A hERG mutation E1039X produced a synergistic lesion on IKs together with KCNQ1-R174C mutation in a LQTS family with three compound mutations.

Congenital long QT syndrome (LQTS) caused by compound mutations is usually associated with more severe clinical phenotypes. We identified a LQTS family harboring three compound mutations in different genes (KCNQ1-R174C, hERG-E1039X and SCN5A-E428K). KCNQ1-R174C, hERG-E1039X and SCN5A-E428K mutations and/or relevant wild-type (WT) cDNAs were respectively expressed in mammalian cells. IKs-like, IKr-like, INa-like currents and the functional interaction between KCNQ1-R174C and hERG-E1039X channels were studied using patch-clamp and immunocytochemistry techniques. (1) Expression of KCNQ1-R174C alone showed no IKs. Co-expression of KCNQ1-WT + KCNQ1-R174C caused a loss-of-function in IKs and blunted the activation of IKs in response to isoproterenol. (2) Expression of hERG-E1039X alone and co-expression of hERG-WT + hERG-E1039X negatively shifted inactivation curves and decelerated the recovery time from inactivation. (3) Expression of SCN5A-E428K increased peak INa, but had no effect on late INa. (4) IKs and IKr interact, and hERG-E1039X caused a loss-of-function in IKs. (5) Immunocytochemical studies indicated that KCNQ1-R174C is trafficking defective and hERG-E1039X is defective in biosynthesis/degradation, but the abnormities were rescued by co-expression with WT. Thus, KCNQ1-R174C and hERG-E1039X disrupted IKs and IKr functions, respectively. The synergistic lesion, caused by KCNQ1-R174C and hERG-E1039X in IKs, is very likely why patients showed more severe phenotypes in the compound mutation case.

Recent advances in genetic testing and counseling for inherited arrhythmias.

Inherited arrhythmias, such as cardiomyopathies and cardiac ion channelopathies, along with coronary heart disease (CHD) are three most common disorders that predispose adults to sudden cardiac death. In the last three decades, causal genes in inherited arrhythmias have been successfully identified. At the same time, it has become evident that the genetic architectures are more complex than previously known. Recent advancements in DNA sequencing technology (next generation sequencing) have enabled us to study such complex genetic traits. This article discusses indications for genetic testing of patients with inherited arrhythmias. Further, it describes the benefits and challenges that we face in the era of next generation sequencing. Finally, it briefly discusses genetic counseling, in which a multidisciplinary approach is required due to the increased complexity of the genetic information related to inherited arrhythmias.

The radio frequency catheter ablation of inter-fascicular reentrant tachycardia: new insights into the electrophysiological and anatomical characteristics.

INTRODUCTION: Macro-reentrant ventricular tachycardias (VT) utilizing the bundle branches and Purkinje fibers have been reported as verapamil sensitive VT (idiopathic left VT), bundle branch reentrant VT (BBRT) and inter-fascicular reentrant tachycardia (inter-fascicular VT). However, diagnostic confusion exists with these VTs due to the difficulty in differentiating between them with conventional electrophysiological (EP) studies. The aim of this study was to clarify the EP and anatomical entity of inter-fascicular VT, and provide successful methods for the radio frequency catheter ablation (RFCA) of inter-fascicular VT. METHODS AND RESULTS: A total of nine patients were included in this study. All patients were diagnosed with idiopathic left VT in the first session, and underwent a second session after a failed RFCA. Detailed EP studies guided by a three-dimensional (3D) mapping system were performed to further analyze the VTs. All VTs were finally diagnosed as inter-fascicular VT. They were successfully cured with RFCA targeting the left anterior or posterior fascicle, which was regarded as a requisite part of the reentrant circuit of the inter-fascicular VT, using 3D and fluoroscopic images combined with a detailed EP investigation instead of the conventional RFCA method targeting Purkinje potentials for the RFCA of idiopathic left VT. CONCLUSIONS: Inter-fascicular VT could be misdiagnosed as idiopathic left VT due to the limitations of the conventional EP study. Failed RFCA in presumptive idiopathic left VT cases has to be carefully investigated by further analysis, and a tailored RFCA strategy targeting the requisite portions of the left fascicles in the inter-fascicular VT reentrant circuit will be required for the successful elimination of the inter-fascicular VT.

Early repolarization pattern: its ECG characteristics, arrhythmogeneity and heritability.

Early repolarization (ER) has been accepted as a benign ECG variant for decades. Two seminal studies challenged this notion and have demonstrated that ER pattern is associated with an increased risk of arrhythmic and cardiac mortality in patients with idiopathic ventricular fibrillation (IVF) and in the general population. Recent clinical studies demonstrate its varying impact as an arrhythmogenic substrate on different diseases. For example, in ER syndrome, a primary electrical disease, ER appears as a major arrhythmogenic substrate for development of VF whereas in patients with coronary artery disease, an ER pattern may exist as a silent substrate, increasing the risk of VF during episodes of cardiac ischaemia. Due to the high prevalence of an ER pattern in the general population and a low VF event rate, it remains challenging to differentiate a malignant ER pattern from a benign form. Recent research suggests that a J-wave amplitude of more than 0.1 mV combined with a descending/horizontal ST segment may constitute a malignant ER pattern. Further studies are however necessary to evaluate its prognostic value for cardiac and arrhythmic death in the general population as well as in cases with a malignant ER pattern. While genetic testing has revealed putative causal DNA variants in sporadic cases, the lack of co-segregation with the disease in affected families suggests that ER syndrome is not monogenic but is likely a complex disorder influenced by multiple genetic as well as environmental factors.

Long term outcome of cavotricuspid isthmus cryoablation for the treatment of common atrial flutter in 180 patients: a single center experience.

OBJECTIVE: Recent literature has shown that common type atrial flutter (AFL) can recur late after cavotricuspid isthmus (CTI) catheter ablation using radiofrequency energy (RF). We report the long term outcome of a large group of patients undergoing CTI ablation using cryothermy for AFL in a single center. METHODS: Patients with AFL referred for CTI ablation were recruited prospectively from July 2001 to July 2006. Cryoablation was performed using a deflectable, 10.5 F, 6.5 mm tip catheter. CTI block was reassessed 30 min after the last application during isoproterenol infusion. Recurrences were evaluated by 12-lead ECG and 24 h Holter recording every clinic visit (1/3/6/9 and 12 months after the procedure and yearly thereafter) or if symptoms developed. RESULTS: The 180 enrolled patients had the following characteristics: 39 women (22%), mean age 58 years, no structural heart disease in 86 patients (48%), mean left atrium diameter 44+/-7 mm and mean left ventricular ejection fraction 57+/-7%. The average number of applications per patient was 7 (3 to 20) with a mean temperature and duration of -88 degrees C and 3 min, respectively. Acute success was achieved in 95% (171) of the patients. There were no complications. After a mean follow-up of 27+/-17 (from 12 to 60) months, the chronic success rate was 91%. The majority of the recurrences occurred within the first year post ablation. One hundred and twenty three patients had a history of atrial fibrillation (AF) prior to CTI ablation and 85 (69%) of those remained having AF after cryoablation. In 20 of 57 (35%) patients without a history of AF prior to CTI ablation, AF occurred during follow-up. CONCLUSIONS: This prospective study showed a 91% chronic success rate (range 12 to 60 months) for cryoablation of the CTI in patients with common type AFL and ratified the frequent association of AF with AFL.

Glaucoma as a complication of superselective ophthalmic angiography.

We report a case of glaucoma that resulted as a complication of superselective ophthalmic angiography in a 67-year-old man with a recurrent olfactory groove meningioma. Superselective angiography in the right ophthalmic artery was performed to confirm the orifice of the feeding arteries during preoperative embolization. Immediately after the fourth injection of contrast medium, the patient suffered from acute angle-closure glaucoma with elevation of intraocular pressure. Early treatment, including laser iridotomy, relieved the symptoms completely.