No abstract

Super-resolution imaging techniques have provided a better understanding of the relationship between the nanoscale organization and function of ryanodine receptors (RyRs) in cardiomyocytes. Recent data have indicated that this relationship is disrupted in heart failure (HF), as RyRs are dispersed into smaller and more numerous clusters. However, RyRs are also hyperphosphorylated in this condition, and this is reported to occur preferentially within the cluster centre. Thus, the combined impact of RyR relocalization and sensitization on Ca2+ spark generation in failing cardiomyocytes is likely complex and these observations suggest that both the nanoscale organization of RyRs and the pattern of phosphorylated RyRs within clusters could be critical determinants of Ca2+ spark dynamics. To test this hypothesis, we used computational modeling to quantify the relationships between RyR cluster geometry, phosphorylation patterns, and sarcoplasmic reticulum (SR) Ca2+ release. We found that RyR cluster disruption results in a decrease in spark fidelity and longer sparks with a lower amplitude. Phosphorylation of some RyRs within the cluster can play a compensatory role, recovering healthy spark dynamics. Interestingly, our model predicts that such compensation is critically dependent on the phosphorylation pattern, as phosphorylation localized within the cluster center resulted in longer Ca2+ sparks and higher spark fidelity compared to a uniformly distributed phosphorylation pattern. Our results strongly suggest that both the phosphorylation pattern and nanoscale RyR reorganization are critical determinants of Ca2+ dynamics in HF.

No abstract

Patients suffering from end stage of chronic kidney disease (CKD) often undergo haemodialysis to normalize the electrolyte concentrations. Moreover, cardiovascular disease (CVD) is the main cause of death in CKD patients. To study the connection between CKD and CVD, we investigated the effects of an electrolyte variation on cardiac signals (action potential and ECG) using a computational model. In a first step, simulations with the Himeno et al. ventricular cell model were performed on cellular level with different extracellular sodium ([Na+]o), calcium ([Ca2+]o) and potassium ([K+]o) concentrations as occurs in CKD patients. [Ca2+]o and [K+]o changes caused variations in different features describing the morphology of the AP. Changes due to a [Na+]o variation were not as prominent. Simulations with [Ca2+]o variations were also carried out on ventricular ECG level and a 12-lead ECG was computed. Thus, a multiscale simulator from ion channel to ECG reproducing the calcium-dependent inactivation of ICaL was achieved. The results on cellular and ventricular level agree with results from literature. Moreover, we suggest novel features representing electrolyte changes that have not been described in literature. These results could be helpful for further studies aiming at the estimation of ionic concentrations based on ECG recordings.

Current multi-scale electrophysiology models capture the processes underlying ECG genesis under physiological and many disease conditions with high fidelity. However, proper representation of the extracellular milieu remains challenging. The human ventricular myocyte model by Himeno et al. is one of the first which faithfully represents the dependence of the action potential (AP) duration on the extracellular calcium concentration ([Ca 2+ ]o). Here, we present a heterogeneous formulation of the Himeno et al. cellular model and integrate it into a multi-scale framework to compute body surface ECGs. We propose 3 variants to account for transmural heterogeneity informed by experimental data and tuned to match AP level features such as repolarization stability. As shown before, an apico-basal gradient of IKs conductance is a likely mechanism causing concordant T-waves. Therefore, we increased IKs in the Himeno et al. model at the apex by a factor of 3.5 compared to the base to obtain an APD shortening of 12.5%. The setup comprising transmural and apico-basal heterogeneity yielded a physiological ventricular ECG. Our novel setup allows to study, for the first time, how realistic changes of the AP under hypo-and hypercalcaemic conditions translate to changes in the ECG. Resulting QT prolongation under hypocalcaemic conditions matched human experimental data.