Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation

NCT05190679 | Completed

• 2 other identifiers: 210819R01HL155197
• Study Type: observational
• Target: 155
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective, case-control study that seeks to learn about the role of genetics in early onset atrial fibrillation (AF) and if genetic testing can be used to improve how the investigators treat atrial fibrillation. The study will enroll 225 participants. Eligible participants will have undergone sequencing for arrhythmia and cardiomyopathy (CM) genes. Based on those results, participants will be recruited for an outpatient research visit with testing that includes cardiac MRI, rest/stress/signal-averaged ECGs, and cardiac monitoring. If an inherited arrhythmia/CM syndrome is diagnosed, guideline-directed changes to medical care will be recommended.

Conditions

Atrial Fibrillation

Keywords

Genetic disease

Outcome Measures

Primary Outcomes (5)

• Number of Participants with Inherited Cardiomyopathy (CM) Syndromes.

  Clinical data and results are reviewed by the Adjudication Committee to determine if criteria for diagnostic endpoints are met for each participant that has completed the phenotyping protocol. The committee will remain blinded to the participant's genotype until the discussion of the clinical phenotyping result has ended. Genetic test results will be revealed and final determination of the diagnosis will be made. The Adjudication Committee will use published diagnostic criteria for specific inherited CM syndromes: Arrhythmogenic cardiomyopathy (AC), Arrhythmogenic Right Ventricular CM (ARVC), Dilated CM (DCM), Hypertrophic CM (HCM), and Left Ventricular Noncompaction CM (LVNC). For AC and DCM, only participants determined to have "definite" AC or DCM according to the diagnostic criteria will be considered as meeting the primary diagnostic endpoint.

  6 weeks

• Number of Participants with Inherited Arrhythmia Syndromes.

  The primary diagnostic endpoint will be determined by the Adjudication Committee using the published criteria for Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Long QT Syndrome (LQTS), Progressive Cardiac Conduction Disease (PCCD), and Short QT Syndrome (SQTS) from the 2013 HRS/EHRA/APHRS Expert Consensus Statement on the Management of Inherited Arrhythmias.

  6 weeks

• Number of Participants with Adverse Structural and Electrophysiologic Changes to the Atria and Ventricles for Inherited Cardiomyopathy Syndromes.

  Quantitative imaging and ECG metrics will compare participants who have a pathogenic or likely pathogenic (P/LP) rare variants linked to a CM disease gene compared to controls. Imaging and ECG metrics will be used to assess adverse structural and electrophysiologic changes to the atria and ventricles from inherited cardiomyopathy syndromes. Quantitative metrics will be assessed from contrast-enhanced MRI, signal-averaged ECG, resting 12- lead ECG, Stress treadmill ECG, and ambulatory ECG monitor. Results will be used to test the hypothesis that cases have increased measures of proarrhythmic structural and electrophysiologic changes compared to controls by imaging and ECG endpoints.

  6 weeks

• Number of Participants with Adverse Structural and Electrophysiologic Changes to the Atria and Ventricles for Inherited Arrhythmia Syndromes.

  Quantitative imaging and ECG metrics will compare participants who have a P/LP rare variants linked to an inherited arrhythmia disease gene and will compare to controls. Imaging and ECG metrics will be used to assess adverse structural and electrophysiologic changes to the atria and ventricles from inherited arrhythmia syndromes. Quantitative metrics will be assessed from resting 12- lead ECG, Stress treadmill ECG, and ambulatory ECG monitor. A procainamide challenge will be used on select participants with a non-diagnostic (type II or III) Brugada pattern identified on their previous resting 12-lead ECG or who are P/LP variant carriers in an identified Brugada susceptibility gene. Results will be used to test the hypothesis that cases have increased measures of proarrhythmic structural and electrophysiologic changes compared to controls by imaging and ECG endpoints.

  6 Weeks

• Number of Participants with Changes in Management of Inherited Arrhythmia and CM Syndromes.

  The Adjudication Committee will determine the management recommendations for each participant at the time of case review. The primary analysis will focus on changes in each management category (e.g., medical therapy, physical activity restrictions, stroke prophylaxis, implantable cardioverter-defibrillator utilization) that resulted from discovery of a rare variant, and a secondary analysis will compare the management in each category regardless of whether it was pre-existing or newly initiated. The participant will be contacted, the results will be reviewed by the principal investigator or coinvestigators to discuss the results of the testing. Any recommendations regarding clinical care will be communicated to the participants existing physicians and ensure adequate follow-up is arranged or will assist the participant in establishing care with a qualified physician.

  6 weeks

Study Arms (3)

Cardiomyopathy Rare Variant Cases

Identified Pathogenic/Likely pathogenic rare variant in cardiomyopathy (CM) gene which include inherited CM syndromes.

Other: None/Observational Studies

Arrhythmia Rare Variant Cases

Identified Pathogenic/Likely pathogenic rare variant in arrhythmia genes.

Other: None/Observational Studies

Controls

No rare variant in CM, arrhythmia, or other atrial fibrillation gene.

Other: None/Observational Studies

Interventions

None/Observational Studies OTHER

This is an observational study and there is no intervention.

Arrhythmia Rare Variant Cases; Cardiomyopathy Rare Variant Cases; Controls

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Previous participants who were enrolled in the Vanderbilt Atrial Fibrillation Registry (IVR#020669), Atrial Fibrillation Ablation Registry (IRB#110881), or Early-onset Atrial Fibrillation Registry (IRB#201666).

You may qualify if:

• Minors \>15 years
• Adult \> 18 years
• Able to provide written informed consent
• Previously enrolled in the Vanderbilt Atrial Fibrillation Registry (IVR#020669)
• Atrial Fibrillation Ablation Registry (IRB#110881)
• Early-onset Atrial Fibrillation Registry (IRB#201666)
• Underwent whole genome sequencing/whole exome sequencing or clinical genetic testing and based on those results meets the genetic criteria for cases and controls as defined as a Cardiomyopathy (CM) Rare Variant (P/LP rare variant in CM gene, Arrhythmia Rare Variant (P/LP rare variant in arrhythmia gene), or a Control (no rare variant in CM, arrhythmia, or other Atrial Fibrillation gene).
• Diagnosis of Atrial Fibrillation prior to age of 65 (\</=65)

You may not qualify if:

• Pregnant women

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (2)

• Shoemaker MB, Shah RL, Roden DM, Perez MV. How Will Genetics Inform the Clinical Care of Atrial Fibrillation? Circ Res. 2020 Jun 19;127(1):111-127. doi: 10.1161/CIRCRESAHA.120.316365. Epub 2020 Jun 18.

  PMID: 32716712 RESULT

• Yoneda ZT, Anderson KC, Quintana JA, O'Neill MJ, Sims RA, Glazer AM, Shaffer CM, Crawford DM, Stricker T, Ye F, Wells Q, Stevenson LW, Michaud GF, Darbar D, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB. Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes. JAMA Cardiol. 2021 Dec 1;6(12):1371-1379. doi: 10.1001/jamacardio.2021.3370.

  PMID: 34495297 RESULT

Related Links

• How Will Genetics Inform the Clinical Care of Atrial Fibrillation?
• Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood samples retained for DNA extraction.

MeSH Terms

Conditions

Atrial Fibrillation; Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• M. B Shoemaker, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Target Duration: 6 Weeks
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: December 28, 2021
• First Posted: January 13, 2022
• Study Start: April 27, 2022
• Primary Completion: March 3, 2026
• Study Completion: March 3, 2026
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)