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Canadian Journal of Cardiology

Rhythm Control and Dementia in Patients With Atrial Fibrillation: A Role for Glymphatic System?

Published:December 15, 2022DOI:https://doi.org/10.1016/j.cjca.2022.11.016
      To the Editor:
      We welcome the review by Blum and Conen, which deals with critical connection between atrial fibrillation (AF) and cognitive impairment in an objective and instructive way.
      • Blum S.
      • Conen D.
      Mechanisms and clinical manifestations of cognitive decline in atrial fibrillation patients: potential implications for preventing dementia.
      Indeed, AF-associated cognitive impairment (AFACI) is an underrecognised category of the dementia spectrum that is potentially targetable for prevention and treatment. Asymptomatic and symptomatic macro– and micro–cerebral embolism is the first to be proposed for AFACI mechanism. Cerebral hypoperfusion due to tachycardia and heart failure, impaired cerebral hemodynamic regulation during irregular cardiac cycles, and neuroendocrine and inflammatory perturbations also may play a role. In addition, the incidence of Alzheimer disease (AD) is higher in patients with AF, and AF is an independent risk factor for AD. Although the mechanism of AD-AF connection is unknown, the shared vascular and genetic risk profile is probably involved. We propose that a mechanistic hypothesis can be added.
      Accumulation of neurotoxic forms of amyloid-β and tau proteins is the key in AD neuropathology. The insufficiency of the glymphatic system, which is the amyloid-β paravascular clearance system, is one of the critical steps in this accumulation.
      • Jessen N.A.
      • Munk A.S.
      • Lundgaard I.
      • Nedergaard M.
      The glymphatic system: a beginner‘s guide.
      The primary drivers of solute exchange between the interstitial space and the cerebrospinal fluid (CSF) in the glymphatic system are arteriolar pulsation and vasomotion. Cardiac diseases such as atrial arrhythmia and heart failure with low ejection fraction may decrease CSF flow with decreased arterial wall pulsatility.
      • Nedergaard M.
      • Goldman S.A.
      Glymphatic failure as a final common pathway to dementia.
      In addition, causes of atherosclerosis, such as hypertension or diabetes, which also cause heart disease, reduce cerebral arteriolar compliance and ultimately pulsatility.
      We would like to add that AF alone reduces glymphatic clearance by disrupting CSF flow rhythmicity. Even in such a distal circulatory bed, AF affects vascular wall wave dynamics and disrupts periodicity of the arteriolar systolic pulsation wave. This deterioration may be more pronounced, especially when there are highly irregular heart beats and pulses with extreme amplitude. Arrhythmia-caused disturbance in the perivascular convection leads to a decrease in its gain. In addition, this irregularity may cause loss of synchronization with vasomotion.
      • Rajna Z.
      • Mattila H.
      • Huotari N.
      • et al.
      Cardiovascular brain impulses in Alzheimer‘s disease.
      Once amyloid-β retention initiates, it directly affects vasomotion negatively, deteriorating neurovascular coupling gradually and perhaps increasing the need for systolic pulse drive. This may become more evident as the disease progresses. Therefore, AFACI cannot be completely eliminated, even if reduced, by anticoagulation. Stable and sustained AF rhythm control is necessary, at least theoretically, for dementia prevention. Amyloid clearance and cerebral blood flow increase provided by rhythm control contribute to the observed benefit.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Blum S.
        • Conen D.
        Mechanisms and clinical manifestations of cognitive decline in atrial fibrillation patients: potential implications for preventing dementia.
        Can J Cardiol. 2023; 39: 159-171
        • Jessen N.A.
        • Munk A.S.
        • Lundgaard I.
        • Nedergaard M.
        The glymphatic system: a beginner‘s guide.
        Neurochem Res. 2015; 40: 2583-2599
        • Nedergaard M.
        • Goldman S.A.
        Glymphatic failure as a final common pathway to dementia.
        Science. 2020; 370: 50-56
        • Rajna Z.
        • Mattila H.
        • Huotari N.
        • et al.
        Cardiovascular brain impulses in Alzheimer‘s disease.
        Brain. 2021; 144: 2214-2226

      Linked Article

      • Mechanisms and Clinical Manifestations of Cognitive Decline in Atrial Fibrillation Patients: Potential Implications for Preventing Dementia
        Canadian Journal of CardiologyVol. 39Issue 2
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          Atrial fibrillation (AF) patients face an approximate 1.5-fold increased risk of cognitive decline compared with the general population. Among poststroke AF patients, the risk of cognitive decline is even higher with an estimated threefold increase. This article provides a narrative review on the current evidence and highlights gaps in knowledge and areas for future research. Although earlier studies hypothesized that the association between AF and cognitive decline is mainly a consequence of previous ischemic strokes, more recent evidence also suggests such an association in AF patients without a history of clinical stroke.
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      • Reply to Saka et al.—Rhythm Control and Dementia in Patients With Atrial Fibrillation: A Role for Glymphatic System?
        Canadian Journal of CardiologyVol. 39Issue 2
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          We agree that additional mechanisms not described in our review contribute to the association between atrial fibrillation and cognitive decline. The authors propose that atrial fibrillation might reduce glymphatic clearance and thereby can lead to accumulation of amyloid-β, which subsequently might explain the higher risk of Alzheimer disease. While some studies suggest an impaired clearance of brain metabolites via the glymphatic system as a potential mechanism for white matter lesions,1 it has to be emphasised that this concept has mainly been described in preclinical studies.
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