Heart Failure Differentially Modulates the Effects of Ivabradine on the Electrical Activity of the Sinoatrial Node and Pulmonary Veins.

BACKGROUND: Ivabradine increases the risk of atrial fibrillation (AF). Heart failure (HF) or sinoatrial node (SAN) dysfunction increases the risk of AF, and pulmonary veins (PVs) play a critical role in the pathophysiology of AF. This study investigated the electrophysiologic effects of ivabradine on SANs and PVs in a rabbit model of HF. METHODS AND RESULTS: Conventional microelectrodes were used to simultaneously record the electrical activities and conduction properties of control and HF rabbit SAN-PV preparations before and after perfusion with ivabradine (0.1, 1, or 10 µmol/L), either alone or with isoproterenol (1 µmol/L). HF SANs exhibited a lower beating rate than the control SANs. SAN automaticity exit blocks and SAN-PV conduction blocks were observed in 25% and 50% of samples, respectively, with P < .05 for HF SANs (n = 8) but not for control SANs (n = 6). Delayed afterdepolarization (DAD) was observed in 37.5% of HF PVs but not in control PVs. HF PVs exhibited a faster beating rate and more severe fibrosis than control PVs. Ivabradine reduced the SAN beating rates and increased the occurrences of SAN-PV conduction blocks and PV DADs in control and HF preparations. However, ivabradine induced SAN automaticity exit blocks only in HF preparations. Isoproterenol induced PV burst firing and shifting electrical conduction in control and HF preparations. A combination of isoproterenol and ivabradine (10 µmol/L) in HF preparations resulted in the highest incidences of PV burst firing and SAN-PV electrical shifting. CONCLUSIONS: HF differentially modulates the effects of ivabradine on the electrical activities of SAN and PVs, which may increase PV arrhythmogenesis and contribute to the risk of AF in HF patients.

An α-glucosidase inhibitor could reduce T-wave alternans in type 2 diabetes patients.

BACKGROUND: We tested the hypothesis that an alpha-glucosidase inhibitor (α-GI), miglitol, is effective in protecting the cardiovascular system in type 2 diabetes mellitus (T2DM). METHODS: We studied 19 hospitalized heart disease patients with T2DM in whom we performed continuous glucose monitoring, Holter electrocardiogram, and ambulatory blood pressure (BP) monitoring simultaneously for 48h. The α-GI miglitol was administered for half of the study period by a cross-over fashion. T-wave alternans (TWA), a marker of future fatal arrhythmic events, was also analyzed by Holter ECG. RESULTS: Of the 19 patients, the measures of glucose variability were significantly lower during miglitol therapy than in control period. BP variability was similar with/without miglitol. However, TWA was significantly lower during the miglitol period compared to control period (63±4.8 vs. 75.8±5.1µV, p=0.032). CONCLUSION: An α-GI, miglitol, can reduce TWA by reducing the fluctuation of glucose in heart disease patients with T2DM.

Effect of GWAS-Identified Genetic Variants on Maximum QT Interval in Patients With Schizophrenia Receiving Antipsychotic Agents: A 24-Hour Holter ECG Study.

BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

Long-Term Antiarrhythmic Effects of Thrombolytic Therapy in Pulmonary Embolism.

BACKGROUND: The role of thrombolytic therapy in acute pulmonary embolism patients is still controversial considering the occurrence of arrhythmias. Short-term effects of thrombolytics are well-known whereas long-term effects on cardiac electrophysiology have not been reported before. The objective of our study was to assess the arrhythmic differences in pulmonary embolism patients who received thrombolytics followed by anticoagulation or anticoagulation alone. METHODS: Sixty patients who received thrombolytic therapy followed by anticoagulation (group 1) and 60 patients who received anticoagulation alone (group 2) were included in this retrospective, single-centre observational study. Twenty-four-hour ambulatory electrocardiography was performed 31 ± 9 months after pulmonary embolism hospitalisation in order to compare arrhythmias originating from both ventricles and atria. RESULTS: The age and gender distribution of the patients were statistically similar. Ventricular arrhythmias were found to be the same between t-PA and non t-PA groups. All types of atrial arrhythmias were found to be increased in non t-PA group even though left and right atrial volume indexes were statistically identical between the two groups. CONCLUSION: In long-term pulmonary embolism, follow-up thrombolytic therapy was demonstrated to have atrial antiarrhythmic effects.

Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects.

AIMS: Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects. METHODS: Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated. RESULTS: AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration-effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience. CONCLUSION: Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.

Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine.

BACKGROUND: Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed. METHODS: Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals. RESULTS: ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%. CONCLUSION: These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures.

Use of continuous ECG for improvements in assessing the standing response as a positive control for QT prolongation.

BACKGROUND: Standing invoked change in QT interval has been identified as a promising autonomic maneuver for the assessment of QT/QTc prolongation in patients with underlying heart abnormalities or as a positive control in healthy volunteers for drug studies. Criticism for its more widespread use is the high variability in reported results and the need for a more standardized methodology with defined normal ranges. METHODS: Forty healthy male subjects underwent continuous ECG collection on the day before dosing in a double-blind, placebo-controlled, randomized, single ascending dose trial. A brisk supine to standing (3 minutes) response was conducted at three time points. Results were grouped by treatment cohort or assessed as a pooled group at each time point. Maximum time and median change from baseline (ΔTmax QTcF, ΔQTcF) were calculated for each individual over sequential 30-second periods staggered by 5 seconds. RESULTS: Maximum ΔQTcF at all time points and in all groups was significant (i.e., the lower bound of 90% CI was > 5 milliseconds) which is the ICH E14 regulatory requirement for a positive control. Variability of the time to maximum response was also reduced 9-fold by the third time period. CONCLUSIONS: Standing invoked ΔQTcF can be utilized to validate the sensitivity of a study for assessment of the QT interval effect of drugs in early development. The methodology may be used to further improve its diagnostic use of long QT syndromes by reducing the variability and allowing adequate definition of normal limits.

Effect of Piracetam and Iron Treatment on Heart Rate Variability in Patients With Breath-Holding Spell.

BACKGROUND: Breath-holding spells are a benign condition primarily seen in 3% to 5% of healthy children aged between six months and five years. Although no specific treatment is recommended due to its benign nature, iron and piracetam are used in severe or recurrent cases. We planned to compare the heart rate variability (HRV) before and after treatment with 24-hour Holter monitoring in patients receiving iron and piracetam treatment and investigate the treatment's effectiveness. METHODS: Twenty-five patients who applied to the outpatient clinic between 2013 and 2015 due to breath-holding spells were included in the study. The patients who received piracetam and iron therapy and underwent 24-hour rhythm Holter monitoring were evaluated retrospectively. RESULTS: Fourteen (56%) of these patients were evaluated as having cyanotic-type and 11 (44%) patients were assessed as having pale-type breath-holding spells. A significant difference was found only between hourly peak heart rate and total power in the group receiving iron treatment. Significant differences were also found among the minimum heart rate, mean heart rate, the standard deviation of RR intervals, the mean square root of the sum of the squares of their difference between adjacent RR intervals, spectpow, and low frequency before and after the treatment in the patients who started piracetam treatment (P < 0.05). CONCLUSIONS: Our study is critical as it is the first to investigate the effects of treatment options on various HRV in patients with breath-holding spells. There were statistically significant changes in HRV parameters in patients receiving piracetam, and the number of attacks decreased significantly. Piracetam treatment contributes positively to the breath-holding spell with regard to efficacy and HRV, therefore it can be used to treat breath-holding spells.

Gene-specific effect of beta-adrenergic blockade on corrected QT interval in the long QT syndrome.

BACKGROUND: In the long QT syndrome (LQTS) the effects of beta-blocker treatment on prevention of cardiac events differs according to the genotype. We aimed to assess the effect of beta-blocker treatment on QT/QTc duration in Type 1 LQTS (LQT1) and Type 2 LQTS (LQT2) patients. METHODS: 24-hour digital Holter ECG were recorded before and after beta-blocking therapy initiation in LQT1 (n = 30) and LQT2 patients (n = 16). QT duration was measured on consecutive 1-minute averaged QRS-T complexes leading to up to 1440 edited QT-RR pairs for each recording. We computed subject- and treatment-specific log/log QT/RR relationships which were used to correct the QT intervals. The QT duration was also evaluated at predefined heart rates and after correction using Bazett and Fridericia coefficients. RESULTS: At baseline, individual QT/RR coefficients were higher in LQT2 than in LQT1 patients (0.53 ± 0.10 vs. 0.40 ± 0.11, P < 0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521 ± 38 vs. 481 ± 39 ms, P < 0.01). Beta-blockers significantly prolonged the mean RR interval (from 827 ± 161 to 939 ± 197 ms, P < 0.0001). The individual QT/RR coefficients were not significantly modified by beta-blockers. Beta-blocker treatment was associated with a prolongation of the QT1000 interval (from 481 ± 39 to 498 ± 43 ms, P < 0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521 ± 38 to 503 ± 32 ms, P < 0.01). CONCLUSIONS: The effect of beta-adrenergic blockade on QTc duration is different in LQT1 and LQT2 patients. Our data suggest that, in LQT1 patients, the well-known positive effect of beta-blockade might be associated with a prolongation of QTc duration. The mechanisms of beta-blockade protection may be different in LQT1 and in LQT2 patients.

Heart rate variability and heart rate turbulence in HIV-infected patients receiving combination antiretroviral therapy.

BACKGROUND: Previous studies have demonstrated the presence of autonomic dysfunction in human immunodeficiency virus (HIV)-infected patients. However, the data in those receiving combination antiretroviral therapy (cART) are conflicting. The aim of this study was to assess the autonomic function using heart rate variability (HRV) and heart rate turbulence (HRT) analysis in HIV-infected patients receiving cART. METHODS: Eighty-one HIV-infected patients receiving cART and 42 control subjects were enrolled in the study. The HRV and HRT parameters were assessed on 24-hour digital Holter electrocardiogram recordings. RESULTS: Baseline characteristics were comparable between HIV-infected and control subjects, except the higher fasting glucose and triglyceride and lower high-density lipoprotein cholesterol observed in HIV-infected patients. All components of HRV were significantly reduced in HIV-infected patients. After adjustment with biochemical parameters, most of the HRV parameters were still significantly reduced in HIV-infected patients. However, HRV parameters reflecting vagal activity were no longer different between 2 groups. In addition, HRT parameters did not differ between HIV-infected and control subjects. The standard deviation of normal-to-normal intervals significantly correlated with CD4 lymphocyte counts in HIV-infected patients but did not with protease inhibitors therapy. CONCLUSIONS: We demonstrated the overall decrease in HRV in HIV-infected patients receiving cART. The metabolic disturbance observed in HIV-infected patients possibly accounted for decreased vagal activity.

Increased risk of antipsychotic-related QT prolongation during nighttime: a 24-hour holter electrocardiogram recording study.

Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR). Mean ± SD nighttime QTcFs were 411.6 ± 29.0, 395.9 ± 21.2, and 387.8 ± 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 ± 23.4, 392.4 ± 18.9, and 382.6 ± 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.

AIMS: To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. METHODS: Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. RESULTS: Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia). CONCLUSION: The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

[Influence of ω-3 PUFAs on predictors of sudden cardiac death in patients with Q-wave myocardial infarction].

OBJECTIVE: To assess effect of ω-3 polyunsaturated fatty acids (PUFAs) on non-invasive predictors of sudden cardiac death (ventricular arrhythmias, QT duration and variability, late ventricular potentials [LVP], microvolt-level T-wave alternans [MTWA], and heart rhythm turbulence [HRT]) in patients with Q-wave myocardial infarction (MI) and ventricular heart rhythm disturbances (VHRD). MATERIAL AND METHODS: The study included 140 men aged 52.5+/-1.3 years with primary diagnosis of Q-wave MI and I-IV Lown grade VHRD. Patients were randomized in 2 groups: index group (A) and control group (B) consisted of 70 persons each. Patients of index and control groups were divided into another 2 groups by severity of arrhythmic syndrome: Al (n=39) and Bl (n=38) with I-III grade VHRDs; A2 (n=31) and B2 (n=32) with IV-V grade VHRDs. In index groups (Al and A2) ω-3 PUFA medicine was administered additionally to standard therapy at a dose of 1 g/day during 6 months. All patients underwent standard clinical examination and 24-hour Holter ECG monitoring on days 10-14 and in 6 months after MI. RESULTS: Decreases of single and paired ventricular extrasystoles, ventricular tachycardia runs, total duration of myocardial ischemia were observed in patients of index groups Al and A2 after ω-3 PUFAs treatment. After 6 months of ω-3 PUFAs treatment significant QT shortening and increase of QTc variability were noted. Numbers of patients with LVP in Al and A2 groups decreased 21.3% (p<0.05) and 38.7% (p<0.0l), with HRT - 20.5% and 29.1% (p<0.05), with MTWA - 18% and 16.1% (p<0.01). In control groups the result was statistically insignificant. CONCLUSION: Administration of 1 g/day of a prescription preparation of 90% ω-3 PUFAs in patients with primary Q-wave MI was associated with decrease of ventricular ectopy severity in patients with low and high grade VHRD and simultaneous reduction of total myocardial ischemia time. ω-3 PUFAs administration for 6 months had marked positive effect on QT duration and variability, LVP, HRT, MTWA.

Comparison of QT/RR relation based on a 15-s averaged ECG and a single beat ECG during atrial fibrillation.

BACKGROUND: The aim of this study was to compare QT/RR relation based on a 15-s averaged beat ECG with a single beat ECG during atrial fibrillation (AF) and to determine which was better to estimate the QT interval after sinus restoration. METHODS AND RESULTS: QT and RR intervals were measured using an automatic QT analyzing system in 33 patients who had both AF and sinus rhythm on the same 24-h Holter ECG recording. In 14 patients, antiarrhythmic drugs (AAD) were administered. QT/RR relations were analyzed from ECG waves obtained by the summation of consecutive QRS-T complexes during each 15-s period (QT/RR-average) and a single beat QRS-T (QT/RR-single). During sinus rhythm, the slope of QT/RR-average did not differ from that of QT/RR-single in patients with and without AAD. On the other hand, during AF, the slope of QT/RR-average was significantly greater than that of QT/RR-single (without AAD: 0.12±0.06 vs. 0.06±0.03, P<0.001; with AAD: 0.15±0.05 vs. 0.08±0.04, P<0.001). During AF, the QT interval at an RR interval of 1.2-s (QT-1.2) determined from QT/RR-average was significantly greater than QT-1.2 from QT/RR-single in patients with and without AAD. QT-1.2 in QT/RR-single during AF was significantly smaller than that during sinus rhythm but QT-1.2 in QT/RR-average during AF was not. CONCLUSIONS: The QT interval after sinus restoration could be estimated better using QT/RR-average than using QT/RR-single during AF.

High-dose sotalol is safe and effective in neonates and infants with refractory supraventricular tachyarrhythmias.

Our objective was to assess the efficacy and safety of high-dose sotalol in neonates and infants with refractory supraventricular tachycardia (SVT). SVT in neonates and infants can be refractory to primary therapies; therefore, secondary agents, e.g., sotalol, are often required to obtain control of SVT. Age-factor nomogram dosing of sotalol is widely used; however, our institution uses greater doses based on body surface area (approximately 150-200 mg/m(2)/d). A retrospective review of 78 inpatients receiving sotalol, after failing another antiarrthymic medication, at our institution from 2001 to 2008 was performed. Corrected QT intervals (QTc), 24-h Holter-monitoring results, and outpatient records were reviewed to assess safety and efficacy for patients ≤ 2 years of age. Median patient age at the time of initiation of therapy was 24 days (range 3-728). Forty-eight patients (62%) were neonates, and 36 (46%) had congenital heart disease. The median sotalol dosage was 152 mg/m(2)/day (range 65-244). The SVT of 70 patients (90%) was controlled with sotalol. No patients experienced significant QTc prolongation or proarrhythmia. Mean duration of follow-up was 3.3 ± 0.24 years. High-dose sotalol allows for safe and rapid control of refractory tachyarrhythmias in this young age group.

A case of atrial tachycardia sensitive to increased caffeine intake.

A 33-year-old Japanese man with atrial tachycardia visited our clinic. He regularly consumed daily alcohol with cola, one cup of regular coffee, and a candy containing 0.7 mg of caffeine per tablet. After stopping his caffeine intake, his arrhythmia ameliorated. Since caffeine might be associated with his arrhythmia, a caffeine load test (equivalent to his daily intake of caffeine) was performed for 4 days. Atrial tachycardia time from a Holter recording was 44.2 minute/day before the caffeine load, compared with 215.2 minute/day during the caffeine load. Plasma caffeine concentration before and during caffeine loading was 3.1 mg/dL and 5.4 mg/dL, respectively. Caffeine use seemed to be an important factor for his atrial tachycardia, since his arrhythmia became worse during caffeine load testing and was ameliorated after the cessation of caffeine.

Effect of omega-3 fatty acids on heart rate variability in depressed patients with coronary heart disease.

OBJECTIVE: To determine whether omega-3 fatty acid (FA) increases the natural log of very low frequency (lnVLF) power, an index of heart rate variability (HRV), and reduces 24-hour heart rate (HR) in depressed patients with coronary heart disease (CHD). Low intake of omega-3 FAs is associated with depression and with low HRV, and all three are associated with an increased risk of death in patients with CHD. METHODS: Thirty-six depressed patients with CHD randomized to receive 50 mg of sertraline and 2 g of omega-3/day, and 36 randomized to sertraline and a placebo, had 24-hour HRV measured at baseline and after 10 weeks of treatment. RESULTS: There was a significant treatment × time interaction for covariate adjusted lnVLF (p = .009), for mean 24-hour HR (p = .03), and for 1-minute resting HR (p = .02). The interaction was not significant for three other measures of HRV. LnVLF did not change over time in the omega-3 arm but decreased in the placebo arm (p = .002), suggesting that omega-3 may have prevented or slowed deterioration in cardiac autonomic function. CONCLUSIONS: The effects of omega-3 FAs on lnVLF and HR, although modest, were detected after only 10 weeks of treatment with 2 g per day of omega-3. Whether a longer course of treatment or a higher dose of omega-3 would further decrease HR, improve other indices of HRV, or reduce mortality in depressed CHD patients should be investigated.

ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial.

OBJECTIVE: To investigate whether there is a difference in occurrence of electrocardiogram changes suggestive of myocardial ischaemia between two different doses of oxytocin. DESIGN: Double-blind randomised controlled trial. SETTING: University hospital in Sweden. POPULATION: A total of 103 healthy women undergoing elective caesarean section under spinal anaesthesia. METHODS: The participants were randomised to 5 or 10 units of oxytocin, given as an intravenous bolus. A Holter monitor was used to record electrocardiograms and non invasive blood pressure and heart rate (HR) was monitored. A blood sample was obtained 12-hour postoperatively. MAIN OUTCOME MEASURES: Depression of the ST segment. SECONDARY OUTCOMES: symptoms, Troponon I levels, mean arterial pressure (MAP), HR and blood loss. RESULTS: There was a significant difference in occurrence of ST depressions associated with oxytocin administration, 4 (7.7%) with 5 and 11 (21.6%) with 10 units, P < 0.05. The absolute risk reduction was 13.9% (95% confidence interval, 0.5-27.3). Decrease of mean MAP from baseline to 2 minutes differed, being 9 mmHg in the 5 unit group and 17 mmHg in the 10 unit group (P < 0.01). The increase in mean HR did not differ. Troponin I levels were increased in four subjects (3.9%). There were no differences in occurrence of symptoms, Troponin I levels, or estimated blood loss. CONCLUSION: ST depressions were associated with oxytocin administration significantly more often in subjects receiving 10 units compared with 5 units. Interventions to prevent hypotension during caesarean section may reduce the occurrence of ST depressions on electrocardiograms.

Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing.

PURPOSE: Evaluate dalcetrapib's potential to prolong QT intervals in healthy subjects. METHODS: This was a single-center, randomized, active and placebo-controlled, six-sequence, three-period cross-over study. Participants [18-65 years; body mass index (BMI) 18-30 kg/m(2)] were randomized to daily doses of dalcetrapib 600 mg (therapeutic) or 3,900 mg (supratherapeutic) or to dalcetrapib-matched placebo for 7 days. On Day 8, subjects received single-dose moxifloxacin 400 mg (active control) or placebo, following the placebo or dalcetrapib, respectively. Electrocardiographic parameters were recorded on Days -1, 1, 7, and 8. The primary endpoint was the difference to placebo of time-matched change from baseline in the study-specific corrected QT interval (QTcS) at seven time-points within 24 h after dalcetrapib 3,900 mg on Day 7. An upper 95% confidence interval (CI) <10 ms confirmed the absence of a significant effect. Pharmacokinetic and lipid-related parameters were measured. RESULTS: Subjects (n = 49) were predominantly male (71%), and all were white, with a mean age of 45 years and mean BMI of 25 kg/m(2). For the primary analysis, the upper 95% CI for dalcetrapib 3,900 mg was <10 ms at all time-points. Similar findings were obtained for dalcetrapib 600 mg. Following the administration of moxifloxacin, the QTcS increased by >5 ms. At Day 7, exposure for dalcetrapib 3,900 mg was approximately eightfold higher than that for dalcetrapib 600 mg [mean area under the plasma concentration-time curve between time 0 and 24 h 68,500 vs. 8,280 ng*h/mL; mean peak concentration 6,810 vs. 861 ng/mL]. Cholesteryl ester transfer protein activity was inhibited by 30%, and high-density lipoprotein cholesterol increased by 26% for dalcetrapib 600 mg. Dalcetrapib was well tolerated. CONCLUSIONS: Dalcetrapib is not associated with QT interval prolongation, even at doses markedly greater than intended therapeutically.

The time course of new T-wave ECG descriptors following single- and double-dose administration of sotalol in healthy subjects.

INTRODUCTION: The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation. METHODS: Twelve-lead digital ECG Holter was recorded in 38 healthy subjects (27 males, mean age = 27.4 + or - 8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using three biomarker categories: conventional ECG time intervals, principal component analysis (PCA) analysis on the T wave, and fully automatic biomarkers computed from a mathematical model of the T wave. RESULTS: QT interval was significantly prolonged starting 1 hour 20 minutes after drug dosing with 160 mg and 1 hour 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes. The duration of manual QT and automatic surrogate QT were strongly correlated (R(2) = 0.92, P < 0.001). The Bland and Altman plot revealed a nonstationary systematic bias (bias = 26.5 ms + or - 1.96*SD = 16 ms). CONCLUSIONS: Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies.