Oxidative stress with hydrogen peroxide (H(2)O(2)) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H(2)O(2) on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H(2)O(2) (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H(2)O(2) caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 microM) but not by its inactive form (KN-92, 1 microM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H(2)O(2) in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate ( approximately 30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.

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 substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability. Methods and Results-We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly (PϽ0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD (PϽ0.01) and MAP amplitude (PϽ0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5-to 8-fold higher and were more heterogeneous in MI compared with control dogs. Conclusions-Chronic

In human hearts with DCM, epicardial reentrant wave fronts and transmural scroll waves were present during VF. Increased fibrosis provides a site for conduction block, leading to the continuous generation of reentry.

The mechanisms are unclear. We induced sustained (Ͼ48 h) AF by rapidly pacing the left atrium (LA) in six dogs. Highdensity computerized mapping was done in the PVs and atria. Results show repetitive focal activations in all dogs and in 12 of 18 mapped PVs. Activation originated from the middle of the PV and then propagated to the LA and distal PV with conduction blocks. The right atrium (RA) was usually activated by a single large wavefront. Mean AF cycle length in the PVs (left superior, 82 Ϯ 6 ms; left inferior, 83 Ϯ 6 ms; right inferior, 83 Ϯ 4 ms) and LA posterior wall (87 Ϯ 5 ms) were significantly (P Ͻ 0.05) shorter than those in the LA anterior wall (92 Ϯ 4 ms) and RA (107 Ϯ 5 ms). PVs in normal dogs did not have focal activations during induced AF. No reentrant wavefronts were demonstrated in the PVs. We conclude that nonreentrant focal activations are present in the PVs in a canine model of pacing-induced sustained AF. arrhythmia; mapping; pacing; pathology; activation cycle length RECENT STUDIES SHOW THAT PAROXYSMAL atrial fibrillation (AF) in humans may be initiated by trains of rapid discharges from the pulmonary veins (PVs) (11) or the ligament of Marshall (LOM), which is located in the posterior wall of the left atrium (LA) (14). Our recent canine experimental study (40) demonstrated repetitive rapid activations within the LOM and the PVs in pacing-induced sustained AF, suggesting that the LOM and PVs play a role in the maintenance of this arrhythmia. However, because only a few electrodes were used to record from the PVs in that study, it was unclear if these rapid activations were due to focal discharge or microreentry. Spach et al. (33) studied human atrial tissues from patients whose ages ranged 1-70 yr. In these tissues, anisotropic propagation was necessary for a reentrant circuit to be contained within an area of 50 mm 2 . In conditions leading to obliteration of side-to-side electrical coupling between fibers (e.g., aging and chronic hypertrophy), microreentry may occur within an even smaller area (0.6 mm in width; 2.6 mm in length). These data indicate that if we were to demonstrate microreentrant circuit, a high-density electrode mapping array is necessary. Therefore, we developed a new computerized mapping system with a high-density electrode mapping array to map the detailed patterns of activation in the PVs and atria of dogs with sustained AF. The interelectrode distance was 1 mm in five dogs and 2.5 mm in one dog. Our purpose was to map PV activity during AF and relate it to possible arrhythmia mechanisms. METHODSThis research protocol was approved by the Institutional Animal Care and Use Committees and conforms to the American Heart Association Guidelines. Mongrel dogs (18-25 kg) were used in the study.Chronic pacing to induce sustained AF. Sustained AF, defined as AF that persists for 48 h off pacing, was induced by intermittent rapid pacing (40) from the LA (N ϭ 6). During the first surgery, we performed a thoracotomy via the left fourth intercostal space. A screw-in bipolar pacin...

Atypical AVNRT with eccentric retrograde left-sided activation was demonstrated in 6% of all patients with AVNRT masquerading as tachycardia using a left-sided accessory pathway. Ablation of the slow pathway at the posterior aspects of the right atrial septum resulted in a cure in these patients.

Acetylcholine chloride (ACh) induces nonstationary meandering reentrant wave fronts in the atrium. We hypothesized that an anatomic obstacle of a suitable size prevents meandering by causing attachment of the reentrant wave front tip to the obstacle. Eight isolated canine right atrial tissues (area, 3.8 x 3.2 cm) were mounted in a tissue bath and superfused with Tyrode's solution containing 10 to 15 mumol/L ACh. Holes with 2- to 10-mm diameters were sequentially created in the center of the tissue with biopsy punches. Reentry was induced by a premature stimulus after eight regular stimuli at 400-ms cycle length. The endocardial activation maps and the motion of the induced reentry were visualized dynamically before and after each test lesion using 509 bipolar electrodes. In the absence of a lesion (n = 8), the induced single reentrant wave front, in the form of a spiral wave, meandered irregularly from one site to another before terminating at the tissue border. Holes with 2- to 4-mm diameters (n = 6) had no effect on meandering. However, when the hole diameters were increased to 6 mm (n = 8), 8 mm (n = 8), and 10 mm (n = 6), the tip of the spiral wave attached to the holes, and reentry became stationary. Transition from meandering to an attached state converted the irregular and polymorphic electrogram to a periodic and monomorphic activity with longer cycle lengths (101 +/- 11 versus 131 +/- 9 ms for no hole versus 10-mm hole, respectively; P < .001). Regression analysis showed a significant positive linear correlation between the cycle length of the reentry and the hole diameter (r = .89, P < .01) and between the cycle length of the reentry and the excitable gap (r = .89, P < .05). We conclude that a critically sized anatomic obstacle converts a nonstationary meandering reentrant wave front to a stationary one. This transition converts an irregular "fibrillation-like" activity into regular monomorphic activity.

Sino-atrial node (SAN) function was evaluated in 46 patients, three of whom had the sick sinus syndrome. Patients were paced from the right atrium for 15 to 180 sec at rates of 90, 110, 130, and 150 beats/min. The rapid cessation of pacing was associated with suppression of the SAN at all paced rates and at all durations of pacing. The observed pause was terminated by a sinus beat in all instances. The duration of pacing had little influence on the duration of the observed pause. The pause increased as the pacing rate was increased until, at a rate of 150 beats/min, a marked decrease in the pause was noted. Atropine (1.5-3.0 mg iv) diminished but did not eliminate the SAN suppression. Subthreshold pacing did not suppress SAN function. Three patients with sick sinus syndrome had a greater degree of SAN suppression than normal patients (4732 ± 415 msec [SSS] M ± sem ; 1041 ± 56 msec for normal patients). The determination of the duration of the pause following cessation of atrial pacing provides a technique for recognition of abnormalities of SAN function.