Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation

Vanderbilt University Medical Center

Status

Enrolling

Conditions

Atrial Fibrillation

Treatments

Other: None/Observational Studies

Study type

Observational

Funder types

Other

NIH

Identifiers

NCT05190679

R01HL155197 (U.S. NIH Grant/Contract)

210819

Details and patient eligibility

About

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.

Full description

This study will address the hypothesis that re-phenotyping patients with AF and pathogenic arrhythmia/CM variants will identify unrecognized underlying genetic disease.

The investigators will recruit from participants sequenced as part of our prospective clinical registries and participants cared for in the Vanderbilt Genetic Arrhythmia Clinic or Meharry Arrhythmia Clinic and enrolled in the Vanderbilt Early-onset Atrial Fibrillation Registry (IRB #201666). Eligible participants will have pathogenic/likely pathogenic (P/LP) rare variants (or matched controls) and will undergo prospective cardiac phenotyping, which will include a cardiac MRI, rest/stress/signal averaged ECGs, blood work, and ambulatory ECG monitoring. A subset of patients will also undergo a procainamide drug challenge. If an inherited arrhythmia/CM syndrome is diagnosed, guideline-directed changes to medical care will be recommended.

This study will define the cardiac phenotype of individuals with AF who have a P/LP rare variant in an inherited arrhythmia or CM disease gene and compare to controls. Participants with a P/LP variant in a cardiomyopathy gene or arrhythmia gene (N=150) will be compared to controls (N=75). Controls will have no P/LP variant and be balanced for sex, race, and ethnicity. The association between P/LP variants and the following endpoints will be tested: 1) imaging and ECG-derived measurements (e.g., ventricular size, function, fibrosis, ectopy); 2) diagnoses (e.g., arrhythmogenic cardiomyopathy (AC), hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Progressive Cardiac Conduction Disease (PCCD); and 3) management changes including new medical therapy, activity restrictions, implantable cardioverter-defibrillator use, or cascade screening. Sample sizes per group have been selected to power the diagnostic and management endpoints. An Adjudication Committee with arrhythmia, CM, and genetics expertise will determine if diagnostic criteria are met and make management recommendations.

Enrollment

225 estimated patients

Sex

All

Ages

15+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

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)

Exclusion criteria

-Pregnant women