Stephen L. Winters

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

BACKGROUNDnL-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.nnnOBJECTIVEnThe 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.nnnMETHODS/RESULTSnOverall, 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.nnnCONCLUSIONnThe 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.

Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.

BACKGROUNDnAdenosine triphosphate (ATP)-sensitive potassium cardiac channels consist of inward-rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9).nnnOBJECTIVEnTo examine the association of mutations in KCNJ8 with Brugada syndrome (BrS) and early repolarization syndrome (ERS) and to elucidate the mechanism underlying the gain of function of ATP-sensitive potassium channel current.nnnMETHODSnDirect sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch-clamp methods were used to study mutated channels expressed in TSA201 cells.nnnRESULTSnThe same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS probands but was absent in 430 alleles from ethnically matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole-cell patch-clamp studies showed a 2-fold gain of function of glibenclamide-sensitive ATP-sensitive potassium channel current when KCNJ8-S422L was coexpressed with SUR2A-wild type. Inside-out patch-clamp evaluation yielded a significantly greater half maximal inhibitory concentration for ATP in the mutant channels (785.5 ± 2 vs 38.4 ± 3 μM; n = 5; P <.01), pointing to incomplete closing of the ATP-sensitive potassium channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/corrected QT intervals, likely owing to their effect to induce an increase in L-type calcium channel current (I(Ca-L)).nnnCONCLUSIONSnOur results support the hypothesis that KCNJ8 is a susceptibility gene for BrS and ERS and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in ATP-sensitive potassium channel current is due to reduced sensitivity to intracellular ATP.

Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators

February 2001 PACE, Vol. 24 Introduction In view of advances in implantable cardioverter defibrillator (ICD) therapy and a paucity of published guidelines for the management of ICDs, the North American Society of Electrophysiology and Pacing, in conjunction with the American College of Cardiology, convened a full day conference on this subject on May 14, 1996. This publication reflects the proceedings from the conference entitled, Consensus Statement on Implantable Cardioverter-Defibrillators: Patient Access to Therapy, Indications, and Guidelines for Use and has been amended to reflect developments and data published since that time. A full list of the participants in this conference is listed below*. Issues presented have been updated and revised to reflect developments and data, which have been published since the meeting was held. The document has gone through a detailed review process of three blinded peer reviewers and four members of the board of trustees. The greater board of trustees then reviewed the document to ensure its accuracy and appropriate reflection of a consensus from the governing members of the North American Society of Pacing and Electrophysiology. Background During the two decades since the first human implantation of an automatic defibrillator (ICD), many refinements in generator and lead technology have occurred, as the use of such devices has risen exponentially. Between 1993 and 1999, the number of ICD units implanted annually in the United States rose from 15,307 to approximately 50,100, an increase of 227%. For the year 2000, implantation of 61,000 ICD systems in the United States and 81,000 worldwide had been projected. Assuming an average cost of

Ventricular Arrhythmia Inducibility Predicts Subsequent ICD Activation in Nonischemic Cardiomyopathy Patients: A DEFINITE Substudy

22,000 per device in the United States, the total domestic expenditure for 2000 has been estimated at 1.342 billion dollars. The projected worldwide expenditure for the year 2000 was estimated at approximately 1.620 billion dollars.

Safety and efficacy of transvenous high-voltage implantable cardioverter-defibrillator leads in high-risk hypertrophic cardiomyopathy patients

Objectives: We evaluated whether electrophysiologic (EP) inducibility predicts the subsequent occurrence of spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial.

Relation of 12-Lead Electrocardiogram Patterns to Implanted Defibrillator-Terminated Ventricular Tachyarrhythmias in Hypertrophic Cardiomyopathy

BACKGROUNDnThe implantable cardioverter-defibrillator (ICD) prevents sudden cardiac death in high-risk patients with hypertrophic cardiomyopathy (HCM). However, recently concerns have been raised regarding the performance of transvenous high-voltage ICD leads (HVL) in this population.nnnOBJECTIVEnThe purpose of this retrospective, multicenter study was to assess the safety and efficacy of HVL in high-risk HCM patients.nnnMETHODSnThe study population consisted of HCM patients who received HVL ICDs and were subsequently followed at seven centers in the United States. Kaplan-Meier survival rates were calculated for HVL and patients. HVL failure was a malfunction caused by a noniatrogenic defect.nnnRESULTSnBetween 1992 and 2007, 324 HCM patients (mean age 47 +/- 16 years) received 343 HVL from three major manufacturers. The average HVL implant duration was 3.3 +/- 2.8 years. Overall, the HVL failure rate was 1.4%/year. However, two models (Sprint Fidelis and Transvene, Medtronic, Inc.) accounted for 60% of HVL failures. Survival probabilities for HVL and patients at 10 years were 93% and 91%, respectively. No deaths or serious injuries were reported, although inappropriate shocks occurred in 12% of cases.nnnCONCLUSIONSnThis multicenter experience shows that HVLs are safe and effective in high-risk HCM patients. However, differences in failure rates were found between lead models.

Inappropriate defibrillator shocks from depolarization : Repolarization mismatch in a patient with hypertrophy cardiomyopathy

Electrocardiographic (ECG) abnormalities are common in hypertrophic cardiomyopathy (HC) and have been associated with the distribution of left ventricular hypertrophy and myocardial fibrosis. Such abnormalities may predispose patients to electrophysiologic instability, ventricular arrhythmias, and sudden cardiac death (SCD). We studied 330 patients with HC who were judged clinically to be at high risk for SCD and therefore received automatic implantable cardioverter-defibrillators (ICDs). Surface 12-lead electrocardiograms acquired at the time of ICD implantation were analyzed and the ECG characteristics of patients with appropriate device interventions for ventricular tachycardia and fibrillation were compared to those patients without appropriate device interventions. The 330 patients were followed for 3.7 +/- 3.0 years after implantation and 57 patients (17%) had appropriate discharges. No differences in the ECG characteristics of patients with and without appropriate device interventions were identified. Markedly increased ECG voltages, QRS duration, left or rightward QRS axis, abnormal Q waves, and QTc or QT dispersion were not associated with appropriate ICD discharge. Conversely, normal electrocardiograms and electrocardiograms normal except for a repolarization abnormality in only 1 anatomic distribution were not associated with freedom from ICD discharge. Moreover, no combination of ECG variables was associated with the likelihood of an appropriate ICD discharge. In conclusion, in a cohort of patients with HC selected because of their high risk for SCD, 12-lead surface electrocardiogram did not predict subsequent appropriate ICD intervention for ventricular tachyarrhythmias and was not useful in risk stratification for sudden death.

Utility and Safety of Axillo-subclavian Venous Imaging with Carbon Dioxide (CO2) Prior to Chronic Lead System Revisions

Despite wide use of dedicated bipolar sensing electrodes in implantable cardioverter‐defibrillator (ICD) systems, oversensing occasionally occurs, leading to unwarranted shocks or antitachycardia pacing. This case report highlights an individual with hypertrophic cardiomyopathy (HCM) who experienced inappropriate shocks from oversensing of repolarization electrograms (T‐waves). During the implantation procedure, no excessive T‐wave amplitudes were detected during sinus rhythm, ventricular pacing, or induced ventricular fibrillation. T‐wave oversensing leading to shocks only developed after maturation of the lead–tissue interface. An adequate safety margin for discrimination between ventricular electrograms and T‐waves could not be assured. Thus, insertion of a new dedicated pacing‐sensing electrode was required. The degree to which intracardiac repolarization signals may be heightened in patients with HCM has not been investigated systematically. However, a relative decrease in the ventricular electrogram amplitude without a concomitant decline of the intracardiac T‐wave amplitude appears to have led to the problem in this patient. Special caution in technique and device selection with a particular emphasis on T‐wave sensing may be prudent when ICDs are implanted in individuals with HCM. Additional programmable variables may also be beneficial in such cases.

Clinical Course and Quality of Life in High-Risk Patients With Hypertrophic Cardiomyopathy and Implantable Cardioverter-Defibrillators

Background: u2002Prior to attempting placement of one or more electrodes to revise existing rhythm control devices, patency of the central veins should be documented, in view of a high incidence of significant chronic occlusions. Since iodinated contrast venography may be contraindicated in select situations, imaging of the axillo‐subclavian venous system with gaseous carbon dioxide (CO2) was evaluated prospectively in 23 consecutive individuals who were considered for revision of previously implanted pacemaker or automatic cardioverter defibrillator lead systems.

Inappropriate antitachycardia pacing: a dangerous component failure or pseudotherapy?

Background: High-risk patients with hypertrophic cardiomyopathy (HCM) are identified by contemporary risk stratification and effectively treated with implantable cardioverter-defibrillators (ICDs). However, long-term HCM clinical course after ICD therapy for ventricular tachyarrhythmias is incompletely understood. Methods and Results: Cohort of 486 high-risk HCM patients with ICDs was assembled from 8 international centers. Clinical course and device interventions were addressed, and survey questionnaires assessed patient anxiety level and psychological well-being related to ICD therapy. Of 486 patients, 94 (19%) experienced appropriate ICD interventions terminating ventricular tachycardia/ventricular fibrillation, 3.7% per year for primary prevention, over 6.4±4.7 years. Of 94 patients, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions; 74 of these 87 (85%) remained in classes I/II without significant change in clinical status over the subsequent 5.9±4.9 years (up to 22). Among the 94 patients, there was one sudden death (caused by device failure; 1.1%); 3 patients died from other HCM-related processes unrelated to arrhythmic risk (eg, end-stage heart failure). Post-ICD intervention, freedom from HCM mortality was 100%, 97%, and 92% at 1, 5, and 10 years, distinctly lower than in ischemic or nonischemic cardiomyopathy ICD trials. HCM patients with ICD interventions reported heightened anxiety in expectation of future shocks, but with intact general psychological well-being and quality of life. Conclusions: In HCM, unlike ischemic heart disease, prevention of sudden death with ICD therapy is unassociated with significant increase in cardiovascular morbidity or mortality, or transformation to heart failure deterioration. ICD therapy does not substantially impair overall psychological and physical well-being.