Defining the Risk of Ventricular Tachycardia in Genetic Cardiomyopathies

NCT ID: NCT06575881

Last Updated: 2026-02-03

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-12-13
• Study Completion Date: 2029-12-31

Brief Summary

The goal of this observational study is to determine if electrophysiologic mapping and cardiac MRI can help identify patients that have genetic forms of cardiomyopathy that are at high risk for development of dangerous ventricular arrhythmias.

The investigators aim to study:

1. the prevalence and mechanism of inducible ventricular tachycardia

2. pace-mapping to define the site of origin of ventricular arrhythmias

3. voltage mapping to define low voltage scar substrate in the basal LV to determine the risk of development of ventricular arrhythmias in patients with genetic forms of cardiomyopathy.

Participants will undergo cardiac MRI before their scheduled procedure and voltage mapping during their scheduled procedure as part of data collection.

Detailed Description

New genomic knowledge is poised to change clinical practice for atrial fibrillation (AF). In 1293 cases previously considered idiopathic, the investigators identified a pathogenic variant in a cardiomyopathy (CM) or arrhythmia gene in ~11% of patients diagnosed with AF before age 608 and went on to show that these patients have a higher risk of mortality and sudden death. The investigators propose tests of specific hypotheses that will address the major knowledge gap of whether and how genetic findings should change clinical management recommendations.

Aim: To use programmed ventricular stimulation at the time of AF ablation or Electrophysiology Study to define the prevalence and mechanism of inducible ventricular tachycardia (VT) (Aim 1A); pace-mapping to define the site of origin of ventricular arrhythmias (Aim 1B); and voltage mapping to define low voltage scar substrate in the basal LV (Aim 1C) in patients with pathogenic TTN variants compared to genotype-negative controls.

The Aim is informed by the observation that life-threatening VT in patients with dilated CM and pathogenic TTN variants most often localizes to the LV outflow tract (LVOT), periaortic region, and basal septum. The investigators found that 39% (27/70) of patients with early-onset AF and pathogenic TTN variants have premature ventricular contractions (PVCs) and non-sustained VT that localize to this same area, which the investigators therefore hypothesize are an early marker of a malignant arrhythmia substrate. Life-threatening ventricular arrhythmias are usually due to scar-related reentry, but a major problem with the LVOT/periaortic region is that scar in this area is hard to detect. To address this limitation, the investigators have published new voltage cutoffs to define scar in the LVOT/periaortic region. The Aim addresses the overarching hypothesis that patients with pathogenic TTN variants have occult scar in the basal LV and are at risk for life-threatening reentrant VT. The investigators will define the mechanism of VT using a combination of entrainment maneuvers with overdrive pacing and the identification of scar with voltage mapping. To facilitate the Aim, the investigators have established a dedicated AF Precision Medicine Clinic to evaluate patients with early onset AF. Fifty percent of these patients undergo AF ablation for symptomatic AF, which the investigators have found is as effective in TTN patients as genotype-negative controls. The investigators will enroll 50 patients with a pathogenic variant in TTN, 50 with a pathogenic variant in other CM genes (e.g., LMNA), and 100 genotype-negative controls.

Conditions

Atrial Fibrillation; Ventricular Tachycardia; Premature Ventricular Contraction

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

TTN-positive

Patients with a pathogenic or likely pathogenic variant in TTN on clinical genetic testing.

No interventions assigned to this group

Gene-positive

Patients with a pathogenic or likely pathogenic variant in a gene other than TTN on clinical genetic testing.

No interventions assigned to this group

Gene-negative

Patients without a pathogenic or likely pathogenic variant in a cardiomyopathy or arrhythmia gene on clinical genetic testing.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Adults aged 18 and older
• Diagnosed with AF, frequent PVCs, or VT before age 60
• Scheduled for catheter-based AF ablation (de-novo or repeat) OR catheter-based PVC ablation OR catheter-based VT ablation
• Able to provide written, informed consent
• P/LP variant in TTN or other CM gene (cases) or identified as a genotype-negative control.

Exclusion Criteria

• Diagnosed with a genetic CM or arrhythmia syndrome prior to ablation procedure
• VUS in 'possibly pathogenic' subgroup (control group only)
• Previous PVC or VT ablation
• LVEF <20%
• Prosthetic mitral or aortic valve
• Contraindication to heparin
• Prior myocardial infarction

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

M. Benjamin Shoemaker

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Dakota Graherr, RN

Role: CONTACT

dakota.grauherr@vumc.org

615-936-6069

Other Identifiers

IRB231260

Identifier Type: -

Identifier Source: org_study_id