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

Abstract

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.

Neurovascular Coupling Impairment in Heart Failure with Reduction Ejection Fraction

“…As HF is a pro-inflammatory state, it induces further damage in this cerebrovascular hemodynamic mechanism [ 24 , 25 ]. In a recent in vivo study by Adamski, M. G. et al, clinical cognitive impairment was associated with cerebral inflammation in HF in mice [ 26 ].…”

Improving Cerebrovascular Function to Increase Neuronal Recovery in Neurodegeneration Associated to Cardiovascular Disease

“…Another target of pre-clinical investigation in attempt to link HF and neurodegeneration is inflammation associated to CBF deficits. In a mouse model of slowly developing HF, vascular CI was observed during the early stages of HF and interestingly, preceded the development of left ventricular dysfunction (Adamski et al, 2018). Precise non-cardiacdependent contributors to such early onset vascular CI still need to be confirmed.…”

“…Precise non-cardiacdependent contributors to such early onset vascular CI still need to be confirmed. However, platelet hyperactivity, contributing to BBB impairment and in turn, cerebral endothelial inflammation and impairment of NO−dependent vasoregulation was put forward to promote the development of CI and lead to a chronic manifestation of CBF deficits during advanced HF (Adamski et al, 2018). Key players involved in this signaling cascade remain unknown and hence, platelet-targeting therapy as strategy FIGURE 1 | Schematic illustration of sphingosine-1-phosphate (S1P) signaling-mediated myogenic tone regulation in vascular smooth muscle cells.…”

Neuroinflammation in heart failure: new insights for an old disease

“…In the context of HFpEF, BBB dysfunction has been reported in cortex and pons (Adamsky et al . ); however, this study was mainly focused in cortex areas related to cognitive impairment and no major attention was put in SNS control areas. Future studies are needed to address the contribution of altered BBB integrity to autonomic dysregulation and cardiac dysfunction in HF.…”