Faculty Bibliography

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca(2+)-signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat myocytes led to an increase in excitation-contraction coupling gain and to more frequent occurrences of spontaneous propagating (Ca2+ waves) and local Ca2+ signals (sparks) with respect to control cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a Ca2+ indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the increased occurrence of spontaneous Ca2+ sparks and waves was associated with a dramatic decrease in intra-SR [Ca2+]. Recombinant CASQ2WT and CASQ2R33Q exhibited similar Ca(2+)-binding capacities in vitro; however, the mutant protein lacked the ability of its WT counterpart to inhibit RyR2 activity at low luminal [Ca2+] in planar lipid bilayers. We conclude that the R33Q mutation disrupts interactions of CASQ2 with the RyR2 channel complex and impairs regulation of RyR2 by luminal Ca2+. These results show that intracellular Ca2+ cycling in normal heart relies on an intricate interplay of CASQ2 with the proteins of the RyR2 channel complex and that disruption of these interactions can lead to cardiac arrhythmia

Cardiologists are involved in evaluating the eligibility of athletes to practise competitive sport and they should therefore be able to identify the electrocardiographic markers of long QT syndrome (LQTS) and short QT syndrome (SQTS). An overview of the clinical criteria to perform measurement of QT interval on 12-lead electrocardiogram is provided herein and several instances in which the diagnosis of either LQTS or SQTS may leave the clinician uncertain are discussed. A critical appraisal of current recommendations for eligibility to competitive sport is also provided as well as some of the authors' personal opinions on the practice of recreational activities in patients with abnormal repolarization

Cardiovascular diseases (CVD) are the leading cause of mortality both in men and women. In Europe, about 55% of all females' deaths are caused by CVD, especially coronary heart disease and stroke. Unfortunately, however, the risk of heart disease in women is underestimated because of the perception that women are 'protected' against ischaemic heart disease. What is not fully understood is that women during the fertile age have a lower risk of cardiac events, but this protection fades after menopause thus leaving women with untreated risk factors vulnerable to develop myocardial infarction, heart failure, and sudden cardiac death. Furthermore, clinical manifestations of ischaemic heart disease in women may be different from those commonly observed in males and this factor may account for under-recognition of the disease. The European Society of Cardiology has recently initiated an extensive 'Women at heart' program to coordinate research and educational initiatives on CVD in women. A Policy Conference on CVD in Women was one of the first steps in the development of this program. The objective of the conference was to collect the opinion of experts in the field coming from the European Society of Cardiology member countries to: (1) summarize the state-of-the-art from an European perspective; (2) to identify the scientific gaps on CVD in women; and (3) to delineate the strategies for changing the misperception of CVD in women, improving risk stratification, diagnosis, and therapy from a gender perspective and increasing women representation in clinical trials. The Policy Conference has provided the opportunity to review and comment on the current status of knowledge on CVD in women and to prioritize the actions needed to advance this area of knowledge in cardiology. In the preparation of this document we intend to provide the medical community and the stakeholders of this field with an overview of the more critical aspects that have emerged during the discussion. We also propose some immediate actions that should be undertaken with the hope that synergic activities will be implemented at European level with the support of national health care authorities

The European Society of Cardiology (ESC) organized a one-day workshop with clinicians, health economic experts, and health technology appraisal experts to discuss the equity of patient access to novel medical technologies in Europe. Two index technologies were considered: implantable cardioverter defibrillators (ICDs) and drug-eluting stents (DES). The use of ICDs range from 35 implants/million population in Portugal to 166 implants/million population in Germany, whereas for implants of DES (as percentage of total stents) it is lowest in Germany at 14% and high in Portugal at 65%. These differences can in part be explained by a lack of structured implementation of guidelines, the direct cost in relation to the overall healthcare budget, and to differences in procedures and models applied by Health Technology Assessment (HTA) agencies in Europe. The workshop participants concluded that physicians need to be involved in a more structured way in HTA and need to become better acquainted with its methods and terminology. Clinical guidelines should be systematically translated, explained, disseminated, updated, and adopted by cardiologists in Europe. Clinically appropriate, consistent and transparent health economic models need to be developed and high-quality international outcome and cost data should be used. A process for funding of a technology should be developed after a positive recommendation from HTA agencies. Both the ESC and the national cardiac societies should build-up health economic expertise and engage more actively in discussions with stakeholders involved in the provision of healthcare

In the last few years, major advancement has been made in the understanding of the genetic basis of inherited arrhythmogenic diseases. Interestingly, the information obtained with the application of molecular genetics to these diseases is now influencing their clinical management, allowing gene-specific risk stratification and gene-specific management. The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene. Since then, several investigators have proposed novel therapeutic approaches based on the identification of the functional consequences of genetic mutations. In some instances, these novel therapies have already been introduced in clinical practice, and data are being collected to establish their long-term efficacy. In this review, we will summarize the current understanding of the molecular bases of inherited arrhythmias, with a specific focus toward discussing the most recent advancements toward the development of gene-specific therapies

Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited diseases predisposing to ventricular arrhythmias and sudden death. Genetic studies linked LQTS and BrS to mutations in genes encoding for cardiac ion channels. Recently, two novel missense mutations at the same codon in the gene encoding the cardiac Na+ channel (SCN5A) have been identified: Y1795C (causing the LQTS phenotype) and Y1795H (causing the BrS phenotype). Functional studies in HEK293 cells showed that both mutations alter the inactivation of Na+ current and cause a sustained Na+ current upon depolarisation. In this paper, a nine state Markov model was used to simulate the Na+ current in wild-type Na+ cardiac channel and the current alterations observed in Y1795C and Y1795H mutant channels. The model includes three distinct closed states, a conducting open state and five inactivation states (one fast-, two intermediate- and two closed-inactivation). Transition rates between these states were identified on the basis of previously published voltage-clamp experiments. The model was able to reproduce the experimental Na+ current in mutant channels just by altering the assignment of model parameters with respect to wild-type case. Parameter assignment was validated by performing action potential clamp experiments and comparing experimental and simulated I(Na) current. The Markov model was subsequently introduced in the Luo-Rudy model of ventricular myocyte to investigate 'in silico' the consequences on the ventricular cell action potential of the two mutations. Coherently with their phenotypes, the Y1795C mutation prolongs the action potential, while the Y1795H mutation causes only negligible changes in action potential morphology

Genetic analysis can be performed to identify the molecular substrate of inherited arrhythmogenic diseases; however, the role of this information in helping the management of patients is still debated. Here, we support the view that the practical value of genetic analysis is different in the various inherited conditions and that it is strongly influenced by the amount of information available in each disease about genotype-phenotype correlations. In some diseases, clinical management of patients is profoundly affected by the type of the underlying genetic defect; therefore, in these conditions, there is a high priority to introduce genetic analysis into clinical practice. In the absence of genotype-phenotype correlations, genetic testing still can be very useful when there is a clinical advantage in establishing presymptomatic diagnosis or when screening of family members may point to reproductive counseling. Finally, there is a high priority for introducing genetic testing for those genetic diseases in which a limited number of genes allow a high yield of successfully genotyped patients. We have developed a 'score' to compare the value of genetic testing in arrhythmogenic diseases and to convey our view that the clinical role of genetic analysis is different in the various inherited cardiomyopathies and channelopathies. Healthcare authorities should become responsive to the advancement of knowledge in this field and should help facilitate access to genotyping for families affected by those conditions in which genetic analysis provides useful information for clinical management