Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics

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• 作者：Yann Prudat ; Roshni V. Madhvani ; Marina Angelini ; Nils P. Borgstom ; Alan Garfinkel ; Hrayr S. Karagueuzian ; James N. Weiss ; Enno de Lange ; Riccardo Olcese ; Jan P. Kucera
• 刊名：The Journal of Physiology
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：594
• 期：9
• 页码：2537-2553
• 全文大小：1.6MB
• ISSN：1469-7793

文摘

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 λ_alt that directly quantifies how an alternating perturbation persists over successive APs. When the propensity to alternans increases, λ_alt decreases from 0 to –1. Our aim was to quantify λ_alt experimentally using stochastic pacing and to examine whether stochastic pacing allows discriminating between voltage-driven and Ca²⁺-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 λ_alt along with additional markers characterizing whether the dependence of APD on previous DIs or CLs is strong (typical for voltage-driven alternans) or weak (Ca²⁺-driven alternans). During the recordings, λ_alt gradually decreased from around 0 towards –1. Intermittent alternans appeared when λ_alt reached –0.8 and was followed by sustained alternans. The additional markers detected that alternans was Ca²⁺ 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 > λ_alt > –0.5). These observations were confirmed in a mathematical model of a rabbit ventricular myocyte. In conclusion, stochastic pacing allows the practical estimation of λ_alt to reveal the onset of alternans and distinguishes between voltage-driven and Ca²⁺-driven mechanisms, which is important since these two mechanisms may precipitate arrhythmias in different manners.