Atrial Fibrillation: A Major Risk Factor for Cognitive Decline

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Atrial fibrillation is a common disease of the elderly, conferring considerable morbidity and mortality related to cardiovascular effects and thromboembolic risks. Anticoagulation, antiarrhythmic medications, and rate control are the cornerstone of contemporary management, whereas ablation and evolving surgical techniques continue to play important secondary roles



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Atrial Fibrillation: A Major Risk Factor for Cognitive Decline

Dawn S. Hui, MD, John E. Morley, MB, BCh, Peter C. Mikolajczak, MD, Richard Lee, MD, MBA,

Am Heart J. 2015;169(4):448-456. 


Atrial fibrillation is a common disease of the elderly, conferring considerable morbidity and mortality related to cardiovascular effects and thromboembolic risks. Anticoagulation, antiarrhythmic medications, and rate control are the cornerstone of contemporary management, whereas ablation and evolving surgical techniques continue to play important secondary roles. Growing evidence shows that atrial fibrillation is also a risk factor for significant cognitive decline through a multitude of pathways, further contributing to morbidity and mortality. At the same time, cognitive decline associated with cryptogenic strokes may be the first clue to previously undiagnosed atrial fibrillation. These overlapping associations support the concept of cognitive screening and rhythm monitoring in these populations. New research suggests modulating effects of currently accepted treatments for atrial fibrillation on cognition; however, there remains the need for large multicenter studies to examine the effects of novel oral anticoagulants, rhythm and rate control, and left atrial appendage occlusion on long-term cognitive function.


Twenty-five percent of people >40 years of age will develop atrial fibrillation (AF).[1] Atrial fibrillation has been clearly established as a cause of embolic stroke from thrombus primarily originating in the atrial appendage.[2,3] Evidence is emerging to suggest that AF may also contribute to less dramatic but equally devastating neurologic decline. Treatment modalities for AF target various aspects, including control of heart rate, conversion of heart rhythm, and elimination of either the nidus for or propensity to form thrombus. The impact of these therapies on cognitive function is unknown. We conducted a systematic review of the literature to examine the current evidence and discuss the epidemiologic association between AF and cognitive function, pathophysiologic mechanisms, and the impact of current AF treatment on cognitive decline.


A systematic electronic literature search was conducted using Medline for studies published from January 1, 2004, to July 1, 2014, including the search phrases: atrial fibrillation, cognitive impairment, and cognitive decline. Articles not in the English language were excluded. Hand-selected references from articles were also reviewed. Studies were categorized into 3 categories based on topic: epidemiology, pathophysiology, and treatment (Figure 1). Further review of epidemiologic studies was restricted to systematic reviews and meta-analyses. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this review.

Figure 1.


QUOROM diagram.


Numerous studies have been conducted examining the association between AF and cognitive impairment, with diverse populations ranging from case series of acute stroke inpatients to community-dwelling population-based longitudinal studies. Because of the heterogeneity of populations, methods, and analysis of the literature, 4 reviews[4,5,6,7]and 3 meta-analyses[8,9,10] () were reviewed, whereas prospective cohort and cross-sectional studies were excluded. In general, studies support a positive association, with relative risk ranging from 1.4 to 2.8, depending on the presence of stroke. Significant heterogeneity was present, precluding a formal meta-analysis in several reviews. Two meta-analyses included studies of patients with strokes, finding significant heterogeneity among studies of broader patients and little heterogeneity when studies were limited to stroke patients[9] or dementia.[10] Only 1 meta-analysis examined studies of patients with normal cognitive function at baseline with no history of stroke, but the outcome examined was incident dementia and not cognitive decline.[8] Of note, the criteria for the diagnosis and classification of AF were noted by many authors to be poor;[5,8,10] 1 semisystematic review noted that 3 studies used a single electrocardiogram, software program, and diagnosis code as the basis for AF diagnosis.[5] New technologic advances with implantable loop recorders having higher sensitivity and specificity[11] may improve the diagnosis and classification in future AF studies.

Table I.  Summary of reviews and meta-analyses of association between AF and cognitive impairment






Mead et al6

Systematic review

n = 10 (4 cross-sectional, 5 case-control, 1 prospective cohort)

Seven showed positive association; 3 showed no association. Substantial variation in methodology and cognition measures precluding meta-analysis

All studies had flawed methodology in at least 1 aspect

Kwok et al9


n = 15 prospective observational (14 pooled for meta-analysis)

Overall OR 2 with significant heterogeneity; significant association in patients with stroke (OR 2.4); borderline significance (OR 1.6) in broader studies


Eggermont et al7

Systematic review

n = 6 (3 case-control, 3 cohort)

Association in several cognitive domains; not all cognitive functions may be impaired


Santangeli et al8


n = 9 prospective observational

HR 1.42. Meta-regression analysis showed only length of study follow-up significantly interacted

Normal cognition at baseline; end point was dementia

Kalantarian et al10


n = 21 (7 cross-sectional, 14 prospective cohort)

RR 2.7 with first-ever or recurrent stroke; RR 1.4 in a broader population including patients with or without a history of stroke


Udompanich et al5

Semisystematic review

n = 11 (3 cross-sectional, 3 case-control, 5 cohort)

8 reported positive association. Among cross-sectional studies, OR 1.7–3.3 for CI, 2.3-fold risk for dementia.

Formal meta-analysis precluded by heterogeneity in design, size, and quality of studies and reporting

Abete et al4


n = 17 (4 cross-sectional, 1 case-control, 11 prospective cohort, 1 post hoc analysis)

Positive association in 14, negative in 3.


Abbreviation:RR, Relative risk.

Mechanistic Insights


As noted in many of the epidemiologic studies, patients with AF often have concurrent diagnoses such as hypertension, previous stroke, and other cardiovascular diseases that confound the association and delineation of underlying mechanism. Atrial fibrillation decreases cardiac output secondarily to loss of atrioventricular synchrony and impairment of left ventricular filling.[12] As a result of this decreased cardiac output, cerebral hypoperfusion may occur, particularly in the elderly in whom compensatory autoregulation is impaired.[13] Regional cerebral blood flow in chronic AF patients without neurologic symptoms was lower than age-matched controls, with a differential from anterior to posterior but not between hemispheres. The magnitude of reduction differed by age, highest in younger patients (17.5% in aged 35–50 years vs 5.5% in age >66).[14] Transcranial Doppler studies of various cardiac dysfunctional states showed lower diastolic cerebral perfusion compared with controls; in AF patients, patients with presyncope had lower diastolic blood flow velocity compared with AF patients without neurologic symptoms.[15] The role of ventricular rates was examined in 1 study that found that, in the presence of AF, both rapid and slow ventricular rates were a major predictor of dementia, showing another theoretic mechanism linking reduced cardiac output to cognitive impairment; however, this study was underpowered and unadjusted.[16] Although the known hemodynamic consequences of AF have been quantified in these studies, no studies have clearly shown an association to cognitive impairment.

Role of Inflammation and Thrombosis Biomarkers

Elevated levels of various inflammatory biomarkers have been associated with AF. Although inflammation is linked to a prothrombotic state, the mechanisms and associations with cognitive impairment remain unclear. Elevated C-reactive protein both independently and incrementally predicted AF in registry data after adjusting for coexisting cardiovascular disease.[17,18] The role of the proinflammatory cytokine interleukin (IL) 6 as a stimulant of C-reactive protein has been demonstrated in human hepatocytes,[19] and a review of studies showed correlation of various inflammatory markers with echocardiographic and clinical risk factors of thromboembolism.[20] Soluble CD40L, another biomarker of enhanced inflammation and platelet aggregation, is elevated in patients with AF[21,22] and related to levels of the angiogenesis factors vascular endothelial growth factor and angiopoietin 2 and the prothrombotic tissue factor.[21] Soluble CD40L was inversely correlated with adinopectin, an anti-inflammatory, antiplatelet agent.[22] Other biomarkers studied include fibrinogen, elevated in both persistent and paroxysmal AF; von Willebrand factor, elevated in persistent AF; and soluble P-selectin, elevated in paroxysmal AF.[23] Data correlating inflammatory markers to clinical outcomes include tumor necrosis factorα as a significant predictor of ischemic stroke[20] and von Willebrand factor as a predictor of stroke/vascular events.[24]D-Dimer, prothrombin fragment 1 + 2, and thrombin-antithrombin complexes were higher in patients with AF who subsequently developed dementia than those without, although this significance became borderline after age adjustment.[25] Cerebral vascular damage leads to local hypoxia and oxidative neurologic damage resulting in increased release of inflammatory cytokines, which can increase production of amyloid precursor protein, resulting in Alzheimer disease (Figure 2);[26,27,28] however, although the evidence supports a proinflammatory, prothrombotic state, the definitive link to cognitive dysfunction remains elusive.

Figure 2.


Atrial fibrillation can result in cognitive dysfunction.

Brain Imaging: Silent Cerebral Ischemia

In persons with persistent or paroxysmal AF, silent cerebral ischemia (SCI) is present in approximately 90% versus 46% of patients in sinus rhythm, with those in persistent AF having significantly more areas of SCI than those in either paroxysmal AF or sinus rhythm.[29] In this study, cognitive performance was significantly worse in patients with AF, but the association between cognitive decline and SCI was not studied. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation study found a 14.7% incidence of SCI among neurologically normal patients in chronic AF and an annual SCI development rate of 1.01% with placebo and 1.57% with warfarin. The sample size was too small to determine the effect of warfarin on incident SCI development, and SCI did not independently predict subsequent stroke.[30] A community-based prospective cohort study of 935 stroke-free patients found that incident AF predicted greater annual average rates of decline in cognitive function, but only in the presence of SCI, whether at entry or on late magnetic resonance imaging (MRI). Silent cerebral ischemia development with incident AF was double that of patients without AF; however, secondary analysis showed that SCI was significantly associated with greater decline in cognitive function even in participants without AF, suggesting that SCI and not AF per se was related to cognitive function.[31]

Brain Volume

Knecht et al[32] found that persons with AF had a reduction in hippocampal volume, a hallmark of amnestic mild cognitive impairment and Alzheimer disease.[33] An autopsy study showed no significant association of hippocampal infarcts with AF, but the method of clinical data collection particularly with regard to AF was limited.[34] Atrial fibrillation, along with hypertension, was a predictor of smaller amygdala volumes, which correlated to visual new learning; however, this study was limited to stroke/transient ischemic attack patients.[35] In elderly patients, only age and number of lacunar infarcts were predictive of cognitive function.[36] In a cross-sectional study in Reykjavik of 4,251 persons without dementia, brain volumes were lower in persons with AF.[37] Longer time from diagnosis of AF and persistent, compared to paroxysmal, AF had a stronger relationship with the reduction in brain volumes. There was a greater reduction in gray matter than white matter, which has been shown to be associated with cerebral hypoperfusion.[38] Treatment with warfarin did not prevent brain volume reduction.

Cerebral Microbleeds

Although the thromboembolic state of AF poses risks of microinfarction and tissue loss, cerebral microbleeds (CMBs) have been associated with AF as well. Atrial fibrillation conferred a 2.21 risk of CMB in stroke/transient ischemic attack patients.[39] When controlling for other small vessel manifestations (white matter hyperintensities and lacunar infarcts), the presence and number of CMB were related to global cognitive function; most of these were lobar in location again suggesting cerebral amyloid angiopathy as an etiology, but this study was in a broader population.[40]



Oral anticoagulation (OAC) has been the mainstay treatment of AF and has documented benefit in stroke reduction.[41] People with AF have twice the risk of dying,[42] and only anticoagulation therapy has been demonstrated to reduce AF-related deaths.[43] Prescribing practices in "real-world" studies have shown a significant rate of anticoagulant omission, ranging from 34%[44] to 59%.[45] Although a number of clinical factors and bleeding risk characteristics may contribute to the low prescribing rate, no single impairment or geriatric characteristic was identified as a barrier to vitamin K antagonist use in an observational study of geriatric inpatients.[46] Cognitive impairment itself may be a patient- or prescriber-related barrier. A retrospective study of outpatients found that mild to moderate cognitive impairment was not associated with delayed time to achieve therapeutic anticoagulation, decreased anticoagulation stability, or more intensive clinic management.[47] However, van Deelen et al[48] found that patients with cognitive impairment and AF had a high likelihood of having poorer control of their international normalized ratio. A study of participants in the ACTIVE-W trial found that lower baseline Mini-Mental State Examination (MMSE) score correlated with poorer OAC control during 1.3 years of follow-up, even after controlling for other factors. Bleeding and vascular events were higher in patients with lower MMSE, but the risk was no longer significant after adjusting for time in therapeutic range, suggesting that, in patients with cognitive dysfunction, excess events could be reduced by improved anticoagulation.[49] However, the effect of anticoagulation on other aspects of cognitive decline has not been well established. In the AFFIRM trial, 72% of strokes occurred after warfarin was stopped or when the international normalized ratio was subtherapeutic.[50] A functional status substudy of AFFIRM showed no difference in MMSE scores between the 2 arms (rhythm vs rate control), regardless of actual rhythm at follow-up or warfarin use; however, OAC use in the substudy was markedly higher compared with previous studies and to the AFFIRM population.[51]

In post hoc analysis of 2 randomized controlled trials (ONTARGET and TRANSCEND), at a median follow-up of 56 months, patients with AF had an increased risk of cognitive decline, new dementia, independence in performing activities of daily living, and admission to a nursing home.[52] This association was independent of previous or incident clinical stroke, and similar to the Reykjavik study, anticoagulation had no effect on a composite outcome of decrease in MMSE score by ≥3 points, dementia, admission to a long-term care facility, and loss of independence in performing activities of daily living. In a very small case-controlled study, persons treated with warfarin had better scores on the Clinical Dementia Rating and Global Deterioration Scale than those treated with aspirin.[53] In a follow-up study to a cohort of the Coagulation Activation and Risk of Stroke in Atrial Fibrillation study of outpatients on OACs, dementia was reduced in patients taking warfarin, although this became of borderline significance after adjusting for age.[25] Decreasing quality of anticoagulation control, measured as categories of time in therapeutic range, was associated with increasing dementia risk (hazard ratio [HR] 2.57–5.34)[54] even after adjustment for age. This association was strongest in patients <80 years old. Cognitive function as a secondary outcome in the BAFTA trial randomizing patients to aspirin or warfarin showed no differences in MMSE scores at early (9 months) or late (33 months) follow-up; however, 43% of patients did not have MMSE data at 33 months, and patients were excluded once a stroke occurred.[55] The variable conclusions from these studies support a need for a well-designed trial measuring the effect of anticoagulation on the development of cognitive dysfunction in persons with AF.

Medical Therapy

A small randomized study examined the effects of combined atorvastatin and ezetimibe therapy on medial temporal lobe atrophy in persons with AF.[56] This study found greater atrophy and worse cognition in the placebo group. The authors also reported a reduction in inflammatory cytokines IL-1RA, IL-2, IL-9, IL-12, and macrophage inflammatory protein 1β, associated with improved cognition in several domains. Amygdala and hippocampal volume decreased for both arms, with significantly less decrease in left amygdala volume in the treatment arm; no correlations were found to changes in white matter lesions.[57] Previous studies in general populations with hypercholesterolemia have suggested that cognitive function decline can be prevented in middle-aged persons but not in older persons.[58] A study of the effect of secondary prevention for vascular events on cognitive function after stroke showed a benefit of antihypertensive therapies and optimal medication therapy for poststroke patients without a history of AF but no benefit in those with AF ().[59]

Table II.  Overview of impact of various medical therapies for AF

Drug treatment





Rhythm, rate control

Chung et al51

Substudy of randomized study (rate vs rhythm control)

n = 245, mean age 69.8 y

No difference in MMSE scores at 3.6 y


Marzona et al52

Post hoc analysis of ONTARGET (randomized to telmisartan ± ramipril) TRANSCEND (randomized to telmisartan vs placebo)

n = 1016 AF at baseline; 2052 new-onset AF

29.2% on OAC; 60.9% on antiplatelet therapy. No difference in composite outcome (P = .7)

Puccio et al53

Case-control study

n = 82 (42 AF, 40 NSR)

No difference in corrected MMSE scores; patients on warfarin vs ASA had better CDR, GLDS, and GDS scores

Barber et al25

Substudy of observational cohort of permanent AF patients

n = 258 (64% on OAC; 26% on ASA)

Reduced dementia prevalence in patients on OCA (18% vs 32%) but borderline significance after age adjustment (OR 0.52, CI 0.26–1.07,P = .08)

Jacobs et al54

Retrospective study of patients on OAC

n = 2605; 69.5% with CHADS2 > 2

Decreasing time in therapeutic range associated with increasing dementia risk (HR 2.57–5.34)

Mavaddat et al55

Randomized trial (warfarin vs ASA)

n = 973

At 2.7-y follow-up, no difference in MMSE (P = .49)


Tendolkar et al56

Double-blind randomized trial (atorvastatin/ezetimibe vs placebo)

n = 34 stroke-free AF patients

At 1 y, improved cognitive speed, long-term memory; decreased systemic inflammatory marker; decreased atrophy of right amygdala and left hippocampus

Lappegard et al57

Double-blind randomized trial (atorvastatin/ezetimibe vs placebo)

n = 34 stroke-free AF patients

At 1 y, correlation between rates of cognitive decline and changes in inflammatory markers (P = .02-.03)

Secondary prevention for vascular events

Douiri et al59

Regression analysis of stroke registry data

n = 4413 stroke patients (5% with AF)

Benefit of poststroke secondary prevention therapies without a history of AF; no benefit in those with AF.

Abbreviations:NSR, Normal sinus rhythm;ASA, aspirin;CDR, Clinical Dementia Rating;GLDS, Global Deterioration Scale;GDS, Geriatric Depression Scale.

Cardiac Surgery and Appendage Occlusion

An area of special interest in the role of atrial fibrillation in cognition is cardiac surgery. Typically, postoperative cognitive impairments are attributed to effects of cardiopulmonary bypass, microemboli from aortic atherosclerosis, and exacerbation by the systemic inflammatory response. The association with AF suggests a potential unexplored mechanism. Nearly a quarter of patients with AF develop delirium after cardiac surgery.[60] This is highly significant compared with other causes of delirium with the exception of older age. In another study, postoperative AF after coronary artery bypass graft surgery portended poorer cognitive function 6 weeks after surgery.[61]

Current AF expert consensus recommends occlusion of the left atrial appendage at the time of cardiac surgery. However, current surgical techniques have variable success rates,[62] and late neurologic events occur even after appendage exclusion with a significant difference in rates related to surgical technique.[63] Most evidence suggests that percutaneous left atrial appendage occlusion in nonvalvular AF is equally effective as warfarin therapy in preventing stroke and transient ischemic attacks.[64] Effects on cognition have not been reported. The LARIAT device has also been used successfully in 80-year-olds but without formal cognitive testing.[65]

Effects of Ablation

In view of the limited use and unclear effect of anticoagulation on cognitive decline in persons with AF, it is important to examine alternatives for improving outcomes. Efimova et al[66] examined the effect of atrioventricular junction ablation and pacemaker implantation on 17 people with AF and medically refractory rapid ventricular rates. At baseline, these patients had decreased perfusion of the inferior frontal and posterior parietal regions of the brain, with 94% demonstrating cognitive deficits on neuropsychological testing. Ablation resulted in improved cerebral blood flow and mentation, including verbal and visual memory, learning, abstract mentation, and psychomotor speed. Positive correlations between systolic blood pressure, cardiac output, improved mentation, and cerebral blood flow were noted.

Catheter ablation procedures pose risks of cerebral embolic events. The radiologic and clinical sequelae have been examined in several studies. Left catheter atrial ablation for symptomatic AF resulted in new ischemic lesions without a decline in cognition in 41% of patients.[67] Six to nine months after ablation, 82% of the lesions were no longer detectable.In a study of 90 patients undergoing ablation, there was a significant decline in both early (day 2) and late (day 90) postprocedural neurocognitive function (28% and 13%, respectively), compared with patients undergoing ablation for supraventricular tachycardia and patients with unablated AF.[68] Univariable analysis showed that increased atrial access time was a risk factor for early and late cognitive decline, whereas diabetes, hypertension, and age had no association. In another study, 14% of patients undergoing elective pulmonary vein isolation (PVI) had new ischemic lesions on MRI after ablation.[69] Compared with controls and with covariance of baseline performance, cognitive function was significantly impaired 3 months later. Herm et al[70] found that new MRI-detected brain lesions were present in 63% of patients after ablation, with persistent glial scar in 13.5% of subjects at 6 months; however, neither persistent brain lesions nor the ablation procedure had significant cognitive effects in several domains at 6-month follow-up.

Cognitive Screening and Future Directions

Recognizing and preventing mild cognitive impairment as persons age is important. Persons with mild cognitive impairment are more likely to forget to take their medicines, have a greater propensity to falling, have worse outcomes after a major adverse event such as surgery, and die earlier.[71–73] In addition, approximately a third of persons with mild cognitive impairment will develop Alzheimer disease 3 years after diagnosis.[74]

In a population-based study of 6,584 participants between ages 55 and 106 years, AF incidence in cognitively impaired persons without dementia was 6%; in those with dementia, it was 13%, both significantly higher than those without cognitive impairment (2.1%).[75] Atrial fibrillation was the strongest risk factor (odds ratio [OR] 8.1) for cognitive impairment in a small population of patients with congestive heart failure,[76] it was the only risk factor independently associated with prestroke cognitive impairment,[77] and its development in patients without previous AF or stroke predicted a faster decline in MMSE scores at mean follow-up of 7 years.[78] In patients with overt stroke, approximately 30% of all cerebral vascular accidents are "cryptogenic" (mechanism of action is unknown). Recently, the CRYSTAL-AF trial showed that within 6 months of loop recorder implantation, 8.9% of people with prior cryptogenic stroke demonstrated at least 1 episode of AF. With standard monitoring, AF was only detected in 1.4% of people. At 3 years, this gap widened to 30% versus 3%.[79] Therefore, persons with even mild cognitive impairment should be investigated for the presence of AF given its higher prevalence and prognostic importance. Those with evidence of vascular lesions in the brain may benefit from investigation for the presence of paroxysmal AF with an implantable loop recorder. Previous studies are likely to have underestimated the true prevalence of AF, especially paroxysmal, and newer monitoring technology expands our ability to diagnose and categorize AF. This will require greater awareness and attention to the possibility of occult AF on the part of clinicians, especially in the younger population.

Because of the importance of cognitive impairment, we recommend that all persons with AF be screened for mild cognitive impairment on a yearly basis. Of persons >65 years old, 11.1% have dementia compared to 5.9% of general population, and AF confers a 40% to 50% higher risk of Alzheimer disease and all-cause dementia, independent of stroke.[80] Although the MMSE has been classically used to screen for dementia, it is a poor tool for diagnosing mild cognitive impairment.[81] Both the St Louis University Mental Status (SLUMS) examination and the Montreal Cognitive Assessment (MoCA) have excellent sensitivity and specificity for mild cognitive impairment and prediction of outcomes.[82,83,84] The MoCA takes approximately 10 minutes to perform, and the SLUMS, 7 Ѕ minutes. Both of these times are too long for a busy clinician to perform. For this reason, we have developed the Rapid Cognitive Screen, which takes 2 Ѕ minutes to perform and, unlike the MiniCog,[85] can identify mild cognitive impairment ().[33]

Table III.  The Rapid Cognitive Screen for mild cognitive impairment

What country did they live in? [1 point]

0–5, dementia; 6–7, MCI; 8–10, normal.

At present, the best treatment to prevent progression of AF-associated cognitive impairment is unknown. As discussed previously, the available data on the benefit of warfarin are controversial. There are no studies examining the effects of the novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) on cognitive function. As noted, a small study by Efimova et al[66] demonstrated improved cognitive function and cerebral perfusion with improved control of ventricular rates during AF. Of note, a recent observational study of 4,212 people with AF who underwent PVI, after 3-year follow-up, demonstrated a significantly decreased incidence of dementia.[86] However, evidence suggesting PVI is associated with ischemic brain lesions and short-term decline in cognitive function raises concerns. Furthermore, long-term studies are needed to determine if strict rate control or rhythm control can prevent progression of AF-associated cognitive impairment.

In conclusion, we advocate all persons with AF be screened for cognitive dysfunction and all patients with cognitive dysfunction be screened for AF. There is a need for a large multicenter study to examine the effects of novel oral anticoagulants, rhythm and rate control, and left atrial appendage occlusion on long-term cognitive function. Moreover, end points of any future study designed to decrease stroke in AF patients should include other aspects of cognitive decline.


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AcknowledgementsNo extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this review.

Am Heart J. 2015;169(4):448-456. © 2015  Mosby, Inc.

Copyright © Mosby-Year Book, Inc. All rights reserved.


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