Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs

Zhou, Shengmei; Chen, Lan S.; Miyauchi, Yasushi; Miyauchi, Mizuho; Kar, Saibal; Kangavari, Simon; Fishbein, Michael C.; Sharifi, Behrooz G.; Chen, Peng Sheng

doi:10.1161/01.res.0000133678.22968.e3

Cited by 306 publications

(331 citation statements)

References 32 publications

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“…Previous studies in dogs showed that NGF protein increases by 7 days post-infarct, and returns to lower levels by 1 month (Zhou, et al, 2004), temporally paralleling changes in peri-infarct sympathetic innervation. Using a rodent model, we show here that i) both NGF mRNA and protein increase in the peri-infarct zone with a time course similar to increased protein reported for canines; ii) the time frame for increased NGF mRNA and protein parallels macrophage and myofibroblast emigration into the peri-infarct; iii) NGF protein and mRNA is localized primarily within peri-infarct macrophages and myofibroblasts, and iv) peri-infarct regions containing NGF-producing inflammatory cells are preferentially hyperinnervated.…”

Section: Cardiac Sympathetic Hyperinnervation As Sequela Of the Inflamentioning

confidence: 87%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…NGF is a potent growth and survival factor for sympathetic neurons (Korsching and Thoenen, 1985;Glebova and Ginty, 2004). Recent evidence indicates that NGF expression is up-regulated in the region of the infarction (Hiltunen, et al, 2001;Zhou, et al, 2004), and infusion of NGF into the stellate ganglion results in cardiac hyperinnervation in canine hearts (Cao, et al, 2000b). However, the cell types involved in post-infarct cardiac NGF production and the neural selectivity of the response are not well defined.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and α-smooth muscle actin immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we cocultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by periinfarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.

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Section: Cardiac Sympathetic Hyperinnervation As Sequela Of the Inflamentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…An early rise of NGF can be observed rapidly after myocardial infarction (hours) and may possibly reflect an early rescue response to support myocardial healing (Meloni et al 2010). Unfortunately, NGF also causes inhomogeneity of sympathetic innervation in the infarction border zone thereby promoting lethal arrhythmias (Zhou et al 2004). Months later, if heart failure develops after MI, the opposite is detected and NGF tissue levels decrease below the normal range.…”

Section: Discussionmentioning

confidence: 99%

Age-related regional differences in cardiac nerve growth factor expression

Saygili

Kluttig

Rana

et al. 2011

AGE

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Age has been identified as an independent risk factor for cardiovascular diseases. A shift of the cardiac autonomic nervous system towards an increase in sympathetic tone has been reported in the elderly. Nerve growth factor (NGF) is the main neurotrophic factor that increases the sympathetic activity of the heart. If there is a shift of NGF expression in old compared to young cardiomyocytes and whether there are regional differences in the heart still remain unclear. Therefore, we chose a rat model of different-aged rats (3-4 days = neonatal, 6-8 weeks = young, 20-24 months=old), and isolated cardiomyocytes from the left and the right atrium (LA, RA), as well as from the left and the right ventricle (LV, RV), were used to determine NGF expression on mRNA and protein levels. In neonatal, young, and old rats, NGF amount in LA and RA was significantly lower as compared to LV and RV. In young and old rats, we found significant higher NGF protein levels in LA compared to RA. In addition, both atria showed an increase in NGF expression between age groups neonatal, young, and old. In both ventricles, we observed a significant decrease in NGF expression from neonatal to young rats and a significant increase from young to old rats. The highest NGF amount in LV and RV was observed in neonatal rats. Regarding tyrosine kinase A receptor (TrkA) expression, the main receptor for NGF signaling, both atria showed the largest expression in old rats; while in LV and RV, TrkA was expressed mainly in young rats. These results point to a contribution of nerve growth factors to the change of autonomic tone observed in elderly patients.

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“…Furthermore, NGF and GAP 3 levels increased in the left stellate ganglion of these dogs 3 days after MI, without a concomitant increase in mRNA, indicating possible retrograde transportation of these proteins to the left stellate ganglion, which then triggers nerve sprouting in noninfarcted left ventricular sites. 48 Further evidence that sympathetic nerve sprouting is arrhythmogenic stems from studies of hypercholesterolemic rabbits compared with normal controls. Rabbits fed a high-cholesterol diet for 8 weeks had significantly higher densities of growth-associated protein 43 (a protein associated with axonal growth cone) and tyrosine hydroxylase, indicating nerve sprouting and sympathetic hyperinnervation.…”

Section: Myocardial Infarction Heart Failure and Sympathetic Innervmentioning

confidence: 99%

The Role of the Autonomic Nervous System in Sudden Cardiac Death

Vaseghi

Shivkumar²

2008

Progress in Cardiovascular Diseases

336

233

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The cardiac autonomic nervous system consists of 2 branches-the sympathetic and the parasympathetic systems-that work in a delicately tuned, yet opposing fashion in the heart. This extrinsic control mechanism can dominate intrinsic regulatory mechanisms that modulate heart rate and cardiac output. These branches differ in their neurotransmitters (norepinephrine and acetylcholine) and exert stimulatory or inhibitory effects on target tissue via adrenergic and muscarinic receptors. Stimulation of the sympathetic branch exerts facilitatory effects on function, increasing heart rate and myocardial contractility, whereas the stimulation of the parasympathetic branch exerts inhibitory effects that decrease heart rate and contractility. The interplay between these two branches is complex and susceptible to control at several levels, from centrally mediated baroreceptors and chemoreceptors to local interneuronal interactions.Alterations in autonomic function occur in several interrelated cardiac conditions including sudden cardiac death, congestive heart failure, diabetic neuropathy, and myocardial ischemia. Although the full extent of these changes has not been elucidated, multiple autonomic remodeling mechanisms have been observed at both the neuronal fiber and myocardial cellular level that contribute to an arrhythmogenic substrate. We describe the anatomy of both systems in this review. However, the review will premdominantly focus on the sympathetic system, whose role in the modulation of cardiac arrhythmias is slightly better delineated. Cardiac Autonomic Innervation: NeuroanatomyBoth branches of the autonomic nervous system are composed of both afferent and efferent as well interneuronal fibers (Fig 1). Sympathetic innervation originates mainly in the right and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart and penetrate into the underlying myocardium similar to coronary vessels and end as sympathetic nerve terminals reaching the endocardium. Based on norepinephrine content studies, a gradient exists in sympathetic innervation from atria to the ventricles and from base to apex of the heart. Therefore, the atria are most densely innervated, but the ventricles are also supplied with a sympathetic network, most densely at the base. 1 Parasympathetic effects are carried by the right and left vagus nerves, originating in the medulla. The vagus nerve further divides into the superior and inferior cardiac nerves, finally merging with the postganglionic sympathetic neurons to form a plexus of nerves at the base of the heart, known as the cardiac plexus. In contrast to sympathetic neurons, after parasympathetic fibers cross the atrioventricular (AV) groove along the surface of the heart,

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Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs

Cited by 306 publications

References 32 publications

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

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

Age-related regional differences in cardiac nerve growth factor expression

The Role of the Autonomic Nervous System in Sudden Cardiac Death

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