Velislav N. Batchvarov

Precision of QT interval measurement by advanced electrocardiographic equipment

The costs of clinical investigations of drug‐induced QT interval prolongation are mainly related to manual processing of electrocardiographic (ECG) recordings. Potentially, however, these costs can be decreased by automatic ECG measurement. To investigate the improvements in measurement accuracy of the modern ECG equipment, this study investigated QT interval measurement by the “old” and “new” versions of the 12SL ECG algorithm by GE Healthcare (Milwaukee, WI, USA) and compared the results to carefully validated and reconciled manual measurements. The investigation used two sets (A and B) of ECG recordings that originated from large clinical studies. Sets A and B consisted of 15,194, and 29,866 10‐second ECG recordings, respectively. All the recordings were obtained with GE Healthcare recorders and were available in digital format compatible with ECG processing software by GE Healthcare. The two sets of recordings differed significantly in ECG quality with set B being substantially more noise polluted. Compared to careful manual QT interval readings in recording set A, the errors of the automatic QT interval measurement were (mean ± SD) +3.95 ± 5.50 ms, and +0.51 ± 12.41 ms for the “new” and “old” 12SL algorithm, respectively. In recording set B, these numbers were +2.41 ± 9.47 ms, and –0.17 ± 14.89 ms, respectively (both differences were highly statistically significant, P < 0.000001). In recording set A, 95.9% and 76.6% of ECGs were measured automatically within 10 ms of the manual measurement by the “new” and “old” versions of the 12SL algorithm, In recording set B, these numbers were 83.9% and 59.5%. The errors made by the “new” and “old” version of 12SL algorithm were practically independent each of the other (correlation coefficients of 0.031 and 0.281 in recording sets A and B, respectively). The study shows that (a) compared to the “old” version of the 12SL algorithm, the QT interval measurement by the “new” version implemented in the most recent ECG equipment by GE Healthcare is significantly better, and (b) the precision of automatic measurement by the 12SL algorithm is substantially dependent on the quality of processed ECG recordings. The improved accuracy of the “new” 12SL algorithm makes it feasible to use modern ECG equipment without any manual intervention in selected parts of drug‐development program.

Technical Mistakes during the Acquisition of the Electrocardiogram

In addition to knowledge of normal and pathological patterns, the correct interpretation of electrocardiographic (ECG) recordings requires the use of acquisition procedures according to approved standards. Most manuals on standard electrocardiography devote little attention to inadequate ECG recordings. In this article, we present the most frequent ECG patterns resulting from errors in limb and precordial lead placement, artifacts in 12‐lead ECG as well as inadequate filter application; we also review alternative systems to the standard ECG, which may help minimize errors.

Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

AIMS The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QTc that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the IKr blocking properties of moxifloxacin and (iii) characterize the QTc F profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects. METHODS The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20-45 years with a body mass index of between 18 to 25 kg m(-2). Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition. RESULTS The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQTc in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QTc F change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QTc F change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QTc F change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration-effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QTc interval. CONCLUSIONS Our findings demonstrate that the food effect by itself leads to a shortening of the QTc interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the Cmax and delays the peak effects on QTc up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QTc prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK-PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QTc prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.

Significance of QRS prolongation during diagnostic ajmaline test in patients with suspected Brugada syndrome

BACKGROUND Current consensus documents on Brugada syndrome recommend the diagnostic intravenous administration of a Na-channel blocker to be stopped when the QRS prolongs to > or =130% of baseline, presumably because of increased arrhythmic risk. OBJECTIVE This study sought to assess QRS prolongation during ajmaline testing and its relation to arrhythmic risk. METHODS We analyzed an electrocardiographic (ECG) database collected during ajmaline testing in 148 patients (92 men, age 36 +/- 15 years). The QRS was measured at baseline and during the 1st to 7th, 10th, and 15th minute after the beginning of ajmaline administration. RESULTS The average QRS prolongation was 36% +/- 16% (range 9% to 88%), not significantly different between positive (n = 30) and negative (n = 118) tests. QRS prolonged to > or =130% during 16 (55%) positive and 71 (61%) negative tests (P = .50), with no clinical side effects. The incidence of ventricular arrhythmias was not significantly different between patients with and without QRS prolongation. Short runs (3 to 8 complexes) of nonsustained ventricular tachycardia occurred in 3 patients with QRS prolongation > or =130%. In 40% of positive tests, prolongation > or =130% occurred earlier by >1 minute than diagnostic Brugada ECG changes, i.e., early termination of the test could possibly have resulted in false-negative outcomes. CONCLUSION QRS prolongation > or =130% occurs in >50% of all tests. In 40% of positive tests it occurs before diagnostic ECG changes. Always terminating the test when QRS prolongs > or =130% could possibly result in loss of important diagnostic information. It is appropriate to adjust the criteria for early termination of the test to the baseline QRS and possibly other factors.

Diagnostic utility of bipolar precordial leads during ajmaline testing for suspected Brugada syndrome

BACKGROUND Leads V(1) and V(2) recorded from the standard position (fourth intercostal space) have insufficient sensitivity to detect the diagnostic type 1 Brugada ECG pattern. OBJECTIVE The purpose of this study was to compare the sensitivity of bipolar leads with a positive pole at V(2) and a negative pole at V(4) or V(5) with that of the standard unipolar lead V(2) for detection of the type 1 Brugada pattern. METHODS We analyzed digital 15-lead ECGs (12 standard leads plus leads V(1) to V(3) recorded from the third intercostal space [V(1h) to V(3h)]) acquired during diagnostic ajmaline testing in 128 patients (80 men, age 37 +/- 15 years) with suspected Brugada syndrome and standard 12-lead ECGs recorded in 229 healthy subjects (111 men, age 33 +/- 4 years). Bipolar leads between V(2) (positive pole) and V(4) or V(5) (leads V(2-4), V(2-5)) were derived by subtracting leads V(4) and V(5) from V(2). All ECGs were examined for the presence of type 1 Brugada pattern. RESULTS During 21 (16.4%) positive ajmaline tests, type 1 pattern was observed in lead V(2h) during 20 tests (95.2%) and in V(2) during 10 tests (47.6%). Type 1 pattern appeared in lead V(2-4) or V(2-5) in all tests when it was present in V(2) and in seven tests during which it was observed in lead V(2h) but not V(2) (17 tests [81%]). Type 1-like pattern was observed in lead V(2-4) or V(2-5) during two nonpositive tests (1.9%) and in one healthy subject (0.4%). CONCLUSION Bipolar leads V(2-4) and V(2-5) are more sensitive than lead V(2) for detection of the type 1 Brugada pattern.

Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers

Food is known to shorten the QTc (QTcI and QTcF) interval and has been proposed as a non‐pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C‐peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QTc interval, whilst C‐peptide has been reported to shorten the QTc interval. Currently there is limited information on the effects of insulin and C‐peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C‐peptide on the QTc interval under the rigorous conditions of a TQT study.

Specificity of elevated intercostal space ECG recording for the type 1 Brugada ECG pattern.

Background: Right precordial (V1–3) elevated electrode placement ECG (EEP‐ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population.

Brugada-Like Changes in the Peripheral Leads during Diagnostic Ajmaline Test in Patients with Suspected Brugada Syndrome

Background: Although cases of Brugada‐type electrocardiographic (ECG) pattern in peripheral (limb) leads have been reported (“atypical” Brugada syndrome [BS]), their incidence in patients investigated for BS is unknown.

Characterization of early repolarization during ajmaline provocation and exercise tolerance testing

BACKGROUND Early repolarization (ER) in the inferior electrocardiogram leads is associated with idiopathic ventricular fibrillation, but the majority of subjects with ER have a benign prognosis. At present, there are no risk stratifiers for asymptomatic ER. OBJECTIVE To examine the response to ajmaline provocation and exercise in potentially high-risk subjects with ER and without a definitive cardiac diagnosis. METHODS Electrocardiographic data were reviewed for ER at baseline and during ajmaline and exercise testing in 229 potentially high-risk patients (mean age 37.7±14.9 years; 55.9% men). ER was defined as J-point elevation in ≥2 consecutive leads and stratified by type, territory, J-point height, and ST-segment morphology. RESULTS Baseline ER was present in 26 (11.4%; 19 men) patients. During ajmaline provocation and exercise, there were no new ER changes. ER with rapidly ascending ST-segment and lateral ER consistently diminished. There were 7 patients with persistent ER during ajmaline and/or exercise. They were all men with inferior or inferolateral ER and horizontal/descending ST segment. Those with persistent ER during exercise were more likely to have a history of unexplained syncope than those in whom ER changes diminished (P<.01). Subtle nondiagnostic structural abnormalities were demonstrated in 3 of these patients. CONCLUSIONS ER with horizontal/descending ST-segment morphology in the inferior or inferolateral leads that persists during exercise is more common in patients with prior unexplained syncope and may identify patients at higher risk of arrhythmic events. ER that persists during ajmaline provocation and/or exercise may reflect underlying subtle structural abnormalities and should prompt further investigation.

Effect of heart rate and body position on the complexity of the QRS and T wave in healthy subjects

We analysed the effect of heart rate and body position on the complexity of the QRS and T wave quantified by the ratio of 2nd/1st eigenvalue from principal component analysis (PCA) (QRS-PCA, T-PCA) using continuous 25 min 12-lead digital ECGs (500 Hz, 4.88 muV resolution) acquired on 2 occasions in supine and standing position in 15 healthy subjects (8 men, age 28.6plusmn7.5 years). In the group as a whole, QRS-PCA and T-PCA did not differ significantly between the two positions. However, the linear correlation coefficient between the PCA parameters and the RR interval varied widely between different subjects in the supine position (QRS-PCA: from 0.002 to 0.61; T-PCA: from 0.01 to 0.65) and even more in standing position (QRS-PCA: from -0.55 to 0.48; T-PCA: from -0.63 to 0.51). In both positions, the intra-subject variability of QRS-PCA and T-PCA was significantly smaller than the inter-subject variability.