Faculty Bibliography

OBJECTIVES: This study compared the effects of beta-blockade on transmural and spatial dispersion of repolarization (TDR and SDR, respectively) between the LQT1 and LQT2 forms of congenital long QT syndrome (LQTS). BACKGROUND: The LQT1 form is more sensitive to sympathetic stimulation and more responsive to beta-blockers than either the LQT2 or LQT3 forms. METHODS: Eighty-seven-lead, body-surface electrocardiograms (ECGs) were recorded before and after epinephrine infusion (0.1 microg/kg body weight per min) in the absence and presence of oral propranolol (0.5-2.0 mg/kg per day) in 11 LQT1 patients and 11 LQT2 patients. The Q-T(end) interval, the Q-T(peak) interval and the interval between T(peak) and T(end) (T(p-e)), representing TDR, were measured and averaged from 87-lead ECGs and corrected by Bazett's method (corrected Q-T(end) interval [cQT(e)], corrected Q-T(peak) interval [cQT(p)] and corrected interval between T(peak) and T(end) [cT(p-e)]). The dispersion of cQT(e) (cQT(e)-D) was obtained among 87 leads and was defined as the interval between the maximum and minimum values of cQT(e). RESULTS: Propranolol in the absence of epinephrine significantly prolonged the mean cQT(p) value but not the mean cQT(e) value, thus decreasing the mean cT(p-e) value in both LQT1 and LQT2 patients; the differences with propranolol were significantly larger in LQT1 than in LQT2 (p < 0.05). The maximum cQT(e), minimum cQT(e) and cQT(e)-D were not changed with propranolol. Propranolol completely suppressed the influence of epinephrine in prolonging the mean cQT(e), maximum cQT(e) and minimum cQT(e) values, as well as increasing the mean cT(p-e) and cQT(e)-D values in both groups. CONCLUSIONS: Beta-blockade under normal sympathetic tone produces a greater decrease in TDR in the LQT1 form than in the LQT2 form, explaining the superior effectiveness of beta-blockers in LQT1 versus LQT2. Beta-blockers also suppress the influence of sympathetic stimulation in increasing TDR and SDR equally in LQT1 and LQT2 syndrome

AIMS: Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome. METHODS AND RESULTS: We recorded a 12-lead electrocardiogram continuously before and after bolus injection (0.1 microg x kg(-1)) of epinephrine followed by continuous infusion (0.1 microg x kg(-1) min(-1)) in 12 LQT1, 10 LQT2, 6 LQT3, and 13 control patients. The QT intervals and previous RR intervals of all beats were measured semi-automatically, and the QTc intervals of all beats were calculated by Bazett's method. The dynamic response of the RR interval to epinephrine was no different between the four groups. The QTc was prolonged remarkably (477+/-42 to 631+/- 59 ms; P<0.0005, % delta prolongation =+32%) as the RR was maximally decreased (at peak of epinephrine), and remained prolonged at steady state conditions of epinephrine (556+/-56 ms; P<0.0005 vs baseline, +17%) in LQT1 patients. Epinephrine also prolonged the QTc dramatically (502+/-23 to 620+/-39 ms; P<0.0005, +24%) at peak of epinephrine in LQT2 patients, but this shortened to baseline levels at steady state (531+/-25 ms; P=ns vs baseline, +6%). The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state. CONCLUSION: Our data suggest that the dynamic response of ventricular repolarization to sympathetic stimulation differs between LQT1, LQT2 and LQT3 syndromes, and may explain why the trigger of cardiac events differs between the genotypes

Pathogenesis of familial inherited arrhythmias is being progressively clarified thanks to the insights provided by molecular biology and by functional studies. Transmembrane or intracellular ion channel mutations have been identified in genetically determined forms of polymorphic ventricular tachycardia and sudden death such as catecholaminergic ventricular tachycardia, long QT syndrome, and Brugada syndrome. The role of molecular abnormalities in the genesis of monomorphic idiopathic ventricular tachycardias is less well defined, mainly because of the lack of a Mendelian pattern of inheritance. Interestingly, the presence of somatic mutations has been suggested as the mechanism for monomorphic ventricular tachycardia originating from the right ventricular outflow tract. The future goals for the application of molecular genetics to the management of cardiac arrhythmias will be to apply molecular genetics for a better risk stratification of affected individuals and to aim for the identification of gene-specific treatment of idiopathic ventricular tachycardia

BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002). CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator

The novel insights provided by the molecular genetic applied to the study of cardiac arrhythmias have just started to scratch the surface of the complex relationships between the genetic abnormalities of ion channel structure and the susceptibility to life threatening ventricular arrhythmias. These crucial pieces of information that are being gathered may have broader implications than those concerning the relatively restricted field of inherited arrhythmogenic diseases. An area of possible crucial application of the molecular genetic of cardiac ion channels, is the so-called drug-induced Torsade de Pointes (TdP) and acquired Long QT Syndrome. This condition is defined as an abnormal response to the administration of a variety of drugs which, in susceptible subjects, may induce an excessive QT interval prolongation and possibly lead to the onset of life-threatening ventricular tachyarrhythmias (drug-induced TdP). The 'proof of concept' that sub-clinical variants of the inherited long QT syndrome may play a causative role has been recently brought to light. However, large population-based studies are still needed in order to quantify the epidemiological relevance of such findings. The future developments in this area of research will lead to the availability of pre-prescription genotyping for the identification of the susceptible subjects and to the development of safer drugs

BACKGROUND: The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. METHODS AND RESULTS: A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc. CONCLUSION: Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations

Molecular genetics applied to the study of inherited arrhythmogenic diseases has profoundly modified our understanding of cardiac electrophysiology providing new information on the crucial pathophysiological role of cardiac ion channels. These data are now putting forth innovative strategies for clinical management of the affected patients. Among these conditions, long QT syndrome (LQTS) was the first to enter the 'genetic era', and nowadays the availability of large population of patients with known mutation allows to draw meaningful genotype-phenotype correlation and genetic-based risk stratification. However, despite the remarkable impact on knowledge, several still poorly defined issues limit the translation of such information into more effective therapeutic stratigies. As an example, despite the evidence of a significant QT shortening potential, the gene-specific therapy of LQTS has still to prove its impact upon the risk of cardiac events. The present article reviews the most critical findings obtained in the last decade in the field of genetic of LQTS in the attempt of underlying its current applicability, limitations and the future perspectives of this knowledge in the management of affected patients

OBJECTIVES: This study assessed the phenotypic variability of LQTS in carriers with the same and with different mutations in the LQT2 gene. BACKGROUND: Mutations of ion-channel genes are known to cause the long QT syndrome (LQTS), a disorder associated with distinctive genotypic-specific electrocardiographic patterns and variable clinical expression. METHODS: Clinical and electrocardiographic characteristics were assessed in five large LQTS families, each with a different mutation of the HERG gene (LQT2; n = 469, 69% genotyped, 102 carriers). One mutation was located on the N-terminus and the other four on the C-terminus of the HERG channel protein. RESULTS: The QTc duration and the frequency of cardiac events (syncope and LQTS-related cardiac arrest/death) were similar among carriers with the five HERG mutations. QTc was as variable in carriers of the same mutation as it was among carriers with different HERG mutations (P = 0.19). Qualitative assessment of the electrocardiograms revealed extensive intra-and interfamilial variability in T-wave morphology. Among carriers with multiple electrocardiograms extending over 2 to 7 years, variation in QTc over time was minimal. A strong association was found between QTc and the occurrence of cardiac events in carriers of all five mutations. CONCLUSIONS: The clinical expression of LQTS was equally variable in carriers from families with the same or different HERG mutations. These findings highlight the complexity of the clinical phenotype in this Mendelian dominant disorder and suggest that one or more modifier genes contribute to the variable expression of this syndrome

The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in 'leaky' channels. SR calcium leak during diastole can generate 'delayed after depolarizations' that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation