Variability in Timing of Spontaneous Calcium Release in the Intact Rat Heart Is Determined by the Time Course of Sarcoplasmic Reticulum Calcium Load

Wasserstrom, J. Andrew; Shiferaw, Yohannes; Chen, Wei; Ramakrishna, S.; Patel, Heetabh; Kelly, James E.; O'Toole, Matthew J.; Pappas, Amanda; Chirayil, Nimi; Bassi, Nikhil; Akintilo, Lisa; Wu, Megan; Arora, Rishi; Aistrup, Gary L.

doi:10.1161/circresaha.110.229294

Cited by 72 publications

(124 citation statements)

References 34 publications

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“…It is widely accepted that DADs are mediated by Ca waves (47)(48)(49)(50), in which spontaneous SR Ca release from a group of adjacent CRUs recruits neighboring CRUs to initiate a propagating wave (51,52). On the other hand, the simulations in Fig.…”

Section: Mechanisms Of Dadsmentioning

confidence: 96%

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

Song

Nivala

et al. 2015

Biophysical Journal

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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., Ca-wave-dependent and Ca-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.

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Section: Mechanisms Of Dadsmentioning

confidence: 96%

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

Song

Nivala

et al. 2015

Biophysical Journal

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“…2, 3, and 4 are related to progressive intracellular Ca loading as the number of paced beats in the train increased (16,17). For example, it is apparent from the traces in Fig.…”

Section: Postpacing Intracellular Ca Loadmentioning

confidence: 99%

“…Because each ventricular myocyte is coupled through gap junctions to an average of 11 other myocytes (14), a single myocyte exhibiting a Ca wave will be voltage-clamped by neighboring quiescent myocytes, attenuating the DAD amplitude by more than an order of magnitude. Only when a large number of myocytes in a region of tissue all develop Ca waves quasi-synchronously within an overlapping time window can the source-sink mismatch be overcome to generate a DAD of appreciable magnitude in the tissue (11)(12)(13)15,16). Thus, after rapid pacing in cardiac tissue, the timing of Ca waves (i.e., the latency period, defined as the time interval between the last paced Ca transient and the onset of a spontaneous diastolic Ca wave) (16,17) in populations of adjacent myocytes plays a key role.…”

Section: Introductionmentioning

confidence: 99%

“…Only when a large number of myocytes in a region of tissue all develop Ca waves quasi-synchronously within an overlapping time window can the source-sink mismatch be overcome to generate a DAD of appreciable magnitude in the tissue (11)(12)(13)15,16). Thus, after rapid pacing in cardiac tissue, the timing of Ca waves (i.e., the latency period, defined as the time interval between the last paced Ca transient and the onset of a spontaneous diastolic Ca wave) (16,17) in populations of adjacent myocytes plays a key role. If the latency periods have a large variance, the Ca waves in the individual myocytes may not summate effectively to overcome the source-sink mismatch and generate a DAD of appreciable amplitude.…”

Section: Introductionmentioning

confidence: 99%

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Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

Liu

Song

et al. 2017

Biophysical Journal

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Spontaneous calcium (Ca) waves in cardiac myocytes underlie delayed afterdepolarizations (DADs) that trigger cardiac arrhythmias. How these subcellular/cellular events overcome source-sink factors in cardiac tissue to generate DADs of sufficient amplitude to trigger action potentials is not fully understood. Here, we evaluate quantitatively how factors at the subcellular scale (number of Ca wave initiation sites), cellular scale (sarcoplasmic reticulum (SR) Ca load), and tissue scale (synchrony of Ca release in populations of myocytes) determine DAD features in cardiac tissue using a combined experimental and computational modeling approach. Isolated patch-clamped rabbit ventricular myocytes loaded with Fluo-4 to image intracellular Ca were rapidly paced during exposure to elevated extracellular Ca (2.7 mmol/L) and isoproterenol (0.25 mmol/L) to induce diastolic Ca waves and subthreshold DADs. As the number of paced beats increased from 1 to 5, SR Ca content (assessed with caffeine pulses) increased, the number of Ca wave initiation sites increased, integrated Ca transients and DADs became larger and shorter in duration, and the latency period to the onset of Ca waves shortened with reduced variance. In silico analysis using a computer model of ventricular tissue incorporating these experimental measurements revealed that whereas all of these factors promoted larger DADs with higher probability of generating triggered activity, the latency period variance and SR Ca load had the greatest influences. Therefore, incorporating quantitative experimental data into tissue level simulations reveals that increased intracellular Ca promotes DAD-mediated triggered activity in tissue predominantly by increasing both the synchrony (decreasing latency variance) of Ca waves in nearby myocytes and SR Ca load, whereas the number of Ca wave initiation sites per myocyte is less important.

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“…The genesis of calcium waves responsible for triggered activity may therefore be spontaneous or induced (dependent on I CaL ). [26][27][28][29][30][31][32] On a cellular level, the prototypical forms of DAD-mediated triggered activity are those related to either inhibition of Na + /K + -ATPase (digitalis derivatives) or catecholaminecAMP stimulation. Although the common denominator for both mediators is intracellular calcium overload and an increased open probability of the SR, divergent paths lead to this outcome.…”

Section: Ventricular Tachycardia Triggered Activitymentioning

confidence: 99%

Ventricular Tachycardia

Lerman

2015

Circ: Arrhythmia and Electrophysiology

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A foundational concept in cardiac electrophysiology is that understanding the cellular mechanism of an arrhythmia provides essential insight for developing targeted therapeutic options. However, current clinical understanding of arrhythmogenic mechanisms other than re-entry is rudimentary, and the means by which to diagnose and differentiate these mechanisms are poorly defined. Grouping these mechanistic subtypes into broad and nonspecific categories, for example, non-re-entry or focal, further underscores our incomplete understanding of these arrhythmias. As the field of cardiac electrophysiology, like the rest of medicine, evolves toward the delivery of cell-based therapies, the need for a deeper understanding of clinical arrhythmia mechanisms and their arrhythmogenic cell lineages is apparent.One major difference between re-entrant and non-reentrant ventricular tachycardia (VT) is that the electrophysiological substrate for re-entry is acquired during postnatal development and is due to anatomic insult (eg, ischemic heart disease or viral myocarditis), whereas the substrate for triggered activity is likely often acquired during embryological development, occurring independent of anatomic injury or structural heart disease. 1,2 These dichotomous electrophysiological substrates, re-entry and non-re-entry, require tailored approaches to confirm diagnosis. In this review, we will elaborate on the development of a methodological approach for diagnosing non-re-entrant VT, which centers on the unique mechanism-specific properties of adenosine. This approach differs substantively from standard laboratory pacing methodologies used to validate the diagnosis of re-entrant arrhythmias and which are founded on the principles of entrainment. 3 AdenosineAdenosine is an endogenous nucleoside that exercises multiple regulatory functions that affect impulse generation and conduction, autonomic function, contractility, coronary vasodilation, and O 2 supply-demand balance. 4 Adenosine is rapidly inactivated as it is taken up by the cell through simple diffusion or a nucleoside transport system and is then deaminated to inosine or phosphorylated to adenosine monophosphate. 5 The plasma half-life of adenosine is <1.5 s. 6 Four-myocardial adenosine receptor subtypes mediate adenosine's effects. Receptors A 1 , A 2a , A 2b , and A 3 are structurally related G-protein-coupled receptors, consisting of 7 transmembrane helices. 7 A 1 and A 3 subtypes inhibit adenylyl cyclase, whereas A 2 subtypes activate it. In the heart, the A 1 R subtype has the highest level of expression and is the receptor that mediates adenosine's electrophysiolgic effects through its activation of heterotrimeric G proteins. 4 Drury and Szent-Gyorgyi 8 made the seminal observation in 1929 that adenosine had a negative chronotropic effect on the heart, causing profound slowing of the sinus rate in dogs. 8 Although research on the cardiac electrophysiological effects of adenosine followed in fits and starts over the next 50 years, the field took flight beginning in...

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Variability in Timing of Spontaneous Calcium Release in the Intact Rat Heart Is Determined by the Time Course of Sarcoplasmic Reticulum Calcium Load

Cited by 72 publications

References 34 publications

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

Ventricular Tachycardia

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