Multi-scale modeling of excitation-contraction coupling in the normal and failing heart.

Here we describe new computational models of cardiac electromechanics starting from the cellular scale and building to the tissue, organ and system scales. We summarize application to human genetic diseases (LQT1 and LQT3) and to modeling of congestive heart failure.

Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model.

The mechanical properties of myocardium vary across the transmural aspect of the left ventricular wall. Some of these functional heterogeneities may be related to differences in excitation-contraction coupling characteristics that have been observed in cells isolated from the epicardial, mid-myocardial and endocardial regions of the left ventricle of many species, including canine. Integrative models of coupled myocyte electromechanics are reviewed and used here to investigate sources of heterogeneous electromechanical behaviour in these cells.

Acetylcholine-induced shortening of the epicardial action potential duration may increase repolarization gradients and LQT3 arrhythmic risk.

Unlike other variants of long QT syndrome, LQT3 patients are particularly susceptible to cardiac events during sleep. Changes in heart rate alone fail to fully account for this phenomenon. We hypothesize that the parasympathetic nervous system may play a role in increasing arrhythmic risk in the mammalian ventricular myocardium via acetylcholine (ACh)-mediated effects on repolarisation gradients and, furthermore, that the effects of ACh exhibit rate dependency.

Arrhythmogenic consequences of Na+ channel mutations in the transmurally heterogeneous mammalian left ventricle: analysis of the I1768V SCN5A mutation.

Background: Congenital mutations in the cardiac Na+ channel (encoded by SCN5A) underlie long QT syndrome type 3. The sea anemone peptide toxin ATX-II mimics the slowed inactivation kinetics characteristic of many long QT type 3 (LQT3) mutations. However, the I1768V SCN5A mutation is associated with faster recovery kinetics, for which there exists no known pharmacologic equivalent.

Contributions of sustained INa and IKv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes.

The roles of sustained components of I(Na) and I(Kv43) in shaping the action potentials (AP) of myocytes isolated from the canine left ventricle (LV) have not been studied in detail. Here we investigate the hypothesis that these two currents can contribute substantially to heterogeneity of early repolarization and arrhythmic risk. Quantitative data from voltage-clamp and expression profiling experiments were used to complete meaningful modifications to an existing "local control" model of canine midmyocardial myocyte excitation-contraction coupling for epicardial and endocardial cells.