Faculty Bibliography

Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K(+) channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K(+) current (I(Ks) )], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Delta544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations

BACKGROUND: The ECG pattern of right bundle branch block and ST-segment elevation in leads V(1) to V(3) (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups. METHODS AND RESULTS: Sixty patients (45 males aged 40+/-15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33+/-38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%). CONCLUSIONS: At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants

BACKGROUND: Defects of the SCN5A gene encoding the cardiac sodium channel are associated with both the LQT3 subtype of long-QT syndrome and Brugada syndrome (BS). The typical manifestations of long-QT syndrome (QT interval prolongation) and BS (ST segment elevation in leads V1 through V3) may coexist in the same patients, which raises questions about the actual differences between LQT3 and BS. Intravenous flecainide is the standard provocative test used to unmask BS in individuals with concealed forms of the disease, and oral flecainide has been proposed as a treatment option for LQT3 patients because it may shorten their QT interval. METHODS AND RESULTS: We tested the possibility that in some LQT3 patients, flecainide might not only shorten the QT interval, but also produce an elevation of the ST segment. A total of 13 patients from 7 LQT3 families received intravenous flecainide using the protocol used for BS. As expected, QT, QTc, JT, and JTc interval shortening was observed in 12 of the 13 patients, and concomitant ST segment elevation in leads V1 through V3 (>/=2 mm) was observed in 6 of the 13. CONCLUSIONS: The data demonstrate that flecainide may induce ST segment elevation in LQT3 patients, raising concerns about the safety of flecainide therapy and demonstrating the existence of an intriguing overlap between LQT3 and BS

The aim of this study was to test the hypothesis that some cases of drug-induced arrhythmias depend on genetic predisposition. Excessive prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some drug-induced arrhythmias might represent cases of 'forme fruste' of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of drug-induced QT prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause drug-induced life-threatening arrhythmias and allow early identification of individuals at risk

BACKGROUND: In the long QT syndrome (LQTS) most life-threatening cardiac events occur in association with physical or emotional stress. However, a minority of patients dies suddenly during sleep; intriguingly, these sleep-related sudden deaths tend to cluster in families. The mechanism(s) underlying this phenomenon and the reason why it occurs in few selected families are unknown. Recently, some of the LQTS genes have been identified leading to three main subgroups (LQT1, LQT2, LQT3) associated respectively with mutations affecting the following ionic currents involved in the control of ventricular repolarization: I(Ks), I(Kr), I(Na). We have recently observed that cardiac events nighttime are rare in LQT1 and frequent in LQT3 patients. METHODS: We studied 26 LQTS patients all genotyped (11 LQT1, 9 LQT2, 6 LQT3) and 26 healthy controls matched by age and gender. Using a specific software, 24-hour ambulatory ECG recordings were performed and the QT interval was measured in order to allow comparison between QTc nighttime and daytime. RESULTS: The main finding is that while LQT1 patients show a trend for modest QTc shortening and LQT2 patients a trend for modest lengthening nighttime versus daytime, LQT3 patients show clear lengthening of the QTc nighttime. These changes are not explained by heart rate changes or by the use of beta-blockers. CONCLUSIONS: The marked tendency for further QT prolongation nighttime, which clearly increases arrhythmic risk, present among LQT3 patients and absent among LQT1 patients, provides an explanation for the gene-specific higher risk for sudden death during sleep for LQT3 compared to LQT1 patients

In five children from the same family who died after unexplained cardiac arrest, Brugada syndrome syndrome was suspected based on the transient manifestation of the typical electrocardiogram pattern in one of them. A mutation in the cardiac sodium-channel confirmed the diagnosis of Brugada syndrome, which suggests that this disease may cause sudden death in children

The long QT syndrome (LQTS) has often been considered as a model to study the abnormalities of cardiac repolarization in humans because it represents a pure electrical disease with no evidence of cardiac structural abnormalities. The arrhythmogenic potential of prolonged ventricular repolarization has been extensively studied both in experimental models and at the clinical level in LQTS patients, and many studies pointed to the pathogenetic role of the dispersion of ventricular recovery times (i.e., dispersion of ventricular repolarization). In the last few years, a new critical knowledge has been achieved thanks to the molecular biology techniques that are unveiling the genetic bases of LQTS. Indeed, the understanding of the genes and mutations that may cause the LQTS opened the way to understanding the molecular determinants of the altered ventricular repolarization that can be found in LQTS patients. From the clinical standpoint, the traditional tools applied for the detection and quantification of the dispersion of ventricular repolarization (monophasic action potential, QT dispersion) showed their effectiveness but also their limitations. More recently, the availability of new algorithms and the development of powerful computerized supports allowed the evaluation of innovative techniques, which now represent possible attractive alternatives intended to quantify the degree of repolarization abnormalities in LQTS patients and possibly to noninvasively quantify the risk of cardiac events

In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events