RESUMO
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.
RESUMO
BACKGROUND: Discordance between studies drives continued debate regarding the best management of asymptomatic severe mitral regurgitation (MR). The aim of the present study was to conduct a systematic review and meta-analysis of management plans for asymptomatic severe MR, and compare the effectiveness of a strategy of early surgery to watchful waiting. METHODS: A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were excluded if they: (I) lacked a watchful waiting cohort; (II) included symptomatic patients; or (III) included etiologies other than degenerative mitral valve disease. The primary outcome of the study was all-cause mortality at 10 years. Secondary outcomes included operative mortality, repair rate, repeat mitral valve surgery, and development of new atrial fibrillation. RESULTS: Five observational studies were eligible for review and three were included in the pooled analysis. In asymptomatic patients without class I triggers (symptoms or ventricular dysfunction), pooled analysis revealed a significant reduction in long-term mortality with an early surgery approach [hazard ratio (HR) =0.38; 95% confidence interval (CI): 0.21-0.71]. This survival benefit persisted in a sub-group analysis limited to patients without class II triggers (atrial fibrillation or pulmonary hypertension) [relative risk (RR) =0.85; 95% CI: 0.75-0.98]. Aggregate rates of operative mortality did not differ between treatment arms (0.7% vs. 0.7% for early surgery vs. watchful waiting). However, significantly higher repair rates were achieved in the early surgery cohorts (RR =1.10; 95% CI: 1.02-1.18). CONCLUSIONS: Despite disagreement between individual studies, the present meta-analysis demonstrates that a strategy of early surgery may improve survival and increase the likelihood of mitral valve repair compared with watchful waiting. Early surgery may also benefit patients when instituted prior to the development of class II triggers.
