2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter-based Ablation

2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter- Based Ablation

The proposed studies will test this hypothesis by randomizing patients with AF to 2-HOBA or placebo 7 days prior to AF ablation to allow 2-HOBA to reach steady-state levels. We hypothesize that tissue injury from AF ablation causes a large release of ROS that react with lipids to generate IsoLGs (Figure 2). In the absence of 2-HOBA, IsoLGs will react within seconds to form IsoLG-macromolecule adducts in atrial tissue, promoting early recurrence of AF. In the presence of 2-HOBA, IsoLGs will rapidly react to form IsoLG-macromolecule adducts in atrial tissue, promoting early recurrence of AF. In the presence of 2-HOBA, IsoLG will preferentially bind to and therefore be inactivated by 2-HOBA thereby sparing injury to the atrial tissue caused by oxidative stress and its contribution to early recurrence of AF. Early recurrence of AF will be measured by ECGs that are recorded once per day by a smartwatch (Apple Watch, Apple Inc., Cupertino, CA) with additional ECGs recorded by the participant if they experience symptoms of AF, or if the smartwatch alerts the participant of a possible AF episode via its auto-detection AF monitoring algorithm. The Apple Watch's AF algorithm is based on sampling of heart rate and variability and will give an audible alarm if those parameters indicate a possible episode of AF. The smartwatch records a single-lead ECG if the participant touches the watch with their contralateral hand. The day and time of the episode is also stored by the smartwatch. At the end of the 28-day follow-up period, study personnel will review the stored ECGs. Blood will be drawn prior to ablation and on post-procedure Day 1 for measurement of IsoLG-adduct levels. DNA will be extracted to explore a pharmacogenomic interaction with haplotypes at the chromosome 4q25 AF risk locus, which: 1) is strongly associated with the development of AF and the early recurrence of AF after ablation27; and 2) has been reported to be a regulator of an anti-oxidant gene program in response to cardiac injury.

The proposed double-blind, randomized, placebo-controlled trial of 2-HOBA in patients undergoing AF ablation is designed to address the following Specific Aims:

Specific Aim 1: To test the hypothesis that treatment with 2-HOBA reduces early recurrence of AF (clinical endpoint)

Specific Aim 2: To test the hypothesis that treatment with 2-HOBA reduces circulating levels of IsoLG-adducts (biochemical endpoint)

Specific Aim 3: To explore the idea that genetic variation at the 4q25 (PITX2) AF susceptibility locus modulates the clinical and biochemical response to 2-HOBA

Inclusion Criteria:

• First time AF ablation with radiofrequency or cryo ablation
• Repeat AF ablation if the patient has persistent AF and ablation of non-pulmonary vein substrate is planned (e.g. posterior wall ablation, mitral or roof line, etc)
• Able to provide written, informed consent
• 22 years of age or older

Exclusion Criteria:

• Planned surgical or hybrid (surgical + catheter) ablation
• Amiodarone within past 3 months
• Use of oral steroids or colchicine
• Pro-inflammatory, rheumatologic disorder (e.g. RA, SLE, IBD, psoriasis, ankylosing spondylitis)
• NYHA Class III/IV Heart Failure
• LVEF <35%
• Active ischemia
• Hypertrophic Cardiomyopathy
• Cardiac or thoracic surgery within 6 months
• Expected life span < 1 year
• Creatinine clearance <30 ml/min
• Prior or planned heart transplantation
• Pregnant women
• Aspirin allergy
• Current use of MAO-I