Changes In T-wave Morphology Research Articles

Diagnostic Accuracy of the Standing Test in Adults Suspected for Congenital Long-QT Syndrome.

Background An elegant bedside provocation test has been shown to aid the diagnosis of long-QT syndrome (LQTS) in a retrospective cohort by evaluation of QT intervals and T-wave morphology changes resulting from the brief tachycardia provoked by standing. We aimed to prospectively determine the potential diagnostic value of the standing test for LQTS. Methods and Results In adults suspected for LQTS who had a standing test, the QT interval was assessed manually and automated. In addition, T-wave morphology changes were determined. A total of 167 controls and 131 genetically confirmed patients with LQTS were included. A prolonged heart rate-corrected QT interval (QTc) (men ≥430 ms, women ≥450 ms) at baseline before standing yielded a sensitivity of 61% (95% CI, 47-74) in men and 54% (95% CI, 42-66) in women, with a specificity of 90% (95% CI, 80-96) and 89% (95% CI, 81-95), respectively. In both men and women, QTc≥460 ms after standing increased sensitivity (89% [95% CI, 83-94]) but decreased specificity (49% [95% CI, 41-57]). Sensitivity further increased (P<0.01) when a prolonged baseline QTc was accompanied by a QTc≥460 ms after standing in both men (93% [95% CI, 84-98]) and women (90% [95% CI, 81-96]). However, the area under the curve did not improve. T-wave abnormalities after standing did not further increase the sensitivity or the area under the curve significantly. Conclusions Despite earlier retrospective studies, a baseline ECG and the standing test in a prospective evaluation displayed a different diagnostic profile for congenital LQTS but no unequivocal synergism or advantage. This suggests that there is markedly reduced penetrance and incomplete expression in genetically confirmed LQTS with retention of repolarization reserve in response to the brief tachycardia provoked by standing.

Monitoring blood potassium concentration in hemodialysis patients by quantifying T-wave morphology dynamics

We investigated the ability of time-warping-based ECG-derived markers of T-wave morphology changes in time (d_{w}) and amplitude (d_a), as well as their non-linear components ({d_w^{{mathrm{NL}}}} and {d_a^{mathrm{NL}}}), and the heart rate corrected counterpart (d_{w,c}), to monitor potassium concentration ([K^{+}]) changes (Delta [K^+]) in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). We compared the performance of the proposed time-warping markers, together with other previously proposed [K^{+}] markers, such as T-wave width (T_w) and T-wave slope-to-amplitude ratio (T_{S/A}), when computed from standard ECG leads as well as from principal component analysis (PCA)-based leads. 48-hour ECG recordings and a set of hourly-collected blood samples from 29 ESRD-HD patients were acquired. Values of d_w, d_a, {d_w^{mathrm{NL}}}, {d_a^{mathrm{NL}}} and d_{w,c} were calculated by comparing the morphology of the mean warped T-waves (MWTWs) derived at each hour along the HD with that from a reference MWTW, measured at the end of the HD. From the same MWTWs T_w and T_{S/A} were also extracted. Similarly, Delta [K^+] was calculated as the difference between the [K^{+}] values at each hour and the [K^{+}] reference level at the end of the HD session. We found that d_{w} and d_{w,c} showed higher correlation coefficients with Delta [K^+] than T_{S/A}—Spearman’s (rho) and Pearson’s (r)—and T_w—Spearman’s (rho)—in both SL and PCA approaches being the intra-patient median rho ge 0.82 and r ge 0.87 in SL and rho ge 0.82 and r ge 0.89 in PCA respectively. Our findings would point at d_{w} and d_{w,c} as the most suitable surrogate of Delta [K^+], suggesting that they could be potentially useful for non-invasive monitoring of ESRD-HD patients in hospital, as well as in ambulatory settings. Therefore, the tracking of T-wave morphology variations by means of time-warping analysis could improve continuous and remote [K^{+}] monitoring of ESRD-HD patients and flagging risk of [K^{+}]-related cardiovascular events.

Effects of β-adrenergic stimulation on fetal heart rate, heart rate variability, and T-wave elevation during brief umbilical cord occlusions in fetal sheep.

Circulating catecholamines are critical for fetal adaptation to hypoxia by regulating fetal heart rate (FHR) and promoting myocardial contractility and peripheral vasoconstriction. They have been hypothesized to contribute to changes in FHR variability (FHRV) and T-wave morphology, clinical indexes of fetal well-being during labor. β-Adrenergic blockade with propranolol does not affect FHRV during labor-like hypoxemia and only attenuated the increase in T-wave height between the episodes of hypoxemia. To further investigate the potential role of catecholamines, we investigated whether pharmacological β-adrenergic stimulation could increase FHRV and T-wave elevation during intermittent labor-like hypoxemia. Nineteen chronically instrumented fetal sheep at 0.85 of gestation received isoprenaline hydrochloride (n = 7) or saline (control, n = 12), followed by three 1-min complete umbilical cord occlusions (UCOs) separated by 4-min reperfusion periods. Before the UCOs, infusion of isoprenaline increased FHR (P < 0.001), absolute-T/QRS ratio (P < 0.001), and one measure of FHRV [root-mean-square of successive RR interval differences (RMSSD), P < 0.05]. UCOs triggered deep FHR decelerations. During UCOs, isoprenaline was associated with increased FHR (P < 0.001) and absolute-T/QRS ratio (P < 0.05), but no effect on T/QRS ratio was observed when normalized to baseline before UCOs (normalized-T/QRS ratio). Between UCOs, isoprenaline increased FHR (P < 0.001) and absolute-T/QRS ratio (P < 0.05) but did not affect normalized-T/QRS ratio or any measures of FHRV. Arterial pressure was not affected by isoprenaline at any point. Our findings indicate that circulating catecholamines regulate FHR but not FHRV during labor-like hypoxemia and promote T-wave elevation between but not during intermittent fetal hypoxemia.

The Repolarization Period during the Head-Up Tilt Test in Children with Vasovagal Syncope.

Background: Electrocardiography (ECG) and the head-up tilt test (HUTT) are vital in clinical work-up in children with vasovagal syncope (VVS). Ventricular repolarization parameters (QT) measured during the HUTT can be indicative of electrical instability; however, these parameters are not frequently assessed. This study aimed to investigate if ventricular repolarization parameters measured during the HUTT could be indicative of future ventricular arrhythmias in children with syncope. Methods: The shape and amplitude of the T-wave and parameters of the repolarization period (QT, QTpeak, Tpeak-Tend) were evaluated in a resting ECG performed on the first day of hospitalization and in ECGs performed during three phases of the HUTT. Results: In the after-tilt phase of the HUTT, 19/30 children displayed a change in T-wave morphology. QTc was significantly longer in VVS I compared to that in VVS II patients, but not in the controls (p = 0.092). Conclusions: We need further follow-up studies to establish the clinical importance of abnormal dynamics of the repolarization period in children with VVS and negative HUTT. Therefore, children with abnormal T-wave refraction and prolonged duration of the TpTe should remain under the care of a cardiological outpatient.

Noninvasive Monitoring of Potassium Fluctuations During the Long Interdialytic Interval

Hemodialysis patients are susceptible to life-threatening arrhythmias whose incidence is markedly higher during the long interdialytic interval due to electrolyte fluctuations. Noninvasive monitoring of electrolyte fluctuations, particularly those of potassium, would enable restoring electrolyte balance before the onset of arrhythmias. This study investigates the feasibility of continuous long-term monitoring of potassium fluctuations using a single-lead electrocardiogram. We evaluate patient-specific T-wave morphology changes in the electrocardiogram using two descriptors: 1) a model-based descriptor, θ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</sub> , developed to account for overall morphology changes, and 2) the currently available descriptor, T <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SA</sub> , sensitive to potassium levels in single-lead electrocardiograms. Electrocardiograms of 15 hemodialysis patients with pre-existent cardiac diseases were acquired continuously over the long interdialytic interval along with blood samples at predetermined time instants. Results reveal that θ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</sub> and T <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SA</sub> respond concordantly with potassium levels, and reacts to potassium lowering medication. The overlapping index of the daily distributions of θ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</sub> and T <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SA</sub> are moderately correlated with changes in potassium levels (r = -0.56 and r = -0.57, respectively). θ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</sub> exhibits circadian variation, peaking amidst morning and decreasing until evening. θ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</sub> appears to be less affected by motion-induced noise, which is preferable for ambulatory monitoring. Although long-term monitoring of potassium fluctuations is feasible even in complicated hemodialysis patients, the presence of concomitant electrolyte (calcium and bicarbonate) imbalances should be accounted for since it can hamper a reliable estimation. Considering that intradialytic T-wave morphologies may differ from the ones manifested between hemodialysis sessions, future studies should also strive to collect blood samples outside of hemodialysis to improve electrolyte estimation methods.

Changes on the electrocardiogram in anorexia nervosa: A case control study

PurposeAnorexia nervosa is a complex psychiatric condition with increased mortality. The electrocardiogram (ECG) may show repolarization changes which may associate with an increased risk of sudden death. Up to 80% of patients may be prescribed psychopharmacotherapies which alter the ECG, potentially compounding arrhythmic risk.This study aimed to describe and improve understanding of ECG changes in eating disorders and assess the effect of psychopharmacotherapies. MethodsAdolescent patients diagnosed with anorexia nervosa were reviewed. ECGs were reviewed by blinded expert reviewers, and repolarization parameters were compared to healthy controls. Patients on and off psychopharmacotherapies were compared. ResultsThirty-eight anorexia nervosa patients off psychopharmacotherapies were age matched to 53 healthy controls. Heart rate was lower in anorexia nervosa patients (56 vs. 74 bpm, p < 0.001). The absolute QT interval was longer in patients compared to controls (408 vs. 383 ms, p < 0.001), but the QTc by Hodges' formula was similar between groups (401 vs. 408 ms, p = 0.16). The prevalence of T-wave flattening and inversion was also similar between groups (13% vs. 4%, p = 0.12) and T-peak to T-end interval (Tpe) was shorter in patients compared to controls (p < 0.01). ECG parameters were similar between patients on and off psychopharmacotherapies aside from off-drug patients showing lower HR (56 vs. 65, p = 0.04). ConclusionsAutonomic and repolarization changes are evident on the ECG of anorexia nervosa patients, though the QTc interval was in fact similar between groups. Changes in T-wave morphology and duration may be promising metrics of repolarization effects of anorexia nervosa.

Electrocardiogram T-Wave Morphology and Amplitude Differences during an Ultramarathon Competition

PURPOSE: The goal of this research is to study the effect of ultramarathon competition on T-wave morphology and amplitude changes. T-wave changes can be an indication of a vast number of conditions with many being of critical nature. This makes understanding what changes ultrarunners are undergoing critical for monitoring and understanding physiological changes associated with ultramarathons. METHODS: In this study, volunteer subjects Male n=25, Female n=20 signed an informed consent, then completed their ultramarathon distance. 12 lead EKGs were measured pre and post-race. EKGs were recorded and analyzed with ECG Synchronous V1.3.1 and statistics were performed in SPSS V21. Paired sample t-tests were used to compare pre and post-race T-wave amplitude values (Pre/Post mean ± SD, p≤0.05). RESULTS: A total of 405 T-waves were analyzed. There was no change in t-wave morphology pre versus post-race for 83.95% (n=340), while 16.05% (n=65) changed morphology (upright, inverted, flat, camel hump and biphasic). Major changes observed were inverted to upright (n=24), upright to inverted (n=9), biphasic to upright (n=9) and camel hump to upright (n=6), other changes only occurred in 1 or 2 leads. Significant changes in T-wave amplitude (mv) pre- to post-race were found in the following leads: (Pre/Post mean ± SD, p≤0.05): lead I (0.168±0.114, 0.254±0.105, t(44)= -4.845; p<0.001); lead II (0.305±0.124, 0.398 ±0.137, t(44)= -4.081; p<0.001); lead aVR (-0.24±0.11, -0.29±0.15, t(44)=0.04); lead aVF (0.231±0.0805, 0.284±0.117, t(44)= -3.666; p<0.001); lead V1 (0.00333±0.136, 0.0973±0.161, t(44)= -5.144; p<0.001); lead V2 (0.358±0.233, 0.528±0.346, t(44)= -5.462; p<0.001); lead V3 (0.440±0.215, 0.590±0.290, t(44)= -5.951; p<0.001), lead V4 (0.480±0.190, 0.589±0.254, t(44)= -3.899; p<0.001), lead V5 (0.168±0.114, 0.254±0.105, t(44)= -4.035; p<0.001), and lead V6 (0.329±0.103, 0.398±0.148, t(44)= -3.348; p<0.001); leads III and aVL showed no change in amplitude. CONCLUSION: From this study, the results show evidence that long-distance running can alter T-wave morphology and amplitude pre- to post-race. Possible causes of these changes include hyperkalemia, cardiac strain, long QT syndrome, Tachycardia Induced cardiomyopathy all in response to the ultramarathon.

High-Resolution Body Surface Potential Mapping in Exercise Assessment of Ischemic Heart Disease

Standard 12-lead ECG exercise testing is commonly used for screening of ischemic heart disease (IHD). We studied if high-resolution body surface potential mapping (HR-BSPM) during exercise offers advantages over current standards in noninvasive evaluation of IHD. This study was carried out on 90 IHD patients and 33 healthy controls. The 67-lead HR-BSPM was recorded at rest and during exercise. Twenty-one ECG parameters including classical ST criteria were compared. The effectiveness of methods was verified based on the results of SPECT and coronary angiography. The most effective parameters in the diagnosis of IHD were: amplitude parameter ΔST60 and δT parameter showing T-wave morphology changes during exercise. The sensitivities/specificities of ΔST60 and δT parameters for the HR-BSPM were 70/69 and 59/62%, while for the standard 12-lead ECG system they were: 63/62 and 59/56%. These results demonstrate the usefulness of HR-BSPM measurements during exercise. HR-BSPM resulted in higher sensitivities and specificities compared to the standard 12-lead exercise test. The advantage was partially associated with observed ischemic changes outside standard precordial leads position that were not visible when using the standard 12-lead exercise test. This justifies research into the optimization of the number and position of ECG leads in exercise testing.

Type 1 diabetes is associated with T-wave morphology changes. The Thousand & 1 Study

BackgroundRepolarization is impaired in patients with type 1 diabetes mellitus (T1DM), and repolarization disturbances are associated with an increased mortality. To study cardiac repolarization, we assessed T-wave morphology in patients with T1DM without known heart disease. Methods855 T1DM patients without known heart disease were matched 1:2 with 1710 people from a background population. Rate-corrected T-wave morphology markers were obtained. Patients were stratified by albuminuria. Results are mean ± standard deviation. ResultsT-waves were flatter (0.398 ± 0.059 vs. 0.382 ± 0.062, p < 0.001) and more asymmetric (0.082 ± 0.068 vs. 0.071 ± 0.084, p = 0.001) in T1DM. Patients with albuminuria had an increased heart rate (normoalbuminuria: 71 ± 13 bpm, microalbuminuria: 75 ± 12 bpm, p < 0.001, macroalbuminuria: 78 ± 12 bpm, p < 0.001) and more asymmetric T-waves (normoalbuminuria: 0.079 ± 0.060, microalbuminuria: 0.094 ± 0.085, p < 0.01, macroalbuminuria: 0.101 ± 0.080, p < 0.01), but the QTc interval remained unchanged. ConclusionsT1DM is associated with changes in T-wave morphology. T-wave asymmetry but not QTc interval is associated with albuminuria in T1DM and may be used for stratification.

Comparison of one- and three-lead ECG to measure cardiac intervals and differentiate drug-induced multi-channel block

IntroductionFDA has established initiatives to characterize clinical and non-clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi-channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived ​from a spatial vectorcardiogram computed using multiple leads. This study compares QT subintervals derived from single lead vs. spatial magnitude (SM) ECG and contrasts information obtained from multilead and single lead ECGs in the canine model. MethodsFour beagle dogs were instrumented with 3-lead Holter monitors to acquire continuous surface ECG recordings for three consecutive days. A 24-h baseline recording was obtained on day 1 followed by administration of dofetilide on day 2 and atropine and dofetilide on day 3. Lead II and SM ECGs were automatically analyzed using the AE-1010 Rhythm Express™ (RE) software (VivaQuant, St. Paul, MN USA) without manual intervention or editing of the results (auto). Five-minute averages of beat-to-beat intervals measured on each lead were compared for agreement assessed by Bland-Altman (BA) statistics and consistency measured as the repeatability standard deviation (SD) from 5-min intervals. The fully automated results were screened by an operator (semi-automated) and compared to automated results. ResultsJTp and TpTe measured using SM lead are less sensitive to changes in posture and respiration related changes in T-wave morphology. The 24-h repeatability SD of 5-min subintervals for JTp and TpTe over the three days was improved by 15.4% and 15.5% respectively with the highest improvements of 23.3% for JTp on day 2 and 25.3% for TpTe on day 3. Drug induced changes in QTcV, QRS, RR, and PR intervals were qualitatively similar between the SM lead and Lead II and in close agreement based on BA statistics. Semi-automated and automated measurements from SM Lead were in close agreement based on BA statistics. DiscussionSingle lead ECG is adequate for PR, RR, QRS, and QT, but produces different and more variable results when assessing QT subintervals relative to the SM lead. Close agreement between automated and semi-automated measurements demonstrates Rhythm Express accuracy and the potential to streamline interval analysis.

The development and validation of an easy to use automatic QT-interval algorithm.

BackgroundTo evaluate QT-interval dynamics in patients and in drug safety analysis, beat-to-beat QT-interval measurements are increasingly used. However, interobserver differences, aberrant T-wave morphologies and changes in heart axis might hamper accurate QT-interval measurements.ObjectiveTo develop and validate a QT-interval algorithm robust to heart axis orientation and T-wave morphology that can be applied on a beat-to-beat basis.MethodsAdditionally to standard ECG leads, the root mean square (ECGRMS), standard deviation and vectorcardiogram were used. QRS-onset was defined from the ECGRMS. T-wave end was defined per individual lead and scalar ECG using an automated tangent method. A median of all T-wave ends was used as the general T-wave end per beat.Supine-standing tests of 73 patients with Long-QT syndrome (LQTS) and 54 controls were used because they have wide ranges of RR and QT-intervals as well as changes in T-wave morphology and heart axis orientation. For each subject, automatically estimated QT-intervals in three random complexes chosen from the low, middle and high RR range, were compared with manually measured QT-intervals by three observers.ResultsAfter visual inspection of the randomly selected complexes, 21 complexes were excluded because of evident noise, too flat T-waves or premature ventricular beats. Bland-Altman analyses of automatically and manually determined QT-intervals showed a bias of <4ms and limits of agreement of ±25ms. Intra-class coefficient indicated excellent agreement (>0.9) between the algorithm and all observers individually as well as between the algorithm and the mean QT-interval of the observers.ConclusionOur automated algorithm provides reliable beat-to-beat QT-interval assessment, robust to heart axis and T-wave morphology.

Efficient Cardiac Risk Assessment based on the T-wave Morphology Changes in Holter ECG Recordings

Efficient Cardiac Risk Assessment based on the T-wave Morphology Changes in Holter ECG Recordings

Clinical and ECG patterns of pseudoinfarction in a young man with type 1 diabetes, diabetic ketoacidosis and normokalaemia

Diabetic ketoacidosis (DKA) can cause changes in the electrocardiogram (ECG) in the form of transient ST-segment depression, QT prolongation, changes in T-wave morphology and the appearance of U wave, possibly due to changes in the serum potassium level. Occasional reports indicate the possibility of transient ST-segment elevation imitating myocardial infarction in the course of hyperkalaemia accompanying DKA. In this article we present a case of a 20-year-old male patient with type 1 diabetes mellitus, DKA and normokalaemia, who experienced severe retrosternal pain, and ECG presented ST-segment elevation imitating acute myocardial infarction of the anterior wall. On the basis of the performed cardiac tests, including laboratory testing, coronary angiography and ultrasound scan, acute coronary syndrome was ruled out. The regression of retrosternal pain and electrocardiographic changes with patient hydration and correction of metabolic disorders suggest the diagnosis of pseudopericarditis, i.e. non-infections irritation of the pericardial membranes due to the loss of fluid in the pericardial sac as a result of dehydration. The diagnosis of acute myocardial infarction based on ST-segment elevation in the ECG recording in a patient with diabetes mellitus and ketoacidosis, without concomitant hyperkalaemia, must be made very carefully, even in the presence of retrosternal pain. The possibility of pseudopericarditis associated with severe dehydration must also be considered.

Diagnostic value of T-wave morphology changes during “QT stretching” in patients with long QT syndrome

Specific T-wave patterns on the resting electrocardiogram (ECG) aid in diagnosing long QT syndrome (LQTS) and identifying the specific genotype. However, provocation tests often are required to establish a diagnosis when the QT interval is borderline at rest. The purpose of this study was to determine whether T-wave morphology changes provoked by standing aid in the diagnosis of LQTS and determination of the genotype. The quick-standing test was performed by 100 LQTS patients (40 type 1 [LQT1], 42 type 2 [LQT2], 18 type 3 [LQT3]) and 100 controls. Logistic regression was used to determine whether T-wave morphology changes provoked by standing added to the already established diagnostic value of QTc stretching in identifying LQTS. During maximal QT stretching, the T-wave morphologies that best discriminated LQTS from controls included "notched," "late-onset," and "biphasic" T waves. These 3 categories were grouped into a category named "abnormal T-wave response to standing." During quick standing, a QTc stretched ≥490 ms increased the odds of correctly identifying LQTS. T-wave morphology changes provoked by standing were most helpful for identifying LQT2, less helpful for LQT1, and least helpful for LQT3. The sudden heart rate acceleration produced by abrupt standing not only increases the QTc but also exposes abnormal T waves that are valuable for diagnosing LQTS.

A new functional data‐based biomarker for monitoring cardiovascular behavior

Cardiac safety assessment in drug development concerns the ventricular repolarization (represented by electrocardiogram (ECG) T-wave) abnormalities of a cardiac cycle, which are widely believed to be linked with torsades de pointes, a potentially life-threatening arrhythmia. The most often used biomarker for such abnormalities is the prolongation of the QT interval, which relies on the correct annotation of onset of QRS complex and offset of T-wave on ECG. A new biomarker generated from a functional data-based methodology is developed to quantify the T-wave morphology changes from placebo to drug interventions. Comparisons of T-wave-form characters through a multivariate linear mixed model are made to assess cardiovascular risk of drugs. Data from a study with 60 subjects participating in a two-period placebo-controlled crossover trial with repeat ECGs obtained at baseline and 12 time points after interventions are used to illustrate this methodology; different types of wave form changes were characterized and motivated further investigation.

Electrocardiographic morphology changes with different type of repolarization dispersions

Background T-wave morphology changes have been linked to heterogeneity of ventricular repolarization and increase of arrhythmia vulnerability. Therefore, century-long debates around the genesis of T wave become even more relevant. Here are some interesting questions for the debates: (1) why T waves are usually concordant with QRS complex? (2) Is there a significant and consistent transmural dispersion of repolarization across heart wall? (3) What kind of T-wave morphology changes can be induced by either transmural or apical-basal dispersion of repolarization? Method The previously developed GE's cell-to-electrocardiogram (ECG) model (GE Healthcare, Milwaukee, WI) was used to study the relation between cellular behavior and the T-wave morphology. The study focused on 2 types of repolarization dispersions: (1) Transmural (from endocardium to epicardium) and (2) Apical-basal (from apex to base of ventricles). More specifically, the transmural dispersions were created by adjusting the slow and fast delayed potassium rectifier current (Iks, Ikr) and transient outward current (Ito), on endocardial, midmyocardial (M cell) and epicardial cells separately. The apical-basal dispersion was adjusted according to the coordinates along the axis from the base to the apex of the ventricle. The contribution of M cell toward T-wave morphology were studied by adjusting the M cell's repolarization time in the range of shorter to longer than those of endocardial repolarization time. Results In the global transmural dispersion cases, QT interval is prolonged from 350 to 450 milliseconds, T-peak to T-end interval (TpTe) is prolonged from 50 to 130 milliseconds, and T-wave notches appeared when the heterogeneity is increased. In the localized transmural dispersion cases, significant T-wave morphology features such as TpTe, T-wave notches appeared in very limited precordial leads. In the global apical-basal dispersion cases, main T-wave change is on the amplitude, and T waves in several precordial leads and lead II turn to positive from negative. And the localized apical-basal dispersion does not generate significant T-wave morphology changes. Conclusions The cell-to-ECG model provides a unique way to study electrophysiology and to link physiologic factors to ECG morphology changes. The simulation results suggest that the apical-basal dispersion of repolarization contributes to positive T wave more than the transmural dispersion. The contribution of localized transmural dispersion to surface ECG is very much localized to certain precordial leads.

Central ECG analysis of resminostat, a new oral histone deacetylase inhibitor (HDACi), in clinical development as anticancer compound.

e13609 Background: Resminostat (4SC-201) is a new, specific, potent, pan-HDAC inhibitor with broad anti-tumor activity in preclinical models and promising clinical characteristics. Methods: 19 patients with advanced solid tumors were treated in a first-in-human trial at increasing oral daily dose levels from 100 mg to 800 mg in repeated 14-day cycles consisting of 5 consecutive treatment days followed by a 9-day rest period. Cardiac function was monitored by pulse rate, blood pressure, troponin levels, and continuous ECG telemetry during the first treatment day. In addition, standard 12-lead rest ECGs were conducted frequently to aid in the determination of potential effects on QT interval prolongation. An intensive profile consisting of 18 single ECGs was performed from day 1 to 5 during cycle 1, and a reduced number of ECGs in the following cycles, if there were no clinically relevant findings. Subsequent to the on-site clinical assessment, ECGs were sent to a core lab for further analysis by a trained cardiologist. PR, QRS, and QT intervals and heart rate (HR) were measured in lead II across 3 consecutive beats using markers for the respective ECG intervals. Results: No signal for drug-induced prolongation of QTc was observed. A dose-dependent increase in HR with a maximum mean increase of up to 22 beats per minute and a corresponding shortening of the PR and QT interval was found. HR correction with Fridericia's formula did not reveal consistent changes in QTc. The incidence of QTcF outliers was very small. The results suggest that resminostat does not affect the duration of myocardial repolarization. At doses ≥ 400 mg, unspecific flattening of the T-wave and slight depression of the ST-segment were observed frequently. However, in some patients such findings were already observed at baseline. No dose-limiting toxicities were seen with regard to cardiac safety in all dose cohorts. Conclusions: Central analysis of phase I ECG measurements did not reveal a drug- induced prolongation of the QTc interval. Drug administration was frequently associated with moderate increases in HR. At higher doses ≥ 400 mg unspecific changes in T-wave morphology and slight ST-segment depression were observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 4SC AG 4SC AG 4SC AG 4SC AG

Covariate Analysis of QTc and T-Wave Morphology: New Possibilities in the Evaluation of Drugs That Affect Cardiac Repolarization

This study adds the dimension of a T-wave morphology composite score (MCS) to the QTc interval-based evaluation of drugs that affect cardiac repolarization. Electrocardiographic recordings from 62 subjects on placebo and 400 mg moxifloxacin were compared with those from 21 subjects on 160 and 320 mg D,L-sotalol. T-wave morphology changes, as assessed by DeltaMCS, are larger after 320 mg D,L-sotalol than after 160 mg D,L-sotalol; and the changes associated with 160 mg D,L-sotalol are, in turn, larger than those associated with moxifloxacin and placebo. Covariate analyses of DeltaQTc and DeltaMCS showed that changes in T-wave morphology are a significant effect of D,L-sotalol. By contrast, moxifloxacin was found to have no significant effect on T-wave morphology (DeltaMCS) at any given change in QTc. This study offers new insights into the repolarization behavior of a drug associated with low cardiac risk vs. one associated with a high risk and describes the added benefits of a T-wave MCS as a covariate to the assessment of the QTc interval.

Electrical Alternans: An Echocardiographic Visual Reference

A 57-year-old male was brought to the emergency department with a chief complaint of left flank and left-sided chest pain. The pain was described as sharp or stabbing in nature and had been present for 1 week. The patient had a history of coronary artery disease but described the pain as “different” than his typical angina. Pertinent associated symptoms included shortness of breath and an increase in pain with inspiration and position changes. His pain was nonradiating, and there was no increased pain with exertion. This patient’s past medical history included hypertension, hepatitis C, tobacco use, alcoholism, and previous cardiac catheterization with stent placement. On arrival, the patient was in no acute distress. His vital signs were heart rate 104 beats/min, blood pressure 101/77 mm Hg, and respiratory rate 20 breaths/min, with a room air oxygen saturation of 100%. His physical examination showed mild bibasilar rales, jugular venous distension, and distant heart sounds. An electrocardiogram (Figure 1) was performed immediately upon arrival and showed total electrical alternans. Within the same lead, the variation in QRS magnitude was obvious (Figure 2), but the P-wave and T-wave variation was much more subtle (Figure 3). Presenting 12-lead electrocardiogram. Leads V2 and V3, showing obvious variation in the amplitude and direction of the QRS complexes. Lead V1 showing subtle changes in P-wave and T-wave morphology; red arrows and blue arrows correspond to separate cardiac cycles. At this time, bedside echocardiography was performed and revealed a large pericardial effusion (Figure 4). The heart was seen to dramatically “swing” within the pericardial fluid, giving an excellent visual reference for the observed electrocardiographic findings (Video Clip S1). Also visualized on this bedside echocardiogram was obvious abnormal right ventricular collapse suspicious for tamponade physiology. At this point, an M-mode interrogation line was placed through the right ventricular free wall and mitral valve leaflets using the long-axis parasternal window. Using M-mode, right ventricular free wall collapse was noted to occur at the same time as mitral valve opening (diastole), confirming tamponade physiology (Video Clip S2). Large pericardial effusion. Given that the patient was stable, cardiology was consulted and took the patient to undergo pericardiocentesis and placement of a drainage catheter. Roughly 800 mL of fluid was removed from the pericardial space on initial drainage. A computed tomography scan of the chest revealed a left upper lobe lung carcinoma later diagnosed as Stage 4 non–small cell lung cancer. The drain was eventually removed and the patient was discharged with the diagnosis of lung cancer and malignant pericardial effusion. Video Clip S1. Bedside echocardiography demonstrating “swinging” of the heart within the pericardial fluid that produces the electrocardiographic pattern of electrical alternans. Video Clip S2. Bedside echocardiography demonstrating the diagnosis of cardiac tamponade using the M-mode function on the ultrasound machine. The video clips are in QuickTime. Please note: Wiley Periodicals Inc. is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Quantitative Analysis of T‐wave Morphology Increases Confidence in Drug‐Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational IKr Inhibitor Lu 35–138

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T-wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I(Kr)-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T-wave morphology as determined by MCS. For subjects taking Lu 35-138, T-wave morphology was a more reliable indicator of I(Kr) inhibition than QTcF (chi(2) = 20.3, P = .001). At 80% study power for identifying a 5-millisecond placebo-adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35-138 on cardiac repolarization.