PO-02-214 JK07 PREVENTS HYPERTENSION-INDUCED ATRIAL FIBROSIS AND ATRIAL FIBRILLATION INDUCIBILITY IN A PIG MODEL

Abstract

An important substrate of atrial fibrillation (AF) is atrial fibrosis, and a higher burden of fibrosis correlates with worse prognosis and therapy resistance. Currently, no therapies exist that target atrial fibrosis. JK07 is a long-acting neuregulin-fusion protein that activates the ERBB4 receptor, which mitigates ventricular fibrosis in models of heart failure. To test the ability of JK07 to reduce atrial fibrosis and AF inducibility in the minipig model of deoxycorticosterone acetate (DOCA, an aldosterone agonist) induced hypertension. Eighteen Aachener minipigs were randomized into three groups: control (CTRL), DOCA + Vehicle (DOCA+VEH) and DOCA+JK07. The control group did not undergo disease induction or therapeutic intervention. To induce hypertension and atrial fibrosis in minipigs in the DOCA+VEH and DOCA+JK07 groups, DOCA pellets were implanted releasing 10 mg/kg DOCA over a period of 60 days. The DOCA-implanted animals underwent weekly treatment with JK07 (0.3 mg/kg; DOCA + JK07) or vehicle control (DOCA + VEH), starting on the day of implantation (total of 9 administrations). After 60 days, arterial blood pressure was measured invasively and a decapolar catheter was placed in the right atrium. AF inducibility was tested by performing 50 burst pacing episodes and quantified as the percentage of “successful” episodes where an AF run ≥ 5 sec could be induced after the burst, out of the 50 attempts. Atrial fibrosis was quantified using AFAT software on Masson trichrome staining of left atrial appendage specimens, isolated after euthanizing the animals. Mean arterial pressure was significantly higher in the DOCA+VEH (142 ± 10 mmHg) and DOCA+JK07 (132 ± 15 mmHg) groups than in the CTRL group (105 ± 8 mmHg, p<0.01), without an effect of JK07. AF inducibility in the DOCA+VEH group was significantly higher than in the CTRL group (66/250 vs. 9/300, p<0.001), and the DOCA + JK07 group (66/250 vs. 8/300, p<0.001). Likewise, the degree of atrial fibrosis was significantly higher in the DOCA+VEH group compared to CTRL (10.32% ± 4.74% surface area vs. 5.28% ± 3.06%, p<0.001) and compared to DOCA+JK07 (10.32% ± 4.74% vs. 3.82% ± 2.68%, p<0.001). JK07 prevents atrial fibrosis and AF inducibility in a porcine DOCA model. The effect of JK07 is unrelated to effects on blood pressure, but probably related to reduced atrial fibrogenesis.