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Development of an Insular Ischemic Stroke Animal Model to Study the Pathophysiology of Atrial Fibrillation Detected after Stroke (AFDAS)

The following abstract was presented as part of London Health Research Day 2018.
 

Research Areas: Neuroscience; Mechanisms of disease
First Author: Victoria Thorburn
Supervisor(s): S. Whitehead, L. Sposato

Introduction:
Atrial fibrillation (AF) is associated with a 5-fold increased risk of ischemic stroke. Recent clinical evidence suggests that stroke can initiate a neurogenic cause of AF, referred to as AF detected after stroke (AFDAS). Specifically, it is thought that stroke involving the insular cortex (IC) contributes to this development of AFDAS, as the IC maintains important regulation of heart rhythm. However, the exact mechanisms underlying this brain-heart paradigm remain unknown. As a first step of an overall experimental initiative to evaluate the pathophysiology of AFDAS, we aimed to develop a rat model of focal insular ischemic stroke to better understand the downstream consequences of insular stroke. 

Hypothesis:
We hypothesize that AFDAS is the consequence of insular cortex damage occurring after stroke, which disrupts autonomic regulation of heart rhythm.

Materials and Methods:
Focal ischemic stroke was induced into either the right (n=8) or left (n=8) insular cortex of 6-month-old male Wistar rats through stereotaxic injection of endothelin-1 (ET-1). Control groups received saline injection (n=7 right IC / n=7 left IC) or no injection (n=6). At 28 days post-stroke, rats were euthanized. Heart tissue was collected and histologically analyzed for left atrial fibrosis (using Masson’s Trichrome stain). Brain tissue was collected and analyzed to identify the extent of local and remote cerebral inflammation, visualized by the presence of activated microglia (using an OX-6 immunohistochemistry stain).

Results:
Left atrial fibrosis was greater in animals with right IC stroke (5.8±1.2%) compared to those with right IC saline injection (0.6±0.1%; p=0.021) and no injection (0.6±0.1%; p=0.004), as well as in animals with left IC stroke (4.5±1.3%) compared to those with left IC saline injection (0.7±0.1%; p=0.020) and no injection (0.6±0.1%; p=0.007). Statistical analysis was performed using a one-way ANOVA followed by a Bonferroni post-hoc test. Additionally, qualitative results indicate a widespread neuroinflammatory response present within the forceps minor of the prefrontal cortex, anterior commissure, striatum, corpus callosum (ipsilateral and contralateral to injection) and posterior ventromedial thalamus (ipsilateral to injection) of both right IC stroke and left IC stroke animals, compared to control groups. 

Discussion and Conclusions: 
We have successfully developed a focal insular ischemic stroke animal model and identified several downstream consequences of insular stroke. Rats subjected to ET-1 induced insular ischemic stroke show significantly greater left atrial fibrosis and secondary neuroinflammation. These findings provide insight into potential mechanisms of post-stroke atrial fibrillation, serving as possible future therapeutic targets for AFDAS.