ERBB4 activation by weekly JK07 infusion prevented the increase in microvascular resistance compared to vehicle in a hypertensive pig model (11.3 vs 19.9 mmHg.s, p=0.018).
RCT (n=18)
randomized
Does weekly infusion of JK07 prevent coronary microvascular dysfunction in a minipig model of hypertensive heart disease?
ERBB4 activation by JK07 prevents coronary microvascular dysfunction and reduces interstitial left ventricular fibrosis in a large animal model of hypertensive heart disease.
Absolute Event Rate: 11.3% vs 19.9%
p-value: p=0.018
Background Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include ERBB4 stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. Objectives To assess the effect NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Methods Hypertensive heart disease was induced in 12 Aachener minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 weeks and compared to 6 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. Results DOCA significantly increased microvascular resistance compared to 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 to controls (from 2415.5 to 4455.5 mmHg/s, p = 0.011), which was also abrogated by JK07 (3107.3 mmHg/s, p = 0.055 vs DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared to DOCA only (2.1 vs. 5.4 %, p = 0.026), but without 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. Conclusions 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.
Tubeeckx et al. (Tue,) conducted a rct in Hypertensive heart disease (n=18). JK07 (NRG1 fusion protein) vs. vehicle was evaluated on Microvascular resistance (p=0.018). ERBB4 activation by weekly JK07 infusion prevented the increase in microvascular resistance compared to vehicle in a hypertensive pig model (11.3 vs 19.9 mmHg.s, p=0.018).