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(Circulation Research. 2004;95:76.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs

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

From the Division of Cardiology, Department of Medicine (S.Z., Y.M., M.M., S Kar, S Kangavari, B.S., P.-S.C.), Cedars-Sinai Medical Center; the Department of Neurology (L.S.C.), Childrens Hospital and the Keck School of Medicine, University of Southern California; and Division of Anatomical Pathology, Department of Pathology (M.C.F.), David Geffen School of Medicine, UCLA, Los Angeles, Calif.

Correspondence to Peng-Sheng Chen, MD, Room 5342, CSMC, 8700 Beverly Blvd, Los Angeles, CA 90048-1865. E-mail chenp{at}cshs.org

Cardiac nerve sprouting and sympathetic hyperinnervation after myocardial infarction (MI) both contribute to arrhythmogenesis and sudden death. However, the mechanisms responsible for nerve sprouting after MI are unclear. The expression of nerve growth factor (NGF), growth associated protein 43 (GAP43), and other nerve markers were studied at the infarcted site, the noninfarcted left ventricle free wall (LVFW), and the left stellate ganglion (LSG) at several time points (30 minutes to 1 month) after MI. Transcardiac (difference between coronary sinus and aorta) NGF levels were also assayed. Acute MI resulted in the immediate elevation of the transcardiac NGF concentration within 3.5 hours after MI, followed by the upregulation of cardiac NGF and GAP43 expression, which was earlier and more pronounced at the infarcted site than the noninfarcted LVFW. However, cardiac nerve sprouting and sympathetic hyperinnervation were more pronounced in the noninfarcted than the infarcted LVFW site and peaked at 1 week after MI. The NGF and GAP43 protein levels significantly increased in the LSG from 3 days (P<0.01 for all) after MI, without a concomitant increase in mRNA. There was persistent elevation of NGF levels in aorta and coronary sinus within 1 month after MI. We conclude MI results in immediate local NGF release, followed by upregulation of NGF and GAP43 expression at the infarcted site. NGF and GAP43 are transported retrogradely to LSG, which triggers nerve sprouting at the noninfarcted LVFW. A rapid and persistent upregulation of NGF and GAP43 expression at the infarcted site underlies the mechanisms of cardiac nerve sprouting after MI.

Key Words: nerve growth factor • nerve sprouting • sympathetic nerve • ventricular arrhythmia

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