JK07 prevents atrial fibrosis and atrial fibrillation inducibility in a porcine DOCA model

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Geconcerteerde Onderzoeksactie (GOA) grant 499 of the University of Antwerp Industrieel OnderzoeksFonds/Strategisch Basisonderzoek 498 (IOF/SBO) research grant of the University of Antwerp BACKGROUND: Atrial fibrosis is a substrate of atrial fibrillation (AF), and higher burdens of fibrosis are associated with resistance to therapy and worse prognosis. Currently, no therapies exist that target atrial fibrosis. JK07 is a long-acting neuregulin-fusion protein that has been shown to decrease ventricular fibrosis in models of heart failure through selective stimulation of the ErbB4 receptor. PURPOSE: To test the ability of JK07 to reduce atrial fibrosis and AF inducibility in minipig model of deoxycorticosterone acetate (DOCA, an aldosterone agonist) induced hypertension. METHODS: 18 Aachener minipigs were randomized into 3 groups: control (CTRL), DOCA + Vehicle (DOCA+VEH) and DOCA+JK07. The control group did not undergo a therapeutic intervention. To induce hypertension and atrial fibrosis, pellets releasing 10 mg/kg DOCA over a period of 60 days were implanted in minipigs in the DOCA+VEH and DOCA+JK07 groups. The DOCA-implanted animals underwent weekly treatment with JK07 (0.3 mg/kg; DOCA + JK07) or its vehicle (DOCA + VEH), starting at 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 ImageJ software on Masson trichrome staining of left atrial specimens, isolated after euthanizing the animals. RESULTS: 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 (14.18 ± 1.81 vs. 8.30 ± 2.52, p<0.001) and compared to DOCA+JK07 (14.18 ± 1.81 vs. 10.65 ± 1.59, p=0.0049). CONCLUSIONS: 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. [Figure: see text] [Figure: see text]