Age-related changes in human cardiomyocytes are closely related to cardiac diseases, especially atrial fibrillation. Restricted availability of biological preparations from the human atrial myocardium complicates experimental studies on the aging processes in cardiomyocytes. In this preliminary study, we used available experimental data on the age-related changes in ionic conductances in canine atrial cardiomyocytes to predict possible consequences of similar remodeling in humans using two mathematical models (Courtemanche98 and Maleckar09) of human atrial cardiomyocytes. The study was performed using the model population approach, allowing one to assess variability in the cellular response to different interventions affecting model parameters. Here, this approach was used to evaluate the effects of age-related parameter modulation on action potential biomarkers in the two models. Simulation results show a significant decrease in the action potential duration and membrane potential at 20% of the action potential duration in aging. These model predictions are consistent with experimental data from mammalians. The action potential characteristics are shown to serve as notable biomarkers of age-related electrophysiological remodeling in human atrial cardiomyocytes. A comparison of the two models shows different behavior in the prediction of repolarization abnormalities.

We identified a single nucleotide variation (SNV) (c.1264A > G) in the KCNQ1 gene in a 5-year-old boy who presented with a prolonged QT interval. His elder brother and mother, but not sister and father, also had this mutation. This missense mutation leads to a p.Lys422Glu (K422E) substitution in the Kv7.1 protein that has never been mentioned before. We inserted this substitution in an expression plasmid containing Kv7.1 cDNA and studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1, using the whole-cell configuration of the patch-clamp technique. Expression of the mutant Kv7.1 channel in both homo- and heterozygous conditions in the presence of auxiliary subunit KCNE1 results in a significant decrease in tail current densities compared to the expression of wild-type (WT) Kv7.1 and KCNE1. This study also indicates that K422E point mutation causes a dominant negative effect. The mutation was not associated with a trafficking defect; the mutant channel protein was confirmed to localize at the cell membrane. This mutation disrupts the poly-Lys strip in the proximal part of the highly conserved cytoplasmic A–B linker of Kv7.1 that was not shown before to be crucial for channel functioning.

Elevated plasma leptin levels, or hyperleptinemia, have been demonstrated to correlate with metabolic syndrome markers, including obesity, and may be an independent risk factor for the development of cardiovascular disease. In this paper, we use cardiac models to study possible effects of hyperleptinemia on the electrophysiological properties of cardiomyocytes and cardiac arrhythmias. We modified the parameters of an improved Gattoni 2016 model of rat ventricular cardiomyocytes to simulate experimental data for the leptin effects on ionic currents. We used four model variants to investigate the effects of leptin-induced parameter modification at the cellular level and in 2D tissue. In all models, leptin was found to increase the duration of the action potential. In some cases, we observed a dramatic change in the shape of the action potential from triangular, characteristic of rat cardiomyocytes, to a spike-and-dome, indicating predisposition to arrhythmias. In all 2D tissue models, leptin increased the period of cardiac arrhythmia caused by a spiral wave and enhanced dynamic instability, manifesting as increased meandering, onset of hypermeandering, and even spiral wave breakup. The leptin-modified cellular models developed can be used in subsequent research in rat heart anatomy models.