ABSTRACT
Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.
ABSTRACT
In this paper, we analyze the epicardial electromechanical response of an in silico cardiac ventricular wedge under both healthy and concentric hypertrophic conditions. This is achieved by taking into account the growth of the wedge thickness and the fiber dispersion that may follow. The electromechanical response is described in terms of some macroscopic measures, i.e. the action potential duration, the conduction velocity, the contractility and the contraction force. Our results suggest that growth reduces the action potential duration and conduction velocity, whilst it increases the contractility and contraction force, yielding an overall negative effect. In presence of fiber dispersion, the action potential duration and conduction velocity are not affected further, whilst the effect on the contractility and contraction force is enhanced.
