Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity

Abstract

The molecular heterogeneity of repolarizing currents produces significant spatial heterogeneity and/or dispersion of repolarization in many mammalian cardiac tissues. Transgenic mice are prominent experimental models for the study of the molecular basis of repolarization and arrhythmias. However, it is debated whether the small mouse heart can sustain physiologically relevant heterogeneity of repolarization. We used a comprehensive model of the mouse action potential (AP) to predict how small a region of the cardiac tissue can maintain spatial gradients of repolarization due to differential expression of channels. Our simulations of a one-dimensional multicellular ring or cable predict that substantial gradients in repolarization and intracellular Ca2+ concentration transients can be maintained through heterogeneity of expression of K+ channels in distances of ∼10 cells that are sufficient to block propagation. The abruptness of expression gradients and the site of stimulation can cause Ca2+ transient oscillations and affect the stability of Ca2+ dynamics and AP propagation. Two different mechanisms of instability of AP propagation in one-dimensional cable occur at fast pacing rates. Transitions from periodic activity to alternans or to irregular behavior were observed. Abrupt gradients of channel expression can cause alternans at slower pacing rates than gradual changes. Our simulations demonstrate the importance of incorporating realistic Ca2+ dynamics and current densities into models of propagated AP. They also emphasize that microscopic aspects of tissue organization are important for predicting large-scale propagation phenomena. Finally, our results predict that the mouse heart should be able to sustain substantial molecularly based heterogeneity of repolarization.

Nonequilibrium Arrhythmic States and Transitions in a Mathematical Model for Diffuse Fibrosis in Human Cardiac Tissue

“…However, if  = 4 and , this distinction is quite prominent at all the values of that we have considered. For studies on transmural heterogeneity in mouse tissue, please refer to [38], [39].…”

Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

“…Computer simulations could provide a potential means to further explore the pro-arrhythmic consequences of RV/LV differences in ionic currents, particularly employing whole heart models [60–63]. However, this would also entail obtaining further independent information on detailed conduction pathway morphology, including extents of fibrosis and cell–cell conductance information in Scn5a +/− hearts.…”

“…However, this would also entail obtaining further independent information on detailed conduction pathway morphology, including extents of fibrosis and cell–cell conductance information in Scn5a +/− hearts. While groups have previously used whole heart models of WT mouse hearts [60], it has been shown previously that Scn5a +/− hearts exhibit heterogeneous fibrosis [2], along with heterogeneous expression of connexin 43 and upregulation of hypertrophic markers including β-MHC and skeletal α-actin [64]. …”

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

“…The one-dimensional (1D) model of mouse ventricular tissue consists of 190 cardiac cells, both for WT and TG mice. Two configurations of the tissue were simulated: a 1D cable and a ring of N ϭ 190 model cells connected end to end with gap junction conductances ggap (7). Cell length was 100 m (7, 41); therefore, the length of the cable and the ring was 19 mm, which is approximately equal to the circumference of a mouse ventricle with a diameter of 6 mm (54).…”

“…The mechanism of [Ca 2ϩ ] i alternans in rodent cardiac tissues has been studied both experimentally and using computer simulations (7,14,38). Diaz et al (14) showed that pharmacological depression of RyRs with tetracaine led to alternans in rat cardiac myocytes.…”