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Publications

Journal Article Ppublish 4 citations

PubMed: 39693238 DOI: 10.1093/brain/awae411

Loss of glymphatic homeostasis in heart failure.

Brain 148(3):985-1000

Authors: Marios Kritsilis, Lotte Vanherle, Marko Rosenholm, René In 't Zandt, Yuan Yao, Kelley M Swanberg, Pia Weikop, Michael Gottschalk, Nagesh C Shanbhag, Jiebo Luo, Kimberly Boster, Maiken Nedergaard, Anja Meissner, Iben Lundgaard

Affiliations

  • Department of Experimental Medical Science, Lund University, 22362 Lund, Sweden.
  • Wallenberg Center for Molecular Medicine, Lund University, 22184 Lund, Sweden.
  • Department of Physiology, Institute of Theoretical Medicine, University of Augsburg, 86159 Augsburg, Germany.
  • Center for Translational Neuromedicine, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
  • Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
  • Lund University Bioimaging Centre, Lund University, 22184 Lund, Sweden.
  • Department of Computer Science, University of Rochester, Rochester, NY 14627, USA.
  • Department of Mechanical Engineering, University of Rochester, Rochester, NY 14627, USA.
  • Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642, USA.

Abstract

Heart failure is associated with progressive reduction in cerebral blood flow 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 heart failure, induced by myocardial infarction, to investigate the effects of heart failure 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-myocardial infarction. Two-photon microscopy revealed that cerebral arterial pulsatility, a major driver of the glymphatic system, was potentiated at this time point, 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-myocardial infarction, suggesting dysregulation of brain fluid dynamics. Additionally, our results showed a correlation between brain clearance and cerebral blood flow. These findings highlight the role of cerebral blood flow as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced cerebral blood flow. 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.

MeSH

Glymphatic System, Heart Failure, Homeostasis, Heart, Brain, Cardiovascular Diseases, Cognitive Dysfunction, Microscopy, Neurology

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