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Relation of Left Atrial Size to Atrial Fibrillation in Patients Aged ≤22 Years
Accepted Manuscript Relation of Left Atrial Size to Atrial Fibrillation in Patients <22 Years of Age Douglas Y. Mah, MD, Divya Shakti, MBBS, MPH, Kimberlee Gauvreau, ScD, Steven D. Colan, MD, Mark E. Alexander, MD, Dominic J. Abrams, MD, David W. Brown, MD PII:
S0002-9149(16)31566-1
DOI:
10.1016/j.amjcard.2016.09.008
Reference:
AJC 22148
To appear in:
The American Journal of Cardiology
Received Date: 10 June 2016 Revised Date:
8 September 2016
Accepted Date: 13 September 2016
Please cite this article as: Mah DY, Shakti D, Gauvreau K, Colan SD, Alexander ME, Abrams DJ, Brown DW, Relation of Left Atrial Size to Atrial Fibrillation in Patients <22 Years of Age, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.008. 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
Relation of Left Atrial Size to Atrial Fibrillation in Patients <22 Years of Age Short Title: Atrial Fibrillation in Pediatrics.
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Douglas Y. Mah, MD1; Divya Shakti, MBBS, MPH1; Kimberlee Gauvreau, ScD1; Steven D. Colan, MD1; Mark E. Alexander, MD1; Dominic J. Abrams, MD1; and David W. Brown, MD1.
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From the Department of Cardiology, Boston Children’s Hospital and Harvard Medical School1.
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Address for Correspondence Douglas Y. Mah Department of Cardiology Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115 Tel: 617-355-7833 Fax: 617-730-0000 Email: [email protected]
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Abstract
Left atrial (LA) dilation has been shown to be associated with atrial fibrillation (AF) in the adult
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population, with some studies indicating that larger LAs are more prone to AF recurrence. The relation of LA size to AF in the pediatric and young adult population has not been investigated.
In this study, all pediatric patients (<22 years of age) who presented to Boston Children’s Hospital
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between January 2002 and December 2012 with AF were reviewed. Patients with significant congenital heart disease, cardiomyopathies, proven channelopathies, prior cardiac surgery, end-stage renal disease,
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or severe lung disease/cystic fibrosis were excluded. Left atrial measurements were taken using the echocardiogram performed at the initial presentation. In total, 48 patients with AF were identified. The median age at presentation was 17.1 years (range 3.7-22.9 years); 38 patients (79%) were male. Eleven patients (23%) had at least one recurrence of their AF. There was no difference in body-mass index, prevalence of systemic hypertension, alcohol, stimulant or illicit drug use between those that had an
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isolated episode of AF versus those that had a recurrence. There was no significant difference in LA dimension Z-scores between groups, with only two patients (1 isolated AF, 1 recurrent AF) having Zscores >2. In conclusion, AF in the young without underlying heart disease is not associated with LA
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dilation.
Key Words Atrial Fibrillation Left Atrial Dilation Pediatrics
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Introduction Atrial fibrillation (AF) is a common arrhythmia in older adults, but is rare in pediatric and young adult patients with structurally and functionally normal hearts. Of the patients presenting to a pediatric
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emergency room, AF was found to make up 5% of all rhythm disturbances1. The cause of AF in the absence of myocardial, valvar, or structural heart disease (primary AF) is unknown, although it can be associated with patients who have an underlying cause for supraventricular tachycardia (i.e.
atrioventricular (AV) node reentrant tachycardia or an accessory pathway)2, 3, and perhaps obesity2. Thus
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far, only adult studies have looked at the relation of left atrial (LA) size and AF4. There have been no
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pediatric studies evaluating LA size and AF. All prior studies have looked at the concomitant presence of an AV reciprocating tachycardia. This study describes the presentation of AF in the largest cohort of pediatric patients studied thus far, and determines the relation of primary AF and LA size in this
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population, hypothesizing that, unlike adult patients, AF in the young is not associated with LA dilation.
Methods
All pediatric patients (<22 years of age) who presented to Boston Children’s Hospital between
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January 2002 and December 2012 with AF were reviewed. Patients with significant congenital heart disease (not including bicommissural aortic valves with normal valvar function and hemodynamically
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insignificant atrial septal defects, ventricular septal defects, or patent ductus arteriosus), cardiomyopathies, proven channelopathies, prior cardiac surgery, prior radiofrequency ablations, endstage renal disease, or severe lung disease such as cystic fibrosis were excluded (n=87). Data gathered included demographic data, method of presentation, symptoms prior to presentation, electrocardiographic and echocardiographic data, electrophysiological characteristics (if an electrophysiology study was performed), and follow-up data. Approval for this study was obtained from the Institutional Review Board of Boston Children’s Hospital.
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All patients who had structurally normal hearts and presented with their first episode of AF were included. Electrocardiograms at time of presentation were evaluated, as well as the electrocardiogram after conversion to sinus rhythm. The echocardiogram performed after the first AF presentation was
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reviewed. Left atrial maximal measurements were performed including apical 4-chamber short and long axis dimensions and area measurement. Single plane maximal LA volume was calculated, as nearly all echocardiogram studies were obtained prior to routine acquisition of 2-chamber imaging of the LA. Twodimensional single plane estimation of LA volume has been shown to have excellent correlation with
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biplane 2-dimensional methods5, and is obtained with the formula V= 8/3π (A2/L), where V=volume, A is
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the LA area, and L is the shortest LA length in either the 4- or 2-chamber views6. As few reports of normal LA 2-dimensional measurements, areas, and single plane volume values exist, a normative dataset of 450 normal, healthy pediatric patients undergoing echocardiography (with completely normal results) was used to generate standard deviations and Z-scores for the included measurements using absolute
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residuals as described by Altman et al.7
Patient blood pressures during their admission and at their first clinic visit were reviewed, with the highest systolic and diastolic measurements recorded. Hypertension was defined when systolic blood
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pressures were determined to be above the 99th percentile based on pediatric guidelines8. Patient height and weight at time of presentation were recorded – obesity was defined as a body-mass index (BMI)
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above 30. Concomitant medications, alcohol use, illicit drug use, and thyroid function were also noted.
If an electrophysiology study was performed, it was done under general anesthesia, with the
patient intubated, sedated and paralyzed. Baseline intervals were measured, followed by single atrial extrastimulation, rapid atrial pacing and single ventricular extrastimulation. Baseline refractory periods were measured. If used, isoproterenol infusion was given as a 0.1 mcg/kg bolus over 1 minute, followed by a 0.01 – 0.02 mcg/kg/min infusion. The presence of an accessory pathway, AV node reentrant tachycardia, and other potential arrhythmia mechanisms were recorded.
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Follow-up data were reviewed, including the initiation of antiarrhythmics and whether the AF recurred. Patients with a single episode of AF were labeled as “isolated AF”. These were compared to
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patients who had at least one recurrence of their AF after their initial presentation ”recurrent AF”.
Categorical variables are expressed as number (percent) and continuous variables as median
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(range). Comparisons between the study and control groups were performed using the Fisher exact test (categorical variables) and the Wilcoxon rank sum test (continuous variables). The Kruskal Wallis and
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Fisher’s exact tests were applied for comparison among multiple groups as indicated.
Results
A total of 48 patients with structurally normal hearts presented with AF. Patient demographics and clinical characteristics are summarized in Table 1. The median age at presentation was 17.2 years
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(3.7-22.9 years). Eleven patients (23%) had at least one recurrence of AF. Median follow-up in the recurrent AF group was 4.9 years (0.9-10.9 years) and 0.1 years (0-5.7 years) in the isolated AF group, including 15 patients who had no follow-up after their single episode of AF. There were 4 isolated AF
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patients who had left ventricular hypertrophy on their echocardiogram, compared to none in the recurrent AF group, but this did not reach statistical significance (p=0.56). Patients with isolated AF were more
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likely to have an inciting event leading to their isolated episode of AF, compared to recurrent AF patients whose episodes were more spontaneous in nature. For the isolated AF group, episodes of AF were preceded by systemic infection (4), trauma to the chest (3), scoliosis surgery (1), albuterol use in the setting of an asthma exacerbation (1) and macrophage activating syndrome (1).
Of the 48 patients with AF, 38 (79%) were male. Out of the 10 female patients in our cohort, only 3 had no inciting event. The remaining patients had their AF preceded by significant alcohol intake
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(1), infection (2), macrophage activating syndrome (1), scoliosis repair (1), significant weight loss (1) or asthma exacerbation (1). Table 2 shows the LA dimension Z-scores for isolated AF and recurrent AF patients. There is no
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significant difference in LA dimension Z-scores between the two groups. There was only one patient in each group that had LA dimensions greater than a Z-score of +2. In the isolated AF group, the patient was a 19-year-old boy with a 4-chamber right-left dimension Z-score of +2.5 and an area-length volume
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Z-score of +2.4. He had no systemic hypertension, left ventricular hypertrophy or dysfunction, but was noted to have been binge drinking the day of presentation. In the recurrent AF group, the patient was a
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13-year old boy, who on echocardiogram had an apical cross sectional area z-score of +2.5 and an arealength volume Z-score of +3.1. This patient was noted to have polymorphic ventricular tachycardia on his electrophysiology study and is being evaluated for short QT syndrome. Of the patients with isolated AF, AF terminated spontaneously in 22 (59%), required electrical cardioversion in 7 (19%), and pharmacological termination in 7 (19%; flecainide 4, propafenone 1,
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amiodarone 1, metoprolol 1). One patient had missing documentation regarding how their AF terminated. Beta-blockers were started on three patients and amiodarone on one patient, the latter of whom had glucose-6-phosphate dehydrogenase deficiency and a systemic infection resulting in death one month
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later from a ventricular fibrillation arrest. Four isolated AF patients went to the electrophysiology lab after their initial presentation due to persistent palpitations – these studies noted concealed left lateral
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pathway in two patients, atrial flutter in one patient and a negative electrophysiology study in one patient. Ten patients had recurrence of their AF after their initial presentation. The median time to
recurrence was 0.9 years (0.03-6.8 years). Termination of their AF at initial presentation was spontaneous in 6 patients, or required electrical (3) or pharmacologic (2) cardioversion. Antiarrhythmics were started on all patients after at least two AF episodes, including atenolol (2), flecainide (3), propafenone (3), sotalol (1) and amiodarone (1). Two recurrences were temporally related to alcohol and/or marijuana use. Three patients underwent an electrophysiology study. One was noted to have AV node reentrant tachycardia, as well as ectopic atrial tachycardia at 17-years of age. Both mechanisms
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were ablated, but the patient continued to have AF afterward and was subsequently started on amiodarone. The second patient had recurrent episodes on flecainide and ultimately went to the electrophysiology lab 5 years after initial presentation (22-years of age) for pulmonary vein isolation; no
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other arrhythmia mechanisms were noted during the procedure. The third patient had inducible AF and polymorphic ventricular tachycardia during his electrophysiology study (16-years old); he is currently being evaluated for short QT syndrome and has transitioned from flecainide to quinidine.
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Discussion
Compared to older adults, AF is uncommon within the pediatric and young adult population. We
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identified 48 patients who presented to our institution with AF and no other significant heart disease; the largest cohort of pediatric AF patients published thus far. A quarter of the patients who present with AF will have another episode of AF during near term follow-up. Left atrial dilation was rare in all AF patients; there was no significant difference in LA dimension Z-scores between patients with isolated AF and recurrent AF.
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Numerous adult studies have demonstrated the significance of LA enlargement. Dilation of the LA has been shown to predict serious cardiovascular events in patients with hypertrophic cardiomyopathy and acute coronary syndromes9, 10. Left atrial dilation is also a predictor for the development of the first
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detected episode of AF in adults with and without underlying heart disease11, the development of AF after cardiac surgery 12, 13, and the likelihood of an AF recurrence after a patient’s initial presentation14, 15.
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Despite the importance of LA dilation and AF in the adult literature, our study was unable to show a relationship between elevated LA dimensions and AF in young patients. The mechanism for AF in young patients may differ from their adult counterparts. More recent
studies have found that LA function may be a more important predictor of AF recurrence than LA size4, 16. In fact, Hong et al. noted that in adult patients with AF, LA function by 2-dimensional strain can be abnormal and is seen prior to LA dilation. It is possible that young patients may have unrecognized LA dysfunction that leads to AF, potentially due to transient metabolic or toxic stressors such as systemic illness or alcohol use. From a genetics perspective, AF in younger patients may also be due to rare
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variants in ion channel function. Patients with early onset AF have been shown to have a higher prevalence of uncommon mutations in genes known to be associated with AF17, 18. Although there was no genetic evaluation of the patients in our cohort, it may be useful to consider in the future as research in
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this field continues to expand19. In terms of the electrophysiologic mechanism, the primary driver of AF in the young may also differ. In adults, rapidly firing foci within the pulmonary veins20 can initiate AF as the rhythm propagates and degenerates through a dilated and fibrosed LA. Adolescents, however, have been shown to have
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isolated foci within the pulmonary veins, cristae terminalis or LA21 that do not degenerate as easily, and
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are more amendable to ablation. Atrial fibrillation in young patients can also be secondary to other, “hidden”, arrhythmia substrates, such as AV reciprocating tachycardias. The presence of a second mechanism has been demonstrated in the pediatric population, with up to 39% of patients in one study having AV node reentrant tachycardia or an accessory pathway mediated tachycardia noted during an electrophysiology study performed after the first episode of AF2. As only a minority of the patients in our
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cohort underwent an electrophysiology study, it possible that other mechanisms of supraventricular tachycardia were not unmasked. However, over 75% of patients presenting with their first episode of AF did not have a recurrence. The isolated AF patients who underwent an electrophysiology study after only
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one episode of AF had recurrent palpitations, thus prompting a more invasive evaluation. Thus, given that the majority of pediatric patients with AF do not recur, an electrophysiology study may not be
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warranted after a single isolated episode, but could be considered if the patient has a second episode of AF or has frequent, unexplained palpitations. Prior to this, patient education and awareness of symptoms may be the only initial intervention required. Finally, the male predominance for AF in young patients has been seen in other studies2. Of the
females that had AF, the majority had acute stressors that may have contributed to their arrhythmia. Why young males appear to be more prone to AF is unclear, although the presence of hypertension or obesity in 25% of our patients, and their proven association with AF in adults22, points towards lifestyle factors that may make males more prone. Conversely, some of our patients may have been active in intense
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endurance training, which has also been linked to AF23, 24. Unfortunately, physical activity and exercise regimens were not recorded consistently in our study. Lower testosterone levels have also been linked to AF in adult men25, but this has yet to be evaluated in the children and young adults.
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The results of this study should be interpreted with an understanding of its limitations. Given the retrospective nature of this study, loss to follow-up may have resulted in missed episodes of recurrent AF in the isolated AF group. Nevertheless, this would not affect our finding that LA dilation is rare in young
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patients with AF. Some patients also could not have their LA dimensions determined, due primarily to image quality that precluded accurate measurements. Finally, of historic importance, the link between
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LA enlargement and AF was difficult to demonstrate without large prospective studies in adult patients. Smaller studies and retrospective analyses were able to show that LA size increases after the initial AF presentation, and with step-wise increases in the LA dimensions, patients were more likely to transition from transient to more chronic forms of AF26, 27. It was not until Vaziri et al.11 evaluated over 1900 patients that echocardiographic predictors of AF emerged, including LA size. Although our study
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represents the largest cohort of pediatric and young adult AF patients studied thus far, it serves only as a foundation for future investigations, with multicenter, prospective studies likely to yield further insights
Acknowledgements
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into this interesting patient population.
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Marga Rivera – Review and measurement of echocardiographic images
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atrial fibrillation. Japanese Heart J 1982;23:677-683.
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Table 1: Baseline Demographics.
Variable
Isolated AF
Recurrent AF
p-
(n=48)
(n=37)
(n=11)
value
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17.1 (3.7-22.9) 17.6 (3.7-22.9) 16.7 (13.6-17.7)
0.21
Male
38 (79%)
28 (76%)
10 (91%)
0.42
Body Mass Index >30mg/m2 (n=31,10)
11 (27%)
9 (29%)
2 (20%)
0.70
Systolic blood pressure >99th percentile (n=36,10)
10 (21%)
7 (19%)
3 (30%)
0.42
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Age at Presentation (years)
Total
8 (17%)
6 (16%)
2 (18%)
1.0
Illicit Drug Use
3 (6%)
3 (8%)
0 (0%)
1.0
2 (4%)
2 (5%)
0 (0%)
1.0
0 (0%)
0 (0%)
0 (0%)
--
4 (9%)
4 (12%)
0 (0%)
0.56
Stimulant Use Hyperthyroidism (n=24,8) Left Ventricular Hypertrophy (n=34,11)
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Alcohol Use
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Values are median (range) or number (percent); AF – Atrial fibrillation
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Variable
(n=29)
(n=9)
p-value
4-chamber Right-Left
0.3 (-1.4, 2.5)
0.27 (-1.4, 2.5)
0.35 (-1.4, 1.6)
0.78
4-chamber Long Axis
-0.2 (-2.8, 1.8)
-0.35 (-1.8, 1.8)
0.16 (-2.8, 1.6)
0.47
Apical 4-chamber Cross Sectional
0.0 (-1.6, 2.5)
0.02 (-1.6, 2.4)
-0.43 (-1.0, 2.5)
0.93
0.42 (-1.2, 2.6)
0.41 (-0.5, 3.1)
0.90
Area Area-length Volume SP
0.4 (-0.2, 1.2)
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Values are median (range)
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(n=38)
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Table 2: Left atrial dimension Z-scores in patients with and without lone atrial fibrillation (AF). Total Isolated AF Recurrent AF
S0002-9149(16)31566-1
DOI:
10.1016/j.amjcard.2016.09.008
Reference:
AJC 22148
To appear in:
The American Journal of Cardiology
Received Date: 10 June 2016 Revised Date:
8 September 2016
Accepted Date: 13 September 2016
Please cite this article as: Mah DY, Shakti D, Gauvreau K, Colan SD, Alexander ME, Abrams DJ, Brown DW, Relation of Left Atrial Size to Atrial Fibrillation in Patients <22 Years of Age, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.008. 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
Relation of Left Atrial Size to Atrial Fibrillation in Patients <22 Years of Age Short Title: Atrial Fibrillation in Pediatrics.
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Douglas Y. Mah, MD1; Divya Shakti, MBBS, MPH1; Kimberlee Gauvreau, ScD1; Steven D. Colan, MD1; Mark E. Alexander, MD1; Dominic J. Abrams, MD1; and David W. Brown, MD1.
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From the Department of Cardiology, Boston Children’s Hospital and Harvard Medical School1.
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Address for Correspondence Douglas Y. Mah Department of Cardiology Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115 Tel: 617-355-7833 Fax: 617-730-0000 Email: [email protected]
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Abstract
Left atrial (LA) dilation has been shown to be associated with atrial fibrillation (AF) in the adult
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population, with some studies indicating that larger LAs are more prone to AF recurrence. The relation of LA size to AF in the pediatric and young adult population has not been investigated.
In this study, all pediatric patients (<22 years of age) who presented to Boston Children’s Hospital
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between January 2002 and December 2012 with AF were reviewed. Patients with significant congenital heart disease, cardiomyopathies, proven channelopathies, prior cardiac surgery, end-stage renal disease,
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or severe lung disease/cystic fibrosis were excluded. Left atrial measurements were taken using the echocardiogram performed at the initial presentation. In total, 48 patients with AF were identified. The median age at presentation was 17.1 years (range 3.7-22.9 years); 38 patients (79%) were male. Eleven patients (23%) had at least one recurrence of their AF. There was no difference in body-mass index, prevalence of systemic hypertension, alcohol, stimulant or illicit drug use between those that had an
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isolated episode of AF versus those that had a recurrence. There was no significant difference in LA dimension Z-scores between groups, with only two patients (1 isolated AF, 1 recurrent AF) having Zscores >2. In conclusion, AF in the young without underlying heart disease is not associated with LA
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dilation.
Key Words Atrial Fibrillation Left Atrial Dilation Pediatrics
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Introduction Atrial fibrillation (AF) is a common arrhythmia in older adults, but is rare in pediatric and young adult patients with structurally and functionally normal hearts. Of the patients presenting to a pediatric
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emergency room, AF was found to make up 5% of all rhythm disturbances1. The cause of AF in the absence of myocardial, valvar, or structural heart disease (primary AF) is unknown, although it can be associated with patients who have an underlying cause for supraventricular tachycardia (i.e.
atrioventricular (AV) node reentrant tachycardia or an accessory pathway)2, 3, and perhaps obesity2. Thus
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far, only adult studies have looked at the relation of left atrial (LA) size and AF4. There have been no
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pediatric studies evaluating LA size and AF. All prior studies have looked at the concomitant presence of an AV reciprocating tachycardia. This study describes the presentation of AF in the largest cohort of pediatric patients studied thus far, and determines the relation of primary AF and LA size in this
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population, hypothesizing that, unlike adult patients, AF in the young is not associated with LA dilation.
Methods
All pediatric patients (<22 years of age) who presented to Boston Children’s Hospital between
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January 2002 and December 2012 with AF were reviewed. Patients with significant congenital heart disease (not including bicommissural aortic valves with normal valvar function and hemodynamically
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insignificant atrial septal defects, ventricular septal defects, or patent ductus arteriosus), cardiomyopathies, proven channelopathies, prior cardiac surgery, prior radiofrequency ablations, endstage renal disease, or severe lung disease such as cystic fibrosis were excluded (n=87). Data gathered included demographic data, method of presentation, symptoms prior to presentation, electrocardiographic and echocardiographic data, electrophysiological characteristics (if an electrophysiology study was performed), and follow-up data. Approval for this study was obtained from the Institutional Review Board of Boston Children’s Hospital.
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All patients who had structurally normal hearts and presented with their first episode of AF were included. Electrocardiograms at time of presentation were evaluated, as well as the electrocardiogram after conversion to sinus rhythm. The echocardiogram performed after the first AF presentation was
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reviewed. Left atrial maximal measurements were performed including apical 4-chamber short and long axis dimensions and area measurement. Single plane maximal LA volume was calculated, as nearly all echocardiogram studies were obtained prior to routine acquisition of 2-chamber imaging of the LA. Twodimensional single plane estimation of LA volume has been shown to have excellent correlation with
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biplane 2-dimensional methods5, and is obtained with the formula V= 8/3π (A2/L), where V=volume, A is
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the LA area, and L is the shortest LA length in either the 4- or 2-chamber views6. As few reports of normal LA 2-dimensional measurements, areas, and single plane volume values exist, a normative dataset of 450 normal, healthy pediatric patients undergoing echocardiography (with completely normal results) was used to generate standard deviations and Z-scores for the included measurements using absolute
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residuals as described by Altman et al.7
Patient blood pressures during their admission and at their first clinic visit were reviewed, with the highest systolic and diastolic measurements recorded. Hypertension was defined when systolic blood
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pressures were determined to be above the 99th percentile based on pediatric guidelines8. Patient height and weight at time of presentation were recorded – obesity was defined as a body-mass index (BMI)
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above 30. Concomitant medications, alcohol use, illicit drug use, and thyroid function were also noted.
If an electrophysiology study was performed, it was done under general anesthesia, with the
patient intubated, sedated and paralyzed. Baseline intervals were measured, followed by single atrial extrastimulation, rapid atrial pacing and single ventricular extrastimulation. Baseline refractory periods were measured. If used, isoproterenol infusion was given as a 0.1 mcg/kg bolus over 1 minute, followed by a 0.01 – 0.02 mcg/kg/min infusion. The presence of an accessory pathway, AV node reentrant tachycardia, and other potential arrhythmia mechanisms were recorded.
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Follow-up data were reviewed, including the initiation of antiarrhythmics and whether the AF recurred. Patients with a single episode of AF were labeled as “isolated AF”. These were compared to
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patients who had at least one recurrence of their AF after their initial presentation ”recurrent AF”.
Categorical variables are expressed as number (percent) and continuous variables as median
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(range). Comparisons between the study and control groups were performed using the Fisher exact test (categorical variables) and the Wilcoxon rank sum test (continuous variables). The Kruskal Wallis and
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Fisher’s exact tests were applied for comparison among multiple groups as indicated.
Results
A total of 48 patients with structurally normal hearts presented with AF. Patient demographics and clinical characteristics are summarized in Table 1. The median age at presentation was 17.2 years
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(3.7-22.9 years). Eleven patients (23%) had at least one recurrence of AF. Median follow-up in the recurrent AF group was 4.9 years (0.9-10.9 years) and 0.1 years (0-5.7 years) in the isolated AF group, including 15 patients who had no follow-up after their single episode of AF. There were 4 isolated AF
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patients who had left ventricular hypertrophy on their echocardiogram, compared to none in the recurrent AF group, but this did not reach statistical significance (p=0.56). Patients with isolated AF were more
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likely to have an inciting event leading to their isolated episode of AF, compared to recurrent AF patients whose episodes were more spontaneous in nature. For the isolated AF group, episodes of AF were preceded by systemic infection (4), trauma to the chest (3), scoliosis surgery (1), albuterol use in the setting of an asthma exacerbation (1) and macrophage activating syndrome (1).
Of the 48 patients with AF, 38 (79%) were male. Out of the 10 female patients in our cohort, only 3 had no inciting event. The remaining patients had their AF preceded by significant alcohol intake
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(1), infection (2), macrophage activating syndrome (1), scoliosis repair (1), significant weight loss (1) or asthma exacerbation (1). Table 2 shows the LA dimension Z-scores for isolated AF and recurrent AF patients. There is no
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significant difference in LA dimension Z-scores between the two groups. There was only one patient in each group that had LA dimensions greater than a Z-score of +2. In the isolated AF group, the patient was a 19-year-old boy with a 4-chamber right-left dimension Z-score of +2.5 and an area-length volume
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Z-score of +2.4. He had no systemic hypertension, left ventricular hypertrophy or dysfunction, but was noted to have been binge drinking the day of presentation. In the recurrent AF group, the patient was a
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13-year old boy, who on echocardiogram had an apical cross sectional area z-score of +2.5 and an arealength volume Z-score of +3.1. This patient was noted to have polymorphic ventricular tachycardia on his electrophysiology study and is being evaluated for short QT syndrome. Of the patients with isolated AF, AF terminated spontaneously in 22 (59%), required electrical cardioversion in 7 (19%), and pharmacological termination in 7 (19%; flecainide 4, propafenone 1,
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amiodarone 1, metoprolol 1). One patient had missing documentation regarding how their AF terminated. Beta-blockers were started on three patients and amiodarone on one patient, the latter of whom had glucose-6-phosphate dehydrogenase deficiency and a systemic infection resulting in death one month
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later from a ventricular fibrillation arrest. Four isolated AF patients went to the electrophysiology lab after their initial presentation due to persistent palpitations – these studies noted concealed left lateral
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pathway in two patients, atrial flutter in one patient and a negative electrophysiology study in one patient. Ten patients had recurrence of their AF after their initial presentation. The median time to
recurrence was 0.9 years (0.03-6.8 years). Termination of their AF at initial presentation was spontaneous in 6 patients, or required electrical (3) or pharmacologic (2) cardioversion. Antiarrhythmics were started on all patients after at least two AF episodes, including atenolol (2), flecainide (3), propafenone (3), sotalol (1) and amiodarone (1). Two recurrences were temporally related to alcohol and/or marijuana use. Three patients underwent an electrophysiology study. One was noted to have AV node reentrant tachycardia, as well as ectopic atrial tachycardia at 17-years of age. Both mechanisms
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were ablated, but the patient continued to have AF afterward and was subsequently started on amiodarone. The second patient had recurrent episodes on flecainide and ultimately went to the electrophysiology lab 5 years after initial presentation (22-years of age) for pulmonary vein isolation; no
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other arrhythmia mechanisms were noted during the procedure. The third patient had inducible AF and polymorphic ventricular tachycardia during his electrophysiology study (16-years old); he is currently being evaluated for short QT syndrome and has transitioned from flecainide to quinidine.
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Discussion
Compared to older adults, AF is uncommon within the pediatric and young adult population. We
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identified 48 patients who presented to our institution with AF and no other significant heart disease; the largest cohort of pediatric AF patients published thus far. A quarter of the patients who present with AF will have another episode of AF during near term follow-up. Left atrial dilation was rare in all AF patients; there was no significant difference in LA dimension Z-scores between patients with isolated AF and recurrent AF.
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Numerous adult studies have demonstrated the significance of LA enlargement. Dilation of the LA has been shown to predict serious cardiovascular events in patients with hypertrophic cardiomyopathy and acute coronary syndromes9, 10. Left atrial dilation is also a predictor for the development of the first
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detected episode of AF in adults with and without underlying heart disease11, the development of AF after cardiac surgery 12, 13, and the likelihood of an AF recurrence after a patient’s initial presentation14, 15.
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Despite the importance of LA dilation and AF in the adult literature, our study was unable to show a relationship between elevated LA dimensions and AF in young patients. The mechanism for AF in young patients may differ from their adult counterparts. More recent
studies have found that LA function may be a more important predictor of AF recurrence than LA size4, 16. In fact, Hong et al. noted that in adult patients with AF, LA function by 2-dimensional strain can be abnormal and is seen prior to LA dilation. It is possible that young patients may have unrecognized LA dysfunction that leads to AF, potentially due to transient metabolic or toxic stressors such as systemic illness or alcohol use. From a genetics perspective, AF in younger patients may also be due to rare
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variants in ion channel function. Patients with early onset AF have been shown to have a higher prevalence of uncommon mutations in genes known to be associated with AF17, 18. Although there was no genetic evaluation of the patients in our cohort, it may be useful to consider in the future as research in
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this field continues to expand19. In terms of the electrophysiologic mechanism, the primary driver of AF in the young may also differ. In adults, rapidly firing foci within the pulmonary veins20 can initiate AF as the rhythm propagates and degenerates through a dilated and fibrosed LA. Adolescents, however, have been shown to have
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isolated foci within the pulmonary veins, cristae terminalis or LA21 that do not degenerate as easily, and
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are more amendable to ablation. Atrial fibrillation in young patients can also be secondary to other, “hidden”, arrhythmia substrates, such as AV reciprocating tachycardias. The presence of a second mechanism has been demonstrated in the pediatric population, with up to 39% of patients in one study having AV node reentrant tachycardia or an accessory pathway mediated tachycardia noted during an electrophysiology study performed after the first episode of AF2. As only a minority of the patients in our
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cohort underwent an electrophysiology study, it possible that other mechanisms of supraventricular tachycardia were not unmasked. However, over 75% of patients presenting with their first episode of AF did not have a recurrence. The isolated AF patients who underwent an electrophysiology study after only
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one episode of AF had recurrent palpitations, thus prompting a more invasive evaluation. Thus, given that the majority of pediatric patients with AF do not recur, an electrophysiology study may not be
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warranted after a single isolated episode, but could be considered if the patient has a second episode of AF or has frequent, unexplained palpitations. Prior to this, patient education and awareness of symptoms may be the only initial intervention required. Finally, the male predominance for AF in young patients has been seen in other studies2. Of the
females that had AF, the majority had acute stressors that may have contributed to their arrhythmia. Why young males appear to be more prone to AF is unclear, although the presence of hypertension or obesity in 25% of our patients, and their proven association with AF in adults22, points towards lifestyle factors that may make males more prone. Conversely, some of our patients may have been active in intense
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endurance training, which has also been linked to AF23, 24. Unfortunately, physical activity and exercise regimens were not recorded consistently in our study. Lower testosterone levels have also been linked to AF in adult men25, but this has yet to be evaluated in the children and young adults.
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The results of this study should be interpreted with an understanding of its limitations. Given the retrospective nature of this study, loss to follow-up may have resulted in missed episodes of recurrent AF in the isolated AF group. Nevertheless, this would not affect our finding that LA dilation is rare in young
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patients with AF. Some patients also could not have their LA dimensions determined, due primarily to image quality that precluded accurate measurements. Finally, of historic importance, the link between
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LA enlargement and AF was difficult to demonstrate without large prospective studies in adult patients. Smaller studies and retrospective analyses were able to show that LA size increases after the initial AF presentation, and with step-wise increases in the LA dimensions, patients were more likely to transition from transient to more chronic forms of AF26, 27. It was not until Vaziri et al.11 evaluated over 1900 patients that echocardiographic predictors of AF emerged, including LA size. Although our study
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represents the largest cohort of pediatric and young adult AF patients studied thus far, it serves only as a foundation for future investigations, with multicenter, prospective studies likely to yield further insights
Acknowledgements
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Marga Rivera – Review and measurement of echocardiographic images
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Table 1: Baseline Demographics.
Variable
Isolated AF
Recurrent AF
p-
(n=48)
(n=37)
(n=11)
value
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17.1 (3.7-22.9) 17.6 (3.7-22.9) 16.7 (13.6-17.7)
0.21
Male
38 (79%)
28 (76%)
10 (91%)
0.42
Body Mass Index >30mg/m2 (n=31,10)
11 (27%)
9 (29%)
2 (20%)
0.70
Systolic blood pressure >99th percentile (n=36,10)
10 (21%)
7 (19%)
3 (30%)
0.42
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Age at Presentation (years)
Total
8 (17%)
6 (16%)
2 (18%)
1.0
Illicit Drug Use
3 (6%)
3 (8%)
0 (0%)
1.0
2 (4%)
2 (5%)
0 (0%)
1.0
0 (0%)
0 (0%)
0 (0%)
--
4 (9%)
4 (12%)
0 (0%)
0.56
Stimulant Use Hyperthyroidism (n=24,8) Left Ventricular Hypertrophy (n=34,11)
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Alcohol Use
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Values are median (range) or number (percent); AF – Atrial fibrillation
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Variable
(n=29)
(n=9)
p-value
4-chamber Right-Left
0.3 (-1.4, 2.5)
0.27 (-1.4, 2.5)
0.35 (-1.4, 1.6)
0.78
4-chamber Long Axis
-0.2 (-2.8, 1.8)
-0.35 (-1.8, 1.8)
0.16 (-2.8, 1.6)
0.47
Apical 4-chamber Cross Sectional
0.0 (-1.6, 2.5)
0.02 (-1.6, 2.4)
-0.43 (-1.0, 2.5)
0.93
0.42 (-1.2, 2.6)
0.41 (-0.5, 3.1)
0.90
Area Area-length Volume SP
0.4 (-0.2, 1.2)
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Values are median (range)
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(n=38)
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Table 2: Left atrial dimension Z-scores in patients with and without lone atrial fibrillation (AF). Total Isolated AF Recurrent AF