Metoprolol-mediated amelioration of sympathetic nerve sprouting after myocardial infarction.

OBJECTIVES: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. METHODS: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBα (IκBα) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time PCR. RESULTS: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBα level. Moreover, metoprolol downregulated IL-1ß, TNF-α and NGF levels, and reduced the density of sympathetic nerve fibers. CONCLUSIONS: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.

Mesenchymal stem cell therapy improves diabetic cardiac autonomic neuropathy and decreases the inducibility of ventricular arrhythmias.

BACKGROUND: Diabetic cardiac autonomic neuropathy (DCAN) may cause fatal ventricular arrhythmias and increase mortality in diabetics. Mesenchymal stem cells (MSCs) can secrete various cytokines and growth factors exerting neurosupportive effects. In this study, we investigated the effect of MSC on DCAN in diabetic rats. METHODS: Forty rats were divided into normal control, diabetes mellitus (DM) control, MSC treatment (6 × 10(6) MSCs via direct myocardial injection) and MSC-conditioned medium group (100 µl via direct myocardial injection). Immunohistochemistry was used to measure choline acetyltransferase (ChAT, a marker for parasympathetic nerves) and tyrosine hydroxylase (TH, a marker for sympathetic nerves) positive nerve fibres in the ventricular myocardium. Heart rate variability and programmed electrical stimulation was used to assess the inducibility of ventricular arrhythmias in the animals. RESULTS: Two weeks after MSC treatment, the density of ChAT- and TH-positive nerve fibres in MSCs and MSC-conditioned medium group was higher than in DM control group (P < 0.05 or P < 0.01). The ChAT/TH ratio in MSC group was higher than in DM control group (0.37 ± 0.014 vs. 0.27 ± 0.020, P < 0.01). The standard deviation of normal-to-normal R-R intervals in MSCs (5.13 ± 0.69) and MSC-conditioned medium group (4.30 ± 0.56) was higher than in DM control group (3.45 ± 0.60, P < 0.05). The inducibility of VAs in the MSC group was lower than in the DM control group. CONCLUSIONS: MSC therapy may promote cardiac nerve sprouting and increase the ratio of parasympathetic to sympathetic nerve fibres. It may also suppress the inducibility of ventricular arrhythmias in the diabetic rats.