Background Low and high dialysate calcium (Ca 2+ ) content may have positive and harmful effects depending on the considered pathological aspect: hemodynamic instability, cardiac arrhythmias, parathormone release, adynamic bone disease, cardio-vascular calcifications. We hypothesized that a time-profiled Ca 2+ concentration would keep the cardiovascular advantages of high Ca 2+ but would reduce the risk of calcium overload. Methods A prospective, multicenter study using a particular hemodiafiltration technique that allows the profiling of electrolytes was designed. Patients (n = 22) underwent randomly a 3-week dialysis session with low and high constant dialysate Ca 2+ (Ld Ca , 1.25 mM and Hd Ca , 2 mM) and profiled Ca 2+ (Pd Ca ), respectively. Plasma and spent dialysate Ca 2+ , systolic and diastolic arterial pressure (SAP, DAP) and QT interval corrected for heart rate (QTc) were analyzed. Results Plasma Ca 2+ concentration decreased in Ld Ca , whereas it increased in Hd Ca and to a lesser extent, in Pd Ca . Total amount of Ca 2+ given to the patient in Pd Ca (15.5 ± 1.0 mmol) was higher than in Ld Ca (4.3 ± 1.6 mmol) but lower than in Hd Ca (21.9 ± 3.3 mmol). SAP and DAP decreased in Ld Ca , whereas it was almost constant in both Hd Ca and Pd Ca . QTc significantly increased, up to critical values (>460 msec), only during Ld Ca . Conclusions Pd Ca seems to retain the advantages of high Ca 2+ in terms of hemodynamic stability and modification of QTc while reducing the excessive positive calcium balance typical of dialysis with high Ca 2+ content.

Sarcoplasmic reticulum (SR) Ca2+ release mediates excitationcontraction coupling (ECC) in cardiac myocytes. It is triggered upon membrane depolarization by entry of Ca2+ via L-type Ca2+ channels (LTCCs), which undergo both voltage- and Ca2+-dependent inactivation (VDI and CDI, respectively). We developed improved models of L-type Ca2+ current and SR Ca2+ release within the framework of the ShannonBers rabbit ventricular action potential (AP) model. The formulation of SR Ca2+ release was modified to reproduce high ECC gain at negative membrane voltages. An existing LTCC model was extended to reflect more faithfully contributions of CDI and VDI to total inactivation. Ba2+ current inactivation included an ion-dependent component (albeit small compared with CDI), in addition to pure VDI. Under physiological conditions (during an AP) LTCC inactivates predominantly via CDI, which is controlled mostly by SR Ca2+ release during the initial AP phase, but by Ca2+ through LTCCs for the remaining part. Simulations of decreased CDI or K+ channel block predicted the occurrence of early and delayed afterdepolarizations. Our model accurately describes ECC and allows dissection of the relative contributions of different Ca2+ sources to total CDI, and the relative roles of CDI and VDI, during normal and abnormal repolarization.

The L-type Ca2+ current (ICa) contributes to the action potential plateau and initiates excitation-contraction coupling in cardiac myocytes. Here we present a kinetic model of L-type Ca2+ channels (LTCCs), based on the Mahajan et al. 7-state Markov model, incorporated into the Shannon et al. model of the rabbit ventricular myocyte, which includes a subcellular restricted space where Ca2+-induced Ca2+ release occurs. LTCC inactivation is both voltage- and Ca2+-dependent (VDI and CDI), the latter being due to Ca2+ binding to calmodulin that is pre-bound to the LTCC.

Aims The Na(+) channel mutation (p.S216L), previously associated with type 3 long-QT syndrome (LQT3) phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada syndrome (BS) ECG pattern. The study was aimed to assess the p.S216L electrical phenotype, its modulation by p.H558R, and to identify abnormalities compatible with a mixed BS-LQT3 phenotype.Methods and results The mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216L-H558R channels), in a mammalian cell line (TSA201). Functional analysis included standard voltage clamp and dynamic clamp with endo-and epicardial action potential waveforms. Expression of S216L channels was associated with a 60% reduction in maximum Na(+) current (I(Na)) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. I(Na) density partially recovered in S216L-H558R channels, but I(Na) inactivation and its recovery were further delayed. The persistent component of I(Na) (I(NaL)) was unchanged. Under dynamic clamp conditions, I(Na) decreased in S216L channels and displayed a 'resurgent' component during late repolarization. In S216L-H558R channels, I(Na) density partially recovered and did not display a resurgent component. I(Na) changes during dynamic clamp were interpreted by numerical modelling.Conclusion The BS pattern of p.S216L might result from a decrease in I(Na) density, which masked gating abnormalities that might otherwise result in a LQT phenotype. The p.H558R polymorphism decreased p.S216L expressivity, partly by lessening p.S216L effects and partly through the induction of further gating abnormalities suitable to blunt p.S216L effects during repolarization.

The substitution of Ba ions for Ca has been widely used to separate voltage-dependent inactivation (VDI) from Ca-dependent inactivation (CDI) of the Ca current (ICa) through L-type Ca channels (LTCCs). However, a modest ion-dependent inactivation of Ba current (IBa) has been shown experimentally. We have incorporated the Mahajan et al. Markov model of LTCC, which describes IBa inactivation as VDI only, into the Shannon et al. excitation-contraction coupling model. We extended the LTCC model to assess whether and how experimental IBa inactivation could be recapitulated by modifying CDL Simulation results show that IBa inactivation measured in rabbit myocytes at physiological temperature can be recapitulated when making the Ca-dependent transition rates 10-fold less sensitive to Ba vs. Ca. Our extended LTCC model provides a more faithful representation of purely VDI during ICa.