pharmaco- logical- Post- Remote-

Ischemia

Modified reperfusion

Less tissue death

Ischemia Ischemia

Modified reperfusion

Less tissue death Less tissue death

Modified reperfusion

Predictable: Perconditioning Unpredictable:

Ischemia

Less tissue death

Drug

Modified reperfusion

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INTERMITTENT PERIPHERAL TISSUE ISCHEMIA DURING CORONARY ISCHEMIA REDUCES MYOCARDIAL INFARCTION THROUGH A KATP DEPENDENT MECHANISM: FIRST DEMONSTRATION OF REMOTE ISCHEMIC PERCONDITIONING

Schmidt MR et al. Am J Physiol Heart Circ Physiol 2007;292:H1883-90. Control Perconditioning 25 50 75 100

p=0.004

Percent myocardial infarction in area at risk

Control Perconditioning 25 50 75 100

p=0.004

Percent myocardial infarction in area at risk

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Remote conditioning in the ambulance

Ambulance Patient

ECG

Randomization

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.5 1

Translation into clinical practice: rIPerC during transportation to pPCI

p=0.033

Salvage Index (median [IQR])

PCI only rIPerC

0.55 0.75 PCI only rIPerC

Bøtker et al. Lancet 2010;373: 727-34

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20 40

Influence of infarct location and vessel patency

LAD

Non-LAD PCI only rIPerC

p=0.011 p=0.94 % of LV (median [IQR]

16 7 4 3

Bøtker et al. Lancet 2010; 373: 727-34

20 40

Infarct Location

Occluded Non-occluded TIMI 0-1 TIMI 2-3 13

p=0.056 p=0.62

9 1 1

Vessel patency

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Relation between AAR and FIS

20 40 60 20 40 60

Difference in slope: 0.16 (0.05; 0.26), p = 0.003

Area at risk (% of LV) Final infarct size (% of LV)

  • PCI only
  • rIPerC

Bøtker et al. Lancet 2010;373: 727-34

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Translation into improvement of LV- function in most severely affected patients

Munk K et al. Circ Cardiovasc Imaging 2010;3:656-662

Patients with LAD STEMI: 30-day EF by echo and gated SPECT

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Further clinical evidence

Rentoukas et al. J Am Coll Cardiol Intv 2010;3:49-55

Effect of rIPerC enhanced by morphine (n=96)

Controls

rIPerC rIPerC+morphine

Achieving full ST-resolution

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Translation into long term benefit Cumulative incidence of MACE

Sloth et al. TCT 2012

p=0.016

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Long term effect of rIPerC

Sloth et al. TCT 2012

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Long term follow-up after RIPC in CABG

Thielman et al. AHA Annual meeting 2012

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Age Medication Medication

Loss of cardioprotective signalling anti-DM (metformin, SU) β-blockers, statins,

Comorbidity

  • pioids,

ACEI, AT1-blockers, NTG, DM, hypertension, cholesterol adenosine a.o.

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

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rIPC in thrombolytically treated STEMI

?

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Experimental results (rats): Remote ischemic perconditioning in evolving stroke

Hahn CD et al. Stroke 2011;42:2960-2962 Focal cerebral ischemia: Transiet middle cerebral artery

  • cclusion 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

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Clinical results

Patients with TIA or ischemic stroke (N=295)

NIHSS on admission

P = 0.016

NIHSS = National Institutes of Health Stroke Scale Dupont et al. Int Stroke Conference, New Orleans 2012

÷rPerC: 14.10 ml (1.60;79.82) + rPerC: 11.89 ml (0.53;63.39)

Median (IQR)

Penumbral salvage

N=149

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Clinical perspectives: combination of stimuli

Wei et al. Circ Res. 2011;108:1220-5

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Perspectives: efficacy of combination

Wei et al. Circ Res. 2011;108:1220-5. Repeated rIPostC improves survival in a rat model of myocardial infarction despite absence

  • f further

reduction of infarct size compared to rIPerC alone

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Underlying mechanisms

Stimulus Effector Cell-signalling Protection Systemic release of circulating conditioning substances

Receptor

Intracellular pathways

Opening of mKATP Closure of MTPT Four cycles of 5 min limb ischemia and 5 min reperfusion

Reduced IS – improved function Antiinflammatory effect Prevents endothelial dysfunction and platelet activation

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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

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Aarhus

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 Møller Pedersen
  • Rebekka Thomsen
  • Jonas Riber Poulsen
  • Lars Ege Rasmussen
  • Runa Poulsen
  • Jacob Johnsen
  • Astrid Drivsholm Sloth