Faculty Bibliography

PURPOSE OF REVIEW: In this article, we summarize the main features of the most common inherited channelopathies, focusing on the findings that advanced the field in the last few years. RECENT FINDINGS: The progress in genetics prompted the discovery of several new genes associated with ion-channel disorders, elucidating new molecular pathways and new arrhythmogenic mechanisms. The diffusion and availability of genetic screening gave a new relevance to the application of genetics not only for diagnosis, but also for risk assessment and therapeutic decisions. As a consequence, the present challenge in the field is represented by the need to use genetic data to develop personalized clinical approaches. SUMMARY: Over a few years, the field of inherited arrhythmogenic diseases has rapidly expanded, thus reshaping clinical management for these conditions. It is now clear that to handle these patients a specialized expertise is needed, able to translate the discoveries derived from basic science studies into the clinical care of the patients.

BACKGROUND: The ONCO-i2b2 platform is a bioinformatics tool designed to integrate clinical and research data and support translational research in oncology. It is implemented by the University of Pavia and the IRCCS Fondazione Maugeri hospital (FSM), and grounded on the software developed by the Informatics for Integrating Biology and the Bedside (i2b2) research center. I2b2 has delivered an open source suite based on a data warehouse, which is efficiently interrogated to find sets of interesting patients through a query tool interface. METHODS: Onco-i2b2 integrates data coming from multiple sources and allows the users to jointly query them. I2b2 data are then stored in a data warehouse, where facts are hierarchically structured as ontologies. Onco-i2b2 gathers data from the FSM pathology unit (PU) database and from the hospital biobank and merges them with the clinical information from the hospital information system. Our main effort was to provide a robust integrated research environment, giving a particular emphasis to the integration process and facing different challenges, consecutively listed: biospecimen samples privacy and anonymization; synchronization of the biobank database with the i2b2 data warehouse through a series of Extract, Transform, Load (ETL) operations; development and integration of a Natural Language Processing (NLP) module, to retrieve coded information, such as SNOMED terms and malignant tumors (TNM) classifications, and clinical tests results from unstructured medical records. Furthermore, we have developed an internal SNOMED ontology rested on the NCBO BioPortal web services. RESULTS: Onco-i2b2 manages data of more than 6,500 patients with breast cancer diagnosis collected between 2001 and 2011 (over 390 of them have at least one biological sample in the cancer biobank), more than 47,000 visits and 96,000 observations over 960 medical concepts. CONCLUSIONS: Onco-i2b2 is a concrete example of how integrated Information and Communication Technology architecture can be implemented to support translational research. The next steps of our project will involve the extension of its capabilities by implementing new plug-in devoted to bioinformatics data analysis as well as a temporal query module.

This review article discusses the genetic bases of cardiac arrest with a specific focus on cardiac channelopathies and right ventricular cardiomyopathy. We review the appropriate use of genetic testing in those patients suspected to have inherited cardiac arrhythmias, highlighting the importance of most genotype-phenotype correlations for risk stratification. The article also presents the most recent views on diagnostic criteria and flowcharts for treatment of patients with inherited arrhythmogenic diseases.

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.

AIMS: The European CRT Survey is a joint initiative of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology evaluating the contemporary implantation practice of cardiac resynchronization therapy (CRT) in Europe. METHODS AND RESULTS: Patients who had a successful CRT implantation were enrolled from 141 centres in 13 countries between November 2008 and June 2009. Baseline demographics, clinical and implantation data were collected, with a follow-up of approximately 1 year (9-15 months). The current report describes clinical outcomes including symptom severity, cardiovascular (CV) hospitalization, and survival. A total of 2438 patients were enrolled, and follow-up data were acquired from 2111 patients (87%). The population included important groups of patients poorly represented in randomized controlled trials, including very elderly patients and those with prior device implantation, atrial fibrillation, and/or QRS duration <120 ms. Investigators reported substantial improvement in New York Heart Association (NYHA) functional class at follow-up. Patient self-assessment indicated that 81% of the patients felt improved, 16% reported no change, and 4% reported deterioration. During follow-up, 207 (10%) patients died, 346 (16%) had a CV hospitalization, and 501 (24%) died or had CV hospitalization. Worse NYHA functional class, atrial fibrillation, ischaemic aetiology, and device type (CRT-P, i.e. CRT alone) were associated with poorer survival. Women had a better outcome, as did patients who had a CRT-D (with an implantable cardioverter defibrillator function) device. CONCLUSIONS: Outcomes including death and hospitalization in this European CRT survey were consistent with results from clinical trials of CRT. At 1 year follow-up, most patients who received a CRT device considered their symptoms improved compared with their pre-implant assessment. Although prospective, this is an observational study of successful CRT implantations, and outcomes in subgroup analyses must be interpreted with appropriate conservatism.