Defining the Risk of Ventricular Tachycardia in Genetic Cardiomyopathies

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.