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Zambelli A.,Medical Oncology Unit | Della Porta M.G.,University of Pavia | Eleuteri E.,Scientific Institute of Veruno NO | De Giuli L.,Molecular Cardiology Laboratories | And 3 more authors.
Breast | Year: 2011

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists. © 2010 Elsevier Ltd. Source

Napolitano C.,Molecular Cardiology Laboratories | Napolitano C.,New York University
Pediatric Cardiology | Year: 2012

Syncope and risk of sudden death due to ventricular tachyarrhythmia are the common manifestations of several inherited disorders. Abnormalities of the genetic makeup may directly affect proteins controlling cardiac excitability in a structurally normal heart. Other diseases manifest primarily with ventricular arrhythmias even though the genetic mutations cause structural abnormalities of the myocardium. This is the case of arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy. Groundbreaking discoveries, starting from the 1990s until the beginning of the current decade, have provided fundamental knowledge on the major genes that confer an increased risk of arrhythmias and sudden death. Stems of such knowledge are the availability of genetic diagnosis, genotype-phenotype correlation, and genotypebased risk stratification schemes currently used in the clinical practice. This review provides a concise description of the known genes and key mechanisms involved in the pathogenesis of inherited arrhythmias. In addition, we outline possibilities, limitations, advantages, and potential threats of genetically screening for these genes. © Springer Science+Business Media, LLC 2012. Source

Dybkova N.,University of Gottingen | Sedej S.,Medical University of Graz | Napolitano C.,Molecular Cardiology Laboratories | Napolitano C.,New York University | And 12 more authors.
Journal of the American College of Cardiology | Year: 2011

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 CaMKIIδc transgenic mice were crossbred with RyR2 R4496C+/- knock-in mice. Results Heart weight-to-body weight ratio in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice. Sarcoplasmic reticulum Ca 2+ content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice. However, relaxation parameters and Ca 2+ decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2 R4496C mice. Sarcoplasmic reticulum Ca 2+ spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca 2+ leak in CaMKIIδc/RyR2 R4496C versus CaMKIIδc myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIδc/ RyR2 R4496C versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIδc/RyR2 R4496C mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p < 0.05) after 14 weeks. Conclusions CaMKIIδc 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. © 2011 American College of Cardiology Foundation. Source

Napolitano C.,Molecular Cardiology Laboratories | Novelli V.,Molecular Cardiology Laboratories | Francis M.D.,Molecular Cardiology Laboratories | Priori S.G.,University of Pavia
Current Opinion in Genetics and Development | Year: 2015

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. © 2015 Elsevier Ltd. Source

Monteforte N.,Molecular Cardiology Laboratories | Cerrone M.,New York University
Cardiac Electrophysiology Clinics | Year: 2010

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by a structurally normal heart and high lethality beginning in early childhood. The identification of its genetic bases made possible the discovery that arrhythmias are caused by intracellular calcium dysregulation. In the 9 years since the description of the genetic substrate of the disease, we have witnessed remarkable progress in the unraveling of the molecular mechanisms underlying its arrhythmogenesis. The impact of these discoveries extends beyond the field of inherited arrhythmias and sheds new light on the arrhythmogenic mechanisms in some more prevalent diseases characterized by abnormal calcium regulation, such as heart failure. Additionally, basic research studies led to the exploration of new therapeutic strategies with potential clinical impact in the near future in reducing the still high incidence of sudden death associated with these conditions. In the current review, the authors discuss the clinical and genetic features of CPVT, highlighting pathophysiologic insights derived from experimental research and future therapeutic targets. © 2010 Elsevier Inc. Source

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