In the RyR2
            <sup>R4496C</sup>
            Mouse Model of CPVT, β-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves

Kashimura, Takeshi; Briston, Sarah J.; Trafford, Andrew W.; Napolitano, Carlo; Priori, Silvia G.; Eisner, David; Venetucci, Luigi

doi:10.1161/circresaha.110.227744

Cited by 97 publications

(87 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimentally, electrophysiological mechanisms of arrhythmogenesis in CPVT have been well elucidated over the past several years (2,3,10,12,16,22). Relevant to our modeling study, Cerrone et al (2) showed that RyR2…”

Section: Discussionsupporting

confidence: 61%

“…Using the technique of optical imaging, Fernandez-Velasco et al (10) showed an increase in Ca 2ϩ sensitivity of RyR2 along with a lowered SOICR threshold in the cardiac myocyte isolated from the RyR2 R4496Cϩ/Ϫ knock-in mouse. Similarly, Kashimura et al (16) confirmed that the RyR2 R4496Cϩ/Ϫ cell had lower SR Ca 2ϩ content and a lower SOICR threshold compared with the RyR2wt counterpart and that BAS-induced increase in SR Ca 2ϩ was sufficient to attain the SOICR threshold resulting in the production of Ca 2ϩ waves in the RyR2 R4496Cϩ/Ϫ but not in the RyR2wt cell. Results of our study are in agreement with observations made in these experimental studies.…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Sung

Hsiao

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Sung RJ, Lo CP, Hsiao PY, Tien HC. Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation. Am J Physiol Heart Circ Physiol 301: H1625-H1638, 2011. First published July 8, 2011 doi:10.1152/ajpheart.00696.2010.-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of ␤-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca 2ϩ channel (ICa,L) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2 R4496Cϩ/Ϫ ) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at Ն0.1 M could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2R4496Cϩ/Ϫ but not in the wildtype via enhancing both I Ca,L and sarcoplasmic reticulum (SR) Ca 2ϩ ATPase (IUP). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient (D) of Յ0.000766*98 cm 2 /ms was required for generating DAD-mediated TA in RyR2R4496Cϩ/Ϫ . Whereas individual reduction of Ca 2ϩ release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either I Ca,L or IUP could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both I Ca,L and IUP exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca 2ϩ cycling and a pharmacological regimen capable of reducing I Ca,L could be an effective adjunctive to ␤-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT. computational modeling; delayed afterdepolarizations; store-overload-induced Ca 2ϩ release; triggered activity CATECHOLAMINERGIC POLYMORPHIC ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by episodic syncope occurring during physical activity or acute emotional distress in individuals without structural heart disease and ECG abnormalities (21, 23). Characteristically, episodes of syncope are usually related to the occurrence of bidirectional or polymorphic ventricular tachycardia that might degenerate into ventricular fibrillation. In ϳ60% of CPVT patients, molecular genetic studies have unfolded that mutations are m...

show abstract

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 81%

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Sung

Hsiao

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Both fast pacing and β-adrenergic stimulation, which potentiates both LCC and the SR Ca 2+ -ATPase (SERCA), tend to increase SR load. Increased SR load together with RyR hyperactivity can then jointly promote the initiation and propagation of intracellular Ca 2+ waves that are the hallmark of SCR (18,19). Beyond this pictorial level, TA remains poorly understood.…”

mentioning

confidence: 99%

Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes

Song

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cardiac myocytes normally initiate action potentials in response to a current stimulus that depolarizes the membrane above an excitation threshold. Aberrant excitation can also occur due to spontaneous calcium (Ca 2+ ) release (SCR) from intracellular stores after the end of a preceding action potential. SCR drives the Na + /Ca 2+ exchange current inducing a "delayed afterdepolarization" that can in turn trigger an action potential if the excitation threshold is reached. This "triggered activity" is known to cause arrhythmias, but how it is initiated and terminated is not understood. Using computer simulations of a ventricular myocyte model, we show that initiation and termination are inherently random events. We determine the probability of those events from statistical measurements of the number of beats before initiation and before termination, respectively, which follow geometric distributions. Moreover, we elucidate the origin of randomness by a statistical analysis of SCR events, which do not follow a Poisson process observed in other eukaryotic cells. Due to synchronization of Ca 2+ releases during the action potential upstroke, waiting times of SCR events after the upstroke are narrowly distributed, whereas SCR amplitudes follow a broad normal distribution with a width determined by fluctuations in the number of independent Ca 2+ wave foci. This distribution enables us to compute the probabilities of initiation and termination of bursts of triggered activity that are maintained by a positive feedback between the action potential upstroke and SCR. Our results establish a theoretical framework for interpreting complex and varied manifestations of triggered activity relevant to cardiac arrhythmias.calcium wave | delayed afterdepolarization | triggered activity | bistability | arrhythmias V entricular arrhythmias, the leading cause of sudden death (1), tend to occur unexpectedly. Understanding their initiation mechanisms remains a major challenge for clinical cardiologists (2). Lethal arrhythmias can occur without any abnormal sign in the ECG, or can be preceded by multiple premature ventricular complexes (PVCs) or short runs of ventricular tachycardia (3). There are many possible sources of randomness that can be responsible for the seemingly unpredictable nature of arrhythmias, such as environmental stresses via neural or metabolic regulations, chaotic dynamics (4, 5), or fluctuations associated with the intrinsic stochasticity of ion channel kinetics (6, 7).During normal contraction, calcium (Ca 2+ ) release from the sarcoplasmic reticulum (SR)-the intracellular Ca 2+ store of a ventricular myocyte-is triggered by Ca 2+ entry into the cell via L-type calcium channels (LCCs), a mechanism known as Ca 2+ -induced Ca 2+ -release (CICR). However, SR Ca 2+ release can also occur spontaneously, as observed in a variety of pathological conditions ranging from heart failure (8, 9) to ischemia (10) to catecholaminergic polymorphic ventricular tachycardia (11)(12)(13)(14). Spontaneous Ca 2+ release (SCR) transi...

show abstract

“…1) [22,46], it seems likely that SERCA activity is reduced to a degree that the resulting slowing of the Ca 2+ uptake into the SR is fully compensated for by Ca 2+ transport via the Na + -Ca 2+ exchanger. Taken together, the data currently available indicate that the reduction in SR Ca 2+ load is predominantly a consequence of a moderately decreased SERCA activity, possibly mediated by reduced PLB phosphorylation and potentially in combination with a reduced set point of SR Ca 2+ content [24] or an increased nonspark diastolic Ca 2+ release [39]. (Fig.…”

Section: Discussionmentioning

confidence: 85%

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Biermann¹,

Bernhardt²,

Neef³

et al. 2014

Thorac cardiovasc Surg

View full text Add to dashboard Cite

Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca 2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca 2+ transients, we investigated Ca 2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca 2+ content was reduced by~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca 2+ sparks and a diminished systolic Ca 2+ release, even though the expression of ryanodine receptors was increased by~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca 2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type

show abstract

In the RyR2 ^R4496C Mouse Model of CPVT, β-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves

Abstract: Conclusions:In the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. ␤-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.

Cited by 97 publications

References 52 publications

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Contact Info

Product

Resources

About

In the RyR2 R4496C Mouse Model of CPVT, β-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves

Abstract: Conclusions:In the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. ␤-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.

Cited by 97 publications

References 52 publications

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Contact Info

Product

Resources

About

In the RyR2 ^R4496C Mouse Model of CPVT, β-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves