Abstract
Background: Cardiac alternans is an important precursor to arrhythmia, facilitating formation of conduction block, and re-entry. Diseased hearts were observed to be particularly vulnerable to alternans, mainly in heart failure or after myocardial infarction. Alternans is typically linked to oscillation of calcium cycling, particularly in the sarcoplasmic reticulum (SR). While the role of SR calcium reuptake in alternans is well established, the role of altered calcium release by ryanodine receptors has not yet been studied extensively. At the same time, there is strong evidence that calcium release is abnormal in heart failure and other heart diseases, suggesting that these changes might play a pro-alternans role.Aims: To demonstrate how changes to intracellular calcium release dynamics and magnitude affect alternans vulnerability.Methods: We used the state-of-the-art Heijman–Rudy and O’Hara–Rudy computer models of ventricular myocyte, given their detailed representation of calcium handling and their previous utility in alternans research. We modified the models to obtain precise control over SR release dynamics and magnitude, allowing for the evaluation of these properties in alternans formation and suppression.Results: Shorter time to peak SR release and shorter release duration decrease alternans vulnerability by improved refilling of releasable calcium within junctional SR; conversely, slow release promotes alternans. Modulating the total amount of calcium released, we show that sufficiently increased calcium release may surprisingly prevent alternans via a mechanism linked to the functional depletion of junctional SR during release. We show that this mechanism underlies differences between “eye-type” and “fork-type” alternans, which were observed in human in vivo and in silico. We also provide a detailed explanation of alternans formation in the given computer models, termed “sarcoplasmic reticulum calcium cycling refractoriness.” The mechanism relies on the steep SR load–release relationship, combined with relatively limited rate of junctional SR refilling.Conclusion: Both altered dynamics and magnitude of SR calcium release modulate alternans vulnerability. In particular, slow dynamics of SR release, such as those observed in heart failure, promote alternans. Therefore, acceleration of intracellular calcium release, e.g., via synchronization of calcium sparks, may inhibit alternans in failing hearts and reduce arrhythmia occurrence.
Highlights
Repolarization alternans, the alternation of long and short action potential durations (APD), has been linked to the incidence of ventricular fibrillation and sudden cardiac death (Pastore et al, 1999; Wilson and Rosenbaum, 2007)
We focus at two features of sarcoplasmic reticulum (SR) release: the dynamics and magnitude, showing that both factors modulate alternans
We hypothesized that the rate of diffusion from network sarcoplasmic reticulum (NSR) to junctional sarcoplasmic reticulum (JSR) could be a key factor in alternans formation
Summary
Repolarization alternans, the alternation of long and short action potential durations (APD), has been linked to the incidence of ventricular fibrillation and sudden cardiac death (Pastore et al, 1999; Wilson and Rosenbaum, 2007). Multiple heart diseases are associated with an increased vulnerability to alternans, heart failure (Kodama et al, 2004; Wilson et al, 2009), as well as hypertrophic cardiomyopathy (Cannon et al, 1986), or myocardial infarction (Gardner et al, 2015). The precise mechanisms by which calcium release properties regulate alternans vulnerability in large mammalian hearts are not known. This may be important to better understand proarrhythmia mechanisms in diseased hearts with altered calcium release mechanisms. Diseased hearts were observed to be vulnerable to alternans, mainly in heart failure or after myocardial infarction. There is strong evidence that calcium release is abnormal in heart failure and other heart diseases, suggesting that these changes might play a pro-alternans role
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