Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia

Abstract

Advances in genetics and molecular biology have provided an extensive body of information on the structure and function of the elementary building blocks of living systems. Genetic defects in membrane ion channels can disrupt the delicate balance of dynamic interactions between the ion channels and the cellular environment, leading to altered cell function. As ion-channel defects are typically studied in isolated expression systems, away from the cellular environment where they function physiologically, a connection between molecular findings and the physiology and pathophysiology of the cell is rarely established. Here we describe a single-channel-based Markovian modelling approach that bridges this gap. We achieve this by determining the cellular arrhythmogenic consequences of a mutation in the cardiac sodium channel that can lead to a clinical arrhythmogenic disorder (the long-QT syndrome) and sudden cardiac death.

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…Computer modeling and simulations are a complementary means to reveal the underlying ionic mechanisms. Many computer modeling studies (41)(42)(43)(44)(45)(46) have been carried out to investigate the mechanisms of EADs, but for the most part these have focused on EADs caused by voltage-driven oscillations, because the AP models lacked detailed spatiotemporal Ca cycling required to simulate Ca waves and oscillations. In this study, we investigated the effects of bidirectional Ca-voltage coupling on the genesis of EADs and DADs in ventricular myocytes, using an AP model with a detailed spatiotemporal Ca cycling regulation incorporating stochastic LCC and RyR openings and experiments of mouse ventricular myocytes.…”

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

“…9 B), predicting little clinical benefit by the addition of the second Na + channel blocker. The rate-dependent increase in mexiletine reduction of I NaL was not accompanied by changes in mexiletine I Kr block, but further addition of flecainide more than the disorder more pronounced at a slow heart rate (Clancy and Rudy, 1999;Clancy et al, 2002). Here, we observe a very pronounced rate dependence of disease-causing late current that is consistent with this gating scheme and, in addition, an overall slowing of inactivation recovery kinetics measured in iPSC-CMs compared with previous measurements in HEK293 cells (Bankston et al, 2007b), that, taken together, exacerbate the role of rate in the patient phenotype and provide a mechanistic channel defect explanation for the efficacy of a combined pacing and pharmacological approach to treatment.…”

“…5 D and Table 1). Altogether, these mutation-induced defects in Na + channel inactivation (increased I NaL , rightshifted steady-state channel availability, and faster recovery from inactivation), measured for this mutation for the first time in iPSC-CMs derived from the proband, are known to contribute markedly to LQT-3 arrhythmia risk (Clancy and Rudy, 1999;Sampson et al, 2010) and thus provide a mechanistic explanation for the proband's clinical phenotype.…”

Modelling the heart: insights, failures and progress

“…6, has been an exciting development. The goal of creating an organ model capable of spanning the whole spectrum of levels from genes (67)(68)(69)(70)(71) to the electrocardiogram (13,32) is within sight, and is one of the challenges of the immediate future. The potential of such simulations for teaching, drug discovery, device development and, of course, for pure physiological insight is only beginning to be appreciated.…”