An experimental model of lacunar infarction: embolization of microthrombi

Microthrombi are undoubtedly the most common embolic material in the cerebral circulation, originating from even minor irregularities of the arterial wall, fibrillating atria, cardiac valves, and patent foramen ovale. Thrombus fragments are globular and likely to completely obstruct terminal vessels. In contrast, previous work with "atheroemboli" of needle-like cholesterol crystals rarely cause occlusions or infarctions instead creating small foci of inflammation. In this work, we asked if microthrombi would occlude terminal vessels and create lacunar type infarctions in the subcortical tissues of the rat brain where, as in human brain, collateral flow is limited relative to the cortex.

Three treatment groups of adult male Sprague-Dawley rats were studied. All groups underwent general anesthesia with monitoring of temperature and blood pressure during cannulation of the right internal carotid artery. In the group embolized with thrombus fragments (n = 12), animals had injections of 300 fragments of thrombus size 60 to 100 microns, the cholesterol group (n = 6) had injections of 300 cholesterol crystals of similar size, and the control group (n = 4) had injections of saline. Brains were harvested at 4 days with perfusion fixation and were examined by immunohistochemical staining for breaks in the blood brain barrier (BBB) (albumin), microglial activation (CD11b), astrocyte activation (GFAP), and infarction (loss of NeuN staining). Size and location of the areas of injury and infarction were recorded.

Clot fragments caused discreet infarcts in 10/12 animals that were 0.1-1.7 mm in diameter and coincided with activation of microglia and astrocytes. In some areas, necrosis was already underway at this early time point. Consistent with our previous work, the infarcts caused by cholesterol crystals were smaller (P = .014). Foci of BBB disruption and microglial activation were distributed throughout the brain whereas areas of infarction were found almost exclusively in subcortical tissues (P = .029).

Injecting microthrombi reproducibly caused areas of necrosis resembling lacunar type infarctions. These were primarily located in the striatum and thalamus presumably because these areas lack the branching, collateral network seen in the cortex. In addition, these data give further evidence that the extent of brain injury from emboli depends upon composition and shape as well as size.