Faculty Bibliography

Recent studies have shown that flecainide may be an effective therapy to prevent life-threatening arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Several hypotheses have been advanced to explain the antiarrhythmic mechanism of flecainide, including Na(+) channel blockade and a direct inhibitory action on the ryanodine receptor. In this article, we review the current literature on the topic and summarize the elements of the existing debate.

OBJECTIVES: The PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) prospective registry was designed to assess the predictive accuracy of sustained ventricular tachycardia/ventricular fibrillation (VTs/VF) inducibility and to identify additional predictors of arrhythmic events in Brugada syndrome patients without history of VT/VF. BACKGROUND: Brugada syndrome is a genetic disease associated with increased risk of sudden cardiac death. Even though its value has been questioned, inducibility of VTs/VF is widely used to select candidates to receive a prophylactic implantable defibrillator, and its accuracy has never been addressed in prospective studies with homogeneous enrolling criteria. METHODS: Patients with a spontaneous or drug-induced type I electrocardiogram (ECG) and without history of cardiac arrest were enrolled. The registry included 308 consecutive individuals (247 men, 80%; median age 44 years, range 18 to 72 years). Programmed electrical stimulation was performed at enrollment, and patients were followed-up every 6 months. RESULTS: During a median follow-up of 34 months, 14 arrhythmic events (4.5%) occurred (13 appropriate shocks of the implantable defibrillator, and 1 cardiac arrest). Programmed electrical stimulation performed with a uniform and pre-specified protocol induced ventricular tachyarrhythmias in 40% of patients: arrhythmia inducibility was not a predictor of events at follow-up (9 of 14 events occurred in noninducible patients). History of syncope and spontaneous type I ECG (hazard ratio [HR]: 4.20), ventricular refractory period <200 ms (HR: 3.91), and QRS fragmentation (HR: 4.94) were significant predictors of arrhythmias. CONCLUSIONS: Our data show that VT/VF inducibility is unable to identify high-risk patients, whereas the presence of a spontaneous type I ECG, history of syncope, ventricular effective refractory period <200 ms, and QRS fragmentation seem useful to identify candidates for prophylactic implantable cardioverter defibrillator.

Blood potassium concentration [K+] has a strong influence on ECG and particularly on T-wave morphology. We previously developed a method to quantify [K+] from ECG analysis. The aims of the study were i) to test this method quantifying [K+] on a larger group of hemodialysis (HD) patients ii) to give a mechanical interpretation of the link between [K+] and ECG by testing the estimator on congenital LQT2 patients. The ECG-based potassium estimator (K-ECG), based on the ratio between the T-wave descending slope and the T-wave amplitude (T-S/A) was tested on 69 HD sessions (23 patients, 3 sessions each) and on 12 LQT2 patients. ECG recordings were acquired and [K+] values were measured from blood samples (K-LAB). The agreement between K-ECG and K-LAB was satisfactory in the HD patients (absolute error: 0.43 +/- 0.28mM). The systematic error was very small (0.05mM) while the standard deviation was 0.5mM. As expected, in LQT2 patients our method significantly underestimated [K+] (error: 1.15 +/- 0.68mM), thus pointing to the I-Kr dependence on extracellular potassium in determining the link between [K+] and T-wave morphology. This method could be effectively applied to monitor patients at risk for hyper- and hypokalemia.

The CARDIO-i2b2 project is an initiative to customize the i2b2 bioinformatics tool with the aim to integrate clinical and research data in order to support translational research in cardiology. In this work we describe the implementation and the customization of i2b2 to manage the data of arrhytmogenic disease patients collected at the Fondazione Salvatore Maugeri of Pavia in a joint project with the NYU Langone Medical Center (New York, USA). The i2b2 clinical research chart data warehouse is populated with the data obtained by the research database called TRIAD. The research infrastructure is extended by the development of new plug-ins for the i2b2 web client application able to properly select and export phenotypic data and to perform data analysis.

Rationale: Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide. Objective: To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2(R4496C+/-) knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia. Methods and Results: Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2(R4496C+/-) mice. Cellular studies were performed with isolated RyR2(R4496C+/-) myocytes. Isoproterenol caused the appearance of spontaneous Ca(2+) transients, which were unaffected by flecainide (6 mumol/L). Flecainide did not affect Ca(2+) transient amplitude, decay, or sarcoplasmic reticulum Ca(2+) content. Moreover, it did not affect the frequency of spontaneous Ca(2+) sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na(+) channel blockade. Conclusions: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2(R4496C+/-) mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca(2+) homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na(+) channel availability and by an increase in the threshold for triggered activity

Informatics for Integrating Biology and the Bedside (i2b2) is an initiative funded by the NIH that aims at building an informatics infrastructure to support biomedical research. The University of Pavia has recently integrated i2b2 infrastructure with a registry of inherited arrhythmogenic diseases. Within this project, the authors created a novel i2b2 cell, named R Engine Cell, which allows the communication between i2b2 and the R statistical software. As survival analyses are routinely performed by cardiology researchers, the authors have first concentrated on making Kaplan-Meier analyses available within the i2b2 web interface. To this aim, the authors developed a web-client plug-in to select the patient set on which to perform the analysis and to display the results in a graphical, intuitive way. R Engine Cell has been designed to easily support the integration of other R-based statistical analyses into i2b2

The L-type cardiac calcium channel (LTCC) plays a prominent role in the electric and mechanical function of the heart. Mutations in the LTCC have been associated with a number of inherited cardiac arrhythmia syndromes, including Timothy, Brugada, and early repolarization syndromes. Elucidation of the genetic defects associated with these syndromes has led to a better understanding of molecular and cellular mechanisms and the development of novel therapeutic approaches to dealing with the arrhythmic manifestations. This review provides an overview of the molecular structure and function of the LTCC, the genetic defects in these channels known to contribute to inherited disorders, and the underlying molecular and cellular mechanisms contributing to the development of life-threatening arrhythmias.

OBJECTIVES: We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS). BACKGROUND: Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited. METHODS: The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry. RESULTS: Multivariate analysis demonstrated that corrected QT interval (QTc) duration (>/=500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced >/=1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events. CONCLUSIONS: Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration

OBJECTIVES: We investigated whether increased Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). BACKGROUND: RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. METHODS: CaMKIIdeltac transgenic mice were crossbred with RyR2(R4496C+/-) knock-in mice. RESULTS: Heart weight-to-body weight ratio in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice. Sarcoplasmic reticulum Ca(2+) content in isolated myocytes was decreased to a similar extent in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice. However, relaxation parameters and Ca(2+) decay at 1 Hz were prolonged significantly in CaMKIIdeltac mice versus CaMKIIdeltac/RyR2(R4496C) mice. Sarcoplasmic reticulum Ca(2+) spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca(2+) leak in CaMKIIdeltac/RyR2(R4496C) versus CaMKIIdeltac myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIdeltac/RyR2(R4496C) versus CaMKIIdeltac mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIdeltac/RyR2(R4496C) mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIdeltac, p < 0.05) after 14 weeks. CONCLUSIONS: CaMKIIdeltac overexpression in RyR2(R4496C+/-) knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor