Abstract P2087: ERBB4-Selective And Sustained Activation By NRG1 Attenuates Atrial Fibrosis And Fibrillation

Abstract

Introduction: Atrial fibrillation (AF) results from electrical and structural remodeling of the atria, in which inflammation and fibrosis play an important role. Current therapy is limited to antiarrhythmic drugs and ablations, but does not target the structural problem. Recent studies showed that neuregulin-1 (NRG1), an epidermal growth factor family member, has anti-fibrotic and anti-inflammatory effects in the myocardium. Purpose: To test the effects of JK07, a NRG1 antibody fusion comprising an ERBB3 antagonistic antibody which selectively signals through ERBB4 preferentially over ERBB3, on atrial fibrosis and AF inducibility. Methods: Atrial samples were harvested from male rats (Wistar Han, 10 weeks old), cut into small pieces (1-2mm 2 ) and kept in low serum medium in the presence or absence of JK07 (5nM). Col1a1 and Col3a1 mRNA was quantified after 24-72 hours. AF inducibility was tested in a first AF model in which male mice (C57BL/6N, 12-15 weeks old) were treated with angiotensin-II (Ang-II, 4 weeks, osmotic mini-pumps, 3000 ng/kg/min), and in a second AF model in which mice were fed with a high fat diet (HFD, 8 weeks, 60% Kcal fat) inducing severe weight gain (56±3% increase compared to 23±4% with regular chow). In both models, AF inducibility was tested by 5 runs of programmed electrical stimulation (PES) with a trans-jugular octapolar catheter. AF inducibility (% mice inducible by ≥3 PES-runs) and duration of PES-induced AF (AF duration) were recorded. Mice were randomized for treatment with vehicle or JK07 (2x/week, 1mg/kg, IV, n=5-7/group). Results: In cultured atrial samples, Col1a1 and Col3a1 mRNA expression gradually increased up to 2-3 fold over 3 days. JK07 robustly attenuated this effect by 59±17% (p<0.05). In mice, both Ang-II and HFD significantly increased AF inducibility and AF duration. In Ang-II mice, JK07 attenuated AF inducibility (from 57% to 20%) and AF duration (from 33.3 ± 15.1 to 1.5 ± 1s). In HFD mice, JK07 significantly attenuated AF inducibility (from 57% to 0%) and AF duration (from 10.9±3.2s to 0.76±0.5s, p<0.05). Conclusions: These results show anti-fibrotic effects by selective ERBB4 stimulation with JK07 in atrial tissue in vitro, together with AF-preventive effects in two unrelated mouse models.