Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes

Yoshio Takemoto; Rafael J Ramirez; Miki Yokokawa; Kuljeet Kaur; Daniela Ponce-Balbuena; Mohamad C Sinno; B Cicero Willis; Hamid Ghanbari; Steven R Ennis; Guadalupe Guerrero-Serna; Bettina C Henzi; Rakesh Latchamsetty; Roberto Ramos-Mondragon; Hassan Musa; Raphael P Martins; Sandeep V Pandit; Sami F Noujaim; Thomas Crawford; Krit Jongnarangsin; Frank Pelosi; Frank Bogun; Aman Chugh; Omer Berenfeld; Fred Morady; Hakan Oral; José Jalife

doi:10.1016/j.jacbts.2016.03.003

Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes

JACC Basic Transl Sci. 2016 Apr;1(3):143-154. doi: 10.1016/j.jacbts.2016.03.003.

Authors

Yoshio Takemoto¹, Rafael J Ramirez¹, Miki Yokokawa², Kuljeet Kaur¹, Daniela Ponce-Balbuena¹, Mohamad C Sinno², B Cicero Willis¹, Hamid Ghanbari², Steven R Ennis¹, Guadalupe Guerrero-Serna¹, Bettina C Henzi¹, Rakesh Latchamsetty², Roberto Ramos-Mondragon¹, Hassan Musa¹, Raphael P Martins¹, Sandeep V Pandit¹, Sami F Noujaim³, Thomas Crawford², Krit Jongnarangsin², Frank Pelosi², Frank Bogun², Aman Chugh², Omer Berenfeld¹, Fred Morady², Hakan Oral², José Jalife¹

Affiliations

¹ Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI.
² Division of Cardiovascular Medicine, Cardiac Arrhythmia Service, University of Michigan, Ann Arbor, MI.
³ Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.

Abstract

Objectives: To determine whether Gal-3 mediates sustained atrial fibrillation (AF)-induced atrial structural and electrical remodeling and contributes to AF perpetuation.

Background: Galectin-3 (Gal-3) mediates extracellular matrix remodeling in heart failure, but its role in AF progression remains unexplored.

Methods: We examined intracardiac blood samples from patients with AF (N=55) to identify potential biomarkers of AF recurrence. In a sheep model of tachypacing-induced AF (N=20), we tested the effects of Gal-3 inhibition during AF progression.

Results: In patients, intracardiac serum Gal-3 levels were greater in persistent than paroxysmal AF and independently predicted atrial tachyarrhythmia recurrences after a single ablation procedure. In the sheep model, both Gal-3 and TGF-β1 were elevated in the atria of persistent AF animals. The Gal-3 inhibitor GM-CT-01 (GMCT) reduced both Gal-3 and TGF-β1-induced sheep atrial fibroblast migration and proliferation in vitro. GMCT (12 mg/kg twice/week) prevented the increase in serum procollagen type III N-terminal peptide seen during progression to persistent AF, and also mitigated atrial dilatation, myocyte hypertrophy, fibrosis, and the expected increase in dominant frequency of excitation. Atria of GMCT-treated animals had significantly less TGF-β1-Smad2/3 signaling pathway activation and expression of α-smooth muscle actin and collagen than saline-treated animals. Ex-vivo hearts from GMCT-treated animals had significantly longer action potential durations and fewer rotors and wavebreaks during AF, and myocytes had lower functional expression of inward rectifier K⁺ channel (Kir2.3) than saline-treated animals. Importantly, GMCT increased the probability of spontaneous AF termination, decreased AF inducibility and reduced overall AF burden.

Conclusions: Inhibiting Gal-3 during AF progression might be useful as an adjuvant treatment to improve outcomes of catheter ablation for persistent AF. Gal-3 inhibition may be a potential new upstream therapy for prevention of AF progression.

Keywords: Atrial fibrillation; Catheter ablation; Fibrosis; Galectin-3; Upstream therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Abstract

Publication types

Grants and funding