Mads Peter Andersen

The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction

INTRODUCTION The Tpeak-Tend interval (TpTe) has been linked to increased arrhythmic risk. TpTe was investigated before and after primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHOD Patients with first-time STEMI treated with pPCI were included (n = 101; mean age 62 years; range 39-89 years; 74% men). Digital electrocardiograms were taken pre- and post-PCI, respectively. Tpeak-Tend interval was measured in leads with limited ST-segment deviation. The primary end point was all-cause mortality during 22 +/- 7 months (mean +/- SD) of follow-up. RESULTS Pre- and post-PCI TpTe were 104 milliseconds [98-109 milliseconds] and 106 milliseconds [99-112 milliseconds], respectively (mean [95% confidence interval], P = .59). A prolonged pre-PCI TpTe was associated with increased mortality (hazard ratio, 10.5 [1.7-20.4] for a cutoff value of 100 milliseconds). Uncorrected QT and heart rate-corrected QT intervals (Fridericia-corrected QT) were prolonged after PCI (QT: 401 vs 410 milliseconds, P = .022, and Fridericia-corrected QT: 430 vs 448 milliseconds, P < .0001). CONCLUSION In patients with STEMI undergoing pPCI, pre-PCI TpTe predicted subsequent all-cause mortality, and the QT interval was increased after the procedure.

New descriptors of T-wave morphology are independent of heart rate

T-wave morphology descriptors are sensitive to drug-induced changes and may be a useful addition to the QT interval in cardiac safety trials. Intrasubject heart rate dependence of T-wave morphology was investigated in a sample of 39 healthy individuals. Ten-second electrocardiograms were obtained from daytime Holter recordings. Duration parameters (QT, ToTe, TpTe, and others), a number of basic T-wave morphology parameters (amplitude, area, and others) as well as advanced morphology descriptors (asymmetry, flatness, and others) were measured automatically. Heart rate dependence was examined by means of analysis of covariance. The results showed clear heart rate dependence for the QT interval (R(2) = 0.53-0.57) and a moderate degree of heart rate dependence for the basic morphology parameters (amplitude, area, and others) (R(2) = 0.17-0.42). Both the advanced T-wave descriptors (asymmetry, flatness, and others), ToTe intervals and TpTe intervals, were practically independent of heart rate (R(2) = 0-0.08), making heart rate correction unnecessary for these parameters.

Identifying drug-induced repolarization abnormalities from distinct ECG Patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

AbstractBackground: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolarization is therefore warranted. Most drugs associated with risk are inhibitors of the rapidly activating delayed rectifier potassium current (Ikr). This current is also inhibited in the congenital type 2 form of the long QT syndrome (LQT2). It is therefore possible that electrocardiographic LQT2 patterns might be used to identify abnormal repolarization patterns induced by drugs. Objective: To develop distinct T-wave morphology parameters typical of LQT2 and investigate their use as a composite measure for identification of d,l-sotalol (sotalol)-induced changes in T-wave morphology. Methods: Three independent study groups were included: a group of 917 healthy subjects and a group of 30 LQT2 carriers were used for the development of T-wave morphology measures. The computerized measure for T-wave morphology (morphology combination score, MCS) was based on asymmetry, flatness and notching, which are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug-induced prolongation of the heart rate corrected QT interval (QTcF) was compared with changes in the computerized measure for T-wave morphology. Effect sizes for QTcF and MCS were calculated at the time of maximum plasma concentrations and for maximum change from baseline. Accuracy for separating baseline from sotalol recordings was evaluated by area under the receiver operating characteristic curves (AUCs) using all recordings from the time immediately post-dose to maximum change. Results: MCS separated baseline recordings from sotalol treatment with higher accuracy than QTcF for the 160 mg dose: (AUC) 84% versus 72% and for the 320 mg dose: (AUC) 94% versus 87%, p < 0.001. At maximum serum-plasma concentrations and at maximum individual change from baseline, the effect sizes for QTcF were less than half the effect sizes for MCS, p< 0.001. Effect sizes at peak changes of the mean were up to 3-fold higher for MCS compared with QTcF, p< 0.001. In subjects receiving sotalol, T-wave morphology reached similarity to LQT2, whereas QTcF did not. Conclusion: Distinct ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has general validity for the identification of drug-induced disturbed repolarization.

TpeakTend interval in long QT syndrome

BACKGROUND The T(peak)T(end) (T(p)T(e)) interval is believed to reflect the transmural dispersion of repolarization. Accordingly, it should be a risk factor in long QT syndrome (LQTS). The aim of the study was to determine the effect of genotype on T(p)T(e) interval and test whether it was related to the occurrence of syncope. METHODS Electrocardiograms were taken in 95 patients with LQTS drawn from the Danish long QT registry (44 patients with KvLQT1, 43 with HERG, and 8 with SCN5A mutations) and manually evaluated for the QT, QT(peak), and RR interval. RESULTS AND CONCLUSION (1) T(p)T(e) cannot be used to distinguish symptomatic from asymptomatic patients with LQTS; (2) HERG patients have longer T(p)T(e) than KvLQT1 patients; and (3) there is no need to heart rate-correct T(p)T(e) intervals in patients with LQTS.

Reference values of electrocardiogram repolarization variables in a healthy population.

INTRODUCTION Reference values for T-wave morphology analysis and evaluation of the relationship with age, sex, and heart rate are lacking in the literature. In this study, we characterized T-wave morphology in a large sample of healthy individuals. METHOD A total of 1081 healthy subjects (83% men; range, 17-81 years) were included. T-wave morphology variables describing the duration, area, slopes, amplitude, and distribution were calculated using 10-second digital electrocardiogram recordings. Multivariate regression was used to test for dependence of T-wave variables with the subject age, sex, and heart rate. RESULTS Lead V5 (men vs women) T-wave variables were as follows: amplitude, 444 versus 317 muV; area, 48.4 versus 33.2 ms mV; Tpeak-Tend interval, 94 versus 92 milliseconds; maximal descending slope, -5.15 versus -3.69 muV/ms; skewness, -0.24 versus -0.22; and kurtosis, -0.36 versus -0.35. Tpeak-Tend interval, skewness, and kurtosis were independent of age, sex, and heart rate (r(2) < 0.05), whereas Bazett-corrected QT-interval was more dependent (r(2) = 0.40). CONCLUSION A selection of T-wave morphology variables is found to be clinically independent of age, sex, and heart rate, including Tpeak-Tend interval, skewness, and kurtosis.

Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology

The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself have been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes on the basis of parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 4 or 5 parameters both resulted in perfect discrimination in a learning set of 36 subjects. In both cases cross-validation of the resulting classifiers showed no misclassifications either.

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindoles propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES=1.92; 95% CI: 1.35-2.49) compared to the mean effect size for QTcF (ES=0.88; 95% CI: 0.52-1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.

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 IKr‐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 IKr inhibition than QTcF (χ2 = 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.

The effect of sertindole on QTD and TPTE

Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, Struijk JJ, Meyer JM, Toft E. The effect of sertindole on QTD and TPTE.

Consideration of QRS complex in addition to ST segment abnormalities in the estimation of the 'risk region' during acute inferior myocardial infarction

BACKGROUND The myocardial area at risk (MaR) has been estimated in patients with acute myocardial infarction (AMI) by using ST segment based ECG methods. However, as the process from ischemia to infarction progresses, the ST segment deviation is typically replaced by QRS abnormalities, causing a falsely low estimation of the total MaR if determined by using ST segment based methods. A previous study showed the value of the consideration of the abnormalities in the QRS complex, in addition to those in the ST segment estimating the total MaR for patients with anterior AMI. The purpose of this study was to investigate the same method for patients with inferior AMI. METHODS Thirty-two patients with acute inferior ST elevation myocardial infarction received (99m)Tc-Sestamibi before percutaneous coronary intervention. SPECT was performed within 2 hours after treatment and was used as a gold standard for the estimation of the total MaR. The ECG recorded at admission in the hospital was used for the ECG estimates of the total MaR. This included a ST segment estimation of the ischemic component of the total MaR (Aldrich score) and an estimation of the infarcted component of the total MaR in the acute phase of AMI by QRS abnormalities (Selvester score). These scores were added for the combined ECG score. RESULTS The ischemic component of the total MaR estimated by the Aldrich score alone no statistically significant correlation with SPECT (r=0.17, p=0.36). The infarcted component of the total MaR estimated by the Selvester score showed a significant correlation with SPECT (r=0.55, p=0.001). When the Aldrich and Selvester scores were combined, the correlation with SPECT improved (r=0.58, p<0.001). Both the Aldrich and Selvester score alone underestimated the mean MaR measured by SPECT (respectively p=0.007 and p<0.0001). There was no statistically significant difference between the mean MaR estimated by the sum of Aldrich and Selvester and the MaR measured by SPECT (p=0.636). CONCLUSION The estimation of the total MaR was more accurate by taking both ST deviation and QRS abnormalities in account than by using either method alone. A new ECG method to determine the total MaR during acute coronary occlusion should consider both its ischemic and infarcted components.