Accepted Manuscript Lone Atrial Fibrillation: Does It Exist? A “White Paper” of the Journal of the American College of Cardiology D. George Wyse, MD, PhD, FACC Isabelle C. Van Gelder, MD, PhD Patrick T. Ellinor, MD, PhD Alan S. Go, MD Jonathan M. Kalman, MBBS, PhD, FACC Sanjiv M. Narayan, MD, PhD, FACC Stanley Nattel, MD Ulrich Schotten, PhD Michiel Rienstra, MD, PhD PII:

S0735-1097(14)00336-2

DOI:

10.1016/j.jacc.2014.01.023

Reference:

JAC 19780

To appear in:

Journal of the American College of Cardiology

Received Date: 1 December 2013 Revised Date:

29 December 2013

Accepted Date: 2 January 2014

Please cite this article as: Wyse DG, Van Gelder IC, Ellinor PT, Go AS, Kalman JM, Narayan SM, Nattel S, Schotten U, Rienstra M, Lone Atrial Fibrillation: Does It Exist? A “White Paper” of the Journal of the American College of Cardiology, Journal of the American College of Cardiology (2014), doi: 10.1016/ j.jacc.2014.01.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT JACC White Paper - Lone Atrial Fibrillation

Lone Atrial Fibrillation: Does It Exist? A “White Paper” of the Journal of the American College of Cardiology

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D. George Wyse, MD, PhD, FACC1; Isabelle C. Van Gelder, MD, PhD2; Patrick T. Ellinor, MD, PhD3; Alan S. Go, MD4; Jonathan M. Kalman, MBBS, PhD, FACC5; Sanjiv M. Narayan, MD, PhD, FACC6; Stanley Nattel, MD7; Ulrich Schotten, PhD8, Michiel Rienstra, MD, PhD2 1

Libin Cardiovascular Institute of Alberta/University of Calgary, Calgary, Alberta, Canada Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 3 Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA 4 Division of Research, Kaiser Permanente Northern California, Oakland, California, USA 5 Department of Cardiology, Royal Melbourne Hospital, and Department of Medicine, University of Melbourne, Melbourne, Australia 6 University of California and Veterans’ Affairs Medical Centers, San Diego, California, USA 7 Department of Medicine and Research Center, Montreal Heart Institute, Université de Montréal, Canada 8 Department of Physiology, University Maastricht, Maastricht, The Netherlands

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Brief Title: Lone AF: Does It Exist? Disclosures The disclosures of the authors are as follows: Dr. Wyse has received honoraria for serving on Data and Safety Advisory Boards for randomized clinical trials sponsored by Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Sanofi Aventis, Biotronik, Boston Scientific/Guidant (Europe), Medtronic and Merck. Dr. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). Dr. Narayan is supported by a grant from the NIH (HL103800). Dr. Narayan is co-author of intellectual property owned by the University of California Regents and licensed to Topera Inc. Topera does not sponsor any research, including that presented here. Dr. Narayan holds equity in Topera, and reports having received honoraria from Medtronic, St. Jude Medical, and Biotronik. Dr. Ellinor is supported by grants from the National Institutes of Health (R01HL092577, R01HL104156, 1K24HL105780) and the American Heart Association to (13EIA14220013). There was no financial supportfor this work other than that provided by the journal for the meeting in Denver. Address for correspondence: D. George Wyse MD PhD Emeritus Professor Department of Cardiac Sciences Libin Cardiovascular Institute/University of Calgary Room GC64, Health Research Innovation Centre 3280 Hospital Dr NW Calgary, AB T2N 4Z6 CANADA Tel: 1-403-220-2052 FAX: 1-403-283-8878 1

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JACC White Paper - Lone Atrial Fibrillation

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ACCEPTED MANUSCRIPT JACC White Paper - Lone Atrial Fibrillation

“I meant what I said, and I said what I meant”(1) … Horton Hatches the Egg by Dr. Seuss

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Abstract The historical origin of the term ‘lone atrial fibrillation (AF)’ predates by 80 years our current understanding of the pathophysiology of AF, the multitude of known etiologies for AF, and our ability to image and diagnose heart disease. The term was meant to indicate AF in whom subsequent investigations could not demonstrate heart disease, but for many practitioners has become synonymous with ‘idiopathic AF’. As the list of heart diseases has expanded and diagnostic techniques have improved, the prevalence of ‘lone AF’ has fallen. The legacy of the intervening years is that definitions of ‘lone AF’ in the literature are inconsistent such that studies of ‘lone AF’ are not comparable Guidelines provide a vague definition of ‘lone AF’ but do not provide direction about how much or what kind of imaging and other testing are necessary to exclude heart disease. There has been an explosion in the understanding of the pathophysiology of AF in the last 20 years in particular. Nevertheless, there are no apparently unique mechanisms for AF in patients categorized as ‘lone AF’. In addition, the term ‘lone AF’ is not invariably useful in making treatment decisions, and other tools for doing so have been more thoroughly and carefully validated. It is therefore recommended that use of the term ‘lone AF’ be avoided. Keywords: lone atrial fibrillation, idiopathic atrial fibrillation, white paper

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Atrial Fibrillation American College of Cardiology American Heart Association AnTticoagulation Risk Factors In Atrial Fibrillation Canadian Cardiovascular Society Severity in Atrial Fibrillation Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/systemic embolus Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/systemic embolus, Vascular disease, Age 65-74 years, Sex = female European Heart Rhythm Association European Society of Cardiology Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk, Stroke Heart Rhythm Society

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Abbreviations list AF ACC AHA ATRIA CCS SAF CHADS2

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Introduction Although reasons for the growing global epidemic of AF(2-5) remain unclear, studies now challenge the traditional tenet that AF is caused primarily by ischemic heart disease secondary to

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arteriosclerosis or other heart disease, with residual cases being ‘idiopathic’ or ‘lone’ AF.

Instead, a plethora of emerging associations with AF, an expanded list of heart disease, as well as improved methods of imaging and a clearer understanding of pathophysiology and genetics

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suggest that AF is rarely idiopathic.(6,7)

This working group posits that the category of lone (‘idiopathic’) AF no longer has either

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mechanistic or clinical utility, causes confusion in the literature because of tremendous variability in its definitions, and should therefore be avoided. Future directions in AF management and research will be better served if AF is classified in a more utilitarian and precise fashion, perhaps using terms that assign both etiologic and mechanistic information when

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appropriate. Unfortunately, our understanding of mechanisms and etiology of AF remains incomplete at this time, making such a classification of AF an ongoing ‘work in progress’. Given these limitations, we believe that clinical risk stratification and decisions about therapy for AF

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are more aptly done by specifying the nature and extent of underlying heart disease and other concomitant diseases like pulmonary diseases, and by using schemes such as CHADS2,

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CHA2DS2VASc, or ATRIA for stroke risk and by EHRA or CCS-SAF for the assessment of symptoms.

In the following sections we will delineate the reasons for recommending this historical term be avoided.

Origin of ‘Lone or Idiopathic Atrial Fibrillation’

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Historically, the term ‘lone AF’ predates our current understanding of the multitude of disorders that likely contribute to the initiation of AF and lead to changes in the heart that could be considered heart disease. Although others had previously noted AF in the absence of heart

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disease, the term ‘lone AF’ was coined 60 years ago in 1954 by Evans and Swann to describe patients for whom ‘subsequent investigation shows that heart disease is absent’.(8) It was, and still is, considered by many to be synonymous with idiopathic AF. The term ‘lone AF’ has been

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widely used, and was generally accepted to comprise a minority of AF cases, though in some reports estimates of approximately 30% were given.(9) Over the past 20 years, there has been an

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explosion of knowledge about AF etiologies and mechanisms and new forms of heart disease. The wide variety of conditions now known to be associated with AF is listed in Table 1.(6,7) The inclusion of some or all these factors and their resultant new heart disease forms has influenced the reported proportion of patients with ‘lone or idiopathic’ AF, as is illustrated in

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Figure 1. Multiple scientific and technical advances have been and continue to be made to identify the mechanisms through which various etiologies lead to AF.(10) While we currently cannot specify the precise mechanisms for AF in each patient, the goal of a mechanistic

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classification for AF is increasingly moving from an inconceivable notion to a realistic scientific objective. At some point in the near future we may be able to classify an individual’s AF based,

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at least in part, on mechanistic considerations. The majority of patients without traditional heart disease likely develop AF as a result of multiple influences, rather than a single proximal ‘cause’. These influences lead to structural changes in the heart that have only recently been imaged or even conceptualized, and could be considered new heart disease forms. Variation in the Definition of ‘Lone Atrial Fibrillation’

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Current AF guidelines define lone AF as AF in younger adults (age 60 years. The selection of an age threshold of 60 years appears arbitrary, and

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is not based on any clear pathophysiological justification. Although only echocardiography is specifically mentioned in guideline definitions, next to patient history and physical examination, the most used diagnostic tests in the literature for exclusion of concomitant diseases were a 12-lead electrocardiogram, transthoracic echocardiography, and selected laboratory testing for thyroid dysfunction, diabetes mellitus, Creactive protein and white blood cell count when an infection was suspected. The majority of

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studies describe that stress testing was only performed if coronary heart disease was clinically suspected. Left ventricular diastolic function measurements were only performed in recent years and cardiac magnetic resonance imaging or other types of assessment for new heart disease

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forms not at all.

Another factor to be considered is that the development of underlying heart disease is often a continuous process over time. Although heart disease is recognized earlier since (non-invasive)

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diagnostic tests have improved, it may manifest as AF before it can be reliably detected using currently available tests.(13,14) The concept of progressive (atrial) remodeling has been around

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for some time and is depicted hypothetically in Figure 3. It therefore remains uncertain if ‘lone AF’ really is AF without heart disease, or in some cases is AF with heart disease that is currently below the threshold for detection.

Given these diverse considerations and limitations in the ability of currently available diagnostic

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testing modalities to reliably rule out all heart disease, the diagnosis of lone AF has limited clinical utility.

Reported Prevalence of ‘Lone Atrial Fibrillation’

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The reported prevalence of lone AF varies widely, ranging from 0.2% to 68% depending on the definition of lone AF, the population studied (Figure 2), and diagnostic tools used.(15,16) The

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Framingham Heart Study reported a lone AF prevalence of 11%, using a lenient definition of hypertension by modern standards (

Lone atrial fibrillation: does it exist?

The historical origin of the term "lone atrial fibrillation" (AF) predates by 60 years our current understanding of the pathophysiology of AF, the mul...
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