National ARVC Data Registry and Bio Bank

Brief Title

National ARVC Data Registry and Bio Bank

Official Title

Canadian National Arrhythmogenic Right Ventricular Cardiomyopathy

Brief Summary

      Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited condition that may
      cause life threatening irregular heart rhythms that often manifest as unexpected cardiac
      arrest or sudden death in early adulthood. The condition is difficult to diagnose and often
      is not noticed until a family member suffers a cardiac arrest or death.

      The Canadian National ARVC registry will collect data from Inherited Heart Rhythm Clinics
      across Canada.



        1. To determine the natural history of ARVC (short/intermediate term), including risk of
           symptomatic arrhythmias and sudden death, for patients with the phenotype and those gene
           positive patients without phenotype evidence of disease.

        2. To understand risk factors for sudden death/appropriate ICD use in ARVC, including test
           characteristics/performance and their relationship to outcomes (ECG, Holter, signal
           averaged ECG, loop recorders, imaging, voltage mapping, T wave alternans, cardiac biopsy
           and biomarkers).

        3. To establish a phenotype genotype correlation, including comparison of patients with
           disease causing mutations, variants of unknown significance (VUS) and Task Force
           Criteria (TFC) positive, gene negative patients

Detailed Description


      Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a familial condition characterized
      by onset of life threatening ventricular arrhythmias in early adulthood, presenting with
      ventricular tachycardia, cardiac arrest or sudden death1. The disease is diagnosed with a
      wide range of tests that focus on imaging the right ventricle and assessing for ambient
      arrhythmia or abnormal electrical substrate.

      These factors are collated into a score that forms the ARVC Task Force Criteria, known to be
      specific but not sensitive 2, 3. These criteria have been revised in 2010, introducing a
      broader and more quantitative approach to diagnosis including genetic testing results,
      intended to enhance sensitivity without reducing specificity 4. An online tool for Task Force
      Criteria calculation has been developed by the Principal Investigator that enables
      calculation in real time, with export to PDF and excel format, free for public use
      ( criteria take into account
      electrocardiographic and imaging findings, along with tissue analysis and family history.
      They account for findings from genetic testing, confounded in part by the unknown
      significance of a positive genetic test in the absence of a phenotype in a disease with
      variable penetrance and expressivity 2, 4-12. The disease is predominantly caused by defects
      in cell-cell adhesion.

      PROJECT APPROVAL PROCESS: For new projects and further analysis

      New projects and proposals for the Canadian National ARVC Registry will be reviewed on a
      case-by-case basis by the Steering Committee. The following items must be included with each
      new proposal:

        1. Project description with necessary background, hypotheses and methodology/protocol

        2. A comprehensive list of funding source(s) with a detailed budget

        3. Local Research Ethics Board (REB) approval


        1. Patients will be approached to participate in the Registry in specialty clinics who are
           involved in the Registry across Canada.

        2. Once informed consent is obtained ARVC affected patients will undergo baseline data
           collection including:

             1. Collection of standard clinical testing for ARVC (if affected patient) according to
                local clinical practice i.e. MRI, ECG etc. Family members will undergo screening as
                deemed necessary by the local investigator

             2. Baseline clinical history

             3. Family history and exercise history

             4. A family pedigree will be constructed.

             5. An online tool for pedigree construction has been developed by the Principal
                Investigator Dr. Andrew Krahn that enables creation of pedigrees in real time as
                well as the linking of patients in a genetics database, with export to PDF format,
                (demonstration version at, contact
                [email protected] for access)

             6. Patients will be enrolled in the database as prevalent cases that were previously
                identified, or incident cases

             7. Other testing if applicable

        3. Genetic Information (if applicable). Once informed consent has been obtained patients
           will undergo baseline data collection and will be invited to participate in the optional
           DNA biobanking arm of the study

        4. Genetic Screening for ARVC is a standard clinical evaluation for individuals with ARVC
           as well as their 1st degree family members this will be done clinically and sent to
           commercial laboratories as per the standard at each of the enrolling centres

        5. If the participant consents to the biobanking arm of the study an additional blood
           sample (Please see the ARVC Lab Manual for details) will be collected at baseline and
           stored for subsequent analysis. These analyses may include measurement of serum Troponin
           T, NT-pro-BNP, C-reactive protein and other biomarkers to determine their association
           with the progression of disease; both in terms of cardiac structure (i.e. change in
           right ventricular volume) and electrical substrate (i.e. number of ICD shocks) over



        1. Patients will be required to provide written informed consent to participate in the

        2. The local Research Ethics Board (REB) must approve all informed consent documents.

        3. All demographic information, clinical testing and genetic results will be entered into a
           password-protected database.

      Core Data Set (required):

      The core data set consists of baseline and follow-up clinical testing that will establish
      participant eligibility according to 2010 Revised Task Force Criteria. The core data set will
      include the following:

        1. Resting ECG

        2. Signal averaged ECG

        3. Transthoracic echocardiogram

        4. Treadmill exercise test

        5. 24 hour Holter monitor

        6. Cardiac MRI

      Additional test results (if clinically indicated):

      The following comprises a typical list of additional test results that may be collected if
      available. These test results can be collected if they are clinically indicated for the

        1. Right ventricular angiography

        2. Right ventricular biopsy

        3. Right ventricular voltage map

        4. Ability to induce ventricular tachycardia at Electrophysiologic testing

        5. Transesophageal echocardiogram

        6. T wave alternans

        7. Cardiac CT scan

      Genetic Testing and Results:

        1. Optional blood drawn for banking at PHRI will be processed at each local site and
           shipped in Cryovials for banking at PHRI in Hamilton, Ontario. Specimen(s) collected
           (i.e. blood, saliva, DNA) will be processed locally before shipping to PHRI.

        2. Blood drawn for standard clinical ARVC genetic testing at commercial laboratories in
           Canada (For example: in Ontario both SickKids Department of Paediatric Laboratory
           Medicine and CHEO Molecular Genetics Diagnostic Laboratory perform ARVC testing) can be
           packaged and shipped according to each of the local sites labs independent

        3. Genetic testing results will be entered into a secure, password-protected database.
           These results are further de-identified with a code list so that there is no linkage to
           clinical data.


      Follow-up visits for the Registry will occur on an annual basis with the following testing:

        1. Resting ECG

        2. Signal averaged ECG

        3. 24 hour Holter Monitor

        4. Clinical History

        5. Screening for any new cardiac symptoms, such as: syncope, palpitations, cardiac arrest,
           ICD implant, ICD therapy and sudden death

      Clinical follow-up data will be collected according to standard local practice. It is ideal
      to reassess participants clinically, however if this is not feasible for some reason - a
      telephone interview can be conducted to assess any new clinical findings or new events that
      have taken place.

      If the site wishes to conduct a telephone follow up - the following clinical testing is still
      required for the annual follow up visit:

        1. Resting ECG

        2. Signal averaged ECG if possible

        3. 24 hour Holter Monitor

      ECGs and Holter tracings can be obtained from remote areas and the findings entered into the
      database for annual follow up purposes.

      3-Year Reassessment:

      After 3 years participation in the study, participants will be reassessed based on the 2010
      task force criteria. This includes the following:

        1. Resting ECG

        2. Signal averaged ECG

        3. Transthoracic echocardiogram

        4. Treadmill exercise test

        5. 24 hour Holter monitor

        6. Cardiac MRI

        7. Clinical History

        8. Screening for any new cardiac symptoms, such as: syncope, palpitations, cardiac arrest,
           ICD implant, ICD therapy and sudden death

      There is currently no obligation to enter data beyond the 3 year mark, however sites are
      encouraged to continue follow up for participants indefinitely. The Registry is open-ended
      and with local REB approval participant's follow up data can continue to be entered as long
      as it is declared in the letter of information originally given to the participant.


      Data points for collection are present in the internet based database (see online demo at ). The database is hosted on the University of British
      Columbia Research Institute Vancouver British Columbia. The research institute is in
      compliance with national Canadian PIPEDA privacy guidelines. Data will be entered directly
      into the e-CRFs for electronic submission to a server located at UBC Research
      Institute,Vancouver BC and will not collect any personal identifiers (password protected
      internet based system).

      Personal identifiers will not be collected and subject confidentiality will be further
      ensured in addition to maintaining de-identification by utilizing subject identification code
      numbers to correspond to data in the computerized files. Original files containing patient
      information will remain on file with the participating Investigator.

      Individual subject medical information obtained as a result of this trial is considered
      confidential and disclosure to third parties is prohibited except for the following reason;
      medical information may be given to the subject's personal physician or to other appropriate
      medical personnel responsible for the subject's welfare. The eCRF (electronic clinical
      research form) system works best in the Internet browser Firefox©. This Internet browser can
      be downloaded from

      Access to the eCRFs will be issued once the site has local Ethics approval. .


      This trial will be conducted in compliance with the protocol, principles laid down in the
      Declaration of Helsinki, Good Clinical Practice (GCP), as defined by the International
      Conference on Harmonization (ICH), where applicable, and all other local regulatory
      requirements. Before study initiation, the enrolling site Investigator must have written and
      dated approval/favorable opinion from the Institutional Review Board/Independent Ethics
      Committee (IRB/IEC) for the protocol, and consent form.

Study Type

Observational [Patient Registry]

Primary Outcome

Natural History of ARVC

Secondary Outcome

 Risk Factors and Sudden Death


Arrhythmogenic Right Ventricular Cardiomyopathy

Study Arms / Comparison Groups

Description:  Probands - Participants diagnosed with ARVC according to the 2010 Task Force Criteria


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

January 2013

Completion Date

August 2020

Primary Completion Date

August 2020

Eligibility Criteria

        Inclusion Requirements:

          1. 2010 Revised Task Force Criteria positive patients (please refer to Appendix 3.0)

          2. 2010 Revised Task Force Criteria borderline patients

          3. Disease causing ARVC pathogenic mutation* carriers with no TFC criteria for ARVC

          4. Variants of unknown significance carriers with ≥1 minor TFC criterion

          5. Age ≥ 2 years

          6. First-degree relatives of 2010 Revised Task Force Criteria positive or borderline

          7. Able and willing to provide informed consent, or has a parent/guardian able and
             willing to provide informed consent and/or able to sign an assent form

               -  A pathogenic mutation is a DNA alteration associated with ARVC/D that alters or
                  is expected to alter the encoded protein in a significant way, is unobserved or
                  rare in a large non-ARVC/D control population, and either alters or is predicted
                  to alter the structure or function of the protein (by computational (in silico)
                  predictions and/or functional validation in a biological model system) or has
                  demonstrated linkage to the disease phenotype in a conclusive pedigree 4.
                  Mutation carriers by definition have a single major Task Force criterion.


        Exclusion Requirements:

          1. Known condition that mimics ARVC - sarcoidosis (biopsy proven or with lung
             involvement), familial dilated cardiomyopathy not compatible with an ARVC variant,
             hypertrophic cardiomyopathy

          2. Known inherited condition that predisposes to sudden death - Long or Short QT
             Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia and Brugada Syndrome

          3. Age < 2 years

          4. Life expectancy less than 1 year

          5. Unable and/or unwilling to provide informed consent




2 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Andrew D Krahn, MD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

University of British Columbia


 Population Health Research Institute

Study Sponsor

Andrew D Krahn, MD, Principal Investigator, University of British Columbia, Dept of Medicine, Head of Cardiology

Verification Date

November 2020