Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001053718
Ethics application status
Approved
Date submitted
28/06/2022
Date registered
28/07/2022
Date last updated
28/07/2022
Date data sharing statement initially provided
28/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Identifying novel cardiovascular markers of exercise intolerance in adults living with atrial fibrillation.
Scientific title
Beyond cardiac function: identifying novel peripheral cardiovascular markers of exercise intolerance in physically inactive adults living with atrial fibrillation.
Secondary ID [1] 307446 0
Nil known.
Universal Trial Number (UTN)
Trial acronym
Linked study record
This is a sub-study to ACTRN12622000922774.

Health condition
Health condition(s) or problem(s) studied:
atrial fibrillation 326814 0
microvascular disease 326815 0
vascular disease 326816 0
exercise intolerance 327109 0
Condition category
Condition code
Cardiovascular 324034 324034 0 0
Other cardiovascular diseases
Cardiovascular 324035 324035 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This study will involve 2x 2-3 hour face-to face sessions at the Deakin's Institute for Physical Activity and Nutrition (IPAN) laboratory. Each session will be conducted at least greater than or equal to 48 hours apart with all measurements to be collected by study researchers.

The first session will be a familiarization session provide the participant of an understanding and awareness of how the ultrasound imaging will be conducted, the set-up on the cycle ergometer and exercising on the ergometer and performing as well as conducting the strength based tests. In addition a fasting blood test (10 hour fast) at an Accredited Laboratory and dual-energy x-ray absorptiometry to assess body composition will be also be collected. This will approximately take 2.5 hours.

The final visit will involve performing contrast-enhanced ultrasound imaging and a graded exercise test to determine the skeletal muscle microvascular blood flow response in participants. A 2 hour fasting period is required prior to testing on this visit and avoiding caffeine for greater than or equal to 6 hours prior to testing.

Contrast-Enhanced Ultrasound Imaging (3 hours): To determine the skeletal muscle microvascular blood flow, contrast-enhanced ultrasound will be performed. The technique involves intravenous infusion of a commercially available contrast agent (Definity, Lantheus Medical Imaging) composed of haemodynamically inert, perflutren lipid microspheres sufficiently small in size to perfuse capillaries. Definity is indicated in diagnostic ultrasound imaging – both liver/kidney assessment (lesion characterisation) and echocardiography (chamber opacification, endocardial border definition and regional wall motion assessment) (Therapeutic Goods Administration approved). A/Prof Keske and her collaborators at the University of Virginia have used Definity for assessment of skeletal muscle perfusion in healthy, insulin resistant and type 2 diabetes humans to assess microvascular responses in skeletal muscle. A standard ultrasound machine will be used to image the vastus lateralis muscle (thigh muscle group) in cross-section. Depth, gain and focus will be optimised for each participant and maintained during repeated imaging sequences. A contrast agent suspension [one vial of Definity (1.5ml) will be added to 20-30 mL of saline] will be infused at 1.5–2.2mL/min (infused rate based on body weight) using a syringe pump. Images will be acquired using ultrasound and analysed using computer software. The acoustic signal generated from the contrast agent microspheres will be measured and is directly proportional to the number of capillaries open/active and volume of blood in the microvascular system. After a high energy pulse of ultrasound, all contrast agent microspheres within the ultrasound beam are destroyed. The rate of contrast agent microspheres reappearance within the ultrasound beam provides an indication of microvascular blood velocity which, combined with microvascular blood volume measurements, is used to determine total microvascular blood flow (i.e., microvascular function). Measurements will be collected before the graded exercise test, immediately following the graded exercise test and 60-mins post graded exercise test.

Other ultrasound imaging (to be captured simultaneously as contrast enhanced imaging of the thigh): Femoral arterial diameter and blood velocity will be measured non-invasively using a high frequency L12-5 linear array transducer interfaced to the ultrasound system. Intra-cranial blood velocity recordings of the middle and posterior cerebral arteries will be measured using non-invasive transcranial Doppler. Extra-cranial blood flow measures of the internal carotid and vertebral arteries will be collected using a high frequency linear array transducer interfaced to the ultrasound system. Recordings of middle cerebral artery velocity and posterior cerebral artery velocity will be made at a frequency of 100Hz, at recommended depths, described in TCD guidelines. Diameter is assessed using 2D ultrasound and velocity assessed by Doppler ultrasound. Artery blood flow (ml/min) is calculated as pr2 x mean velocity x 60. Where radius (r) is cm and mean velocity is cm/s.

Graded Exercise Test (within the 3 hours of contrast-enhanced ultrasound scanning): Participants will then be asked to sit on an upright cycle-ergometer and undergo one graded exercise test. Aerobic/exercise capacity (VO2 peak) will then be assessed during a symptom-limited cardiopulmonary exercise test. After a 5-minute rest period participants will begin cycling (approximately 60 revolutions per minute [RPM]) at a workload of 20-W which will increase stepwise at 10-20-W increments every 2 minutes thereafter until the participant is either exhausted and cannot maintain a cycling cadence of greater than or equal to 60 revolutions per minute, the participant wishes to stop, or if clinical signs or symptoms of metabolic or cardiorespiratory abnormalities appear. Expired respiratory gases will be collected through a breath-by-breath pneumotach system connected to gas analysers. The breath-by-breath data will be averaged for each 15 sec interval, and the mean values for oxygen (VO2), carbon dioxide (VCO2), ventilation (VE), and respiration exchange ratio (RER) for each interval will be calculated. Each graded exercise test will take between 8-12 minutes. Electrocardiography (ECG) will be recorded continuously, and blood pressure measured during, throughout, and after exercise. An ultrasound system will be used before exercise, immediately after exercise, and 30 minutes after exercise, to determine cardiac function, thigh arterial blood flow, and muscle microvascular blood flow responses to maximal exercise. A venous blood sample will be taken before exercise, immediately after exercise, and 15 and 30 minutes post-exercise. Samples will be analysed for lactate, oxygen saturation and blood glucose levels.

1 repetition maximum testing (15 minutes): The participant will first complete progressive warm-up sets at a light to moderate-intensity load (rating of perceived exertion [RPE]: 10-12/20) of 5 repetitions, then 3 repetitions. The load selection will be completed by the supervising Accredited Exercise Physiologist which will be progressed based on the participant’s RPE. Following the warm-up, the weight will then be increased for an attempt to determine the participant’s 1RM. If the participant can successfully complete the lift with safe technique and reporting they could complete another repetition, the weight will then be increased again by the Accredited Exercise Physiologist based off the RPE and the repetitions in reserve (ie. how many more repetitions they think they could complete at that load). A 3-5 minutes rest will be provided between attempts, with the aim to obtain the 1RM within 3 attempts. The maximum weight attempted with safe and correct technique without being able to be repeated will be recorded as the 1RM for the chest press and leg press, respectively.

Hand Grip Strength (5 minutes): To determine if a participant is at risk of sarcopenia, hand grip strength will be evaluated using the American Society of Hand Therapists (ASHT) protocol. Participants will sit in an armless chair with the elbow bent to 90 degrees and will be instructed to grip the handle of a hand grip dynamometer with the thumb facing up towards the sky. A researcher will instruct the participant to grip the handle as hard as they possibly can for three seconds using their right hand. The researcher will encourage the participant throughout the hand grip assessment and record the hand grip strength from the dynamometer in kilograms. After the right hand has been assessed, a hand grip assessment of the left hand will be completed. Three trials will be taken on each hand and will be averaged to obtain the hand grip score for the right and left hand, respectively.

Venous Blood Sampling: Research staff qualified to perform cannulation and venepuncture will collect blood samples via intravenous catheter and venepuncture. 10mL of venous blood will be taken at each timepoint. Additionally, an accredited commercial pathology laboratory - Dorevitch Pathology (located on campus) will be used to collect fasting blood samples and for processing. These will be collected by one of the certified phlebotomists at Dorevitch Pathology. Participants may be provided with a Dorevitch Pathology request form where the participant can elect to go to the Dorevitch Pathology centre at Deakin University Burwood or one of their accredited laboratories of their choice. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way. Samples collected at Deakin University will be stored in a -80 degree freezer and labelled with a deidentified code.

Dual-energy x-ray absorptiometry (DXA): will be used to assess total body fat and lean body mass (LBM). In addition, the DXA and Hologic software will be used to assess fat mass in the abdominal region as well as bone mineral density to exclude osteoporosis. The participants will be asked to lie-down on their back on the DXA table in light closing (no metal) or a gown for approximately 10-15 minutes while the machine scans their body. All DXA measurements will be conducted by trained a and accredited staff at Deakin University.

Physical Activity Levels and Sedentary Time (minutes/week): These measures will be collected using the ActiGraph wGT3X-BT accelerometer (ActiGraph, Pensacola, Florida) worn over the right hip for 7 days (5 weekdays and 2 weekend days), excluding water-related activities (e.g. bathing or swimming). The widely used ActiGraph wGT3X-BT accelerometer is a lightweight, compact accelerometer that captures movement across three axes (y-, x- and z-axis), and is valid and reliable across a range of physical activity intensities and modes.
Intervention code [1] 323895 0
Early Detection / Screening
Comparator / control treatment
Healthy age and sex matched controls will be recruited to compare skeletal microvascular blood flow responses and exercise intolerance to atrial fibrillation participants.
Control group
Active

Outcomes
Primary outcome [1] 331824 0
Skeletal muscle microvascular blood flow as assessed by contrast-enhanced ultrasound.
Timepoint [1] 331824 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Primary outcome [2] 331825 0
Exercise intolerance as assessed by peak oxygen uptake (VO2peak). Participants will complete the assessment on an upright cycle-ergometer and VO2peak will be determined using a breath-by-breath gas analyser. After a 5-minute rest period participants will begin cycling (approximately 60 revolutions per minute [RPM]) at a workload of 20-W which will increase stepwise at 10-20-W increments every 2 minutes thereafter until the participant is either exhausted and cannot maintain a cycling cadence of greater than or equal to 60 RPM, the participant wishes to stop, or if clinical signs or symptoms of metabolic or cardiorespiratory abnormalities appear. The breath-by-breath data will be averaged for each 15 sec interval, and the mean values for oxygen (VO2), carbon dioxide (VCO2), ventilation (VE), and respiration exchange ratio (RER) for each interval will be calculated. The highest VO2 mean score obtained over a 15 second interval in the final attempted stage of the graded exercise test will be deemed the peak oxygen uptake. Breath-by-breath data and physiological measures will be collected for safety and monitoring purposes.
Timepoint [2] 331825 0
Visit 2.
Secondary outcome [1] 411292 0
Cardiac function as assessed via echocardiographic assessment of the heart using a commercial ultrasound machine.
Timepoint [1] 411292 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Secondary outcome [2] 411308 0
Fasting blood glucose as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [2] 411308 0
Visit 1
Secondary outcome [3] 411309 0
Glycosylated haemoglobin as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [3] 411309 0
Visit 1
Secondary outcome [4] 411310 0
Total cholesterol as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [4] 411310 0
Visit 1
Secondary outcome [5] 411311 0
Low density lipoprotein cholesterol. as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [5] 411311 0
Visit 1
Secondary outcome [6] 411312 0
High density lipoprotein cholesterol as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [6] 411312 0
Visit 1
Secondary outcome [7] 411313 0
C-reactive protein as assessed by fasting venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [7] 411313 0
Visit 1
Secondary outcome [8] 411314 0
Body composition as assessed by dual-energy x-ray absorptiometry. Components to be collected are lean muscle mass, fat mass and bone mineral density. The participants will be asked to lie-down on their back on the DXA table in light closing (no metal) or a gown for approximately 10-15 minutes while the machine scans their body. All DXA measurements will be conducted by trained and accredited staff at Deakin University.
Timepoint [8] 411314 0
Visit 1
Secondary outcome [9] 411315 0
Physical activity levels - these measures will be collected using the ActiGraph wGT3X-BT accelerometer (ActiGraph, Pensacola, Florida) worn over the right hip for 7 days (5 weekdays and 2 weekend days), excluding water-related activities (e.g. bathing or swimming).
Timepoint [9] 411315 0
7 consecutive days after Visit 1
Secondary outcome [10] 411316 0
Sedentary levels - these measures will be collected using the ActiGraph wGT3X-BT accelerometer (ActiGraph, Pensacola, Florida) worn over the right hip for 7 days (5 weekdays and 2 weekend days), excluding water-related activities (e.g. bathing or swimming).
Timepoint [10] 411316 0
7 consecutive days after Visit 1
Secondary outcome [11] 411320 0
Upper body strength as assessed via one repetition maximum chest press
Timepoint [11] 411320 0
Visit 1
Secondary outcome [12] 411321 0
Lower body strength as assessed via one repetition maximum leg press
Timepoint [12] 411321 0
Visit 1
Secondary outcome [13] 411322 0
Whole body strength via hand grip strength dynamometer.
Timepoint [13] 411322 0
Visit 1
Secondary outcome [14] 412087 0
Cerebrovascular blood flow using non-invasive transcranial Doppler. Extra-cranial blood flow measures of the internal carotid and vertebral arteries will be collected using a high frequency linear array transducer interfaced to the ultrasound system
Timepoint [14] 412087 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Secondary outcome [15] 412088 0
Femoral arterial diameter and blood velocity: will be measured non-invasively using a high frequency L12-5 linear array transducer interfaced to the ultrasound system.
Timepoint [15] 412088 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Secondary outcome [16] 412089 0
Fibrinogen as assessed via venous blood sampling. Samples will be taken at Deakin University, Burwood Campus and at an accredited commercial pathology laboratory - Dorevitch Pathology or the participant will be provided the request form to take to an accredited lab of their choosing. These will be collected via intravenous cannulation by a certified phlebotomists at Dorevitch Pathology. All venous blood samples processed by Dorovitch Pathology will have a deidentified code and results will be emailed to PI Way.
Timepoint [16] 412089 0
Visit 1.
Secondary outcome [17] 412349 0
Lactate via venous blood sampling.
Timepoint [17] 412349 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Secondary outcome [18] 412350 0
Blood glucose levels via venous blood sampling.
Timepoint [18] 412350 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.
Secondary outcome [19] 412351 0
Oxygen saturation via venous blood sampling.
Timepoint [19] 412351 0
Visit 2. Repeated measures: pre-graded exercise test, immediately post-graded exercise test and 30 minutes post- graded exercise test.

Eligibility
Key inclusion criteria
(i) clinical diagnosis of atrial fibrillation as confirmed by a physician with supporting electrocardiogram; (ii) physically inactive (less than or equal to 150 mins exercise per week).

For healthy volunteers, they must be physically inactive (less than or equal to 150 mins exercise per week) without a diagnosis of atrial fibrillation.
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(i) uncontrolled atrial fibrillation (resting heart rate greater than or equal to 110 bpm); (ii) other cardiovascular disease including coronary artery disease or heart valve disease; (iii) pulmonary hypertension; (iv) heart failure or poor ejection fraction (less than or equal to 50%); (v) critical limb ischemia including peripheral artery disease or previous revascularisation or other surgical treatment for peripheral artery disease; (vi) history of malignancy within past 5 years (except for non-melanoma skin cancers); (vii) uncontrolled hypertension (resting brachial blood pressure greater than or equal to 160/100 mmHg); (viii) Other musculoskeletal conditions and non-cardiovascular barriers to exercise/physical activity; (ix) currently engages in structured exercise or physical activity greater than or equal to 150 minutes per week; (x) successful ablation; (xi) pregnancy/lactation.

The exclusion criteria applies to both atrial fibrillation and healthy-control participants.

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
As this is an exploratory study, no formal sample size calculation is required. We aim to recruit 22 atrial fibrillation participants and 22 healthy controls.

A two-way ANOVA with time (before the exercise test and immediately after the exercise test, and 30-minutes post—exercise test) as the within-subjects factor and group (atrial fibrillation vs healthy control) as the between-subjects factor. Significant interaction and main effects will be explored by a Bonferroni post-hoc with corrections for multiple comparisons to determine if significant differences exist between groups for skeletal muscle microvascular function and blood flow, and all other outcomes. A multiple linear regression will be used to determine the variables that predict exercise tolerance (VO2 peak).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/08/2022
Actual
Date of last participant enrolment
Anticipated
30/09/2023
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
44
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 37918 0
3125 - Burwood

Funding & Sponsors
Funding source category [1] 311715 0
University
Name [1] 311715 0
Alfred Deakin Postdoctoral Fellowship - Deakin University
Country [1] 311715 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country
Australia
Secondary sponsor category [1] 313179 0
None
Name [1] 313179 0
Address [1] 313179 0
Country [1] 313179 0
Other collaborator category [1] 282351 0
Individual
Name [1] 282351 0
A/Prof Michelle Keske
Address [1] 282351 0
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country [1] 282351 0
Australia
Other collaborator category [2] 282352 0
Individual
Name [2] 282352 0
Dr. Lewan Parker
Address [2] 282352 0
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country [2] 282352 0
Australia
Other collaborator category [3] 282353 0
Individual
Name [3] 282353 0
Dr. Hannah Thomas
Address [3] 282353 0
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country [3] 282353 0
Australia
Other collaborator category [4] 282354 0
Individual
Name [4] 282354 0
Ms. Sian O'Gorman
Address [4] 282354 0
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country [4] 282354 0
Australia
Other collaborator category [5] 282355 0
Individual
Name [5] 282355 0
Dr. Andrew Betik
Address [5] 282355 0
Melbourne Campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country [5] 282355 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311166 0
Deakin University Human Research Ethics Committee (DUHREC)
Ethics committee address [1] 311166 0
Ethics committee country [1] 311166 0
Australia
Date submitted for ethics approval [1] 311166 0
Approval date [1] 311166 0
15/06/2022
Ethics approval number [1] 311166 0
2022-008

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120182 0
Dr Kimberley Way
Address 120182 0
Deakin University, Melbourne campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country 120182 0
Australia
Phone 120182 0
+61 3 9246 8894
Fax 120182 0
Email 120182 0
kim.way@deakin.edu.au
Contact person for public queries
Name 120183 0
Kimberley Way
Address 120183 0
Deakin University, Melbourne campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country 120183 0
Australia
Phone 120183 0
+61 3 924 68894
Fax 120183 0
Email 120183 0
kim.way@deakin.edu.au
Contact person for scientific queries
Name 120184 0
Kimberley Way
Address 120184 0
Deakin University, Melbourne campus, 221 Burwood Highway, Burwood, Victoria, 3125
Country 120184 0
Australia
Phone 120184 0
+61 3 924 68894
Fax 120184 0
Email 120184 0
kim.way@deakin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data collected during the trial.
When will data be available (start and end dates)?
After the primary publication is published with no end date.
Available to whom?
Only researchers who provide a methodologically sound proposal to the Principal Investigator
Available for what types of analyses?
Only to achieve the aims in the approved proposal.
How or where can data be obtained?
By contacting the Principal Investigator, Dr. Kimberley Way: kim.way@deakin.edu.au.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16486Ethical approval    384281-(Uploaded-28-06-2022-11-18-02)-Study-related document.pdf



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