Abstract-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 (PϽ0.01 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 Ⅲ nerve sprouting Ⅲ sympathetic nerve Ⅲ ventricular arrhythmia W e previously demonstrated that heterogeneous cardiac nerve sprouting and sympathetic hyperinnervation play important roles in arrhythmogenesis and sudden cardiac death in both human patients and animal models of myocardial infarction (MI). 1-6 However, the mechanisms and time course of nerve sprouting after MI are unclear. Nerve growth factor (NGF) is a neurotrophin that supports the survival and differentiation of sympathetic neurons and enhances target innervation. 7,8 NGF also regulates the synthesis of neurofilament and tubulin proteins, promotes Schwann cell migration, 9 modulates synaptic transmission between sympathetic neurons and cardiac myocytes, 10 and increases the half-life of growth associated protein-43 (GAP43). 11 Overexpression of NGF within the heart of transgenic mice causes hyperinnervation. 12 Peripheral nerve injury results in increased local NGF expression, which facilitates nerve regeneration. 13 It is possible that increased NGF expression also underlies the mechanisms of cardiac nerve sprouting after ischemic injury and MI. In the present study, we sampled blood and harvested tissues from the left ventricle and from the left stellate ganglion at different time points after experimental canine MI. NGF expression and the magnitude of cardiac nerve sprouting...

Background-The relationship between autonomic activation and the mechanisms of paroxysmal atrial fibrillation remains unclear. Methods and Results-We implanted a pacemaker and a radio transmitter in 7 dogs (group 1). After baseline recording, we paced the left atrium at 20 Hz for 1 week and then monitored left stellate ganglion nerve activity, left vagal nerve activity, and left atrial electrogram without pacing for 24 hours. This protocol repeated itself until sustained atrial fibrillation (Ͼ48 hours) was induced in 3Ϯ1 weeks. In another 6 dogs (group 2), we cryoablated left and right stellate ganglia and the cardiac branch of the left vagal nerve during the first surgery and then repeated the same pacing protocol until sustained atrial fibrillation was induced in 7Ϯ4 weeks (Pϭ0.01). There were 4Ϯ2 episodes of paroxysmal atrial fibrillation per day and 10Ϯ3 episodes of paroxysmal atrial tachycardia per day in group 1. Simultaneous sympathovagal discharges were observed to immediately precede the onset of atrial arrhythmias in 73% of episodes. In comparison, group 2 dogs had no paroxysmal atrial fibrillation (Pϭ0.046) or paroxysmal atrial tachycardia (PϽ0.001) episodes. Nerve sprouting, sympathetic hyperinnervation, and a massive elevation of transcardiac norepinephrine levels occurred in both groups. Conclusions-Intermittent rapid left atrial pacing results in sympathetic hyperinnervation, paroxysmal atrial fibrillation, and paroxysmal atrial tachycardia. Simultaneous sympathovagal discharges are common triggers of these arrhythmias. Cryoablation of extrinsic sympathovagal nerves eliminated paroxysmal atrial fibrillation and paroxysmal atrial tachycardia, which suggests that simultaneous sympathovagal discharges and these arrhythmias are causally related. Because cryoablation only delayed but did not prevent sustained atrial fibrillation, autonomic nerve activity is not the only factor that determines atrial fibrillation maintenance. (Circulation. 2008; 118:916-925.)

The reduction of sympathovagal balance at night in ambulatory dogs was due to reduced sympathetic discharge rather than a net increase of vagal discharge. The tachybrady syndrome in CHF might be triggered by an intermittent short burst of SGNA that resulted in tachycardia and sinus node suppression. Simultaneous sympathovagal discharge is a cause of long PAT episodes. These data indicate that there is an association between the specific patterns of autonomic nerve discharges and cardiac arrhythmia during CHF.