Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation

Abstract

-Cardiacspecific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes. To test this, we examined 5-to 6-mo-old transgenic (TG) mice that overexpress NGF in heart and their wild-type (WT) littermates using echocardiography, invasive catheterization, histology, and catecholamine assays. In TG mice, hypertrophy of the right ventricle was evident (ϩ67%), but the left ventricle was only mildly affected (ϩ17%). Left ventricular (LV) fractional shortening and fractional area change values as indicated by echocardiography were similar between the two groups. Catheterization experiments revealed that LV ϮdP/dt values were comparable between TG and WT mice and responded similarly upon isoproterenol stimulation, which indicates lack of ␤-adrenergic receptor dysfunction. Although norepinephrine levels in TG LV tissue were approximately twofold those of WT tissue, TG plasma levels of the neuronal norepinephrine metabolite dihydroxyphenyglycol were fivefold those of WT plasma. A greater neuronal uptake activity was also observed in TG LV tissue. In conclusion, overexpression of NGF in heart leads to sympathetic hyperinnervation that is not associated with detrimental effects on LV performance and is likely due to concomitantly enhanced norepinephrine neuronal uptake. echocardiography; myocardial contraction; catecholamine; transgenic; nerve growth factor CARDIAC SYMPATHETIC TONE IS enhanced under conditions of heart failure (13, 14). Prolonged and excessive sympathoadrenergic stimulation of heart leads to adverse biological consequences such as myocardial cell death, hypertrophy, and fibrosis (30). In the setting of heart failure, preferential activation of cardiac sympathetic nerves contributes to norepinephrine (NE) spillover from heart to plasma at 5-50 times the normal rate depending on the severity of the disease (14). Such enhanced NE spillover is due to both an increase in nerve firing rate and an attenuation in NE reuptake (14). Elevated plasma NE levels bear prognostic value (22) and have been linked to hemodynamic abnormalities and mortality in patients (6, 26). Within this context, the therapeutic efficacy of ␤-blockers in patients with heart failure has been well documented (10, 17).The detrimental effects of enhanced adrenergic stimulation have been confirmed by recent studies on transgenic (TG) mice, which show that cardiac restricted overexpression of ␤ 1 -, ␤ 2 -, and ␣-adrenergic receptors (ARs) and G s ␣ protein all result in cardiomyopathy and premature death (9,12,21,25,28). Cardiac targeted overexpression of nerve growth factor (NGF), a neurotrophin that is essential for sympathetic neuronal differentiation, maturation, and survival (20, 27, 37), leads to ...

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

“…Transgenic mice overexpressing NGF in the heart show elevated cardiac catecholamine levels and sympathetic hyperinnervation. 23, 24 Cao et al 25 reported that a prolonged (5 weeks) infusion of NGF into the left stellate ganglion of dogs after myocardial infarction induces hyperinnervation, which results in ventricular tachyarrythmias and sudden cardiac death. However, in vivo, nerve sprouting was not observed as early as 1 week after the beginning of NGF application.…”

“…Therefore, these findings identified NGF as an acute positive regulator of NET function. Kiriazis et al 23 reported that mice overexpressing NGF in the heart show a doubled NE reuptake via NET as compared with healthy wild-type mice. However, in healthy mice, Ͼ95% of the released NE is taken up by the NET.…”

Echocardiographic assessment of global left ventricular function in mice

“…In these cases, the calculation of the percentage of fractional area shortening [LV-FAS(%)] (often also fractional area change) using endocardial areas traced from a parasternal short-axis view is more applicable. 15,16 FASð%Þ ¼ LVEDA À LVESA LVEDA Â 100…”

Forever Young?

“…9 Overexpression of NGF in mice leads to sympathetic hyperinnervation and cardiac hypertrophy 10 but left ventricular (LV) function remains normal. 11 Preservation of ventricular structure and function in these transgenic mice has been attributed to enhanced NE reuptake associated with hyperinnervation. 11 Increased NGF expression in heart also occurs after myocardial infarction 12,13 and in early stages of diabetes.…”

“…11 Preservation of ventricular structure and function in these transgenic mice has been attributed to enhanced NE reuptake associated with hyperinnervation. 11 Increased NGF expression in heart also occurs after myocardial infarction 12,13 and in early stages of diabetes. 14 Enhanced production of NGF by viable tissue at the perimeter of infarcted myocardium can cause regional sympathetic hyperinnervation, and it has been proposed that the resulting heterogeneous innervation pattern increases risk for ventricular fibrillation and sudden death.…”