Vascular Cognitive Impairment Linked to Brain Endothelium Inflammation in Early Stages of Heart Failure in Mice

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Katarzyna Byk¹  Joanna M. Wierońska²  Mateusz G. Adamski³  Dawid Kaczor³  Magdalena Sternak³  Stefan Chlopicki³  Kamil Przyborowski³  Tasnim Mohaissen³  Monika Malinowska⁴  Grzegorz Wilczyński⁴  Iwona Czaban⁴  Kristina S. Lyngsø⁵  Pernille B.L. Hansen⁵ 

[1] Institute of Nuclear Physics, Polish Academy of Sciences, Warsaw, Poland;Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland;Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland;Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw, Poland;University of Southern Denmark, Odense, Denmark;

关键词: blood‐brain barrier;    cognitive impairment;    endothelium;    heart failure;    platelet;   

DOI  :  10.1161/JAHA.117.007694

来源: DOAJ

【 摘 要 】

BackgroundAlthough advanced heart failure (HF) is a clinically documented risk factor for vascular cognitive impairment, the occurrence and pathomechanisms of vascular cognitive impairment in early stages of HF are equivocal. Here, we characterize vascular cognitive impairment in the early stages of HF development and assess whether cerebral hypoperfusion or prothrombotic conditions are involved. Methods and ResultsTgαq*44 mice with slowly developing isolated HF triggered by cardiomyocyte‐specific overexpression of G‐αq*44 protein were studied before the end‐stage HF, at the ages of 3, 6, and 10 months: before left ventricle dysfunction; at the stage of early left ventricle diastolic dysfunction (with preserved ejection fraction); and left ventricle diastolic/systolic dysfunction, respectively. In 6‐ to 10‐month‐old but not in 3‐month‐old Tgαq*44 mice, behavioral and cognitive impairment was identified with compromised blood‐brain barrier permeability, most significantly in brain cortex, that was associated with myelin sheet loss and changes in astrocytes and microglia. Brain endothelial cells displayed increased E‐selectin immunoreactivity, which was accompanied by increased amyloid‐β1‐42 accumulation in piriform cortex and increased cortical oxidative stress (8‐OHdG immunoreactivity). Resting cerebral blood flow measured by magnetic resonance imaging in vivo was preserved, but ex vivo NO‐dependent cortical arteriole flow regulation was impaired. Platelet hyperreactivity was present in 3‐ to 10‐month‐old Tgαq*44 mice, but it was not associated with increased platelet‐dependent thrombogenicity. ConclusionsWe report for the first time that vascular cognitive impairment is already present in the early stage of HF development, even before left ventricle systolic dysfunction. The underlying pathomechanism, independent of brain hypoperfusion, involves preceding platelet hyperreactivity and brain endothelium inflammatory activation.

【 授权许可】

Unknown