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

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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