Abstract
BackgroundPreclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction. Closed chest pig left anterior descending coronary artery (LAD) ischemia reperfusion (I/R) models are valuable and clinically relevant. Knowledge on the influence of experimental design on infarct size (IS) in these models is a prerequisite for suitable models. To this end, we investigated the impact of several experimental features (occlusion and follow-up time and influence of area at risk (AAR)) on IS.MethodsA total of fifty-one female Landrace pigs were subjected to closed chest LAD balloon occlusion and evaluated in three substudies with varying protocols. To assess the relationship between time of occlusion and the IS, 18 pigs were subjected to 60-, 75- and 90 min of occlusion and terminated after 24 h of follow-up. Influence of prolonged follow-up on IS was studied in 18 pigs after 75 min of occlusion that were terminated at 1, 3 and 7 days. The relation between AAR and IS was studied in 28 pigs after 60 min of occlusion and 24 h of follow-up. The relation between VF, number of shocks and IS was studied in the same 28 pigs after 60 min of occlusion.ResultsIncreasing occlusion time resulted in an increased IS as a ratio of the AAR (IS/AAR). This ranged from 53 ± 23% after 60 min of occlusion to 88 ± 2.2% after 90 min (P = 0.01). Increasing follow-up, from 1 to 3 or 7 days after 75 min of occlusion did not effect IS/AAR. Increasing AAR led to a larger IS/AAR (r2 = 0.34, P = 0.002), earlier VF (r2 = 0.32, P = 0.027) and a higher number of shocks (r2 = 0.29, P = 0.004) in pigs subjected to 60 min of occlusion.ConclusionsThese experiments describe the association of occlusion time, follow-up duration, AAR and VF with IS in closed chest pig LAD I/R models. These results have important implications for future I/R studies in pigs and can serve as a guideline for the selection of appropriate parameters and the optimal experimental design.
Highlights
Preclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction
Duration of ischemia and infarct size (IS) in closed chest left anterior descending coronary artery (LAD) ischemia reperfusion (I/R) model For head to head comparison of the influence of occlusion time, closed chest LAD occlusion was performed in a total of eighteen pigs with varying occlusion times of 60 min (n = 6), 75 min (n = 8) and 90 min (n = 4)
In each group one pig died during infarct induction due to refractory Ventricular fibrillation (VF) leaving fifteen for final analysis ((60 min (n = 5), 75 min (n = 7), 90 min (n = 3))
Summary
Preclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction. Knowledge on the influence of experimental design on infarct size (IS) in these models is a prerequisite for suitable models To this end, we investigated the impact of several experimental features (occlusion and follow-up time and influence of area at risk (AAR)) on IS. During an acute myocardial infarction (MI) due to abrupt occlusion of a coronary artery, the area of the myocardium that becomes ischemic is known as the area at risk (AAR). This AAR becomes totally infarcted when the coronary artery remains occluded. The restoration of the coronary blood flow, can paradoxically result in additional damage to the myocardium This phenomenon is known as ischemia/reperfusion (I/R) injury [3]. I/R injury is regarded an important target to preserve myocardial tissue and subsequent cardiac function [4]
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