NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

Abstract

BackgroundN-Acetylcystein (NAC) reduces the reperfusion injury and infarct size in experimental macroangiopathic stroke. Here we now investigate the impact of NAC on the development of the histopathology of microangiopathic cerebrovascular disease including initial intravasal erythrocyte accumulations, blood–brain-barrier (BBB)-disturbances, microbleeds and infarcts.MethodsSpontaneously Hypertensive Stroke-Prone Rats (SHRSP) were treated with NAC (12 mg/kg body weight, daily oral application for three to 30 weeks) and compared to untreated SHRSP. In all rats the number of microbleeds, thromboses, infarcts and stases were quantified by HE-staining. Exemplary brains were stained against von Willebrand factor (vWF), IgG, Glutathione and GFAP.ResultsNAC animals exhibited significant more microbleeds, a greater number of vessels with BBB-disturbances, but also an elevation of Glutathione-levels in astrocytes surrounding small vessels. NAC-treatment reduced the numbers of thromboses, infarcts and arteriolar stases.ConclusionsNAC reduces the frequency of thromboses and infarcts to the expense of an increase of small microbleeds in a rat model of microangiopathic cerebrovascular disease. We suppose that NAC acts via an at least partial inactivation of vWF resulting in an insufficient sealing of initial endothelial injury leading to more small microbleeds. By elevating Glutathione-levels NAC most likely exerts a radical scavenger function and protects small vessels against extended ruptures and subsequent infarcts. Finally, it reveals that stases are mainly caused by endothelial injuries and restricted thromboses.

Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats

“…We have recently conducted several longitudinal studies using spontaneously hypertensive stroke-prone rats (SHRSP), an animal model that is widely accepted to be the most valid model of human CSVD [1,5,6], and found that CSVD is initiated by subtle, early microvascular dysfunction that ultimately leads to a breakdown in the blood–brain barrier, an activated coagulatory state, and an intraluminal accumulation of erythrocytes that are visible as “stases” using conventional histology [7-11]. The resultant increasing vessel wall fragility leads to small perivascular bleeds and reactive (complete) hyaline fibrin thromboses with associated infarcts [7].…”

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort

“…40 This sudden hemodynamic change could trigger the appearance of microbleeds on background of the moderate to severe VWF multimer defect observed in patients with AS undergoing TAVR (or surgical aortic valve replacement 11,31 ) or in patients with acute valve dysfunction. 9,10,29,30 The report that CMBs are observed in animal models combining VWF defect with high blood pressure 24 but not in those of VWF defect without high blood pressure 41 are consistent with this hypothesis. The role of the sudden change in hemodynamic conditions likely explains why, despite the presence of a VWF multimer defect, the prevalence of CMBs in patients with AS before the procedure was not much higher than the one observed in a general population of the same age.…”

“… 18 VWF also modifies and damages blood–brain barrier permeability in certain pathologic settings 39 and might favor cerebral vessel wall rupture with consecutive microbleeds. 24 …”

“…The combination of VWF inactivation and high pulse pressure may trigger cerebral bleeding, suggesting that a VWF multimer defect could also increase the risk of CMBs in the setting of high pulse pressure. 24 …”