Complex Early and Delayed Afterdepolarization Dynamics caused by Voltage-Calcium Coupling in Cardiac Myocytes

Please cite this article in press as: Song et al., Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes, Bio- physical Journal (2015), http://dx.doi.org/10.1016/j.bpj.2015.03.011 Biophysical Journal Volume 108 April 2015 1–14 Article Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes Zhen Song, 1,2 Christopher Y. Ko, 1,2 Michael Nivala, 1,2 James N. Weiss, 1,2,3 and Zhilin Qu 1,2, * Cardiovascular Research Laboratory, 2 Department of Medicine (Cardiology), and 3 Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California ABSTRACT Early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) are voltage oscillations known to cause cardiac arrhythmias. EADs are mainly driven by voltage oscillations in the repolarizing phase of the action potential (AP), while DADs are driven by spontaneous calcium (Ca) release during diastole. Because voltage and Ca are bidirectionally coupled, they modulate each other’s behaviors, and new AP and Ca cycling dynamics can emerge from this coupling. In this study, we performed computer simulations using an AP model with detailed spatiotemporal Ca cycling incorporating stochastic openings of Ca channels and ryanodine receptors to investigate the effects of Ca-voltage coupling on EAD and DAD dynamics. Simulations were complemented by experiments in mouse ventricular myocytes. We show that: 1) alteration of the Ca transient due to increased ryanodine receptor leakiness and/or sarco/endoplasmic reticulum Ca ATPase activity can either promote or suppress EADs due to the complex effects of Ca on ionic current properties; 2) spontaneous Ca waves also exhibit complex effects on EADs, but cannot induce EADs of significant amplitude without the participation of I Ca,L ; 3) lengthening AP duration and the occurrence of EADs promote DADs by increasing intracellular Ca loading, and two mechanisms of DADs are identified, i.e., calcium-wave-dependent and a calcium-wave-independent; and 4) Ca-voltage coupling promotes complex EAD patterns such as EAD alternans that are not observed for solely voltage-driven EADs. In conclusion, Ca-voltage coupling combined with the nonlinear dynamical behaviors of voltage and Ca cycling play a key role in generating complex EAD and DAD dynamics observed experimentally in cardiac myocytes, whose mechanisms are complex but analyzable. INTRODUCTION Early afterdepolarizations (EADs) and delayed afterdepola- rizations (DADs) are known to cause arrhythmias in a vari- ety of cardiac diseases, including long QT syndromes (1–3), catecholaminergic polymorphic ventricular tachycardia (CPVT) (4,5), and heart failure (6,7). EADs are voltage oscillations that occur during the repolarizing phases of the action potential (AP). By prolonging the AP duration (APD) regionally, EADs can increase dispersion of refracto- riness, forming a tissue substrate vulnerable to reentry. Furthermore, if EADs reach the threshold to propagate out this region as premature ventricular contractions, they can serve as triggers to induce reentry. DADs, on the other hand, are voltage oscillations during diastole. By depolariz- ing the resting membrane potential regionally, DADs can cause conduction block (8), and, if they reach the threshold for sodium (Na) channel activation, can generate triggered activity (TA) manifesting as premature ventricular contrac- tions that induce reentry. EADs occur in the setting of reduced repolarization reserve, such as long QT syndromes, and have classically been attributed to voltage-driven oscillations in the repola- rizing phase of the AP, although spontaneous sarcoplasmic Submitted October 29, 2014, and accepted for publication March 10, 2015. *Correspondence: zqu@mednet.ucla.edu reticulum (SR) calcium (Ca) release has also been proposed as an important mechanism. DADs, on the other hand, are promoted by Ca cycling disorders, such as CPVT and digi- talis toxicity, which promote Ca-driven oscillations. Heart failure represents a combination of reduced repolarization reserve and abnormal Ca cycling resulting from electrical and excitation-contraction coupling remodeling processes driven by both genetic transcriptional and posttranslational signaling components. In all of these settings, it is common for EADs and DADs to coexist and influence each other. This is because membrane voltage is strongly affected by Ca-sensitive ionic currents, and, conversely, cellular Ca loading is strongly influenced by voltage-dependent ionic currents, referred to as bidirectional Ca-voltage coupling. Ca-voltage coupling can promote complex AP dynamics in the heart (9). Analyzing the interactions between EADs and DADs (and voltage and Ca-cycling coupling dynamics in general), however, has been challenging, because the Ca cycling dynamics (e.g., Ca waves and oscillations) result from a spatially distributed heterogeneous network of Ca release units (CRUs) in the cell. The Ca waves emanating from various subcellular regions integrate to depolarize dia- stolic membrane voltage by activating Ca-sensitive inward currents including the Na-Ca exchange (NCX) current (I NCX ) and Ca-activated nonselective cation channels (I ns(Ca) ), generating DADs. Similarly, spontaneous SR Ca Editor: Randall Rasmusson. O 2015 by the Biophysical Society http://dx.doi.org/10.1016/j.bpj.2015.03.011 BPJ 6468