Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study

Abstract

Mechanical alternans in cardiac muscle is associated with intracellular Ca 2ϩ alternans. Mechanisms underlying intracellular Ca 2ϩ alternans are unclear. In previous experimental studies, we produced alternans of systolic Ca 2ϩ under voltage clamp, either by partially inhibiting the Ca 2ϩ release mechanism, or by applying small depolarizing pulses. In each case, alternans relied on propagating waves of Ca 2ϩ release. The aim of this study is to investigate by computer modeling how alternans of systolic Ca 2ϩ is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, with each element contains L-type Ca 2ϩ current, a subspace into which Ca release takes place, a cytoplasmic space, sarcoplasmic reticulum (SR) release channels [ryanodine receptor (RyR)], and uptake sites (SERCA). Interelement coupling is via Ca 2ϩ diffusion between neighboring subspaces via cytoplasmic spaces and network SR spaces. Small depolarizing pulses were simulated by step changes of cell membrane potential (20 mV) with random block of L-type channels. Partial inhibition of the release mechanism is mimicked by applying a reduction of RyR open probability in response to full stimulation by L-type channels. In both cases, systolic alternans follow, consistent with our experimental observations, being generated by propagating waves of Ca 2ϩ release and sustained through alternation of SR Ca 2ϩ content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca 2ϩ alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing. sarcoplasmic reticulum; computer modeling; diffusion; computer model UP TO 50% OF DEATHS SEEN IN heart failure are sudden and likely, therefore, to be due to cardiac arrhythmias. In heart failure, up to 40% of patients exhibit a phenomenon known as mechanical alternans (19), when the force of contraction of the heart alternates between strong and weak. A related phenomenon is microvolt T-wave alternans, detectable in the ECG (1) and considered to be especially arrhythmogenic. Many cardiac arrhythmias are thought to be due to irregularity of Ca 2ϩ handling (11,30,36) by the sarcoplasmic reticulum (SR), the main source of Ca 2ϩ for cardiac contraction. Systolic Ca 2ϩ release occurs via Ca 2ϩ -induced Ca 2ϩ release (CICR), triggered by Ca 2ϩ entry on L-type Ca 2ϩ channels (3). In mechanical alternans, large and small contractions follow each other (10,13,27) due to alternation of systolic Ca 2ϩ (21,40). In isolated cardiac cells, alternans of systolic Ca 2ϩ is associated with alternans of cell shortening (16). Systolic Ca alternans are also associated with alternans of action potential duration (6,22,31) and alternans of the T-wave of the ECG (31).Changes in amplitude and timing of Ca release during systole can influence the action potential shape by acting on Ca-sensitive currents, e.g., Na/Ca exchange (NCX) causing ECG abnormalities and the arrhythmogenicity of systolic Ca alternans.Previous work in our laborat...

Nonlinear onset of calcium wave propagation in cardiac cells

“…In particular, we showed that when the system is paced close to the Ca wave onset then the beat-to-beat response of the system displays Ca transient alternans. This finding is consistent with experimental and theoretical studies [19,21,22] showing that large amplitude alternans of the Ca transient during alternans corresponds to a release sequence where Ca waves are observed on the large beat, but not on the small. This nonlinear response is due to the steep release load relationship that is observed near the wave onset transition.…”

“…Fluorescence imaging under these conditions demonstrated that waves propagate only on alternate beats, indicating that wave propagation played a key role in the instability to alternans. Using a computational model Tao et al [21] showed that indeed Ca alternans can be caused by wave propagation which occurred at alternate beats. In a later study Li et al [22] showed that spatial heterogeneity of the Ca signaling system made atrial cells more prone to Ca waves, which led to a steep SR load dependence of release which caused alternans.…”

Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models

“…The mechanisms of Ca i -driven alternans have been analyzed in many previous studies (11,37,44,46). The exact dynamical mechanism by which fibroblast-myocyte coupling promoting Ca i alternans is not completely clear, but the early I to -like phase of I gap appears to play a key role, since increasing I to in the rabbit ventricular model had the same dynamical effects (Fig.…”

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

“…This mechanism requires that Ca DSRL alternate concomitantly with SR Ca release, but the refractoriness of SR Ca release is not explicitly required. Subsequent mathematical analyses and simulation studies either potentiated this theory (30,45,57,64,69,71) (41), and the importance of refractoriness in Ca alternans has been demonstrated in later studies (32,58). Therefore, the above experimental studies raise the issue of the roles of SR Ca and refractoriness of SR Ca release in the genesis of Ca alternans.…”

“…This mechanism requires that Ca DSRL alternate concomitantly with SR Ca release, but the refractoriness of SR Ca release is not explicitly required. Subsequent mathematical analyses and simulation studies either potentiated this theory (30,45,57,64,69,71) or used it to study subcellular Ca alternans dynamics (21,56). On the other hand, experimental studies in rabbit ventricular myocytes by Picht et al (41) and in cat atrial myocytes by Huser et al (25) showed that Ca alternans can occur without Ca DSRL alternans.…”