scholarly journals Spontaneous calcium release in tissue from the failing canine heart

2009 ◽  
Vol 297 (4) ◽  
pp. H1235-H1242 ◽  
Author(s):  
Gregory S. Hoeker ◽  
Rodolphe P. Katra ◽  
Lance D. Wilson ◽  
Bradley N. Plummer ◽  
Kenneth R. Laurita
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Tissue Level ◽  
Calcium Handling ◽  
Canine Heart ◽  
Myocardial Cells ◽  
Spontaneous Release ◽  
Adrenergic Stimulation ◽  
Electrical Instability ◽  
Delayed Afterdepolarization

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during β-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.

Ryanodine receptor dysfunction and triggered activity in the heart

2007 ◽  
Vol 292 (5) ◽  
pp. H2144-H2151 ◽  
Author(s):  
Rodolphe P. Katra ◽  
Toshiyuki Oya ◽  
Gregory S. Hoeker ◽  
Kenneth R. Laurita
Keyword(s):  
Ryanodine Receptor ◽  
Transmembrane Potential ◽  
Calcium Release ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Adrenergic Stimulation ◽  
Triggered Activity ◽  
Multiple Regions ◽  
Rapid Pacing ◽  
Almost All

Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation ( n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and β-adrenergic stimulation (20–150 μM rapamycin, 0.2 μM isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium ( P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.

scholarly journals Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation

2013 ◽  
Vol 112 (2) ◽  
pp. 246-256 ◽  
Author(s):  
Daniel M. Johnson ◽  
Jordi Heijman ◽  
Elizabeth F. Bode ◽  
David J. Greensmith ◽  
Henk van der Linde ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Ventricular Myocytes ◽  
Adrenergic Stimulation

scholarly journals Arrhythmia Mechanisms and Spontaneous Calcium Release: I - Multi-scale Modelling Approaches

2018 ◽  
Author(s):  
Michael A. Colman
Keyword(s):  
Single Cell ◽  
Calcium Release ◽  
Cell Model ◽  
Single Cells ◽  
Computational Modelling ◽  
Calcium Handling ◽  
Spontaneous Release ◽  
Multi Scale ◽  
Cellular Models ◽  
Tissue Models

AbstractMotivationSpontaneous sub-cellular calcium release events (SCRE), controlled by microscopic stochastic fluctuations of the proteins responsible for intracellular calcium release, are conjectured to promote the initiation and perpetuation of rapid arrhythmia associated with conditions such as heart failure and atrial fibrillation: SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. However, translation of single-cell data to the tissue scale is non-trivial due to complex substrate considerations. Computational modelling provides a viable approach to dissect these multi-scale mechanisms, yet there remains a significant challenge in accurately and efficiently modelling this probabilistic behaviour in large-scale tissue models. The aim of this study was to develop an approach to overcome this challenge.MethodsThe dynamics of SCRE under multiple conditions (pacing rate, beta-stimulation, disease remodelling) in a computational model of stochastic, spatio-temporal calcium handling were analysed in order to develop Spontaneous Release Functions, which capture the variability and properties of SCRE matched to the full cell model. These functions were then integrated with tissue models, comprising idealised 2D sheets as well as full reconstructions of ventricular and atrial anatomy.ResultsThe Spontaneous Release Functions accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions observed in the full single-cell model. Differences between cellular models and conditions where enhanced at the tissue scale, where the emergence of a focal excitation is largely an all-or-nothing response. Generalisation of the approaches was demonstrated through integration with an independent cell model, and parameterisation to an experimental dataset.ConclusionsA novel approach has been developed to dynamically model SCRE at the tissue scale, in-line with behaviour observed in detailed single-cell models. Such an approach allows evaluation of the potential importance of SCRE in arrhythmia in both general mechanistic and disease-specific investigation.

scholarly journals Studying dyadic structure–function relationships: a review of current modeling approaches and new insights into Ca2+ (mis)handling

2017 ◽  
Vol 11 ◽  
pp. 117954681769860 ◽  
Author(s):  
Mary M Maleckar ◽  
Andrew G Edwards ◽  
William E Louch ◽  
Glenn T Lines
Keyword(s):  
Heart Disease ◽  
Sarcoplasmic Reticulum ◽  
Structure Function ◽  
Cardiac Myocytes ◽  
Calcium Release ◽  
Calcium Handling ◽  
Protein Distribution ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Calcium Dependent

Excitation–contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation–contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells’ calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation–contraction coupling have been increasingly employed to probe these structure–function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.

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