Faculty Bibliography

The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one Long QT syndrome type 3 (LQT3) and one Brugada syndrome (BrS) families, were investigated by means of numerical modeling of ventricular action potential (AP). A Markov model capable of reproducing a wild-type as well as a mutant sodium current (I(Na)) was identified and was included into the Luo-Rudy ventricular cell model for action potential (AP) simulation. The characteristics of endocardial, midmyocardial, and epicardial cells were reproduced by differentiating the transient outward current (I(TO)) and the ratio of slow delayed rectifier potassium (I(Ks)) to rapid delayed rectifier current (I(Kr)). Administration of flecainide and mexiletine was simulated by appropriately modifying I(Na), calcium current (I(Ca)), I(TO), and I(Kr). Y1795C prolonged AP in a rate-dependent manner, and early afterdepolarizations (EADs) appeared during bradycardia in epicardial and midmyocardial cells; flecainide and mexiletine shortened AP and abolished EADs. Y1795H resulted in minimal changes in the APs; flecainide but not mexiletine induced APs heterogeneity across the ventricular wall that accounts for the ST segment elevation induced by flecainide in Y1795H carriers. The AP abnormalities induced by Y1795H and Y1795C can explain the clinically observed surface ECG phenotype. For the first time by modeling the effects of flecainide and mexiletine, we are able to gather mechanistic insights on the response to drugs administration observed in affected patients

BACKGROUND: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. METHODS: We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. RESULTS: Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. CONCLUSIONS: Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons

Several relatively uncommon, but important cardiovascular diseases are associated with increased risk for acute cardiac events during exercise (including sudden death), such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and myo-pericarditis. Practising cardiologists are frequently asked to advise on exercise programmes and sport participation in young individuals with these cardiovascular diseases. Indeed, many asymptomatic (or mildly symptomatic) patients with cardiomyopathies aspire to a physically active lifestyle to take advantage of the many documented benefits of exercise. While recommendations dictating the participation in competitive sport for athletes with cardiomyopathies and myo-pericarditis have recently been published as a consensus document of the European Society of Cardiology, no European guidelines have addressed the possible participation of patients with cardiomyopathies in recreational and amateur sport activities. The present document is intended to offer a comprehensive overview to practising cardiologists and sport physicians of the recommendations governing safe participation in different types of competitive sport, as well as the participation in a variety of recreational physical activities and amateur sports in individuals with cardiomyopathies and myo-pericarditis. These recommendations, based largely on the experience and insights of the expert panel appointed by the European Society of Cardiology, include the most up-to-date information concerning regular exercise and sports activity in patients with cardiomyopathies and myo-pericarditis

The European Society of Cardiology (ESC) has recently promoted the 'Women at Heart' program in order to organize initiatives targeted at promoting research and education in the field of cardiovascular diseases in women. Comparisons of the gender differences in specific disease and treatment trends across Europe are provided by analyzing data from the Euro Heart Surveys. A Policy Conference has been organized with the objective to summarize the state of the art from an European perspective, to identify the scientific gaps and to delineate the strategies for changing the misperception of cardiovascular diseases in women, improving risk stratification, diagnosis, and therapy from a gender perspective and increasing women representation in clinical trials. A Statement from the Policy Conference has been provided and published in the European Heart Journal. Synergic activities should be undertaken at European level with the support of national scientific societies, European institutions, national health care authorities, patients' associations, and foundations. The commitment of the Board of the ESC is that these initiatives contribute to increase the awareness across Europe that cardiovascular disease is the primary cause of death in women and to improve the knowledge of risk factors, presentation and treatment of cardiovascular diseases in women

Beta-adrenergic receptor-mediated cAMP or protein kinase A (PKA)-dependent modulation of cardiac potassium currents controls ventricular action potential duration (APD) at faster heart rates. HERG (KCNH2) gene mutations are associated with congenital long-QT syndrome (LQT2) and affect IKr activity, a key determinant in ventricular repolarization. Physical activity or emotional stress often triggers lethal arrhythmias in LQT2 patients. Beta-adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3epsilon. In LQT2 families, we identified three novel heterozygous HERG mutations (G965X, R1014PfsX39, V1038AfsX21) in the C-terminus that led to protein truncation and loss of a PKA phosphorylation site required for binding of 14-3-3epsilon. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3epsilon is of physiological significance in humans. Upon co-expression with 14-3-3epsilon, mutant channels still bound 14-3-3epsilon but did not respond with a hyperpolarizing shift in voltage dependence as seen in wild-type channels. Co-expression experiments of wild-type and mutant channels revealed dominant-negative behavior of all three HERG mutations. Simulations of the effects of sympathetic stimulation of HERG channel activity on the whole-cell action potential suggested a role in rate-dependent control of APD and an impaired ability of mutant cardiac myocytes to respond to a triggered event or an ectopic beat. In summary, the attenuated functional effects of 14-3-3epsilon on C-terminally truncated HERG channels demonstrate the physiological importance of coupling beta-adrenergic stimulation and HERG channel activity

A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility to ventricular tachyarrhythmia and sudden cardiac death has been described by Brugada et al. in 1992. This disease is now frequently called 'Brugada syndrome' (BrS). The prevalence of BrS in the general population is unknown. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese). Syncope, typically occurring at rest or during sleep (in individuals in their third or fourth decades of life) is a common presentation of BrS. In some cases, tachycardia does not terminate spontaneously and it may degenerate into ventricular fibrillation and lead to sudden death. Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance. In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability. Since the use of the implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest, the identification of high-risk subjects is one of the major goals in the clinical decision-making process. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients with multiple recurrences

CONTEXT: Analysis of predictors of cardiac events in hereditary long-QT syndrome (LQTS) has primarily considered syncope as the predominant end point. Risk factors specific for aborted cardiac arrest and sudden cardiac death have not been investigated. OBJECTIVE: To identify risk factors associated with aborted cardiac arrest and sudden cardiac death during adolescence in patients with clinically suspected LQTS. DESIGN, SETTING, AND PARTICIPANTS: The study involved 2772 participants from the International Long QT Syndrome Registry who were alive at age 10 years and were followed up during adolescence until age 20 years. The registry enrollment began in 1979 at 5 cardiology centers in the United States and Europe. MAIN OUTCOME MEASURES: Aborted cardiac arrest or LQTS-related sudden cardiac death; follow-up ended on February 15, 2005. RESULTS: There were 81 patients who experienced aborted cardiac arrest and 45 who had sudden cardiac death; 9 of the 81 patients who had an aborted cardiac arrest event experienced subsequent sudden cardiac death. Significant independent predictors of aborted cardiac arrest or sudden cardiac death during adolescence included recent syncope, QTc interval, and sex. Compared with those with no syncopal events in the last 10 years, patients with 1 or 2 or more episodes of syncope 2 to 10 years ago (but none in the last 2 years) had an adjusted hazard ratio (HR) of 2.7; (95% confidence interval [CI], 1.3-5.7; P<.01) and an adjusted HR of 5.8 (95% CI, 3.6-9.4; P<.001), respectively, for life-threatening events; those with 1 syncopal episodes in the last 2 years had an adjusted HR of 11.7 (95% CI, 7.0-19.5; P<.001) and those with 2 or more syncopal episodes in the last 2 years had an adjusted HR of 18.1 (95% CI, 10.4-31.2; P<.001). Irrespective of events occurring more than 2 years ago, QTc of 530 ms or longer was associated with increased risk (adjusted HR, 2.3; 95% CI, 1.6-3.3; P<.001) compared with those having a shorter QTc. Males between the ages of 10 and 12 years had higher risk than females (HR, 4.0; 95% CI, 1.8-9.2; P = .001), but there was no significant risk difference between males and females between the ages of 13 and 20 years. Among individuals with syncope in the past 2 years, beta-blocker therapy was associated with a 64% reduced risk (HR, 0.36; 95% CI, 0.18-0.72; P<.01). CONCLUSIONS: In LQTS, the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. Among patients with recent syncope, beta-blocker treatment was associated with reduced risk