The Link Between Persistent Atrial Fibrillation and Dementia Suzanne A. Feigofsky, M.D.

Disclosures Medtronic St. Jude Medical Medtronic TYRX Employer-Iowa Heart Center/Mercy-Des Moines

Persistent Atrial Fibrillation Persistent AF is a condition in which the abnormal heart rhythm continues for more than a week. It may stop on its own, or it can be stopped with treatment. Journal of Cardiovascular Electrophysiology 2003, 14:443-445

Dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. Alzheimer’s disease: 60-80% of all cases Vascular Dementia: 10-20% of all cases Nonspecific Dementia/Senile Dementia Heart Rhythm 2010;7:433-437

Atrial Fibrillation and Dementia: Innocent bystander or Smoking Gun? The risk for dementia tends to increase with increasing age. The prevalence of atrial fibrillation increases with increasing age. Approximately 9% of people 80 years and older are affected. Both atrial fibrillation and dementia have similar risk factors: Hypertension, diabetes, coronary artery disease, systemic inflammation Heart Rhythm 2010;7:433-437

The Rotterdam Study Stroke. 1997;28:316-321 Population based prospective cohort study of the elderly 6584 participants aged 55-106 years studied between 1990-1993 635 (9.6%) had cognitive impairment without dementia 276 (4.2%) were diagnosed with dementia 206: Alzheimer’s 49: Vascular dementia 29: other dementia Atrial fibrillation found in 195 (3%) 3.3% of men 2.7% of women Stroke. 1997;28:316-321

Age Differences and Risk for Dementia with Atrial Fibrillation Stroke. 1997;28:316-321

Gender Differences and Risk for Dementia with Atrial Fibrillation Stroke. 1997;28:316-321

Study Weaknesses There is a potential for survival bias due to cross- sectional analysis Only 1 ECG was performed, perhaps missing atrial fibrillation or other arrhythmias A history of stroke was not an exclusion

Study Conclusions There was a significant association between atrial fibrillation and dementia, particularly in younger subjects and women. There appeared to be an association with vascular dementia and Alzheimer’s disease concomitant with cerebrovascular disease. A causal relationship could NOT be established

Intermountain Heart Collaberative Study Prospective trial following 37,025 patients over an average of 5 years. (89% white, mean age 60.6 +/- 17.9) Patients with pre-existing dementia or atrial fibrillation were excluded. Primary Objective: Confirm the independent risk of Atrial Fibrillation and Alzheimer’s Dementia. Secondary Objective: Determine the impact of atrial fibrillation in those subsequently diagnosed with dementia (ie: mortality risk) Heart Rhythm 2010;7:433-437

Results 27% of the enrolled patients developed atrial fibrillation. 4.1% developed dementia There was an increased incidence of all dementia subtypes in patients with atrial fibrillation. In those patients with dementia, the co-existence of atrial fibrillation was associated with an earlier cognitive decline. There was a statistically significant association between dementia and total mortality. The presence of atrial fibrillation further increased this risk among all dementia subtypes. Heart Rhythm 2010;7:433-437

Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) 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. Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) 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. Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) 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. Heart Rhythm 2010 7, 433-437DOI: (10.1016/j.hrthm.2009.12.004) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Atrial Fibrillation and the Risk of Incident Dementia: A Meta-Analysis Heart Rhythm 2012;9:1761-1768

Heart Rhythm 2012 9, 1761-1768.e2DOI: (10.1016/j.hrthm.2012.07.026) Selection process of studies included in the meta-analysis. Heart Rhythm 2012 9, 1761-1768.e2DOI: (10.1016/j.hrthm.2012.07.026) Copyright © 2012 Heart Rhythm Society Terms and Conditions

Heart Rhythm 2012;9:1761-1768

All studies had a prospective observational design. All tested the association between the presence of atrial fibrillation at baseline and the risk of incident dementia All studies included a population of elderly patients (61-84 years) who were followed for a mean of 7.7 years (+/-9.1yrs) No patients had evidence of cognitive impairment or acute stroke at baseline.

Heart Rhythm 2012 9, 1761-1768.e2DOI: (10.1016/j.hrthm.2012.07.026) Forest plot showing the individual and pooled adjusted hazard ratios (HR) of incident dementia comparing patients with atrial fibrillation (AF) vs those without AF. Square boxes denote HR. The dimension of each square box denotes the weight from random effect analysis. Horizontal lines represent 95% confidence interval (CI). The study by Rastas et al14 did not report the adjusted HR and was included for sensitivity analysis (see Methods). Heart Rhythm 2012 9, 1761-1768.e2DOI: (10.1016/j.hrthm.2012.07.026) Copyright © 2012 Heart Rhythm Society Terms and Conditions

The pooled data included >77,000 patients with normal cognitive function at baseline and whom had not suffered from an acute stroke. Atrial fibrillation, independently from other confounders, increased the risk of developing dementia. It remains “controversial” whether atrial fibrillation should be considered a “risk factor” for dementia. It would certainly be reasonable to consider screening atrial fibrillation patients for dementia

Atrial Fibrillation and Brain Volume Cross-sectional analysis 4251 patients without dementia. Mean age 75+/- 5 years. 330 participants had atrial fibrillation Those who only had atrial fibrillation <4 weeks after open heart surgery were excluded Duration of atrial fibrillation was calculated from the date of the first diagnosis until the date of the study examination 41.8% paroxysmal (n=138) 58.2% persistent/permanent (n=192) The mean duration of atrial fibrillation was 7.6 +/- 7 years Median value 6 years. Range 0-41 years Stroke.2013;44:1020-1025

Stroke.2013;44:1020-1025

Stroke.2013;44:1020-1025 (adjusted for age, sex, education) BMI, height, smoking, EtOH, lipids, HTN,, DM, MI, CHF, infarct on brain MRI) Stroke.2013;44:1020-1025

Stroke.2013;44:1020-1025

Stroke.2013;44:1020-1025

Mean brain volume expressed as percentage of total intracranial volume (with standard error [SE] bars) in individuals without atrial fibrillation (AF), with paroxysmal AF, and with persistent/permanent AF. Adjusted for age, sex, education level, hypertension, myocardial infarction, diabetes mellitus, heart failure, smoking, alcohol consumption, hypercholesterolemia, body mass index, height, and cerebral infarcts on magnetic resonance imaging. Mean brain volume expressed as percentage of total intracranial volume (with standard error [SE] bars) in individuals without atrial fibrillation (AF), with paroxysmal AF, and with persistent/permanent AF. Adjusted for age, sex, education level, hypertension, myocardial infarction, diabetes mellitus, heart failure, smoking, alcohol consumption, hypercholesterolemia, body mass index, height, and cerebral infarcts on magnetic resonance imaging. Hrafnhildur Stefansdottir et al. Stroke. 2013;44:1020-1025 Copyright © American Heart Association, Inc. All rights reserved.

Study Findings There was a significant association between atrial fibrillation and lower total brain gray and white matter volumes. The loss of volume was stronger with persistent/permanent atrial fibrillation as well as the duration of the arrhythmia. This suggests a possible cumulative effect The difference in volume between individuals with and without atrial fibrillation is equal to 1.5 years of normal loss of brain volume. When adjusting for other cardiovascular factors, atrial fibrillation was associated with memory impairment, but not with impairment in executive function or speed processing. Stroke.2013;44:1020-1025

Framingham Offspring Study: Association between AFib and MRI Brain Volumes 2144 participants in a cross sectional analysis 1533 participants were analyzed in the longitudinal change in MRI (between 1-4 years after inclusion MRI) 54% women At the time of MRI 3.4% (73 participants) had atrial fibrillation these patients were older, more likely to be men and had a higher prevalence of vascular disease Atrial fibrillation was associated with smaller frontal lobe volumes There was a decrease in total brain volume and lobar volumes, but this was no longer significant after adjustment for vascular risk factors Heart Rhythm 2016;13:2020-2024

Conclusions Atrial fibrillation is associated with an increased risk for dementia. This association appears to be stronger for younger patients and possibly women Possible mechanisms include: Microemboli and micro infarction possibly resulting in brain atrophy Decreased cerebral blood perfusion related to decreased cardiac output (loss of atrial kick) Altered cerebral blood perfusion due to beat to beat variability More data is needed on the relationship of a rhythm control strategy, ablation, and the development of dementia