Faculty Bibliography

Dysregulated intracellular Ca(2+) signaling is implicated in a variety of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia. Spontaneous diastolic Ca(2+) release (DCR) can induce arrhythmogenic plasma membrane depolarizations, although the mechanism responsible for DCR synchronization among adjacent myocytes required for ectopic activity remains unclear. We investigated the synchronization mechanism(s) of DCR underlying untimely action potentials and diastolic contractions (DCs) in a catecholaminergic polymorphic ventricular tachycardia mouse model with a mutation in cardiac calsequestrin. We used a combination of different approaches including single ryanodine receptor channel recording, optical imaging (Ca(2+) and membrane potential), and contractile force measurements in ventricular myocytes and intact cardiac muscles. We demonstrate that DCR occurs in a temporally and spatially uniform manner in both myocytes and intact myocardial tissue isolated from cardiac calsequestrin mutation mice. Such synchronized DCR events give rise to triggered electrical activity that results in synchronous DCs in the myocardium. Importantly, we establish that synchronization of DCR is a result of a combination of abbreviated ryanodine receptor channel refractoriness and the preceding synchronous stimulated Ca(2+) release/reuptake dynamics. Our study reveals how aberrant DCR events can become synchronized in the intact myocardium, leading to triggered activity and the resultant DCs in the settings of a cardiac rhythm disorder.

The discovery of the genetic basis of inherited arrhythmias has paved the way for an improved understanding of arrhythmogenesis in a wide spectrum of life-threatening conditions. In vitro expression of mutations and transgenic animal models have been instrumental in enhancing this understanding, but the applicability of results to the human heart remains unknown. The ability to differentiate induced pluripotent stem cells (iPSs) into cardiomyocytes enables the potential to generate patient-specific myocytes, which could be used to recapitulate the features of inherited arrhythmias in the context of the patient's genetic background. Few studies have been reported on iPS-derived myocytes obtained from patients with heritable arrhythmias, but they have demonstrated the applicability of this innovative approach to the study of inherited arrhythmias. Here we review the results achieved by iPS investigations in arrhythmogenic syndromes and discuss the existing challenges to be addressed before the use of iPS-derived myocytes can become a part of personalized management of inherited arrhythmias.

MobiGuide is a project devoted to the development of a patient-centric decision support system based on computerized clinical guidelines for chronic illnesses including Atrial Fibrillation (AF). In this paper we describe the process of (1) identifying guideline recommendations that will require patients to take actions (e.g., take measurement, take drug), thus impacting patients' daily-life behavior, (2) eliciting from the medical experts the corresponding set of personalized operationalized advices that are not explicitly written in the guideline (patient-tailored workflow patterns) and (3) delivering this advice to patients. The analysis of the AF guideline has resulted in four types of patient-tailored workflow patterns: therapy-related advisors, measurements advisors, suggestions for dealing with interventions that may require modulating patient therapy, and personalized packages for close monitoring of patients. We will show how these patterns can be generated using information stored in a patient health record that embeds clinical data and data about the patient's personal context and preferences.

This paper describes our approach for fostering and facilitating communication among patients and caregivers in the context of shared decision making, i.e., when decisions must be taken not only on the basis of scientific evidence but also of the patient's preferences and context. This happens because clinical practice guidelines cannot provide recommendations for every possible situation, and cannot foresee every change in a patient's context, which might imply the deviation from a previously acknowledged recommendation. Within the EU-funded project MobiGuide (www.mobiguide-project.eu), supporting remote patient management, we propose decision theory as a methodological framework for a tool that, during face to face encounters, is used to tailor pre-defined, generic decision models to the individual patient, by involving the patient himself in the customization of the model parameters. Although this approach is not appropriate for all patients, it leads, in well-chosen cases, to a more informed choice, with potentially better treatment compliance.

In order to support and improve the efficiency of clinical research in specific health area, the University of Pavia and the IRCCS Fondazione Salvatore Maugeri of Pavia (FSM) are developing and implementing an i2b2 based platform, designed to collect data coming from hospital clinical practice and scientific research. The work made in FSM is committed to support an affordable, less intrusive and more personalized care, increasing the quality of clinical practice as well as improving the scientific results. Such a aim depends on the application of information and communication technologies and the use of data. An integrated data warehouse has been implemented to support clinicians and researchers in two medical fields with a great impact on the population: oncology and cardiology. Furthermore the data warehouse approach has been tested with administrative information, allowing a financial view of clinical data.

Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged--the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L-type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology.