Dennis L. Kuchar

Prediction of serious arrhythmic events after myocardial infarction: Signal-averaged electrocardiogram, holter monitoring and radionuclide ventriculography

Noninvasive assessment was undertaken before hospital discharge in 210 patients who had recovered from acute myocardial infarction. This comprised signal-averaged electrocardiography, Holter monitoring and radionuclide left ventriculography. An abnormal signal-averaged electrocardiogram was defined as the presence of a low voltage signal less than 20 microV in the terminal 40 ms of the filtered QRS complex or a long filtered QRS complex greater than 120 ms. During a follow-up period of 6 months to 2 years (median 14 months), 15 patients had arrhythmic events: eight died suddenly and seven presented with sustained, symptomatic ventricular tachycardia. Using univariate analysis, abnormalities in each of the three noninvasive tests were able to predict arrhythmic events. Stepwise logistic regression demonstrated that each test was independently significant in predicting outcome, with a left ventricular ejection fraction less than 40% being the most powerful variable (beta = 2.8, p less than 0.005). This process generated an algorithm that allowed assessment of combinations of variables: the finding of an abnormal signal-averaged electrocardiogram in the presence of an ejection fraction less than 40% identified patients with a 34% probability of arrhythmic events. By contrast, in patients with left ventricular dysfunction but a normal signal-averaged tracing, the risk of arrhythmic events was 4% (p less than 0.001). This combination of variables was associated with a sensitivity of 80% and a specificity of 89%. Hence, using a combination of noninvasive tests after myocardial infarction, patients can be stratified according to risk of serious arrhythmic events.

Signal-averaged electrocardiogram for evaluation of recurrent syncope

Signal-averaged electrocardiography (ECG) was performed in 150 consecutive patients presenting with syncope, to determine its diagnostic role in identifying patients with ventricular tachycardia (VT) and in determining their long-term prognosis. Patients also underwent a standardized investigational protocol to independently determine a cause of syncope. Twenty-nine patients had a late potential, 107 had a normal signal-averaged electrocardiogram and 14 had bundle branch block on 12-lead ECG. Signal-averaged ECG identified a late potential in 16 of 22 patients with VT and was normal in 101 of 114 patients in whom syncope was attributed to causes other than VT or remained unexplained (sensitivity 73%, specificity 89%, predictive accuracy 55%). In patients with coronary artery disease, the predictive accuracy increased to 82%. Absence of a late potential identified a group of patients with a very low incidence of VT. During follow-up of 1 to 20 months (median 11), 15 patients (10%) died, 6 suddenly. There was no significant difference in survival or recurrence of syncope between patients with and without a late potential. Signal-averaged ECG can noninvasively identify patients with serious ventricular arrhythmias among an unselected group presenting with syncope.

Electrocardiographic Localization of the Site of Origin of Ventricular Tachycardia in Patients With Prior Myocardial Infarction

The utility of the 12 lead electrocardiogram (ECG) in identifying the site of origin of sustained ventricular tachycardia in patients with previous myocardial infarction was studied. A new mapping grid, based on biplanar fluoroscopic imaging of the heart, was utilized for the definition of left ventricular endocardial sites. On the basis of QRS configurations resulting from left ventricular endocardial pacing at disparate sites in 22 patients (Group I), ECG features that were specific for particular sites were identified and used to construct an algorithm. Apical and basal sites were differentiated by the QRS configuration in leads V4 and aVR, anterior and inferior sites by that in leads II, III and V6 and septal and lateral sites were differentiated using leads I, aVL and V1. The algorithm was used to predict the site of earliest endocardial activation during 44 episodes of sustained ventricular tachycardia in a second group of 42 patients (Group II) in a blinded fashion. Anterior sites were correctly predicted in 83% of cases, inferior sites in 84%, septal sites in 90% and lateral sites in 82% of cases. Apical and basal sites were each correctly predicted in 70% of cases, whereas intermediate sites were less well predicted (29 to 55%) on the basis of QRS configuration. Precise localization of the site of origin of ventricular tachycardia (in all three planes) was achieved in 17 cases (39%), and in 16 cases (36%) the site of origin was immediately adjacent to the predicted site. Prediction of the site of origin of ventricular tachycardia from the 12 lead ECG may serve as a useful, time-saving adjunct to, but not a substitute for, activation sequence mapping during ventricular tachycardia.

Natural history of late potentials in the first ten days after acute myocardial infarction and relation to early ventricular arrhythmias

Serial signal-averaged electrocardiograms (ECGs) were performed every 48 hours in 50 patients admitted to the coronary care unit with acute myocardial infarction. The prevalence of late potentials was 32% at presentation (mean time to recording 12.4 +/- 6.6 hours after onset of chest pain) and increased progressively throughout the hospital stay. New late potentials were recorded in patients with no prior acute myocardial infarction as early as 3 hours after the onset of chest pain and as late as 8 days. Late potentials appeared transiently in only 3 patients. The detection of late potentials in the initial signal-averaged ECG identified patients with clinically significant early ventricular arrhythmias with a sensitivity of 80% and specificity of 72%. The predictive accuracy was 38% for a positive test and 94% for a negative test. Patients with early ventricular arrhythmias had significantly lower voltage in the terminal 40 ms of the filtered QRS complex (16 +/- 8 vs 32 +/- 19 microV, p less than 0.01) than those without arrhythmias. The signal-averaged ECG may be useful in identifying patients at high risk of developing clinically significant early ventricular arrhythmias after acute myocardial infarction.

R222Q SCN5A Mutation Is Associated With Reversible Ventricular Ectopy and Dilated Cardiomyopathy

OBJECTIVES The goal of this study was to characterize a variant in the SCN5A gene that encodes the alpha-subunit of the cardiac sodium channel, Nav1.5, which was identified in 1 large kindred with dilated cardiomyopathy (DCM) and multiple arrhythmias, including premature ventricular complexes (PVCs). BACKGROUND Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established. METHODS Family members underwent clinical evaluation and screening of the SCN5A and LMNA genes. Cellular electrophysiology and computational modeling were used to determine the functional consequences of the mutant Nav1.5 protein. RESULTS An R222Q missense variant located in a Nav1.5 voltage-sensing domain was identified in affected family members. Patch-clamp studies showed that R222Q Nav1.5 did not alter sodium channel current density, but did left shift steady-state parameters of activation and inactivation. Using a voltage ramp protocol, normalized current responses of R222Q channels were of earlier onset and greater magnitude than wild-type channels. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant and a potential cause of DCM. In R222Q carriers, there were only modest responses to heart failure therapies, but PVCs and DCM were substantially reduced by amiodarone or flecainide, which are drugs that have sodium channel-blocking properties. CONCLUSIONS The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented.

Prediction of successful suppression of sustained ventricular tachyarrhythmias by serial drug testing from data derived at the initial electrophysiologic study

This study investigated whether data available after the initial electrophysiologic study in patients with sustained ventricular tachyarrhythmia could identify those patients in whom serial drug testing is likely to be efficacious. One hundred six patients with inducible sustained ventricular tachyarrhythmia, whose initial study included short-term drug testing with intravenous procainamide, were evaluated. The baseline arrhythmia induced (in the absence of all antiarrhythmic drugs) was monomorphic tachycardia with a cycle length greater than 200 ms in 81 patients and ventricular flutter or fibrillation in the remaining 25 patients. After intravenous infusion of procainamide (1,250 +/- 300 mg), a ventricular tachyarrhythmia could still be induced in 80 patients during testing with up to three extrastimuli. Serial drug testing with one to four trials of oral conventional and investigational agents was then undertaken. Evaluation of 15 clinical, hemodynamic and electrophysiologic variables by stepwise logistic regression identified two independent predictors of successful response to oral antiarrhythmic drugs: 1) noninducibility of ventricular tachycardia after intravenous procainamide (p less than 0.001), and 2) left ventricular ejection fraction greater than or equal to 40% (p less than 0.05). Subgroup analysis combining each of these variables identified patients with a high, intermediate or low probability of finding a successful oral drug regimen. Patients whose arrhythmia was suppressed by intravenous procainamide had a 100% likelihood (if left ventricular ejection fraction was greater than or equal to 40%) or an 87% likelihood (if ejection fraction was less than 40%) of responding to an oral regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Epistatic Effects of Potassium Channel Variation on Cardiac Repolarization and Atrial Fibrillation Risk

OBJECTIVES The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF). BACKGROUND The K(+) channels play a major role in atrial repolarization but single mutations in cardiac K(+) channel genes are infrequently present in AF families. The collective effect of background K(+) channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored. METHODS Genes encoding the major cardiac K(+) channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model. RESULTS Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K(+) channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K(+) channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization. CONCLUSIONS Families with AF show an excess of rare functional K(+) channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

Left Ventricular Mechanical Assist Devices and Cardiac Device Interactions: An Observational Case Series

Background: Nonpulsatile left ventricular assist devices (LVADs) are increasingly used for treatment of refractory heart failure. A majority of such patients have implanted cardiac devices, namely implantable cardioverter‐defibrillators (ICDs) or cardiac resynchronization therapy‐pacemaker (CRT‐P) or cardiac resynchronization therapy‐defibrillator (CRT‐D) devices. However, potential interactions between LVADs and cardiac devices in this category of patients remain unknown.

Usefulness of sotalol in suppressing ventricular tachycardia or ventricular fibrillation in patients with healed myocardial infarcts

The electrophysiologic effects and antiarrhythmic efficacy of oral sotalol were investigated in 42 patients with coronary artery disease and prior myocardial infarction who presented with ventricular tachycardia (VT), ventricular fibrillation (VF) or syncope. The mean left ventricular ejection fraction was 36 +/- 9%. Baseline programmed cardiac stimulation initiated sustained VT (26 patients) or VF (16). The induced arrhythmia was not suppressed by conventional antiarrhythmic drugs in any patient (3 +/- 2 trials/patient). The mean daily dosage of sotalol was 221 +/- 84 mg. The right ventricular effective refractory period increased from 247 +/- 25 to 273 +/- 26 ms with sotalol (p = 0.0001) and the corrected QT interval increased from 431 +/- 35 to 456 +/- 62 ms (p = 0.02). Arrhythmia suppression was defined as no sustained VT or VF in response to programmed cardiac stimulation using up to 3 extrastimuli. Induced VT or VF was suppressed by sotalol therapy in 10 (24%) patients (group 1). Group 1 patients had faster induced arrhythmias at the baseline study than patients whose induced ventricular arrhythmia was not suppressed (group 2). The mean left ventricular ejection fraction tended to be higher in group 1 patients (p = 0.07). Fourteen patients (including 9 group 1 patients) continued receiving sotalol after discharge. In 2 group 2 patients, sotalol was combined with a class IA antiarrhythmic drug. During a mean follow-up period of 7.9 +/- 4.9 months, 2 patients had recurrent VT and in 2 others sotalol was discontinued due to side effects.

Inappropriate rate change in minute ventilation rate responsive pacemakers due to interference by cardiac monitors.

Observations of inappropriate rate increase in five patients with minute ventilation rate responsive implanted pacemakers (Telectronics Meta) are reported. Pacing rate increases were observed immediately upon connection of the resting patients to two brands of widely used cardiac monitors, and one commonly used echocardiograph. In some circumstances, the rate increase remained until monitor disconnection; in others the rate increase was transient, lasting about 20 seconds. A hardware thoracic resistance variation simulator was constructed and connected to one of the pacemakers to test sensitivity to rate modifying interference from external sources. This demonstrated that the sensitivity to interference is dependent upon the frequency of the interfering signal and is highest in the range 10–60 kHz. that peak currents as low as 10 μA can cause maximum rate increase, and that the signals injected into patients by several cardiac monitors, for purposes of lead‐off detection or respiratory monitoring, fall into the frequency range at which the pacemaker is most susceptible to interference.