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Atrial fibrillation and cognitive function in the absence of stroke

Longitudinal studies have shown that dementia is more common in patients diagnosed with atrial fibrillation ( AF ) even in the absence of stroke.
A meta-analysis of eight prospective studies evaluating the relationship between atrial fibrillation and incident dementia in patients without stroke and baseline normal cognitive function included a total of 77 668 patients of whom 15% had atrial fibrillation.

After a mean follow-up of about 8 years, 6.5% of patients developed dementia. Atrial fibrillation was independently associated with increased risk of incident dementia ( hazard ratio, HR=1.42, 95% CI 1.17–1.72; P less than 0.001 ).

This result was confirmed by a longitudinal analysis from the Cardiovascular Health Study including 5150 participants without baseline history of stroke.

Incident atrial fibrillation occurred in 11% of patients, with faster decline in mean cognitive function scores, measured using the Modified Mini Mental State Examination ( 3MSE ), compared with patients in sinus rhythm.
Although both atrial fibrillation and dementia are diseases of aging, in two large observational studies the highest RR of dementia was observed in younger AF patients less than 70 years of age.
A recent cross-sectional study indicated that in individuals with heart failure with reduced and preserved systolic ejection fraction, atrial fibrillation was associated with an adjusted higher odds of presence and severity of prevalent cognitive impairment.

In people with 80 years or more the relationship between atrial fibrillation and dementia seems to be mostly mediated by concomitant risk factors.

The relationship between atrial fibrillation and cognitive decline may occur through a variety of pathological mechanisms.
Given the relationship between atrial fibrillation and stroke, vascular dementia may be an obvious contributor to cognitive decline, encompassing both multi-infarct dementia and vascular dementia.

The second form of dementia in AF patients is Alzheimer’s disease, which is the most common type of dementia overall.
Atrial fibrillation has been identified as a risk factor for Alzheimer’s disease.
Alzheimer’s disease is the result of accumulation of abnormally folded beta-amyloid and tau proteins forming cerebral plaques which exert cytotoxic effects leading to cerebral atrophy.

Interestingly, misfolded atrial natriuretic peptides may lead to development of amyloid fibrils and deposits in the atria of elderly patients with atrial fibrillation causing a specific atrial cardiomyopathy classified as EHRAS IVa.

However, if atrial fibrillation and Alzheimer’s disease share a common link with regards to protein misfolding and amyloidgenesis, it does not appear to be through the APOE ε4 allele.

Other studies suggest that the occurrence of Alzheimer’s disease is related to hypoperfusion, inflammation, oxidative stress, and endothelial dysfunction.
All these factors may be induced by several non-cardiac diseases resulting in an atrial cardiomyopathy which in turn, leads to atrial fibrillation in the sense of both atrial fibrillation and Alzheimer’s disease being the result of third confounding factors.

Additionally, several circulating biomarkers of oxidative stress, inflammation, and endothelial dysfunction are elevated during atrial fibrillation.
These factors are also linked to cerebral small vessel disease; therefore, atrial fibrillation may provide a specific milieu for non-stroke related cognitive decline and dementia.
For example, hippocampal atrophy in AF patients may be mediated by altered cerebral perfusion due to irregular R-R intervals, abnormal or rapid heart rate, and reduced blood pressure caused by atrial fibrillation, since the hippocampus is one of the most perfusion-sensitive structures of the brain.

Interestingly, patients with atrial fibrillation had lower total brain volume when compared with those without atrial fibrillation, independent of cerebral emboli in a large cross-sectional study.
In addition, recently, atrial fibrillation was associated with a decrease in total cerebral blood flow and brain perfusion in an unselected elderly cohort.
These results may, at least in part, explain the association of atrial fibrillation with reduced relative brain volume and cognitive impairment.

A number of trials are currently examining, as the primary or secondary outcome, the effect of different therapies including anticoagulation and of different interventions on cognitive function in patients with atrial fibrillation.
The results of these studies will help to improve our understanding of the relationship between atrial fibrillation and cognitive function and provide us with more data for possible prevention of cognitive decline by treatment of atrial fibrillation. ( Xagena )

Source: Dagres N et al, Europace, 2018