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...

Hypertension is associated with sympathetic hyperactivity. To represent this neural-myocyte coupling, and to elucidate the mechanisms underlying sympathetic control of the cardiac pacemaker, we developed a new (to our knowledge) cellular mathematical model that incorporates signaling information from cell-to-cell communications between the sympathetic varicosity and sinoatrial node (SAN) in both normotensive (WKY) and hypertensive (SHR) rats. Features of the model include 1), a description of pacemaker activity with specific ion-channel functions and Ca(2+) handling elements; 2), dynamic β-adrenergic modulation of the excitation of the SAN; 3), representation of ionic activity of sympathetic varicosity with NE release dynamics; and 4), coupling of the varicosity model to the SAN model to simulate presynaptic transmitter release driving postsynaptic excitability. This framework captures neural-myocyte coupling and the modulation of pacemaking by nitric oxide and cyclic GMP. It also reproduces the chronotropic response to brief sympathetic stimulations. Finally, the SHR model quantitatively suggests that the impairment of cyclic GMP regulation at both sides of the sympathetic cleft is crucial for development of the autonomic phenotype observed in hypertension.

Mechanical contraction alternans of the heart is associated with fatal cardiac death. It is manifested by Twave alternans in the ECG, and is thought to be possibly related to intracellular Ca 2+ transient alternans released from the sarcoplasmic reticulum (SR). However, it is unclear yet how beat-to-beat alternans of intracellular Ca 2+ transient is produced. In this study investigated the mechanism(s) underlying the genesis of intracellular Ca 2+ alternans produced at slow pacing rates by using a mathematical model of a spatially extended cardiac cell with a cluster of coupled ryanodine receptor (RyR) elements. It was shown that the intracellular Ca 2+ alternans was generated by propagating waves of Ca 2+ release and sustained through alternation of SR Ca 2+ content that has a stiff relationship with the Ca 2+ transient. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca 2+ alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.