ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease.

Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include V-erb-b avian erythroblastic viral oncogene homology-type 4 (ERBB4) stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. This work assess the effect of NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Hypertensive heart disease was induced in 12 Aachen minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 wk and compared with six controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method. DOCA significantly increased microvascular resistance compared with controls (from 14.5 to 19.9 mmHg·s, P = 0.028). This increase was abrogated by JK07 (11.3 mmHg·s, P = 0.018 vs. DOCA). dP/dtmax increased by DOCA compared with controls (from 2,415.5 to 4,455.5 mmHg/s, P = 0.011), which was also abrogated by JK07 (3,107.3 mmHg/s, P = 0.055 vs. DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared with DOCA only (2.1 vs. 5.4%, P = 0.026), but without a difference in perivascular fibrosis (P = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, microvascular vessel thickness, inflammatory cytokines, or endothelial activation. ERBB4 activation by JK07 can prevent CMD in a DOCA hypertensive pig model. The exact mechanism of the protective effects of JK07 on microvascular resistance remains elusive however.NEW & NOTEWORTHY CMD is implicated in numerous cardiac diseases, for which only a few therapeutic options are available. Stimulation of the ERBB4/NRG1 pathway has shown beneficial effects in preclinical models of heart failure. JK07 is a selective ERBB4 agonist of interest. JK07 was able to prevent the increase in microvascular resistance in a DOCA-induced hypertensive pig model, as measured by the bolus thermodilution method.