Rational prediction of pharmacological treatment options for a novel KCNH2- linked variant of the Short QT Syndrome

Congenital disorders of cardiac repolarization are associated with risk of serious arrhythmias and sudden death. The Long QT Syndrome (LQTS) is well-established to predispose towards torsades de pointes [1]. The Short QT Syndrome (SQTS) is a more recently discovered condition involving abbreviated repolarization that predisposes to atrial and ventricular arrhythmias and sudden death [2]. It is characterized by short QT intervals on the electrocardiogram, frequently with tall upright T waves and by a poor rate adaptation of the QT interval: short QT intervals persist even at slow heart rates [2-4]. Due to the risk of sudden death, SQTS patients are often treated with implantable cardioverter defi brillators (ICDs). Mutations to genes that encode critical components of cardiac potassium channels have been implicated in the syndrome: KCNH2 in SQT1, KCNQ1 in SQT2 and KCNJ2 in SQT3 [2-4]. Of successfully genotyped cases, the most prevalent mutations affect KCNH2 [3]. KCNH2 (alternative nomenclature hERG: human-Etherà- go-go-Related Gene) is responsible for encoding the pore-forming protein of channels that mediate the cardiac rapid delayed rectifi er current, IKr [5]. IKr is vital for normal ventricular repolarization, evidenced by the fact that lossof- function mutations in hERG-mediated subunits underpin the LQT2 form of congenital Long QT Syndrome [1,5]. Gainof- function mutations in hERG-mediated subunits underpin variant 1 (SQT1) of the SQTS [2,3]...

Paradoxes of causal loops in spacetime

There is, among some scientists and philosophers, the idea that any theory that would allow the time travel would introduce causal issues. These types of temporal paradoxes can be avoided by the Novikov self-consistency principle or by a variation in the interpretation of many worlds with interacting worlds. The world in which we live has, according to David Lewis, a Parmenidean ontology: "a manifold of events in four dimensions," and the occupants of the world are the 4-dimensional aggregates of the stages - "temporal lines". The causal loops in backwards time travel involve events that appear to "come from nowhere," paradoxical "self-existent" objects or information, resulting in a bootstrap paradox. Many believe that causality loops are not impossible or unacceptable, but only inexplicable. DOI: 10.13140/RG.2.2.28792.7040

Towards limiting QT interval prolongation and arrhythmia risk in citalopram use

N/A (Commentary

Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806

Transient outward potassium current (I(to)) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation–contraction coupling. Small molecule activators of I(to) may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I(to). This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I(to). Whole cell patch‐clamp recordings of I(to) and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μmol/L NS5806 increased ventricular I(to) with a leftward shift in I(to) activation and accelerated restitution. At higher concentrations, stimulation of I(to) was followed by inhibition. The EC (50) for stimulation was 1.6 μmol/L and inhibition had an IC (50) of 40.7 μmol/L. NS5806 only inhibited atrial I(to) (IC (50) of 18 μmol/L) and produced a modest leftward shifts in I(to) activation and inactivation, without an effect on restitution. 10 μmol/L NS5806 shortened ventricular action potential duration (APD) at APD (20)‐APD (90) but prolonged atrial APD. NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio‐selective effect on Na(+) channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I(to). NS5806 discriminates between rabbit ventricular and atrial I(to,) with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I(to)

Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation

The T618I KCNH2-encoded hERG mutation is the most frequently observed mutation in genotyped cases of the congenital short QT syndrome (SQTS), a cardiac condition associated with ventricular fibrillation and sudden death. Most T618I hERG carriers exhibit a pronounced U wave on the electrocardiogram and appear vulnerable to ventricular, but not atrial fibrillation (AF). The basis for these effects is unclear. This study used the action potential (AP) voltage clamp technique to determine effects of the T618I mutation on hERG current (I(hERG)) elicited by APs from different cardiac regions. Whole-cell patch-clamp recordings were made at 37 °C of I(hERG) from hERG-transfected HEK-293 cells. Maximal I(hERG) during a ventricular AP command was increased ∼4-fold for T618I I(hERG) and occurred much earlier during AP repolarization. The mutation also increased peak repolarizing currents elicited by Purkinje fibre (PF) APs. Maximal wild-type (WT) I(hERG) current during the PF waveform was 87.2 ± 4.5% of maximal ventricular repolarizing current whilst for the T618I mutant, the comparable value was 47.7 ± 2.7%. Thus, the T618I mutation exacerbated differences in repolarizing I(hERG) between PF and ventricular APs; this could contribute to heterogeneity of ventricular-PF repolarization and consequently to the U waves seen in T618I carriers. The comparatively shorter duration and lack of pronounced plateau of the atrial AP led to a smaller effect of the T618I mutation during the atrial AP, which may help account for the lack of reported AF in T618I carriers. Use of a paired ventricular AP protocol revealed an alteration to protective I(hERG) transients that affect susceptibility to premature excitation late in AP repolarization/early in diastole. These observations may help explain altered arrhythmia susceptibility in this form of the SQTS