Tsu-Juey Wu

BACKGROUND: Sympathetic nerve activity is known to be important in ventricular arrhythmogenesis, but there is little information on the relation between the distribution of cardiac sympathetic nerves and the occurrence of spontaneous ventricular arrhythmias in humans. METHODS AND RESULTS: We studied 53 native hearts of transplant recipients, 5 hearts obtained at autopsy of patients who died of noncardiac causes, and 7 ventricular tissues that had been surgically resected from the origin of ventricular tachycardia. The history was reviewed to determine the presence (group 1A) or absence (group 1B) of spontaneous ventricular arrhythmias. Immunocytochemical staining for S100 protein, neurofilament protein, tyrosine hydroxylase, and protein gene product 9.5 was performed to study the distribution and the density of sympathetic nerves. The average left ventricular ejection fraction was 0.22+/-0.07. A total of 30 patients had documented ventricular arrhythmias, including ventricular tachycardia and sudden cardiac death. A regional increase in sympathetic nerves was observed around the diseased myocardium and blood vessels in all 30 hearts. The density of nerve fibers as determined morphometrically was significantly higher in group 1A patients (total nerve number 19.6+/-11.2/mm(2), total nerve length 3.3+/-3.0 mm/mm(2)) than in group 1B patients (total nerve number 13.5+/-6.1/mm(2), total nerve length 2.0+/-1.1 mm/mm(2), P<0. 05 and P<0.01, respectively). CONCLUSIONS: There is an association between a history of spontaneous ventricular arrhythmia and an increased density of sympathetic nerves in patients with severe heart failure. These findings suggest that abnormally increased postinjury sympathetic nerve density may be in part responsible for the occurrence of ventricular arrhythmia and sudden cardiac death in these patients.

BACKGROUND: Whether or not the muscle bundle within the ligament of Marshall (LOM) can serve as the origin of focal atrial fibrillation (AF) is unknown. METHODS AND RESULTS: A total of 28 consecutive patients with paroxysmal AF underwent balloon-occlusion coronary sinus angiograms to identify the vein of Marshall (VOM). Attempts were then made to advance a 1.5-French electrophysiological catheter into the VOM via the coronary sinus orifice. In 17 of the 28 patients (10 of 17 were men aged 38+/-15 years), cannulation was successful. Double potentials were registered in 8 of these 17 patients. The first potential corresponded with local left atrial activation. The second potential was shorter and narrower than the first. The sequence of activation in the second potential in the VOM was proximal to distal. In 6 patients with direct VOM recordings, we documented that the origin of AF was in the muscle bundle within the LOM. Radiofrequency catheter ablation aimed at the insertion site of the VOM successfully terminated AF in 4 of these 6 patients. CONCLUSIONS: (1) It is possible to cannulate and to record electrical potentials from the VOM. (2) The characteristics of the double potentials within the VOM suggest that the second potential is from the muscle bundle (Marshall bundle) within the LOM. (3) The Marshall bundle may be the origin of focal AF in some patients.

The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.

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 111+/-76 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 470+/-406 and 231+/-126 per mm(2), respectively, which was significantly (P:<0.001) higher than the nerve density in control tissues (25+/-32 and 88+/-40 per mm(2), respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317+/-36 and 155+/-85 per mm(2), respectively, and was significantly (P:<0.001) higher than the nerve density in control tissues (9+/-13 and 30+/-7 per mm(2), respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119+/-61 and 91+/-40 per mm(2), respectively, which was significantly (P:<0.001) higher than the nerve density in control tissues (10+/-15 and 38+/-39 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 nerve sprouting and sympathetic hyperinnervation are present in a canine model of sustained AF produced by prolonged right atrial pacing. The magnitude of nerve sprouting and hyperinnervation was higher in the right atrium than in the left atrium.

BACKGROUND: In dogs, chronic rapid pacing may result in sustained atrial fibrillation (AF). However, activation patterns in pacing-induced sustained AF are unclear. METHODS AND RESULTS: We induced sustained AF (>48 hours) in 6 dogs by rapid pacing for 139+/-84 days. We then performed computerized atrial epicardial mappings and recorded the activations in the ligament of Marshall (LOM) and the pulmonary veins (PVs). During AF, mean activation cycle length in the right atrial free wall (126+/-17 ms) was significantly longer than that in the left atrial free wall (96+/-5 ms, P:=0.006). In addition, mean activation cycle length in the left atrial free wall was significantly longer than that in the LOM (84+/-5 ms, P:<0.001), the left inferior PV (81+/-4 ms, P:=0.001), and the left superior PV (85+/-7 ms, P:=0.003). Similarly, the dominant frequency was highest in the LOM and the PVs (range 11.2 to 13.3 Hz), followed by the left and right atria (P:<0.001). In all dogs studied, rapid and complicated electrograms were consistently observed at the LOM and the PVs. During AF, both wandering wavelets and organized reentry were present. There were more wave fronts in the left atrium than in the right atrium (P:<0.001). CONCLUSIONS: In chronic pacing-induced sustained AF, the LOM and the PVs are the sources of rapid activations. The mechanism by which the left atrium activates faster and has more wave fronts than the right atrium may relate to the fact that the left atrium is closer to the sources of rapid activations.