Date Published: August 1, 2017
Publisher: American Physiological Society
Author(s): Jakub Tomek, Blanca Rodriguez, Gil Bub, Jordi Heijman.
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.
We used computational modeling to provide insights into the modulation of repolarization and CaT alternans by β-AR stimulation. We found that β-AR stimulation abolishes both forms of alternans in NZ as well as BZ models, representing the surviving myocardium surrounding an infarct with increased susceptibility to alternans. Repolarization alternans was primarily driven by beat-to-beat fluctuations in Ca2+ cycling. Both direct modulation of RyR2 properties by β-AR stimulation as well as indirect modulation of SR Ca2+ release through the effects of other β-AR targets can abolish CaT alternans and thereby repolarization alternans. Although cell-to-cell coupling influenced the occurrence of alternans, β-AR stimulation was able to inhibit alternans formation both in single cell and multicellular simulations. Together, these findings suggest that BZ hyperinnervation may antagonize the development of proarrhythmic repolarization alternans.
B. Rodriguez was supported by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (100246/Z/12/Z), the British Heart Foundation Centre of Research Excellence in Oxford (RE/13/1/30181), an NC3R Infrastructure for Impact award (NC/P001076/1), an Engineering and Physical Sciences Research Council Impact Acceleration Award (EP/K503769/1), and the ComBioMed project funded by the European Union’s Horizon 2020 research and innovation program (Grant Agreement 675451). J. Heijman was supported by the Netherlands Organization for Scientific Research (NWO/ZonMW Veni 91616057).
No conflicts of interest, financial or otherwise, are declared by the author(s).
J.T., B.R., G.B., and J.H. conceived and designed research; J.T. and J.H. performed experiments; J.T., B.R., G.B., and J.H. analyzed data; J.T., B.R., G.B., and J.H. interpreted results of experiments; J.T. and J.H. prepared figures; J.T. and J.H. drafted manuscript; J.T., B.R., G.B., and J.H. edited and revised manuscript; J.T., B.R., G.B., and J.H. approved final version of manuscript.