β-Adrenergic receptor stimulation inhibits proarrhythmic alternans in postinfarction border zone cardiomyocytes: a computational analysis

Abstract

The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca²⁺ and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation. The BZ model developed Ca²⁺ transient alternans at slower pacing cycle lengths than the control model, suggesting that the BZ may promote spatially heterogeneous alternans formation in an infarcted heart. β-AR stimulation abolished alternans. By evaluating all combinations of downstream β-AR stimulation targets, we identified both direct (via ryanodine receptor channels) and indirect [via sarcoplasmic reticulum (SR) Ca²⁺ load] modulation of SR Ca²⁺ release as critical determinants of Ca²⁺ transient alternans. These findings were confirmed in a human ventricular cardiomyocyte model. Cell-to-cell coupling indirectly modulated the likelihood of alternans by affecting the action potential upstroke, reducing the trigger for SR Ca²⁺ release in one-dimensional strand simulations. However, β-AR stimulation inhibited alternans in both single and multicellular simulations. Taken together, these data highlight a potential antiarrhythmic role of sympathetic hyperinnervation in the BZ by reducing the likelihood of alternans and provide new insights into the underlying mechanisms controlling Ca²⁺ transient and repolarization alternans.NEW & NOTEWORTHY We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of β-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that β-adrenergic stimulation inhibits alternans and provide novel insights into underlying mechanisms, adding to a recent controversy about pro-/antiarrhythmic effects of postmyocardial infarction hyperinnervation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/%CE%B2-ar-stimulation-and-alternans-in-border-zone-cardiomyocytes/.

Keywords: alternans; border zone; calcium; computational modeling; myocardial infarction; β-adrenergic receptor stimulation.

Fig. 1.

Mechanisms of alternans and effects of β-adrenergic receptor (β-AR) stimulation. A: schematic representation of Ca²⁺ handling in ventricular cardiomyocytes, where Ca²⁺ influx via L-type Ca²⁺ current (I_CaL) triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) via type 2 ryanodine receptors (RyR2). The Ca²⁺ then diffuses within the cell and is transported back to the SR via SERCA2a. Within the SR, two compartments are modeled: the junctional SR (JSR; the compartment containing RyR2s) and the network SR (NSR; containing SERCA2a). The predominant mechanisms of Ca²⁺ transient (CaT) alternans are based on RyR2 refractoriness (where the alternation of Ca²⁺ is driven by incomplete recovery from a sufficiently large release, inducing a small release only) or release-reuptake mismatch (where the alternans is due to reuptake insufficiency after a sufficiently large release). B: comparison of normalized CaT from the study of Gardner et al. (16) (left column) and our computational model (right column) under similar conditions. The experimental data come from mice, whereas the simulated traces are from a canine model, explaining the difference in duration and shape of CaTs. The heterozygous (HET)-sham trace is from myocardial infarction (MI)-free control mice; the knockout (KO)-sham trace is from MI-free mice with protein tyrosine phosphatase receptor-σ (PTPσ; an antireinnervation factor) knocked out, resulting in increased sympathetic innervation. The HET-MI trace is a trace from the denervated border zone (BZ), and the KO-MI trace is a trace from the hyperinnervated BZ. Hyperinnervation or simulated β-AR-stimulation with isoproterenol (ISO) abolished CaT alternans in the BZ.

Fig. 2.

Effect of β-AR stimulation on the rate dependence of alternans. A: membrane potential and Ca²⁺ transients of the following four model configurations at a basic cycle length (BCL) of 400 ms: NZ cell, BZ cell, β-AR-stimulated (1.0 µmol/l ISO) NZ cell (NZ + ISO), and β-AR-stimulated BZ cell (BZ + ISO). B: analogous plot at a BCL of 260 ms, showing action potential (AP) duration (APD) and CaT alternans in NZ and BZ cases in the absence of β-AR stimulation. C and D: APD and CaT rate dependence curves for the four simulated configurations. Bifurcation in NZ and BZ curves indicates the occurrence of alternans. The dotted lines represent the mean of minimum and maximum APD during alternans. E and F: alternans ratio for APD and CaT alternans in the four groups.

Fig. 3.

Role of SR Ca²⁺ release magnitude in alternans. A−C: AP (A), cytosolic Ca²⁺ concentration (B), and SR Ca²⁺ release flux (J_rel; C) for two combinations of downstream β-AR stimulation effects (phosphorylated I_CaL and I_Kur, solid line; phosphorylated I_Ks and I_NaK, dashed line) at a BCL of 260 ms. D and E: magnitude of APD (D) and CaT (E) alternans for all 2⁷ = 128 different combinations of downstream effects of β-AR without RyR2 activation versus the integral of J_rel over two consecutive APs; the two conditions shown in A–C are indicated with arrows.

Fig. 4.

Effect of SR Ca²⁺ load on alternans. SR Ca²⁺ release flux (A), JSR (B) and NSR (C) Ca²⁺ concentrations, and Ca²⁺ transport between the NSR and JSR (D) are shown for the following three simulations: C1 (a combination of β-AR-stimulated downstream effects with high release and no alternans), C2 (a combination of β-AR-stimulated downstream effects with relatively high release, manifesting alternans), and C3 (C2 with NSR Ca²⁺ content changed to that of C1 at the beginning of the plotted period).

Fig. 5.

Effect of acute introduction of single RyR2 activation changes on alternans. Release duration (A), diastolic Ca²⁺ concentration in the subspace (B), SR Ca²⁺ release integral (C), SR Ca²⁺ uptake integral (D), maximal NSR Ca²⁺ content (E), and fractional JSR emptying (F) are shown as a function of the AP index after stabilization (APs of 2,437–2,480 are shown from a sequence of 2,500 APs, with RyR2 activation from an AP index of 0, corresponding to an AP of 2,440). The model was paced at a BCL of 260 ms under control conditions or with selective changes to RyR2 time constants (τ), RyR2 amplitude of SR Ca²⁺ release (Amp), or JSR Ca²⁺ leak.

Fig. 6.

Sensitivity analysis of the effects of altered RyR2 gating on alternans. Alternans amplitude is shown for different combinations of τ and Amp properties of RyR2, either with increased JSR leak (A) or without (B). Similarly, B and D show the integral of SR Ca²⁺ release over two consecutive APs with or without the presence of increased JSR leak, respectively.

Fig. 7.

Effects of β-AR stimulation on alternans in one-dimensional strand simulations. A: CaTs along a 256-cell strand at a BCL of 260 ms for the control model, model with increased I_Na, and model with increased I_Na and homogenous β-AR stimulation. B: CaT and APD alternans ratio along the strand for the three model versions. C: mechanism underlying the absence of alternans in the control model (solid line) compared with the model with increased I_Na (dashed line) and the abolishment of alternans by β-AR stimulation (dashed-dotted line) as evident from AP, CaT, I_CaL, and SR Ca²⁺ release flux. Note the smaller I_CaL under control conditions. Slightly different positions along the strand are shown for the three conditions to enhance the presentation.

Fig. 8.

Differences in β-adrenergic sensitivity between the NZ and BZ. APD (A) and CaT (B) alternans magnitude and fraction of phosphorylated RyR2 (C) versus ISO concentration are shown at a BCL of 260 ms for a NZ cell, BZ cell, and a BZ cell with desensitized β-AR (−25% expression). D and E: comparison of SR Ca²⁺ release flux at a BCL of 500 ms between the NZ and BZ in the absence (D) or presence (E) of β-adrenergic stimulation (10 nmol/l ISO).

Fig. A1.

Currents and sites affected by β-adrenergic stimulation are given in gray font. Components on the background of a gray ellipse and/or circle are remodeled under conditions representing the infarct border zone.

Fig. A2.

Comparison of the original and modified model of β-AR stimulation-dependent RyR2 regulation in a NZ cell, also showing traces from a NZ cell without β-AR stimulation. A, C, and E contain traces of membrane potential, free intracellular Ca²⁺, and Ca²⁺ release flux from the SR (having different x-axis) in a cell paced at a BCL of 260 ms. As the cell without β-AR stimulation manifests alternans, both alternating beats are shown. B, D, and F show the same variables but at a BCL of 400 ms, when no alternans is present.

Fig. A3.

Comparison of the original and modified model of β-AR stimulation-dependent RyR2 regulation in a BZ cell, also showing traces from a BZ cell without β-AR stimulation. A, C, and E contain traces of membrane potential, free intracellular Ca²⁺, and Ca²⁺ release flux from the SR (having different x-axis) in a cell paced at a BCL of 260 ms. As the cell without β-AR stimulation manifests alternans, both alternating AP phenotypes are shown. B, D, and F show the same variables but at a BCL of 400 ms.

Fig. A4.

SR Ca²⁺ release in the original versus RyR2-modified human ventricular cardiomyocyte model at a BCL of 260 ms (A) and 400 ms (B). In both cases, even and odd beats are shown to facilitate the evaluation of presence of alternans. C: minimum and maximum APD of both cell types at each tested BCL (with average shown with dashed line). Alternans with amplitude larger than 1 ms was present between BCLs of 230 and 280 ms in the original model only. In both models, a 2:1 block occurred at BCLs below 230 ms.