Yasushi Miyauchi

Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs

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.

Aging-related increase to inducible atrial fibrillation in the rat model.

Aging and Atrial Fibrillation. Introduction: Aging is associated with atrial interstitial fibrosis and increased incidence of atrial fibrillation (AF). We hypothesized that aged rats are suitable for study of aging‐related AF and that partial atrial cellular uncoupling induced with heptanol in young rats mimics aging‐related AF.

High resolution mapping of the pulmonary vein and the vein of Marshall during induced atrial fibrillation and atrial tachycardia in a canine model of pacing-induced congestive heart failure.

OBJECTIVESnThe study examined the activations in the pulmonary veins (PVs) and the vein of Marshall (VOM) during atrial fibrillation (AF) in dogs with congestive heart failure (CHF).nnnBACKGROUNDnThe patterns of activation within the PVs and the VOM during AF in CHF are unclear.nnnMETHODSnWe induced CHF in nine dogs by rapid ventricular pacing. The patterns of activation during induced AF were studied one week after ceasing ventricular pacing.nnnRESULTSnThe duration of induced AF averaged 80.7 +/- 177.3 s. The termination of low-amplitude fractionated activity in the PVs preceded the termination of AF in 25 of 29 episodes. High-density mapping (1-mm resolution) showed that the PV was activated by a focal wave front independent of left atrial (LA) activation in 22 AF episodes. Frequent intra-PV conduction blocks and multiple wave fronts in the PVs were recorded during 10 AF episodes. Focal activations were observed within the VOM in 4 of 12 episodes of AF. Three atrial tachycardia (AT) episodes originated from a focus within a PV. Histological studies showed extensive fibrosis in the PVs and in the atria. The PVs in five normal dogs did not have focal or fractionated activity during induced AF.nnnCONCLUSIONSnAtrial fibrillation in canine CHF is associated with independent focal activations in the PVs and the VOM, and with complex wave fronts within the PVs. The PVs may also serve as the origin of AT. These findings suggest that electrical and anatomical remodeling of the PVs and the VOM are important in the maintenance of AF and AT in dogs with CHF.

Thoracic veins and the mechanisms of non-paroxysmal atrial fibrillation

OBJECTIVEnThe purpose of this article is to review the importance of thoracic veins in the maintenance of sustained (non-paroxysmal) atrial fibrillation (AF).nnnMETHODSnThoracic veins, including the pulmonary veins (PVs), vein of Marshall (VOM) and the superior vena cava (SVC), have muscle sleeves that connect to the atria. It is well known that electrical activities can be recorded within these venous structures. In some incidences, these thoracic veins may serve as the trigger and/or the substrate for paroxysmal AF. The importance of thoracic veins in chronic (sustained) AF is less well appreciated. Therefore, we review the literature to determine if thoracic veins are important in the maintenance of sustained AF.nnnRESULTSnOur recent study demonstrated that repetitive rapid electrical activities are present in the PVs and in the VOM during pacing-induced sustained AF in dogs. Because of these repetitive rapid activities, these thoracic veins have shorter activation cycle lengths than that of the left atrium, which, in turn, has shorter cycle lengths than that of the right atrium. Others have demonstrated that PV isolation in humans can result in a cure of sustained human AF in >80% of patients undergoing concomitant surgery.nnnCONCLUSIONnThese findings suggest that repetitive rapid activities within the thoracic veins may be responsible for the maintenance of non-paroxysmal (sustained) AF.

Induction of atrial fibrillation and nerve sprouting by prolonged left atrial pacing in dogs.

The authors hypothesized that rapid electrical stimulation can induce nerve sprouting in canine atria, and that LA pacing is more effective than RA pacing in inducing sustained AF. Chronic rapid (20 Hz) LA epicardial pacing was performed in six dogs. Sustained AF (>48 hours) was induced within 23 ± 8 days, which was much faster than that with RA endocardial pacing using the same protocol (139 ± 84 days, P < 0.05). Nerves were identified by immunocytochemical techniques. In all dogs, growth‐associated protein 43‐positive (sprouting) nerve density was highest near the pacing site, and the rapid LA pacing resulted in differential nerve sprouting among the LA, left superior pulmonary vein (LSPV), interatrial septum (IAS), and RA (5521 ± 1496, 3154 ± 2355, 3953 ± 1164, 1559 ± 1077 μm2/mm2, respectively, P = 0.0032). Tyrosine hydroxylase‐positive (sympathetic) nerve density were not significantly different among groups (2726 ± 1165, 1586 ± 558, 2156 ± 1741, 1509 ± 1242 μm2/mm2, respectively). The nerves were inhomogeneously distributed. LA epicardial pacing induced sustained AF much faster than RA endocardial pacing and rapid electrical stimulation can induce inhomogeneous nerve sprouting near the pacing site. (PACE 2003; 26:2247–2252)

Downregulation of immunodetectable atrial Connexin40 in a canine model of chronic left ventricular myocardial infarction: Implications to atrial fibrillation

Background: The substrate(s) for atrial fibrillation associated with chronic left ventricular myocardial infarction remain poorly defined. Since atrial connexin40 has a rapid turnover rate and may cause atrial fibrillation, we hypothesized that chronic left ventricular myocardial infarction downregulates atrial Connexin40 and increases atrial fibrillation vulnerability. Methods and Results: The left anterior descending coronary artery was occluded distal to the first diagonal branch in five dogs and studied 7 weeks later. Five dogs with no left anterior descending coronary artery occlusion served as control. Vulnerability to atrial fibrillation was tested by burst atrial stimulation (50 milliseconds for 3 seconds). Atrial fibrillation was induced in all myocardial infarction dogs, lasting from 20 seconds to several minutes. In contrast, only rapid repetitive activity and short-lasting atrial fibrillation (< 5 seconds) could be induced in control dogs. The mean refractory periods of epicardial RA and LA appendages were not significantly different in the two groups. Mean left ventricular myocardial infarction size was 17 ± 4% of the left ventricle. Histologic analyses showed no signs of atrial ischemic injury or interstitial fibrosis in either group. Atrial myocyte diameter measured at the level of the nuclei of longitudinally sectioned myocytes was not significantly different in the two groups (10.1 ± 1.2 pm vs. 10.2 ± 1.2 pm; P = 0.3). Atrial Connexin40 (both left and right atria) in the left ventricular myocardial infarction group was highly heterogeneous and had significantly smaller total area stained than in the control (0.48 ± 0.09% vs. 0.82 ± 0.13%; P < 0.01). Conclusions: Chronic left ventricular myocardial infarction downregulates immunodetectable atrial Connexin40, a property that might contribute to the increased atrial fibrillation vulnerability in this model.