Dissecting the Effects of Ischemia and Reperfusion on the Coronary Microcirculation in a Rat Model of Acute Myocardial Infarction

Abstract

BackgroundMicrovascular injury (MVI) after coronary ischemia-reperfusion is associated with high morbidity and mortality. Both ischemia and reperfusion are involved in MVI, but to what degree these phases contribute is unknown. Understanding the etiology is essential for the development of new potential therapies.Methods and FindingsRats were divided into 3 groups receiving either 30 minutes ischemia, 90 minutes ischemia or 30 minutes ischemia followed by 60 minutes reperfusion. Subsequently hearts were ex-vivo perfused in a Langendorff-model. Fluorescence and electron microscopy was used for analysis of capillary density, vascular permeability and ultrastructure. Most MVI was observed after 30 minutes ischemia followed by 60 minutes reperfusion. In comparison to the 30’ and 90’ ischemia group, wall thickness decreased (207.0±74 vs 407.8±75 and 407.5±71, p = 0.02). Endothelial nuclei in the 30’-60’ group showed irreversible damage and decreased chromatin density variation (50.5±9.4, 35.4±7.1 and 23.7±3.8, p = 0.03). Cell junction density was lowest in the 30’-60’ group (0.15±0.02 vs 2.5±0.6 and 1.8±0.7, p<0.01). Microsphere extravasation was increased in both the 90’ ischemia and 30’-60’ group.ConclusionsIschemia alone for 90 minutes induces mild morphological changes to the coronary microcirculation, with increased vascular permeability. Ischemia for 30 minutes, followed by 60 minutes of reperfusion, induces massive MVI. This shows the direct consequences of reperfusion on the coronary microcirculation. These data imply that a therapeutic window exists to protect the microcirculation directly upon coronary revascularization.

Research update for articles published in EJCI in 2014

“…Firstly, the integrity and functionality of the endothelial cells (EC) after a myocardial infarction (MI) were evaluated in a rodent model of MI by determining nuclear damage, cell-to-cell connections and endothelium permeability. In consonance with our results, EC injury post-MI began during the ischaemic conditions, reaching its maximum after reperfusion [8]. Secondly, EC dysfunction plays a pivotal role in microvascular obstruction (MVO), which is a strong long-term predictor of mortality post-MI.…”

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“…This is consistent with studies reporting that IMH is associated with larger infarcts sizes, decreased myocardial salvage and, impaired left ventricular function in patients showing ST-elevation myocardial infarction (STEMI) and was associated with increased adverse cardiovascular events [ 36 , 37 ], however the small sample size in this study was insufficient to extrapolate any significant findings from this cohort and as such these specimens were excluded from all subsequent experiments. The pathogenesis of IMH remains unknown, however it has been suggested that the microvascular blockage of the vasculature during reperfusion injury decreases the integrity of the vascular walls, while reperfusion aggravates this permeability and enhances endothelial leakage into the infarcted tissue [ 38 ]. Nonetheless, 4-MetT failed to decrease the infarct size irrespective of the presence or absence of IMH.…”

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“…The sections were stained with uranyl acetate (for 10 min) and lead citrate (for 5 min), and observed using a transmission electron microscope (H-7650, Hitachi, Tokyo, Japan) at an accelerating voltage of 80 kV. The quantification of TEM images was performed by referring to previous publications 60 , 61 . Briefly, 20 randomly selected cell-cell contact sites were captured, and the number of desmosome-like structures and their length in each contact sites were measured in a blind manner.…”