Reduced Myocardial Nerve Growth Factor Expression in Human and Experimental Heart Failure

Abstract

Abstract-Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained.Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (nϭ11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (nϭ11, PϽ0.05). In a rat model of CHF, a 40% reduction (PϽ0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (PϽ0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 mol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. Key Words: heart failure Ⅲ nerve growth factor Ⅲ sympathetic nervous system T he clinical features and adverse prognosis associated with congestive heart failure (CHF) represent the result of a complex interplay between impaired cardiac performance and neurohormonal activation. Sympathetic nervous system excitation has been well documented to exist in CHF, based on measurements of plasma catecholamines, 1 radiotracer isotope dilution determination of norepinephrine (NE) spillover rates to plasma, 2 and measurement of multiunit postganglionic muscle sympathetic nerve discharge rates. 3 Coupled with these data, recent observational and clinical trial data highlight the adverse effect of prolonged sympathetic overactivity in CHF patients. 4 -7 In addition to the documentation of a systemic increase in sympathetic tone in CHF, neurochemical studies of the rate of regional NE spillover indicate considerable regional heterogeneity in the pattern of sympathetic activation, this typically occurring earliest and being most elevated in the myocardium. 2,8 Although the rate of NE spillover from cardiac sympathetic neurons to plasma is dependent on the nerve firing rate, 9 other factors including the neuronal reuptake rate and innervation anatomy are of importance. Within this context, the paradoxical observation of reduced sympathetic nervous innervation density in the failing heart despite increased catecholamine overflow remains unexplained. 10

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

“…The presence of fewer sympathetic nerves in the myocardium despite a high level of NGF 3 weeks after MI induction suggests that RDN counteracts NGFmediated nerve growth in the infarcted heart. In infarcted heart failure models, NGF has been shown to be downregulated in response to sympathetic hyperactivity, 22 and this can lead to decreased sympathetic nerve density in the failing heart. Similarly, RDN may have mitigated the sympathetic hyperactivity seen after MI in our animal model and, therefore, attenuated the downregulation of NGF.…”

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats

“…These differences may be related to the extent of infarction as larger infarcts can result in frank congestive heart failure, and this has been linked to cardiac NGF depletion and diminished sympathetic axon density (Kaye, et al, 2000;Qin, et al, 2002). Similarly, reduced NGF levels have been noted in patients with acute coronary symptoms as well as in atherosclerotic coronary vascular tissue (Chaldakov, et al, 2004;Manni, et al, 2005).…”

“…Postmortem analyses of infarcted human myocardium show abnormal increases in numbers of sympathetic axons adjacent to the site of injury (Cao, et al, 2000a). Ischemic injury appears to be the cause of the remodeling, as coronary artery ligation induces hyperinnervation in dogs (Lai, et al, 2000;Zhou, et al, 2004) and rats (Ahonen, et al, 1975;Paessens and Borchard, 1980;Holmgren, et al, 1981;Vracko, et al, 1990;Kaye, et al, 2000;Li, et al, 2004). Through enhanced norepinephrine-mediated myocardial depolarization, abnormally increased sympathetic nerve density may be proarrhythmogenic and represent a significant factor in post-infarct sudden cardiac death.…”

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

“…13 In both experimental and clinical CHF, myocardial NGF expression is diminished. 14,15 To test the hypothesis of whether NGF improves the cardiac sympathetic nerve function in experimental CHF, NGF was directly injected into stellate ganglia of rats with transverse aortic constriction (TAC), which have been characterized previously by overt heart failure, depleted NE stores, and an impaired NE reuptake. 5,16 …”