Sympathetic Nerves and Myocyte Necrosis

The left ventricle is richly supplied with sympathetic nerves, which are spatially localized next to cardiac myocytes in a fashion that permits the rapid transmission of autonomic signals via the release of norepinephrine. Previous investigation in the heart has largely focused on the local release and reuptake kinetics of norepinephrine in conjunction with its downstream receptor-mediated events. Nevertheless, accumulating data indicate that the crosstalk between myocardial sympathetic nerves and cardiac myocytes appears to be much more complex. In addition to the co-release of other vasoactive peptides such as neuropeptide Y, sympathetic nerves can also modulate the expression of trophic factors such as nerve growth factor (NGF) and are a potential source of nitric oxide (NO) production via the neuronal NO synthase. Collectively, these can have diverse chronic effects on target tissues such as the heart, which could alter endogenous free radical scavenging mechanisms in pathophysiological states1 as well as the expression of ion channels involved in depolarization and repolarization.2 The loss of this crosstalk could alter the myocyte response to ischemia. In this issue of Circulation Research, Huang and colleagues3 provide provocative in vivo experimental data to support the notion that the sympathetic nerves modulate oxidant-mediated injury to the heart after ischemia. Chronically instrumented swine with regional sympathetic denervation were subjected to short-term hibernation using a 40% reduction in blood flow for 90 minutes followed by reperfusion for 4 days. Although flow and function were similarly matched during ischemia, the regionally denervated heart developed greater myocardial stunning than the innervated heart. Furthermore, while short-term hibernation was a reversible insult in the innervated heart, denervated animals developed histological evidence of neutrophil infiltration and micronecrosis when examined 4 days after reperfusion. This was accompanied by enhanced 3-nitrotyrosine activation in myocytes examined 1 hour after reperfusion. Protein nitration and micronecrosis in myocytes could be prevented with the free radical scavenger N-2-mercaptopropionyl glycine (MPG) or chronic administration of N -nitro-L-arginine (L-NA). The authors conclude that the denervated heart is subjected to increased stunning and microinfarction (with normal triphenyl tetrazolium chloride [TTC] staining) through a mechanism that involves NO and/or reactive oxygen species. These findings contrast with those previously reported by this group after total coronary occlusion in the regionally denervated heart of the dog where there was no effect of denervation on infarct size.4 Possible reasons for this are the fact that the heart was not reperfused in the prior study, or the reliance on TTC staining to assess infarction in the previous study may have underestimated micronecrosis. As the authors point out, the effects of sympathetic innervation on the development of myocyte necrosis and stunning after ischemia highlight the importance of studying the complexity of cell-cell interactions in intact in vivo models versus isolated heart preparations that, by their nature, are acutely denervated. Although denervation is an attractive mechanism to resolve differences regarding the effects of NO on myocardial injury between in vivo and in vitro studies,5 there are several features unique to the present experiments that may limit extrapolation of the findings to acute isolated heart preparations. First, the topical phenol technique evaluated chronic denervation versus the acute denervation encountered in the isolated heart. Tissue norepinephrine levels and the norepinephrine uptake-1 mechanism remain intact in acutely denervated hearts,6 and additional time would be required for any chronic myocyte alterations related to denervation to develop. Second, the isolated heart has both sympathetic and parasympathetic denervation while epicardial phenol results in selective sympathetic denervation. Even though the heart is not under tonic parasympathetic control, it is plausible that the neural response to ischemia could differ from that when the heart is regionally denervated. For example, there is evidence that sympathetic nerves modulate the production of NGF from cardiac parasympathetic nerves.7 Thus, although sympathetic denervation modulates the myocyte response to ischemia in this model, it will be essential to determine whether similar effects occur in the acutely denervated heart. A surprising observation that is unique to this model of ischemia is the apparent dissociation between normal TTC staining, which is the standard to assess irreversible injury in studies of total coronary occlusion, and pathological quantitation of micronecrosis and inflammation. This difference was not trivial since 10% of the risk area of the denervated heart (predominantly subendocardial) had micronecrosis when evaluated 4 days after ischemia. Previous studies have demonstrated excellent correlation between acute and late TTC and pathology in models of total coronary occlusion.8 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Veterans Affairs Western New York Health Care System and the Departments of Medicine, Physiology and Biophysics at the University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY. Correspondence to John M. Canty, Jr, MD, University at Buffalo, Division of Cardiology, Biomedical Research Building, Room 345, 3435 Main St, Buffalo, NY 14214. E-mail [email protected] (Circ Res. 2003;93:796-798.) © 2003 American Heart Association, Inc.