The Prevalence and Significance of Low QRS Voltages in Young Healthy Individuals and Athletes
Conditions: Sudden Cardiac Death, Sudden Cardiac Arrest, Sudden Cardiac Death Due to Cardiac Arrhythmia, Arrhythmogenic Right Ventricular Cardiomyopathy, Arrhythmogenic Left Ventricular Cardiomyopathy, Dilated Cardiomyopathy
Sponsor: Imperial College London

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Study Protocol for,
The prevalence and significance of low QRS voltages in young healthy
individuals and athletes
Version 4
Date: 22/06/2023
MAIN SPONSOR: Imperial College London
FUNDERS: Royal Brompton Hospital Charity/Cardiac Risk in the Young
STUDY COORDINATION CENTRE: Royal Brompton Hospital
IRAS Project ID: 283055
REC reference: 23/PR/0361
NCT05799833

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Protocol for non-CTIMP
The prevalence and significance of low QRS voltages in young healthy
individuals and athletes
Version 4
Date: 22/06/2023
MAIN SPONSOR: Imperial College London
FUNDERS: Cardiac Risk in the Young/British Heart Foundation
STUDY COORDINATION CENTRE: Royal Brompton Hospital
IRAS Project ID: 283055
REC reference: 23/PR/0361
Protocol authorised by:
Name & Role
Date
Signature
Dr Sabiha Gati
31/10/2022

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Study Management Group
Chief Investigator: Dr Sabiha Gati
Co-investigators: Professor Sanjay Sharma, Professor Dudley Pennell, Dr Nirmitha
Jayaratne
Statistician: Winston Banya
Study Management: Dr Nirmitha Jayaratne
Study Coordination Centre - Royal Brompton Hospital
For general queries, supply of study documentation, and collection of data, please
contact:
Study Coordinator: Dr Sabiha Gati
Address: Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
Registration: GMC 6106246
Tel: 07966660767
E-mail: S.gati@rbht.nhs.uk
Fax: N/A
Web address: N/A
Clinical Queries
Clinical queries should be directed to Dr Nirmitha Jayaratne who will direct the query
to the appropriate person
Sponsor
Imperial College London is the main research Sponsor for this study. For further
information regarding the sponsorship conditions, please contact the Head of
Regulatory Compliance at:
Research Governance and Integrity Team
Imperial College London and Imperial College Healthcare NHS Trust
Room 215, Level 2, Medical School Building
Norfolk Place
London, W2 1PG
Tel: 0207 594 1862
Imperial College - Research Governance and Integrity Team (RGIT) Website

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Funder:
Cardiac Risk in the Young Charity
This protocol describes the “The prevalence and significance of low QRS voltages in young
healthy individuals and athletes” study and provides information about procedures for entering
participants. Every care was taken in its drafting, but corrections or amendments may be necessary.
These will be circulated to investigators in the study. Problems relating to this study should be
referred, in the first instance, to the Chief Investigator.
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and Social
Care Research. It will be conducted in compliance with the protocol, the Data Protection Act and other
regulatory requirements as appropriate.
Table of Contents
Page No
1. INTRODUCTION.................................................................................................... 7
1.1. BACKGROUND................................................................................................... 7
1.2. RATIONALE FOR CURRENT STUDY................................................................ 8
2. STUDY OBJECTIVES............................................................................................ 8
3. STUDY DESIGN.....................................................................................................8
3.1. STUDY OUTCOME MEASURES........................................................................ 9
4. PARTICIPANT ENTRY...........................................................................................9
4.1. PRE-REGISTRATION EVALUATIONS............................................................... 9
4.2. INCLUSION CRITERIA........................................................................................9
4.3. EXCLUSION CRITERIA...................................................................................... 9
4.4. WITHDRAWAL CRITERIA...................................................................................9
5. ADVERSE EVENTS............................................................................................... 9
5.1. DEFINITIONS...................................................................................................... 9
5.2. REPORTING PROCEDURES........................................................................... 10
6. ASSESSMENT AND FOLLOW-UP...................................................................... 11
7. STATISTICS AND DATA ANALYSIS................................................................... 11
8. REGULATORY ISSUES.......................................................................................11
8.1. ETHICS APPROVAL......................................................................................... 12
8.2. CONSENT......................................................................................................... 12
8.3. CONFIDENTIALITY...........................................................................................12
8.4. INDEMNITY....................................................................................................... 12
8.5. SPONSOR.........................................................................................................13
8.6. FUNDING.......................................................................................................... 13
8.7. AUDITS..............................................................................................................13
9. STUDY MANAGEMENT.......................................................................................13
10. PUBLICATION POLICY......................................................................................13
11. REFERENCES................................................................................................... 13

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GLOSSARY OF ABBREVIATIONS
LQRSV
Low QRS Voltage
SCD
Sudden Cardiac Death
CMR
Cardiac Magnetic Resonance
ECG
Electrocardiogram
TFTs
Thyroid function tests
PVCs
Premature Ventricular complexes
DCM
Dilated Cardiomyopathy
ARVC
Arrhythmogenic right ventricular cardiomyopathy
LGE
Late Gadolinium Enhancement
CPET
Cardiopulmonary exercise testing
ICD
Implantable cardioverter defibrillator
VO2
Baseline oxygen consumption
AT
Anaerobic threshold
V˙E/V˙CO2
Ventilatory efficiency for carbon dioxide
RER
Respiratory exchange ratio
KEYWORDS
Low QRS Voltage
Low QRS amplitude
Sudden Cardiac Death
Cardiac magnetic resonance
Myocardial fibrosis
Premature Ventricular complexes

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Dilated Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy
Late Gadolinium Enhancement
Implantable cardioverter defibrillator
Cardiopulmonary exercise testing
Athletes
Genetic inheritance
Non sustained ventricular tachycardia
STUDY SUMMARY
TITLE
The prevalence and significance of low QRS voltages in young
healthy individuals and athletes
DESIGN
Cross sectional Observational study
AIMS
The study aims to investigate the prevalence and significance of low QRS
voltages in young healthy individuals and athletes aged 17-35 years old.
OUTCOME MEASURES
1. Prevalence of low QRS voltages in athletes and young non-athletic
population on ECG analysis.
2. Prevalence of myocardial fibrosis in the young athletic and non-athletic
population with low QRS.
Exploratory secondary outcomes:

The proportion of individuals with low QRS complexes and myocardial
fibrosis with rare protein altering variant in a cardiomyopathy gene.

Exercise
related
ventricular
premature
beats
or
a
ventricular
premature beat burden of > 500 beats on a Holter monitor.
POPULATION
240 total study population: 60 athletes with low QRS voltage and 60 age
and sex matched control group of athletes with normal QRS voltage, 60
non-athletes with low QRS voltage and 60 sex and age matched controls
with normal QRS voltage
ELIGIBILITY
Inclusion criteria for athletes and non-athletes with low QRS complexes:
Asymptomatic and body mass index <30.
Exclusion Criteria for Controls and Athletes: Individuals with cardiac
symptoms; past medical history of cardiac disease; family history of SCD
<40 years old or cardiomyopathy; previous myocarditis; lung disease;
individuals with pacemakers, defibrillators; pregnant women; advanced
kidney and/or liver disease; no known thyroid disease, T-wave inversion
or other training unrelated ECG changes, significant valvular heart
disease or intra-cardiac shunt on echocardiography.
DURATION
2022- 2027

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1. INTRODUCTION
1.1.
BACKGROUND
Low QRS Voltages in the Limb Leads in the general population: There is limited evidence in
the literature that low QRS voltages (defined as QRS amplitude of <0.5mV in the limb leads)
may be associated with left ventricular myocardial fibrosis and a predisposition to serious
ventricular arrhythmias and SCD.1,2,5 Low QRS voltages on the 12-lead ECG are thought to
reflect conditions that impair the transmission of electrical signals in the heart. The
prevalence of low QRS complexes in the general population is between 0.3-2%.5–8 However,
this
includes
individuals
with
chronic
obstructive
pulmonary
disease,
undiagnosed
hypothyroidism, obesity, large pleural and pericardial effusion, severe left ventricular systolic
dysfunction
and
infiltrative
cardiomyopathies, which
are also associated with
low
voltages.6,7,17–20,9–16
The prevalence of low QRS voltages and their significance in
young healthy individuals (17-35 years old) is not fully understood.
Low QRS Voltages in the Limb Leads in Athletes: Sudden cardiac death (SCD) is one of the
leading causes of death in athletes .21–23 The majority of deaths are attributable to hereditary,
structural or electrical pathologies which can be identified by abnormalities on the resting 12-
lead ECG. Distinguishing physiological changes due to regular physical training resulting
from increased vagal tone and increased chamber size and wall thickness 24 from those of
potentially life threatening cardiac conditions can be challenging. The 2010 European
Society of Cardiology recommendations for ECG interpretation in athletes25 and the more
recent international recommendations26 provide a clear guide to aid ECG interpretation in
athletes and are supported by a growing evidence base24.
Low QRS voltages (<0.5mV in the limb leads and <1.0 mV in the precordial leads) do not
feature in the current international recommendations27 due to a lack of robust evidence. In a
recent study in Italian competitive athletes demonstrated that the prevalence of low QRS
voltages was 1.1%.5 Five athletes with low QRS voltages and exercise induced arrhythmias
underwent
CMR
showing
biventricular
arrhythmogenic
cardiomyopathy
or
idiopathic
myocardial scar in two individual. n another study involving Italian Olympian athletes
demonstrated that the prevalence of low QRS voltages of 4%.28
All athletes were
investigated with ECG, echocardiography, maximal exercise test and 24-hour Holter
recoding. The researchers did not identify any correlation between low QRS voltages and
left ventricular morphology on echocardiography although premature ventricular beats were
more frequent in athletes with low QRS voltages compared with athletes with normal QRS
voltages (39% vs 7%).
Furthermore, no cardiac events were recorded over a follow-up
period of 5±2 years. The main limitation of this study is that athletes with low QRS
voltages did not have CMR for the assessment of myocardial fibrosis. In a study of 35
competitive athletes
with
isolated
non-ischaemic
LV scar
by
CMR and
ventricular
arrhythmias, Zorzi et al reported that 20% of this cohort exhibited low QRS voltages.4 A
larger study in athletes and healthy individuals with low QRS voltages versus a
control population using CMR is required.
Cardiovascular Magnetic Resonance in Athletes: There has been a substantial rise in the
use of CMR for assessing athletes with ECG repolarisation changes.
CMR has high
reproducibility and provides detailed tissue characterisation. CMR with gadolinium contrast
provides the unique ability to detect myocardial inflammation and fibrosis. T1 mapping
enables the detection of interstitial fibrosis and T2 mapping detects myocardial oedema.
Assessment of extracellular volume (ECV) provides quantitative assessment of cellular vs

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extracellular composition. Such techniques can play a pivotal role in understanding tissue
changes contributing to low QRS voltages.
1.2.
RATIONALE FOR CURRENT STUDY
The limitations of the above studies described are that not all athletes with low QRS voltages
undertook a CMR evaluation to determine sensitivity, specificity, and positive predictive
value of disease prediction. Therefore there is a need for a larger study in athletes and
healthy individuals with low QRS voltages versus a control population using CMR to further
evaluate the findings on these studies.
We postulate that left ventricular lateral/inferior wall subepicardial wall myocardial fibrosis in
young individuals and athletes manifests as small QRS voltages on the ECG. In turn,
myocardial fibrosis in athletes and young non-athletic individuals may reflect a pathogenic or
likely pathogenic mutation in genes associated with cardiomyopathies. Such an approach to
evaluating low QRS voltages in athletes should ultimately help determine the precise
significance of small QRS complexes in young apparently healthy non-athletic individuals
and athletes. The outcomes will facilitate the development of new recommendations on ECG
interpretation in young individuals and athletes and identify young people at risk of SCD.
We hypothesise that in athletes and non-athletic subjects aged 17-35 years old with low
QRS voltages: 1. The prevalence of myocardial fibrosis is greater. 2. The prevalence of
known/likely pathogenic mutations in genes associated with DCM/AVC is greater.
2. STUDY OBJECTIVES
Primary objective is to investigate the prevalence and significance of low QRS voltages in
young healthy individuals and athletes aged 17-35 years old.
This study will also aim to inform updated current international recommendations on ECG
interpretation in athletes. The results of this study will have an impact on athletes worldwide,
even if an ICD was not implanted there are several measures that would mitigate the risk of
sudden death such as advise to abstain from vigorous exercise, regular surveillance for risk
stratification, screening of first-degree relatives to identify others who may be affected.
Study Design and Period: Cross sectional, observational study over 5 years
3. STUDY DESIGN
Cross sectional observational study
Study Population: 60 apparently healthy athletes and 60 apparently healthy non-athletes.
Controls: The control population will consist of 60 sex and aged matched healthy athletes
with normal QRS complexes (paired for the athlete group with low QRS complexes) and 60
non athletes (paired for the non-athlete group with low QRS complexes).
Study duration: 60 months

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3.1.
STUDY OUTCOME MEASURES
Primary outcomes: 1. Prevalence of low QRS voltages in athletes and young non-athletic
population on ECG analysis. 2. Prevalence of myocardial fibrosis in the young athletic and
non-athletic population with low QRS.
Exploratory secondary outcomes: 3. The proportion of individuals with low QRS
complexes and myocardial fibrosis with rare protein altering variant in a cardiomyopathy
gene. 4. Exercise related ventricular premature beats or a ventricular premature beat burden
of > 500 beats on a Holter monitor.
PLANNED SUBGROUP ANALYSIS: We will investigate whether concomitant exercise
related ventricular premature beats or a ventricular premature beat burden of > 500 beats on
a Holter monitor predict myocardial fibrosis in athletes and non-athletes with low QRS
complexes.
4. PARTICIPANT ENTRY
4.1.
PRE-REGISTRATION EVALUATIONS
12-lead ECG: A standard 12-lead ECG will be performed using either a MAC 5000 or MAC
5500 digital resting ECG recorder
Blood Test: A thyroid function test will be performed to ensure participants meet the inclusion
criteria and do not have thyroid disease as a potential confounding factor to this study.
4.2.
INCLUSION CRITERIA
Inclusion criteria: athletes and non-athletes with low QRS complexes who are asymptomatic
and with a body mass index <30.
4.3.
EXCLUSION CRITERIA
Exclusion Criteria for Controls and Athletes: Individuals with cardiac symptoms; past medical
history of cardiac disease; family history of SCD <40 years old or cardiomyopathy; previous
myocarditis; lung disease; individuals with pacemakers, defibrillators; pregnant women;
advanced kidney and/or liver disease; no known thyroid disease, T-wave inversion or other
training unrelated ECG changes, significant valvular heart disease or intra-cardiac shunt on
echocardiography.
4.4.
WITHDRAWAL CRITERIA
Study participants can decide to withdraw from the study at any point
5. ADVERSE EVENTS
5.1.
DEFINITIONS
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.
Serious Adverse Event (SAE): any untoward medical occurrence or effect that:

Results in death

Is life-threatening – refers to an event in which the subject was at risk of death
at the time of the event; it does not refer to an event which hypothetically might
have caused death if it were more severe

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
Requires
hospitalisation,
or
prolongation
of
existing
inpatients’
hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect
Medical judgement should be exercised in deciding whether an AE is serious in other
situations. Important AEs that are not immediately life-threatening or do not result in death
or hospitalisation but may jeopardise the subject or may require intervention to prevent one
of the other outcomes listed in the definition above, should also be considered serious.
5.2.
REPORTING PROCEDURES
All adverse events should be reported. Depending on the nature of the event the reporting
procedures below should be followed.
Any questions concerning adverse event reporting
should be directed to the Chief Investigator in the first instance.
5.3.1 Non serious AEs
All such events, whether expected or not, should be recorded- it should be specified if only
some non-serious AEs will be recorded, any reporting should be consistent with the purpose
of the trial end points.
5.3.2 Serious AEs
An SAE form should be completed and emailed to the Chief Investigator within 24 hours.
However, relapse and death due to an pre-existing condition, and hospitalisations for
elective treatment of a pre-existing condition do not need reporting as SAEs.
All SAEs should be reported to Dr Sabiha Gati where in the opinion of the Chief Investigator,
the event was:

‘related’, ie resulted from the administration of any of the research procedures;
and

‘unexpected’, ie an event that is not listed in the protocol as an expected
occurrence
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.
The Chief Investigator must also notify the Sponsor of all related and unexpected SAEs.
Local investigators should report any SAEs as required by their Local Research Ethics
Committee, Sponsor and/or Research & Development Office.
Contact details for reporting SAEs
RGIT@imperial.ac.uk
CI email (and contact details below)
S.gati@rbht.nhs.uk
Fax: N/A
Please send SAE forms to: lowQRS@rbht.nhs.uk
Tel: 07977 352296 (Mon to Fri 09.00 – 17.00)

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6. ASSESSMENT AND FOLLOW-UP
Participants who require ongoing clinical surveillance will be followed up in the specialist
services at Royal Brompton Hospital. Individuals living afar will be referred to their primary
care physician to instigate a formal referral to the relevant local specialist clinic.
Any relevant incidental findings on the cardiac MRI that is directly not related to the heart
would be referred to the primary care physician for appropriate investigations and onward
referral if required.
LOSS TO FOLLOW UP: To minimise loss to attendance there will be telephone and written
communication during and after investigation. NHS details will be obtained from athletes so
that GPs can be contacted for up-to-date details should participants be uncontactable.
END OF THE STUDY: The study will be completed following completion of all investigations
as outlined in the study protocol, availability and analysis of data including genetic results on
all 240 subjects (120 athletes and 120 young individuals). The pre-planned date for
completion is 30 November 2025.
7. STATISTICS AND DATA ANALYSIS
The study to contain 240 participants as per the power calculation below.
POWER CALCULATION:
Athletes: Given a 4% prevalence of low QRS complexes in athletes28 a sample of 2,500
athletes’ ECGs would be expected to yield 100 cases of athletes with low QRS. In a study by
Zorzi et al4, 20% of athletes with myocardial fibrosis exhibited low QRS complexes in the
limb leads, while the athletes with normal QRS had no myocardial fibrosis. Based on these
parameters, for a power of 90% and 5% significance, a sample size of 55 athletes with low
QRS complexes and 55 athletes with normal QRS is required to detect a difference in
proportion of myocardial fibrosis. Allowing for a 5% exclusion rate following eligibility, we will
recruit 60 athletes with and 60 athletes without low QRS complexes for further investigations.
Young Population: Given a 2% prevalence of low QRS complexes in the general
population and taking into consideration that 36.5% of the UK population is young (aged 14-
44 years old), a review of 12,000 young individuals’ ECGs would be expected to yield 88
cases with low QRS. Again, using the study by Zorzi et al4, and assuming these parameters
to hold in the general population of young people, for a power of 90% and 5% significance, a
sample size of 55 young people with low QRS complexes and 55 young people with normal
QRS is required to detect a difference in proportion of scar. Allowing for a 5% exclusion rate
following eligibility, we will recruit 60 young people with and 60 young people without low
QRS complexes for further investigations.
Data and all appropriate documentation will be stored for a minimum of 10 years after the
completion of the study, including the follow-up period.
8. REGULATORY ISSUES

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8.1.
ETHICS APPROVAL
The Study Coordination Centre has obtained approval from the Central London Research
Ethics Committee (REC) and Health Research Authority (HRA). The study must also receive
confirmation of capacity and capability from each participating NHS Trust before accepting
participants into the study or any research activity is carried out. The study will be conducted
in accordance with the recommendations for physicians involved in research on human
subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions.
8.2.
CONSENT
Consent to enter the study must be sought from each participant only after a full explanation
has been given, an information leaflet offered and time allowed for consideration. Signed
participant consent should be obtained. The right of the participant to refuse to participate
without giving reasons must be respected. After the participant has entered the study the
clinician remains free to give alternative treatment to that specified in the protocol at any
stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should
be recorded.
In these cases the participants remain within the study for the purposes of
follow-up and data analysis.
All participants are free to withdraw at any time from the
protocol treatment without giving reasons and without prejudicing further treatment.
8.3.
CONFIDENTIALITY
Collection, storage and assessment of participant data will abide by the GMC good medical
practice guide and general data protection regulation (GDPR). Case Report Forms (CRF)
will be designed by the chief investigator (CI). Required data will be put on the project
database under patients pseudo-anonymised ID. Research staff will enter all research data
onto a password protected excel spreadsheet. Only research team members will have
access to this spreadsheet via data sharing agreements following patient consent. Master
spreadsheet will be stored on secure servers in Royal Brompton Hospital. Consent Forms
and patient ID log will be stored securely with the investigator site file at participating sites
and will only be accessible to the research team. Original CRF with patient identifiable
details will be stored in patients’ medical records and clinical results will be stored as per
standard hospital guidelines for investigations which are part of standard of care and will be
kept confidential. The Hospital PACS system will store all CMR images in line with hospital
protocols. All genetic data will be stored on the Imperial college HPC and in line with Imperial
College FoM policies for storage and publication of genetic data from human subjects. All
information will be de-identified, but with linked IDs. We will comply with the Hospital and
University policies on managing confidentiality and data security and consult with the
Hospital and College’s Joint Research Compliance Office to ensure that only robustly
anonymised data will be made publicly available, and all data sharing activities comply with
GDPR.
The Chief Investigator will preserve the confidentiality of participants taking part in the study
and is registered under the Data Protection Act.
Data will be pseudo-anonymised.
8.4.
INDEMNITY
Imperial College London holds negligent harm and non-negligent harm insurance policies
which apply to this study.

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8.5.
SPONSOR
Imperial College London will act as the main Sponsor for this study.
Delegated
responsibilities will be assigned to the NHS trusts taking part in this study.
8.6.
FUNDING
Cardiac Risk in the young charitable organisation is funding this study.
8.7.
AUDITS
The study may be subject to audit by Imperial College London under their remit as sponsor
and other regulatory bodies to ensure adherence to GCP and the UK Policy Frame Work for
Health and Social Care Research.
9. STUDY MANAGEMENT
The day-to-day management of the study will be co-ordinated through Dr Nirmitha Jayaratne
- Clinical Research fellow to Dr Sabiha Gati.
10.PUBLICATION POLICY
It is expected that all parties involved in the publication of content in any specific journal (the
publisher, editors, authors, and reviewers) will follow the guidelines on best practice and
publication ethics based on the journal policy. The Journal to which the manuscript will be
submitted is committed to investigating cases of alleged editor, author, and reviewer
misconduct arising from its activities, and will follow COPE Guidelines in all cases.
11.REFERENCES
1.
Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A,
Basso C, Bauce B, Brunckhorst C, Bucciarelli-Ducci C, Duru F, Elliott P, Hamilton RM,
Haugaa KH, James CA, Judge D, Link MS, Marchlinski FE, Mazzanti A, Mestroni L,
Pantazis A, Pelliccia A, Marra MP, Pilichou K, Platonov PGA, Protonotarios A,
Rampazzo A, Saffitz JE, Saguner AM, Schmied C, Sharma S, Tandri H, Te Riele
ASJM, Thiene G, Tsatsopoulou A, Zareba W, Zorzi A, Wichter T, Marcus FI, Calkins
H. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current
diagnostic criteria and differential diagnosis. Eur Heart J. 2019;Available from:
https://doi.org/10.1093/eurheartj/ehz669
2.
Usoro AO, Bradford N, Shah AJ, Soliman EZ. Risk of mortality in individuals with low
QRS voltage and free of cardiovascular disease. Am J Cardiol. 2014;113:1514–1517.
3.
Finocchiaro G, Papadakis M, Robertus J-L, Dhutia H, Steriotis AK, Tome M, Mellor G,
Merghani A, Malhotra A, Behr E, Sharma S, Sheppard MN. Etiology of Sudden Death
in Sports: Insights From a United Kingdom Regional Registry. J Am Coll Cardiol.
2016;67:2108–2115.
4.
Zorzi A, Perazzolo Marra M, Rigato I, De Lazzari M, Susana A, Niero A, Pilichou K,
Migliore F, Rizzo S, Giorgi B, De Conti G, Sarto P, Serratosa L, Patrizi G, De Maria E,
Pelliccia A, Basso C, Schiavon M, Bauce B, Iliceto S, Thiene G, Corrado D.
Nonischemic Left Ventricular Scar as a Substrate of Life-Threatening Ventricular
Arrhythmias and Sudden Cardiac Death in Competitive Athletes. Circ Arrhythm
Electrophysiol. 2016;9.
5.
Zorzi A, Bettella N, Tatangelo M, Del Monte A, Vessella T, Poscolieri B, Crescenzi C,
Pegorin D, D’Ascenzi F, Pescatore V, Giada F, Sarto P, Calò L, Schiavon M, Gregori
D, Hadley DM, Drezner JA, Pelliccia A, Corrado D. Prevalence and clinical
significance of isolated low QRS voltages in young athletes. Eur Eur pacing,
arrhythmias, Card Electrophysiol J Work groups Card pacing, arrhythmias, Card Cell

Research Governance
and Integrity Team
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Electrophysiol Eur Soc Cardiol. 2022;
6.
Chinitz JS, Cooper JM, Verdino RJ. Electrocardiogram voltage discordance:
interpretation of low QRS voltage only in the limb leads. J Electrocardiol.
2008;41:281–286.
7.
Madias JE. Low QRS voltage and its causes. J Electrocardiol. 2008;41:498–500.
8.
Fraley MA, Birchem JA, Senkottaiyan N, Alpert MA. Obesity and the
electrocardiogram. Obes Rev. 2005;6:275–281.
9.
Alpert MA, Terry BE, Cohen M V, Fan TM, Painter JA, Massey C V. The
electrocardiogram in morbid obesity. Am J Cardiol. 2000;85:908–10, A10.
10.
Bruch C, Schmermund A, Dagres N, Bartel T, Caspari G, Sack S, Erbel R. Changes
in QRS voltage in cardiac tamponade and pericardial effusion: reversibility after
pericardiocentesis and after anti-inflammatory drug treatment. J Am Coll Cardiol.
2001;38:219–226.
11.
Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Phillips MC. Pericardial effusion:
relation of clinical echocardiographic and electrocardiographic findings. J
Electrocardiol. 1984;17:115–121.
12.
Eisenberg MJ, de Romeral LM, Heidenreich PA, Schiller NB, Evans GTJ. The
diagnosis of pericardial effusion and cardiac tamponade by 12-lead ECG. A
technology assessment. Chest. 1996;110:318–324.
13.
Hamer JP, Janssen S, van Rijswijk MH, Lie KI. Amyloid cardiomyopathy in systemic
non-hereditary amyloidosis. Clinical, echocardiographic and electrocardiographic
findings in 30 patients with AA and 24 patients with AL amyloidosis. Eur Heart J.
1992;13:623–627.
14.
Madias JE. Transient attenuation of the amplitude of the QRS complexes in the
diagnosis of Takotsubo syndrome. Eur Hear journal Acute Cardiovasc care.
2014;3:28–36.
15.
Madias JE, Agarwal H, Win M, Medepalli L. Effect of weight loss in congestive heart
failure from idiopathic dilated cardiomyopathy on electrocardiographic QRS voltage.
Am J Cardiol. 2002;89:86–88.
16.
Oliver C, Marin F, Pineda J, Lujan J, Climent VE, Garcia A, Arrarte V, Sogorb F. Low
QRS voltage in cardiac tamponade: a study of 70 cases. Int. J. Cardiol. 2002;83:91–
92.
17.
Parameswaran R, Maniet AR, Goldberg SE, Goldberg H. Low electrocardiographic
voltage in pericardial effusion. Chest. 1984;85:631–634.
18.
Pinamonti B, Dreas L, Bussani R, Mestroni L, Silvestri F, Tanganelli P, Camerini F.
[Cardiac amyloidosis. Invasive and noninvasive diagnosis]. G Ital Cardiol.
1987;17:1016–1030.
19.
Rodman DM, Lowenstein SR, Rodman T. The electrocardiogram in chronic
obstructive pulmonary disease. J Emerg Med. 1990;8:607–615.
20.
Sorbello A, Giudice JC, Papa LA. The relationship of low voltage on the
electrocardiogram and chronic obstructive pulmonary disease. Clin Cardiol.
1982;5:657–660.
21.
Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in
National Collegiate Athletic Association athletes. Circulation. 2011;123:1594–1600.
22.
Harmon KG, Asif IM, Maleszewski JJ, Owens DS, Prutkin JM, Salerno JC, Zigman ML,
Ellenbogen R, Rao AL, Ackerman MJ, Drezner JA. Incidence, Cause, and
Comparative Frequency of Sudden Cardiac Death in National Collegiate Athletic
Association Athletes: A Decade in Review. Circulation. 2015;132:10–19.
23.
Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young
competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.
Circulation. 2009;119:1085–1092.
24.
Sharma S, Drezner JA, Baggish A, Papadakis M, Wilson MG, Prutkin JM, La Gerche

Research Governance
and Integrity Team
Template Ref: RGIT_TEMP_027
Template V6.0 04Nov2021
Page 15 of 16
© Imperial College of Science, Technology and Medicine
A, Ackerman MJ, Borjesson M, Salerno JC, Asif IM, Owens DS, Chung EH, Emery
MS, Froelicher VF, Heidbuchel H, Adamuz C, Asplund CA, Cohen G, Harmon KG,
Marek JC, Molossi S, Niebauer J, Pelto HF, Perez M V, Riding NR, Saarel T,
Schmied CM, Shipon DM, Stein R, Vetter VL, Pelliccia A, Corrado D. International
recommendations for electrocardiographic interpretation in athletes. Eur Heart J.
2018;39:1466–1480.
25.
Corrado D, Pelliccia A, Heidbuchel H, Sharma S, Link M, Basso C, Biffi A, Buja G,
Delise P, Gussac I, Anastasakis A, Borjesson M, Bjørnstad HH, Carrè F, Deligiannis
A, Dugmore D, Fagard R, Hoogsteen J, Mellwig KP, Panhuyzen-Goedkoop N,
Solberg E, Vanhees L, Drezner J, Estes N a M, Iliceto S, Maron BJ, Peidro R,
Schwartz PJ, Stein R, Thiene G, Zeppilli P, McKenna WJ. Recommendations for
interpretation of 12-lead electrocardiogram in the athlete. Eur Heart J. 2010;31:243–
59.
26.
Uberoi A, Stein R, Perez M V, Freeman J, Wheeler M, Dewey F, Peidro R, Hadley D,
Drezner J, Sharma S, Pelliccia A, Corrado D, Niebauer J, Estes NAM 3rd, Ashley E,
Froelicher V. Interpretation of the electrocardiogram of young athletes. Circulation.
2011;124:746–757.
27.
Drezner JA, Sharma S, Baggish A, Papadakis M, Wilson MG, Prutkin JM, Gerche A
La, Ackerman MJ, Borjesson M, Salerno JC, Asif IM, Owens DS, Chung EH, Emery
MS, Froelicher VF, Heidbuchel H, Adamuz C, Asplund CA, Cohen G, Harmon KG,
Marek JC, Molossi S, Niebauer J, Pelto HF, Perez M V, Riding NR, Saarel T,
Schmied CM, Shipon DM, Stein R, Vetter VL, Pelliccia A, Corrado D. International
criteria for electrocardiographic interpretation in athletes: Consensus statement. Br J
Sports Med. 2017;51:704 LP – 731.
28.
Mango F, Caselli S, Luchetti A, Pelliccia A. Low QRS voltages in Olympic athletes:
Prevalence and clinical correlates. Eur J Prev Cardiol. 2020;2047487320914758.
29.
Rawlins J, Carre F, Kervio G, Papadakis M, Chandra N, Edwards C, Whyte GP,
Sharma S. Ethnic differences in physiological cardiac adaptation to intense physical
exercise in highly trained female athletes. Circulation. 2010 [cited 2010 Sep
8];121:1078–85.
30.
Halliday BP, Gulati A, Ali A, Guha K, Newsome S, Arzanauskaite M, Vassiliou VS,
Lota A, Izgi C, Tayal U, Khalique Z, Stirrat C, Auger D, Pareek N, Ismail TF, Rosen
SD, Vazir A, Alpendurada F, Gregson J, Frenneaux MP, Cowie MR, Cleland JGF,
Cook SA, Pennell DJ, Prasad SK. Association Between Midwall Late Gadolinium
Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy
and Mild and Moderate Left Ventricular Systolic Dysfunction. Circulation.
2017;135:2106–2115.
31.
Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-
sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent
marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42:873–879.
32.
Biffi A, Pelliccia A, Verdile L, Fernando F, Spataro A, Caselli S, Santini M, Maron BJ.
Long-term clinical significance of frequent and complex ventricular tachyarrhythmias
in trained athletes. J Am Coll Cardiol. 2002;40:446–452.
33.
James CA, Jongbloed JDH, Hershberger RE, Morales A, Judge DP, Syrris P, Pilichou
K, Domingo AM, Murray B, Cadrin-Tourigny J, Lekanne Deprez R, Celeghin R,
Protonotarios A, Asatryan B, Brown E, Jordan E, McGlaughon J, Thaxton C, Kurtz CL,
van Tintelen JP. International Evidence Based Reappraisal of Genes Associated With
Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome
Resource Framework. Circ Genomic Precis Med. 2021;14:e003273.
34.
Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L, Brown E, Celeghin R, Edwards M,
Fan J, Ingles J, James CA, Jarinova O, Johnson R, Judge DP, Lahrouchi N, Lekanne
Deprez RH, Lumbers RT, Mazzarotto F, Medeiros Domingo A, Miller RL, Morales A,

Research Governance
and Integrity Team
Template Ref: RGIT_TEMP_027
Template V6.0 04Nov2021
Page 16 of 16
© Imperial College of Science, Technology and Medicine
Murray B, Peters S, Pilichou K, Protonotarios A, Semsarian C, Shah P, Syrris P,
Thaxton C, van Tintelen JP, Walsh R, Wang J, Ware J, Hershberger RE. Evidence-
Based Assessment of Genes in Dilated Cardiomyopathy. Circulation. 2021;144:7–19.
35.
Harmon KG, Drezner JA, Wilson MG, Sharma S. Incidence of sudden cardiac death
in athletes: a state-of-the-art review. Heart. 2014;100:1227–1234.
Appendix 1.
Summary of investigations, treatment and assessments
Recruitment (48 months)
Athletes’ ECGs
= 2500
Young
population ECGs
= 12,000
Athletes with low
QRS
60
Young
population with
low QRS
60
Athletes with
Normal ECGs
60
Young
population with
Normal ECGs
60
Consent
Appointment Date
Online booking system for appointments for 30 days
Testing at Royal Brompton Hospital (One-Stop-Shop)
Blood test: TFTs
CMR
Exercise
testing/CPET
24-Hour Holter
Results Reporting (2-weeks)
Patient letter summarising tests
results
GP letter communicating and
advising on abnormal findings
Athletes with and without low QRS
and myocardial fibrosis
Young population with and without
low QRS and myocardial fibrosis
Genetic Testing for DCM/AVC Panel
N= 25
N=25
Genetic Results Reporting (6 months)
Statistical analysis of results and write-up (12 months)