title: Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics.
abstract: Beat-to-beat alternation (alternans) of the cardiac action potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes. To prevent alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of alternans. Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically. We also show that stochastic pacing permits the estimation of further markers distinguishing between voltage-driven and calcium-driven alternans. Our study opens the perspective to use stochastic pacing during clinical investigations and in patients with implanted pacing devices to determine the susceptibility to, and the type of alternans, which are both important to guide preventive or therapeutic measures.
  
  
  
  Alternans of the cardiac action potential (AP) duration (APD) is a well-known arrhythmogenic mechanism. APD depends on several preceding diastolic intervals (DIs) and APDs, which complicates the prediction of alternans. Previous theoretical studies pinpointed a marker called λalt that directly quantifies how an alternating perturbation persists over successive APs. When the propensity to alternans increases, λalt decreases from 0 to -1. Our aim was to quantify λalt experimentally using stochastic pacing and to examine whether stochastic pacing allows discriminating between voltage-driven and Ca(2+) -driven alternans. APs were recorded in rabbit ventricular myocytes paced at cycle lengths (CLs) decreasing progressively and incorporating stochastic variations. Fitting APD with a function of two previous APDs and CLs permitted us to estimate λalt along with additional markers characterizing whether the dependence of APD on previous DIs or CLs is strong (typical for voltage-driven alternans) or weak (Ca(2+) -driven alternans). During the recordings, λalt gradually decreased from around 0 towards -1. Intermittent alternans appeared when λalt reached -0.8 and was followed by sustained alternans. The additional markers detected that alternans was Ca(2+) driven in control experiments and voltage driven in the presence of ryanodine. This distinction could be made even before alternans was manifest (specificity/sensitivity >80% for -0.4 > λalt  > -0.5). These observations were confirmed in a mathematical model of a rabbit ventricular myocyte. In conclusion, stochastic pacing allows the practical estimation of λalt to reveal the onset of alternans and distinguishes between voltage-driven and Ca(2+) -driven mechanisms, which is important since these two mechanisms may precipitate arrhythmias in different manners.
authors.affiliation: Department of Physiology, University of Bern, Bern, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Prudat
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Roshni V
authors.initials: RV
authors.lastname: Madhvani
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Angelini
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: Nils P
authors.initials: NP
authors.lastname: Borgstom
authors.affiliation: Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
authors.affiliation: Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
authors.affiliation: Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.
authors.forename: Enno
authors.initials: E
authors.lastname: de Lange
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Olcese
authors.affiliation: Department of Physiology, University of Bern, Bern, Switzerland.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kucera
mesh_terms: D000200:Action Potentials; D000818:Animals; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000502:physiology*; D011817:Rabbits