Repolarization In Men Research Articles

Influence of baseline QTc on sotalol-induced prolongation of ventricular repolarization in men and women.

The extent of sotalol-induced QTc prolongation on the electrocardiogram, is variable among subjects and influenced by sex. However, the influence of baseline QTc on the extent of drug-induced QTc prolongation remains unclear. This was studied around peak plasma concentration in a large cohort of 376 healthy male and 614 healthy female subjects who received 80 mg of sotalol orally. Baseline QTc was 379 ± 16 ms in men and 393 ± 15 ms in women (P< .0001). The change in QTc from baseline was highly variable among both sexes and was greater in women than in men (26.5± 13.2 vs.13.0±10.8ms; P< .0001). The slope of the regression line between QTc on sotalol and baseline QTc did not significantly differ from unity in men and in women, indicating that the extent of QTc prolongation with sotalol was not influenced by baseline QTc. Assessing QTc after administration of an IKr blocker may be more important than measuring a baseline QTc.

An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer

PurposePhase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed.MethodsPatients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day − 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety.ResultsForty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1–2 in severity. No patients discontinued due to QTc prolongation or AEs.ConclusionThe effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.

Race- and sex-associated differences in rate-adjusted QT, QTpeak, ST elevation and other regional measures of repolarization: The Atherosclerosis Risk in Communities (ARIC) Study

BackgroundData are limited about race-and sex-associated differences in prognostically important ECG measures of regional repolarization. Methods and resultsThe normal reference group from the Atherosclerosis Risk in Communities (ARIC) study included 8,676 white and African-American men and women aged 40–65years. Exclusion criteria included cardiovascular disease, hypertension, diabetes and major ECG abnormalities. Notable sex differences (p<0.001) were observed in the upper 98% limits for rate-adjusted QTend (QTea) which was 435ms in white and African-American men and 445ms in white and African-American women, and for left ventricular epicardial repolarization time (RTepi) which was 345ms in white and African-American men and 465ms in white and African-American women. These sex differences reflect earlier onset and end of repolarization in men than in women. Upper normal limits for STJ amplitude in V2–V3 were 100μV in white and African-American women, 150μV in white men and 200μV in African-American men (p<0.001 for sex differences), and for other chest leads, aVL and aVF 50μV in white women, 100μV in African-American women, 100μV in white men and 150μV in African-American men (p<0.001 for sex and race differences). ConclusionsShorter QTea and RTepi in men than in women reflect earlier onset and end of repolarization in men. STJ amplitudes in African-American men were higher than in other subgroups by race and sex. These sex and race differences need to be considered in clinical and epidemiological applications of normal standards.

Is there a significant transmural gradient in repolarization time in the intact heart?

Is there a significant transmural gradient in repolarization time in the intact heart?

Dietary Linolenic Acid and Adjusted QT and JT Intervals in the National Heart, Lung, and Blood Institute Family Heart Study

The goal of this study was to examine whether higher consumption of total linolenic acid was associated with rate-adjusted QT and JT intervals (QTrr and JTrr, respectively). Higher intake of fish omega-3 fatty acids and plant omega-3 such as alpha-linolenic acid is associated with lower risk of myocardial infarction. While long-chain omega-3 can inhibit ventricular arrhythmia, it is not known whether alpha-linolenic acid influences ventricular repolarization. We studied 3,642 subjects from the National Heart, Lung, and Blood Institute Family Heart study who were free of myocardial infarction, left ventricular hypertrophy, pacemaker, and with QRS <120 ms. We used the 95th percentile of the gender-specific distribution of QTrr and JTrr to define abnormally prolonged repolarization. Within each gender, we created age- and energy-adjusted tertiles of linolenic acid and used regression models for analyses. Mean age was 50 years, and average intake of total linolenic acid was 0.74 g/day. There was an inverse association between consumption of linolenic acid and QTrr and JTrr (p for trend 0.001 and 0.0005, respectively). From the lowest (reference) to the highest gender-, age-, and energy-adjusted tertile of linolenic acid, multivariable adjusted odds ratios for prolonged QTrr were 1.0, 0.74 (95% confidence interval [CI] 0.57 to 0.96), and 0.59 (95% CI 0.44 to 0.77), respectively (p for trend 0.0003). Corresponding values for JTrr were 1.0, 0.73 (95% CI 0.52 to 1.03), and 0.59 (95% CI 0.40 to 0.87), respectively (p for trend 0.009). Exclusion of subjects taking drugs known to influence QT did not influence this association. Higher intake of dietary linolenic acid might be associated with a reduced risk of abnormally prolonged repolarization in men and women.

Sample Size, Power Calculations, and Their Implications for the Cost of Thorough Studies of Drug Induced QT Interval Prolongation

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140 subjects per group. However, the required study size may be substantially reduced in investigations based on within-subject comparisons (e.g., crossover studies or studies of several parallel groups each crossing over an active treatment with placebo). While simple measurement approaches with ad-hoc heart rate correction still lead to requirements of >150 subjects, the combination of best data quality with most accurate individualized heart rate correction decreases the variability of QTc measurements in each individual very substantially. In the data of this study, the average of standard deviations of QTc values calculated separately in each individual was only 5.2 ms. Such a variability in QTc data translates to only 18 subjects per study group (e.g., the size of a complete one-group crossover study) to detect 5 ms QTc change with an 80% power. Cost calculations show that by involving the most stringent ECG handling and measurement, the cost of a thorough QT/QTc study may be reduced to approximately 25%-30% of the cost imposed by the simple ECG reading (e.g., three complexes in one lead only).

Changes in myocardial repolarization in patients undergoing balloon valvuloplasty for congenital pulmonary stenosis: evidence for contraction-excitation feedback in humans.

Alterations in ventricular loading conditions lead to changes in action potential duration and arrhythmias via contraction-excitation feedback; a decrease in load leads to prolongation of repolarization. To determine whether changes in right ventricular load alter ventricular repolarization in man, the corrected QT interval, a measure of overall ventricular repolarization, was measured in 32 patients before and after valvuloplasty for pulmonary stenosis. Right ventricular systolic pressure decreased (82.5 +/- 30.7 to 40.5 +/- 9.5 mm Hg, p less than .001) and the QTc increased concurrently (409.1 +/- 24.3 to 440.7 +/- 28.0 msec, p less than .001) after successful valvuloplasty. The increase in QTc was most marked for those patients with a greater than 30 mm Hg decrease in right ventricular pressure (40.0 +/- 23.3 vs 16.3 +/- 21.3 msec, p = .006). In a subset of seven patients in whom monophasic action potentials were recorded, monophasic action potential duration, a measure of local repolarization, was prolonged (230.0 +/- 24.3 vs 216.9 +/- 21.9, p less than .001) after successful valvuloplasty, confirming that the QTc prolongation reflected changes in local ventricular repolarization. In addition, during nine acute right ventricular outflow tract occlusions in a subset of six patients, monophasic action potential duration shortened (206.6 +/- 17.6 vs 221.7 +/- 20.9 msec, p less than .01) and early afterdepolarizations developed consistent with contraction-excitation feedback. These data suggest that, in humans, changes in mechanical load are associated with changes in ventricular repolarization consistent with contraction-excitation feedback.

Estimation of Ventricular Repolarization in Man by Monophasic Action Potential Recording Technique

Myocardial monophasic action potentials (MAP) can be recorded with the aid of suction or contact electrodes applied endocardially via a catheter. The technique necessitates high input impedance amplifiers with infinite time constant. A bipolar technique improves signal quality with regard to electrical contamination around the rapid upstroke of the MAP. Mechanical artefacts in the recordings are common and may be explained by catheter movement induced by atrial or ventricular contractions. The MAP signal can be used for a precise measurement of time of local excitation and for the study of atrial as well as ventricular repolarization. The technique has mostly been applied in the exploration of atrial and ventricular repolarization in healthy hearts and during different cardiac arrhythmias. Furthermore, several studies have documented the electrophysiological action of antiarrhythmic drugs upon the human heart. Concluding from 576 different investigations we consider the technique to have no serious side-effects.

Clinical electrophysiologic study of antiarrhythmic properties of flecainide: Acute intraventricular delayed conduction and prolonged repolarization in regular paced and premature beats using intracardiac monophasic action potentials with programmed stimulation

Flecainide acetate is one of the few antiarrhythmic drugs that substantially delay myocardial repolarization in tissue preparations. The potential clinical benefit of this mechanism stimulated our study of the acute effects of this agent on intraventricular conduction and repolarization in man. Thus three normals and six patients were studied before and after an intravenous dose of 2 mg of flecainide/kg. We determined ventricular effective refractory period (VERP) and recorded monophasic action potentials (MAP) from the right ventricle during induction of ventricular ectopic beats with coupling intervals of VERP +1, +30, +40, and +50 msec. Flecainide induced significant prolongations of MAP (+9.6%, p < 0.01) and VERP (+9.8%, p < 0.05) during regular pacing, as well as delayed intraventricular conduction time (+16.8%, p < 0.05). The MAP of the earliest inducible ventricular ectopic beat was even more markedly prolonged (+19.0%, p < 0.001) and at coupling intervals 30 to 50 msec longer than VERP such considerable prolongation remained (+14.2%, p < 0.001). In addition, this study illustrates the utility of the MAP ventricular recording method, combined with programmed ventricular stimulation, in demonstrating clinical electrophyslologic properties directly comparable with those of microelectrode investigations.

Effect of intravenous melperone on atrial repolarization in man.

The effect of 10 mg of melperone intravenously on the duration of the right atrial monophasic action potential was studied in seven patients and one healthy volunteer. Melperone induced an increase of the atrial monophasic action potential duration by 13%, 15 min after intravenous injection of the drug. This prolongation was a consistent finding but was within the limits of normal intra-individual variation and considerably smaller than normal inter-individual differences. However, the observations warrant studies to evaluate the effect of the drug in different cardiac arrhythmias.

Sotalol-induced delayed ventricular repolarization in man

Sotalol is the only beta-adrenergic blocking agent, that has been shown to produce delayed repolarization following acute administration. In this study an intravenous injection of 40–100 mg sotalol was given to eight patients with chronic atrial fibrillation. One patient was reverted to sinus rhythm, while the other patients were electro-converted 2 h after the injection. Three patients still in sinus rhythm 24 h later received chronic treatment for at least 12 weeks. They maintained sinus rhythm throughout the study. Identical electrophysiological investigations were performed after the acute injection and after chronic treatment. Following acute administration, sotalol produced a consistent increase in the ventricular repolarization time as measured from refractory periods and monophasic action potential duration, the change being of the magnitude of 13 to 17%. After chronic treatment the three remaining patients still showed an increase in the ventricular repolarization time, but no conclusions can be made from these few observations. However, the study confirms the existence of a class III mode of action at the cellular level following intravenous sotalol injections of40–100 mg in man.

Atrial repolarization in man. Effect of beta-receptor blockade.

Atrial repolarization in man. Effect of beta-receptor blockade.