Review
Mechanisms, Clinical Significance, and Prevention of Cognitive Impairment in Patients With Atrial Fibrillation

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Abstract

Atrial fibrillation (AF) and dementia are major health issues, with growing evidence suggesting a consistent association between AF and all forms of dementia. Although dementia and AF share several risk factors, the association appears to be independent of a history of clinical stroke and other comorbidities such as hypertension, heart failure, and diabetes. Proposed mechanisms linking AF to cognitive decline include altered hemodynamics resulting in cerebral hypoperfusion, inflammation, genetic factors, and silent cerebral ischemia due to subclinical microemboli. Evidence in support of the microembolization hypothesis includes the much higher incidence of silent cerebral ischemia detected in imaging studies in patients with AF, the association between presence of silent cerebral ischemia and cognitive dysfunction, and a “dose response” relationship between extent of silent cerebral ischemia and degree of cognitive impairment. Preventive therapies are currently being investigated and include anticoagulation, antiplatelet therapy, statins, pharmacological rhythm and rate control treatment strategies for AF, and catheter ablation procedures. Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) trial is currently assessing whether oral anticoagulation can prevent cognitive decline in patients at low risk of overt stroke. Considering the strong and independent association between AF and neurocognitive outcomes and the major clinical implications, evidence-based preventive approaches are critically required to diminish the health burden from the scourge of dementia and related conditions.

Résumé

La fibrillation auriculaire (FA) et la démence sont des enjeux majeurs de santé pour lesquels de plus en plus d’évidences montrent un lien entre FA et toutes les formes de démence. Bien qu'ils partagent de nombreux facteurs de risques, l'association semble indépendante des antécédents d'accident vasculaire cérébral ou d'autres comorbidités comme l'hypertension, l'insuffisance cardiaque ou le diabète. Les mécanismes suspectés d'expliquer l'association entre FA et démence inclus l'hypoperfusion cérébrale, l'inflammation, les facteurs génétiques et l'ischémie cérébrale silencieuse. Parmi les données probantes supportant l'hypothèse micro-embolique, on note : une augmentation de la prévalence de l'ischémie cérébrale silencieuse sur les examens d'imagerie chez les patients en FA, une association entre ischémie cérébrale silencieuse et dysfonction cognitive, ainsi qu'une relation « dose-effet » entre le nombre de lésions d'ischémie cérébrale silencieuse et le degré d'atteinte cognitive. Les thérapies préventives qui sont actuellement explorées sont les suivantes : anticoagulation, thérapie antiplaquettaire, statines, contrôle du rythme pharmacologique ou par ablation par cathéter et contrôle de la fréquence cardiaque. L’étude BRAIN AF (Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation) évalue actuellement si une anticoagulation par voie orale peut prévenir le déclin cognitif chez les patients à faible risque d'accident vasculaire cérébral. Compte tenu de l'association forte et indépendantes qui existe entre FA et troubles cognitifs et les répercussions cliniques majeures, des approches préventives fondées sur des preuves.

Section snippets

Cognitive Impairment and AF

Cognition encompasses several essential brain functions including memory, language, intuition, judgement, and the capacity to learn. Cognitive disorders range from mild impairment, such as a decline in memory and mental functions that does not affect daily life, to outright dementia, which exerts a toll on normal activities and relationships. Numerous longitudinal and cross-sectional studies have addressed the link between AF and cognitive impairment and dementia (Table 1). Most have reported a

Silent cerebral ischemia

Multiple studies have reported a positive association between AF and silent cerebral ischemia. In a recent meta-analysis, AF was associated with a greater than twofold increase in the odds of having silent cerebral ischemia as detected in imaging studies. These seemingly subclinical events appear to bear clinical relevance. For example, in the Cardiovascular Health Study, silent cerebral ischemia was associated with mild cognitive impairment and, in the Rotterdam Scan Study, it more than

Anticoagulation

Figure 3 and Table 2 provide an overview of therapeutic modalities studied in the prevention of cognitive dysfunction in patients with AF. Several observational studies, including post hoc analyses of clinical trials, have assessed the association between anticoagulation therapy and silent cerebral ischemia or neurocognitive outcomes in patients with AF. The most recent data come from the Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes in Atrial Fibrillation Patients Who Have

AF Ablation

Whether or not AF ablation can prevent cognitive decline on long-term follow-up remains unknown. From the prospective Intermountain AF study, Bunch et al. compared 4212 consecutive patients who underwent AF ablation with 16,848 control participants with AF (matched for age and sex).56 Dementia, defined according to ICD-9 codes, occurred in 0.2% of patients with AF ablation compared with 0.9% of control participants (P < 0.0001). The Early Treatment of Atrial Fibrillation for Stroke Prevention T

Conclusions

Numerous observational studies have described an association between AF and cognitive dysfunction ranging from mild impairment to overt dementia. The association appears to be independent of manifest stroke and of the several risk factors common to both entities. The most convincing pathophysiological mechanism linking AF to cognitive impairment is silent cerebral ischemia due to microembolization. Cerebral hypoperfusion and inflammation might likewise play a role. Genetic predisposing factors

Clinical Perspective

  • Observational studies suggest that AF is independently associated with a ≥ 40% higher risk for dementia, with a stronger association in younger patients (ie, younger than 70-75 years).

  • Proposed pathophysiological mechanisms linking AF to cognitive dysfunction include silent cerebral ischemia, cerebral hypoperfusion, inflammation, reduction in hippocampal brain volume, and genetic factors.

  • Although catheter ablation of AF is associated with an acutely heightened risk for cognitive decline, some

Disclosures

Drs Rivard and Khairy are lead investigators of the BRAIN-AF trial, of which the pilot phase was supported in part by an investigator-initiated grant from Bayer Inc, Canadian Stroke Prevention Network and the Montreal Heart Institute Foundation.

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