Faculty Bibliography

OBJECTIVES: We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS). BACKGROUND: The LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms. METHODS: Sixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes. RESULTS: Patients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005). CONCLUSIONS: In this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations

BACKGROUND: The possibility of saving persons with sudden cardiac arrest (SCA) lowers of 10% every minute since the beginning of the event. The early defibrillation (within 4 min) of a person with SCA performed by first responders suitably trained increases the survival rate up to 50%. The basic aim is that early defibrillation is performed as soon as possible by the first responder. METHODS: Within the Public Access Defibrillation (PAD) 'Napoli Cuore' Project, 220 highway patrol agents of the Campania Region district were trained through theoretical and practical courses to acquire suitable psychomotor skills to perform the first aid. The learning evaluation was performed with a written exam and a practical test to assess how much every agent had learned about basic life support-defibrillation (BLS-D) schemes. RESULTS: 98.5% of the participants passed the exams and obtained the BLS-D rescuer license, and 15.5% of them obtained the highest score. The analysis of the report cards showed that most of the participants expressed an excellent opinion about this experience. CONCLUSIONS: To implement a PAD project it is necessary to awaken all the structures involved in the campaign against SCA. Hence, it is important that all emergency specialists, public institutions and police departments work all together to make everyone feels safe

220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (InsP(3)) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP(3) receptor

Among several conditions that can be responsible for sudden cardiac death (SCD), an important role is played by long QT syndrome (LQTS). LQTS is a congenital electric heart disease that can be asymptomatic or have very severe clinical manifestation, leading to cardiac arrest. In fact, the first manifestation of LQTS can be hyperkinetic ventricular arrhythmias. The presence of LQTS should be considered in all cases of SCD where autopsy is negative for anatomic and histopathological findings. In these cases, after an accurate anamnesis, a genetic screening should always be performed. The screening on LQTS genes is performed on DNA extracted from paraffin-embedded tissues. Making a proper diagnosis in such cases can help to find new affected subjects among the family members of SCD victims and treat them. In these cases, if the pathologist does not make a correct diagnosis, can he or she be sued for malpractice?

This presentation deals with the molecular substrates of the inherited diseases leading to genetically determined cardiac arrhythmias and sudden death. In the first part of this article the current knowledge concerning the molecular basis of cardiac arrhythmias will be summarized. Second, we will discuss the most recent evidence showing that the picture of the molecular bases of cardiac arrhythmias is becoming progressively more complex. Thanks to the contribution of molecular genetics, the genetic bases, pathogenesis, and genotype-phenotype correlation of diseases--such as the long QT syndrome, the Brugada syndrome, progressive cardiac conduction defect (Lenegre disease), catecholaminergic polymorphic ventricular tachycardia, and Andersen syndrome--have been progressively unveiled and shown to have an extremely high degree of genetic heterogeneity. The evidence supporting this concept is outlined, with particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in terms of the relationships between genetic defect(s) and genotype(s), as well as gene-to-gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways

BACKGROUND: The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. METHODS AND RESULTS: We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. CONCLUSIONS: LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits