Stretch-Activated Current Can Promote or Suppress Cardiac Alternans Depending on Voltage-Calcium Interaction

Abstract

Cardiac alternans has been linked to the onset of ventricular fibrillation and ventricular tachycardia, leading to life-threatening arrhythmias. Here, we investigated the effects of stretch-activated currents (ISAC) on alternans using a physiologically detailed model of the ventricular myocyte. We found that increasing ISAC suppresses alternans if the voltage-Ca coupling is positive or the alternans is voltage driven. However, for electromechanically discordant alternans, which occurs when the alternans is Ca driven with negative voltage-Ca coupling, increasing ISAC promotes Ca alternans. In addition, if action potential duration-Ca transients show quasiperiodicity, we observe a biphasic effect of ISAC, i.e., suppressing quasiperiodic oscillation at small stretch but promoting electromechanically discordant alternans at larger stretch. Our results demonstrate how ISAC interacts with coupled voltage-Ca dynamical systems with respect to alternans.

Figure 1

(A) Schematic representation of the computational model. (B) Illustration of positive and negative Ca_i→V_m coupling. Positive (negative) coupling refers to the case in which a large Ca_i transient at a given beat tends to prolong (shorten) the APD of that beat. (C) Illustration of concordant and discordant alternans during steady-state pacing. To see this figure in color, go online.

Figure 2

(A and B) Tracings of APs for long APD (A) and short APD (B) at a PCL of 300 ms with no SACs (black) and I_SAC with stretch λ = 1.05 (blue) and λ = 1.10 (red). I_SAC traces are shown at the bottom. Note the similarity of the traces I_SAC and V_m. E_SAC is the reversal potential of I_SAC. (C) Stability boundaries for positive coupling (black line, without I_SAC; green, cyan, and red lines, with increased stretch). Positive coupling means that a larger Ca lengthens the APD; μ and τ_f are two instability parameters that promote Ca and voltage alternans, respectively. (D) Stability boundaries for negative coupling (black line, without I_SAC; green, cyan, and red, with increased stretch). Negative coupling means that a larger Ca shortens the APD; μ and τ_f are two instability parameters that promote Ca and voltage alternans, respectively. To see this figure in color, go online.

Figure 3

(A–C) Representative curves with no SACs (black) and I_SAC with stretch λ = 1.05 (blue) and λ = 1.10 (red) for positive coupling (circled numbers are the same as in Fig. 2C). (D–F) Evolution of APD and Ca_i^peak during an increase of stretch from λ = 1.0 to λ_max = 1.10. (G–I) Dynamic APD restitution curves. APD_n+1 plotted versus DI_n = PCL-APD_n. Dotted lines show PCL = 300 ms. To see this figure in color, go online.

Figure 4

(A–C) Representative curves with no SACs (black) and I_SAC stretch λ = 1.05 (blue) and λ = 1.10 (red) for negative coupling (circled numbers are the same as in Fig. 2D). (D–F) Evolution of APD and Ca_i^peak during an increase of stretch from λ = 1 to λ_max = 1.10. (G–I) Dynamic APD restitution curves. APD_n+1 plotted versus DI_n = PCL-APD_n. Dotted lines show PCL = 300 ms. To see this figure in color, go online.

Figure 5

(A and B) Dynamic APD restitution curves for resting potentials E_SAC = −20 mV (A) and −50 mV (B). APD_n+1 plotted versus DI_n = PCL-APD_n. To see this figure in color, go online.

Figure 6

Relationship among I_CaL (red), Ca_i (blue), I_NCX (cyan), and I_SAC (green) during discordant alternans for stretch λ = 1.0, 1.05, and 1.10. To see this figure in color, go online.

Figure 7

Dome alternans due to I_SAC. (A) SACs promote dome alternans at slow heart rates. (B) Bifurcation diagrams, APD versus PCL. With SACs (λ = 1.1), dome alternans was observed between 691 ms and 449 ms. APs were periodic when PCL was <449 ms. To see this figure in color, go online.

Figure 8

Effects of SACs in isotonic conditions. SACs have qualitatively the same effects in isometric and isotonic conditions. (A) SACs suppress concordant alternans. From the top: voltage versus time, [Ca]_i versus time, sarcomere length L_m versus time, and I_SAC versus time. (B) SACs promote discordant alternans. Note that in this simulation, since changes in the Ca²⁺ transient due to a change in the affinity of troponin for Ca²⁺ binding had little effect (8), we did not include them in the model. To see this figure in color, go online.