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GLOBAL MYOCARDIAL ISCHEMIA AND REPERFUSION

GLOBAL MYOCARDIAL ISCHEMIA AND REPERFUSION. M.KUDUVALLI. DEFINITION. GLOBAL MYOCARDIAL ISCHEMIA REFERS TO A REDUCTION IN OXYGEN SUPPLY TO THE WHOLE OF THE MYOCARDIUM DUE TO AN INADEQUATE CORONARY BLOOD FLOW, DESPITE ADEQUATE OXYGEN CONTENT OF THE PERFUSATE

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GLOBAL MYOCARDIAL ISCHEMIA AND REPERFUSION

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  1. GLOBAL MYOCARDIAL ISCHEMIA AND REPERFUSION M.KUDUVALLI

  2. DEFINITION • GLOBAL MYOCARDIAL ISCHEMIA REFERS TO A REDUCTION IN OXYGEN SUPPLY TO THE WHOLE OF THE MYOCARDIUM DUE TO AN INADEQUATE CORONARY BLOOD FLOW, DESPITE ADEQUATE OXYGEN CONTENT OF THE PERFUSATE • TO BE DIFFERENTIATED FROM MYOCARDIAL HYPOXIA

  3. PROTECTIVE MECHANISMS AGAINST MYOCARDIAL ISCHEMIA IN THE NORMAL HEART • BLOOD IS CONTINUOUSLY MODIFIED • FOR CORRECT COMPOSTITION • FOR REMOVAL OF PARTICULATE AND GASEOUS EMBOLI • MYOCARDIAL OXYGEN SUPPLY IS KEPT IN BALANCE WITH DEMAND • HIGH DEGREE OF AUTOREGULATION OF CORONARY BLOOD FLOW

  4. MYOCARDIAL VULNERABILITY TO ISCHEMIC DAMAGE DURING CPB • PREOPERATIVE FUNCTIONAL CLASS • VENTRICULAR HYPERTROPHY • CORONARY ARTERY DISEASE • CYANOTIC CONG. HEART DISEASE • ISCHEMIA PRIOR TO CPB • PREOPERATIVELY IN CARDIOGENIC SHOCK • ANAESTHESIA • MANIPULATION OF THE HEART

  5. VENTRICULAR HYPERTROPHY • TRANSMURAL GRADIENTS OF ENERGY SUBSTRATE UTILIZATION MARKEDLY INCREASED • XANTHINE OXIDASE LEVELS MARKEDLY INCREASED • SUPEROXIDE DISMUTASE LEVELS MARKEDLY DECREASED • ADEQUATE REPERFUSION OF HYPERTROPHIED MYOCARDIUM MORE DIFFICULT

  6. CHRONIC HEART FAILURE • CHRONICALLY DEPLETED OF ENERGY CHARGE • ENERGY CHARGE IS THE ENERGY PRODUCING CAPACITY OF THE PARTICULAR COMBINATION OF ADENINE NUCLEOTIDES PRESENT IN THE MITOCHONDRIA AND CYTOPLASM OF THE MYOCARDIAL CELL. • NORMALLY 0.85. • WOULD BE 1.0 IF ALL THE NUCLEOTIDES WERE PRESENT ONLY AS ATP

  7. EVENTS DURING CPB WHICH CAUSE ISCHEMIA • ABNORMAL PERFUSATE COMPOSITION • PERSISTENT VENTRICULAR FIBRILLATION • INADEQUATE MYOCARDIAL PERFUSION • VENTRICULAR DISTENSION • VENTRICULAR COLLAPSE • CORONARY EMBOLISM • CATECHOLAMINES • AORTIC CROSS-CLAMP • REPERFUSION

  8. ABNORMALITIES IN PERFUSATE • DENATURED PLASMA PROTEINS • HIGH LEVELS OF FREE FATTY ACIDS • VASOACTIVE SUBSTANCES • CAPILLARY SLUDGING (PREDISPOSED TO BY HEPARINIZATION BY INCREASING THE SEDIMENTATION RATE) • GAS AND PARTICULATE MICRO-EMBOLI

  9. VENTRICULAR FIBRILLATION • INCREASED MYOCARDIAL WALL TENSION • INCREASED MVO2 • IMPAIRED SUBENDOCARDIAL BLOOD FLOW • ABOVE EFFECTS POTENTIATED BY • VENTRICULAR DISTENSION • VENTRICULAR HYPERTROPHY • CORONARY ARTERY DISEASE

  10. INADEQUATE MYOCARDIAL PERFUSION • PERFUSION PRESSURE IS VARIABLE AND NONPULSATILE • CVR INCREASED DUE TO • ABNORMALITIES OF PERFUSATE COMPOSITION AND VISCOSITY • MICROEMBOLI • ALTERED LYMPH FLOW • MYOCARDIAL OEDEMA AFTER LONG CPB • LOSS OF AUTOREGULATION

  11. STRATEGIES TO IMPROVE MYOCARDIAL PERFUSION • KEEP PERFUSION GRADIENT BETWEEN 50 – 70 mmHg • HIGHER PERFUSION PRESSURE IN CAD, HYPERTROPHIC VENTRICLES, AND IF VF OCCURS • ?? PULSATILE FLOW

  12. VENTRICULAR DISTENSION • CAUSES INCREASED MYOCARDIAL WALL TENSION AND MVO2 • REDUCES SUBENDOCARDIAL PERFUSION DUE TO INCREASED INTRACAVITY PRESSURE • POTENTIATED BY • INADEQUATE VENOUS RETURN • AORTIC INSUFFICIENCY • VF • INCREASED PV RETURN AND NONCORONARY COLLATERAL FLOW IN THE QUIESCENT HEART • POST-REPAIR CARDIAC FAILURE

  13. STRATEGIES TO PREVENT VENTRICULAR DISTENSION • OPTIMIZE VENOUS DRAINAGE • OPTIMIZE CPB FLOW RATES • VENT THE LEFT HEART • EARLY DEFIBRILLATION • EARLY CROSS CLAMPING IN AORTIC INCOMPETENCE • VASODILATORS MAY HELP SOMETIMES

  14. VENTRICULAR COLLAPSE • PREDISPOSES TO ISCHEMIA IN THE PERFUSED, EMPTY, BEATING HEART • CHANGES IN MYOCARDIAL COMPRESSIVE FORCES AND VENTRICULAR GEOMETRY CAUSE SUBENDOCARDIAL ISCHEMIA, ESPECIALLY IN HYPERTROPHIC, SMALL-CHAMBERED VENTRICLES

  15. CORONARY EMBOLISM • GAS OR PARTICULATE • REDUCE INCIDENCE BY • APPROPRIATE FILTERS IN THE CIRCUIT • VENTING OF VEIN GRAFTS • ADEQUATE DEAIRING OF CHAMBERS

  16. INOTROPES DURING WEANING FROM CPB • ENDOGENOUS CATACHOLAMINES ALREADY HIGH AT THE END OF CPB • PROLONGED USE OF HIGH DOSE EXOGENOUS INOTROPES DISPROPORTIONATELY INCREASES MVO2 • STRATEGY • OPTIMIZE HR, PRELOAD, AFTERLOAD PRIOR TO USE OF INOTROPES • MECHANICAL SUPPORT IN PLACE OF VERY HIGH INOTROPIC SUPPORT

  17. AORTIC CROSS CLAMP • PROBLEMS WITH NORMOTHERMIC ISCHEMIC ARREST • PERSISTENT ELECTRICAL AND MECHANICAL ACTIVITY DURING MUCH OF THE ISCHEMIC PERIOD DEPLETES HIGH ENERGY PHOSPHATE AND COMPROMISES POST-REPAIR VENTRICULAR PERFORMANCE • SAFE ISCHEMIC TIME INSUFFICIENT TO COMPLETE MOST REPAIRS • INTERMITTENT CROSS CLAMP WITH PERIODS OF REPERFUSION DOES LITTLE TO IMPROVE OPERATING CONDITIONS OR PREVENT MYOCARDIAL NECROSIS. ACTUALLY MAY BE DELETERIOUS COMPARED TO A LONGER SINGLE PERIOD OF ISCHEMIA

  18. AORTIC CROSS CLAMP • RAPID CESSATION OF ELECTRO-MECHANICAL ACTIVITY FOLLOWING CROSS CLAMP DESIRABLE BOTH FOR EXPOSURE AND MYOCARDIAL PRESERVATION • DIFFERENCES IN MYOCARDIAL VULNERABILITY MAKE IT IMPOSSIBLE TO PREDICT A ‘SAFE’ PERIOD OF ISCHEMIA • EXTENT OF NECROSIS IS DIRECTLY PROPORTIONAL TO THE DURATION OF AORTIC CROSS CLAMP

  19. STRATEGIES FOR MINIMIZING DELETERIOUS EFFECTS OF AORTIC CROSS CLAMP • MINIMIZE THE DURATION WITH A WELL THOUGHT OUT AND EFFICIENTLY EXECUTED REPAIR • MANIPULATE MYOCARDIAL METABOLISM DURING THE PERIOD OF CROSS CLAMP – ‘MYOCARDIAL PROTECTION’

  20. PATHOPHYSIOLOGY OF GLOBAL MYOCARDIAL ISCHEMIA  HIGH ENERGY PHOSPHATE PRODUCTION PERSITENT HIGH ENERGY PHOSPHATE UTILIZATION DECREASED HIGH ENERGY PHOSPHATE AVAILABILITY

  21. DECREASED HIGH ENERGY PHOSPHATE AVAILABILITY FAILURE OF CALCIUM REGULATION FAILURE OF CELLULAR VOLUME REGULATION INCREASED INTRACELLULAR SODIUM INCREASED INTRACELLULAR CALCIUM ACTIVATION OF CALCIUM ATPASES ACTIVATION OF CALCIUM LIPASES MITOCHONDRIAL CALCIUM OVERLOAD INTRACELLULAR OEDEMA HIGH ENERGY PHOSPHATE UTILIZATION  HIGH ENERGY PHOSPHATE PRODUCTION

  22. OXIDATIVE PHOSPHORYLATION CEASES WHEN PO2 FALL BELOW 5 – 10 mmHg • DURING ISCHEMIA, THE MAIN SOURCES OF HIGH ENERGY PHOSPHATE ARE CREATINE PHOSPHATE AND ANAEROBIC PRODUCTION OF ATP • ANAEROBIC PRODUCTION OF ATP IS SELF- LIMITED BECAUSE OF ACCUMULATION OF METABOLITES SUCH AS LACTATE, PYRUVATE AND PROTONS, WHICH EVENTUALLY INHIBIT ESSENTIAL ENZYME SYSTEMS

  23. CP AND ATP LEVELS DECLINE RAPIDLY FOLLOWING GLOBAL ISCHEMIA BECAUSE OF PERSISTENT ENERGY UTILIZATION FOR ELECTROMECHANICAL AND BASAL METABOLIC ACTIVITY • THERE IS AN INITIAL RAPID REDUCTION OF ACTIVE DEVELOPMENT OF MYOCARDIAL TENSION WITHOUT A RISE IN RESTING TENSION • SUBSEQUENTLY, RESTING TENSION INCREASES UNTIL A PLATEAU IS REACHED • PROLONGED ISCHEMIA RESULTS IN SEVERE MYOCARDIAL CONTRACTURE

  24. ENERGY UTILIZATION IS CLOSELY LINKED TO MOVEMENT OF CALCIUM IONS TRANSPORT OF CALCIUM INTO THE MYOCYTE (CONSUMES LITTLE ENERGY) RISE IN INTRACELLULAR CALCIUM TRIGGERS A SERIES OF REGULATORY REACTIONS RESULTING IN MYOCARDIAL CONTRACTION AND ENERGY UTILIZATION ENERGY DEPENDENT TRANSPORT OF CALCIUM TO OUTSIDE THE CELL FOR MYOCARDIAL RELAXATION

  25. INCREASED PRODUCTION AND ACCUMULATION OF H+ IONS AND FREE FATTY ACIDS LOW PRODUCTION OF ATP DUE TO ANAEROBIC METABOLISM INCREASED CYTOSOLIC CONCENTRATION OF IONIZED CALCIUM RELEASE OF INTRACELLULAR LIPOPROTEIN LIPASE FORMATION OF RIGOR BONDS BETWEEN CONTRACTILE PROTEINS WITH PERSISTENT ENERGY UTILIZATION LOSS OF CELL INTEGRITY AND FUNCTION

  26. DAMAGE FROM GLOBAL MYOCARDIAL ISCHEMIA • INVOLVES • MYOCYTES • VASCULAR ENDOTHELIUM • SPECIALIZED CONDUCTION CELLS

  27. (MYOCARDIAL STUNNING) (MYOCARDIAL NECROSIS)

  28. MYOCARDIAL STUNNING • DEFINED AS REVERSIBLE DEPRESSION OF SYSTOLIC AND DIASTOLIC MYOCARDIAL FUNCTION, WITHOUT MYOCARDIAL NECROSIS, THAT ACCOMPANIES, AND FOR A TIME FOLLOWS, MYOCARDIAL ISCHEMIA • STUNNED MYOCARDIUM HAS BEEN SHOWN TO HAVE A HIGH, NOT LOW, OXYGEN CONSUMPTION

  29. HYPOTHETICAL CAUSES OF MYOCARDIAL STUNNING • ISCHEMIA INDUCED INFLUX OF CALCIUM INTO THE MYOCARDIAL CELLS • RELEASE OF OXYGEN-DERIVED FREE RADICALS, PRESUMABLY BY ACTIVATED NEUTROPHILS IN THE FIRST FEW MINUTES OF REPERFUSION • PROLONGED POST-ISCHEMIC DEPLETION OF MYOCARDIAL CELL ENERGY CHARGE • POST-ISCHEMIC IMPAIRMENT OF CORONARY BLOOD FLOW OR CORONARY RESERVE • APOPTOSIS (PROGRAMMED CELL DEATH)

  30. MYOCARDIAL NECROSIS • END STAGE OF A COMPLEX PROCESS • INITIATED BY THE ONSET OF GLOBAL MYOCARDIAL ISCHEMIA • MAINTAINED BY CONTINUING ISCHEMIA • AGGRAVATED BY REPERFUSION • COMMONER WHEN ISCHEMIC PERIOD IS ‘EXCESSIVE’ • HOWEVER, ‘EXCESSIVE’ IS DIFFICULT TO DEFINE

  31. INITIAL MICROSCOPIC CHANGES • GROSS MICROSCOPY • CELLULAR SWELLING • ULTRASTRUCTURAL CHANGES • LOSS OF GLYCOGEN GRANULES • INTRACELLULAR AND ORGANELLE SWELLING • LATE MICROSCOPIC CHANGES • GROSS MICROSCOPY • FURTHER CELLULAR SWELLING • DISRUPTION OF REGULAR MYOFIBRILLAR PATTERN • CONTRACTURE BANDS • ULTRASTRUCTURAL CHANGES • CELLULAR AUTOLYSIS • STRUCTURAL DEGENERATION OF INTRACELLULAR ORGANELLES

  32. ENDOTHELIAL CELL DAMAGE • ENDOTHELIAL CELL SWELLING DEVELOPS DURING ISCHEMIA AND BECOMES MORE PROMINENT DURING REPERFUSION • AFFECTS THE SECRETION OF EDRF AS WELL AS ENDOTHELINS (CONSTRICTORS) • CONTRIBUTE TO THE ‘WHOLE BODY INFLAMMATORY RESPONSE’ TO CPB • CAN CAUSE INCREASE IN CVR, AND OBSTRUCTION TO CAPILLARY PERFUSION DURING REPERFUSION – THE ‘NO REFLOW’ PHENOMENON

  33. SPECIALIZED CONDUCTION CELL DAMAGE • BECOME NON-FUNCTIONAL EARLY IN THE COURSE OF GLOBAL MYOCARDIAL ISCHEMIA • RECOVERY TAKES LONGER THAN RECOVERY OF MYOCYTES

  34. ALL THE PATHOLOGICAL CHANGES DESCRIBED OCCUR PREFERENTIALLY IN THE SUBENDOCARDIAL LAYERS OF THE MYOCARDIUM, WITH THE SUBEPICARDIAL LAYERS BEING LEAST AFFECTED

  35. CAN GLOBAL MYOCARDIAL ISCHEMIA BE BENEFICIAL? THE CONCEPT OF ISCHEMIC PRECONDITIONINGAND ITS POTENTIAL APPLICATION IN CARDIAC SURGERY

  36. DEFINED AS THE CONCEPT OF ENDOGENOUS ADAPTATION TO SUBLETHAL GLOBAL ISCHEMIA RESULTING IN PROTECTION AGAINST A LONGER LETHAL ISCHAEMIC EPISODE • HAS BEEN DEMONSTRATED EXPERIMENTALLY IN ANIMAL HEARTS, AND ALSO IN CLINICAL CIRCUMSTANCES IN HUMANS IN A FEW STUDIES

  37. POSSIBLE MECHANISMS OF PRECONDITIONING • INITIALLY THOUGHT TO BE DUE MANIFESTATION OF INCREASED COLLATERAL FLOW • PRESENT RESEARCH HYPOYHETISES THE EFFECTS TO BE MEDIATED BY ADENOSINE AND A SIGNAL TRANSDUCTION PATHWAY INVOLVING G-PROTEINS, A PHOSPHOLIPASE AND PROTEIN KINASE C (PKC) • ANOTHER HYPOTHESIS INVOLVED ATP-DEPENDANT K+ CHANNELS

  38. SHOWN TO HAVE MAXIMUM BENEFIT WHEN THE ISCHEMIC PERIOD IS A SINGLE EPISODE OF 3 - 5 MINS, ABOUT 3 - 5 MINS PRIOR TO THE PROLONGED ISCHEMIC PERIOD • THE BENEFITS WEAR OFF BEYOND ABOUT 2 HOURS OF PROLONGED ISCHEMIA • BENEFITS SEEN MAXIMALLY WITH LIMITING INFARCT SIZE AND ARRHYTHIAS AFTER THE ISCHEMIC PERIOD • HAS NOT BEEN SHOWN TO HAVE SIGNIFICANT BENEFITS IN DECREASING MYOCARDIAL STUNNING RELATED LOW CARDIAC OUTPUT

  39. REPERFUSION AFTER GLOBAL MYOCARDIAL ISCHEMIA • POST ISCHEMIA, THE MYOCARDIUM IS COMPOSED OF A HETEROGENOUS POPULATION OF CELLS • IRREVERSIBLE DAMAGED • MINIMALLY DAMAGED • STUNNED MYOCARDIAL CELLS

  40. POOR MYOCARDIAL PROTECTION BEFORE AND DURING CROSS CLAMP • LARGE MASS OF IRREVERSIBLY DAMAGED CELLS LEADING USUALLY TO PATIENT DEATH • OPTIMAL PROTECTION • VIABLE MYOCARDIUM AND SURVIVAL WITH MINIMUM INTERVENTIONS • SUBOPTIMAL PROTECTION • POPULATION OF STUNNED CELLS WHOSE FATE DEPENDS ON REPERFUSION MANAGEMENT

  41. ABNORMALITIES ENCOUNTERED DURING REPERFUSION ELECTRICAL HETEROGENOUS ACTIVITY INCREASED AUTOMATICITY STRUCTURAL MYOCARDIAL OEDEMA PLATELET DEPOSITION VASCULAR INJURY VASCULAR COMPRESSION BIOCHEMICAL ACIDOSIS DECREASED OXYGEN UTILIZATION DECREASED H-E-P PRODUCTION INCREASED CATACHOLAMINES INCREASED CELLULAR CALCIUM INCREASED FREE RADICALS MECHANICAL IMPAIRED SYSTOLIC AND DIASTOLIC FUNCTION

  42. THE RESPONSE OF MYOCARDIAL CELLS TO UNCONTROLLED REPERFUSION DEPENDS IN LARGE PART ON THE TIME-RELATED POINT ALONG THE PATHWAY TO CELL DEATH THAT HAS BEEN REACHED DURING THE PERIOD OF ISCHEMIA • THE CRITICAL POINT AT WHICH THE ‘EXPLOSIVE CELLULAR RESPONSE’ TO UNCONTROLLED PERFUSION IS SEEN CANNOT BE DEFINED

  43. MYOCARDIAL RESPONSE TO REPERFUSION • MYOCARDIAL STUNNING • REPERFUSION ARRHYTHMIAS • VENTRICULAR TACHYCARDIA • VENTRICULAR FIBRILLATION • STONE HEART • HARD AND FIBRILLATING HEART • MAY INVOLVE ONLY SOME REGIONS OF THE HEART, TYPICALLY THE BASILAR PORTION OF THE LEFT VENTRICLE AND THE SUBENDOCARDIUM • INDICATES USUALLY THAT THE HEART HAS REACHED THE POINT OF ‘NO-RETURN’, THOUGH NOT NECESSARILY SO.

  44. ENDOTHELIAL CELL DAMAGE DUE TO REPERFUSION • MINIMAL AFTER ISCHEMIA, ALMOST EXCLUSIVELY POTENTIATED BY REPERFUSION • SWELLING OF ENDOTHELIAL CELLS, AGGREGATION OF NEUTROPHILS AND PLATELET PLUGS CAUSE MICROVASCULAR OBSTRUCTION • ADDITIONALLY, MYOCARDIAL OEDEMA CAN ALSO COMPRESS THE MICROVASCULATURE LEADING TO INHOMOGENEOUS REPERFUSION, OR SOMETIMES, THE ‘NO-REFLOW’ PHENOMENON

  45. MOLECULAR BASIS OF REPERFUSION RESPONSE • INFLUX OF CALCIUM INTO MYOCYTES, ESPECIALLY ACCUMULATION IN MITOCHONDRIA • RELEASE OF COMPLEMENT FRAGMENTS SUCH AS C5a FROM ISCHEMIC MYOCARDIUM • CHEMOTACTIC FOR NEUTROPHILS, WHICH • PLUG MYOCARDIAL CAPILLARIES • RELEASE LARGE AMOUNT OF OXYGEN DERIVED FREE RADICALS • RELEASE ARACHIDONIC ACID METABOLITES WHICH CAUSE ENDOTHELIAL INJURY, PLATELET AGGREGATION AND VASOCONSTRICTION

  46. MECHANISM OF OXYGEN DERIVED FREE RADICAL PRODUCTION ON REPERFUSION

  47. CONTROLLED REPERFUSION • MINIMIZES THE PERSISTENCE OF MYOCARDIAL STUNNING INTO THE POST-CPB PERIOD • PROVIDES FOR OPTIMAL RECOVERY OF FUNCTION OF REVERSIBLY DAMAGED MYOCARDIUM • RESUSCITATES MYOCYTES THAT WOULD OTHERWISE HAVE UNDERGONE NECROSIS

  48. CONTROLLED REPERFUSION CONSISTS OF THE FOLLOWING: • MAINTINING ELECTROMECHANICAL QUIESCENCE DURING THE FIRST 3 – 5 MINS. OF REPERFUSION • PERMITS MORE RAPID REPLETION OF MYOCARDIAL ENERGY CHARGE • MINIMIZES REGIONAL HETEROGENECITY OF FLOW • MINIMIZES MYOCARDIAL ENERGY EXPENDITURE TILL RECOVERY HAS BEEN ESTABLISHED • MINIMIZES INTRACELLULAR ACCUMULATION OF CALCIUM • LARGE BUFFERING CAPACITY OF REPERFUSATE TO COMBAT ACCUMULATED ACIDOSIS

  49. MINIMIZING DAMAGE BY OXYGEN-DERIVED FREE RADICALS • MAINTAINING LOW CALCIUM IN THE INITIAL PERFUSATE TO PREVENT INTRACELLULAR ACCUMULATION OF CALCIUM • SUBTRATE ENHANCEMENT OF THE REPERFUSATE FOR REPLETION OF ENERGY CHARGE • MAINTAINING LOW PERFUSION PRESSURES AROUND 30 – 40 mmHg DURING THE FIRST COUPLE OF MINUTES OF REPERFUSION TO MINIMIZE ENDOTHELIAL CELL DAMAGE AND SWELLING

  50. SUGGESTED STRATEGIES FOR CONTROLLED REPERFUSION • USING BLOOD AS THE REPERFUSATE INSTEAD OF CRYSTALLOID • RBCs CONTAIN ABUNDANT FREE RADICAL SCAVENGERS • BUFFERING CAPACITY OF BLOOD PROTEINS • SUBSTRATE ENHANCEMENT s/a GLUTAMATE OR L-ASPARTATE • BUFFERING AGENTS SUCH AS HYDROXYMETHYAL AMINOMETHANE AND HISTIDINE • LOW CALCIUM CONTENT

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