Non-Linear Dynamics of Cardiac Alternans: Subcellular to Tissue-Level Mechanisms of Arrhythmia
Keyword
T-wave alternanscalcium handling
cardiac alternans
pattern formation
repolarization alternans
subcellular alternans
Journal title
Frontiers in PhysiologyDate Published
2012Publication Volume
3Metadata
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Cardiac repolarization alternans is a rhythm disturbance of the heart in which rapid stimulation elicits a beat-to-beat alternation in the duration of action potentials and magnitude of intracellular calcium transients in individual cardiac myocytes. Although this phenomenon has been identified as a potential precursor to dangerous reentrant arrhythmias and sudden cardiac death, significant uncertainty remains regarding its mechanism and no clinically practical means of halting its occurrence or progression currently exists. Cardiac alternans has well-characterized tissue, cellular, and subcellular manifestations, the mechanisms and interplay of which are an active area of research.Citation
Gaeta SA, Christini DJ. Non-linear dynamics of cardiac alternans: subcellular to tissue-level mechanisms of arrhythmia. Front Physiol. 2012 May 31;3:157. doi: 10.3389/fphys.2012.00157. PMID: 22783195; PMCID: PMC3389489.DOI
10.3389/fphys.2012.00157Scopus Count
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Dynamical Mechanism for Subcellular Alternans in Cardiac MyocytesRationale: Cardiac repolarization alternans is an arrhythmogenic rhythm disturbance, manifested in individual myocytes as a beat-to-beat alternation of action potential durations and intracellular calcium transient magnitudes. Recent experimental studies have reported "subcellular alternans," in which distinct regions of an individual cell are seen to have counterphase calcium alternations, but the mechanism by which this occurs is not well understood. Although previous theoretical work has proposed a possible dynamical mechanism for subcellular alternans formation, no direct evidence for this mechanism has been reported in vitro. Rather, experimental studies have generally invoked fixed subcellular heterogeneities in calcium-cycling characteristics as the mechanism of subcellular alternans formation. Objective: In this study, we have generalized the previously proposed dynamical mechanism to predict a simple pacing algorithm by which subcellular alternans can be induced in isolated cardiac myocytes in the presence or absence of fixed subcellular heterogeneity. We aimed to verify this hypothesis using computational modeling and to confirm it experimentally in isolated cardiac myocytes. Furthermore, we hypothesized that this dynamical mechanism may account for previous reports of subcellular alternans seen in statically paced, intact tissue. Methods and results: Using a physiologically realistic computational model of a cardiac myocyte, we show that our predicted pacing algorithm induces subcellular alternans in a manner consistent with theoretical predictions. We then use a combination of real-time electrophysiology and fluorescent calcium imaging to implement this protocol experimentally and show that it robustly induces subcellular alternans in isolated guinea pig ventricular myocytes. Finally, we use computational modeling to demonstrate that subcellular alternans can indeed be dynamically induced during static pacing of 1D fibers of myocytes during tissue-level spatially discordant alternans. Conclusion: Here we provide the first direct experimental evidence that subcellular alternans can be dynamically induced in cardiac myocytes. This proposed mechanism may contribute to subcellular alternans formation in the intact heart.
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A Class of Monte-Carlo-Based Statistical Algorithms for Efficient Detection of Repolarization AlternansCardiac repolarization alternans is an electrophysiologic condition identified by a beat-to-beat fluctuation in action potential waveform. It has been mechanistically linked to instances of T-wave alternans, a clinically defined ECG alternation in T-wave morphology, and associated with the onset of cardiac reentry and sudden cardiac death. Many alternans detection algorithms have been proposed in the past, but the majority have been designed specifically for use with T-wave alternans. Action potential duration (APD) signals obtained from experiments (especially those derived from optical mapping) possess unique characteristics, which requires the development and use of a more appropriate alternans detection method. In this paper, we present a new class of algorithms, based on the Monte Carlo method, for the detection and quantitative measurement of alternans. Specifically, we derive a set of algorithms (one an analytical and more efficient version of the other) and compare its performance with the standard spectral method and the generalized likelihood ratio test algorithm using synthetic APD sequences and optical mapping data obtained from an alternans control experiment. We demonstrate the benefits of the new algorithm in the presence of Gaussian and Laplacian noise and frame-shift errors. The proposed algorithms are well suited for experimental applications, and furthermore, have low complexity and are implementable using fixed-point arithmetic, enabling potential use with implantable cardiac devices.
