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Cardiac arrhythmias are initiated in regions that undergo cellular remodeling as a result of disease. Using a sub-cellular model of myocardium, we studied the mechanism of block caused by tissue microstructure remodeling: cell geometry [quantified as length/width (L/W) cell ratio] and cell-to-cell coupling (G(j)). Heterogeneities in cell L/W ratio and G ( j ) lead to block when excitability is reduced and the corresponding space constant λ (in the direction of propagation) increases by >40 %. Tissue architectures with elongated cells (i.e. large cell L/W ratios) that are better coupled (i.e. large G(j)) are less prone to block at sites of regional heterogeneities in cell geometry and/or cell coupling than tissue architectures consisting of cells with smaller L/W ratios and/or poorer coupling. Whether an increase in tissue anisotropic ratio (ANR) is arrhythmogenic or not depends on the cellular mechanism of the increase: ANR leads to an increased risk of block when G(j) decreases, but to a decreased risk of block when cell L/W ratio increases. Our findings are useful to understand the mechanisms of block in cardiac pathologies that result in tissue architecture remodeling.

Unlabelled: Effect of Stretch on Conduction and Cx43., Introduction: In disease states such as heart failure, myocardial infarction, and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties than adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin-angiotensin system (RAS)., Methods and Results: In an open-chest canine model, a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312-electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post-stretch vs baseline: 51.5 ± 5.2 vs 55.3 ± 8.1 cm/s, P = 0.24, n = 11), but significantly reduced transverse conduction velocity (28.7 ± 2.5 vs 35.4 ± 5.4 cm/s, P < 0.01). It also reduced total Cx43 expression, by Western blotting, compared with nonstretched RV of the same animal (86.1 ± 32.2 vs 100 ± 19.4%, P < 0.02, n = 11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95 ± 1.4% vs control 8.74 ± 1.2%, P < 0.05). Olmesartan, an angiotensin II blocker, prevented the stretch-induced changes in Cx43 levels, localization, and conduction., Conclusion: Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch-induced activation of the RAS., (© 2010 Wiley Periodicals, Inc.)

We have studied the effect of cell geometry on propagation velocity of the cardiac impulse using a subcellular computer model of myocardium. Variation of cell size has only small effects on longitudinal and transverse conduction velocities, when the ratio of cell length/width is constant, for cell sizes (length x width) between (60 microm x 20 microm) and (120 microm x 40 microm). The results were not dependent on gap-junction conductance (range 0.25-1 microS), gap-junction distribution, or the specific tissue architecture. Longitudinal conduction velocity increased with the cell length/width ratio and transverse velocity decreased. The cell length/width ratio was a good estimator of the anisotropic ratio. In conclusion, cell length/width ratio is more important than cell size in determining conduction velocity.

Introduction: The importance of beta receptor blockade for the antiarrhythmic action of sotalol has not been completely elucidated. We determined how beta receptor blockade interacts with the effects of potassium channel blockade on reentrant circuits., Methods and Results: Sustained ventricular tachycardia was induced by programmed stimulation in dogs 4 days after left anterior coronary artery occlusion and reentrant circuits in the epicardial border zone (EBZ) mapped. The effects of the beta receptor-blocking drug, esmolol, the potassium channel-blocking drug d-sotalol, which lacks beta receptor-blocking effects, and the combination of the two drugs on the reentrant circuits that cause tachycardia were determined. Esmolol did not alter the ability to induce tachycardia. Small changes in the location or extent of lines of block in reentrant circuits accounted for small decreases or increases in tachycardia cycle lengths. d-Sotalol prolonged the lines of block in reentrant circuits, slowed propagation around the circuits, and prolonged tachycardia cycle length, but it did not stop tachycardia or prevent the induction of tachycardia. The combination of esmolol and d-sotalol prevented the initiation of sustained tachycardia. The stimulated premature impulse either blocked before reentering or traversed the circuit several times prior to blocking in a region of fractionated electrograms. The addition of esmolol to d-sotalol abolished the reverse use-dependent effects of d-sotalol alone on effective refractory period (ERP) and significantly prolonged ERP in the area of the reentrant circuit., Conclusion: Beta receptor blockade is important for the antiarrhythmic effects of d,l-sotalol on reentrant ventricular tachycardia in this model. The mechanism is speculative but may involve potentiation of d-sotalol actions to prolong ERP or effects on gap junctions.

Cardiac arrhythmias are caused by alterations in the electrophysiologic properties of the cardiac cells, which affect the characteristics of the transmembrane potentials. The electrophysiologic properties that cause arrhythmias are automaticity, triggered activity, and reentrant excitation. Each of these mechanisms is described in terms of the characteristics of the transmembrane potentials and how these influence the appearance of the arrhythmia on the electrocardiogram.

We have investigated the role of wave-front curvature on propagation by following the wave front that was diffracted through a narrow isthmus created in a two-dimensional ionic model (Luo-Rudy) of ventricular muscle and in a thin (0.5-mm) sheet of sheep ventricular epicardial muscle. The electrical activity in the experimental preparations was imaged by using a high-resolution video camera that monitored the changes in fluorescence of the potentiometric dye di-4-ANEPPS on the surface of the tissue. Isthmuses were created both parallel and perpendicular to the fiber orientation. In both numerical and biological experiments, when a planar wave front reached the isthmus, it was diffracted to an elliptical wave front whose pronounced curvature was very similar to that of a wave front initiated by point stimulation. In addition, the velocity of propagation was reduced in relation to that of the original planar wave. Furthermore, as shown by the numerical results, wave-front curvature changed as a function of the distance from the isthmus. Such changes in local curvature were accompanied by corresponding changes in velocity of propagation. In the model, the critical isthmus width was 200 microns for longitudinal propagation and 600 microns for transverse propagation of a single planar wave initiated proximal to the isthmus. In the experiments, propagation depended on the width of the isthmus for a fixed stimulation frequency. Propagation through an isthmus of fixed width was rate dependent both along and across fibers. Thus, the critical isthmus width for propagation was estimated in both directions for different frequencies of stimulation. In the longitudinal direction, for cycle lengths between 200 and 500 milliseconds, the critical width was < 1 mm; for 150 milliseconds, it was estimated to be between 1.3 and 2 mm; and for the maximum frequency of stimulation (117 +/- 15 milliseconds), it was > 2.5 mm. In the transverse direction, critical width was between 1.78 and 2.32 mm for a basic cycle length of 200 milliseconds. It increased to values between 2.46 and 3.53 mm for a basic cycle length of 150 milliseconds. The overall results demonstrate that the curvature of the wave front plays an important role in propagation in two-dimensional cardiac muscle and that changes in curvature may cause slow conduction or block.

Propagation, re-entry and the effects of stimuli within the conduction system can be studied effectively with computer models when the pertinent membrane properties can be represented accurately in mathematical form. To date, no membrane models have been shown to be accurate representations during repolarisation and recovery of excitability, although for the Purkinje membrane the DiFrancesco-Noble (DN) model has become a possibility. The paper examines the DN model, restates its equations and compares simulated waveforms in a number of propagation contexts to experimental measurements reported in the literature. The objective is to determine whether or not the DN model reproduced phenomena such as supernormality, shortening in action potential duration during pacing rate increases, alternation of duration with changes in rhythm, graded responses and 'all-or-none' repolarisation in a quantitatively realistic way, as each of these come from time and space dependencies not directly a part of the ionic current measurements on which the DN model is based. The results show that the DN equations correctly simulate these situations and support the goal of having a model that is broadly applicable to Purkinje tissue, including refractory period properties and response to electrical stimulation.