Regulation of sympathetic plasticity in the heart

Abstract

Following myocardial infarction, elevated sympathetic neuronal sprouting at the infarct border region leads to hyperexcitability which increases the risk of arrhythmias and sudden cardiac death. Surviving individuals with impaired cardiac functions are prone to develop congestive heart failure, which is also associated with sympathetic hyperexcitability. As a result, beta-adrenergic receptor blockers are commonly administered to reduce adverse symptoms. Therefore our first goal was to attenuate inflammation in order to reduce sympathetic hyperinnervation in the infarct border region. Our second goal was to study the effect of beta-blockers on cardiac sympathetic innervation. Inflammatory cells in the infarct release nerve growth factor (NGF) contributing to sympathetic neuronal sprouting. To reduce inflammation, we administered dexamethasone post-infarction. Although the treatment reduced body weight, it failed to reduce infarct sympathetic hyperinnervation. However, dexamethasone is not a selective treatment and may have side effects that promote neuronal sprouting. Because our lab had previously shown that macrophages within the infarct express NGF, we depleted macrophages by clodronate liposome administration. In association with macrophage reduction, the number of myofibroblasts was slightly decreased but T-cell numbers were unchanged. Immunoblots showed that mature NGF was decreased by clodronate liposome treatment, and this change resulted mainly from the decrease of NGF-immunoreactivity (-ir) in macrophages and to a lesser extent NGF-ir in myofibroblast, but NGF-ir in T-cells was not altered. In concert with the reduction of NGF, sympathetic hyperinnervation was suppressed. These findings suggest that macrophage NGF expression is central to the development of sympathetic hyperinnervation and may be a valuable therapeutic target. Secondly, alpha or beta-blockers were administered post-infarction. While border region sympathetic hyperinnervation was unchanged, beta-blockers substantially increased sympathetic innervation in non-ischemic regions of the heart. Control hearts displayed similar hyperinnervation and administration of metoprolol showed that this response was selective for beta 1-blockade. While two days after beta-blocker treatment withdrawal, adrenergic receptors were not supersensitized, ventricular functions were enhanced by neuronal norepinephrine store release with tyramine, consistent with increased sympathetic neuroeffector functions. To determine if beta-adrenoceptor activation modulates sympathetic innervation density via cardiac NGF synthesis, norepinephrine release was suppressed by chemical sympathectomy. Sympathetic depletion upregulated the translation of some proNGF isoforms but total NGF was unchanged. Consistently, adrenergic receptor activation did not modulate cardiomyocyte NGF synthesis in vitro. To examine potential direct effects of beta-blockers on sympathetic neurons, cultures were incubated with propranolol or metoprolol, and these treatments resulted in elevated outgrowth. Similarly, the inhibition of norepinephrine synthesis by alpha-methyl-p-tyrosine enhanced sprouting. Simultaneous incubation in dobutamine reversed outgrowth confirming that sympathetic plasticity is regulated by beta 1 adrenergic auto-receptors. In conclusion, targeting macrophage NGF synthesis may provide a valuable strategy to reduce border region sympathetic hyperinnervation. In addition, despite the wide clinical use of beta-blockers, cardiac sympathetic hyperinnervation resulting from the treatment can alter ventricular functions and may contribute to severe adverse effects upon withdrawal.