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Left atrial microvascular endothelial dysfunction, myocardial inflammation and fibrosis after selective insular cortex ischemic stroke

  • Author Footnotes
    1 Equal contributions as lead authors.
    Brittany Balint
    Footnotes
    1 Equal contributions as lead authors.
    Affiliations
    Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University. 339 Windermere Rd, London, ON N6A 5A5, Canada

    Heart & Brain Laboratory, Western University, 339 Windermere Rd, London, ON, N6G 5A5, Canada

    Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada
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  • Author Footnotes
    1 Equal contributions as lead authors.
    Victoria Jaremek
    Footnotes
    1 Equal contributions as lead authors.
    Affiliations
    Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University. 339 Windermere Rd, London, ON N6A 5A5, Canada

    Heart & Brain Laboratory, Western University, 339 Windermere Rd, London, ON, N6G 5A5, Canada

    Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada
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  • Victoria Thorburn
    Affiliations
    Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University. 339 Windermere Rd, London, ON N6A 5A5, Canada

    Heart & Brain Laboratory, Western University, 339 Windermere Rd, London, ON, N6G 5A5, Canada

    Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada
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  • Author Footnotes
    2 Equal contributions as senior authors.
    Shawn N. Whitehead
    Footnotes
    2 Equal contributions as senior authors.
    Affiliations
    Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University. 339 Windermere Rd, London, ON N6A 5A5, Canada

    Heart & Brain Laboratory, Western University, 339 Windermere Rd, London, ON, N6G 5A5, Canada

    Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada
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  • Author Footnotes
    2 Equal contributions as senior authors.
    Luciano A. Sposato
    Correspondence
    Corresponding author at: Room A10-322 UH, 339 Windermere Road, London, ON N6A 5A5, Canada.
    Footnotes
    2 Equal contributions as senior authors.
    Affiliations
    Heart & Brain Laboratory, Western University, 339 Windermere Rd, London, ON, N6G 5A5, Canada

    Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada

    Department of Clinical Neurological Sciences, London Health Sciences Centre, Schulich School of Medicine and Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada

    Department of Epidemiology & Biostatistics, Schulich School of Medicine & Dentistry, Western University, 339 Windermere Rd, London, ON N6A 5A5, Canada

    Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St. N., London, ON N6A 5B7, Canada

    Lawson Research Institute, 750 Base Line Rd E, London, ON N6C 2R5, Canada
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  • Author Footnotes
    1 Equal contributions as lead authors.
    2 Equal contributions as senior authors.

      Highlights

      • Ischemic stroke induced left atrial endothelial dysfunction, inflammation and fibrosis.
      • Changes were more severe in the periphery of pulmonary vein ganglionated plexi.
      • There was no evidence of myocardial necrosis, suggesting non-ischemic mechanisms.
      • There was no increase of troponin T, B-Natriuretic peptide or left atrial enlargement.
      • Local dysautonomic and inflammatory mechanisms are possible culprits.

      Abstract

      Background

      Insular cortex (IC) ischemic strokes are associated with increased risk of cardiac arrhythmias. We have previously hypothesized that the anatomical substrate for post-stroke neurogenic arrhythmias comprises stroke-induced left atrium (LA) coronary microvascular endothelial dysfunction (CMED), and myocardial inflammatory infiltration (MII) leading to myocardial fibrosis. We investigated whether selectively induced IC ischemic stroke in rats results in histopathological changes in the LA.

      Methods

      Insular ischemic stroke was induced in 6-month old male Wistar rats via unilateral stereotaxic injection of endothelin-1 into the left or right IC. The control group consisted of rats injected with saline. We histologically examined the LA 28 days after stroke for CMED, MII, and fibrosis. We performed linear regression analyses to assess correlation between the 3 histopathological outcomes. We compared these findings in the distal LA and the LA-pulmonary vein border (LA-PV border), a region of rich autonomic innervation.

      Results

      Right and left IC stroke led to CMED, MII, and fibrosis in the LA. MII was significantly correlated with CMED and fibrosis. The LA-PV border had significantly greater MII and fibrosis than the distal LA. There were no differences in coronary microvascular and myocardial changes between left and right IC strokes.

      Conclusions

      Left and right insular ischemic strokes resulted in CMED, MII, and fibrosis, the pathological hallmark of arrhythmogenic LA tissue. Since these changes were greater within the LA-PV border than in the distal LA tissue, the role of preganglionic fibers at the ganglionated plexi as part of neurogenic arrhythmogenesis warrants further investigation.

      Keywords

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