Myocardial Reperfusion Injury

Myocardial Reperfusion InjuryLooking beyond primary PCIDr. Dibbendhu Khanra SR1

Introduction

Are we missing something?Despite timely PPCI with STEMI mortality decreased to 7% but heart failure increased to 22% (1 year after event)Infarct Size (IS) is the major determinant major determinant

How much we are missing?

50% of the myocardial infarct size is due to reperfusion injury

What we miss is really importantUnlike ischemia Tempo and moment of reperfusion can be controlled

With the limelight on ischemia driven therapy reperfusion injury is always ignored

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Reperfusion a forgotten evil

Even when post-PPCI coronary flow appears normal (TIMI flow 3) 30 40% of these patients actually have evidence of MVO What we see is not REAL

Ishemic limelightmyocardial reperfusion is essential to salvage viable myocardium, it comes at a price

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What can we do about it??

Prepare your heart so that it hurts lessFind a way to reduce the damageIschemic conditioning Pharmacological cardioprotection

Conditioning

four 5 min cycles of alternating occlusion and reflow of LAD applied immediately before 90 min of occlusion and 3days of reperfusion, resulted in a 75% reduction in MI size in the canine heartIschemic Preconditioning30 years agoDisadvantage: to intervene (directly to heart) before occurrence of the ischaemic event which is not possible in the case of an acute MIIs ischemia always bad?

This seminal observation, termed ischaemic preconditioning (IPC), has been replicated in all species tested, including humans, and can be readily applied to other organs and tissues. After reperfusion, IPC remains the most powerful intervention for reducing MI size in ischaemic hearts. Over the past 3decades, almost 9,000 papers have been published on this topic.Despite these potential beneficial effects, the need to intervene on the heart directly and the inherent risk of thromboembolization arising from clamping an atherosclerotic aorta have prevented IPC from being adopted in this clinical setting.to intervene before occurrence of the ischaemic event, which is not possible in the case of an acute MI9

15 years agothree cycles of 30s LAD occlusion and reflow within 1 min of myocardial reperfusion could reduce MI size by 44% in canine hearts reduced myocardial reperfusion injury seen in postconditioned heartsIschemic Post-reconditioningDisadvantage: it can only be performed (directly to heart) the cathlab during PCI but many patients still receive thrombolytic therapy

Inflation deflation with angioplasty balloon LIMITS infarct size

BUT further studies are necessary

Cardioprotection elicited by RIPC could be transferred from one region of the heart to Another and one organ to other organ

RIPC: three-5 min cycles of ischaemia and reperfusion using a BP cuff applied to the upper arm.RIC protocol to STEMI patients in the ambulance en route to the PPCI centre, Botker et al .were able to demonstrate increased myocardial salvageRemoteConditioning

dummy arm13

Inflation deflation with BP cuff LIMITS infarct sizeGive your arm in STEMI

Give your arm in elective PCIInflation deflation with BP cuffsLIMITS infarct size

BUT further studies are necessary

Conditioning HeartFirst window of protectionSecond window of protectionSecond window of protectionFirst window of protectionRIPerCDelayedRIPostRemoteRIPostRIPCIPCIschaemia Reperfusion Injury

Conditioning can be done across the preiod of ischemia injury and reperfsuion17

Common mediators of Conditioning

Reperfusion and cardioprotection

Jennings et al, 1960Is Reperfusion always good?Lethal cardiomyocyte injury following reperfusion

The dark side of reperfusionArrythmia Myocardial Stunning Microvascular obstructionNo reflowMicrovascular hemorrhage

Microvascular obstructioninability to reperfuse a previously ischemic regionKurg et al, 1966No reflow flow to the infarct myocardium may be markedly reduced despite the angiographic documentation of reflow in the infarct-related artery

Its essential to salvage myocardium but it comes with a price

MVO in reperfused-STEMI:larger MI sizeworse LV ejection fraction, adverse LV remodelling,worse short-termworse long-term outcomes21

How reperfusion causes injury?

Assessment of reperfusion Injury?

Intracoronary catheter Flow reserve, wedge pressureMyocardial Blush GradeCoronary TIMI Frame CountCK/ troponin ST resolution Myocardial Contrast EnhancementSPECTMRI Gd enhancement

Pharmacological cardioprotectionCalcium overload oxidative damage mitochondial injuryInflammation vasoconstriction ion channel modulators antioxidants MPTP inhibitors anti-inflammatories vasodialatorsAre there proof-of-concept trials?

Beta - Blocker

Statin

Statin

In retrospective analysis GRACE 18% of chronic nitrate users were diagnosed with STEMI compared with 41% of nitrate-naive patients. 82% of nitrate users presented with nonSTEMI compared with 59% of patients who were nitrate naive. antecedent nitrate use was associated with lower CK-MB and troponin levels, regardless of acute coronary syndrome type.(Ambrosio el al. EHJ 2010)

In patients with stable angina, pre-treatment wit intravenous nitroglycerin 24 h before an exercise tolerance test improved functional capacity and electrocardiographic manifestations of ischemia (Jneid el al. Circulation 2005)

Patients who received nitroglycerin had improvement in ST-segment shifts, regional wall motion abnormalities, and chest pain scores after balloon inflation compared with patients who received saline (Lessar et al, circulation 2001)

Nitrates

NAC

Study nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes AMISTAD I236STEMIThrombolysis6mTc SPECT3hr IV Adenosine infusion vs placeboDecrease in infarct sizeas well as improve in clinical outcomeDecrease infarct size is ony in AWMIAdverese outcome in non-AWMIAMISTAD 22118STEMIThrombolysis6mTc SPECT3hr IV Adenosine infusion (high dose vs low dose) vs placeboDecrease in infarct size with high dose adenosineBUT no improve in clinical outcomeFavourable clinical outcome in patients who received adenosine and reperfusiontherapy within 3.17 h of symptom onsetPREVENTICARUStrial260STEMIElective PCI 6mCPKTrop IIntracoronary adenosineNo benefit in infarct size as well as clinical outcomeadenosinewas administered as an intracoronary bolus. REFLO STEMI260STEMIPCI1 yrCMRICAGSTRIntracoronary adenosineVs nitrprussideOngoing bivalirudin plus bail-out glycoprotein IIb/IIIA inhibitors usedREOPEN AMI240STEMIPCI 1 yrCMRISTRIntracoronary adenosine vs nitroprusside

Adenosine improves MVObivalirudin plus bail-out glycoprotein IIb/IIIA inhibitors used

Adenosine

Exanetide

ANP

IonchannelmodulationStudy nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes ESCAMI959STEMIPCI6mCKMBSTRNa/H exchange (NHE)Eniporidedid not limit infarct size or improve clinicaloutcomeSMART59AMIPCI1mCTFCSTRNikorandilIV+IC vs IC vs placeboImproves infarct sizeIV+IC > IC

J-WIND-KATPAMIPCI1mCMRINikorandil infusionIntravenous nicorandil didNot limit infarct sizeno increase of LVEF, although oral nicorandil during follow-up increased LVEF.MAGIC6213STEMI1m-2 g IV bolus of MgSO4, followed by a 17 g infusion of MgSO4 over 24 hno effect on 30-day mortalityNo indication for the routine administration of intravenous magnesium in patients with STEMI

Study nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes EPO-AMI136AMIPCI6M-EPO vs placeboEF increasesIn LAD subgroup EF significantly increased Ferrario et al30AMIPCI6mCPKEPOhigher expression of the anti-apoptotic and pro-angiogenic

lower expression of the pro-apoptotic pro-in flammatory genes. they showedsmaller infarct size in EPO treated group

CD34+ cell mobilisation 72 h after admission was greater in the EPO-treated patient group

EPO: success stories

EPO: failuresStudy nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes Woo et al47STEMIPCI4dCPKMRIEPO vs placeboNo thromboticor hypertensive side effects.

it did not reduce the infarct sizeSmall sizeSmall FU timeLudman et al51STEMIPCI4mCPKTrop MRIEPO vs placeboEPO treatment failed to reduce MI sizedoubled the incidence of microvascular obstruction, LV dialation, LV massOtt et alREVIVAL 368STEMIPCI6mMRIEPO vs placeboerythropoietin treatment did not improve left ventricular ejection fraction or reduce infarct size but mayincrease clinical adverse events6-month incidence of death, recurrent myocardial infarction, stroke or target vesselRevascularization are moreREVEAL138STEMIPCIMRIEPO vs placeboa singleintravenous bolus of epoetin alfa did not reduce infarct size and was associated with higher ratesof adverse cardiovascular eventsit may be associated with increased infarct size inolder patients

Study nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes Piot et alNEJM200858STEMIPCI5dMRICPK

TropCyclosporineVs placeboSmaller infarct size in cyclospiorne groupBUT not in terms of Trop CIRCUSCung et alNEJM2015970STEMIPCI1yr-ClinicaloutcomeCyclosporineVs placeboNo change in clinical outcome-CYCLE410STEMIPCI6MTropSTRCyclosporineVs placeboNo change in clinical outcomeNo improvement in infrct size

Cyclosporine

Study nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes APEX AMI5754STEMIPCI30d-pexelizumab infusion No difference in MACE or mortality at 30 days-HALT MI420STEMIPCI30dSPECTInhibitors of the CD11/CD18No change in infarct size even in AWMIIncreased infection with higher doseFIRE234STEMIPCI30dCMRIFX06, a naturally occurring peptide derived from human fibrinFX06 reduced infarct sizetotal late enhancement was not significantly different

Anti-inflammatory

Nitrites

Nitrites

Therapeutic HypothermiaStudy nPatient selectionFollow upInfarct size measurementTreatment protocolMain outcomesNotes COOLMI570AMI3dCPK myoendovascular cooling catheter in ivc thru femoral veinNo overall limitation of infarct size BUT cooling