Defining the Risk of Ventricular Tachycardia in Genetic Cardiomyopathies

April 30, 2026 updated by: James L. Laws, Vanderbilt University Medical Center

Defining the Risk of Ventricular Tachycardia in Genetic Forms of Early-onset Atrial Fibrillation

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:

the prevalence and mechanism of inducible ventricular tachycardia
pace-mapping to define the site of origin of ventricular arrhythmias
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.

Study Overview

Status

Recruiting

Conditions

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.

Study Type

Observational

Enrollment (Estimated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Dakota Graherr, RN
Phone Number: 615-936-6069
Email: dakota.grauherr@vumc.org

Study Locations

United States
- Tennessee
  - Nashville, Tennessee, United States, 37232
    - Recruiting
    - Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

Adult
Older Adult

Accepts Healthy Volunteers

Sampling Method

Non-Probability Sample

Study Population

Young patients with atrial fibrillation, frequent PVCs, or VT that are scheduled to undergo procedural management of their arrhythmia.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Number of groups / cohorts

Cohorts and Interventions

Group / Cohort
TTN-positive Patients with a pathogenic or likely pathogenic variant in TTN on clinical genetic testing.
Gene-positive Patients with a pathogenic or likely pathogenic variant in a gene other than TTN on clinical genetic testing.
Gene-negative Patients without a pathogenic or likely pathogenic variant in a cardiomyopathy or arrhythmia gene on clinical genetic testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventricular Tachycardia Inducibility Time Frame: During procedure	Patients will undergo an electrophysiology study (EP study) as part of the research or clinical protocol for the procedure. Inducible VT (yes/no) with the EP study will be the primary outcome measure.	During procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Site and Substrate of Ventricular Ectopy Time Frame: During procedure	Localization of ventricular ectopy or arrhythmia will be evaluated during the procedure by electoanatomic mapping, and the assessment of scar burden in this area (by voltage mapping) will be secondary outcomes for Aims 1B and 1C.	During procedure

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 13, 2023

Primary Completion (Estimated)

December 1, 2028

Study Completion (Estimated)

December 1, 2029

Study Registration Dates

First Submitted

August 26, 2024

First Submitted That Met QC Criteria