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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 Ca(2+) 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 Ca(2+) 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) Ca(2+) load] modulation of SR Ca(2+) release as critical determinants of Ca(2+) 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 Ca(2+) 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 Ca(2+) 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/.

Original publication

DOI

10.1152/ajpheart.00094.2017

Type

Journal article

Journal

Am J Physiol Heart Circ Physiol

Publication Date

01/08/2017

Volume

313

Pages

H338 - H353

Keywords

alternans, border zone, calcium, computational modeling, myocardial infarction, β-adrenergic receptor stimulation, Action Potentials, Adrenergic beta-Agonists, Animals, Arrhythmias, Cardiac, Autonomic Nervous System, Calcium Signaling, Cell Communication, Computer Simulation, Dogs, Heart, Humans, Models, Cardiovascular, Myocardial Infarction, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Time Factors, Ventricular Remodeling