Cardiac Repolarization In Healthy Subjects Research Articles

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects.

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680mg in eight subjects. Part2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part1. During Part2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects.

A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects

PurposeThe International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. MethodsThe study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days −1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated. FindingsOf the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure. ImplicationsThe findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.

Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects

Macitentan is an orally active dual endothelin receptor antagonist, which demonstrated a reduction of the risk of morbidity/mortality events in pulmonary arterial hypertension patients. This double-blind, randomized, placebo- and positive-controlled, four-way crossover thorough QTc study was designed to investigate the effects of therapeutic and supratherapeutic doses of macitentan on cardiac repolarization in healthy male and female subjects. Each subject received the following treatments: moxifloxacin 400 mg, macitentan 10 mg, macitentan 30 mg, and placebo. Each treatment period lasted 9 days and was followed by at least 10 days of washout. The primary endpoint of this study was the baseline-adjusted, placebo-corrected QT interval corrected using the Fridericia method (ΔΔQTcF). Pharmacokinetic (PK), safety, and tolerability assessments were performed during each treatment.A total of 64 subjects were randomized. The upper bound of the 2-sided 90% confidence interval for ΔΔQTcF following macitentan was <10 ms at all time points and no correlation was observed between ΔΔQTcF and PK parameters. Findings in the analysis of the morphological patterns of the ECGs were randomly distributed across all treatments and did not indicate an association with macitentan. Macitentan was well tolerated in this study. Headache and nasopharyngitis were the most frequently reported adverse events. No effects on clinical laboratory and vital signs parameters were observed.In summary, repeated doses of macitentan 10 mg and 30 mg did not indicate any pro-arrhythmic potential.

Evaluation of the effect of mericitabine at projected therapeutic and supratherapeutic doses on cardiac repolarization in healthy subjects: A thorough QT/QTc study.

Mericitabine, the di-isobutyl ester prodrug of the cytidine nucleoside analog, is a potent and selective hepatitis C virus NS5B polymerase inhibitor. This thorough QT/QTc study evaluated the effect of mericitabine on cardiac repolarization in healthy subjects. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study. A total of 60 subjects were enrolled and randomized to receive a single dose of mericitabine 1,500 mg, 9,000 mg, moxifloxacin 400 mg and placebo in randomly assigned treatment sequences, with at least 14 days between doses. The primary endpoint was the mean difference in baseline-adjusted QT interval using a study-specific correction method (QTcS) between mericitabine and placebo. The upper one-sided 95% confidence interval for the placebo-subtracted change from baseline in QTcS was <10 milliseconds and the mean difference from placebo was <5 milliseconds at all time points for both mericitabine doses. The positive control moxifloxacin caused a pronounced increase in QTcS that peaked 4 hours after oral administration. Furthermore, there was no trend of a concentration-dependent effect of mericitabine on QTcS. In conclusion, mericitabine does not have a clinically or statistically significant effect on cardiac repolarization in healthy subjects at single doses up to 9,000 mg.

Effect of Vortioxetine on Cardiac Repolarization in Healthy Adult Male Subjects: Results of a Thorough QT/QTc Study.

This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2-sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects.

EVP-6124, an alpha7 nicotinic acetycholine receptor partial agonist, did not delay cardiac repolarization in healthy subjects

EVP-6124, an alpha7 nicotinic acetycholine receptor partial agonist, did not delay cardiac repolarization in healthy subjects

A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects

This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 μg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 μg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. Based on ΔQTcF and ΔQTcI assessments, exenatide 10 μg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. This study demonstrated that single-dose exenatide 10 μg was not associated with clinically meaningful prolongation of the QTc interval.

Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects

Objective: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization.Methods: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 μg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTcF). The primary endpoint was the largest mean time-matched change in QTcF from baseline (day 1). Safety and tolerability were monitored.Results: Moxifloxacin gave a maximum time-matched change in QTcF versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 μg resulted in maximum QTcF changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated.Conclusions: Repeated administration of roflumilast at doses ≤ 1000 μg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects.Clinical trial registration number: ISRCTN63818313

Effects of Prulifloxacin on Cardiac Repolarization in Healthy Subjects

Prulifloxacin, a broad-spectrum fluoroquinolone, is quantitatively transformed after oral administration into ulifloxacin, the active metabolite. On the basis of preclinical data suggesting that prulifloxacin is not likely to prolong the QT interval, a trial to assess the potential effects of prulifloxacin on QT and corrected QT (QTc) interval in humans was performed. Fifty-two healthy subjects were randomized into three groups to receive prulifloxacin 600 mg, moxifloxacin 400mg and placebo once daily for 5 days, using a crossover, double-blind versus placebo, moxifloxacin-controlled study. At baseline and days 1 and 5, three 12-lead digital ECGs were recorded before and up to 24 hours after dosing at nine predefined timepoints. Blood samples were also collected at each treatment timepoint. ECG data were analysed in a blinded manner by a centralized laboratory using skilled readers. QT values were corrected for heart rate using an individual correction method (QTcI) as the primary variable, and Fridericia's method as reference. In forty-eight subjects who completed the study, compared with placebo, prulifloxacin had no relevant effect on cardiac repolarization, with the largest mean QTcI increase being 3.97 ms (one-sided 95% CI 0.01, 7.93), whereas moxifloxacin demonstrated the expected positive effect (maximum mean QTcI increase of 12.0 ms, one-sided 95% CI 8.66, 15.34), thus demonstrating the good sensitivity of the study. A statistically significant correlation between QTcI changes and plasma concentrations was found for moxifloxacin but not for ulifloxacin. Prulifloxacin at steady state after therapeutic doses has no significant effects on the QTc interval and thus should prove to have no cardiac liability.

A single-dose, placebo- and moxifloxacin-controlled 3-period study of the effects of temsirolimus on cardiac repolarization in healthy subjects

2551 Background: Temsirolimus (CCI-779) is a novel selective inhibitor of the mammalian target of rapamycin (mTOR) approved by the US FDA for the treatment of patients with advanced renal cell carcinoma. This study was designed to assess the effect of a single dose of 25 mg IV temsirolimus on the corrected QT interval (QTc) in healthy subjects. Methods: Fifty-eight (58) healthy subjects were enrolled in this 3-period crossover study. In periods 1 and 2, subjects were administered IV placebo either alone or with open-label oral moxifloxacin. In period 3, subjects were administered 25 mg IV temsirolimus. Serial ECGs were digitally captured in triplicate and manually over read by a central vendor. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 hour time point). Secondary endpoints and objectives included estimates of effect at 12 additional time points, population PKPD analyses, and categorical summaries of interval data. Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc as compared with placebo. Results: Temsirolimus had no effect on the QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% CIs for the time-matched change from baseline difference from placebo was less than 10 msec without evidence of QTc trends or relationship to temsirolimus or sirolimus whole blood concentrations. Mean concentrations were comparable to those observed in patients with renal cell carcinoma following administration of 25 mg IV temsirolimus. Moxifloxacin produced a statistically significant increase in the QTc interval as compared with placebo. No relevant PKPD relationship was seen using linear or Emax models. No subject in this study had a QTc interval exceeding 450 msec and no subjects had a change from baseline &gt;30 msec. Conclusions: We conclude that therapeutic exposures of temsirolimus are not associated with changes in QTc interval that reach the level of regulatory significance, according to ICH E14 guidance. The findings are consistent with the lack of QTc interval prolongation observed in studies of cancer patients. [Table: see text]

Effect of levetiracetam on cardiac repolarization in healthy subjects: A single-dose, randomized, placebo- and active-controlled, four-way crossover study

Background: Nonantiarrhythmic drugs may have the potential to prolong the QT interval, leading to potentially fatal ventricular tachycardias, including torsades de pointes.Objective: This study evaluated the potential of the newer-generation, multiple-action antiepileptic drug levetiracetam, which binds to the synaptic vesicle protein SV2A, to affect cardiac repolarization, as detected by prolongation of the QT/corrected QT (QTc) interval.Methods: This was a single-dose, randomized, placebo- and active-controlled, 4-way crossover study in healthy subjects. Subjects were randomly allocated to 1 of 4 different administration sequences. Each sequence included 3 double-blind treatments (levetirace-tam 1000 mg, levetiracetam 5000 mg, and placebo) and 1 open-label treatment (moxifloxacin 400 mg). Triplicate electrocardiograms (ECGs) were obtained at baseline and at various time points over 24 hours after each treatment using continuous Holter monitoring. ECGs were read centrally in a blinded manner. Blood samples for the determination of plasma concentrations of levetiracetam and moxifloxacin were collected before dosing and at 0.5, 1, 1.5, 2, 4, 6, 12, and 24 hours after dosing, within 5 minutes after the ECG recordings. The QT interval was corrected for heart rate using a sex- and study-specific correction (QTcss) as the primary outcome measure and Fridericia's correction (QTcF)as a secondary outcome measure. The primary analysis was performed on the time-matched, baseline-subtracted QTcss (ΔQTcss). The maximum ΔQTcss difference between each active treatment and placebo (ΔΔTcss) was derived from a mixed-effect analysis of variance. Clinical laboratory tests, standard 12-lead ECGs, and vital signs were monitored at regular intervals. Spontaneously reported adverse events were recorded throughout the study.Results: Fifty-two healthy, nonsmoking subjects (26 men, 26 women; 37 white, 9 black, 3 Hispanic, and 3 Asian/Pacific Islander) with a mean (SD) age of 28.4 (7.5) years (range, 18-45 years) and a mean weight of 71.5 (12.6) kg (range, 49-103 kg) participated in the study. Levetiracetam did not significantly prolong the QTcss. The upper bound of the 1-sided 95% CI for the maximum ΔΔTcss was 8.0 milliseconds for levetiracetam 1000 mg and 8.1 milliseconds for levetiracetam 5000 mg, with mean estimates of 4.0 and 4.1 milliseconds, respectively; similar results were obtained for the maximum ΔΔQTcF. Moxifloxacin significantly prolonged the QTcss, with a lower bound of the 1-sided 95% CI for the maximum ΔΔQTcss of 3.7 milliseconds and a mean estimate of 7.7 milliseconds. There was no statistically significant relationship between measured ΔQTcss and the levetiracetam plasma concentration, whereas a significant linear relationship was observed between measured ΔQTcss and the moxifloxacin plasma concentration (slope estimate: 4.4 milliseconds/[μg/mL]); 95% CI, 3.2-5.7; P < 0.001). No unexpected safety concerns arose based on reported adverse events, clinical laboratory evaluations, physical examinations, vital signs, or ECG monitoring during the course of the study.Conclusion: This randomized, placebo- and active-controlled study in healthy adult subjects found no clinically relevant changes in the QTc interval after a single levetiracetam dose of 1000 or 5000 mg.

Elevated plasma fatty acid concentrations prolong cardiac repolarization in healthy subjects

High fatty acid concentrations have been shown to stimulate sympathetic nervous system activity, which may modify ventricular repolarization and thus the Q-T interval on electrocardiogram recordings. The aim of this study was to investigate whether acute elevations of plasma fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion, and sympathetic nervous system activity in healthy nonobese subjects. Thirty-two healthy subjects (x +/- SD: 48+/-7 y of age) received an infusion of 10% triacylglycerol emulsion plus heparin (a bolus of 200 U followed by 0.2 U min(-1) * kg body wt(-1) for 180 min); on another occasion and in random order, the same subjects received a saline infusion. Compared with the saline infusion, infusion of 10% triacylglycerol emulsion increased plasma fatty acids (P<0.001) and was associated with an increase in mean blood pressure (P<0.05), heart rate (P<0.05), Q-Tc (P<0.01), Q-Tc dispersion (P<0.01), and plasma epinephrine (P<0.005). Furthermore, individual changes in plasma epinephrine correlated with changes in Q-Tc (r = 0.60, P<0.001) and Q-Tc dispersion (r = 0.53, P< 0.02) even after adjustment for age, sex, and body mass index (P<0.03 for all correlations). Only changes in plasma fatty acids (P = 0.04) and plasma epinephrine (P = 0.006) concentrations were significantly and independently associated with the lengthening of the Q-T interval. Our study showed that elevated plasma fatty acid concentrations might affect cardiac repolarization, at least in part because of an increase in plasma catecholamines.