David A. Golod

Effects of anisotropy on the development of cardiac arrhythmias associated with focal activity

Abstract. The anisotropy that normally exists in the myocardium may be either enhanced in peri-infarction zones by loss of lateral cell connections or reduced by redistribution of gap junctions. To test how the degree of anisotropy affects the development of ectopic focal activity, we carried out computer simulations in which a model of an ectopic focus is incorporated as the central element of a two-dimensional sheet of ventricular cells. At low values of intercellular coupling conductance (Gc), the focus region is spontaneously active, but the limited intercellular current flow inhibits propagation. At high Gc, automaticity is suppressed by the loading effects of the surrounding cells. At intermediate Gc, the ectopic activity may propagate into the sheet. In the case of isotropic coupling, the minimum size of the focus region for propagation to occur (in terms of number of collaborating cells within the focus) is as small as approximately ten cells, and this number decreases with increasing anisotropy. Thus, the presence of anisotropy facilitates the development of ectopic focal activity. We conclude that the remodeling that occurs in peri-infarction zones may create a substrate that either facilitates (enhanced anisotropy) or inhibits (reduced anisotropy) the development of cardiac arrhythmias associated with ectopic focal activity.

Determinants of action potential initiation in isolated rabbit atrial and ventricular myocytes

Action potential conduction through the atrium and the ventricle of the heart depends on the membrane properties of the atrial and ventricular cells, particularly with respect to the determinants of the initiation of action potentials in each cell type. We have utilized both current- and voltage-clamp techniques on isolated cells to examine biophysical properties of the two cell types at physiological temperature. The resting membrane potential, action potential amplitude, current threshold, voltage threshold, and maximum rate of rise measured from atrial cells (-80 ± 1 mV, 109 ± 3 mV, 0.69 ± 0.05 nA, -59 ± 1 mV, and 206 ± 17 V/s, respectively; means ± SE) differed significantly ( P < 0.05) from those values measured from ventricular cells (-82.7 ± 0.4 mV, 127 ± 1 mV, 2.45 ± 0.13 nA, -46 ± 2 mV, and 395 ± 21 V/s, respectively). Input impedance, capacitance, time constant, and critical depolarization for activation also were significantly different between atrial (341 ± 41 MΩ, 70 ± 4 pF, 23.8 ± 2.3 ms, and 19 ± 1 mV, respectively) and ventricular (16.5 ± 5.4 MΩ, 99 ± 4.3 pF, 1.56 ± 0.32 ms, and 36 ± 1 mV, respectively) cells. The major mechanism of these differences is the much greater magnitude of the inward rectifying potassium current in ventricular cells compared with that in atrial cells, with an additional difference of an apparently lower availability of inward Na current in atrial cells. These differences in the two cell types may be important in allowing the atrial cells to be driven successfully by normal regions of automaticity (e.g., the sinoatrial node), whereas ventricular cells would suppress action potential initiation from a region of automaticity (e.g., an ectopic focus).

Experimental Model for an Ectopic Focus Coupled to Ventricular Cells

BACKGROUND We used a mathematical model of a sinoatrial nodal cell (SAN model) electrically coupled to real ventricular cells (VCs) to investigate action potential conduction from an automatic focus. METHODS AND RESULTS Since input resistance of a VC is less than that of an SAN cell, coupling of the SAN model, with a size factor of 1, to a VC produced either (1) spontaneous pacing at the slower rate of the SAN model but without driving (activation) of the VC for lower values of coupling conductance (Gj) or (2) inhibition of pacing of the SAN model by electrical coupling to the VC for higher values of Gj. When the SAN model was adjusted in size to be 3 to 5 times larger than a sinoatrial nodal cell, thus making effective SAN model capacitance 3 to 5 times larger and input resistance 3 to 5 times smaller, the SAN model propagated activity to the coupled VC for Gj above a critical value. When the VC was paced at 1 Hz, the coupled cell pair demonstrated a stable rhythm of alternating cycle lengths and alternating conduction directions. By increasing pacing frequency to 2 Hz, we converted this rhythm to a regular 2-Hz frequency in which each action potential originated in the VC. More complex periodic interactions were observed at intermediate cycle lengths and lower or higher values of Gj. CONCLUSIONS The phenomena we observed demonstrate the critical role of the size of an automatic focus as well as the coupling in the propagation of activity from the focus into surrounding myocardium.

Propagation of the cardiac action potential from an ectopic focus into a two-dimensional sheet of ventricular cells

We have carried out computer simulations in which a model of an ectopic focus is incorporated as the central element of a two-dimensional sheet of ventricular cells in which the coupling conductances may be different in the X and Y directions and a specific region of lack of coupling conductance may serve as a resistive barrier. We determined the critical size of the central element for successful propagation of its action potential into the sheet and found that this critical size was decreased when anisotropy was present compared to the isotropic case and was further decreased when the central site of stimulation was close to the resistive barrier. We conclude that the normal existence of anisotropy and enhancement of the degree of anisotropy under pathophysiological conditions may play a facilitating role in the development of ectopic foci which may lead to cardiac arrhythmias.