Faculty Bibliography

OBJECTIVE: Taking into account patients' preferences has become an essential requirement in health decision-making. Even in evidence-based settings where directions are summarized into clinical practice guidelines, there might exist situations where it is important for the care provider to involve the patient in the decision. In this paper we propose a unified framework to promote the shift from a traditional, physician-centered, clinical decision process to a more personalized, patient-oriented shared decision-making (SDM) environment. METHODS: We present the theoretical, technological and architectural aspects of a framework that encapsulates decision models and instruments to elicit patients' preferences into a single tool, thus enabling physicians to exploit evidence-based medicine and shared decision-making in the same encounter. RESULTS: We show the implementation of the framework in a specific case study related to the prevention and management of the risk of thromboembolism in atrial fibrillation. We describe the underlying decision model and how this can be personalized according to patients' preferences. The application of the framework is tested through a pilot clinical evaluation study carried out on 20 patients at the Rehabilitation Cardiology Unit at the IRCCS Fondazione Salvatore Maugeri hospital (Pavia, Italy). The results point out the importance of running personalized decision models, which can substantially differ from models quantified with population coefficients. CONCLUSIONS: This study shows that the tool is potentially able to overcome some of the main barriers perceived by physicians in the adoption of SDM. In parallel, the development of the framework increases the involvement of patients in the process of care focusing on the centrality of individual patients.

Long QT syndrome (LQTS) is one the best characterized disorders among all inherited arrhythmogenic syndromes. A multi-parametric risk stratification scheme, which includes clinical variables (QTc, gender) and the main LQTS genotypes, was defined in the early 2000s and is currently used in clinical practice. However, the evidence of a marked phenotypic variability, even in the presence of the same genetic mutation has puzzled many investigators since the discovery of LQTS genes. Practically, variable expression in LQTS often limits the predictive accuracy of risk stratification markers. Therefore, in a subset of cases, the identification of subjects at a high risk of life-threatening arrhythmias and sudden death is difficult. The discovery of common genetic variants that explain the heritable components of the human electrocardiogram, including QT interval, generated the hypothesis that genetic modifiers may account for phenotypical variability in LQTS. Despite the fact that multiple SNPs have been linked to QT interval duration, clinical applications of any findings are limited by the small effect sizes conferred by single SNPs and incomplete knowledge on their functional consequences. Nevertheless, the possibility of introducing SNP genotyping in risk stratification schemes to improve patient-specificity is an attractive goal. Here we review the currently available evidence and future perspectives for the inclusion of genetic modifiers in the clinical management of LQTS.

The inclusion of patients' perspectives in clinical practice has become an important matter for health professionals, in view of the increasing attention to patient-centered care. In this regard, this report illustrates a method for developing a visual aid that supports the physician in the process of informing patients about a critical decisional problem. In particular, we focused on interpretation of the results of decision trees embedding Markov models implemented with the commercial tool TreeAge Pro. Starting from patient-level simulations and exploiting some advanced functionalities of TreeAge Pro, we combined results to produce a novel graphical output that represents the distributions of outcomes over the lifetime for the different decision options, thus becoming a more informative decision support in a context of shared decision making. The training example used to illustrate the method is a decision tree for thromboembolism risk prevention in patients with nonvalvular atrial fibrillation.

BACKGROUND:Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS:In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS:A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS:These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.

The main task of decision support systems based on computer-interpretable guidelines (CIG) is to send recommendations to physicians, combining patients' data with guideline knowledge. Another important task is providing physicians with explanations for such recommendations. For this purpose some systems may show, for every recommendation, the guideline path activated by the reasoner. However the fact that the physician does not have a global view of the guideline may represent a limitation. Indeed, there are instances (e.g. when the clinical presentation does not perfectly fit the guideline) in which the analysis of alternatives that were not activated by the system becomes warranted. Furthermore possibly valid alternatives could not be activated due to lack of data or wrong knowledge representation. This paper illustrates a CIG implementation that complements the two functionalities, i.e., sending punctual recommendations and allowing a meaningful navigation of the entire guideline. The training example concerns atrial fibrillation management.

Today the ECG is still, over 100 years after its invention (Willem Einthoven 1903), the most commonly used diagnostic procedure in clinical cardiology. In recent years, we have accumulated knowledge that has significantly expanded the diagnostic possibilities of ECG, through the recognition of patterns associated with a number of primary electrical diseases of the myocardium, the so-called inherited arrhythmogenic diseases. These clinical entities are caused by gene mutations that determine a substrate leading to the onset of life-threatening rhythm disturbances. The study of ECG abnormalities in these diseases showed characteristic phenotypic traits, which in combination with information derived from molecular genetics, have allowed using the ECG as a prognostic tool as well as a diagnostic test. The assessment of genotype-phenotype correlations in inherited arrhythmogenic diseases has allowed to advance the idea of the ECG as an inheritable trait. Such heritable quantitative traits are potentially related to the risk of sudden death in the general population, which is known to have a familial predisposition. This article summarizes the pathophysiology and phenotypic manifestation of the main arrhythmogenic diseases. Also shown are current possibilities and limitations of the use of a simple and low-cost technology, not only as a tool for diagnosis but also as a tool to identify prognostic markers. We will show how, rather surprisingly, the ECG often allows extracting the most important information for appropriate risk classification and clinical management.

BACKGROUND: -Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection from cardiac arrest and the use of the implantable defibrillator in the pediatric population is limited by side effects. There is therefore a rational to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of Calsequestrin 2 (CASQ2) wild type gene in a CPVT knock-in mice model carrying the CASQ2R33Q/R33Q (R33Q) mutation. METHODS AND RESULTS: -We engineered an Adeno-Associated Viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild type (AAV9-CASQ2) plus GFP to infect: 1) newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9 and 12 months to investigate the ability of the infection to prevent the disease; 2) adult R33Q mice studied after 2 months to assess if the AAV9-CASQ2 delivery could revert the CPVT phenotype. In both protocols we observed the restoration of physiological expression and interaction of CASQ2, Junctin and Triadin, the rescue of electrophysiological and ultrastructural abnormalities in Calcium Release Units present in R33Q mice and the lack of life-threatening arrhythmias. CONCLUSIONS: -Our data demonstrate that viral gene transfer of wild type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of CPVT and this curative effect lasts for one year after a single injection of the vector thus posing the rationale for the design of a clinical trial.

OBJECTIVE: We explored whether subclinical alterations of sarcoplasmic reticulum (SR) Ca2+ release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a human RyR2R4496C+/- gain-of-function mutation in response to pressure overload. BACKGROUND: RyR2 dysfunction causes increased diastolic SR Ca2+ release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure (HF). METHODS: Functional and structural properties of wild-type (WT) and CPVT-associated RyR2R4496C+/- hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). RESULTS: WT and RyR2R4496C+/- hearts had comparable structural and functional properties at baseline. After TAC, RyR2R4496C+/- hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilatation and reduced fractional shortening, ultimately resulting in overt HF. RyR2R4496C+/--TAC cardiomyocytes showed increased incidence of spontaneous SR Ca2+ release events, reduced Ca2+ transient peak amplitude and SR Ca2+ content as well as reduced SR Ca2+-ATPase2a and increased Na+/Ca2+-exchange protein expression. HF phenotype in RyR2R4496C+/--TAC mice was associated with increased mortality due to pump failure, but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca2+ spark frequency in RyR2R4496C+/--TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2R4496C+/--TAC mice. CONCLUSIONS: The combination of subclinical congenital alteration of SR Ca2+ release and pressure overload promotes eccentric remodeling and HF death in RyR2R4496C+/- mice, and pharmacological RyR2 stabilization prevents this deleterious interaction. These findings imply potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca2+ release.