Background-Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. Methods and Results-We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (meanϮSEM capacitance, 89Ϯ2 pF versus 71Ϯ2 pF in control, nϭ160 cells per group, PϽ0.001). CHF significantly reduced the density of L-type Ca 2ϩ current (I Ca ) by Ϸ30%, of transient outward K ϩ current (I to ) by Ϸ50%, and of slow delayed rectifier current (I Ks ) by Ϸ30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca 2ϩ currents were not altered by CHF. CHF increased transient inward Na ϩ /Ca 2ϩ exchanger (NCX) current by Ϸ45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8Ϯ4 to 535Ϯ82 seconds (PϽ0.01). Conclusions-Experimental CHF selectively decreases atrial I to , I Ca , and I Ks , increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF

One form of inherited long QT syndrome, LQT2, results from mutations in HERG1, the human ether-a-gogo-related gene, which encodes a voltage-gated K ؉ channel ␣ subunit. Heterologous expression of HERG1 gives rise to K ؉ currents that are similar (but not identical) to the rapid component of delayed rectification, I Kr , in cardiac myocytes. In addition, N-terminal splice variants of HERG1 and MERG1 (mouse ERG1) referred to as HERG1b and MERG1b have been cloned and suggested to play roles in the generation of functional I Kr channels. In the experiments here, antibodies generated against HERG1 were used to examine ERG1 protein expression in heart and in brain. In Western blots of extracts of QT-6 cells expressing HERG1, MERG1, or RERG1 (rat ERG1) probed with antibodies targeted against the C terminus of HERG1, a single 155-kDa protein is identified, whereas a 95-kDa band is evident in blots of extracts from cells expressing MERG1b or HERG1b. In immunoblots of fractionated rat (and mouse) brain and heart membrane proteins, however, two prominent high molecular mass proteins of 165 and 205 kDa were detected. Following treatment with glycopeptidase F, the 165-and 205-kDa proteins were replaced by two new bands at 175 and 130 kDa, suggesting that ERG1 is differentially glycosylated in rat/mouse brain and heart. In human heart, a single HERG1 protein with an apparent molecular mass of 145 kDa is evident. In rats, ERG1 protein (and I Kr ) expression is higher in atria than ventricles, whereas in humans, HERG1 expression is higher in ventricular, than atrial, tissue. Taken together, these results suggest that the N-terminal alternatively spliced variants of ERG1 (i.e. ERG1b) are not expressed at the protein level in rat, mouse, or human heart and that these variants do not, therefore, play roles in the generation of functional cardiac I Kr channels.Long QT syndrome is an acquired or an inherited disorder that can cause syncope and sudden death resulting from episodic ventricular arrhythmias and ventricular fibrillation (1, 2). The characteristic feature identified in surface electrocardiograms of affected individuals is prolongation of the QT interval, consistent with the underlying cause of long QT syndrome being a defect in ventricular repolarization (3, 4). One form of inherited long QT syndrome, LQT2, was localized to chromosome 7 (5), and shown to result from mutations (6) in the human ether-a-go-go-related gene, originally referred to as HERG (7). With the identification of additional members of the ether-a-go-go-related gene (ERG) family (8), the terminology HERG1 seems more appropriate (9).HERG1 encodes a polypeptide with a predicted molecular mass of 127 kDa and a predicted sequence and membrane topology similar to that of other voltage-gated K ϩ channel ␣ subunits (10 -12). Heterologous expression of HERG1 in Xenopus oocytes (10 -12) and in HEK-293 cells (14 -16) reveals voltage-gated K ϩ currents that are similar to the rapid component of delayed rectification, I Kr , in myocardial cells (17)(18)(19)(20)(21)(...

Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Current models present inconsistencies with experimental data, which limit further progress. In this study, we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling, from ionic to whole-organ dynamics, including the electrocardiogram. Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade. In addition, the process uncovers new theoretical insights into the biophysical properties of the L-type calcium current, which are critical for sodium and calcium dynamics. These insights enable the reformulation of L-type calcium current, as well as replacement of the hERG current model.