Calibration of ionic and cellular cardiac electrophysiology models

© 2020 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under: Analytical and Computational Methods > Computational Methods Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Cellular Models

Minimally invasive therapy of upside-down stomach: A single-center experience

Introduction: The aim of this study is to evaluate short-term and long-term outcomes of minimally invasive therapy in Type IV hiatal hernia (upside-down stomach). Patients and Methods: A retrospective study of 58 consecutively operated patients with Type IV hiatal hernia between 1998 and 2015 was conducted. Short-term outcome was evaluated using Clavien-Dindo classification and long-term outcomes using phone survey and subjective assessment of patients at least 1 year following surgery. Results: Laparoscopic hiatoplasty was performed in all patients, with gastropexy in 55.2%, fundoplication in 39.6%, and combination of fundoplication and gastropexy in 5.2%. Complications were observed in 6.9%. Two early reoperations (within 30 days) due to acute reherniation were necessary. Adverse events occurred in seven cases – pleural opening and peroperative bleeding. Three patients were reoperated laparoscopically 2–17 months after the first surgery due to receiving partial stomach herniation. In 67.2% of patients, long-term subjective quality of life assessment was available. Eighty percent of them were completely satisfied, without recurrence of preoperative symptoms. Conclusion: Elective laparoscopic surgery of hiatal hernia Type IV is a safe procedure, which has all the benefits of minimally invasive therapy with favorable short- and long-term results

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation

Aims Mutations in KCNQ1, encoding for Kv7.1, the alpha-subunit of the I-Ks channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. Methods and results K557E carriers had moderate QTc prolongation that augmented significantly during exercise. I-Ks characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused I-Ks loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in I-Ks density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT I-Ks by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of I-Ks at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during beta-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. Conclusion K557E causes I-Ks loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant I-Ks is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients