Due to multiple factors, time to administration of lytic therapy or emergent percutaneous coronary intervention (PCI) in acute ST segment elevation myocardial infarction (STEMI) may be delayed, resulting in loss of additional myocardial tissue. These delays are virtually impossible to overcome in remote regions, and are associated with increased mortality. Recent small animal studies show the potential for oxygen therapeutic nanoparticles - dodecafluoropentane e m u l s i o n (DDFPe) to reduce both myocardial infarct and stroke size duringprolongedmyocardialischemia.Ourrecentdataina murineacute STEMIm o d e l indicatesthatasingledoseofDDFPedecreasesmyocardialdamageby75%inmodelsthat examineischemiaalone,andbyabout30%inmodelswithischemiawithreperfusion(I/R),alongwith significantreductioninapoptosis.ThedosesusedintheI/Rmodelswereone-thirdthedoseusedinthe ischemiaalonemodel.IVDDFPesignificantlydecreasesbraindamageinanI/Rstrokemodel.However,the efficacyofDDFPehasnotbeentestedinalargeanimalmodel,orinmodelsofprolongedmyocardialischemia followedbyreperfusioninaclinicallyrelevantsettingmimickingatheroscleroticplaquerupture.We hypothesizethatuseofthesenanoparticlesearlyinthecareofacuteSTEMIwilldecreaseoreliminate myocardialdamagefromprolongedmyocardialischemiafollowedbyreperfusion.Firstwewilldemonstratethe abilityofDDFPetoreachtheriskareainacuteischemiaviacollateralflow,andreducetheformationof mitochondrialreactiveoxygenspeciesthataretheprimarymediatorsinischemiareperfusioninjury.Wewill correlateDDFPedeliverywithregionalmyocardialbloodflowusingneutronactivatedmicrospheres(NAM). Secondly,wewilladministerIVDDFPeduringaprolongedfour-hourperiodofmyocardialischemiainan atheroscleroticpigmodel,followedbyreperfusion.DDFPepresencewithintheriskareawillbecorrelatedwith regionalmyocardialbloodflowintheriskarea.AtfourweekspostinfarctionwewillexamineLVejection fractionwithmagneticresonanceimaging(MRI),numberofinfarctedsegmentswithdelayedenhancement MRI,andactualinfarctsizewithpost-mortemEvansBlueandtriphenyltetrazoliumchloridestaining.DDFPe hasatwo-yearshelf-lifeandhasanactiveINDforstroke.Verificationofitseffectivenessinthistrialwouldlead toINDsubmissionforacardioprotectiontrial.DDFPecouldbedeployedintheambulanceoruponarrivalto thehospitaltomaintaintissueoxygenationandreduceI/Rdamagefollowingpercutaneouscoronary revascularization.ThiswouldhaveprofoundimplicationsintheearlymanagementofacuteSTEMI,asthe abilityofthisoxygentherapeutictoreduceischemicdamageduetohypoxiacouldprolongthetime window in which patients would be eligible for percutaneousinterventions, andallowpatientseveninremotelocations toreachdefinitive care. Ultimately we predict this will preserve ejection fraction and prevent heart failure and arrhythmic complications f o l l o w i n g S T E M I that still complicate current state of the art therapies.
Thisprojectwilltestwhetheranultrasoundcontrastagentwhichcancarrylargequantitiesofoxygen (oxygentherapeutic)canbeusedtoreduceheartdamageinheartattackvictims.Thistherapeutic,if proveneffective,mayhaveprofoundimpactontheamountofheartdamagecausedbyaheartattack, andallowpatientstosurviveeveniftheirheartattackoccursinregionsthatarelongdistancesfrom hospitals.
