Search

Magnesium (Mg) is a crucial element for cardiovascular system and its deficiency results in a variety of cardiac arrhythmias. The aim of this study is to determine the effect of oral Mg supplementation on the frequency of ventricular extrasystoles (VES) in children. Magnesium supplementation was given to 42 children who had VES without structural heart disease. Clinical, electrocardiographic, and Holter monitoring studies were reviewed. The mean baseline 24 h VES burden on Holter monitoring was 10.26% ± 4.13% and it was decreased to 6.62% ± 3.88% after. There was no significant difference between the pre-treatment serum Mg levels and the decrease in the frequency of VES. In conclusion, oral Mg therapy was found to be effective at suppressing VES in children regardless of serum Mg levels. Large and randomized studies are needed to demonstrate the effect of magnesium on VES suppression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients at our pediatric outpatient clinic were offered 24-h Holter electrocardiogram (ECG) before and after 3-month period of dietary supplementation with omega-3 fatty acids to monitor the effect on heart rate variability (HRV) and arrhythmias., Methods: The study included 17 children (mean age: 11.6 ± 4.9 years) with >1% premature ventricular contractions (PVC) at baseline. 24-h Holter ECG monitoring was performed before and after omega-3 fatty acid supplementation (mean duration: 143 days)., Results: Compared with 86 age-matched healthy control children, baseline HRV was significantly reduced and mean heart rate was significantly increased in children with frequent PVC. After omega-3-fatty acid supplementation, the mean heart rate decreased from 92.6 ± 3.4 bpm to 83.9 ± 9.9 bpm (p = 0.001), while global HRV showed a significant increase [standard deviation of all NN intervals (SDNN): 148.1 ± 34.4 ms vs. 126.5 ± 39.3 ms, p = 0.022)]. Enhanced vagal activity was indicated by significantly higher square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD) (42.3 ± 12.6 vs. 33.2 ± 14.8; p = 0.0003). PVC percentage significantly decreased by 45% (6.9 ± 7.0% vs. 12.1 ± 8.2%; p = 0.014)., Conclusions: Omega-3-fatty acid supplementation caused a 45% reduction in frequent PVC in children with structurally healthy hearts. This antiarrhythmic effect was likely attributable to improved autonomic function, which is consistent with previous findings in children with obesity, attention deficit disorder, and short stature., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Phase 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., Methods: Patients 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., Results: Forty-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., Conclusion: The 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.

Background: Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known., Methods: Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT-interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24-hr period as well as at daytime and nighttime., Results: QTcBaz over 24-hr was shorter at 1D (414 ± 20 ms, p  < .001) and at 3M (414 ± 20 ms, p  < .001) than at baseline (418 ± 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 ± 19 ms, p  < .001) but similar at 3M (406 ± 19 ms, p  = .355) compared to baseline (407 ± 19 ms). Daytime QTcBaz was shorter at 1D ( p  < .001) and at 3M ( p  = .007), whereas daytime QTcFri was longer at 1D ( p  < .05) but similar at 3M ( p  = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M., Conclusions: Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

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.

The QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100 pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin. IA injection of vehicle or 5 pmol UII had no effect on the various parameters. At the 50-pmol dose, UII evoked its usual increase in PDA with a peak value observed 15 min after the injection (+22% from baseline, P<0.001). This hypertensive effect of UII was accompanied by a significant increase in the RR interval (+18%, P<0.001), i.e. a bradycardia, and these effects remained constant until the end of the recording. The highest dose of UII evoked similar hypertensive and bradycardic effects. Of interest, the QT interval did not change during the bradycardic action of UII (50 and 100 pmol) but the QTc interval significantly decreased. In trout pre-treated with urantide, a peptidic antagonist of UT, the hypertensive and bradycardic actions of 50 pmol UII were reduced 3-fold and no change occurred in the QT and QTc intervals. In trout pre-treated with blockers of the autonomic nervous system, the hypertensive effect of UII was maintained but no change appeared in RR, QT and QTc intervals. IA injections of 50 pmol URPs were without action on the preceding parameters. IA administration of 50 pmol AVT provoked quite similar increase in PDA, and elevation of the RR interval to those evoked by IA injection of UII but, in contrast to UII, AVT injection induced a highly significant and sustained prolongation of the QT interval compared to baseline (+7%, P<0.001) without change in QTc. Our results are indicative of a lack of QT interval change during UII-evoked bradycardia but not after AVT-induced bradycardia and suggest for the first time that some compensatory mechanism specific for the UII peptide is working to stabilize the QT interval. Further research is needed to elucidate the mechanism involved in this action of UII. The potential for UII to prevent detrimental prolongation of cardiac ventricular repolarization might be questioned., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (© 2015 The British Pharmacological Society.)

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., (© 2014 Wiley Periodicals, Inc.)

An 88-year-old man was admitted with fatigue, dizziness, and heart palpitations. Both the electrocardiogram and Holter confirmed the existence of sinus bradycardia and sinus arrest. One hour prior to the onset of symptoms, he received levobunolol hydrochloride solution topically. The levobunolol hydrochloride solution was discontinued and the bradycardia resolved. He was diagnosed as having intermittent sinus bradycardia and sinus arrest, induced by topical β-blocker therapy. Levobunolol hydrochloride solution is an effective therapy for ocular hypertension, probably by reducing aqueous fluid production. However, it can induce cardiac side effects such as bradyarrhythmia and should be used with caution in elderly patients or patients with cardiac disease.

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., (©2013 Wiley Periodicals, Inc.)

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., (©2013 Wiley Periodicals, Inc.)

Purpose: Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization., Methods: Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF)., Results: There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies., Conclusion: There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

Background: Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or a disproportional increase in HR during exercise. β-blocker or calcium channel-blocker therapy is often noneffective or not well tolerated. The HR reduction on ivabradine is similar to β-blockers but in some patients its efficacy to resolve all IST-related symptoms is limited. The aim of the study was to assess the efficacy and safety of combining ivabradine with metoprolol succinate in patients with refractory highly symptomatic IST., Methods: Twenty patients (36 ± 10 years; 16 women) with IST were enrolled. All patients received metoprolol succinate 95 mg single dose during the first month of the study. After 4 weeks of treatment with metoprolol, ivabradine was administered as adjuvant therapy up to 7.5 mg twice daily. Holter monitoring and treadmill stress test were performed at baseline, after 4, and 8 weeks of the study, respectively., Results: We observed significant and similar reduction in resting HR both for metoprolol and for combined therapy compared to the baseline. The mean HR during daily activity was significantly lower on ivabradine and metoprolol compared to monotherapy with β-blocker. The combined treatment yielded a significant increase in exercise capacity as assessed by treadmill stress test. After 4 weeks of combined therapy a significant reduction in IST-related symptoms, measured by means of the European Heart Rhythm Association score, was observed., Conclusion: Combining ivabradine with metoprolol is an effective and well-tolerated treatment option for IST in patients with refractory to monotherapy.

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., (©2013, Wiley Periodicals, Inc.)

Background: In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability., Objective: This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review., Data and Methods: 57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated. Only moxifloxacin and placebo arms, including their baselines, were considered. The options of using no baseline correction, time-averaged baseline correction, and time-matched baseline correction were examined and compared., Results: QTc values exhibited a diurnal pattern, with longer QTc intervals during sleep preserved when correcting for a time-averaged baseline. Post-dose and baseline QTc values were highly correlated (mean ρ = 0.80, range 0.56-0.98 and mean ρ = 0.79, range 0.50-0.96 in the placebo and moxifloxacin groups, respectively). The variability of raw QTc values was substantially larger than that of baseline-adjusted QTc values. The difference in the point estimate of QTc differences between moxifloxacin and placebo differed by up to ± 4 ms between the time-averaged and the time-matched baseline corrections. Statistical tests indicate that assumptions of time-averaged baseline and no baseline correction are not appropriate., Conclusions: Baseline correction in parallel TQT studies leads to more precise QTc estimates. Because of possible inaccuracy introduced by time-averaged baseline correction, the time-matched baseline correction appears to be preferable for a parallel TQT study to both reduce the intrinsic variability due to circadian patterns and obtain more accurate point estimates.

Objective: To investigate the influence of acid reflux on chest pain and ischemic events and the effects of cardiac drugs on acid reflux in patients with coronary artery disease (CAD) and refractory chest pain., Methods: Simultaneous 24-hour esophageal pH monitoring and 24-hour continuous electrocardiogram (ECG) (Holter) results were obtained for 64 patients. Ischemic events and cardiac drug prescriptions were compared between the patients with and without gastroesophageal reflux disease (GERD). Patients fulfilling the GERD criteria received 14-day therapy with omeprazole at a dose of 20 mg bid. The results of the 24-hour pH monitoring, Holter and the SF-36 questionnaire were compared before treatment and again after two weeks of therapy., Results: GERD was identified in 38 (69%) patients, with 49% of all chest pain occurring in association with acid reflux. A higher incidence (p=0.033) and longer duration (p=0.040) of ischemic events were observed in the GERD (+) patients. More frequent combined use of cardiac drugs was found in the GERD (+) patients. However, fewer ischemic events and greater total SF-36 survey scores were noted after PPI therapy in the GERD (+) patients., Conclusion: Acid reflux is common in patients with CAD and refractory chest pain. Refractory chest pain in patients with CAD can be partially noncardiac chest pain (NCCP) secondary to acid reflux. The combined use of common cardiac drugs may predispose or aggravate GERD. Short-term proton pump inhibitor (PPI) therapy not only restores a normal esophageal pH, but also significantly improves the general health-related quality of life (HRQL) of patients.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A 27-year-old male who had been on methadone therapy for 6 months was investigated with a 12-lead digital holter because of a prolonged QT on a standard 12-lead electrocardiogram (ECG). The patient had 24-hour holter recording on and off methadone therapy and multiple digitized 12-lead ECG data were captured for on-screen measurement of the QT interval. For each 24-hour period QT-HR pairs were plotted on the QT nomogram showing QT prolongation on methadone but not when it was ceased. This provides a highly accurate method for evaluating drug-induced QT prolongation.

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.

This study investigated the effect of eslicarbazepine acetate (ESL) on cardiac repolarization in healthy adult volunteers. A randomized, placebo/active-controlled, 4-period crossover study was conducted in 67 participants. In 3 periods, participants received once-daily doses of ESL 1200 mg, ESL 2400 mg, and placebo for 5 days; in 1 period, participants received placebo on days 1 to 4 and a 400-mg moxifloxacin single dose on day 5. In each period, 24-hour 12-lead Holter monitoring was performed on days -;1 (baseline) and 5. There was no clinically relevant effect of ESL 1200 mg and 2400 mg versus placebo on cardiac depolarization or repolarization as measured by the QRS or QTc intervals, respectively. Mean PR interval increased following ESL 1200 mg and 2400 mg, but there was no participant with a PR interval above the upper limit of the normal range (200 ms). The upper bound of the 95% confidence interval for the placebo-corrected change from baseline of the individually corrected QT interval (QTcI) following administration of ESL 1200 mg and ESL 2400 mg was <10 ms at every time point. Moxifloxacin caused an increase in QTcI above the 10-ms threshold for clinical significance at several time points, demonstrating assay sensitivity. It is concluded that administration of ESL 1200 mg and ESL 2400 mg did not induce a clinically significant prolongation of the QTcI interval., (2012 American College of Clinical Pharmacology.)

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.

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.

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 µg, aclidinium 800 µg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 µg, -1.8 milliseconds at 5 minutes for 800 µg, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 µg and were detected only up to 1 hour after the 800-µg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 µg, has a favorable cardiovascular safety profile with no effect on QT interval.

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.

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.

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.

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 epinephrine test has been shown to be a powerful tool to predict the genotype of congenital long QT syndrome (LQTS). The aim of this study was to evaluate its role in the diagnosis and management of LQTS in children. The test (using the Shimizu protocol) was conducted in patients with some evidence of LQTS but in whom clinical and management decisions were challenging (n = 41, age 9.6 +/- 3.9 years, 19 female). LQT1, LQT2, and negative responses to epinephrine were obtained in 16, 5, and 20 subjects, respectively. LQTS gene positivity was obtained in two subjects. Beta-blocker therapy was started in all subjects with a positive epinephrine response (n = 21) and in some negative responders because of their strong LQTS phenotype (n = 10). No therapy was given to the subset with less convincing features of LQTS who had also responded negatively to epinephrine (n = 10). Follow-up for 3.0 +/- 2 years was uneventful in both management groups. Due to the discordance with genotyping, the epinephrine test cannot be used to diagnose genotype-positive LQTS but when used in combination with phenotype assessment and genetic screening, it could enable better management decisions.

Unlabelled: URGENCY: Frequency of warm reductions (FWR) is the independent risk factor increasing frequency of the general death rate, sudden death rate and death rate from cardiovascular diseases. Aim of the work was to study dynamics of parameters of cardiovascular system in Patients with Stable Angina (SA) and Congestive Heart Failure (CHF) treated with Ivabradin within six months were investigated., Materials and Methods: 78 patients having symptoms of SA and CHF and also FWR more than 70 per 1 minute treated the maximum dose blokatorov, are divided into 2 groups. The patient of the first group (40 people) to standard therapy was added ivabradin. Patients of the second group (38 people) received the standard treatment of a SA and CHF. Before and after six months of the treatment the following findings were evaluated: the 6 minute walk test results, echocardiographic parameters, of heart rate variability (HRV), von Willebrand factor, endothelium dependent and independent vasodilation, main arteries rigidity., Results: The complex therapy including ivabradin, at examined patients promotes heart rate fall, to reduction of quantity of attacks of a stable angina and number of the accepted tablets of nitroglycerine, increase of CHF functional class, increase in shock volume left ventricular (LV) and certainly diastolichesky volume LV, to decrease in activity of the factor of Willebrand, quality of life. Indicators of HRV, endothelium dependent and independent vasodilation, main arteries rigidity during against 6 monthly therapies improve, but do not reach reliability degree.

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.

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.

Background: Alcohol intoxication is associated with deterioration of cardiac nervous function and increased mortality., Patients and Methods: Therefore, 14 patients (eight male, six female; 24-59 years) with pure ethanol intoxication and toxic levels of 210-520 mg/dl in the blood were prospectively investigated. For evaluation of changes in sympathetic and vagal modulation, an analysis of heart rate variability (HRV) was performed., Results: The results show that HRV in general is suppressed in dependence on blood alcohol levels. Most correlation was found in short-term variability of frequency domain (HF power) after logarithmic transformation (p < 0.001). Also the discrimination of moderate versus severe intoxication was greatest in HF power (p < 0.001). During recovery, all HRV parameters increased to significantly higher figures within 24 h (p < 0.001), but elevated LF/HF ratio as a sign of sympathetic predominance continued over the whole observation period (p < 0.001 to reference). Regarding the danger of possibly life-threatening arrhythmias, the LF/HF ratio showed significantly increased figures in the period of maximal development of supraventricular and ventricular arrhythmias (p = 0.001 to 24-h mean of LF/HF)., Conclusion: These results underline the longer-lasting hyperadrenergic state during "holiday heart syndrome". The still depressed cardiac autonomic nervous system after 24 h, especially in the vagal activity-describing part, might be basically relevant for later occurrence of cardiovascular complications, if additional trigger factors become present.

We conducted a retrospective study of a set of previously published electrocardiographic data to investigate the possible direct association between levels of particulate air pollution and changes in ventricular repolarization -- the cardiac electrophysiologic process that manifests itself as the T wave* of the electrocardiogram (ECG) and that is definitively linked to and responsible for increased arrhythmogenesis. The published findings from this data set demonstrated a clear cardiac effect, namely, a reduction in heart rate variability (HRV) parameter values with increased levels of particulate air pollution (Pope et al. 2004), suggesting possible arrhythmogenic effects. Given this positive finding and the well-established sensitivity of cardiac repolarization to physiologic, pharmacologic, and neurologic interventions, and in light of emerging novel tools for assessing repolarization, we hypothesized that high levels of particulate air pollution would alter repolarization independent of changes in heart rate and, consequently, would increase arrhythmogenic risk. The likely mechanism of any deleterious effects on repolarization would be alteration of sodium, calcium, and potassium channels. The channel's structure, function, and kinetics are responsible for generating the cellular action potentials, which, when summed over the entire heart, result in the waves recorded by the ECG. A positive finding would provide evidence that increased levels of air pollution may be directly linked to increases in arrhythmogenic risk and, potentially, sudden cardiac death. The study population consisted of 88 nonsmoking, elderly subjects in whom multiple, continuous, 24-hour, 2-channel ECG recordings were collected, along with blood samples to evaluate inflammatory mechanisms (not pursued in the current study). The concentration of fine particulate matter (PM2.5, particulate matter with an aerodynamic diameter < or = 2.5 microm) in daily samples was measured or estimated and used to trigger recording sessions for days considered to have "low" or "high" PM2.5 concentrations. Each subject participated in one to five recordings over the study period, and all subjects lived within the greater Salt Lake Valley in Utah. We reanalyzed these recordings using custom software that incorporated a magnitude function of the ECG -- the root mean square of all recorded leads (RMS ECG) -- to determine the following for each beat in the 24-hour recording: cycle length (RR); RR dispersion; the interval between the RMS R- and T-wave peaks (RT), a robust estimate of mean duration of ventricular action potential; the width of the RMS T wave (TW), a robust estimate of the range of repolarization times that relates to repolarization dispersion and arrhythmogenesis; the RMS QT interval (QT) measured from the QRS onset to T-wave offset of the RMS ECG; and the regression slopes of RT versus RR, QT versus RR, and TW versus RR, which provide estimates of so-called repolarization restitution, or rate dependency of repolarization, which also is associated with arrhythmogenesis. The study findings did not support the original hypothesis and demonstrated a lack of sensitivity of repolarization to changes in PM2.5 concentrations. None of the repolarization variables showed a statistically significant change between days of low and high PM2.5 concentrations, although we observed statistically significant differences for some variables using fixed-effects modeling. However, we did find a significant decrease in the standard deviation of cycle length, in concert with findings in the original study that showed a decrease in HRV parameter values. There was a slight but statistically insignificant increase in the width of the TW between recordings from days of low and days of high PM2.5, suggesting that, in a setting of prolonged exposure to high levels of PM, the original hypothesis might be supported. We conclude that in this study the short-term (day-today) differences in air pollution, specifically PM2.5 concentration, did not affect ventricular repolarization. A likely explanation for the negative result is that the day-today variability of repolarization (arising from autonomic influences, activity, and heart rate) far outweighs the changes that might be induced by air pollution, if any. In addition, the study may have been underpowered. The findings do not refute the possibility of the deleterious repolarization effects of PM, particularly over prolonged periods of exposure, but suggest the need for exposure studies that provide better controls. In light of recent studies, it is also likely that in an at-risk population -- for example, patients compromised with heart disease -- repolarization changes may be more apparent.

Background: Amitriptyline is one of the major tricyclic antidepressants, and the data on amitriptyline poisoning in children are limited., Objectives: To present our experiences with amitriptyline poisoning in children, particularly with regard to its effects on electrocardiogram (ECG) and relation with clinical status., Methods: Clinical, laboratory, and electrocardiographic findings in 52 children admitted with amitriptyline poisoning were reviewed. Patients were divided into 2 groups according to age, as 6 years or younger (group A) and older than 6 years (group B)., Results: Mean age was 4.6 +/- 3.0 years. Thirty-one patients were male, and 41 were 6 years or younger. Ingested amitriptyline dose was known in 23 patients (range, 2.3 mg/kg-27 mg/kg). The most frequent findings were lethargy (76.9%), sinus tachycardia (57.7%), and coma (48.1%). Four patients had a history of convulsion. The most common laboratory abnormalities were hyponatremia (26.9%) and leukocytosis (25%). Elevated transaminase levels were observed in 4 patients. In ECG, 11 (22.4%) patients had QTc prolongation and in 4 (8.2%) of them, it was significant. In 4 patients (8.2%), the QRS duration was 100 ms or longer and in 15 patients, the R wave in aVR was 3 mm or longer. The frequencies of clinical, laboratory, and electrocardiographic findings were similar between the 2 age groups (P > 0.05). No clinically apparent arrhythmias were observed. The positive predictive value of a widened QRS was 100% in terms of coma. None of the patients with an R wave in aVR of less than 3 mm developed convulsion; thus, the negative predictive value of an R wave in aVR of 3 mm or longer was 100% in terms of convulsion., Conclusions: Amitriptyline poisoning may result in severe toxicity. Frequencies of clinical, laboratory, and ECG findings were similar in the 2 age groups. Amitriptyline overdose results in some ECG changes that can possibly help to predict the results of poisoning. Absence of an R wave in aVR of 3 mm or longer predicts seizures with a high negative predictive value, and a QRS duration of 100 or longer ms predicts coma with a high positive predictive value.

Background: Reliable, automated QT analysis would allow the use of all the ECG data recorded during continuous Holter monitoring, rather than just intermittent 10-second ECGs., Methods: BioQT is an automated ECG analysis system based on a Hidden Markov Model, which is trained to segment ECG signals using a database of thousands of annotated waveforms. Each sample of the ECG signal is encoded by its wavelet transform coefficients. BioQT also produces a confidence measure which can be used to identify unreliable segmentations. The automatic generation of templates based on shape descriptors allows an entire 24 hours of QT data to be rapidly reviewed by a human expert, after which the template annotations can automatically be applied to all beats in the recording., Results: The BioQT software has been used to show that drug-related perturbation of the T wave is greater in subjects receiving sotalol than in those receiving moxifloxacin. Chronological dissociation of T-wave morphology changes from the QT prolonging effect of the drug was observed with sotalol. In a definitive QT study, the percentage increase of standard deviation of QT(c) for the standard manual method with respect to that obtained with BioQT analysis was shown to be 44% and 30% for the placebo and moxifloxacin treatments, respectively., Conclusions: BioQT provides fully automated analysis, with confidence values for self-checking, on very large data sets such as Holter recordings. Automatic templating and expert reannotation of a small number of templates lead to a reduction in the sample size requirements for definitive QT studies.

Background: Concern for drug-induced QT prolongation has caused significant investment in QT measurement to safety-test new compounds. Manual methods are expensive and time-consuming. Reliable automatic methods would be highly desirable., Methods: Twelve-lead Holter recordings were annotated beat-to-beat by an automatic algorithm for global QRS onset and T offset. T offset was established from the time of peak T downslope plus a rate-dependent offset, analogous to the "tangent method," wherein T offset is determined by extrapolating the T downslope to an intersection with the baseline., Results and Conclusions: Variances of the beat-to-beat QT measurements were in the range 2.5-3.4 ms over three distinct databases, including a large heart failure database. Application to a moxifloxacin/placebo control database of 29 subjects showed excellent results.

Effect of therapy with 1-adrenoblocker bisoprolol and inhibitor of If channels ivabradine on parameters of 24-hour ECG monitoring (24hECGM) was studied in 64 patients with ischemic heart disease (stable angina) and chronic obstructive pulmonary disease (COPD). At the first stage all patients received bisoprolol. Parameters of external respiration function (ERF) and 24h ECG were registered before and after 4 months of bisoprolol administration. At stage 2 indications were determined for inclusion of ivabradine in the treatment scheme. At the background of therapy with bisoprolol we obtained significant lowering of heart rate (HR) both during day and night, as well as significant diminution of magnitude and duration of ischemic ST depression. In 44% of patients target HR range was not achieved. This conditioned the necessity to administer ivabradine. Therapy of patients with stable angina and concomitant COPD should begin with cardioselective -adrenoblockers (bisoprolol). Incorporation of inhibitor of If channels ivabradine in the treatment scheme is indicated if during treatment with -adrenoblockers average 24 hour HR according to data of 24hECGM exceeds 70 beats/min and deterioration of bronchial conductance according to ERF data occurs.

Introduction: Following the Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps) (French Health Authority) recommendations in 2001, which impose the rigorous follow-up (electrocardiogram [ECG] and ionogram) of patients treated with antipsychotics (AP), a monitoring protocol was elaborated and set up in the Caen psychiatric hospital in April 2002. Protocol evaluation compared with fixed aims was performed after two years' follow-up., Aim of the Study: This protocol had to answer a triple aim: better identification of patients at risk, ensure in-treatment monitoring, be simple and adapted to daily practice., Inclusion Criteria: A systematic admission check-up (S0) which includes cardiological and biological controls and after one and six months' treatment control (S1 and S6) were recommended. The major risk factors (RF) researched were long QT interval, bradycardia and hypokaliemia., Results: The initial monitoring was conducted in 601 patients (that only corresponded to 17% of hospital admission active files during the considered period). Means delays before obtaining an ECG were three times those obtained existing biological check-ups (11 days versus three days after date of admission). Systematic and integrated characterisation controls on admission were not respected. We noted that two-third of patients admitted during this period were hospitalized for only five days, although the mean time to obtain an ECG is of 11 days. This delay (approximately one week) between ECG and biological check-up is not compatible with a complete patient RF evaluation. Respectively, 83 and 68 patients were controlled under treatment at S1 and S6. Only half of the patients were controlled at the one-month (S1) and 16% at the six-months' theoretical dates (S6). These delays are inappropriate, notably with regard to the mean time of hospitalisation (15-17 days). The incidence of major RF was higher in treated (71%) than in non-treated patients. Major RF presence at S0 was not systematically associated with an AP treatment contraindication. The excessive delay before the first ECG could partially explain why this initial check-up was not able to detect a pretreatment contraindication. On the other hand, AP treated patients who presented at least one major RF at S0 were more frequently monitored at S1 than patients who did not (26% versus 13%, p=0.05). Among the 168 patients treated with AP or other drugs prolonging the QT interval at risk, 33 had at least one follow-up. This risk population was not better controlled than the initial cohort., Discussion: Protocol evaluation is essential to improve its interest and feasibility. If systematic characterisation is simple, its application in practice is very difficult. The second version of the protocol presented here proposes to substitute the systematic ECG characterisation with the classification on admission of patients in "risk groups" that will condition the subsequent monitoring. Risk groups are identified into two RF types: those which are not related to AP treatment and those which are therapeutic attitude is adapted according to initial QTcorrigé (QTc), its progression between S0 and S (seven days) and kaliemia.

The agents used for nuclear stress testing (NST) including adenosine, dobutamine, and dipyridamole, are generally well tolerated and the incidence of serious complications associated with their use in NST is relatively low. Adenosine possesses a potent inhibitory effect on the atrioventricular (AV) node and may induce a transient conduction defect which could result in first-, second-, or third-degree heart block in some patients. The use of the potent AV nodal blocker adenosine for nuclear stress testing in patients with evidence of underlying conduction system disease may result in serious complications. We present the case of a 79-year-old man who had sustained second-degree AV block requiring permanent pacemaker implantation following adenosine infusion for nuclear stress testing. We also review the literature regarding the association between adenosine NST and AV block.

Background: In patients with cardiac sarcoidosis, ventricular arrhythmias and/or conduction disturbances are frequently observed and sometimes fatal. However, few reports on disease activity and arrhythmic events in cardiac sarcoidosis are available., Objective: The purpose of this study was to investigate the relationship between disease activity and arrhythmic events in cardiac sarcoidosis and the effect of corticosteroid therapy., Methods: The study population consisted of 15 cardiac sarcoidosis patients with new-onset symptomatic arrhythmia, including eight patients admitted once for complete atrioventricular block (CAVB), five patients admitted once for sustained ventricular tachycardia (VT), and two patients admitted twice for two arrhythmic events (one for CAVB and the other for sustained VT). Disease activity was evaluated by gallium-67 citrate (Ga) scintigraphy. All patients with positive Ga uptake were treated with corticosteroids, and arrhythmic events were evaluated by repeat Holter recordings., Results: Positive uptake of Ga was observed in 8 (80%) of the 10 CAVB events and in 1 (14%) of the 7 sustained VT events (80% vs 14%, P = .02). Corticosteroids abolished myocardial Ga uptake in all nine patients with positive Ga uptake. After corticosteroid therapy was started, AV conduction improved in 5 of 9 CAVB patients (including 8 patients with new-onset CAVB and one patient with history of CAVB). However, ventricular arrhythmias were not improved after corticosteroid therapy., Conclusion: In cardiac sarcoidosis patients, CAVB develops mainly during the active phase of the disease. Early treatment with corticosteroids might improve AV conduction disturbance. However, sustained VT is not closely linked with disease activity and frequently develops in the advanced stage of disease.

Several studies in conscious animals have reported parasympathetic dysfunction in the eyes following exposure to cholinesterase inhibitors. Given the similarities between the autonomic innervation in the eye and the heart, it is possible that parasympathetic dysfunction could also occur in the heart. Therefore, the present study assessed time domain indices of heart rate variability in conscious rats surgically implanted with telemetric transmitters to investigate the hypothesis that multiple exposures to the nerve agent sarin would result in muscarinic receptor desensitization and parasympathetic dysfunction in the heart. Animals exposed to sarin vapor on multiple occasions developed parasympathetic dysfunction in the eye characterized by an attenuated response to light and a diminished miotic response to sarin vapor exposure. However, the same dose of sarin vapor failed to produce any effects on either time domain indices of HRV or the magnitude of the tachycardia induced by atropine, suggesting that autonomic control in the heart was not affected. It is possible that the dose of sarin used in the present study was insufficient to inhibit cardiac acetylcholinesterase (AChE). Additional studies utilizing higher doses of sarin may be able to inhibit cardiac AChE, producing overstimulation of cardiac muscarinic receptors, ultimately resulting in desensitization and parasympathetic dysfunction.

Background: Inhalational anesthetics may prolong QTc interval (QT interval corrected for heart rate) of the ECG and cause life-threatening arrythmias. The effects of desflurane on QTc interval and cardiac rhythm have not been reported previously in children. We assessed the effects of desflurane anesthesia on QTc interval and cardiac rhythm and compared them with sevoflurane anesthesia in children., Methods: The study was performed on 20 children admitted for inguinal hernia repair, with normal QTc intervals. Anesthesia was induced with propofol and intubation was achieved with vecuronium. Anesthesia was maintained with 2% sevoflurane (group I, n = 11) or 6% desflurane (group II, n = 9) and 66% nitrous oxide in oxygen. Electrocardiogram recordings were obtained by Holter recorder. QTc intervals were measured at baseline, 5, 10, 15, and 30 min after inhalation., Results: None of the patients had significant arrythmia with desflurane anesthesia. One patient in the sevoflurane group had single, bigemini and multiform ventricular extrasystoles. There was no statistically significant difference in the baseline QTc values of the groups. Desflurane significantly prolonged QTc interval 5 min after induction until 30 min of anesthesia compared with baseline values (P = 0.029), while no significant prolongation was observed with sevoflurane (P = 0.141)., Conclusions: Use of 2% sevoflurane during maintenance of anesthesia does not significantly prolong QTc interval while 6% desflurane significantly prolonged QTc interval in children with normal QTc interval undergoing inguinal herniorrhaphy.