The factors that contribute to the occurrence of sudden cardiac death (SCD) in patients with chronic myocardial infarction (MI) are not entirely clear. The present study tests the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of ventricular tachycardia (VT), ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and complete atrioventricular (AV) block, we induced cardiac sympathetic nerve sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion (experimental group, n=9). Another 6 dogs with MI and complete AV block but without NGF infusion served as controls (n=6). Immunocytochemical staining revealed a greater magnitude of sympathetic nerve sprouting in the experimental group than in the control group. After MI, all dogs showed spontaneous VT that persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0 days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d, P<0.05). Four dogs in the experimental group but none in the control group died suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and AV block augments sympathetic nerve sprouting and creates a high-yield model of spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be an important determinant of SCD in chronic MI.

Background-Long-term rapid atrial pacing may result in atrial fibrillation (AF) in dogs. Whether there is histological evidence for neural remodeling is unclear. Method and Results-We performed rapid right atrial pacing in 6 dogs for 111Ϯ76 days to induce sustained AF. Tissues from 6 healthy dogs were used as controls. Immunocytochemical staining of cardiac nerves was performed using anti-growth-associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. In dogs with AF, the density of GAP43-positive and TH-positive nerves in the right atrium was 470Ϯ406 and 231Ϯ126 per mm 2 , respectively, which was significantly (PϽ0.001) higher than the nerve density in control tissues (25Ϯ32 and 88Ϯ40 per mm 2 , respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317Ϯ36 and 155Ϯ85 per mm 2 , respectively, and was significantly (PϽ0.001) higher than the nerve density in control tissues (9Ϯ13 and 30Ϯ7 per mm 2 , respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119Ϯ61 and 91Ϯ40 per mm 2 , respectively, which was significantly (PϽ0.001) higher than the nerve density in control tissues (10Ϯ15 and 38Ϯ39 per mm 2 , respectively). Furthermore, in dogs with AF, the right atrium had a significantly higher nerve density than the left atrium. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves within each sampling site. Conclusions-Significant

Abstract-The intramural dynamics of ventricular fibrillation (VF) remain poorly understood. Recent investigations have suggested that stable intramural reentry may underlie the mechanisms of VF. We performed optical mapping studies of VF in isolated swine right ventricles (RVs) and left ventricles (LVs). Nine RV walls were cut obliquely in their distal edge exposing the transmural surface. Six LV wedge preparations were also studied. Results showed that intramural reentry was present. In RV, 28 of 44 VF episodes showed reentry; 15% of the activation pathways were reentrant. Except for 4 episodes, reentry was transmural, involving subendocardial structures as the papillary muscle (PM) or trabeculae. In LV, reentry was observed in 27 of 27 VF episodes; 23% of the activations were part of reentrant pathways (PϽ0.05 compared with RV). All LV reentrant pathways were truly intramural (confined to the wall) and were frequently located at the PM insertion. In both ventricles, reentry was spatially and temporally unstable. Histological studies showed abrupt changes in fiber orientation at sites of reentry and wave splitting. Connexin 40 immunostaining demonstrated intramyocardial Purkinje fibers at sites of reentry in the PM root and around endocardial trabeculae. Our results confirm that reentry is frequent-but unstable-in the myocardial wall during VF. In RV, reentry is mostly transmural and requires participation of subendocardial structures. The LV has a greater incidence of reentry and is intramural. Anisotropic anatomic structures played key roles in the generation of wave splitting and in the maintenance of reentry. Key Words: intramural reentry Ⅲ fibrillation Ⅲ anisotropy Ⅲ Purkinje Ⅲ papillary muscle O ur current knowledge of the activation dynamics that take place during ventricular fibrillation (VF) derives from multiple endocardial and/or epicardial mapping studies. [1][2][3][4][5] On the basis of these data, VF has been characterized by spatiotemporal heterogeneity because of the coexistence of both organized reentry and fragmented wavelets. 3,4,6,7 However, the intramural dynamics of VF remain largely unexplored because of the lack of an experimental model that allows for intramural mapping of VF. Recent studies 8,9 have suggested that rapid and stable intramural reentry might serve as the source of VF. Intramural reentry has been previously demonstrated during ventricular tachycardia or fibrillation, 1,10 -13 but whether stable intramural reentry occurs during VF and to what extent is it required to maintain VF are unanswered questions. We have developed an experimental model to study intramural patterns of activation during VF. Our results confirm that reentry is indeed frequently seen in the myocardial wall. Substantial differences are noted between right ventricle (RV) and left ventricle (LV). We also demonstrate that anatomic structures played key roles in the generation of wave splitting and in the maintenance of reentry. Materials and Methods RV PreparationThe experimental model has been previously...

The rat model is suitable for study of aging-related AF. Uniform partial atrial cellular uncoupling with heptanol perfusion in the young rats, although promoting inducible AT, does not mimic aging-related AF. The results suggest that heterogeneous atrial interstitial fibrosis and atrial cell hypertrophy might contribute to the aging-related increase in atrial conduction slowing, conduction block, and inducible AF in the old rat model.

Background-The role of papillary muscle (PM) in the generation and maintenance of reentry is unclear. Methods and Results-Computerized mapping (477 bipolar electrodes, 1.6-mm resolution) was performed in fibrillating right ventricles (RVs) of swine in vitro. During ventricular fibrillation (VF), reentrant wave fronts often transiently anchored to the PM. Tissue mass reduction was then performed in 10 RVs until VF converted to ventricular tachycardia (VT). In an additional 6 RVs, procainamide infusion converted VF to VT. Maps showed that 77% (34 of 44) of all VT episodes were associated with a single reentrant wave front anchored to the PM. Purkinje fiber potentials preceded the local myocardial activation, and these potentials were recorded mostly around the PM. When PM was trimmed to the level of endocardium (nϭ4), sustained VT was no longer inducible. Transmembrane potential recordings (nϭ5) at the PM revealed full action potential during pacing, without evidence of ischemia. Computer simulation studies confirmed the role of PM as a spiral wave anchoring site that stabilized wave conduction. Conclusions-We conclude that PM is important in the generation and maintenance of reentry during VT and VF.

Whether or not the excitation-contraction (E-C) uncoupler diacetyl monoxime (DAM) and cytochalacin D (Cyto D) alter the ventricular fibrillation (VF) activation patterns is unclear. We recorded single cell action potentials and performed optical mapping in isolated perfused swine right ventricles (RV) at different concentrations of DAM and Cyto D. Increasing the concentration of DAM results in progressively shortened action potential duration (APD) measured to 90% repolarization, reduced the slope of the APD restitition curve, decreased Kolmogorov-Sinai entropy, and reduced the number of VF wave fronts. In all RVs, 15-20 mmol/l DAM converted VF to ventricular tachycardia (VT). The VF could be reinduced after the DAM was washed out. In comparison, Cyto D (10-40 micromol/l) has no effects on APD restitution curve or the dynamics of VF. The effects of DAM on VF are associated with a reduced number of wave fronts and dynamic complexities in VF. These results are compatible with the restitution hypothesis of VF and suggest that DAM may be unsuitable as an E-C uncoupler for optical mapping studies of VF in the swine RVs.

Corticosteroid therapy may be effective for ventricular arrhythmias in the early stage, but less effective in the late stage.

NGF infusion to the LSG in dogs with MI and CAVB resulted in increased QT interval and incidence of ventricular tachycardia, ventricular fibrillation, and SCD, whereas NGF infusion to the RSG shortened QT interval and reduced the incidence of ventricular tachycardia. These findings indicate that QT interval prolongation is causally related to the occurrence of ventricular arrhythmia in dogs with nerve sprouting, MI, and CAVB.