Reply to the Editor—Altered in vivo systolic function in the short QT syndrome anticipated in silico

Abstract

A recent article by Frea et al 1 in HeartRhythm provides new evidence for altered systolic function in patients with the short QT syndrome (SQTS). They studied 15 patients with the SQTS (7 with the hERG mutation-linked SQT1 variant, 3 with KCNQ1 mutation-linked SQT2 variant, and 5 without known mutations) by using tissue Doppler imaging and speckle tracking electrocardiography to reveal reduced left ventricular contraction and increased mechanical dispersion in the SQTS group as compared with healthy controls. 1 A longer myocardial performance index was seen in patients with the SQTS, but without significant alterations in isovolumetric contraction and relaxation times, implying that this results from reduced ejection time. Over half of the patients with the SQTS also displayed pathological values of global longitudinal shortening, which correlated positively with corrected QT interval shortening. 1 Mechanical dispersion affected the final stage of contraction in patients with the SQTS. 1 In 2013, we published a simulation study in which the functional effects of SQTS K þ channel mutations were incorporated into human ventricular electromechanical models. 2 The incorporation of the SQT1 N588K hERG mutation profoundly reduced the intracellular calcium transient, leading to greatly reduced active force. The SQT3 D172N Kir2.1 mutation, which predominantly influences late repolarization, produced a more modest effect. 2 Once stretch-activated channels (SACs) were incorporated into the base model, the effects of the SQT mutations on the Ca 2þ transient and force generation were reduced and reduced further if SAC Ca 2þ permeability was incorporated. 2 Under simulated action potential clamp, shorter action potentials led to a reduced sarcoplasmic reticulum Ca 2þ content and Ca 2þ transients in the control model, implicating abbreviated repolarization itself as a driver of altered contractility; the mitigating effects of SAC incorporation correlated with changes in Na þ homeostasis and sodium-calcium exchange (NCX) activity. 2 The extent to which mechanisms demonstrated in our "proof-ofconcept" simulations, made in the absence of any compensatory remodeling, apply to the modest but significant systolic dysfunction in patients with the SQTS 1 remains to be established. However, given the important findings of Frea et al, 1 further investigation of altered mechanical function in the SQTS is now warranted. Reply to the Editor-Altered in vivo systolic function in the short QT syndrome anticipated in silicoOur group recently demonstrated an in vivo association between short QT syndrome (SQTS) and a slight but significant systolic dysfunction. 1 Hancox and colleagues 2 partially anticipated this report showing an interesting correlation between SQTS channel mutations (mostly HERG mutation) and shortening of action potential with an in vitro reduction in Ca 2þ transient and force generation. These 2 studies seem to suggest that the association between SQTS and systolic impairment may be explained by 3 mechanisms: a greater...

A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes

“…In addition, the middle panel of Fig 2 shows that the amplitude of the Ca 2+ transient is reduced for the SQT1 situation compared to the wild type case, especially for rabbit and adult human CMs. Such reduced Ca 2+ transient amplitudes have been observed in earlier computational studies of the N588K SQT1 mutation [ 50 , 51 ], and this effect is in agreement with speckle-tracking echocardiography and Doppler imaging that have shown decreased left ventricular contraction in patients with SQT syndrome [ 52 , 53 ]. The main goal of this study is to find combinations of drugs that alter the currents in the SQT1 case so that the AP and Ca 2+ transient becomes very similar to the wild type AP and Ca 2+ transient.…”

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond

“…Whereas isovolumic contraction and relaxation appeared unaffected (as described previously), 107 systolic ejection time was shortened and global longitudinal strain was reduced ( Figure 4A ). In follow-up analyses, 109 a correlation was found between the short QT interval, mechanical dispersion, and reduced ejection time ( Figure 4B ) and linked to the subclinical systolic dysfunction. A comparable interplay between shortened repolarization and reduced contractile function was found using computational modelling.…”

Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome

“…In electromechanically coupled human ventricle cell models, incorporation of the N588K mutation reduced [Ca 2+ ] i transients and contractile force, while in three-dimensional ventricle models the timing of maximum deformation (contraction) was delayed by N588K compared to wild-type I Kr [72]. A subsequent clinical report was published in which SQTS patients were investigated with Doppler imaging and speckle tracking electrocardiography; this showed some decrease in left ventricular contraction and increased mechanical dispersion in SQTS patients compared to healthy controls [78][79][80]. Computational analysis of the effects of the I560T mutation has also shown abbreviation of ventricular APD and simulated QT intervals [12].…”