Clinical trial NCT05190679: Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation
Official title: Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Atrial Fibrillation
Keywords: Genetic disease
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2022-01-13
Enrollment: 225
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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).

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with Inherited Cardiomyopathy (CM) Syndromes.
timeFrame: 6 weeks
measure: Number of Participants with Inherited Arrhythmia Syndromes.
timeFrame: 6 weeks
measure: Number of Participants with Adverse Structural and Electrophysiologic Changes to the Atria and Ventricles for Inherited Cardiomyopathy Syndromes.
timeFrame: 6 weeks
measure: Number of Participants with Adverse Structural and Electrophysiologic Changes to the Atria and Ventricles for Inherited Arrhythmia Syndromes.
timeFrame: 6 Weeks
measure: Number of Participants with Changes in Management of Inherited Arrhythmia and CM Syndromes.
timeFrame: 6 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: M. B Shoemaker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.