ERBB4 activation as a new therapy for atrial remodeling and fibrillation

The neuregulin-1/erythroblastic leukemia viral oncogene homolog (ERBB) signaling system is essential for cardiac embryonic development and function. Its activation during heart failure exerts compensatory effects by acting on cardiomyocytes and mitigating ventricular fibrosis.

We investigated whether selective ERBB4 activation suppresses atrial fibrillation (AF) in minipigs and mice in the absence of heart failure and assessed its effects on atrial cardiomyocytes and atrial fibrosis. ERBB4 stimulation was achieved using JK07, a recombinant fusion protein consisting of a receptor-activating fragment of human neuregulin-1 and a humanized antagonistic ERBB3 IgG1 antibody.

To increase AF susceptibility, minipigs were exposed to deoxycorticosterone acetate and mice were fed a high-fat diet (HFD). AF was induced by programmed electrical stimulation. Atrial fibrosis was quantified histologically, and transcriptomic profiling of atrial cardiomyocytes was performed in minipigs. Atrial cardiomyocyte-intrinsic antiarrhythmic effects were evaluated in mice fed an HFD and in human conditionally immortalized atrial cardiomyocytes using optical voltage mapping.

JK07 significantly reduced AF inducibility and total AF duration in both deoxycorticosterone acetate minipigs and mice fed an HFD without affecting the atrial effective refractory period. In minipigs, JK07 attenuated atrial fibrosis, prevented conduction slowing, and reversed disease-associated atrial cardiomyocyte transcriptional remodeling. In contrast, mice fed an HFD exhibited minimal atrial fibrosis, which was not affected by JK07, suggesting an atrial cardiomyocyte-intrinsic antiarrhythmic mechanism. Consistently, JK07 completely suppressed pacing-induced reentrant activity in human conditionally immortalized atrial cardiomyocytes without affecting action potential duration or conduction velocity.

ERBB4 activation by JK07 suppresses AF inducibility in 2 independent models and has effects on both atrial structural remodeling and atrial cardiomyocyte-intrinsic arrhythmogenic mechanisms.