Abstract WP425: Blood Brain Barrier Disruption and Vascular Cognitive Impairment in Early Stages of Heart Failure Development in Tgαq*44 Mice
Introduction: Advanced heart failure (HF) with subsequent hypoperfusion is a well-recognized clinical risk factor for the development of Vascular Cognitive Impairment (VCI), with early mechanisms yet to be identified. Tgαq*44 mice are a transgenic model of slowly developing HF and peripheral endothelial dysfunction due to cardiomyocyte-specific overexpression of G protein αq*44 where VCI has not been assessed.
Hypothesis: We hypothesized that Tgαq*44 mice develop VCI at early/compensated stages of HF, due to dysfunction of brain endothelium - essential for the blood brain barrier (BBB) function.
Methods: Tgαq*44 and control FVB mice at the age of 6, 10 and 14 months (m) were studied. Novel Object Recognition (NOR) test (n=8/gr.; 6,10,14 m) was used to assess cognition. BBB permeability was assessed (n=3/gr.; 6,10 m) based on concentration of intravenously injected, fluorescently labeled molecules of increasing sizes (0.6 - 40000kD), in dissected and perfused brain homogenates. Expression of inflammatory activation markers for glia (IBA-1) and astrocytes (GFAP) in brain sections (n=2/gr.; 6,10 m) was assessed with confocal microscopy.
Results: NOR test showed that Tgαq*44 mice compared to age matched controls are cognitively impaired based on decrease in recognition index (p=0.0002 at 6m and p=0.05 at 10m). Figure A illustrates progress in cognitive impairment in mice from 6th to 14th m (p=0.001). BBB permeability test revealed increased BBB damage in whole brain (p=0.001 at 6m) and in cortex and pons (respectively p=0.01 and 0.001 at 10m). Figure B illustrates activation of astrocytes (GFAP- red) and glia (IBA-1 -green) in 6m Tgαq*44 vs. FVB mice.
Conclusions: We conclude that at early stages, HF induces VCI via mechanisms related to the impairment of BBB permeability and suggests that VCI precedes the development of clinical stage of HF. We also identify Tgαq*44 mice as a new model of naturally developing VCI with isolated HF and subsequent impairment of BBB permeability.
Author Disclosures: M.G. Adamski: None. M. Sternak: None. J.M. Wieronska: None. I. Czaban: None. M. Malinowska: None. G.M. Wilczynski: None. A. Pilc: None. S. Chlopicki: None.
- © 2016 by American Heart Association, Inc.