Abstract
The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.
Highlights
Coronary disease represents an immense global health challenge, accounting for nearly 9 million deaths worldwide each year [1], and is projected to increase in treatment cost by nearly 100% by the year 2030 [2]
While improvements in medical and procedural therapies have undoubtedly decreased the morbidity and mortality associated with myocardial infarction (MI), there remains a dire need for advanced therapeutics in mitigating the progression to heart failure following acute ischemic events
We previously demonstrated that NRG encapsulated within a HG could be released gradually over a course of 14 days, and that intramyocardial administration of this hydrogel-encapsulated neuregulin (NRG-HG) therapy at the time of MI in adult mice significantly increased cardiomyocyte survival and proliferation, and enhanced post-MI ventricular function [18]
Summary
Coronary disease represents an immense global health challenge, accounting for nearly 9 million deaths worldwide each year [1], and is projected to increase in treatment cost by nearly 100% by the year 2030 [2]. Our group and others have built upon the strategy of reactivating regenerative mechanisms after MI and previously established that exogenous administration of neuregulin-1β (NRG) induces cardiomyocyte proliferation and improves cardiac function in small and large animal models of MI and ischemic cardiomyopathy [16,17,18]. An initial clinical finding that suggested the potential benefits of NRG administration was the depressive cardiac effects of the breast cancer drug trastuzumab, in which the inhibition of the ErbB4 tyrosine kinase pathway led to heart failure in some patients [23]. This observation suggested that NRG’s activation of this pathway could yield cardioprotective effects [24]
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