Defining the Risk of Ventricular Tachycardia in Genetic Cardiomyopathies
Purpose
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. We 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.
Conditions
- Atrial Fibrillation
- Ventricular Tachycardia
- Premature Ventricular Contraction
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- ) Adults aged 18 and older; 2) Diagnosed with AF, frequent PVCs, or VT before age 60; 3) Scheduled for catheter-based AF ablation (de-novo or repeat) OR catheter-based PVC ablation OR catheter-based VT ablation; 4) Able to provide written, informed consent; 5) 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; 2) VUS in 'possibly pathogenic' subgroup (control group only); 3) Previous PVC or VT ablation; 4) LVEF <20%; 5) Prosthetic mitral or aortic valve; 6) Contraindication to heparin; 8) Prior myocardial infarction
Study Design
- Phase
- Study Type
- Observational [Patient Registry]
- Observational Model
- Cohort
- Time Perspective
- Prospective
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
| 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. |
Recruiting Locations
Nashville, Tennessee 37232
More Details
- Status
- Recruiting
- Sponsor
- Vanderbilt University Medical Center
Detailed Description
New genomic knowledge is poised to change clinical practice for atrial fibrillation (AF). In 1293 cases previously considered idiopathic, we 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. We 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. We have 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 we 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, we 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. We 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, we 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 we have found is as effective in TTN patients as genotype-negative controls. We 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.