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/.
Highlights
NEW & NOTEWORTHY We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of -adrenergic stimulation in ventricular cardiomyocytes
Increasing the Naϩ current amplitude by 25% resulted in robust Ca2ϩ transient (CaT) and APD alternans throughout the strand, which could be inhibited by simulated -AR stimulation (Fig. 7, A and B)
We found that -AR stimulation abolishes both forms of alternans in normal zone (NZ) as well as border zone (BZ) models, representing the surviving myocardium surrounding an infarct with increased susceptibility to alternans
Summary
That lack of reinnervation after MI predicts future occurrence of SCD [2, 13]. -AR agonists have been used to suppress repolarization alternans in some studies [14, 18, 26, 56] but increased alternans in others [36]. We used the canine cardiomyocyte model by Heijman et al [19], including the downstream effects of -AR stimulation by arbitrary concentrations of the -AR agonist isoproterenol (ISO) on L-type Ca2ϩ current (ICaL), phospholamban (PLB), slowly activating delayed rectifier Kϩ current (IKs), RyR2, troponin I (TnI), fast Naϩ current (INa), Naϩ-Kϩ pump current (INaK), and ultrarapid plateau Kϩ current (IKur). A diagram of the model is provided in APPENDIX A. The model can reproduce, among other things, ISO-dependent changes in cAMP levels, target phosphorylation, and electrophysiological properties, including action potential (AP) duration (APD) and CaT amplitude. The number of parameter differences between phosphorylated and nonphosphorylated formulations has been reduced from four to three (activation constant, increased SR Ca2ϩ leak, and maximum release current multiplier); full details and motivation are provided in APPENDIX B
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