Transmural Dispersion Of Ventricular Repolarization Research Articles

Association of transmural dispersion of ventricular repolarization (Tpeak-Tend interval) with components of metabolic syndrome: data from the ESSE-RF3

Aim. To study the associations of the Tpeak-Tend interval (TpTe) with components of metabolic syndrome (MS) in a sample of Novosibirsk residents.Material and methods. The study included 1042 residents of Novosibirsk (510 (48,9%) men) aged 35-74 years. The examination included the collection of demographic and social data, anthropometry, blood pressure (BP) measurement, and electrocardiography (ECG). MS was determined according to the 2013 criteria. The TpTe interval from the peak, as the maximum positive or negative T wave deviation, to the end of the T wave, was measured manually in lead V5. The corrected TpTe (cTpTe) interval was used in the study.Results. The cTpTe is inversely associated with female sex (B 3,390, 95% confidence interval (CI): (-5,516-2,504), p=0,001). The cTpTe interval is associated with a blood pressure (BP) ≥140/90 mm Hg (B 3,154, 95% CI: (1,614-4,688), p=0,001), low-density lipoprotein cholesterol (LDL-C) >3,0 mmol/l (B 1,818, 95% CI: (0,409-3,544), p=0,030), regardless of other MS components, sex and age. The cTpTe interval was higher in individuals with BP ≥140/90 mm Hg compared with individuals with BP <140/90 mm Hg (69,08 95% CI: 67,59-70,66 vs 65,93 95% CI: 64,60-67,24; p=0,001), and in persons with LDL-C >3,0 mmol/l (68,41 95% CI: 67,11-69,63 vs 66,60 95% CI: 65,02-68,23; p=0,023), compared with individuals with LDL-C <3,0 mmol/l.Conclusion. The cTpTe interval, considered as an indicator of transmural dispersion of ventricular repolarization, is shorter in women than in men and is associated with hypertension and atherogenic dyslipidemia, regardless of other MS components.

Relationship of the T-wave Tpeak-Tend interval with conduction system disorders in arterial hypertension.

The Tpeak-Tend interval of the T wave has emerged as a new electrocardiographic marker of increased transmural dispersion of ventricular repolarization. We aimed to determine the presence of cardiac conduction system disorders in patients with systemic arterial hypertension (SAH) who have altered Tpeak-Tend interval of the T wave. The 67 patients with SAH were divided into two groups. Those with prolonged (≥ 77 ms) Tpeak-Tend intervals, 21 (31%) patients were in the study group. Those with normal (< 77 ms) Tpeak-Tend intervals, 46 (69%) patients were in the control group. Alteration of ventricular repolarization manifested as a prolongation of the Tpeak-Tend interval was detected by computerized electrocardiographic analysis tools. The median value of QRS complex duration was significantly wider in the study group as compared to the control group (110 ± 12 ms vs. 94 ± 8 ms p < 0.001). There was a significantly greater incidence of left anterior hemiblock in the study group (14% vs. 0% p < 0.04). The median value of the QTc interval was significantly greater in the study group (440 ± 26 vs. 422 ± 15 p < 0.01). There was a significantly greater incidence of patients with prolonged QTc interval in the study group (33% vs. 11% p < 0.02). The median value of the Tpeak-Tend interval was significantly greater in the study group (84 ± 5 ms vs. 65 ± 4 ms p < 0.001), as well as, the Tpeak-Tend/QTc ratio in the study group (0.19 ± 0.1 vs. 0.16 ± 0.1 p < 0.001). There is a significantly greater ventricular repolarization disorders and abnormalities of the cardiac conduction system in SAH patients who possess altered Tpeak-Tend interval of the T wave.

No Association Between T-peak to T-end Interval on the Resting ECG and Long-Term Incidence of Ventricular Arrhythmias Triggering ICD Interventions.

Background and ObjectivesPotential of using the T-peak to T-end (TpTe) interval as an electrocardiographic parameter reflecting the transmural dispersion of ventricular repolarization (TDR) to identify patients (pts.) with higher risk of malignant ventricular arrhythmias (MVA) for better selection of candidates for implantable cardioverter-defibrillator (ICD) in primary prevention (PP) of sudden cardiac death (SCD) remains controversial. The primary objective of this study was to investigate the relationship between the TpTe interval in patient’s preimplantation resting 12-lead electrocardiogram (ECG) and the incidence of MVA resulting in appropriate ICD intervention (AI). The secondary objective was to assess its relationship to overall mortality.MethodsA total of 243 consecutive pts. with severe left ventricular (LV) systolic dysfunction after myocardial infarction (MI) with a single-chamber ICD for PP of SCD from one implantation center were included. Excluded were all pts. with any other disease that could interfere with the indication of ICD implantation. Primarily investigated intervals were measured manually in accordance with accepted methodology. Data on ICD interventions were acquired from device interrogation during regular outpatient visits. Survival data were collected from the databases of health insurance and regulatory authorities.ResultsWe did not find a significant relationship between the duration of the TpTe interval and the incidence of MVA (71.5 ms in pts. with MVA vs. 70 ms in pts. without MVA; p = 0.408). Similar results were obtained for the corrected TpTe interval (TpTec) and the ratio of TpTe to QT interval (76.3 ms vs. 76.5 ms; p = 0.539 and 0.178 vs. 0.181; p = 0.547, respectively). There was also no significant difference between the duration of TpTe, TpTec and TpTe/QT ratio in pts. groups by overall mortality (71.5 ms in the deceased group vs. 70 ms in the survivors group; HR 1.01; 95% CI, 0.99–1.02; p = 0.715, 76.3 ms vs. 76.5 ms; HR 1.01; 95% CI, 0.99–1.02; p = 0.208 and 0.178 vs. 0.186; p = 0.116, respectively).ConclusionThis study suggests no significant association of overall or MVA-free survival with ECG parameters reflecting TDR (TpTe, TpTec) in patients with systolic dysfunction after MI and ICD implanted for primary prevention.

Echocardiography and Electrocardiography Variables Correlate With the New York Heart Association classification: An Observational Study of Ischemic Cardiomyopathy Patients.

The aim of our study was to determine whether combinations of ultrasound echocardiography (UCG) and electrocardiography (EKG) parameters correlated with the functional status of ischemic cardiomyopathy (ICM) patients according to the New York Heart Association (NYHA) classification system.We assessed 536 elderly Chinese ICM patients according to the NYHA criteria, which included 196 patients with type 2 diabetes mellitus (T2DM). All of the patients underwent UCG. Transmural dispersion of ventricular repolarization was examined using EKG. Cumulative odds logistic regression was performed to evaluate associations between NYHA class and the demographic, clinical, UCG, and EKG variables based on the odds ratio (OR) and 95% confidence interval (CI). A Pearson analysis was also performed to examine correlations between the NYHA classification and the UCG and EKG variables.Based on the NYHA assessment, 140, 147, 138, and 111 patients were identified as class I, II, III and IV, respectively. A comparison of UCG and EKG variables based on T2DM status showed that CO and Tp-e differed significantly between all NYHA classes (P < .05 for all), with values of each increasing with increasing NYHA class regardless of T2DM status. Multivariate logistic regression analysis showed that the disease course (OR: 1.30; 95% CI: 1.20-1.40), heart rate (OR: 1.16; 95% CI: 1.12-1.21), T wave peak to endpoint (Tp-e; OR: 1.22; 95% CI: 1.18-1.27), dispersion of the QT interval (OR: 0.98; 95% CI: 0.95-1.22), left ventricular fractional shortening (OR: 0.82; 95% CI: 0.78-0.87), cardiac output (CO; OR: 5.58; 95% CI: 3.08-10.13) were significantly associated with the NYHA class (P < .0001 for all). A Pearson correlation analysis showed that Tp-e (r = 0.75982, P < .0001), CO (r = 0.56072, P < .0001), and stroke volume (r = -0.14839, P = .0006) significantly correlated with the NYHA class.An index consisting of Tp-e and CO will be useful for corroborating the results of the NYHA assessment of ICM patients.

Evaluation of the Tp-e Interval and Tp-e/QT Ratio in Patients with Mitral Annular Calcification

Objective: Mitral annular calcification (MAC) is regarded as a manifestation of cardiovascular disease. Recent studies have shown that prolongation of the interval between the peak and end of the T wave on electrocardiogram (Tp-e), which is accepted as an index of transmural dispersion of ventricular repolarization, and the Tp-e/QT ratio are associated with ventricular arrhythmias. In the present study, we aimed to evaluate ventricular repolarization using the Tp-e interval and Tpe/ QT ratio in patients with MAC. Methods: Fifty patients with MAC (27 females and 23 males; mean age 71.6 ± 8.0 years) and 50 patients without MAC (26 females and 24 males; mean age 69.3 ± 6.2 years) were included in this study. Maximum and minimum QT and Tp-e intervals as well as corrected values according to heart rate were calculated using a 12- lead electrocardiogram. QT dispersion and Tp-e/QT ratios were calculated. All parameters were compared between the two groups. Results: Patients with MAC had significantly higher Tp-e (75.8 ± 11.6 vs. 62.1 ± 8.7; p<0.001) and cTp-e intervals (84.9 ± 14.3 vs. 67.5 ± 9.7; p<0.001), Tp-e/QT (0.19 ± 0.02 vs. 0.15 ± 0.02; p<0.001) and cTp-e/QT ratios (0.19 ± 0.03 vs. 0.15 ± 0.02; p<0.001), and cQT values (390.1 ± 31.5 vs. 373.8 ± 26.1; p=0.006) compared with the control subjects. There were positive correlations between E/Em ratio and cTp-e interval (r=0.396; p=0.004) and between the E/Em ratio and cTp-e/QT ratio (r=0.535; p<0.001) in the MAC group. Conclusion: Our findings indicate that the patients with MAC had higher Tp-e and cTp-e intervals and Tp-e/QT and cTp-e/QT ratios compared with the subjects without MAC.

Tpeak-to-Tend/QT is an independent predictor of early ventricular arrhythmias and arrhythmic death in anterior ST elevation myocardial infarction patients.

The aim of our study was to analyse the markers of transmural dispersion of ventricular repolarization, especially Tpeak-to-Tend and Tpeak-to-Tend /QT ratio, in patients with anterior ST elevation myocardial infarction on admission and to evaluate their association with in-hospital life-threatening arrhythmias and mortality. A total of 223 consecutive patients with anterior wall ST elevation myocardial infarction admitted to our Division of Cardiology between January 2010 and December 2012 were prospectively evaluated. A standard electrocardiogram was obtained on admission and then analysed. The primary end point was constituted by in-hospital ventricular arrhythmias and arrhythmic death. At univariate analysis heart rate (odds ratio = 1.03; 95% confidence intervals 1.006-1.05; p=0.001), maximal ST elevation (odds ratio =1.25; 95% confidence intervals 1.10-1.43; p=0.0001), QTc Bazett (odds ratio = 1.01; 95% confidence intervals 1.006-1.02; p=0.002), QT dispersion (odds ratio = 1.02; 95% confidence intervals 1.002-1.04; p=0.02) and both Tpeak-to-Tend and Tpeak-to-Tend/QT (odds ratio = 1.02; 95% confidence intervals 1.01-1.03; p<0.0001 and OR = 1.07; 95% confidence intervals 1.03-1.11; p<0.0001 respectively) were significantly associated with ventricular arrhythmias and arrhythmic mortality. Of note, Tpeak-to-Tend /QT remained a predictor of early ventricular arrhythmias and arrhythmic death (odds ratio = 1.04; 95% confidence intervals 1.003 - 1.10; p=0.03) independently from heart rate and maximal ST elevation. Receiver operating characteristic curve analysis showed that Tpeak-to-Tend /QT values <0.31 had a predictive negative value of 92% for the prediction of the composite outcome. Tpeak-to-Tend /QT was an independent predictor of early ventricular arrhythmias and arrhythmic mortality in patients with anterior ST elevation myocardial infarction. Especially, Tpeak-to-Tend /QT <0.31 may identify a subgroup of ST elevation myocardial infarction patients with low risk of early arrhythmias and arrhythmic death.

Effect of intravenous zoledronic acid infusion on electrocardiographic parameters in patients with osteoporosis.

The aim of the present study was to evaluate the early and late effects of ZA therapy on ECG parameters which might be associated with the tendency for atrial and ventricular arrhythmias. Consecutive patients with osteoporosis who were admitted to our clinic between December 2013 and December 2014 and who were scheduled to receive ZA infusion constituted our study population. Twelve-lead surface ECGs were obtained from all patients before and after ZA infusion on the same day as well as 1month after the infusion. All ECG parameters were measured and compared with each other for each patient. Data of 100 patients were used in the analysis (9 male; 70.5±11.6years of age). There were no significant differences between repeated measurements regarding pmax, pmin, and p dispersion values. QT max and QT min values were significantly increased after infusion; however, there were no significant changes in QT dispersion, Tp-e interval, and Tp-e dispersion values. ZA infusion did not affect P wave dispersion both at the immediate post-infusion period and 1month after infusion. QT values were significantly increased early after ZA infusion; however, there were no significant differences in parameters reflecting disparity of ventricular recovery times and transmural dispersion of ventricular repolarization. Based on these observations, it may be suggested that ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias.

Effect of intravenous amiodarone on QT and T peak–T end dispersions in patients with nonischemic heart failure treated with cardiac resynchronization-defibrillator therapy and electrical storm

BackgroundThe effect of intravenous amiodarone on spatial and transmural dispersion of ventricular repolarization in patients receiving cardiac resynchronization therapy (CRT) remains unclear. MethodsWe studied 14 patients with nonischemic heart failure who received CRT with a defibrillator, experienced electrical storm and were treated with intravenous amiodarone. Each patient underwent 12-lead electrocardiography (ECG) and 187-channel repolarization interval-difference mapping electrocardiography (187-ch RIDM-ECG) before and during the intravenous administration of amiodarone infusion. ResultsA recurrence of ventricular tachyarrhythmia was observed in 2 patients during the early period of intravenous amiodarone therapy. Intravenous amiodarone increased the corrected QT interval (from 470±52ms to 508±55ms, P=0.003), but it significantly decreased the QT dispersion (from 107±35ms to 49±27ms, P=0.001), T peak–T end (Tp–e) dispersion (from 86±17ms to 28±28ms, P=0.001), and maximum inter-lead difference between corrected Tp–e intervals as measured by using the 187-ch RIDM-ECG (from 83±13ms to 50±19ms, P=0.001). ConclusionsIntravenous amiodarone suppressed the electrical storm and decreased the QT and Tp–e dispersions in patients treated by using CRT with a defibrillator.

Analysis of the spatial and transmural dispersion of repolarization and late potentials derived using signal-averaged vector-projected 187-channel high-resolution electrocardiogram in patients with early repolarization pattern

BackgroundElectrophysiological characteristics of early repolarization syndrome (ERS), i.e., the spatial and transmural dispersion of ventricular repolarization and ventricular late potentials can be evaluated using a signal-averaged vector-projected 187-channel high-resolution electrocardiogram (187-ch SAVP-ECG). We investigated these characteristics as markers of ventricular fibrillation and sudden cardiac arrest in patients presenting with an ER pattern. MethodsThe 187-ch SAVP-ECGs were recorded for 8 patients with idiopathic ventricular fibrillation associated with ERS (ERS patients), and 5 patients with an ER pattern without arrhythmic events (ER pattern patients). ResultsThe ER pattern was located in the inferior leads (n=7), lateral leads (n=1), or both inferior and lateral leads (n=5). The corrected RT(RTc) (peak point of the R wave − positive maximum peak of the first derivative of the T wave interval corrected using the Bazett formula) interval and T(peak-end)-c interval from the 187 channels were calculated. Late potentials were positive in 7 of 8 ERS patients and in 3 of 5ER pattern patients (P=0.25). The average RTc was shorter in patients with ERS (192.6±29.8ms vs. 234.0±25.5ms, P=0.04). However, average T(peak-end)-c interval did not differ between the 2 groups. ConclusionLate ventricular potentials were common in ERS and ER pattern patients. Lethal arrhythmia in ERS patients appeared to be related to the relatively short average repolarization time rather than the spatial and transmural dispersion of repolarization.

The peak-to-end of the T wave in the limb ECG leads reflects total spatial rather than transmural dispersion of ventricular repolarization in an anthopleurin-A model of prolonged QT interval

Previous studies have showed that the interval between the peak and the end of the T wave (Tp-e) is a marker of transmural dispersion of ventricular repolarization. We studied the relationship between (a) the Tp-e on local pseudo transmural electrograms (pseudo transmural Tp-e) or limb leads of body surface electrocardiogram (surface Tp-e) and (b) the intracardiac left ventricular (LV) repolarization during a drug-induced QT-interval prolongation. Using open-chested canine intact hearts treated by anthopleurin-A, transmural LV electrograms were recorded via needle electrodes placed in the basoanterior, midanterior, apicoanterior, basolateral, midlateral, and apicolateral LV wall. Recovery time (RT) was calculated as an index of local repolarization at each transmural unipolar electrode. This model showed slower heart rate-dependent heterogeneous distribution of ventricular repolarization both along the basal to apical axis and along the transmural axis. RT was longer at the LV apex than at the base and longer in the lateral than in the anterior wall during the slower heart rate. A high correlation was found between surface Tp-e and total LV dispersion. In contrast, pseudo transmural Tp-e correlated with transmural RT dispersion. The shortest RT in the heart roughly corresponded to the peak, as did the longest RT with the end of the T wave on the surface electrocardiogram. During drug-induced QT-interval prolongation with a large apicobasal and anterolateral dispersion of ventricular repolarization, the Tp-e in the limb leads expresses spatial (total) distribution of repolarization in the whole left ventricle.

Abstract 9015: Correlation between Spatial Repolarization and Peak-to-end of the T Wave on Transmural Left Ventricular and Body Surface Electrocardiographic Recordings

Background. Previous studies showed that Tp-e is a marker of transmural dispersion of ventricular repolarization. Objectives. We studied the relationship between a) the interval between peak and end of the T wave (Tp-e) on local transmural electrograms (transmural Tp-e) or body surface ECG (surface Tp-e) and b) the intracardiac left ventricular (LV) repolarization during QT interval prolongation. Methods. Using a canine anthopleurin-A model, transmural LV electrograms were recorded via needle electrodes placed in the baso-anterior, mid-anterior, apico-anterior, baso-lateral, mid-lateral, and apico-lateral LV wall. Recovery time (RT) was calculated as an index of local repolarization at each transmural unipolar electrode. Results. RT was longer at the LV apex than that at the base, and longer in the lateral than in the anterior wall. A high correlation was found between transmural Tp-e and the transmural RT-dispersion (figure 1). On the other hand, surface Tp-e was correlated with total spatial LV RT-dispersion, though not with transmural RT-dispersion (figure 2). The slope of the linear correlation between surface Tp-e and total spatial LV RT-dispersion was 1.04 (P &lt; 0.001), whereas betwwen surface Tp-e and averaged transmural RT-dispersion was 0.25 (P &lt; 0.001). The shortest RT in the heart corresponded to the peak, whereas the longest RT coincided with the end of the T wave on the surface ECG. Conclusions. Surface Tp-e may overestimate the transmural dispersion of LV repolarization, and seems to express the special distribution of repolarization in the whole LV during iatrogenic QT interval prolongation.

Vanoxerine: Cellular Mechanism of a New Antiarrhythmic

There remains an unmet need for safe and effective antiarrhythmic drugs, especially for the treatment of atrial fibrillation. Vanoxerine is a drug that is free of adverse cardiac events in normal volunteers, yet is a potent blocker of the hERG (hK(v)11.1) cardiac potassium channel. Consequently,we hypothesized that vanoxerine might also be a potent blocker of cardiac calcium (Ca) and sodium (Na) currents, and would not affect transmural dispersion of repolarization. The whole cell patch clamp technique was used to measure currents from cloned ion channels overexpressed in stable cell lines and single ventricular myocytes. We measured intracellular action potentials from canine ventricular wedges and Purkinje fibers using sharp microelectrode technique. We found that vanoxerine was a potent hK(v)11.1 blocker, and at submicromolar concentrations, it blocked Ca and Na currents in a strongly frequency-dependent manner. In the canine ventricular wedge preparation vanoxerine did not significantly affect transmural action potential waveforms, QT interval or transmural dispersion of repolarization. Vanoxerine (1) is a potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency-dependent especially for Na and Ca channels; and (3) transmural dispersion of ventricular repolarization is unaffected. The multichannel block and repolarization uniformity resemble the effects of amiodarone, the exemplar atrial fibrillation drug. Vanoxerine is a completely different chemical and has none of amiodarone's toxic effects. Vanoxerine has characteristics of a potentially effective and safe antiarrhythmic.

Gender and Age Effects on Ventricular Repolarization Abnormality in Japanese General Carriers of a G643S Common Single Nucleotide Polymorphism for the KCNQ1 Gene

The KCNQ1 single nucleotide polymorphism (SNP), G643S, is known to be associated with secondary long QT syndrome (LQTS) and to cause a mild reduction in KCNQ1 current. However, the precise incidence and its association with QT intervals remain unknown in the greater cohort of the population in Japan. The genotype was screened at codon 643 of KCNQ1 in 992 residents of a farming community. Eighty-eight individuals (female/male =52/36, 8.9%) were found to have a heterozygous G643S SNP. Matching both gender and age, we randomly selected 243 control (G643G) cases and compared the electrocardiogram parameters in both groups; QT, QTf (QT corrected by Fridericia's formula) intervals, the peak and the end of the T wave (Tpe) interval, and the Tpe/QT ratio. The latter 2 reflect the transmural dispersion of ventricular repolarization (TDR). In G643S carriers, both Tpe and Tpe/QT were significantly longer than in non-carriers, without significant QT prolongation. Both genders showed a tendency for an increase in QTf with aging. In females, both Tpe and Tpe/QT showed a similar significant increase with age, which was not observed in males. In elderly females, G643S might be an independent risk factor for secondary LQTS by causing a greater TDR.

Tpeak-Tend Interval as an Index of Global Dispersion of Ventricular Repolarization: Evaluations Using Monophasic Action Potential Mapping of the Epi- and Endocardium in Swine

The ECG interval from the peak to the end of the T wave (Tpeak-Tend) has been used as an index of transmural dispersion of ventricular repolarization (DVR). The correlation between the Tpeak-Tend interval and the global DVR, however, has not been well-evaluated. Monophasic action potentials (MAPs) were recorded from 51+/-10 epicardial and 64 +/- 9 endocardial sites in the left ventricles of 10 pigs, and from 41+/-4 epicardial and 53+/-2 endocardial sites in the right ventricles of 2 of the 10 pigs using the CARTO mapping system. The end of repolarization times over the epi- and endocardium were measured, and the end of repolarization dispersions over the epicardium (DVR-epi), over the endocardium (DVR-endo) and over both (DVR-total) were calculated. The QTpeak, QTend and Tpeak-Tend intervals as well as the QTpeak and QTend dispersions were obtained from the simultaneously recorded 12-lead ECG. The maximal Tpeak-Tend intervals (57+/-7 ms) were consistent with the DVR-total (58+/-11 ms, p>0.05), and significantly correlated with the DVR-total (r=0.64, p<0.05). However, the mean Tpeak-Tend intervals (44+/-5 ms), and Tpeak-Tend intervals from lead II (41+/-6 ms) and V5 (43+/-5 ms) were all significantly smaller than and poorly correlated with the DVR-total, as were the QTpeak and QTend dispersions (15+/-2 ms vs. 21+/-4 ms). The maximal Tpeak-Tend interval may be used as a noninvasive estimate for the global DVR, but not the QTpeak and QTend dispersions, nor the mean Tpeak-Tend interval and that from a single lead.

Effect of autonomic nervous system on the transmural dispersion of ventricular repolarization in intact canine.

The effect of the autonomic nerves on the transmural dispersion of ventricular repolarization in intact canine was investigated. By using the monophasic action potential (MAP) recording technique, monophasic action potentials (MAPs) of the epicardium (Epi), midmyocardium (Mid) and endocardium (Endo) were recorded simultaneously by specially designed plunge-needle electrodes at the left ventricular free wall in 12 open-chest dogs. MAPD90 and transmural dispersion of repolarization among three myocardial layers as well as the incidence of the EAD before autonomic nervous stimulation and during autonomic nervous stimulation were compared. The results showed that the MAPD90 of Epi, Mid and Endo before autonomic nervous stimulation were 278 +/- 11 ms, 316 +/- 16 ms and 270 +/- 12 ms respectively, the MAPD90 of Mid was significantly longer than that of Epi or Endo (P<0.01). MAPD90 of Epi, Mid and Endo were shortened by 19 +/- 4 ms, 45 +/- 6 ms, 18 +/- 3 ms respectively during sympathetic stimulation. Compared with that of the control, the transmural dispersion of repolarization during sympathetic stimulation was shortened from 44 +/- 4 ms to 15 +/- 3 ms (P<0.01), but early afterdepolarizations were elicited in the Mid of 5 dogs (41%) during sympathetic stimulation. Parasympathetic stimulation did not significantly affect the MAPD90 in the three layers. It is concluded that there is the transmural dispersion of ventricular repolarization in intact canine. Sympathetic stimulation can reduce transmural dispersion of repolarization, but it can produce early afterdepolarizations in the Mid. Parasympathetic stimulation does not significantly affect the transmural dispersion of ventricular repolarization.

P2722 Tpeak-tend interval as an index of transmural dispersion of ventricular repolarization. Verification using monophasic action potential mapping of the epi- and endocardium in swine

P2722 Tpeak-tend interval as an index of transmural dispersion of ventricular repolarization. Verification using monophasic action potential mapping of the epi- and endocardium in swine

Gender differences in ventricular repolarization: terminal T wave interval was shorter in women than in men.

The incidence of sudden death is lower in women than in men, although women have a longer QT interval and are more prone to develop torsades de points than men. It has been recently proposed that the time interval between the apex and end of the T wave (Ta-e) represents the transmural dispersion of ventricular repolarization. Gender and age differences in Ta-e interval have not been fully assessed previously. Standard surface 12-lead ECGs recorded in 760 healthy subjects (382 women, 0-88 years of age) were studied. The intervals from j-point to the apex of the T wave (JaT) and to the end of the T wave (JeT) were measured in lead V5 in each ECG and corrected by preceding RR intervals using the formula of Bazett (JaTc and JeTc). The Ta-e and Ta-e/JeT ratio were also evaluated. Both JaTc and JeTc intervals were significantly longer in women aged > 20 years than in men of the same age (P < 0.0001). The difference was due to shortening of these intervals after puberty in men. However, the Ta-e interval was significantly shorter in women than in men (P < 0.05) and subsequently the Ta-e/JeT ratio was significantly smaller in women than in men (P < 0.0001). The results showed gender differences in the Ta-e interval and JaTc and JeTc intervals in healthy adults, and suggest that the small transmural dispersion of repolarization in women, in spite of the long JaTc and JeTc intervals, might be a beneficial antiarrhythmic property.

Association between HERG K897T polymorphism and QT interval in middle-aged finnish women

ObjectivesThe aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BackgroundThe length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. MethodsQT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV2, and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. ResultsThe allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 ± 99 ms) and Tpeak-Tend intervals (143 ± 95 ms) than females with the genotype AA (441 ± 69 ms and 116 ± 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. ConclusionsThe common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.

Experimental study of the effect of autonomic nervous system on the transmural dispersion of ventricular repolarization under acute myocardial ischemia in vivo.

The effect of the autonomic nerves on the transmural dispersion of ventricular repolarization (TDR) under acute myocardial ischemia in intact canine was investigated. Using the monophasic action potential (MAP) recording technique, MAPs of the epicardium (Epi), mid-myocardium (Mid) and endocardium (Endo) were recorded simultaneously by specially designed plunge-needle electrodes at the left ventricular free wall under acute myocardial ischemia in 12 open-chest dogs. MAPD90 and TDR among three myocardial layers as well as the incidence of the early afterdepolarization (EAD) before autonomic nervous stimulation and during autonomic nervous stimulation were compared. It was found that 10 min after acute myocardial ischemia, TDR was increased from 55 +/- 8 ms to 86 +/- 15 ms during sympathetic stimulation (P < 0.01). The TDR (53 +/- 9 ms) during parasympathetic stimulation was not significantly different from that of the control (55 +/- 8 ms) (P > 0.05). The EAD was elicited in the Mid of 2 dogs (16%) 10 min after acute myocardial ischemia, but the EAD were elicited in the Mid of 7 dogs (58%) during sympathetic stimulation (P < 0.01). It was concluded that: (1) Sympathetic stimulation can increase the transmural dispersion of repolarization and induce early afterdepolarizations in the Mid under acute myocardial ischemia, which provide the opportunity for the ventricular arrhythmia developing; (2) Parasympathetic stimulation has no significant effect on the transmural dispersion of repolarization under myocardial ischemia.

In vivo measurement of QT prolongation, dispersion and arrhythmogenesis: application to the preclinical cardiovascular safety pharmacology of a new chemical entity.

In addition to in silico and in vitro measurements, cardiac electrophysiology in experimental animals plays a decisive role in the selection of a potential 'cardio-safe' new chemical entity (NCE). The present synopsis critically reviews such in vivo techniques in experimental animals. In anaesthetized guinea-pigs, surface ECG recordings readily identify the typical effects of Class I to IV anti-arrhythmic compounds and of If blockers such as zatebradine on ECG intervals and morphology, but also of non-cardiovascular NCEs affecting cardiac electrical activity via ion channels or neurogenic mechanisms. QT/RR plots indicate that bradycardia is a dominant effect of IKr blockers (dual modulation by IKr of sinus node activity and ventricular repolarization). Nevertheless, correction of QT with Bazett's formula usually distinguishes between drug-induced heart rate reduction and real prolongation of ventricular repolarization (QTc). The anaesthetized guinea-pig model thus is a useful tool for first line in vivo testing of an NCE for effects on cardiac electrophysiology, in particular when combined with measurements of drug levels in plasma and heart tissues. In anaesthetized dogs, advanced ECG analyses identify drug-induced effects on atrial and ventricular intervals, on temporal and transmural dispersion of ventricular repolarization and on incidences of early after-depolarizations. This can be combined with complete haemodynamic, pulmonary and pharmacokinetic analyses in one preparation. However, compound doses/plasma levels needed for effects on ventricular repolarization in this model are substantially higher than those identified in guinea-pigs, at least for IKr blocking compounds. Therefore, we use this 'information-rich' canine model as a second line approach. In awake, trained and appropriately instrumented dogs, readings of surface ECG in combination with cardio-haemodynamic and behavioural assessments can be performed after the administration of an NCE via the expected therapeutic route, including oral medication. However, at higher doses the compound under scrutiny may induce overall behavioural side-effects, related to its primary pharmacological action, such as gastrokinetic repercussions or CNS-mediated sedation or excitation. Such primary pharmacological effects are bound to compromise the evaluation of real drug-induced changes on cardiac electrophysiology, readily identified by resource-friendly setups in smaller animals. Therefore, we use such paradigms as an imperative, final cardiovascular check-up, before a 'First in Man' administration of the NCE. In anaesthetized, methoxamine-challenged rabbits, arrhythmogenic effects of IKr blockers (torsades de pointes) and of dual channel INa/IKr blockers (conduction disturbances) are readily identified. Drug-induced QT dispersion rather than a 'simple' QTc prolongation determines the ventricular arrhythmogenic effect of IKr blockers. The latter effect also depends on the rate of drug delivery (plasma levels vs. heart level, equilibrium throughout the myocardium). Therefore, we use models sensitized for arrhythmogenesis to document further the profile of a comparatively 'cardio-safe' NCE. We conclude that the interpretation of an integrated profile of activity of an NCE on in vitro and in vivo cardiovascular parameters, in comparison with the characteristics of its primary pharmacology and target disease, determines its eventual selection via a scientific, rather than a 'checklist' or 'menu' approach to cardiovascular safety pharmacology. Appropriate tests in experimental animals play a key role in this process.