Clinical Significance of J Waves in Patients Undergoing Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest.

BACKGROUND: Hypothermia is associated with the development of J waves. However, little is known about the impact of these electrocardiogram (ECG) findings on the development of ventricular arrhythmias and patient outcomes during therapeutic hypothermia (TH) postresuscitation from out-of-hospital cardiac arrest (OHCA). We investigated the prevalence of J waves in OHCA patients prior to and during TH. Additionally, we explored the incidence of atrial and ventricular arrhythmias and in-hospital mortality for patients with and without J waves either at baseline, during TH, or both. METHODS: We conducted a retrospective analysis of patients who suffered OHCA and underwent TH (goal temperature of 32-34°C). Fifty-nine patients were stratified dependent upon the presence of or the development of J waves on surface ECGs. Descriptive analysis and logistic regression modeling were used to assess the population differences and mortality, respectively, between patients who developed J waves during TH and those who did not. RESULTS: There was no difference in the development of in-hospital atrial or ventricular arrhythmias between patients with J waves present during TH (16%) and those without (17.6%, P = 0.834). Compared to patients without J waves at baseline and during TH, those with J waves present both at baseline and during TH had significantly worse survival (hazard ratio = 12.42, P = 0.046). CONCLUSIONS: While J waves are common ECG findings during TH in patients resuscitated from OHCA, our study demonstrated an increase in mortality for patients with J waves present both at baseline and during TH.

Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database.

BACKGROUND: The Cardiac Safety Research Consortium (CSRC) provides both "learning" and blinded "testing" digital electrocardiographic (ECG) data sets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This article reports the first results from a blinded testing data set that examines developer reanalysis of original sponsor-reported core laboratory data. METHODS: A total of 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 181 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer-measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. RESULTS: Developer and sponsor-reported baseline-adjusted data were similar with average differences <1 ms for all intervals. Both developer- and sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject SD for triplicate QTcF measurements was significantly lower for developer- than sponsor-reported data (5.4 and 7.2 ms, respectively; P < .001). CONCLUSION: The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared with the sponsor-reported study, without the use of a manual core laboratory. These findings indicate that CSRC ECG data sets can be useful for evaluating novel methods and algorithms for determining drug-induced QT/QTc prolongation. Although the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG technologies applied for QT/QTc measurement is illustrated.

Wireless remote monitoring of reconstructed 12-lead ECGs after ablation for atrial fibrillation using a hand-held device.

OBJECTIVE: Atrial fibrillation (AF) surveillance using a wireless handheld monitor capable of 12-lead electrocardiogram reconstruction was performed, and arrhythmia detection rate was compared with serial Holter monitoring. METHODS: Twenty-five patients were monitored after an AF ablation procedure using the hand-held monitor for 2 months immediately after and then for 1 month approximately 6 months postablation. All patients underwent 12-lead 24-hour Holter monitoring at 1, 2, and 6 months postablation. RESULTS: During months 1-2, 425 of 2942 hand-held monitor transmissions from 21 of 25 patients showed AF/atrial flutter (Afl). The frequency of detected arrhythmias decreased by month 6 to 85/1128 (P < .01) in 15 of 23 patients. Holter monitoring diagnosed AF/Afl in 8 of 25 and 7 of 23 patients at months 1-2 and month 6, respectively (P < .01 compared with wireless hand-held monitor). Af/Afl diagnosis by wireless monitoring preceded Holter detection by an average of 24 days. CONCLUSIONS: Wireless monitoring with 12-lead electrocardiogram reconstruction demonstrated reliable AF/Afl detection that was more sensitive than serial 12-lead 24-hour Holter monitoring.

Short QT interval in clinical practice.

The last ten years have seen a growing interest in clinical scenarios, where a short QT interval may play a role, especially because of an increased risk of sudden cardiac death in some situations. One such entity is Short QT Syndrome, which has emerged as a rare, but very malignant disease, in particular when the QT interval is very short. A short QT interval has also been noticed in some patients with other arrhythmic syndromes such as Idiopathic Ventricular Fibrillation, Brugade Syndrome and Early Repolarization Syndrome, but the role of a short QT interval in these settings is so far not known. Hypercalcemia often leads to shortening of the QT interval, but there are no data in humans to suggest an increased risk of sudden cardiac death in this setting. In addition, a shorter-than-usual QT interval has been reported in patients with Chronic Fatigue Syndrome and in response to atropine, catecholamine and Hyperthermia. When a short QT interval is encountered in daily clinical practice, these various scenarios needs to be considered, but it is still not possible to come up with clear guidelines for how to work up and risk stratify such individuals. Genetic testing is only useful in very few and the value of an electrophysiologic study, Holter monitoring or stress testing to assess QT adaptation to heart rate and T wave morphology analysis may all be helpful, but not well-established, tests in this setting.

Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects.

BACKGROUND: Improved automated methods for electrocardiographic (ECG) analysis are needed, particularly for drug development purposes. OBJECTIVES: This study compared a novel fully automated method for ECG analysis (QTinno; NewCardio, Santa Clara, CA) to 2 semiautomated digital methods: global measurement from the earliest QRS onset to the latest T-wave offset on representative superimposed beats (global) and tangent measurement on 3 consecutive beats in one lead (tangent). METHODS: All 3 methods were used to determine uncorrected and rate-corrected QT interval duration (QT and QTcF) and related metrics in 1422 digital 12-lead ECGs from a phase 1 drug study. Global and tangent annotations were manually adjusted by the same 3 cardiologists wherever necessary. No adjustments were made in QTinno determinations. RESULTS: QTinno returned QTcF change from time-matched baseline (DeltaQTcF) that differed minimally from both global and tangent methods (mean pairwise difference: 0.1 millisecond between QTinno and global, 1.1 milliseconds between QTinno and tangent). The average absolute QT and QTcF intervals by QTinno were approximately 5 milliseconds longer than global and 25 milliseconds longer than by tangent. QTinno had lower intrinsic variability for DeltaQTcF than either global or tangent (between-subject SD: QTinno 4.0 milliseconds, global 5.6 milliseconds, tangent 6.4 milliseconds; within-subject SD: QTinno 4.8 milliseconds, global 7.4 milliseconds, tangent 10.6 milliseconds). All methods were robust in detecting the largest placebo-adjusted mean time-matched DeltaQTcF (15-25 milliseconds) induced by study drug. CONCLUSIONS: The methods show good agreement for drug-induced QTc prolongation. Lower intrinsic variability of DeltaQTcF by QTinno could facilitate smaller sample sizes or increase study power in thorough QTc studies.

Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure.

PURPOSE: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers. METHODS: In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day -1 to Day 2), and at the follow-up visit (Day 7 [±2 days]). FINDINGS: Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001-0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine. IMPLICATIONS: In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.

Brugada syndrome: report of the second consensus conference.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Short QT syndrome: mechanisms, diagnosis and treatment.

Short QT syndrome is an inheritable primary electrical disease of the heart that was discovered in 1999. The disorder is characterized by an abnormally short QT interval (<300 ms) and a propensity to atrial fibrillation, sudden cardiac death or both. As in the case of long QT syndrome, more than one relevant genetic mutation has been identified that can lead to a short QT interval on electrocardiography; so far two have been identified. Shortening of the effective refractory period combined with increased dispersion of repolarization is the likely substrate for re-entry and life-threatening tachyarrhythmias. Thus far, 22 people have been classified as having short QT syndrome: 15 from the actual measurement of a short QT interval on electrocardiograms and 7 by history after they died from sudden cardiac death. Several cases, especially among children, have probably been overlooked, since the shortness of the QT interval becomes apparent only at heart rates less than 80 beats/min. The best form of treatment is still unknown, but prevention of atrial fibrillation has been accomplished by propafenone. Implantation of an implantable cardioverter defibrillator is recommended for prevention of sudden cardiac death.

The use of roxifiban (DMP754), a novel oral platelet glycoprotein IIb/IIIa receptor inhibitor, in patients with stable coronary artery disease.

INTRODUCTION: Intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have a significant beneficial impact on the outcomes of patients undergoing high-risk coronary interventions and in the stabilization of patients with unstable angina pectoris refractory to conventional medical treatment. The role of long-term treatment with oral platelet GP IIb/IIIa receptor inhibitors in patients with coronary artery disease is unproven. This study examined the dose-response effect on inhibition of platelet aggregation by roxifiban (DMP754), a novel oral platelet GP IIb/IIIa receptor inhibitor, and its safety and tolerability in patients with a history of chronic stable angina pectoris. METHODS: Ninety-eight patients were randomized to receive either a placebo or 1 of 8 oral dosages of roxifiban. Twenty-two patients were enrolled in multiple-dose regimens, bringing the total study population to 120. The oral dosages were 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 2.5 mg/day for up to 30 days. RESULTS: Pharmacodynamic response of roxifiban was clearly dose-dependent. Platelet aggregation inhibition in response to 10 micromol/L slope adenosine diphosphate was sustained throughout the study period (up to 1 month). No serious adverse events, including significant major bleeding events, were associated with roxifiban treatment. Minor bleeding was reported in 5% of participants in the placebo group (1 of 21 cases) versus 26% in the study group (26 of 99 cases). Incidence of minor bleeding associated with roxifiban 2 and 2.5 mg/day was significantly (p < or = 0.05) greater than that with placebo. Adverse events, including gastrointestinal disorders, platelet and clotting disorders, and urinary tract disorders, were observed in 1 of 21 cases (5%) in the placebo group and in 12 of 99 cases (12%) in the study group. Reversible thrombocytopenia without other complications developed in two patients. CONCLUSIONS: Roxifiban-induced inhibition of platelet aggregation was dose-dependent and sustained throughout the study period: higher drug dosages correlated with higher levels of platelet inhibition and higher incidence of minor bleeding events. No serious adverse events were observed at any dosage. Thus, roxifiban appears to be a potent oral platelet GP IIb/IIIa receptor inhibitor that is clinically well-tolerated and deserves further study as a new treatment strategy in patients with chronic stable angina pectoris.

Detection of acute myocardial infarction from serial ECG using multilayer support vector machine.

Acute Myocardial Infarction (AMI) remains a leading cause of mortality in the United States. Finding accurate and cost effective solutions for AMI diagnosis in Emergency Departments (ED) is vital. Consecutive, or serial, ECGs, taken minutes apart, have the potential to improve detection of AMI in patients presented to ED with symptoms of chest pain. By transforming the ECG into 3 dimensions (3D), computing 3D ECG markers, and processing marker variations, as extracted from serial ECG, more information can be gleaned about cardiac electrical activity. We aimed at improving AMI diagnostic accuracy relative to that of expert cardiologists. We utilized support vector machines in a multilayer network, optimized via a genetic algorithm search. We report a mean sensitivity of 86.82%±4.23% and specificity of 91.05%±2.10% on randomized subsets from a master set of 201 patients. Serial ECG processing using the proposed algorithm shows promise in improving AMI diagnosis in Emergency Department settings.

Computerized extraction of electrocardiograms from continuous 12-lead holter recordings reduces measurement variability in a thorough QT study.

Continuous Holter recordings are often used in thorough QT studies (TQTS), with multiple 10-second electrocardiograms (ECGs) visually selected around predesignated time points. The authors hypothesized that computer-automated ECG selection would reduce within-subject variability, improve study data precision, and increase study power. Using the moxifloxacin and placebo arms of a Holter-based crossover TQTS, the authors compared interval duration measurements (IDMs) from manually selected to computer-selected ECGs. All IDMs were made with a fully automated computer algorithm. Moxifloxacin-induced changes in baseline- and placebo-subtracted QT intervals were similar for manual and computer ECG selection. Mean 90% confidence intervals were narrower, and within-subject variability by mixed-model covariance was lower for computer-selected than for manual-selected ECGs. Computer ECG selection reduced the number of subjects needed to achieve 80% power by 40% to 50% over manual. Computer ECG selection returns accurate ddQTcF values with less measurement variability than manual ECG selection by a variety of metrics. This results in increased study power and reduces the number of subjects needed to achieve desired power, which represents a significant potential source cost savings in clinical drug trials.