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Atrial Fibrillation, Cognitive Decline And Dementia

Atrial fibrillation (AF) is the most common


clinically significant arrhythmia in the world
It is estimated that, in the United States alone,
the number of people who suffer AF is
approximately 2.5 million, being 1.5 times
more often in men than in women.
Despite the decline in morbidity and mortality
from cardiovascular disease in general due to
advances in prevention and treatment, AF has
not followed a similar trend.
Over the coming years, the incidence of AF is
expected to increase

More than 20% of people aged >70 years have


mild cognitive impairment
Approximately 800,000 individuals develop mild
cognitive impairment and >500,000 develop
dementia annually in the United States
The total number of new cases of dementia
worldwide is about 7.7 million, which means a
new case every four seconds
It is estimated that worldwide, 35.6 million
people were living with dementia in 2010, and
this figure is expected to double every 20 years,
65.7 million in 2030 and 115.4 million in 2050

We conducted a review of the literature to examine


the current evidence supporting an association of
AF with cognitive function, dementia and mild
cognitive impairment (MCI),
describe the predictors of cognitive outcomes in
persons with AF,
summarize the potential pathophysiologic
mechanisms,
discuss the preventive interventions specific for AF,
and
explore the potential impact of current AF treatments
on cognitive decline

To inform this review, we searched PubMed for


publications through June 1, 2016, using the
search query [atrial fibrillation AND (dementia
OR cognitive impairment OR cognitive decline)],
which considered the previous terms in any field
as well as occurring as MeSH terms.
We considered publications mostly from the past 5
years (November 1, 2010 and more recent),
though we did not exclude frequently referenced
older publications, and selected those
considered relevant.

Atrial Fibrillation and Cognitive


Function
In a study in Germany including
122 stroke-free individuals with
AF and 564 individuals without
AF undergoing a detailed
cognitive assessment, those
with AF performed significantly
worse in tasks of learning,
memory, and executive
function

Atrial Fibrillation and Cognitive


Function
analysis of the US-based
Atherosclerosis Risk in Communities
(ARIC) Study, including 325
individuals who underwent detailed
cognitive assessment and heart
rhythm monitoring during a
maximum of 14 days, found that
persistent but not paroxysmal AF
was associated with lower cognitive
function.
These findings suggest that AF
burden, in addition to its presence,
may influence cognitive function

Atrial Fibrillation and Cognitive


Decline
Cross-sectional studies have methodological
problems that limit the interpretation of their
results. Longitudinal studies with repeated
assessment of cognitive function provide a more
rigorous assessment of the association of AF with
cognition
An analysis of 31,506 participants in the multinational ONTARGET and TRASCEND trials
followed up by a median of 5 years found that
those who had AF at baseline or developed it
during the study had a 13% increased risk of
cognitive decline, defined as a decrease of 3 or
more points in the Mini-Mental State Examination
(MMSE) test

Atrial Fibrillation and Cognitive


Decline
among 935 stroke-free participants in the
ARIC Study, incident AF was associated
with faster decline in measures of executive
function and verbal fluency
Of interest, this association was only present
among individuals with subclinical cerebral
infarcts, suggesting that vascular disease
may mediate the link between AF and
cognitive decline

Atrial Fibrillation and


Prevalence of Dementia and
MCI
Among 6584 participants age 55 and older,

those with AF had more than double the


prevalence of dementia compared to those
without AF. The association was stronger in
women and younger (<65 years of age)
participants (a community-based prospective
cohort in Ommord, a suburb of Rotterdam)
A history of stroke among those with AF was
not enough to account for the association,
supporting the presence of alternative
mechanisms

Atrial Fibrillation and


Prevalence of Dementia and
MCI
More recent studies, conducted in smaller

samples have replicated the associations,


demonstrating higher prevalence of
dementia (both Alzheimers disease-type
and vascular dementia) among individuals
with AF compared to those without AF,
independently of potential confounders

Atrial Fibrillation and Incidence


of Dementia
The elevated incidence of stroke in AF
patients explains a relationship between AF
and the development of vascular dementia
Several prospective studies have shown that
AF is also linked with an elevated risk of
other dementias, including Alzheimers
disease, independently of clinical vascular
events

Atrial Fibrillation and Incidence


of Dementia
An analysis of 3,045 community-dwelling
individuals in the Seattle area of the US
found that developing AF was associated
with a 50% increase in the risk of receiving a
diagnosis of Alzheimers disease.
This association was present in individuals with
and without clinically recognized stroke

Atrial Fibrillation and Incidence


of Dementia
Increased risk of dementia associated with AF
has been reported in a secondary analysis of
the ONTARGET and TRASCEND trials,12 the
Finnish CAIDE study,20 and the Rotterdam
cohort
Further confirmation of this association came
from an analysis in a large administrative
databases in Taiwan, including >600,000
individuals, showing a 42% increased risk of
dementia in those with AF versus those
without AF

Atrial Fibrillation and Incidence


of Dementia
A recent systematic review and meta-analysis
pooling some of these previous studies and
others reported a hazard ratio (95%
confidence interval) of dementia of 1.42
(1.171.72) comparing individuals with AF to
those without AF

Atrial Fibrillation and Brain


Abnormalities
AF patients have higher burden of silent cerebral
infarcts and white matter disease, and may have
increased prevalence of cerebral microbleeds
These lesions may explain the fastest cognitive
decline and elevated dementia risk among AF
patients
The presence of these abnormalities may also
impact the management of AF patients, for
example influencing decisions about prescribing
oral anticoagulation or not

Atrial Fibrillation and Brain


Abnormalities
In 4251 participants of the Icelandic populationbased Age, Gene/Environment SusceptibilityReykjavik Study, AF was associated with lower brain
volume and grey matter
Similar to cross-sectional study in individuals from a
community-based study in southeastern Minnesota
An autopsy study in 134 individuals with and 194
without AF found that the prevalence of Alzheimers
disease neuropathologic changes (neuritic plaques,
neurofibrillatory tangles) was higher in individuals
with permanent AF than in those without AF

Predictors of Cognitive
Impairment and Dementia in
Persons with Atrial
Fibrillation
Some studies have found that higher CHADS2
and CHA2DS2-VASc scores, stratification
schemes commonly used to inform
anticoagulant treatment in persons with AF,
predict dementia in these patients
This association is not surprising, given that
age, possibly the strongest predictor of
dementia, is part of the scores. Dementiaspecific risk models are likely to provide
more accurate predictions

Predictors of Cognitive
Impairment and Dementia in
Persons with Atrial
data
from the Intermountain Healthcare Clinical
Fibrillation
Pharmacist Anticoagulation Service, in Utah, US, reported
that low percent of time in the therapeutic range among
users of vitamin K antagonists were at higher risk of
dementia due to under- or overcoagulation
Though informative, these studies are limited in that they
cannot determine whether baseline cognitive function
confounds the association between suboptimal oral
anticoagulation and the future risk of dementia. For
example, individuals with worse cognitive function at the
time of initiation of oralanticoagulation may have more
problems following an adequate therapeutic regime and
would be at higher risk of being diagnosed with dementia
later on

Mechanisms Linking Atrial


Fibrillation, Cognitive
Decline and Dementia Risk

An obvious pathway linking AF with cognitive


decline or dementia is the elevated risk of stroke
among AF patients. AF is associated with at least
a doubling of stroke risk,32 and the effects of
stroke on cognitive function are well established
However, elevated stroke risk does not completely
mediate the increased risk of dementia and
cognitive decline associated with AF.
Other mechanisms such as silent cerebral infarcts,
microbleeds associated with oral anticoagulation,
and cerebral hypoperfusion are likely to play a
role

Mechanisms Linking Atrial


Fibrillation, Cognitive
Decline and Dementia Risk

AF more than doubles the risk of silent cerebral


infarcts independently of stroke
a subset of stroke-free participants of the ARIC
study who had repeated brain MRIs approximately
12 years apart, we showed that AF was associated
with cognitive decline only among individuals who
developed incident silent cerebral infarcts
The hypercoagulable state resulting from AF is
certain to play a role in this mechanism and,
consequently, anticoagulation may be effective to
prevent adverse cognitive outcomes in patients
with AF

Mechanisms Linking Atrial


Fibrillation, Cognitive
Decline and Dementia Risk

AF could increase dementia risk through its impact


on cardiac function
Patients with AF have been found to have reduced
cerebral perfusion,37 and restoration of sinus
rhythm in AF patients through cardioversion or
ablation leads to improvements in cerebral blood
flow
Reduced diastolic function and low cardiac index,
both potential consequences of AF, have been
associated with incident dementia in prospective
studies

Mechanisms Linking Atrial


Fibrillation, Cognitive
Decline
and
Dementia
Risk
AF is an established risk factors for heart failure,42

which in turn can worsen cerebral hypoperfusion


Microbleeds are relatively frequent and have been linked
with an increased risk of cerebral hemorrhage, lacunar
infarcts, and degenerative changes of the brain matter
Oral anticoagulation in persons with AF can increase the
risk of the development of microbleeds or worsen the
impact of existing ones on cognitive function. In the
community-based Rotterdam study, individuals using
coumarin anticoagulants had a higher prevalence and
incidence of microbleeds. This risk was particularly
higher among individuals with greater variability in
anticoagulation control

Mechanisms Linking Atrial


Fibrillation, Cognitive
Decline and Dementia Risk

Analysis of several community-based studies


have demonstrated that presence of
electrocardiographic left atrial abnormality,
a marker of atrial cardiopathy, is associated
with increased risk of ischemic stroke,
mostly non-lacunar, and vascular brain
injury even in the absence of AF

Prevention of Cognitive
Impairment in Persons with
Atrial
CurrentFibrillation
guidelines recommend oral

anticoagulation for stroke prevention in most


individuals with AF
Decreased stroke risk in patients receiving
adequate anticoagulation should consequently
lead to reduced risk of adverse cognitive
outcomes
Improved anticoagulation control could be
particularly effective in high-risk individuals, for
example those who already have some cognitive
impairment

Prevention of Cognitive
Impairment in Persons with
Atrial
Fibrillation
A recent
clinical trial including 973 elderly

patients with AF found that patients randomized


to warfarin had less cognitive decline than
those randomized to aspirin after 33 months of
follow-up, though the differences were not
statistically significant
A recent analysis comparing risk of dementia in
patients with AF using warfarin or non-vitamin K
oral anticoagulants (NOACs) reported lower risk
of dementia among NOAC than warfarin users

Prevention of Cognitive
Impairment in Persons with
Atrial
Fibrillation
A randomized
trial of weight loss and risk factor
management in 150 AF patients led to clinically
significant reductions in AF burden and
symptoms, and improved cardiac function
Similar findings were obtained in 355 AF
patients participating in a weight loss
intervention, where those who experience
sustained weight loss had reductions in AF
burden and were more likely to remain in sinus
rhythm

Prevention of Cognitive
Impairment in Persons with
Atrial
RecentFibrillation
studies indicate that dietary

intervention and improved blood pressure


control can prevent AF. Whether these
interventions in turn could lead to reduced
risk of dementia and cognitive decline
remains undetermined.

Conclusion
A growing and consistent body of literature
supports a role for AF as a risk factor for
cognitive decline and dementia
The mechanisms responsible for this association
are diverse and go beyond the well-established
increased stroke risk in persons with AF
Future research needs to deepen the
understanding of those mechanisms and, more
importantly, develop interventions that reduce
the burden of adverse cognitive outcomes
associated with AF.