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

Jakub Tomek*, Blanca Rodriguez, Gil Bub, Jordi Heijman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Web of Science)

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 beta-adrenergic receptor (beta-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. beta-AR stimulation abolished alternans. By evaluating all combinations of downstream beta-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, beta-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 beta-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that beta-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-borderzone- cardiomyocytes/.

Original languageEnglish
Pages (from-to)H338-H353
Number of pages16
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume313
Issue number2
DOIs
Publication statusPublished - Aug 2017

Keywords

  • alternans
  • beta-adrenergic receptor stimulation
  • border zone
  • myocardial infarction
  • calcium
  • computational modeling
  • SUDDEN CARDIAC DEATH
  • T-WAVE ALTERNANS
  • SARCOPLASMIC-RETICULUM CA2+
  • ACUTE MYOCARDIAL-INFARCTION
  • VENTRICULAR-FIBRILLATION
  • SYMPATHETIC INNERVATION
  • ELECTRICAL ALTERNANS
  • HEART-FAILURE
  • ADRENOCEPTOR STIMULATION
  • CALCIUM ALTERNANS

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