QT dispersion as an attribute of T-loop morphology

BACKGROUND: The suggestion that increased QT dispersion (QTD) is due to increased differences in local action potential durations within the myocardium is wanting. An alternative explanation was sought by relating QTD to vectorcardiographic T-loop morphology. METHODS AND RESULTS: The T loop is characterized by its amplitude and width (defined as the spatial angle between the mean vectors of the first and second halves of the loop). We reasoned that small, wide ("pathological") T loops produce larger QTD than large, narrow ("normal") loops. To quantify the relationship between QTD and T-loop morphology, we used a program for automated analysis of ECGs and a database of 1220 standard simultaneous 12-lead ECGs. For each ECG, QT durations, QTD, and T-loop parameters were computed. T-loop amplitude and width were dichotomized, with 250 microV (small versus large amplitudes) and 30 degrees (narrow versus wide loops) taken as thresholds. Over all 1220 ECGs, QTDs were smallest for large, narrow T loops (54.2+/-27.1 ms) and largest for small, wide loops (69. 5+/-33.5 ms; P<0.001). CONCLUSIONS: QTD is an attribute of T-loop morphology, as expressed by T-loop amplitude and width

Validation of automatic measurement of QT interval variability

Background Increased variability of beat-to-beat QT-interval durations on the electrocardiogram (ECG) has been associated with increased risk for fatal and non-fatal cardiac events. However, techniques for the measurement of QT variability (QTV) have not been validated since a gold standard is not available. In this study, we propose a validation method and illustrate its use for the validation of two automatic QTV measurement techniques. Methods Our method generates artificial standard 12-lead ECGs based on the averaged P-QRS-T complexes from a variety of existing ECG signals, with simulated intrinsic (QT interval) and extrinsic (noise, baseline wander, signal length) variations. We quantified QTV by a commonly used measure, short-term QT variability (STV). Using 28,800 simulated ECGs, we assessed the performance of a conventional QTV measurement algorithm, resembling a manual QTV measurement approach, and a more advanced algorithm based on fiducial segment averaging (FSA). Results The results for the conventional algorithm show considerable median absolute differences between the simulated and estimated STV. For the highest noise level, median differences were 4±6 ms in the absence of QTV. Increasing signal length generally yields more accurate STV estimates, but the difference in performance between 30 or 60 beats is small. The FSA algorithm proved to be very accurate, with most median absolute differences less than 0.5 ms, even for the highest levels of disturbance. Conclusions Artificially constructed ECGs with a variety of disturbances allow validation of QTV measurement procedures. The FSA algorithm provides highly accurate STV estimates under varying signal conditions, and performs much better than traditional beat-by-beat analysis. The fully automatic operation of the FSA algorithm enables STV measurement in large sets of ECGs

Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages

Cardiolog

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands:An Analysis of Toxicity, Efficacy, and Predictive Markers

Background: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. Patients and Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non–clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P =.038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P =.000). On-treatment increase in eosinophils by week 8 predicted improved OS (P =.003), PFS (P =.000), and TTF (P =.014), whereas a decrease of neutrophils was associated with significantly better TTF (P =.023). Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation

Normal Values of QT Variability in 10-s Electrocardiograms for all Ages

Aims: QT variability is a promising electrocardiographic marker. It has been studied as a screening tool for coronary artery disease and left ventricular hypertrophy, and increased QT variability is a known risk factor for sudden cardiac death. Considering that comprehensive normal values for QT variability were lacking, we set out to establish these in standard 10-s electrocardiograms (ECGs) covering both sexes and all ages. Methods: Ten-second, 12-lead ECGs were provided by five Dutch population studies (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study). ECGs were recorded digitally and processed by well-validated analysis software. We selected cardiologically healthy participants, 46% being women. Ages ranged from 11 days to 91 years. After quality control, 13,828 ECGs were available. We assessed three markers: standard deviation of QT intervals (SDqt), short-term QT variability (STVqt), and QT variability index (QTVI). Results: For SDqt and STVqt, the median and the lower limit of normal remained stable with age. The upper limit of normal declined until around age 45, and increased strongly in the elderly, notably so in women. This implies that a subset of the population, small enough not to have appreciable effect on the median, shows a high degree of QT variability with a possible risk of arrhythmias or worse, especially in women. Otherwise, sex differences were negligible in all three measurements. For QTVI, median, and normal limits decreased until age 20, and steadily went up afterwards except for the lower limit of normal, which flattens off after age 65. Conclusion: We report the first set of normal values for QT variability based on 10-s ECGs, for all ages and both sexes

Comparison of automated interval measurements by widely used algorithms in digital electrocardiographs

Background: Automated measurements of electrocardiographic (ECG) intervals by current-generation digital electrocardiographs are critical to computer-based ECG diagnostic statements, to serial comparison of ECGs, and to epidemiological studies of ECG findings in populations. A previous study demonstrated generally small but often significant systematic differences among 4 algorithms widely used for automated ECG in the United States and that measurement differences could be related to the degree of abnormality of the underlying tracing. Since that publication, some algorithms have been adjusted, whereas other large manufacturers of automated ECGs have asked to participate in an extension of this comparison. Methods: Seven widely used automated algorithms for computer-based interpretation participated in this blinded study of 800 digitized ECGs provided by the Cardiac Safety Research Consortium. All tracings were different from the study of 4 algorithms reported in 2014, and the selected population was heavily weighted toward groups with known effects on the QT interval: included were 200 normal subjects, 200 normal subjects receiving moxifloxacin as part of an active control arm of thorough QT studies, 200 subjects with genetically proved long QT syndrome type 1 (LQT1), and 200 subjects with genetically proved long QT syndrome Type 2 (LQT2). Results: For the entire population of 800 subjects, pairwise differences between algorithms for each mean interval value were clinically small, even where statistically significant, ranging from 0.2 to 3.6 milliseconds for the PR interval, 0.1 to 8.1 milliseconds for QRS duration, and 0.1 to 9.3 milliseconds for QT interval. The mean value of all paired differences among algorithms was higher in the long QT groups than in normals for both QRS duration and QT intervals. Differences in mean QRS duration ranged from 0.2 to 13.3 milliseconds in the LQT1 subjects and from 0.2 to 11.0 milliseconds in the LQT2 subjects. Differences in measured QT duration (not corrected for heart rate) ranged from 0.2 to 10.5 milliseconds in the LQT1 subjects and from 0.9 to 12.8 milliseconds in the LQT2 subjects. Conclusions: Among current-generation computer-based electrocardiographs, clinically small but statistically significant differences exist between ECG interval measurements by individual algorithms. Measurement differences between algorithms for QRS duration and for QT interval are larger in long QT interval subjects than in normal subjects. Comparisons of population study norms should be aware of small systematic differences in interval measurements due to different algorithm methodologies, within-individual interval measurement comparisons should use comparable methods, and further attempts to harmonize interval measurement methodologies are warranted

Electrocardiographic Criteria for Left Ventricular Hypertrophy in Children

Previous studies to determine the sensitivity of the electrocardiogram (ECG) for left ventricular hypertrophy (LVH) in children had their imperfections: they were not done on an unselected hospital population, several criteria used in adults were not applied to children, and obsolete limits of normal for the ECG parameters were used. Furthermore, left ventricular mass (LVM) was taken as the reference standard for LVH, with no regard for other clinical evidence. The study population consisted of 832 children from whom a 12-lead ECG and an M-mode echocardiogram were taken on the same day. The validity of the ECG criteria was judged on the basis of an abnormal LVM index, either alone or in combination with other clinical evidence. The ECG criteria were based on recently established age-dependent normal limits. At 95% specificity, the ECG criteria have low sensitivities (<25%) when an elevated LVM index is taken as the reference for LVH. When clinical evidence is also taken into account, the sensitivity improved considerably (<43%). Sensitivities could be further improved when ECG parameters were combined. The sensitivity of the pediatric ECG in detecting LVH is low but depends strongly on the definition of the reference used for validation

Radiation Damage to Bull Sperm Motility. II: Proton Irradiation and Respiration Measurements

Diluted bull semen samples were bombarded with a 24 Mev proton beam. Dose response curves for the fraction of cells which survived the bombardment and for the average velocity of the surviving cells were measured. Target theory indicated a cross section of the sensitive volume of 2.1 × 10(-10) cm(2). Respiration measurements showed that the oxidative phosphorylation in the sperm remained coupled after the bombardments. The efficiency with which free energy from ATP hydrolysis was converted into mechanical work by the sperm was found to decrease after proton bombardment. The half-value dose for this effect was two and a half times higher than the half-value dose for motility damage. These respiration measurements indicate that the damage due to the bombardment is not to the metabolic system or to the contractile system in the sperm flagellum, but to a control system for the motility. The results of the target theory shows that this control system is localized in a small element of approximately 1600 A diameter. The centriole is tentatively proposed as being this control element