Clinical Trial: Mayo AVC Registry and BioBank
Study Status: Enrolling by invitation
Recruit Status: Enrolling by invitation
Study Type: Observational
Official Title: The Mayo Clinic Arrhythmogenic Ventricular Cardiomyopathy Registry
Brief Summary:
Arrhythmogenic ventricular cardiomyopathy (AVC) is a genetic condition which affects the heart and can lead to heart failure and rhythm problems, of which, sudden cardiac arrest or death is the most tragic and dangerous. Diagnosis and screening of blood-relatives is very difficult as the disease process can be subtle, but sufficient enough, so that the first event is sudden death.
The Mayo Clinic AVC Registry is a collaboration between Mayo Clinic, Rochester, USA and Papworth Hospital, Cambridge University Hospitals, Cambridge, UK. The investigators aim to enroll patients with a history of AVC or sudden cardiac death which may be due to AVC, from the US and UK. Family members who are blood-relatives will also be invited, including those who do not have the condition. Data collected include symptoms, ECG, echocardiographic, MRI, Holter, loop recorder, biopsies, exercise stress testing, blood, buccal and saliva samples.
Objectives of the study:
- Discover new genes or altered genes (variants) which cause AVC
- Identify biomarkers which predict (2a) disease onset, (2b) disease progression, (2c) and the likelihood of arrhythmia (ventricular, supra-ventricular and atrial fibrillation)
- Correlate genotype with phenotype in confirmed cases of AVC followed longitudinally using clinical, electrocardiographic and imaging data.
- Characterize desmosomal changes in buccal mucosal cells with genotype and validate with gold-standard endomyocardial biopsies
Detailed Summary:
Sudden cardiac arrest (SCA) accounts for over 360,000 deaths in the US and 400,000 in Europe per annum, including thousands under the age of 40 who die unexpectedly and without warning. Whilst the majority of SCAs are triggered by heart attacks, in those under the age of 40 years this tends to be due to genetic heart disease, which if identified early may save lives of other family members. Epidemiological and post-mortem studies have shown arrhythmogenic ventricular cardiomyopathy (AVC) as a leading cause of SCA, responsible for up to 25% of deaths in this age group.
AVC is a highly clinically and genetically heterogeneous condition, which results in fibro-fatty replacement of myocardium which may lead to ventricular dysfunction, heart failure, electrical rhythm disturbances and SCD. Although AVC predominantly affects the right ventricle (ARVC), it can affect both the right and left ventricle, or the LV in isolation (ALVC) and result in a type of dilated cardiomyopathy (DCM) with a propensity for arrhythmia (aDCM). Recent reports of aDCM with a familial distribution suggests this is undiagnosed AVC, reflecting heterogeneity and limited understanding. AVC is considered a disease of the desmosome (cell-adhesion proteins) and this has led to identification of desmosomal mutations (plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin), mostly inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity. Non-desmosomal genes have also been discovered (desmin, titin, RYR2, transforming growth factor -3, transmembrane protein 43 and phospholamban). Together, these only account for 50-60% of known AVc-related mutations, with the remainder being genetically undetermined. Additionally, multiple mutations also exist within families and within individuals further compounding the complexity of AVC. Inter and intra-familial variabilit
Sponsor: Mayo Clinic
Current Primary Outcome:
- Genotyping [ Time Frame: 3 years ]Using family 'trios' discover novel pathogenic variants and characterize them
- Correlate genotype with phenotype [ Time Frame: 3-6 years ]Correlate genotype with phenotype in confirmed cases of AVC followed longitudinally as per 2010 Task Force Criteria
Original Primary Outcome: Same as current
Current Secondary Outcome:
- Natural history and secular trends of AVC [ Time Frame: 3-6 years ]Test blood-based biomarkers (such high-sensitivity CRP, high-sensitivity troponin, NT-proBNP and miRNA) which predict disease onset, disease progression, and the likelihood of arrhythmia.
- Natural history and secular trends of AVC [ Time Frame: 3-6 years ]Discover ECG-based biomarkers which predict disease onset, disease progression, and the likelihood of arrhythmia.
- Natural history and secular trends of AVC [ Time Frame: 3-6 years ]Discover MRI-based biomarkers which predict disease onset, disease progression, and the likelihood of arrhythmia.
- Cellular and Tissue phenotyping [ Time Frame: 3 years ]Characterize desmosomal changes in buccal mucosal cells with endomyocardial biopsies and/or in vivo tissue characterization by cardiac MRI or cardiac CT
- Risk factors for sudden death or appropriate ICD discharge [ Time Frame: 5-10 years ]Test the performance of biomarkers and risk factors to outcomes of sudden death and/or appropriate ICD therapies by modeling.
Original Secondary Outcome: Same as current
Information By: Mayo Clinic
Dates:
Date Received: January 30, 2017
Date Started: January 2016
Date Completion: December 2031
Last Updated: February 7, 2017
Last Verified: February 2017
