Cognitive impairment is one of the most common co-occurring chronic conditions among
elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms
are not completely understood. It is hypothesized that in addition to decreased cardiac
output, increases in central-and consequentially, cerebral-venous pressure (backward
failure) also contribute significantly to the genesis of cognitive impairment. To
test this hypothesis and elucidate the specific pathogenic role of venous congestion
in the brain, we have established a novel model of increased cerebral venous pressure:
mice with jugular vein ligation (JVL). To test the hypothesis that increased venous
pressure in the brain contributes to the development of cognitive deficits by causing
blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation,
in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function
(radial arm water maze), gait function (CatWalk), and motor coordination (rotarod)
were tested post-JVL. Neurovascular coupling responses were assessed by measuring
changes in cerebral blood flow in the whisker barrel cortex in response to contralateral
whisker stimulation by laser speckle contrast imaging through a closed cranial window.
Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining)
were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene
expression profile was assessed by a targeted qPCR array. After jugular vein ligation,
mice exhibited impaired spatial learning and memory, altered motor coordination, and
impaired gait function, mimicking important aspects of altered brain function observed
in human heart failure patients. JVL did not alter neurovascular coupling responses.
In the brains of mice with JVL, significant extravasation of IgG was detected, indicating
blood-brain barrier disruption, which was associated with histological markers of
neuroinflammation (increased presence of activated microglia) and a pro-inflammatory
shift in gene expression profile. Thus, cerebral venous congestion per se can cause
blood-brain barrier disruption and neuroinflammation, which likely contribute to the
genesis of cognitive impairment. These findings have relevance to the pathogenesis
of cognitive decline associated with heart failure as well as increased cerebal venous
pressure due to increased jugular venous reflux in elderly human patients.
