Mark Marieb

Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death

BACKGROUND L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

BACKGROUND BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart. OBJECTIVES The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Inappropriate Shocks Delivered by an ICD as a Result of Sensed Potentials from a Transcutaneous Electronic Nerve Stimulation Unit

Although the potential for transcutaneous electronic nerve stimulation (TENS) units to interfere with appropriate function of cardiac pacemakers is well documented, an adverse interaction between a TENS unit and an ICD has never been reported. We describe a patient in whom a TENS unit created an electrical artifact that was interpreted by a transvenous ICD as ventricular fibrillation, leading to the delivery of inappropriate therapy. TENS units should be used with caution in patients with ICDs.

Double sequential external shocks for refractory ventricular fibrillation

OBJECTIVES A technique for terminating refractory ventricular fibrillation is described. BACKGROUND Refractory ventricular fibrillation can occur in up to 0.1% of electrophysiologic studies. Animal studies have shown that rapid sequential shocks may reduce ventricular fibrillation threshold. METHODS Five patients of 2,990 consecutive patients in a 3-year period experienced refractory ventricular fibrillation during 5,450 routine electrophysiologic studies. Multiple shocks were delivered by means of a single defibrillator. Double sequential shocks were delivered externally 0.5 to 4.5 s apart by means of two defibrillators with separate pairs of electrodes. RESULTS In all patients, standard defibrillation was unsuccessful, but all were successfully resuscitated using the double sequential shocks. CONCLUSIONS This report stresses the importance of an additional defibrillator being readily available during electrophysiologic testing. This technique of rapid, double sequential external shocks may have general applicability, providing a simple and potentially lifesaving approach to refractory ventricular fibrillation.

Causes of impaired consciousness while driving a motorized vehicle

T frequency of motor vehicle accidents in patients previously diagnosed with ventricular arrhythmias or vasovagal syncope has been reported.1–5 However, the converse, namely, the incidence of arrhythmias and vasovagal syncope in patients presenting with impaired consciousness while driving, has not been previously determined. This information is critical to help guide evaluation and management decisions and avoid future potentially lethal incidents. Our study examines the incidence of different etiologies of impaired consciousness while driving in motorists referred to the electrophysiologic service for evaluation. • • • We retrospectively reviewed the records of all patients who presented with impaired consciousness while driving personal or commercial vehicles between November 1985 and March 2000 at the Hospital of Saint Raphael, New Haven, Connecticut. Impaired consciousness was defined as syncope or presyncope. Patients were excluded if impaired consciousness was believed to be related to alcohol intoxication, illicit drug use, or as a secondary event as a result of the trauma of the accident. In all, 71 patients were identified with unexplained impaired consciousness while driving, and were referred to the electrophysiologic service for further evaluation. These 71 patients represent the study group. Medical history, physical examination, electrocardiogram, pertinent laboratory data, and chest x-ray were recorded in all patients. The results of Holter and electrocardiographic monitoring, echocardiography, carotid ultrasound, electroencephalography, and brain imaging were also collected and analyzed. All 71 patients underwent electrophysiologic evaluation in addition to routine workup for impaired consciousness. Electrophysiologic evaluation included tilt-table testing, electrophysiologic studies, and interrogation of implantable cardiac defibrillators, if present. Patients with structural heart disease underwent electrophysiologic study as the initial test, followed by tilttable testing if no etiology was convincingly demonstrated by the electrophysiologic study. Patients without evidence for structural heart disease underwent a tilttable test followed by electrophysiologic study; if they gave a cogent history of rapid palpitations accompanying the event, the electrophysiologic study was the initial diagnostic study. Patients who had a cardiac defibrillator had the device interrogated as the initial strategy, with further evaluation only if no tachyarrhythmic events in the device’s memory log were temporally correlated with the driving-related incident. The tilt-table test was performed by tilting the patients to 70° for 30 minutes. If the patient remained asymptomatic and had no known coronary disease, an isoproterenol infusion was begun and its rate titrated to increase the baseline heat rate by 25% for an additional 15 minutes. A tilt-table test was considered positive if syncope or presyncope was elicited with consistent hemodynamic changes and prodromal symptoms similar to the clinical event. During electrophysiologic study, a supraventricular tachycardia was considered the cause of impaired consciousness if a sustained supraventricular tachycardia could be induced, with or without isoproterenol, with accompanying adverse changes in hemodynamics. Ventricular tachycardia was only considered to be the cause of impaired consciousness if sustained monomorphic ventricular tachycardia could be elicited or if long bursts of symptomatic nonsustained ventricular tachycardia were seen. Advanced atrioventricular block was diagnosed if the block could be produced at paced cycle lengths 500 ms, or if spontaneous or procainamideinduced infra-Hisian block was noted. Baseline characteristics, cardiovascular history, and diagnostic testing of the study group are listed in Table 1.Three patients had 2 events while driving and 3 patients had 3 driving-related events. A presumptive diagnosis for impaired consciousness was made in 57 of 71 patients (80%) based on clinical findings and test results (Figure 1). Vasovagal syncope was diagnosed in 21 patients (30%) in whom a suggestive history was supported by a positive tilttable test result. Eighteen patients (25%) had supraventricular tachycardia induced during electrophysiologic study. Ventricular tachycardia was confirmed in 12 patients (17%). In 6 patients, ventricular tachycardia was found upon interrogation of their cardiac defibrillators after the accident. In another 6 patients, ventricular tachycardia was induced at electrophysiologic study. Advanced atrioventricular block was documented in 7 patients (10%), vestibular disease in 1 patient, and a seizure in 1 patient who had a negative electrophysiologic study result and a positive 24-hour ambulatory electroencephalograph. Three patients had a positive tilt-table test as well as inducible supraventricular tachycardia at electrophysiologic study and were included in both of the previously mentioned categories. Treatment based on these established diagnoses prevented recurrent episodes of impaired consciousFrom the Hospital of Saint Raphael and Yale University School of Medicine, New Haven, Connecticut. Dr. Schoenfeld’s address is: Cardiac Electrophysiology and Pacer Laboratory, Hospital of Saint Raphael, 330 Orchard Street, Suite 210, New Haven, Connecticut 06511. E-mail: Mschoenfeld@srhs.org. Manuscript received November 15, 2002; revised manuscript received and accepted February 12, 2003.

Psychosocial and Cardiac Outcomes of Yoga for ICD Patients: A Randomized Clinical Control Trial

Because as many as 46% of implantable cardioverter defibrillator (ICD) patients experience clinical symptoms of shock anxiety, this randomized controlled study evaluated the efficacy of adapted yoga (vs usual care) in reducing clinical psychosocial risks shown to impact morbidity and mortality in ICD recipients.

Inability to communicate with ICDs: an underreported failure mode.

BLITZER, M.L., et al.: Inability to Communicate with ICDs: An Underreported Failure Mode. The inability to perform telemetry on an ICD may have many potential causes. We report three recently identified cases where such a finding was indicative of unexpected device failure. Two of these cases involved identical failure mechanisms resulting from arcing of current within the high voltage hybrid. This placed the device into a high current state that caused rapid and complete battery depletion. There were no company alerts issued regarding this systematic problem. A multicenter arrhythmia device/lead database would be extremely useful in providing timely and unbiased information concerning device problems.

Optic Neuropathy Following Amiodarone Therapy

Ocular changes during treatment with amiodarone are almost universal but are rarely serious. In this article we describe three patients from a single electrophysiology practice in whom optic neuropathy developed during treatment with amiodarone. All three patients were more than 65 years of age. The doses of amiodarone ranged from 100 to 400 mg/day, and the time intervals between the initiation of the amiodarone therapy and the appearance of first symptoms of optic neuropathy were 5 to 19 months. Two patients had bilateral involvement, and one had only unilateral involvement. Whether this result was due solely to amiodarone therapy, to the underlying poor health of these patients, or to the combination of these two factors is uncertain. These findings prompt us to recommend that all patients who receive amiodarone undergo complete ophthalmologic examinations, including careful evaluation of the ocular fundus regularly during such therapy. No randomized study had been undertaken to determine the true incidence of complications associated with this medication.

Extraction of a Micra Transcatheter Pacing System: First-in-human experience

Clinical trials investigating the safety and effectiveness of transcatheter leadless pacemakers in humans are ongoing. These devices offer the benefits of cardiac pacing with the potential for a significant decrease in many of the risks associated with conventional pacing systems, including hematoma formation, pneumothorax, lead-related complications, and vascular obstruction. Human evaluation of the Medtronic Micra Transcatheter Pacing System (Medtronic, Minneapolis, MN) began in 2013, and the device is currently undergoing clinical investigation. The devices are implanted via a femoral venous approach and use a novel tined system for fixation to the right ventricular endocardium. The pacemakers can be readily retrieved at the time of implantation, but no data exist regarding the ability to remove these devices in humans after the initial implantation procedure. We report the first successful extraction of a Micra Transcatheter Pacing System, 3 weeks after initial device implantation.

3D Real-Time Intracardiac Echocardiographic Visualization of Atrial Structures Relevant to Atrial Fibrillation Ablation

cardiac imaging is critical for the success of interventional electrophysiological procedures. Fluoroscopy is highly beneficial for real-time catheter visualization, but it uses ionizing radiation and fails to provide detailed cardiac anatomy. Magnetic resonance imaging and computed tomography