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Experimental cardioprotection inMyocardial Ischemia and Reperfusionassessed by sestamibi-MPI

Effects of glutamine, glutamate and erythropoietin

Jens Kristensen

Summary: 

The project was performed at Departmentof Nuclear Medicine, Department of Cardiology and Clinical Institute, AarhusUniversity Hospital, Skejby and consists of4 experimental substudies. The mainissues studied were the use of sestamibi-MPI as outcome parameter applied in theearly reperfusion phase as well aspotential adjunctive treatments tomyocardial ischemia. A porcineexperimental coronary ischemia-reperfusion model using sestamibi-MPI asearly outcome parameter, was applied.
Study 1 investigated the performance ofsestamibi-MPI as early outcomeparameter compared to a standardhistochemical technique. Ischemicpreconditioned groups as well as a controlgroup, both exposed to 45 min of indexischemia were studied. The studiedshowed that ex vivo tissue level sestamibidefect sizes closely parallelled the TTCdetermined defect sizes in both groups.The in vivo SPECT defect sizes wereoverestimated compared to thehistochemically determined defect sizes,but when infarct size was corrected for theischemic area at risk, the correlation wasvery good, thus demonstrating that theSPECT overestimation is inherent in theSPECT process per se, while sestamibiperformed well at tissue level.
Study 2 investigated a metabolic principlefor potential beneficial properties inmyocardial ischemia and applied the sameexperimental model as in study 1. Atcellular level glutamine and glutamatesupports resumption of oxidativemetabolism after severe myocardialischemia as well as supporting anaerobicATP production during ischemia.
Glutamate is ambiguous by carrying toxicproperties in non myocardial organs in theconcentrations being cardioprotective,while glutamine seems to be devoid ofthese toxicities. Even though the intendedconcentrations of glutamine were obtainedthe results was very clearly negative.
Glutamine increased systemic vascularresistance possibly of importance inopposing potential myocardial protectiveeffects. Infarct sizes actually turned outlarger in the glutamine than in the controlgroup. Further studies were therefore notperformed.
Instead study 3 examined the effect of thehematopoietic hormone erythropoietin inthe same model as above. EPO haveexperimentally been shown to beneuroprotective by means of antiapoptoticeffects in cerebral ischemia and a fewrodent studies had suggested beneficialeffects in myocardial ischemia as well.EPO was administered preischemicallycorresponding to time intervals of earlyand delayed ischemic preconditioning,since EPO has been proposed to be activeby IP-like mechanisms. This study turnedout equally negative and no beneficialeffects could be demonstrated in the short-term. EPO may possess properties on thevasculature potentially harmful inmyocardial ischemia, such as increasingthe sensitivity to sympathetic stimuli.
Study 4 was therefore performed as asubstudy to study 3 and investigating theacute hemodynamic effects of EPO in anon-ischemic model and the response ofco-administration of a sympathetic agonist(dopamine). In the short-term EPOincreased pulmonary vascular resistanceand tended to increase myocardialcontractility with addition of dopamine,while cardiac output only increasedsignificantly with addition of dopamine inthe control group.
In conclusion Sestamibi-MPI in the earlyreperfusion phase correlated well with ahistochemical method in determininginfarct size as assessed ex vivo, when theinfarct sizes were corrected for theischemic area at risk. Neither of theproposed cardioprotective interventionsstudied showed any beneficial effects inthe applied porcine model. Glutamineincreased systemic vascular resistance,glutamate increased cardiac output. EPOincreased sensitivity to dopamine asmanifested by increased pulmonaryvascular resistance with addition ofdopamine.