Abstract
Introduction: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable to re-entry. Potential electromechanical consequences of the SQTS are less well-understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS.Methods and Results: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K+ channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on [Ca2+]i transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch-activated channel current (Isac). Without Isac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca2+]i transients, sarcomere length shortening and contractile force. When Isac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca2+ transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control.Conclusion: The incorporation of Isac appears to be an important consideration in modeling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.
Highlights
Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death
Whilst we have investigated the effects of Isac on attenuation of force reduction in the SQTS setting, it is possible that alternative mechanisms may be involved such as calcium transport controlled by feedback of SR filling via storeoperated Ca2+ channels (SOC) (Kusters et al, 2005; Kowalewski et al, 2006; Berna-Erro et al, 2012)
The results of the simulations in this study raise a question as to whether electromechanical coupling involving Isac offsets a negative inotropic effect of ventricular action potential abbreviation that might otherwise occur for K+-channel linked SQTS
Summary
Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. The short QT syndrome (SQTS) was first recognized as a distinct clinical entity in 2000 (Gussak et al, 2000). It is characterized by an abnormally short QT interval on the ECG with a QTC interval of ∼320 ms or less, tall and peaked T-waves, and increased Tpeak−Tend width (Anttonen et al, 2009; Patel and Pavri, 2009; Couderc and Lopes, 2010; Cross et al, 2011; Gollob et al, 2011). For SQT1, these mutations are to the KCNH2 (hERG) gene encoding the α-subunit of the rapidlyactivating delayed rectifier K+ channel IKr (Brugada et al, 2004; Hong et al, 2005a; Sun et al, 2011). SQT4–SQT6 are due, respectively, to loss-of-function mutations to the CACNA1C, CACNB2b (Antzelevitch et al, 2007) and CACNA2D1 (Templin et al, 2011) genes encoding the α1C, β2b, and α2δ-1- subunits of the L-type Ca2+ channel
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