Atrial Electromechanical Function in Middle-aged Endurance Athletes With and Without Atrial Fibrillation
Conditions: Paroxysmal Atrial Fibrillation
Sponsor: University of Toronto

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Atrial electromechanical function in athletes with and without AFib 
October 4th, 2017 
Atrial electromechanical function in middle-aged endurance athletes 
with and without Atrial Fibrillation 
 
Principal Investigator: E Vecchiarelli 
 
Version Date: October 4th, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Atrial electromechanical function in athletes with and without AFib 
October 4th, 2017 
1.0 RESEARCH OBJECTIVES  
1.1 Study Rationale 
Despite extensive literature characterizing cardiac structure, function and 
electrical conduction in sedentary patients with AF, no data exists in athletic populations 
with AF. Measurement of these parameters would provide insight into the mechanisms 
and pathophysiology of exercise-induced AF, as well as the functional consequences of 
paroxysmal AF in this cohort. These data may inform the management of AF in athletes 
who continue to train and provide the basis for developing prognostic indicators in a 
population at greater risk for AF development, particularly in middle-age. Accordingly, 
this study will examine cardiac function, specifically left ventricular and left atrial phasic 
function in the presence of paroxysmal AF in endurance trained athletes. Secondly, atrial 
electromechanical function will be assessed in athletes to further explore functional 
parameters that may provide prognostic value. 
1.2 Objectives 
1) to assess and compare left atrial phasic volumes and function (as measured by ejection 
fraction and strain) at rest and during submaximal exercise in middle-aged endurance 
trained athletes with AF and age-matched healthy endurance trained athletes without AF.  
2) to compare atrial electromechanical delay (AEMD) in middle aged endurance-trained 
athletes with AF to age-matched healthy non-AF endurance trained athletes. An 
exploratory objective will be to determine whether there is a correlation between P-wave 
duration and AEMD. 
1.3 Hypotheses 

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1) It is expected that left atrial strain will be impaired in athletes with AF compared to 
athletes without AF at both rest and during submaximal exercise- though impairments 
will be more pronounced during submaximal exercise. Specifically, it is hypothesized 
that left atrial (LA) reservoir function will be reduced in athletes with AF, as it is a strong 
predictor for AF.  
2) It is expected that despite similar left atrial size, athletes with AF will have 
significantly prolonged AEMD compared to age-matched athletes without AF.  
Additionally, it is hypothesized that P wave duration and AEMD will be correlated, 
suggesting AEMD may be a sensitive and precise measure for atrial fibrosis. 
2.0 STUDY POPULATION 
This will be a cross-sectional cohort study involving: Male endurance trained 
athletes who have been diagnosed with paroxysmal AF (AF-ET) and 2) and male 
endurance trained athletes without diagnosis or history of AF or AF symptoms (H-ET).  
The study will be limited to male participants given the higher prevalence of AF 
compared to females. 
Global Inclusion Criteria: Participants eligible will be male endurance athletes 
(between ages of 45 and 65). Subjects will be life-long participants (20 years +) of 
prolonged, intensive endurance running, cycling, rowing or triathlons.  Athletes must be 
involved in year-round training and competition (in at least one or more events per year).  
Unrestricted participation history of light-intensity activity (eg. golf, walking etc) will be 
allowed. 
Inclusion Criteria for H-ET: This group will be a referent population that is recruited 
from an existing cohort from our previously conducted study ‘Cardiac Consequences of 

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Endurance Exercise.’ Participants who have had prescreening, completed a resting signal 
averaged ECG, cMRI and Holter monitoring will be eligible.  
Inclusion Criteria for Athletes with AF: The same criteria of athletic training as the 
athletes without AF (H-ET) will be used. This cohort will be recruited on the basis of 
having being diagnosed with paroxysmal AF in the last four (4) years. Specific criteria 
for paroxysmal AF diagnosis are: an absence of consistent P waves, irregular fibrillatory 
waves, variation in RR intervals, and atrial tachycardia (350-600 bpm) lasting for longer 
than 30 seconds and terminating in 48 hours time. Diagnosis will be verified using 
clinical charts that include either ambulatory 12-lead ECG readings or Holter monitor 
detection of AF. Subjects will be included regardless of medical treatment for AF which 
may include rate and/or rhythm control, either chronically or acutely (‘pill-in-a-pocket’ 
upon onset of episodes). All participants must be in sinus rhythm during all assessments. 
Global Exclusion Criteria: 1) >1 hour of resistance training per week (risk of concentric 
remodeling), 2) BMI < 20 kgm-2 or > 25 kgm-2, 3) treatment or prior diagnosis of 
coronary artery disease or cardiomyopathy, valvular disease, hypertension, heart failure, 
diabetes, history of thyroid disorder, diagnosis of sleep apnea, current/recent viral or 
chronic illness, chronic inflammatory disease, 4) recreational drug use or excessive 
alcohol consumption (using accepted standards) 5) previous or current smoking, 6) 
contraindication to MRI.  
Exclusion Criteria specific for AF group: 1) presence of atrial flutter, 2) previous 
ablation, 3) cessation of exercise > 6 months post diagnosis of AF, 4) inability to provide 
verification of AF diagnosis. 

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2.2 Sample Size 
The primary outcome measure for the first hypothesis is atrial reservoir function, 
as measured by myocardial strain imaging by echocardiography. There are no data 
describing atrial phasic function in athletes with AF. Accordingly sample size was 
determined using the average difference in reservoir strain in a cohort of middle aged 
(51.78  6.83 years) patients with lone AF, compared to healthy middle aged (48.97  
7.65 years) controls with no presence of AF or other cardiovascular related disease. Left 
atrial reservoir strain was reported as: (29.01  5.63 %) in patients with AF compared to 
(35.5  4.77 %) in healthy adults. Accordingly, the mean difference between groups was 
6.49  5.2. Thus, based on an alpha of 0.05 and power of 0.8, 11 participants are 
necessary in each group.  
 
The primary outcome measure for the second hypothesis is AEMD. No previous 
literature has examined AEMD in endurance athletes, nor is there established reference 
values for healthy adults. Previous literature has demonstrated patients with paroxysmal 
AF to have significantly greater delays in inter-atrial EMD, as well as both left and right 
AEMD. However, it has been suggested that specifically intra-left AEMD is a significant 
marker for the development of AF, and was correlated to P-wave dispersion, left atrial 
diameter and left atrial area (45). Accordingly, sample size was determined using the 
difference in left AEMD in a cohort of otherwise healthy middle-aged patients (48.3  
11.1 years) with lone AF compared to healthy middle-aged (45.2  4.8 years) controls 
with no presence of lone AF.   Left-atrial EMD was reported as: 21.8  9.1 ms in AF 
patients and 14.1  4.9 ms in controls (difference of 7.7  7 ms). Thus, based on an alpha 
of 0.05 and power of 0.8, 15 participants are necessary in each group (n=30). 

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Accordingly, the more conservative calculation of 15 per group will be used. However, in 
our experience, poor imaging quality lead to unanalyzable data may occur in 10-15% of 
the sample, therefore we will recruit 17 per group to ensure adequate statistical power.  
 
2.3 Recruitment 
Healthy endurance athletes will be recruited from our email list serve of previous 
‘Cardiac Consequences of Endurance Exercise’ participants.  Interested participants will 
contact either the principal investigator or co-investigators through email or phone.  
Subjects with AF will be recruited by advertisement to local athletic clubs, emails 
to the GTA cardiology community for referrals and word of mouth. We have 
considerable experience in the recruitment of healthy endurance and recreationally 
trained subjects from both cycling and running clubs within the GTA. In addition we will 
seek referrals from cardiology and electrophysiology practices within the GTA using 
existing collaborative ties at teaching hospitals and by personal communication. We also 
have access to contact information of several athletes with AF who were excluded from 
our previous study who expressed interest in participating in a research study should one 
arise.  These individuals will be provided with an email recruitment advertisement in 
which they will be prompted to contact the investigators by telephone or email in 
interested.  
Initial screening for major inclusion/exclusions will be performed by the student 
investigator by telephone. If there is interest in participating following a telephone 
discussion, an information package including the informed consent will be sent 
electronically if possible, and subjects will be requested to meet in the Heart Health 

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laboratory located within the Goldring Center for High Performance Sport at the 
University of Toronto to submit their informed consent, receive further information 
should there be additional questions and undergo the initial assessment. 
2.4 Methods 
General Procedures 
All participants will be assessed at the same time of day.  Participants will be asked to 
abstain from exercise on the day before and the day of each study visit.   
Visit One: Participant Screening/Consent/ Graded Exercise Testing / 
Echocardiography 
The first visit will take place at the Heart Health Laboratory. Prior to attending the first 
visit, participants will have received consent forms and a 2-week Exercise Diary through 
email.  Participants will complete consent form and have the opportunity to ask questions 
as needed upon their first visit, as well as return the 2-week Exercise Diary. Participants 
will be then familiarized with the procedures of the study.  Participants will undergo 
basic anthropometric assessment to determine body mass (weight and height) and resting 
blood pressure. Following this, participants will be fitted with a 12-lead ECG and 
proceed to complete resting and submaximal exercise echocardiography, performed by a 
trained sonographer.  Emphasis will be on left atrial volume, phasic function and AEMD. 
Exercise will be on a semi-recumbent cycle ergometer designed for stress 
echocardiography (Ergoline 1200EL). Imaging will be performed at rest, followed by a 
two-minute warm up.  Participants will then cycle at 100 bpm for 5 minutes and at 130 
bpm for 5 minutes; imaging will be initiated 2 minutes into each stage. During a 30-min 
rest period, participants will complete a Lifetime Physical Activity Questionnaire 

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Participants will then proceed to have a maximal cardiopulmonary exercise treadmill test 
with a HR monitor (Polar V800).  
 
Visit Two: Resting Signal Averaged ECG/ Cardiac Magnetic Resonance 
Imaging/Holter Monitor 
 
The second visit will only be required for athletes with atrial fibrillation (AF-ET), 
as the healthy endurance athletes will have completed this visit during their participation 
in a previous REB-approved study. Visit 2 will be completed at St. Michael’s Hospital. 
Prior to attending this visit, participants will undergo venipuncture by trained 
phlebotomist for assessment of serum creatinine and calculation of GFR to confirm 
normal kidney function, required for LGE administration (see below). On the day of, 
participants will first have a standard signal averaged ECG performed. Following this, 
subjects will undergo resting cardiac imaging using (cMRI) (Siemens MAGNETOM 
Skyra 3.0T with TIM and DOT technology) by a trained technician. Proceeding cMRI, 
participants will be fitted for a 48 hour Holter monitor that will assess cardiac rhythm 
over 2 days (at home), in which participants will refrain from exercise for the first day, 
and will complete a typical bout of exercise on the second day. 
2.7 Detailed Procedures 
2.7.1 Graded Exercise Testing 
A graded exercise test will be completed at the Heart Health Laboratory. Maximal 
oxygen consumption (VO2MAX) will be determined by indirect calorimetry obtained 
during graded exercise testing on a motorized treadmill (Full Vision TMX4125) using a 
calibrated metabolic cart (VMax Encore, CareFusion). Expired gases will be collected 
and averaged over 10 second intervals. Maximal effort will be confirmed by a plateau of 

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oxygen uptake despite increasing workrates and secondary criteria will include 
achievement of age- predicted maximum heart rate (208 - (0.7 X AGE))X[60] and a 
respiratory exchange ratio > 1.15. Standard measures of expired gases will be performed. 
Continuous measures of HR during exercise using a electronic heart rate monitor (Polar 
Inc.) will be integrated to data recording of the metabolic cart. A 3-lead ECG will be 
established and recorded every minute. A physician will be on site during exercise testing 
with an AED located within 5 meters. 
2.7.2 Resting and Submaximal Echocardiography 
Participants will undergo transthoracic echocardiography (GE E9 Imaging 
System) at the Heart Health Laboratory, provided the individual is in sinus rhythm. 
Imaging will be performed by a trained sonographer, and images will be obtained 
according to the criteria of the American society of echocardiography guidelines. 
Subjects will be initially placed in a supine position on a purpose-built imaging/cycle 
ergometer (Ergoline 1200E), for assessment of resting cardiac structure and function. 
During exercise, subjects will be repositioned to a 45 degree semi-upright position with 
minor left caudal tilt to optimize imaging. Cycle ergometry will be performed concurrent 
with echocardiography.  
For all acquisitions, two-dimensional apical (two and four chamber view) and 
parasternal (long and short axis) imaging will be performed for dimensional and 
functional parameters of the atria and of the ventricles at a frame rate of 60-80 (fps).  
Volume and size measurements will be normalized to body surface area. 
Echocardiograph imaging will primarily be used for functional measures at rest and 
exercise; structural assessment of chambers will be determined using cMRI. Emphasis 

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will be on left atrial reservoir function, as this parameter has provided robust insight into 
AF-associated impairment even in the presence of normal LA size. Left atrial volumes 
will be measured at different time points of the cardiac cycle. Atrial maximal volume 
(LA max) will be measured at the end of ventricular systole, prior to the opening of the 
mitral valve; atrial pre-A volume (LA PRE-A) will be measured prior to onset of atrial 
contraction (beginning of P wave); atrial minimal volume (LA min) will be measured at 
the closure of the mitral valve. Accordingly, LA phasic volumes and emptying fractions 
will be calculated.  Left and right ventricular volumes and ejection fraction will be 
calculated by the modified bi-plane Simpson’s method. Images for LA strain will be 
obtained using Speckle Tracking echo. Strain measures will include global longitudinal 
strain, peak atrial longitudinal strain, and atrial phasic strain (reservoir: during ventricular 
systole, conduit: during early ventricular diastole and booster: during late ventricular 
diastole). Left ventricular strain during ventricular systole, early diastole and late diastole 
will also be measured. Pulsed-wave Doppler interrogation of transmitral flow will be 
obtained at the septal and lateral mitral annulus to determine flow velocities during early 
(E) and late (A) diastole, as well as the E/A ratio. Tissue Doppler imaging will also be 
performed at the septal and lateral mitral annulus to determine myocardial systolic (Sm), 
early diastolic (Em) and late diastolic (Am) velocities. Care will be taken to minimize 
gain and all analyses of DTI and Doppler flow patterns will be conducted according to 
current ASE guidelines84-86. The collection of these images will allow us to calculate 
intracardiac volumes and indices of diastolic and systolic function. 
 
2.7.3 Atrial Electromechanical Delay 

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Tissue Doppler Echocardiography will be performed by transducer frequencies of 3-
4MHz, adjusting the spectral pulsed Doppler signal filters until a Nyquist limit of 15-
20cm/s and using the minimal optimal gain. The monitor sweep speed will be set to 50-
100mm/s to optimize the spectral delay of myocardial velocities. In apical 4-chamber 
view, the pulsed Doppler sample volume will be placed at the lateral and septal sides of 
the mitral annulus and the right-ventricular (RV) tricuspid annulus to obtain tissue 
Doppler velocities. The time intervals from the onset of the P wave (ECG) to the 
beginning of the Am wave (on echo) will be measured from the lateral mitral annulus 
(lateral PA), septal mitral annulus (septal PA), and RV tricuspid annulus (tricuspid PA).  
The timing of mechanical activation of each sample point is dependent on the distances 
of each point to the sinoatrial node (SA). Accordingly, the RV tricuspid annulus is the 
earliest (closest) and the lateral mitral annulus is the latest (farthest) point to be activated 
by impulses from the SA node. The difference between any two reference points reflects 
the mechanical delay between these two points Inter-AEMD will be defined as the 
difference between the lateral PA and tricuspid PA, intra-right AEMD will be defined as 
the difference between the septal PA and tricuspid PA, and intra-left AEMD will be 
defined as the difference between the lateral PA and septal PA. 
2.6.3 Signal Averaged ECG 
 
Signal averaged-ECG will be recorded at St. Michael’s hospital. Acquisition and 
analysis will be performed in the same manner in which the athletes without AF would 
have received at a prior visit for another REB-approved study. Briefly, the subject will be 
in supine position, in a room free from electrical interference. Three bipolar orthogonal 
leads (x,y,z) will be used. Electrode placement will be according to the following: X 

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electrodes in the left and right mid-axillary line of the 4th intercostal space; Y electrodes 
in the left mid-clavicular line at the level of the abdomen; Z electrode placed in the mid-
clavicular line in the 4th intercostal space. A P-wave template will be generated and 
averaged P-wave signals will be filtered using a spectral filter. Measurements will 
include filtered P-wave duration (ms) and root mean square voltage in the terminal 20 ms 
of the P-wave (mv). 
2.7.4 Cardiac Magnetic Resonance Imaging 
 
All athletes with AF will undergo resting cardiac magnetic resonance imaging 
(cMRI) at St. Michael’s hospital, following methods used for previous REB-approved 
study). MRI will be performed supine in a 3.0T scanner (Siemens MAGNETOM Skyra 
3.0T with TIM and DOT technology); images will be obtained on end-expiration breath 
holds. Vertical long-axis cine images will be prescribed from axial scout images by 
aligning the left ventricular (LV) apex with the center of the mitral valve.  From these LV 
long-axis images, the horizontal long-axis plane will be obtained by aligning the 
midpoint of the left ventricular apex and mitral valve.  These pilot 4-chamber and 2-
chamber views provide the reference images on which a stack of contiguous short-axis 
slices will be prescribed, covering the left atrium and left ventricle.  Depending on the 
LV long-axis length, 8-12 contiguous slices will cover the entire left ventricle. Providing 
normal creatine levels are verified (see above), delayed enhancement MRI will be 
acquired 10 minutes after contrast agent injection of gadolinium (0.1 mmol/kg body 
weight, Multihance, Bracco Diagnostic Inc, Princeton, NJ) (MRI contrast agent does not 
contain iodine and does not damage the kidneys.  Subjects refusing gadolinium will still 
be studied.  Imaging will be used for cardiac structure and volumetric assessments of the 

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atria and ventricles (max and min volume, EDV and ESV).  All data analysis will be 
performed using CMR42 (Circle Imaging, Calgary, Canada).  End-diastolic frames are 
defined as the image with the largest ventricular volume in each series, and end-systolic 
as the image with the smallest volume.  Endocardial and epicardial borders on these 
frames will be manually traced.  From this data, LV and RV ejection fraction, end 
diastolic/end systolic and stroke volume indices will be calculated.  Manual tracing of 
endocardial borders of short-axis images at atrial end-diastole and atrial end-systole will 
allow for calculation of LA end-diastolic volume and end-systolic volume.  
 
 
2.8 Data Analysis 
 
All variables will be expressed as mean and standard deviation.  Differences in 
outcome measures (AEMD, atrial phasic function, atrial dimensions) will be assessed 
using a series of independent t-tests between the athletes with AF and athletes without 
AF. A 2-way repeated measures analysis of variance (ANOVA) will be used to compare 
resting and exercise values between and within groups. Covariates will be included when 
appropriate, including age, years since AF diagnosis, and number of AF episodes. Atrial 
size and relation to ECG parameters may be studied for correlational analyses. 
Significance will be set at p<0.05. Analysis will be performed using SPSS software.