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.

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.

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.

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.

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.

Algorithm for quantitative 3 dimensional analysis of ECG signals improves myocardial diagnosis over cardiologists in diabetic patients.

UNLABELLED: Acute myocardial infarction (AMI) diagnosis in type II diabetes (DM2) patients is difficult and ECG findings are often non-diagnostic or inconclusive. We developed computer algorithms to process standard 12-lead ECG input data for quantitative 3-dimensional (3D) analysis (my3KGTM), and hypothesized that use of the my3KGTM's array of over 100 3D-based AMI diagnostic markers may improve diagnostic accuracy for AMI in DM2 patients. METHODS: We identified 155 consecutive DM2 patients age >25 yrs with chest discomfort or shortness of breath who were evaluated at an urban emergency department (130 patients (pts)) or the cardiac catheterization laboratory (25 pts) for possible AMI. The first digital 12-lead ECG for each patient, obtained within 30 min of presentation, was evaluated by (1) 2 blinded expert cardiologists, and (2) my3KGTM. In each case, the ECG was classified as either likely AMI or likely non-AMI. "Gold standard" was the final clinical diagnosis. Statistical analysis was McNemar's test with continuity correction. RESULTS: The 155 DM2 patients were 50% male, mean age 56.8 ± 12.0 yrs; 44 pts had a final clinical diagnosis of AMI (17 ST Elevation Myocardial Infarctions (STEMI), 27 Non-ST Elevation Myocardial Infarctions (NSTEMI)) and 111 had no AMI. CONCLUSIONS: Relative to standard 12L ECG read by cardiologists, quantitative 3D ECG analysis showed significant and substantial gains in sensitivity for AMI diagnosis in DM2 patients, without loss in specificity. Sensitivity gains were particularly high in patients exhibiting NSTEMI, the most common form of AMI in DM2.

Wireless monitoring of reconstructed 12-lead ECG in atrial fibrillation patients enables differential diagnosis of recurrent arrhythmias.

UNLABELLED: Differential diagnosis of symptomatic events in post-ablation atrial fibrillation (AF) patients (pts) is important; in particular, accurate, reliable detection of AF or atrial flutter (AFL) is essential. However, existing remote monitoring devices usually require attached leads and are not suitable for prolonged monitoring; moreover, most do not provide sufficient information to assess atrial activity, since they generally monitor only 1-3 ECG leads and rely on RR interval variability for AF diagnosis. A new hand-held, wireless, symptom-activated event monitor (CardioBip; CB) does not require attached leads and hence can be conveniently used for extended periods. Moreover, CB provides data that enables remote reconstruction of full 12-lead ECG data including atrial signal information. We hypothesized that these CB features would enable accurate remote differential diagnosis of symptomatic arrhythmias in post-ablation AF pts. METHODS: 21 pts who underwent catheter ablation for AF were instructed to make a CB transmission (TX) whenever palpitations, lightheadedness, or similar symptoms occurred, and at multiple times daily when asymptomatic, during a 60 day post-ablation time period. CB transmissions (TXs) were analyzed blindly by 2 expert readers, with differences adjudicated by consensus. RESULTS: 7 pts had no symptomatic episodes during the monitoring period. 14 of 21 pts had symptomatic events and made a total of 1699 TX, 164 of which were during symptoms. TX quality was acceptable for rhythm diagnosis and atrial activity in 96%. 118 TX from 10 symptomatic pts showed AF (96 TX from 10 pts) or AFL (22 TX from 3 pts), and 46 TX from 9 pts showed frequent PACs or PVCs. No other arrhythmias were detected. Five pts made symptomatic TX during AF/AFL and also during PACs/PVCs. CONCLUSIONS: Use of CB during symptomatic episodes enabled detection and differential diagnosis of symptomatic arrhythmias. The ability of CB to provide accurate reconstruction of 12 L ECGs including atrial activity, combined with its ease of use, makes it suitable for long-term surveillance for recurrent AF in post-ablation patients.

Wireless remote monitoring of atrial fibrillation using reconstructed 12-lead ECGs.

UNLABELLED: Remote surveillance is important for patients with atrial fibrillation (AF). Atrial signal recognition with conventional monitoring devices is difficult; remote AF detection is predominantly accomplished by R-R interval analysis. Twelve lead ECG (12L) displays atrial activity and remains the gold standard for AF diagnosis. CardioBip is a portable wireless patient-activated event monitor providing signal reconstruction of a 12L waveform (12CB) using 5 leads and patient-specific transformation matrices. We hypothesized that atrial signal analysis with 12CB can detect atrial activity and improve AF detection. METHODS: 18 patients with AF undergoing DC cardioversion (CV) were studied. Separate 12-lead P and QRS patient-specific transformation matrices were created at baseline AF. Multiple wireless 12CB transmissions were performed 3-7 days before and up to 2 weeks after CV. Rhythm was confirmed with 12-lead ECGs (12L). In SR the number of leads with visible P waves (atrial signal > 0.05 mV), and P wave polarity were analyzed. In AF, the number of leads with AF signal were compared (fibrillatory [f] waves >0.025 mV). RESULTS: Fourteen of 18 patients successfully cardioverted to SR and 4 failed; thus, 14 SR and 22 AF transmissions were analyzed. SR P wave was visible on 141/168 leads on 12L and 137/168 on 12CB (126 true pos [TP] and 11 false pos [FP] relative to 12L; p=0.26). In 126 leads with P waves in both 12L and 12CB, the methods agreed on P wave polarity in 125. In AF, F waves were visible in 178/264 leads on 12L and 189/264 leads on 12CB (144 TP, 45 FP; p=0.27). All 5 AF relapses were successfully detected by 12CB based on atrial activity. CONCLUSION: 12CB is not inferior to 12L in detecting atrial signal in SR and AF, and shows excellent potential for remote wireless monitoring of AF patients.

Wireless remote monitoring of myocardial ischemia using reconstructed 12-lead ECGs.

CardioBip (CB) is a hand-held patient-activated device for recording and wireless transmission of reconstructed 12-lead ECG (12CB) based on patient specific matrices. It has 5 contact points: 3 precordial and 2 on the device top serving as limb leads when touched by index fingers. To determine whether CB could be used to monitor coronary disease (CAD) patients, we compared 12CB to simultaneous 12-lead ECGs (12L) in patients with CAD, pre-and post-exercise treadmill testing (ETT). The study goals were to assess: (1) whether 12CB can accurately reconstruct and wirelessly transmit 12-lead ECGs in CAD patients during ETT recovery; (2) whether 12CB can be used to evaluate ST segment changes in patients with exercise-induced ischemia.

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.

Vectorcardiographic and electrocardiographic criteria to distinguish new and old left bundle branch block.

BACKGROUND: There are no established criteria to differentiate new from old left bundle branch block (LBBB). This complicates management of patients with LBBB and suspected acute coronary syndrome. OBJECTIVES: The purpose of this study was to develop electrocardiographic (ECG) criteria to differentiate new and old LBBB. METHODS: All LBBB tracings (n = 3,706) in a hospital ECG database were retrieved. New (<24 hours, n = 39) and old (>24 hours, n = 1,760) LBBB tracings were identified. QRS and T-wave amplitudes, directions, and durations were measured digitally. Vectorcardiograms were reconstructed from 12-lead ECGs using inverse Dower transform and analyzed with Cardio3KG software. Receiver operator characteristic (ROC) curves were used to develop decision rules to distinguish new and old LBBB. RESULTS: The new LBBB group had larger T-vector magnitude (1.20 +/- 0.07 vs. 0.71 +/- 0.01 mV), smaller QRS vector magnitude (2.13 +/- 0.12 vs. 2.47 +/- 0.02 mV), and a lower QRS/T vector magnitude ratio (QRS/T; 1.79 +/- 0.03 vs. 3.92 +/- 0.04) compared with the old LBBB group (mean +/- standard error of the mean, P <.001). The ratio of deepest S to largest T wave in precordial leads (Max S/T) was significantly smaller in the new compared with in the old LBBB group (1.66 +/- 0.05 vs. 3.54 +/- 0.08; P <.001). A decision rule using QRS/T <2.25 and Max S/T <2.5 had 100% sensitivity and 96%-68% specificity in diagnosing new LBBB, including subsets of patients with tachycardia and ischemia. CONCLUSIONS: QRS/T and Max S/T allow accurate discrimination between new and old LBBB suitable for both computerized and manual analysis. If confirmed in prospective studies, this finding can improve management of patients with chest pain and LBBB.

Visual 3Dx: algorithms for quantitative 3-dimensional analysis of ECG signals.

INTRODUCTION: The 12-lead ECG is useful for cardiac diagnosis but has limited sensitivity and specificity. To address this, we developed the Visual3Dx, a comprehensive method for describing cardiac electrical activity in time and space. The Visual3Dx transforms the ECG input into a time-variable heart vector, and normalizes each lead input to assure equal representation from all cardiac regions. METHODS: We compared the Visual3Dx to the standard 12-lead ECG for detection of acute myocardial ischemia (AMI) in 2 clinical models. Model 1 was AMI after 90 s of balloon coronary occlusion in 117 cases. Model 2 was 122 consecutive patients who: (1) presented to an urban emergency department with chest pain; (2) were admitted to coronary care and developed elevated cardiac troponin levels; and (3) had coronary arteriography within 6 hrs. RESULTS: In Model 1, the 12 lead ECG developed ST segment deviation diagnostic of AMI in 78/117 occlusions (67%), whereas using the same input ECG data, the Visual3Dx was diagnostic of AMI in 105/117 occlusions (90%; p<0.001). In Model 2, the first 12 lead ECG was diagnostic of AMI in 80/122 (66%), whereas the Visual3Dx was diagnostic in 103/122 (84%). In both Models, the largest sensitivity gains were seen in left circumflex and right coronary artery occlusions. CONCLUSIONS: The Visual3Dx is a promising tool for 3D quantitative analysis of cardiac electrical activity that may improve diagnosis of AMI, especially in electrically remote regions of the heart. Additional studies will define diagnostic specificity and further improve 3D biomarkers of AMI.