Abstract
Short QT syndrome (SQTS) is a genetic disease characterized by constantly short QT intervals and high risks of sudden death. SQTS6 is one of the identified SQTS genotype variants associated with the CACNA2D1 S755T mutation. However, the pathogenesis of SQTS induced arrhythmias remains unclear. To identify the underlying mechanisms of SQTS6 induced arrhythmias, a multi-scale human ventricle model comprising cell to organ levels was built. Cellular data was fitted at the cell level to reproduce the electrophysiological alterations reported in experiments. The influences were further explored at tissue and organ levels using idealized strand or tissue sheet models, and realistic ventricular slice and three-dimensional organ models. Simulation results suggested that, at the cellular level, the action potential duration (APD) and the effective refractory period (ERP) of myocytes were significantly abbreviated in the mutation condition. The unevenly changed APD and ERP led to transmural heterogeneity remodeling, and resulted in decreased temporal vulnerability. In addition, the S755T mutation shortened the critical length for initiating reentrant spiral waves, which enhanced the spatial vulnerability and provided substrates for reentry arrhythmias. Regarding the sustainability of arrhythmias, the evoked spiral waves or scroll waves persisted in the mutation condition but did not persist in the wild-type condition. The present study clearly suggested that the CACNA1DC S755T mutation can facilitate the initiation and maintenance of ventricular arrhythmias, and therefore contributes to higher risks of ventricular arrhythmias in SQTS6 patients.
Highlights
Short QT syndrome (SQTS) is a rare but dangerous inherited cardiac channelopathy characterized by marked shortened QT intervals, and is associated with an increased risk of abnormal heart rhythms and even sudden cardiac death (SCD) in individuals with a structurally normal heart
action potential duration (APD) and effective refractory period (ERP) of adjacency cell types ( MCELL−ENDO, MCELL−EPI) were reduced; (iii) simulation results of vulnerable windows using the 1D strand suggested that the S755T mutation decreased the temporal vulnerability; (iv) simulation results with the idealized 2D tissue revealed that the S755T mutation shortened the critical length for initiating reentry arrhythmia; patients with SQTS6 tend to have higher risks of developing reentry arrhythmias from a view of tissue spatial vulnerability; (v) simulation results from realistic 2D and 3D models demonstrated that the S755T mutation facilitated the maintenance of reentry
Simulation results show that the significantly decreased ICaL in the mutation condition led to abbreviated APD and ERP in all cell types
Summary
Short QT syndrome (SQTS) is a rare but dangerous inherited cardiac channelopathy characterized by marked shortened QT intervals, and is associated with an increased risk of abnormal heart rhythms and even sudden cardiac death (SCD) in individuals with a structurally normal heart. [10] and anion exchanger (SQTS8) [11]. Among these variants, SQTS6 is caused by mutations to the CACNA2D1 gene where a serine to threonine substitution occurred (i.e., p.Ser755Thr, or S755T). Due to that the CACNA2D1 gene encodes the Cavα2δ − 1 subunit of the L-type calcium channel, the corresponding ionic current ICaL is the major affected current. According to the experimental observations by Templin et al [9], both the channel kinetics and the conductance of ICaL could be changed in the mutation condition. Small positive shifts of both activation and inactivation curves were found in those cells with the mutant Cavα2δ − 1 subunit, and the amplitude of ICaL was significantly reduced by more than 70%
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