Download Atrial fibrillation is independently associated with senile

Atrial fibrillation is independently associated with senile,
vascular, and Alzheimer’s dementia
T. Jared Bunch, MD,*† J. Peter Weiss, MD,*† Brian G. Crandall, MD,*† Heidi T. May, PhD, MSPH,†
Tami L. Bair, RN,† Jeffrey S. Osborn, MD,*† Jeffrey L. Anderson, MD,† Joseph B. Muhlestein, MD,†
Benjamin D. Horne, PhD, MSPH,† Donald L. Lappe, MD,† John D. Day, MD, FHRS*†
From the *Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Murray, Utah; †Department of
Cardiology, Intermountain Medical Center, Murray, Utah.
BACKGROUND The aging population has resulted in more patients living with cardiovascular disease, such as atrial fibrillation
(AF). Recent focus has been placed on understanding the longterm consequences of chronic cardiovascular disease, such as a
potential increased risk of dementia.
OBJECTIVE This study sought to determine whether there is an
association between AF and dementia and whether their coexistence is an independent marker of risk.
METHODS A total of 37,025 consecutive patients from the large
ongoing prospective Intermountain Heart Collaborative Study database were evaluated and followed up for a mean of 5 years for
the development of AF and dementia. Dementia was sub-typed
into vascular (VD), senile (SD), Alzheimer’s (AD), and nonspecified (ND).
RESULTS Of the 37,025 patients with a mean age of 60.6 ⫾ 17.9
years, 10,161 (27%) developed AF and 1,535 (4.1%) developed
dementia (179 VD, 321 SD, 347 AD, 688 ND) during the 5-year
follow-up. Patients with dementia were older and had higher rates
of hypertension, coronary artery disease, renal failure, heart fail-
Dementia is a disorder that is characterized by impairment of memory and at least one additional cognitive domain. The consequences of dementia must represent a decline from the previous level of function and impact quality
of life and daily function. Because of an aging population,
dementia is an increasing problem as it primarily affects
elderly patients. Alzheimer’s disease (AD) is the most common form of dementia in the elderly, accounting for 60% to
80% of cases, followed by vascular dementia (VD), which
accounts for 10% to 20%.1,2 Dementia in general tends
to increase with increasing age,3–5 diabetes,6 –10 hyperten-
Drs. Bunch, Weiss, Crandall, and Osborn have received speaker’s
honorarium (minor) from Boston Scientific. Dr. Day is a consultant (minor)
for Boston Scientific and St. Jude Medical. Address reprint requests and
correspondence: Dr. T. Jared Bunch, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Eccles Outpatient Care Center,
5169 Cottonwood Street, Suite 510, Murray, Utah 84107. E-mail address:
[email protected]. (Received September 3, 2009; accepted December 3, 2009.)
ure, and prior strokes. In age-based analysis, AF independently
was significantly associated with all dementia types. The highest
risk was in the younger group (⬍70). After dementia diagnosis,
the presence of AF was associated with a marked increased risk of
mortality (VD: hazard ratio [HR] ⫽ 1.38, P ⫽ .01; SD: HR ⫽ 1.41,
P ⫽ .001; AD: HR ⫽ 1.45; ND: HR ⫽ 1.38, P ⬍.0001).
CONCLUSION AF was independently associated with all forms of
dementia. Although dementia is strongly associated with aging,
the highest risk of AD was in the younger group, in support of the
observed association. The presence of AF also identified dementia
patients at high risk of death.
KEYWORDS Atrial fibrillation; Dementia; Alzheimer’s; Hypertension; Aging; Stroke
ABBREVIATIONS AD ⫽ Alzheimer’s disease; AF ⫽ atrial fibrillation; HR ⫽ hazard ratio; ICD ⫽ International Classification of
Diseases; ND ⫽ nonspecified dementia; SD ⫽ senile dementia;
VD ⫽ vascular dementia
(Heart Rhythm 2010;7:433– 437) © 2010 Heart Rhythm Society. All
rights reserved.
sion,6,10 –13 smoking history,14 and systemic inflammation.15,16
Atrial fibrillation (AF) is the most common arrhythmia
encountered in clinical practice, and similar to dementia, its
prevalence increases with age. It is a significant risk factor
for thromboembolic stroke, and affects up to 9% of the
population by age 80.17,18 It also independently increases
total mortality in patients with and without cardiovascular
disease.19 Hypertensive heart disease and coronary heart
disease are the most common underlying disorders in patients with AF in developed countries.20,21 Similar to the
association with dementia, the risk of AF increases with
age,21 diabetes,22 hypertension,21 and increases in systemic
inflammation.23,24
Recent data have emerged to show an association between AF and AD progression.13 This observation is not
surprising because the disease states of dementia and AF
share similar background risk factors. Furthermore, AF has
been independently linked to memory impairment, cognitive decline, and general dementia in patients without pre-
1547-5271/$ -see front matter © 2010 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2009.12.004
434
existing disease.25–27 Nonetheless, more studies are required to verify and confirm the independent risk of AD in
AF patients. In addition, it is unclear whether those patients
with AF and dementia represent a high-risk group for longterm adverse outcomes. To understand the independent risk
of AF and dementia and their combined long-term outcomes, we studied the association in a large patient population with comparison of results across multiple age strata.
The primary objective was to confirm the independent risk
of AF and AD. The secondary objective was to determine
the impact of AF in those subsequently diagnosed with AD
and other dementia types on risk of mortality.
Methods
We examined the Intermountain Heart Collaborative Study
database to examine an association of AF and dementia.28
This database includes all patients who receive care within
the Intermountain Healthcare system and were seen by
cardiologists with consent to participate in research. The
population studied as noted in the prior publications is
predominantly white (89%), with other races as follows:
Hispanic 7%, Polynesian/Asian 1%, black 2%, and Native
American 1%. We studied 37,026 consecutive patients who
had a mean of 5 years of follow-up. Patients with preexisting dementia or AF were excluded. Extracted clinical
variables were based on inpatient and outpatient clinical
visits and included age, hypertension, diabetes, hyperlipidemia, renal failure, smoking history, prior myocardial infarction or cerebral vascular accident, and heart failure.
Included in the extracted data was use of medications (3hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
[statins], angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and diuretics). In
20,471 patients, an ejection fraction was available through
search of the echocardiogram database.
Patients’ AF status was determined by searching the
hospital discharge summary for diagnostic (International
Classification of Diseases, Ninth Revision [ICD-9]) codes
for AF at index and previous admissions to Intermountain
Healthcare hospitals (Salt Lake City, Utah, and its surrounding areas) and by searching the electrocardiographic database of all Intermountain Healthcare hospitals, which was
maintained on electronic records. The electrocardiogram
database includes electrocardiograms, ambulatory monitors,
and symptom- and auto-triggered event monitors from all
Intermountain Healthcare facilities. These databases are updated daily with completion of the dictated medical reports
and physician review of the ordered electrocardiograms.
Dementia was studied in general and as subtypes. Dementia was subtyped into AD, VD, senile dementia (SD),
and nonspecified dementia (ND) based on diagnostic ICD
code (ICD-9 codes 290 to 294, 331, or equivalent). The
subtype ND comprised all dementia types searched. To
assess the reliability of ICD-9 codes for end point analysis,
we examined the study variable diabetes mellitus and found
a 95% accuracy between the diagnosis from the ICD-9
Heart Rhythm, Vol 7, No 4, April 2010
codes and demographic data entered in the coronary angiogram database in those presenting for catheterization.
The other study end point considered was mortality (allcause and coronary artery disease–related mortality [ICD-9
codes 410 to 414 or equivalent]). Deaths were determined
by telephone survey, hospital records, and Utah State Health
Department records (death certificates), and were verified
through Social Security death records. Patients not listed as
deceased in any registry were considered to be alive.
The Student t-test and the chi-square statistic were used
to evaluate baseline and clinical characteristics among patients with and without AF. Multivariable Cox hazard regression analysis (SPSS version 15.0; SPSS Inc., Chicago,
Illinois) was used to evaluate the association of AF with the
incidence of the study end points. Final models entered the
significant (P ⬍.05) and confounding (10% change in hazard ratio [HR]) covariables. Two-tailed P values of ⬍.05
were designated as nominally significant. To assess the
reliability of ICD-9 codes for end point analysis, we examined the study variable diabetes and found a 95% accuracy
in the information from the ICD-9 codes and demographic
data entered in the coronary angiogram database in those
presenting for catheterization.
Results
Of the 37,025 patients with a mean age of 60.6 ⫾ 17.9 years
studied, 10,161 (27%) developed AF and 1,535 developed
(4.1%) dementia (179 VD, 321 SD, 347 AD, 688 ND)
during the 5-year follow-up. The basic demographics of the
patient population listed and compared by AF status are
shown in Table 1. Patients with AF were older and had
higher rates of hypertension, coronary artery disease, renal
failure, heart failure, and prior strokes. Statin use was similar between the groups. On average, the ejection fraction
was lower in the AF group. Patients with AF were more
likely to be treated with an angiotensin-converting enzyme
inhibitor or beta-blocker. Over the 5-year study period of
follow-up, there was an increased incidence of dementia in
general and all dementia subtypes in those patients with AF
(ND: 1.3% (355) vs. 3.3% (333), P ⬍.0001; AD: 0.7%
(199) vs. 1.5% (148), P ⬍.0001; SD: 0.6% (161) vs. 1.6%
(160), P ⬍.0001; VD: 0.3% (89) vs. 0.9% (90), P ⬍.0001)
(Figure 1). The average time to the development of dementia was modestly distinct between subtypes (AD: 1285.3 ⫾
1220.3 days; VD: 1280.5 ⫾ 1258.8 days; SD: 1206.8 ⫾
1141.5 days). Across all dementia states, the cognitive decline occurred earlier in patients with AF versus no AF
(AD: 1225.4 ⫾ 1184.4 vs. 1340.0 ⫾ 1253.7; VD: 1224.6 ⫾
1244.8 vs. 1336.4 ⫾ 1278.2; SD: 1110.8 ⫾ 1121.1 vs.
1300.7 ⫾ 1158.7). In this population, all patients who developed both AF and dementia (n ⫽ 764), developed AF
first, but the dementia diagnosis could have occurred simultaneously with AF or after AF diagnosis.
We examined the multivariable-adjusted age-based association of AF and dementia (Figure 2). For nonspecific
dementia, the greatest risk with AF was in the younger
cohort (ⱕ70 years) and declined in a linear fashion in the
Bunch et al
Table 1
Atrial Fibrillation and Dementia
435
Baseline patient characteristics in general and compared by the presence of atrial fibrillation
Variable
Overall (37,025)
Non-AF (26,864)
AF (10,161)
P value
Age (yrs)
Male
Hypertension
Hyperlipidemia
Diabetes
Renal failure
Smoking
Family history
Myocardial infarction
Cerebral vascular accident
Heart failure
Statin
ACE inhibitor
ARB
Beta-blocker
Diuretic
EF (n ⫽ 20,471)
60.6 ⫾ 17.9
60.1%
44.0%
39.3%
15.7%
1.3%
14.7%
28.2%
6.0%
3.6%
1.1%
31.7%
3.5%
0.9%
4.7%
3.8%
58.7 ⫾ 16.2
57.8 ⫾ 18.9
59.5%
43.8%
41.3%
15.7%
1.1%
15.6%
30.0%
5.4%
3.2%
0.8%
31.7%
3.6%
0.8%
5.0%
3.3%
60.0 ⫾ 15.9
68.1 ⫾ 12.2
61.5%
44.3%
34.2%
15.6%
1.8%
12.3%
23.4%
7.6%
4.7%
1.8%
31.9%
3.2%
1.1%
4.2%
5.2%
55.5 ⫾ 16.6
⬍.0001
⬍.0001
.40
⬍.0001
.82
⬍.0001
⬍.0001
⬍.0001
⬍.0001
⬍.0001
⬍.0001
.68
.03
.009
.001
⬍.0001
⬍.0001
ACE ⫽ angiotensin-converting enzyme; AF ⫽ atrial fibrillation; EF ⫽ ejection fraction; ARB ⫽ angiotensin receptor blocker.
next 2 age strata. A similar association was found with AD,
with the greatest risk in the young (odds ratio 2.30, P ⫽
.001) with no apparent association in older patients. Both
SD and VD were more likely to occur in AF patients in the
2 younger groups (ⱕ70 and 70 to 79 years).
There was also a significant association between dementia and total mortality (ND: HR ⫽ 1.61, P ⬍.0001; AD:
HR ⫽ 1.46, P ⬍.0001; SD: HR ⫽ 1.51, P ⬍.0001; VD:
HR ⫽ 2.14, P ⬍.0001). The presence of AF further increased the risk of general mortality across all dementia
subtypes (Figure 3). The increased risk of death with dementia was greatest in the younger groups (ⱕ70: ND: HR ⫽
1.71, P ⫽ .002; AD: HR ⫽ 2.05, P ⫽ .005; SD: HR ⫽ 1.55,
P ⫽ .10; VD: HR ⫽ 2.07, P ⫽ .007) and became nonsignificant in the older groups (80 to 89, ⱖ90 years). Over the
follow-up period, there was a total of 775 computed tomography scans and 343 magnetic resonance imaging studies.
Figure 1
The incidence of dementia by the patient’s AF status. There is
a significant increase in dementia in general and in all subtypes in patients
with AF.
Of those, 106 patients received both. From these studies,
156 patients were identified as having a stroke. This accounts for 87% of those classified as having vascular dementia.
Discussion
AF was independently associated with risk of all forms of
dementia. Although dementia is strongly associated with
aging, the highest risk of AD was in the younger AF group,
in support of the observed association. The presence of AF
in all dementia subtypes identified patients at higher risk of
mortality. This mortality risk was most prominent in the
youngest population studied.
Age remains the strongest risk factor for dementia, particularly for AD.3 In a community-based study, the estimated annual incidence of AD was 0.6% for patients ages
65 to 69 years, 1.0% for those 70 to 74 years, 2.0% for those
75 to 79 years, 3.3% for those 80 to 84 years, and 8.4% for
Figure 2
Multivariate-adjusted odds ratios based on dementia type and
age subgroup. Younger patients who had AF were at higher risk for all
types of dementia. The association diminished with advancing age and
becomes nonsignificant.
436
Figure 3
Multivariate-adjusted hazard ratios for long-term risk of mortality in patients who have dementia and AF. In all forms of dementia,
patients with AF have significantly increased rates of total mortality.
those 85 years and older.4 In a similar fashion, AF increases
in a nearly linear manner with age. If the disease association
was driven primarily by shared acquired risk factors, then an
increase of each disease state should increase in a similar
manner. The observation in these data that the highest multivariate-adjusted risk of dementia in AF patients was in the
youngest cohort minimizes the potential confounding variable of age.
Similar to age-based risk, patients with AF often have
hypertension. The relationship between hypertension and
dementia is not quite as clear. There seems to be an increased risk both in patients with high blood pressure6,10 –12
and in those with low blood pressure.29,30 Also, hypertension is associated with certain subtypes of dementia and not
others, and the relevance of the association is often age- and
disease-specific.31,32 In this study, the incidence of hypertension was similar in the AF and non-AF groups. In determining the independent risk of dementia in AF patients,
adjustment for hypertension did not influence the significant
association.
An interesting observation in these data was that hypertension was common, but often undertreated with pharmacologic agents. Outside of diuretics that were used slightly
more often in the AF group, there were similar hypertension
treatment trends in the AF and non-AF groups. Prior studies
have sought to determine whether hypertension treatment
can attenuate dementia risk. Although there are conflicting
data, the majority of studies suggest a slight decreased risk
of cognitive impairment in hypertensive patients who have
controlled versus poorly controlled pressure.33–37 This undertreatment of hypertension is an important limitation to
these data, and also represents an area for future study to
determine whether treatment of hypertension in AF patients
will alter the observed disease state association.
The role of inflammation in the pathogenesis of dementia
remains an area of active investigation. Systemic markers of
Heart Rhythm, Vol 7, No 4, April 2010
inflammation and hemostasis have been shown to be associated with cognitive decline.15 In an interesting study of
more than 4,000 patients, the association between inflammatory markers (C-reactive protein and interleukin-6) and
cognitive decline was modest, but was much stronger in
those with inherited risk.16 Similarly, the role of AF and
inflammation is an area of investigation. Recently, we found
that AF increases highly sensitive C-reactive protein in a
linear and independent manner in patients without and with
coexistent cardiovascular diseases.24 Studies are required to
investigate whether early targeted treatment of inflammation can influence the development of AF, dementia, or the
combined disease state.
There are many potential intriguing mechanisms that
may explain these observations. One is that AF and dementia both may be caused by early vascular disease from
central hypertension or microvascular dysfunction. Those
patients with AF with underlying comprised vascular/microvascular dysfunction may be more likely to have cerebral
perfusion dysfunction and to manifest dementia earlier. Patients with AF are more likely to develop heart failure, both
systolic and diastolic, which may serve as a distinct mechanism underlying reduced cerebral perfusion.38 AF is also
associated with silent cerebral infarctions and transient ischemic attacks.39 – 41 The long-term impact of multiple small
subclinical strokes underlies the early cognitive decline observed in this study. This possibility brings up the question
of whether aggressive rhythm management or anticoagulation may improve outcomes. Finally, as discussed previously, dementia increases in those patients with elevated
markers of systemic inflammation. AF independently increases systemic inflammation beyond other cardiac risk
factors,24 and may thereby accelerate the inflammationmediated progressive cognitive decline.
The long-term mortality rate of dementia patients with
AF is increased. The higher mortality rates were seen in all
forms of dementia. The highest hazard was primarily noted
in the younger cohorts. Previous studies have shown that
patients with dementia who develop AF have faster rates of
cognitive decline.13 The increased mortality in patients with
earlier presentations of dementia and more rapid progression of dementia has been previously reported.42 Our data
are unique in that they show that AF identifies additional
risk in these patients. It is unknown whether treatment of AF
will decrease this additional risk.
Our study has several limitations. It is an epidemiologic
study from a large health care database that we have used to
identify associations but not to establish causality or mechanisms. The study relies on physicians to make and document the disease states. Furthermore, the treatment of patients is individualized, and this may directly influence risks
of morbidity and mortality. However, the data were derived
from a very large database of consecutive patients with an
average of 5 years of follow-up, and insight is gleaned into
the association of AF and dementia. Regarding arrhythmia
diagnosis, by using ICD-9 codes, a comprehensive electro-
Bunch et al
Atrial Fibrillation and Dementia
cardiogram database, and medical records to determine the
presence of AF, the actual incidence of the arrhythmia in
our study population may be higher than we reported due to
subclinical events. However, the size of the population
studied should minimize the influence of this potential limitation. Similar to AF, dementia and dementia subtypes
were determined by ICD-9 codes, and these were assigned
by the caring physicians. Therefore, there may have been
some mischaracterization of dementia subtype. Nonetheless, the association of AF with dementia was seen dramatically across all subtypes, supporting the findings in general.
Conclusion
AF was independently associated with all forms of dementia. Although dementia is strongly associated with aging, the
highest risk of AD was in the younger group, in support of
the observed association. The presence of AF also identified
dementia patients at high risk of death. These findings
require further investigation and confirmation in an effort to
understand and prevent dementia as well as to optimally
manage dementia patients at higher risk of adverse outcomes.
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