Loss of glymphatic homeostasis in heart failure

Abstract Heart failure (HF) is associated with progressive reduction in cerebral blood flow (CBF) and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of HF, induced by myocardial infarction (MI), to investigate the effects of HF with reduced ejection fraction on the brain’s glymphatic function. Using dynamic contrast-enhanced MRI and high-resolution fluorescence microscopy, we found increased solute influx from the CSF spaces to the brain, i.e. glymphatic influx, at 12 weeks post MI. Two-photon microscopy revealed that cerebral arterial pulsatility, a major driver of the glymphatic system, was potentiated at this timepoint, and could explain this increase in glymphatic influx. However, clearance of proteins from the brain parenchyma did not increase proportionately with influx, while a relative increase in brain parenchyma volume was found at 12 weeks post MI, suggesting dysregulation of brain fluid dynamics. Additionally, our results showed a correlation between brain clearance and CBF. These findings highlight the role of CBF as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced CBF. This study paves the way for future investigations into the effects of cardiovascular diseases on the brain's clearance mechanisms, which may provide novel insights into the prevention and treatment of cognitive decline.