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

Journal article

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/.

Authors: Tomek, J; Rodriguez, B; Bub, G; Heijman, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Physiological Society
• Journal: American Journal of Physiology - Heart and Circulatory Physiology
• Volume: 313
• Issue: 2
• Pages: H338-H353
• Publication date: 2017-08-01
• Acceptance date: 2017-05-23
• DOI: 10.1152/ajpheart.00094.2017
• EISSN: 1522-1539
• ISSN: 0363-6135
• Pmid: 28550171
• Language: English
• Keywords: Time Factors; Humans; Arrhythmias, Cardiac; Action Potentials; Ryanodine Receptor Calcium Release Channel; Myocytes, Cardiac; Computer Simulation; Autonomic Nervous System; Dogs; Ventricular Remodeling; Sarcoplasmic Reticulum; Myocardial Infarction; Animals; Heart; Calcium Signaling; Cell Communication; Adrenergic beta-Agonists; Models, Cardiovascular