Sung RJ, Wu YH, Lai NH, Teng CH, Luo CH, Tien HC, Lo CP, Wu S. ␤-Adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study. Am J Physiol Heart Circ Physiol 298: H33-H44, 2010. First published October 23, 2009 doi:10.1152/ajpheart.00232.2009.-Timothy syndrome (TS) is a malignant form of congenital long QT syndrome with a mode of arrhythmia onset often triggered by enhanced sympathetic tone. We sought to explore mechanisms by which ␤-adrenergic stimulation (BAS) modulates arrhythmogenesis and to identify potential targeted sites of antiarrhythmic therapy in TS. Using a dynamic Luo-Rudy ventricular myocyte model incorporated with detailed intracellular Ca 2ϩ cycling, along with its one-dimensional multicellular strand, we simulated various clinical scenarios of TS, with stepwise increase in the percentage of G406R Cav1.2 channels from 0 to 11.5 and 23%, and to 38.5 and 77%, respectively, for heterozygous and homozygous states of TS1 and TS2. Progressive prolongation of action potential duration (APD) and QT interval, accompanied by amplification of transmural dispersion of repolarization, steepening of APD restitution, induction of delayed afterdepolariztions (DADs), and both DAD and phase 3 early afterdepolariztion-mediated triggered activities, correlated well with the extent of G406R Cav1.2 channel mutation. BAS amplified transmural dispersion of repolarization, steepened APD restitution, and facilitated inducibility of DAD-mediated triggered activity. Systematic analysis of intracellular Ca 2ϩ cycling revealed that sarcoplasmic reticulum Ca 2ϩ ATPase (uptake current) played an essential role in BAS-induced facilitation of DAD-mediated triggered activity and, in addition to L-type calcium current, it could be an effective site of antiarrhythmic therapy under the influence of BAS. Thus G406R Cav1.2 channel mutation confers not only a trigger, but also a substrate for lethal ventricular arrhythmias, which can be exaggerated by BAS. It is suggested that, besides ␤-adrenergic blockers and L-type calcium current channel blockers, an agent aimed at reduction of sarcoplasmic reticulum Ca 2ϩ ATPase uptake current may provide additional antiarrhythmic effect in patients with TS.congenital long QT syndrome; computational biology; sudden cardiac death; ventricular arrhythmias TIMOTHY SYNDROME (TS) IS A subtype (LQT8) of congenital long QT syndrome, which clinically manifests multisystem involvement (e.g., syndactyly, dysmorphic facial features, autism, etc.) (20,21). In association with marked QT prolongation, arrhythmias are the most serious aspect of its clinical features. These include bradycardia, atrioventricular block, polymorphic ventricular tachycardia, and ventricular fibrillation. Molecular genetic studies have revealed that patients with TS have mutations in the CACNA1C gene that result in "near complete" elimination of voltage-dependent inactivation (VDI) of the L-type calcium current (I Ca,L ) (Ca v 1.2) channel, le...

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Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, “ion channelopathies”, in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice.

Background: Atrial fibrillation (AF) increases the risk of dementia. Whether the pharmacological rhythm control of AF can reduce the risk of dementia compared to the rate control strategy remains unclear. We hypothesize that the rhythm control strategy is better than the rate control strategy in preventing dementia. Methods: AF patients aged ≥65 years were identified from the Taiwan National Health Insurance Database. Patients receiving anti-arrhythmic drugs at a cumulative defined daily dose (cDDD) of >30 within the first year of enrollment constituted the rhythm control group. Patients who used rate control medications for a cDDD of >30 constituted the rate control group. A multivariate Cox hazards regression model was used to determine the hazard ratio (HR) for dementia. Results: A total of 3382 AF patients (698 in the rhythm control group; 2684 in the rate control group) were analyzed. During a 4.86 ± 3.38 year follow-up period, 414 dementia events occurred. The rhythm control group had a lower rate of dementia than the rate control group (adjust HR: 0.75, p = 0.031). The rhythm control strategy reduced the risk of dementia particularly in those receiving aspirin (p = 0.03). Conclusions: In patients with AF, pharmacological rhythm control was associated with a lower risk of dementia than rate control over a long-term follow-up period, particularly in patients receiving aspirin treatment.

Sung RJ, Lo CP, Hsiao PY, Tien HC. Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation. Am J Physiol Heart Circ Physiol 301: H1625-H1638, 2011. First published July 8, 2011 doi:10.1152/ajpheart.00696.2010.-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of ␤-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca 2ϩ channel (ICa,L) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2 R4496Cϩ/Ϫ ) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at Ն0.1 M could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2R4496Cϩ/Ϫ but not in the wildtype via enhancing both I Ca,L and sarcoplasmic reticulum (SR) Ca 2ϩ ATPase (IUP). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient (D) of Յ0.000766*98 cm 2 /ms was required for generating DAD-mediated TA in RyR2R4496Cϩ/Ϫ . Whereas individual reduction of Ca 2ϩ release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either I Ca,L or IUP could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both I Ca,L and IUP exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca 2ϩ cycling and a pharmacological regimen capable of reducing I Ca,L could be an effective adjunctive to ␤-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT. computational modeling; delayed afterdepolarizations; store-overload-induced Ca 2ϩ release; triggered activity CATECHOLAMINERGIC POLYMORPHIC ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by episodic syncope occurring during physical activity or acute emotional distress in individuals without structural heart disease and ECG abnormalities (21, 23). Characteristically, episodes of syncope are usually related to the occurrence of bidirectional or polymorphic ventricular tachycardia that might degenerate into ventricular fibrillation. In ϳ60% of CPVT patients, molecular genetic studies have unfolded that mutations are m...