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The ERBB4 agonist JK07 Mitigates Atrial Remodeling and Inducibility of Atrial Fibrillation in Mice and Minipigs
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Authors
Jens Van Fraeyenhove*
Michiel R.L. Tubeeckx*
Bo Goovaerts
Julie Cools
Siel Van den Bogaert
Tim De Coster
Juan Zhang
Yile Fu
Eike M. Wulfers
Arthur Bezerra
Samuel L. Murphy
Nele Vandersickel
LLewelyn H. Roderick
Daniël A. Pijnappels
Antoine A.F. de Vries
Erik Fransen
Guido Y. De Meyer
Hein Heidbuchel
Vincent F.M. Segers*
Gilles W. De Keulenaer*
* = equal authorship
Brief Summary
This study investigates JK07, an epidermal growth factor family member, that has anti-fibrotic and anti-inflammatory effects in the myocardium. This means that it targets the structural underlying problem of cardiac arrhythmias. You could compare it with an agent that dials the clock back. It makes heart tissue better by removing / diminishing the amount of structural defects. It was also shown that it has preventative properties. Therefore it shows promise to become a target for future clinical testing and perhaps an eventual therapy.
EHRA 2023 (Young Investigator Award)
JK07 prevents atrial fibrosis and atrial fibrillation inducibility in a porcine DOCA model
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: (Left) JK07 prevents AF inducibility (right) JK07 prevents left atrial fibrogenesis
BCVS 2022 Scientific Sessions
ERBB4-Selective And Sustained Activation By NRG1 Attenuates Atrial Fibrosis And Fibrillation
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 (1-2mm2) 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.
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