Masaaki Yashima

Pulmonary Veins and Ligament of Marshall as Sources of Rapid Activations in a Canine Model of Sustained Atrial Fibrillation

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.

Relation Between Ligament of Marshall and Adrenergic Atrial Tachyarrhythmia

BACKGROUND The mechanism of the adrenergic atrial tachyarrhythmia is unclear. We hypothesize that the ligament of Marshall (LOM) is sensitive to adrenergic stimulation and may serve as a source of the adrenergic atrial tachyarrhythmia. METHODS AND RESULTS We performed computerized mapping studies in isolated-perfused canine left atrial tissues from normal dogs (n=9) and from dogs with chronic atrial fibrillation (AF) induced by 10 to 41 weeks of rapid pacing (n=3). Before isoproterenol, spontaneous activity occurred in only one normal tissue (cycle length, CL >1300 ms). During isoproterenol infusion, automatic rhythm was induced in both normal tissues (CL=578+/-172 ms) and AF tissues (CL=255+/-29 ms, P<0.05). The origin of spontaneous activity was mapped to the LOM. In the AF tissues, but not the normal tissues, we observed the transition from rapid automatic activity to multiple wavelet AF. Ablation of the LOM terminated the spontaneous activity and prevented AF. Immunocytochemical studies of the LOM revealed muscle tracts surrounded by tyrosine hydroxylase-positive (sympathetic) nerves. CONCLUSIONS We conclude that the LOM is richly innervated by sympathetic nerves and serves as a source of isoproterenol-sensitive focal automatic activity in normal canine atrium. The sensitivity to isoproterenol is upregulated after long-term rapid pacing and may contribute to the development of AF in this model.

Role of Papillary Muscle in the Generation and Maintenance of Reentry During Ventricular Tachycardia and Fibrillation in Isolated Swine Right Ventricle

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 (n = 4), sustained VT was no longer inducible. Transmembrane potential recordings (n = 5) 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.

Mechanism of Acceleration of Functional Reentry in the Ventricle Effects of ATP-Sensitive Potassium Channel Opener

BACKGROUND The effect of effective refractory period (ERP) shortening on the vulnerability and characteristics of induced functional reentry in the ventricle remain poorly defined. We hypothesized that ERP shortening increases ventricular vulnerability to reentry and accelerates its rate, as is the case in the atrium. METHODS AND RESULTS The epicardial surfaces of 19 isolated and superfused canine right ventricular slices (4x4 cm and <2 mm thick) were mapped with 480 bipolar electrodes 1.6 mm apart. Vulnerability was tested during pacing at a cycle length (CL) of 600 ms and with a single premature stimulus of 5-ms duration at increasing current strength of 1 to 100 mA. Cromakalim (10 micromol/L), an ATP-sensitive potassium channel opener, caused a significant (P<0. 001) shortening of the ERP but had no effect on conduction velocity. Cromakalim increased (P<0.01) the vulnerability (product of current and the stimulus coupling interval) for reentry induction. Reentry had a significantly shorter CL and lasted for a longer duration (P<0. 001). The central core around which the wave front rotated became smaller, which caused shortening of the CL of reentry. A significant (P<0.001) linear correlation was found between core size and reentry CL. These effects of cromakalim were reversible. Two-dimensional simulation studies using the modified Luo-Rudy I model of cardiac action potential, in which the refractory period was variably shortened by a progressive increase of the time-independent potassium conductance, reproduced the experimental findings. CONCLUSIONS ERP shortening by an ATP-sensitive potassium channel opener increases ventricular vulnerability to reentry and accelerates its rate by decreasing the core size around which the wave front rotates.

Mechanism of Procainamide-Induced Prevention of Spontaneous Wave Break During Ventricular Fibrillation Insight Into the Maintenance of Fibrillation Wave Fronts

BACKGROUND Ventricular fibrillation (VF) is maintained by 2 mechanisms: first by reentry formation and second by spontaneous wave break or wave splitting. We hypothesized that spontaneous wave break results from a critical shortening of the action potential duration (APD) during VF and that its prevention by procainamide eliminates spontaneous wave break. METHODS AND RESULTS The endocardial surfaces of 7 isolated, perfused swine right ventricles were mapped with a 3.2x3.8 cm plaque with 477 bipolar electrodes. Activation pattern during VF was visualized dynamically while simultaneously recording epicardial action potentials with a glass microelectrode. APD restitution curves were constructed during VF (dynamic) and during S(1)S(2) protocols. At baseline, VF was maintained by 5.3+/-1 wavelets. Procainamide (PA) at 10 microgram/mL decreased the number of wavelets to 3.5+/-1 (P<0.05). At baseline VF was maintained by spontaneous wave break and by new reentrant wave front formation. PA eliminated spontaneous wave break during VF while having no effect on reentry formation. PA increased the cycle length of the VF (148.5+/-41.2 ms vs 81+/-10 ms, P<0.01) and the core area of the reentry from 5.8 to 14.5 mm(2) (P<0.05). Dynamic APD restitution curve during VF showed that PA eliminated the initiation of activation with APDs shorter than 30 ms. The effects of PA on cellular properties and wave front dynamics were reversed during 60 minutes of drug-free perfusion. CONCLUSIONS Critically short APDs during VF promote spontaneous wave break. Their elimination with PA, however, maintains VF by generating new reentrant wave front.

Obstacle-induced transition from ventricular fibrillation to tachycardia in isolated swine right ventricles: insights into the transition dynamics and implications for the critical mass.

OBJECTIVES The study was done to test the hypothesis that an artificial anatomical obstacle prevents the maintenance of ventricular fibrillation (VF) by stabilizing reentrant wavefronts (RWF) and increases the critical mass (CM) of myocardium required to sustain VF. BACKGROUND Artificial obstacles can anchor RWF in simulated models of VF. Whether an artificial obstacle affects multiple-wavelet VF in real tissue is unclear. METHODS The endocardial surfaces of seven isolated, perfused swine right ventricles were mapped using a plaque of 477 bipolar electrodes with 1.6-mm resolution. An 8-mm hole was punched in the tissue. The CM was reached by tissue mass reductions, at which VF converted to periodic activity (ventricular tachycardia, VT). RESULTS After the creation of the obstacle, the VF cycle length increased from 71.6+/-18.4 ms to 87.5+/-13.0 ms (p<0.05). The obstacle, together with the papillary muscle, facilitated the transition from VF to VT by serving as attachment sites for the RWF. When one RWF attaches to the obstacle and another attaches to the papillary muscle, it may result in stable VT with figure-eight patterns. The CM for VF in the presence of an 8-mm hole (28.7+/-3.8 g) was higher than in the control group (swine right ventricles without holes, 24.0+/-3.4 g, p<0.05). CONCLUSIONS An artificial anatomical obstacle induces slowing and regularization of VF, impairs the persistence of VF as judged by an increase of the CM, and can convert VF to VT by serving as an attachment site to reentrant excitation.

Relation Between Cellular Repolarization Characteristics and Critical Mass for Human Ventricular Fibrillation

Critical Mass for Human Ventricular Fibrillation. Introduction: The critical mass for human ventricular fibrillation (VF) and its electrical determinants are unclear. The goal of this study was to evaluate the relationship between repolarization characteristics and critical mass for VF in diseased human cardiac tissues.

Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium

OBJECTIVES We sought to evaluate the effects of progressive shortening of the action potential duration (APD) on atrial wave front stability. BACKGROUND The mechanisms of conversion from atrial flutter to atrial fibrillation (AF) are unclear. METHODS Isolated canine right atria were perfused with 1 to 5 micromol/l of acetylcholine (ACh). We mapped the endocardium by using 477 bipolar electrodes and simultaneously recorded transmembrane potentials from the epicardium. The APD(90) was measured during regular pacing (S(1)) with cycle lengths of 300 ms. Atrial arrhythmia was induced by a premature stimulus (S(2)). RESULTS At baseline, only short runs of repetitive beats (<10 cycles) were induced. After shortening the APD(90) from 124 +/- 15 ms to 72 +/- 9 ms (p < 0.01) with 1 to 2.5 micromol/l of ACh, S(2) pacing induced single, stable and stationary re-entrant wave fronts (307 +/- 277 cycles). They either anchored to pectinate muscles (5 tissues) or used pectinate muscles as part of the re-entry (4 tissues). When ACh was raised to 2.5 to 5 micromol/l, the APD(90) was further shortened to 40 +/- 12 ms (p < 0.01); S(2) pacing induced in vitro AF by two different mechanisms. In most episodes (n = 13), AF was characterized by rapid, nonstationary re-entry and multiple wave breaks. In three episodes with APD(90) <30 ms, AF was characterized by rapid, multiple, asynchronous, but stationary wave fronts. CONCLUSIONS Progressive APD shortening modulates atrial wave front stability and converts atrial flutter to AF by two mechanisms: 1) detachment of stationary re-entry from the pectinate muscle and the generation of multiple wave breaks; and 2) formation of multiple, isolated, stationary wave fronts with different activation cycle lengths.

Transmembane Potential Properties of Atrial Cells at Different Sites of a Spiral Wave Reentry: Cellular Evidence for an Excitable but Nonexcited Core

Transmembrane action potentials (TAPs) were recorded during simultaneous mapping of a reentrant wavefront induced in canine isolated atria. The activation pattern was visualized dynamically using a high resolution electrode catheter mapping system. During functional reentry (spiral wave), cells in the core of the spiral wave remained quiescent near their resting membrane potential. Cells away from the core progressively gained TAP amplitude and duration, and at the periphery of the spiral wave the cells generated TAPs with full height and duration. During anatomical reentry, when the tip of the wavefront remained attached to the obstacle (a condition of high source‐to‐sink ratio), the TAP near the obstacle had normal amplitude and duration. However, when the tip of the wavefront detached from the obstacle (condition of lowered source‐to‐sink ratio) the TAP lost amplitude and duration. These results are consistent with the theory that the source‐to‐sink ratio determines the safety factor for wave propagation and wave block near the core. With decreasing source‐to‐sink ratio, TAP progressively decreases in amplitude and duration. In the center of the core, the cells, while excitable, remain quiescent near their resting potential. This decrease reflects a progressive decrease in the source‐to‐sink ratio. TAP vanishes in the core where cells remain quiescent near their resting potential. Functional and meandering reentrant wavefronts are compatible with the spiral mechanism of reentry where block at the rotating point is provided by the steep curvature of the wave tip.

Nicotine Increases Spatiotemporal Complexity of Ventricular Fibrillation Wavefront on the Epicardial Border Zone of Healed Canine Infarcts

Background: The influence of a pharmacologic agent on wavefront dynamics during ven tricular fibrillation (VF) in a setting of remodeled and healed myocardial infarction (MI) remains poorly explored. We hypothesized that nicotine, by virtue of its complex direct and indirect cardiovascular effects, increases wavefront complexity during VF. Specifically, we sought to determine whether nicotine increases the number and complexity (approximate entropy) of wavelets during stage II VF in hearts with healed MI. Methods and Results: The left anterior descending coronary artery was permanently occluded in five mongrel dogs and wavefront dynamics during VF studied 5 to 6 weeks after occlusion in the open-chest anesthetized state. VF was induced by rapid pacing and the acti vation pattern mapped on the surviving epicardial border zone (EBZ) of the left ventricle with a plaque (3.2 x 3.8 cm) having 477 bipolar electrodes 1.6 mm apart. VF was mapped before and 20 minutes after 5 μg/kg/min nicotine infusion. Nicotine with a mean arterial plasma con centration of 127 ± 76 ng/mL (range 57 to 240 ng/mL) significantly (P < .01) increased the number of wavelets from 3.8 ± 0.4 to 5 ± 0.41. The increased number of wavelets was caused by an increase (P < .01) in the spontaneous breakup of wavefronts from 4.1 ± 0.9 times/s to 6.9 ± 1.1 times/s. Wavebreak over the EBZ was functional in nature as no breakup occurred dur ing normal sinus rhythm. Approximate entropy, a measure of complexity, significantly (P < .01) increased after nicotine administration from 0.23 ± 0.02 to 0.28 ± 0.01. Conclusions: Nicotine increases the number of wavelets and their complexity during VF by promoting spontaneous wavebreak over the EBZ of healed MI.