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

ABSTRACT: BACKGROUND:Although 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 RESULTS:Tg?q*44 mice with slowly developing isolated HF triggered by cardiomyocyte-specific overexpression of G-?q*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 Tg?q*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-?1-42 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 Tg?q*44 mice, but it was not associated with increased platelet-dependent thrombogenicity. CONCLUSIONS:We 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.

SUBMITTER: Adamski MG

PROVIDER: S-EPMC5907583 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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

Adamski Mateusz G MG Sternak Magdalena M Mohaissen Tasnim T Kaczor Dawid D Wierońska Joanna M JM Malinowska Monika M Czaban Iwona I Byk Katarzyna K Lyngsø Kristina S KS Przyborowski Kamil K Hansen Pernille B L PBL Wilczyński Grzegorz G Chlopicki Stefan S

Journal of the American Heart Association 20180326 7

<h4>Background</h4>Although 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.<h4>Methods and results</h4>Tgαq*44 mice with slowly developing isolated HF triggered by car ...[more]

PMID: 29581224

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Project description:BACKGROUND:Previous studies suggest that heart failure (HF) is an independent risk factor for cognitive decline. A better understanding of the relationship between HF, cognitive status, and cognitive decline in a community-based sample may help clinicians understand disease risk. OBJECTIVE:To examine whether persons with HF have a higher prevalence of cognitive impairment and whether persons developing HF have more rapid cognitive decline. DESIGN:This observational cohort study of American adults in the Atherosclerosis Risk in Communities (ARIC) study has two components: cross-sectional analysis examining the association between prevalent HF and cognition using multinomial logistic regression, and change over time analysis detailing the association between incident HF and change in cognition over 15 years. PARTICIPANTS:Among visit 5 (2011-2013) participants (median age 75 years), 6495 had neurocognitive information available for cross-sectional analysis. Change over time analysis examined the 5414 participants who had cognitive scores and no prevalent HF at visit 4 (1996-1998). MEASUREMENTS:The primary outcome was cognitive status, classified as normal, mild cognitive impairment [MCI], and dementia on the basis of standardized cognitive tests (delayed word recall, word fluency, and digit symbol substitution). Cognitive change was examined over a 15-year period. Control variables included socio-demographic, vascular, and smoking/drinking measures. RESULTS:At visit 5, participants with HF had a higher prevalence of dementia (adjusted relative risk ratio [RRR] = 1.60 [95% CI 1.13, 2.25]) and MCI (RRR = 1.36 [1.12, 1.64]) than those without HF. A decline in cognition between visits 4 and 5 was - 0.07 standard deviation units [- 0.13, - 0.01] greater among persons who developed HF compared to those who did not. Results did not differ by ejection fraction. CONCLUSION:HF is associated with neurocognitive dysfunction and decline independent of other co-morbid conditions. Further study is needed to determine the underlying pathophysiology.

Project description:INTRODUCTION:Nonfocal transient neurological attacks (TNAs) are associated with an increased risk of future dementia, but it is unclear whether TNAs are also associated with concurrent cognitive impairment. We hypothesized that recent TNAs are related to worse cognitive functioning. We tested our hypothesis in patients with heart failure, as these patients are at risk of cerebral hypoperfusion, which might play a role in the etiology of TNAs. METHODS:We performed neuropsychological testing in all patients with heart failure enrolled in the Heart Brain Connection study. We assessed global cognition, attention-psychomotor speed, executive functioning, memory and language. All patients were interviewed with a standardized questionnaire on the occurrence of TNAs in the preceding 6 months. We studied associations between TNAs and cognitive functioning with linear and logistic regression analyses, adjusted for age, sex and education. We performed additional analyses in patients without previous stroke or TIA and in patients without brain infarction on MRI. RESULTS:Thirty-seven (23%) of 158 patients (mean age 70 years, 67% men) experienced one or more TNAs. Patients with a recent TNA were more likely to be impaired on???1 cognitive domains than patients without TNAs [41% vs. 18%, adjusted odds ratio 4.6, 95% confidence interval (CI) 1.8-11.8]. Patients with TNAs performed worse than patients without TNAs on global cognition (mean difference in z scores -?0.36, 95% CI -?0.54 to -?0.18), and on the cognitive domains attention-psychomotor speed (mean difference -?0.40, 95% CI -?0.66 to -?0.14), memory (mean difference -?0.57, 95% CI -?0.98 to -?0.15) and language (mean difference -?0.47, 95% CI -?0.79 to -?0.16). These associations were independent of cardiac output and volume of white matter hyperintensities. Subgroup analyses in patients without previous stroke or TIA or brain infarction on MRI (n?=?78) yielded comparable results, with the exception of the cognitive domain language, which was no longer different between patients with and without TNAs. CONCLUSION:Among patients with heart failure, TNAs are associated with cognitive impairment, which warrants the need for more clinical awareness of this problem.

Dataset Information

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

Publications

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

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