ERBB4 stimulation mitigates atrial fibrillation and remodeling in a porcine DOCA model

Abstract

Abstract Background Before patients have spontaneous AF, pathologic remodeling is often already extensively present in the atria, creating a substrate for AF. Currently, no therapies exist that target this atrial remodeling, that can be divided into electrical (ion channel alterations) and structural (fibrosis, dilatation) remodeling. JK07 is a long-acting neuregulin-fusion protein with preventive effects towards 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 the 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) and DOCA+JK07. The control group did not undergo disease induction or therapeutic intervention. To induce hypertension and atrial fibrosis, pellets releasing 100 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 vehicle control (DOCA), 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 total attempts per group. Atrial fibrosis was quantified using ImageJ software on Masson trichrome staining of atrial specimens. 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). The degree of fibrosis in the left atrial free wall was significantly higher in the DOCA group compared to CTRL (12.16 ± 5.06 vs. 5.14 ± 1.57, p=0.0089) and compared to DOCA+JK07 (12.16 ± 5.06 vs. 5.47 ± 3.69, p=0.026). Similar results were also found in the right atrial free wall and left and right atrial appendage. Conclusions ERBB4 stimulation prevents atrial fibrotic remodeling 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.ERBB4 stimulation prevents AF inductionERBB4 stimulation prevents fibrosis