Circadian Models of Serum Potassium, Sodium, and Calcium Concentrations in Healthy Individuals and Their Application to Cardiac Electrophysiology Simulations at Individual Level

Abstract

In the article a brief description of the biological basis of the regulation of human biological clocks was presented in order to introduce the role of circadian rhythms in physiology and specifically in the pharmacological translational tools based on the computational physiology models to motivate the need to provide models of circadian fluctuation in plasma cations. The main aim of the study was to develop statistical models of the circadian rhythm of potassium, sodium, and calcium concentrations in plasma. The developed ion models were further tested by assessing their influence on QT duration (cardiac endpoint) as simulated by the biophysically detailed models of human left ventricular cardiomyocyte. The main results are model equations along with an electronic supplement to the article that contains a fully functional implementation of all models.

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

“…The population variability effect was mimicked by applying the virtual population generator as described previously 46 , 49 . The heart rate and plasma ions variability were represented in the simulation by adding circadian variation 49 , 50 , 51 . The Cardiac Safety Simulator system was able to accurately recover the RR (inter‐beat) intervals (data not shown).…”

The Benefits and Limitations of Point of Care Testing for Patients with Diabetes Who are Acutely Unwell

“…This is particularly relevant to glucose where delays of 15 min or more have been shown to reduce clinical accuracy to below the ISO standards [29]. The effect of the timing of the samples, however, is unlikely to be as significant for sodium or potassium as they do not have the same degree of post-prandial peaks and troughs as glucose and have a more stable diurnal variation [30]. The venous BGA and laboratory sample were taken from the same venepuncture sample, which might explain the increased level of agreement noted.…”

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

“…The CSS platform combines electro-physiologically based models of the human left ventricular cardiomyocytes and a database of human physiological, genotypic, and demographic data thus allowing generation of a virtual realistic population variability in cardiac physiology during simulations (13,22). Specifically, the CSS platform accounts for circadian variability in heart rate as well as plasma electrolyte (Na + , K + and Ca 2+ ) concentrations using covariate models derived from actual clinical data (23). Epidemiological and covariate models which take into account the effect of gender and age on ventricular heart wall thickness, cardiomyocyte volume and capacitance, and sarcoplasmic reticulum volume are also built into the CSS platform for the north European Caucasian population with healthy heart physiology (15).…”