Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.

Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease.

AIMS: To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD). METHODS AND RESULTS: The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009]. CONCLUSION: For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

A Rare Case Report of Flecainide-Induced Left Bundle Branch Block (LBBB) and Transient Cardiomyopathy.

Flecainide is an antiarrhythmic agent that has been reported to have numerous cardiotoxic effects, including the development of arrhythmias and the reduction of left ventricular ejection fraction (LVEF). However, it is not commonly reported as a cause for left bundle branch block and cardiomyopathy. In this case report, we present the case of a 67-year-old female patient who developed transient cardiomyopathy and left bundle branch block (LBBB) secondary to flecainide therapy. The patient's condition improved upon cessation of flecainide.

QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study.

We compared heart rate-corrected QT interval (QTc) and its within- and between-subject variability, in ECGs recorded several days apart for 207 patients with schizophrenia (age range 19-60 yr) with age- and gender-matched healthy controls. Patients had higher heart rates (mean±s.d.) than controls [75±15 beats per minute (bpm) vs. 63±10 bpm; p<0.0001]. QTc by Bazett's formula (QTcB) overestimated QTc interval at high heart rates; consequently QTcB was longer in patients (412±24 ms) than in controls (404±24 ms; p=0.0003). QTc by Fridericia's method (QTcF), which was not influenced by heart rate, was comparable (398±22 ms in patients vs. 401±19 ms in controls; p=0.17). Between-subject variability in QTcF was similar in patients (17 ms) and controls (16.2 ms) but within-subject variability was larger (13.1 ms vs. 10 ms, respectively). Thus, a larger sample size is required when thorough QTc studies with a cross-over design are performed in patients with schizophrenia than in healthy subjects; sample size is not increased for studies with a parallel design. Last, QTcF is preferred over QTcB in schizophrenia patients with higher heart rates.

Morphological abnormalities in baseline ECGs in healthy normal volunteers participating in phase I studies.

BACKGROUND & OBJECTIVES: Morphological abnormalities in 12-lead electrocardiograms (ECGs) are seen in subgroups of healthy individuals like athletes and air-force personnel. As these populations may not truly represent healthy individuals, we assessed morphological abnormalities in ECG in healthy volunteers participating in phase I studies, who are screened to exclude associated conditions. METHODS: ECGs from 62 phase I studies analyzed in a central ECG laboratory were pooled. A single drug-free baseline ECG from each subject was reviewed by experienced cardiologists. ECG intervals were measured on five consecutive beats and morphological abnormalities identified using standard guidelines. RESULTS: Morphological abnormalities were detected in 25.5 per cent of 3978 healthy volunteers (2495 males, 1483 females; aged 18-76 yr); the presence was higher in males (29.3% vs. 19.2% in females; P<0.001). Rhythm abnormalities were the commonest (11.5%) followed by conduction abnormalities (5.9%), axis deviation (4%), ST-T wave changes (3.1%) and chamber enlargement (1.4%). Incomplete right bundle branch block (RBBB), short PR interval and right ventricular hypertrophy were common in young subjects (<20 yr) while atrial fibrillation, first degree atrioventricular block, complete RBBB and left anterior fascicular block were more prevalent in elderly subjects (>65 yr). Prolonged PR interval, RBBB and intraventricular conduction defects were more common in males while sinus tachycardia, short PR interval and non-specific T wave changes were more frequent in females. INTERPRETATION & CONCLUSIONS: Morphological abnormalities in ECG are commonly seen in healthy volunteers participating in phase I studies; and vary with age and gender. Further studies are required to determine whether these abnormalities persist or if some of these disappear on follow up.

Choice of an alternative lead for QT interval measurement in serial ECGs when Lead II is not suitable for analysis.

INTRODUCTION: Conventionally, QT interval is measured in lead II. There are no data to select an alternative lead for QT measurement when it cannot be measured in Lead II for any reason. METHODS AND RESULTS: We retrospectively analyzed ECGs from 1906 healthy volunteers from 41 phase I studies. QT interval was measured on the median beat in all 12 leads. The mean difference in QT interval between lead aVR and in Lead II was the least, followed by aVF, V5, V6 and V4; lead aVL had maximum difference. The T wave was flat (<0.1 mV) in Lead II in 6.9% of ECGs; it was also flat in 20% of these ECGs (1.4% of all ECGs) in Leads aVR, aVF and V5. CONCLUSIONS: When QT interval cannot be measured in Lead II, the best alternative leads are aVR, aVF, V5, V6 and V4 in that sequence. It differs maximally from that in Lead II in Lead aVL.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers.

INTRODUCTION: We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS: QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS: All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION: The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.

Estimating Myocardial Infarction Size With a Simple Electrocardiographic Marker Score.

Background Myocardial infarction (MI) size is a key predictor of prognosis in post-MI patients. Cardiovascular magnetic resonance (CMR) is the gold standard test for MI quantification, but the ECG is less expensive and more widely available. We sought to quantify the relationship between ECG markers and cardiovascular magnetic resonance infarct size. Methods and Results Patients with prior MI enrolled in the DETERMINE (Defibrillators to Reduce Risk by Magnetic Resonance Imaging Evaluation) and PRE-DETERMINE Trial and Registry were included. ECG leads were analyzed for markers of MI: Q waves, fragmented QRS, and T wave inversion. DETERMINE Score=number of leads with [Q waves×2]+[fragmented QRS]+[T wave inversion]. Left ventricular ejection fraction (LVEF) and infarct size as a percentage of left ventricular mass (MI%) were quantified by cardiovascular magnetic resonance. The Modified Selvester Score estimates MI size from 37 ECG criteria. In 551 patients (aged 62.1±10.9 years, 79% men, and LVEF=40.3±11.0%), MI% increased as the number of ECG markers increased (P<0.001). By univariable linear regression, the DETERMINE Score (range 0-26) estimated MI% (R2=0.18, P<0.001) with an accuracy approaching that of LVEF (R2=0.22, P<0.001) and higher than the Modified Selvester Score (R2=0.09, P<0.001). By multivariable linear regression, addition of the DETERMINE Score improved estimation of MI% over LVEF alone (P<0.001) and over Modified Selvester Score alone (P<0.001). Conclusions In patients with prior MI, a simple ECG score estimates infarct size and improves infarct size estimation over LVEF alone. Because infarct size is a powerful prognostic indicator, the DETERMINE Score holds promise as a simple and inexpensive risk assessment tool.

Z-score for benchmarking reader competence in a central ECG laboratory.

BACKGROUND: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z-scores to define reader competence. METHODS: Two hundred ECGs were read by 24 experts and the mean and standard deviation (SD) of QT measurements calculated for each ECG. Z-scores ([QT(reader)- mean QT(experts)]/ SD(experts)) for each ECG and mean of absolute Z-scores of all ECGs read by a reader were calculated. The highest mean absolute Z-score of experts was considered the cutoff to define competence. Hundred of these standardized ECGs were used to assess performance of readers from the central laboratory. RESULTS: All experts had mean absolute Z-scores < or = 1.5. Using this cutoff, one of 28 experienced readers and 7 of 15 trainees had unacceptable Z-scores. After re-training, all achieved Z-scores <1.5. Comparing histograms of actual Z-scores of the 100 ECGs of readers with unacceptable scores with that of the reader with the best Z-score showed two patterns. Readers with histograms having a peak and tails similar to that of the best reader, but with leftward or rightward shift, consistently made shorter or longer QT measurements, respectively. A histogram with a flatter peak and wider tails, suggested that measurements were long in some ECGs and short in others. CONCLUSION: Mean absolute Z-score is useful to assess competence for measuring the QT interval on ECGs. Analysis of histograms can pinpoint problems in QT measurements.

Intra- and interreader variability in QT interval measurement by tangent and threshold methods in a central electrocardiogram laboratory.

BACKGROUND: The QT interval can be measured by tangent (QT(Tan)) and threshold (QT(Thr)) methods; the better method is the one with lower reader variability. METHODS: QT(Tan) and QT(Thr) were measured twice in 100 digital electrocardiograms (ECGs) by 8 experienced readers in a central laboratory. For QT(Thr), the end of the T wave was the point where the T wave reached the isoelectric baseline; for QT(Tan), it was the point where a line from the peak of the T wave through the steepest part of the descending limb intercepted the isoelectric baseline. RESULTS: The average absolute intrareader variability ranged from 3.4 to 6.9 milliseconds for QT(Tan) and from 3.5 to 5.2 milliseconds for QT(Thr). By analysis of variance, intrareader SD of QT(Tan) was 7.0 and 7.5 milliseconds for QT(Thr); interreader SD was 13.1 milliseconds for QT(Tan) and 11.9 milliseconds for QT(Thr). QT(Tan) was shorter than QT(Thr) in 96 of the 100 ECGs, it exceeded QT(Thr) in 4 ECGs, which had prominent U waves. CONCLUSIONS: For trained readers in a central ECG laboratory using sophisticated on-screen tools for QT measurement in high-quality digital ECGs, between- and within-reader variability are comparable for QT(Tan) and QT(Thr). However, QT(Tan) is consistently shorter than QT(Thr) by up to 10 milliseconds.

Differences between QT and RR intervals in digital and digitized paper electrocardiograms: contribution of the printer, scanner, and digitization process.

BACKGROUND: Prints of electrocardiograms (ECGs) are often sent to core laboratories, where they are scanned, converted to a digital format, and read on-screen. These ECGs may differ from the original ECG because of variability introduced by the printer, scanner, or digitization software. METHODS: Digital ECGs were recorded in 50 volunteers simultaneously using electrocardiographs from 2 different manufacturers. QT and RR intervals were measured on-screen on the digitized ECGs. To study the contribution of individual steps in the digitization process, differences in RR interval between 2 prints each of 50 digital ECGs, 2 scanned files of 50 prints, 2 digitized files from 50 scanned files, and 2 readings of 50 digitized ECGs (intrareader variability) were analyzed. RESULTS: Repeatability coefficient for RR interval measurement was 18.5 milliseconds for machine 1 and 21 milliseconds for machine 2. Contributions of the printer were 6.5 milliseconds for machine 1 and 9.0 milliseconds for machine 2, digitization process was 5.5 milliseconds, and reader variability was 8.0 milliseconds. Variability of the scanner was negligible. CONCLUSIONS: The printer and digitization process account for significant differences in interval measurements in digitized ECGs.

Sudden Death in Patients With Coronary Heart Disease Without Severe Systolic Dysfunction.

Importance: The majority of sudden and/or arrhythmic deaths (SAD) in patients with coronary heart disease occur in those without severe systolic dysfunction, for whom strategies for sudden death prevention are lacking. Objective: To provide contemporary estimates of SAD vs other competing causes of death in patients with coronary heart disease without severe systolic dysfunction to search for high-risk subgroups that might be targeted in future trials of SAD prevention. Design, Setting, and Participants: This prospective observational cohort study included 135 clinical sites in the United States and Canada. A total of 5761 participants with coronary heart disease who did not qualify for primary prevention implantable cardioverter defibrillator therapy based on left ventricular ejection fraction (LVEF) of more than 35% or New York Heart Association (NYHA) heart failure class (LVEF >30%, NYHA I). Exposures: Clinical risk factors measured at baseline including age, LVEF, and NYHA heart failure class. Main Outcomes and Measures: Primary outcome of SAD, which is a composite of SAD and resuscitated ventricular fibrillation arrest. Results: The mean (SD) age of the cohort was 64 (11) years. During a median of 3.9 years, the cumulative incidence of SAD and non-SAD was 2.1% and 7.7%, respectively. Sudden and/or arrhythmic death was the most common mode of cardiovascular death accounting for 114 of 202 cardiac deaths (56%), although noncardiac death was the primary mode of death in this population. The 4-year cumulative incidence of SAD was lowest in those with an LVEF of more than 60% (1.0%) and highest among those with LVEF of 30% to 40% (4.9%) and class III/IV heart failure (5.1%); however, the cumulative incidence of non-SAD was similarly elevated in these latter high-risk subgroups. Patients with a moderately reduced LVEF (40%-49%) were more likely to die of SAD, whereas those with class II heart failure and advancing age were more likely to die of non-SAD. The proportion of deaths due to SAD varied widely, from 14% (18 of 131 deaths) in patients with NYHA II to 49% (37 of 76 deaths) in those younger than 60 years. Conclusions and Relevance: In a contemporary population of patients with coronary heart disease without severe systolic dysfunction, SAD accounts for a significant proportion of overall mortality. Moderately reduced LVEF, age, and NYHA class distinguished SAD and non-SAD, whereas other markers were equally associated with both modes of death. Absolute and proportional risk of SAD varied significantly across clinical subgroups, and both will need to be maximized in future risk stratification efforts.

Stable atrial sensing on long-term follow up of VDD pacemakers.

BACKGROUND: The hemodynamic advantages of maintaining AV synchrony through AV synchronous pacing are widely known as compared to single chamber pacing. DDD pacemaker implantation entails higher cost and is technically more challenging than the VDD pacemaker. METHODS: Seventy one patients underwent VDD lead (Biotronik GmbH, St. Jude Medical and Medtronic Inc.) implantation at KEM hospital, Mumbai during a period of 3 years through subclavian, axillary and cephalic routes for degenerative, post-surgical or congenital high grade atrioventricular or complete heart block. They were followed up regularly for ventricular threshold and P wave amplitude of the floating atrial dipole. RESULTS: Follow up data of almost 95% of patients is available for a period of 15.8 +/- 6.7 months. P wave amplitude at implant was 2.1 +/- 0.7mV and at follow up 1.1 +/- 0.6mV with mean ventricular threshold of <0.5V at implant and <1V at follow-up. CONCLUSION: Implantation of a single lead VDD pacemaker is possible in all patients with symptomatic AV block and intact sinus node function without any technical complications. P wave sensing is reliable and consistent with floating atrial lead at an average follow up of 15.8 months, providing an excellent alternative to DDD pacemaker implantation.

Baseline and new-onset morphologic ECG abnormalities in healthy volunteers in phase I studies receiving placebo: changes over a 6-week follow-up period.

Morphological ECG abnormalities occur in 5-12% healthy adults participating in early phase clinical trials. We retrospectively analyzed 16,472 12-lead ECGs recorded at multiple time points in 420 volunteers (282 males, 138 females; aged 18-76 years) randomized to receive placebo from 19 Phase I studies to see if some baseline ECG abnormalities may disappear or new abnormalities may appear during the study. One hundred forty-four (34.3%) subjects had abnormal baseline ECGs, of which 66 (44.8%) reverted to normal during follow-up. Of 276 (65.7%) subjects with normal baseline ECGs, 118 (42.8%) developed ECG abnormalities over the next 6 weeks. Common baseline abnormalities included sinus bradycardia, R wave transition abnormalities, right axis deviation, non-specific T wave changes and atrial premature complexes. On follow-up ECGs, prolonged QT interval, first-degree AV block, sinus bradycardia, short PR interval, and R wave transition abnormalities reverted to normal. Common new-onset abnormalities in subjects with normal baseline ECGs included sinus bradycardia, prolonged QT interval, non-specific T wave changes, R wave transition abnormalities, and sinus tachycardia. Thus, transient morphological ECG changes may occur in healthy volunteers possibly due to diurnal variation, effect of food, hormones, or autonomic changes. This should be considered when interpreting "treatment-emergent" ECG changes in clinical trials.

Effect of number of replicate electrocardiograms recorded at each time point in a thorough QT study on sample size and study cost.

In a "thorough QT/QTc" (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within-subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost-effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day -1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject-specific (QTcI) formulas. Within-subject and between-subject standard deviations for QTcF obtained by repeated-measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within- and between-subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per-ECG and per-subject costs.

Limb lead interchange in thorough QT/QTc studies.

The investigators analyzed 85,133 electrocardiograms (ECGs) recorded in 484 subjects from 5 thorough QT/QTc studies (3 using Holter devices, 2 using 12-lead ECGs) for inadvertent limb lead interchanges using a dedicated quality control process in a central ECG laboratory. Limb lead interchanges were present in 2919 (3.4%) ECGs in 17.9% of subjects and were more frequent with Holter devices (7.5% vs 0.8%, P < .0001), where leads remain connected for prolonged periods, affecting data from several time points. Left arm-left leg interchange was seen in 54% of 12-lead ECGs and right arm-left arm interchange in 38%. The ECG device itself could identify 21.7% of interchanges, whereas experienced readers blinded to subject and visit identified 79% of interchanges; 21% of interchanges were identified only during the quality control process. If correctly identified, QT measurement could be performed in a precordial lead. If undiagnosed, incorrect QT interval measurements and morphological diagnosis may confound results.

QT dispersion and viable myocardium in patients with prior myocardial infarction and severe left ventricular dysfunction.

BACKGROUND: QT dispersion (QTd) has been found to correlate to the amount of viable myocardium in patients with Q-wave myocardial infarction and well-preserved LV function. However, this relationship is unknown in patients with severe left ventricular dysfunction. METHODS: Thirty-four patients with prior large myocardial infarction and severe left ventricular dysfunction underwent Tc-99m sestamibi single photon emission cardiac tomography (SPECT) and F-18 fluorodeoxyglucose (FDG) SPECT. Viability was defined as a defect relative count density (DCD) of at least 20% greater on FDG SPECT. QTd, corrected QT dispersion (QTcd), and QT coefficient of variation (cv) in patients with viable myocardium was compared to those without viable myocardium in the infarct area. RESULTS: Thirteen patients were excluded from analysis for poor FDG images or inadequate ECG tracings. Of the remaining patients, 10 (48%) were found to have viability on FDG SPECT. QTd, QTcd, and QTcv in patients with viability were: 58 +/- 22 ms, 61 +/- 23 ms, and 4.81 +/- 1.76%, respectively, which did not differ significantly from those in patients without viability (QTd = 56 +/- 14 ms, QTcd = 70 +/- 16 ms and Qtcv = 5.06 +/- 1.20% [P = NS]). Moreover, neither FDG defect size, nor LVEF correlated with QTd. CONCLUSIONS: This study indicates no relationship between QTd and viability in patients with myocardial infarction and severe left ventricular dysfunction.

The effect of head-upright tilt table testing for vasovagal syncope on P-wave duration.

Fluid shifts in vasovagal syncope may be reflected in electrocardiographic P-wave duration. We examined the effect of head-upright tilt-table testing (HUT) on P-wave duration among patients with positive or negative HUT. P-wave duration was measured at baseline and several post-HUT time points. In patients with a positive HUT, the test was immediately discontinued. P-wave duration measurements obtained at the completion of the test or when symptoms occurred were compared to baseline measurements. The P-wave duration among patients with a positive HUT was significantly reduced at the onset of symptoms as compared to baseline (-14.0 ms, P = .0054) and 2-minute tilt measurements (-11.3 ms, P = .0246). P-wave duration measurements were not reduced in patients experiencing a negative HUT at any follow-up time. We showed a significant reduction in P-wave duration among patients experiencing positive HUT that suggests a dynamic relationship between atrial volume and P-wave duration.