Electrocardiographic imaging of the arrhythmogenic substrate of Brugada syndrome: Current evidence and future perspectives.

Brugada syndrome is responsible for about 20% of sudden cardiac deaths in patients with apparently normal hearts. Basic and clinical research has elucidated some of the mechanisms that are responsible for life-threatening ventricular arrhythmias in this syndrome. Delays in activation and repolarization over the right ventricular outflow tract are the most likely cause of the ECG typical pattern and arrhythmogenesis. Invasive epicardial and endocardial mapping has identified the epicardium as the principal region of interest for these anomalies, and areas of fragmented potentials at invasive mapping are a target for epicardial ablation. Noninvasive mapping systems have been developed to study the epicardial depolarization and repolarization and may be particularly useful in assessing the epicardial arrhythmogenic substrate of Brugada syndrome for both clinical and research purpose. This review focuses on recent advances in this field.

Myo-inositol and d-chiro-inositol oral supplementation ameliorate cardiac dysfunction and remodeling in a mouse model of diet-induced obesity.

Obesity is an independent risk factor to develop cardiac functional and structural impairments. Here, we investigated the effects of supplementation of inositols on the electrical, structural, and functional cardiac alterations in the mouse model of high fat diet (HFD) induced obesity. Three groups of C57BL6 mice (n = 16 each) were studied: j) HFD feeding; jj) HFD feeding + inositols from week 9 to 13; jjj) standard diet feeding. Study observation period was 13 weeks. Inositols were administered as mixture of myo-inositol and d-chiro-inositol in the drinking water. Effects of inositols were evaluated based on electrical, structural, and functional cardiac features, autonomic sympatho-vagal balance and arrhythmogenic susceptibility to adrenergic challenge. Heart samples were collected for histological evaluations and transcriptional analyses of genes involved in defining the shape and propagation of the action potential, fatty acid metabolism and oxidative stress. Inositol supplementation significantly restored control values of heart rate and QTc interval on ECG and of sympatho-vagal balance. Moreover, it blunted the increase in left ventricular mass and cardiomyocyte hypertrophy, reversed diastolic dysfunction, reduced the susceptibility to arrhythmic events and restored the expression level of cardiac genes altered by HFD. The present study shows, for the first time, how a short period of supplementation with inositols is able to ameliorate the HFD-induced electrical, structural and functional heart alterations including ventricular remodeling. Results provide a new insight into the cardioprotective effect of inositols, which could pave the way for a novel therapeutic approach to the treatment of HFD obesity-induced heart dysfunction.

Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium.

Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J-Tpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of Tpeak-Tend, whereas J-Tpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J-Tpeakc was prolonged by each dose, but Tpeak-Tend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.

Vein of Marshall ethanol infusion for persistent atrial fibrillation: VENUS and MARS clinical trial design.

BACKGROUND: Although pulmonary vein isolation (PVI) is effective in the treatment of paroxysmal atrial fibrillation (AF), its success rates in persistent AF are suboptimal. Ablation strategies to improve outcomes including additional lesions beyond PVI have not consistently shown benefit. Recurrence as perimitral flutter (PMF) is a common form of ablation failure. The vein of Marshall (VOM) contains myocardial connections and abundant sympathetic and parasympathetic innervation implicated in the genesis and maintenance of AF, and is anatomically co-localized with the mitral isthmus, the ablation target of PMF. VOM ethanol infusion is effective in targeting these arrhythmia substrates. OBJECTIVE: To test the safety and efficacy of VOM ethanol infusion when added to PVI in patients undergoing either de novo ablation of persistent AF or after a previous ablation failure. STUDY DESIGN: VENUS-AF and MARS-AF are prospective, multicenter, randomized, controlled trials. VENUS-AF will enroll patients undergoing their first catheter ablation of persistent AF. MARS-AF will enroll patients undergoing ablation after previous ablation failure(s). Patients (n = 405) will be randomized to PVI alone or in combination with VOM ethanol infusion. The primary endpoints include procedural safety and freedom from AF or atrial tachycardia (AT) of more than 30 seconds on 30-day continuous event monitors at 6 and 12 months after randomization procedure (single-procedure success), off antiarrhythmic drugs. Key secondary endpoints include AF burden, freedom from AF/AT after repeat procedures and quality of life. CONCLUSIONS: The VENUS-AF and MARS-AF will determine the safety and potential rhythm control benefit of VOM ethanol infusion when added to PVI in patients with persistent AF undergoing de novo or repeat ablation, respectively.

Flecainide Versus Procainamide in Electrophysiological Study in Patients With Syncope and Wide QRS Duration.

OBJECTIVES: This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients with syncope and bundle branch block (BBB). BACKGROUND: Patients with syncope and BBB are at risk of developing atrioventricular block. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal His-ventricular interval. There is little data on differences between different class I drugs. METHODS: This was a prospective study of all consecutive patients undergoing EPS for syncope and BBB at a single center (January 1, 2012 to June 30, 2017). Of those patients with negative baseline EPS, 2 cohorts were compared: group A (historical cohort: procainamide) and group B (flecainide). RESULTS: During the study, 271 patients (age 73.9 ± 12.1 years, 64.9% male, QRS duration: 139.4 ± 13.9 ms) underwent EPS. In 166, baseline EPS was negative and class I drug challenge was performed (90 procainamide, 76 flecainide). The final value and percentage increase in the His-ventricular interval (76 ± 16 ms vs. 64 ± 10 ms and 22.5 ± 6.2% vs. 11.8 ± 5.3%; p < 0.001) and diagnostic yield (14.5% vs. 7.8%, p = 0.04) were higher with flecainide. No differences were found in baseline characteristics. During follow-up (25.8 ± 6.3 months), 39 patients (24.8%) with negative EPS (19.2% with flecainide vs. 30.1% with procainamide: relative risk: 5.1; 95% confidence interval: 2.6 to 10.2; p < 0. 001) received a pacemaker. CONCLUSIONS: Flecainide has a higher diagnostic yield than does procainamide in patients with BBB, syncope, and negative baseline EPS due to a greater increase of the His-ventricular interval. Additionally, there is a lesser need for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.

Moderate alcohol consumption is associated with atrial electrical and structural changes: Insights from high-density left atrial electroanatomic mapping.

BACKGROUND: Regular alcohol intake is an important modifiable risk factor associated with atrial fibrillation (AF) and left atrial (LA) dilation. OBJECTIVE: The purpose of this study was to determine the impact of different degrees of alcohol consumption on atrial remodeling using high-density electroanatomic mapping. METHODS: We enrolled 75 patients before AF ablation to undergo high-density LA mapping (CARTO, Biosense Webster) using a multipolar catheter. The Confidense algorithm was used to create maps during distal coronary sinus pacing at 600 ms. Bipolar voltage and complex atrial activity were assessed, and isochronal activation maps were created to determine global conduction velocity (CV). Patients were classified as lifelong nondrinkers, mild drinkers (2-7 drinks/week), or moderate drinkers (8-21 drinks/week). RESULTS: High-density electroanatomic mapping (mean 1016 ± 445 points per patient) was performed on 25 lifelong nondrinkers, 25 mild drinkers (4.4 ± 2.3 drinks/week), and 25 moderate drinkers (14.0 ± 4.2 drinks/week). Moderate drinkers had significantly lower mean global bipolar voltages (1.53 ± 0.62 mV vs 1.89 ± 0.45 mV; P = .02), slower CV (33.5 ± 14.4 cm/s vs 41.7 ± 12.1 cm/s; P = .04), and a higher proportion of complex atrial potentials (7.8% ± 4.7% vs 4.5% ± 2.7%; P = .004) compared to nondrinkers. Global voltage and CV did not differ significantly in mild drinkers, but there was a significant increase in global complex potentials (6.6% ± 4.6%; P = .04) and regional low-voltage zones (<0.5 mV) in the septum and lateral wall (P <.05) compared with nondrinkers. CONCLUSION: Regular moderate alcohol consumption, but not mild consumption, is an important modifiable risk factor for AF associated with lower atrial voltage and conduction slowing. These electrical and structural changes may explain the propensity to AF in regular drinkers.

Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine.

BACKGROUND: Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca2+) cycling abnormalities. Late sodium current (INa,L) is enhanced in HF and promotes Ca2+ overload; however, mechanisms underlying an antiarrhythmic effect of INa,L blockade in HF remain unclear. OBJECTIVE: The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca2+ cycling. METHODS: Transmural dual optical mapping of Ca2+ transients and action potentials was performed in wedge preparations from 8 HF and 8 control (normal) dogs. Susceptibility to action potential duration alternans (APD-ALT) and Ca2+ transient alternans (Ca-ALT) was compared at baseline and with ranolazine (5-10 µM). RESULTS: HF increased APD- and Ca-ALT compared to normal (both P <.05), and ranolazine suppressed APD- and Ca-ALT in both groups (P <.05). The incidence of spatially discordant alternans (DIS-ALT) was increased by HF (8/8) compared to normal (4/8; P <.05), and ranolazine decreased DIS-ALT in HF (4/8; P <.05).Not only did ranolazine mitigate HF-induced Ca2+ overload, it also attenuated APD-ALT to Ca-ALT gain (amount of APD-ALT produced by Ca-ALT). In HF, APD-ALT to Ca-ALT gain was significantly increased (0.55 ± 0.02) compared to normal (0.44 ± 0.02; P <.05) and was normalized by ranolazine (0.36 ± 0.05; P <.05), representing a complementary mechanism by which INa,L blockade suppressed cardiac alternans. CONCLUSION: Ranolazine attenuated arrhythmogenic cardiac alternans in HF, both by suppressing Ca-ALT and decreasing the coupling gain of APD-ALT to Ca-ALT. Blockade of INa,L may reverse impaired Ca2+ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of INa,L blockade in HF.

Slow Potential at the Entrance of the Slow Conduction Zone in the Reentry Circuit of a Verapamil-Sensitive Atrial Tachycardia Originating From the Atrioventricular Annulus.

BACKGROUND: Slow conduction zone in a verapamil-sensitive reentrant atrial tachycardia originating from atrioventricular annulus is composed of calcium channel-dependent tissue. We examined whether there was a slow potential (SP) at the entrance of the slow conduction zone. METHODS AND RESULTS: We first identified the pacing site from where manifest entrainment and orthodromic capture of the earliest atrial activation site were demonstrated in 40 atrioventricular annulus patients with atrioventricular annulus. Radiofrequency energy was then delivered 2 cm proximal to the earliest atrial activation site in the direction of entrainment pacing site and gradually advanced toward the earliest atrial activation site until atrial tachycardia termination to localize the entrance of the slow conduction zone. Electrogram characteristics were analyzed at successful and unsuccessful ablation sites. During sinus rhythm, SP was observed at all 40 successful sites, but was observed at only 12 unsuccessful sites (P<0.0001). During sinus rhythm, there was no significant difference in electrogram amplitude nor width of atrial electrogram between successful and unsuccessful sites (0.407±0.281 versus 0.487±0.447 mV [P=0.1989] and 37.0±9.2 versus 38.9±8.0 ms [P=0.1773]); however, SP amplitude and width at successful sites were significantly greater than those at unsuccessful sites (0.110±0.049 versus 0.025±0.046 mV [P<0.0001] and 38.8±13.4 versus 8.1±13.2 ms [P<0.0001]). During atrial tachycardia, SP amplitude was significantly attenuated (0.088±0.042 versus 0.110±0.049 mV, P<0.001) and SP width was significantly prolonged (47.8±14.1 versus 38.8±13.4 ms, P<0.0001) at successful sites. CONCLUSIONS: SP was observed during sinus rhythm at the entrance of the slow conduction zone; however, SP amplitude was attenuated and SP width was prolonged during atrial tachycardia, suggesting that SP reflects the characteristics of calcium channel-dependent tissue involved in atrioventricular annulus reentry circuit.

Probing flecainide block of INa using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch-clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization. Automated current- and voltage-clamping, with an overall success rate of 55.0 ±â€¯11.3%, indicated that 90% of hPSC-CMs displayed ventricular-like action potential (AP) and the ventricular cardiomyocytes (VCMs) derived from the two hESC lines expressed similar levels of INa, ICaL, Ikr and If and similarly lacked Ito and IK1. These well-characterized hPSC-VCMs could also be readily adapted for automated assays of pro-arrhythmic drug screening. As an example, we showed that flecainide (FLE) induced INa blockade, leftward steady-state inactivation shift, slowed recovery from inactivation in our hPSC-VCMs. Since single-cell EP assay is insufficient to predict drug-induced reentrant arrhythmias, hPSC-VCMs were further reassembled into 2D human ventricular cardiac monolayers (hvCMLs) for multi-cellular electrophysiological assessments. Indeed, FLE significantly slowed the conduction velocity while causing AP prolongation. Our RNA-seq data suggested that cell-cell interaction enhanced the maturity of hPSC-VCMs. Taken collectively, a combinatorial approach using single-cell EP and hvCMLs is needed to comprehensively assess drug-induced arrhythmogenicity.

Therapy Of Cardiac Arrhythmias In Children: An Emerging Role Of Electroanatomical Mapping Systems.

INTRODUCTION: Cardiac arrhythmias are challenging diseases in childhood. Most of them in pediatric subjects (90.2%) are atrioventricular reentrant tachycardias and atrioventricular nodal reentrant tachycardias. The standard 12-lead ECG is a highly accurate diagnostic tool but an invasive electrophysiological study is often required. The main concern about this kind of procedures is their invasive nature and the need of radiations, so antiarrhythmic agents are currently the first line therapy. However, they often show side effects and can be insufficient for the rate control. MATERIALS AND METHODS: We performed a systematic research on Embase and PubMed. We found 563 articles and selected the most representative 50. DISCUSSION: Management of cardiac arrhythmias could be very difficult in several scenarios, especially in children with body weight <15 kg and age <4 years. In general, pediatric subjects show a cumulative risk of malignancy greater than adults, having greater life expectancy. On this basis the guiding principle during radiation delivery in electrophysiological procedures is "as low as reasonably achievable" (acronym: ALARA). The development of 3-dimensional (3D) electroanatomical mapping systems allowed significant reduction of exposure. The most recently reported experiences demonstrate safety and feasibility of fluoroless ablation in the most common arrhythmias in children, even in challenging conditions. CONCLUSION: The first reasonable approach in cardiac arrhythmias involving younger patients seems to be pharmacological. However antiarrhythmic drugs pose problems both in terms of side effects and often have poor efficacy. Expertise in electrophysiological techniques is constantly increasing and the development of new technologies allow us to encourage the use of electroanatomical mapping systems in order to reduce the radiation exposure in children undergoing to catheter ablation, especially for accessory pathways.

Intralesional versus intracoronary administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention in patients with acute coronary syndromes: A meta-analysis of randomized controlled trials.

BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) have been regarded as an adjuvant regimen to deal with no-reflow. However, whether intralesional (IL) administration of GPIs improves myocardial reperfusion without increasing bleeding in patients with acute coronary syndrome (ACS) compared with intracoronary (IC) administration has not been well addressed. Our meta-analysis aimed to evaluate the efficacy and safety of IL versus IC administration of GPIs for patients with ACS during percutaneous coronary intervention. METHODS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and Cambridge Scientific Abstracts from January 2007 to May 2017. Thrombolysis in Myocardial Infarction (TIMI) 3 flow, corrected TIMI frame count (CTFC), and complete ST-segment resolution (>70%) were selected as the primary outcomes. Major adverse cardiac events (MACEs) were the secondary outcome, and major bleeding complications were the safety outcome. Data analysis was conducted using the Review Manager 5.3 software. RESULTS: Six randomized controlled trials were included in our meta-analysis. Compared with IC, IL obtained better results in terms of TIMI grade 3 flow [odds ratio (OR) 2.29; 95% confidence intervals (CIs) 1.31-4.01; P = .004], CTFC [weighted mean difference (WMD) -4.63; 95% CI -8.82 to -0.43; P = .03], and complete ST-segment resolution (OR 1.55; 95% CI 1.12-2.14; P = .008). There was a trend toward decreased MACE in the IL administration groups, which was not of statistical significance (OR 0.63; 95% CI 0.30-1.31; P = .22). No significant difference was found between the two groups in terms of in-hospital major bleeding events (OR 2.52; 95% CI .66 to 9.62; P = .18). CONCLUSION: IL administration yielded favorable outcomes in terms of myocardial tissue reperfusion as evidenced by the improved TIMI flow grade, CTFC, complete ST-segment resolution, and decreased MACE without increasing in-hospital major bleeding events. The IL administration of GPIs can be recommended as the preferred regimen to guard against no-reflow.

Cardiologist's point of view: Novel ECG biomarkers and in silico models for proarrhythmic risk prediction: Are we ready?

The CiPA initiative is well underway, but in its early stages. Are we ready for it? There are several issues that bear on the success of this multidisciplinary effort related to (1) the final testing paradigm that will result, (2) the way in which discrepancies in test methods will be handled, (3) commercialization of the testing methods, (4) quantitative understanding of arrhythmia risk of the 6 non-hERG channels being tested, (5) validity of the CiPA drug list, and (6) ultimate clinical validation.

Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative.

Voltage gated ion channels are central in defining the fundamental properties of the ventricular cardiac action potential (AP), and are also involved in the development of drug-induced arrhythmias. Many drugs can inhibit cardiac ion currents, including the Na+ current (INa), L-type Ca2+ current (Ica-L), and K+ currents (Ito, IK1, IKs, and IKr), and thereby affect AP properties in a manner that can trigger or sustain cardiac arrhythmias. Since publication of ICH E14 and S7B over a decade ago, there has been a focus on drug effects on QT prolongation clinically, and on the rapidly activating delayed rectifier current (IKr), nonclinically, for evaluation of proarrhythmic risk. This focus on QT interval prolongation and a single ionic current likely impacted negatively some drugs that lack proarrhythmic liability in humans. To rectify this issue, the Comprehensive in vitro proarrhythmia assay (CiPA) initiative has been proposed to integrate drug effects on multiple cardiac ionic currents with in silico modelling of human ventricular action potentials, and in vitro data obtained from human stem cell-derived ventricular cardiomyocytes to estimate proarrhythmic risk of new drugs with improved accuracy. In this review, we present the physiological functions and the molecular basis of major cardiac ion channels that contribute to the ventricle AP, and discuss the CiPA paradigm in drug development.

Heart rate, blood pressure and repolarization effects of an energy drink as compared to coffee.

The goal of this study was to investigate the impact of energy drinks on haemodynamic and cardiac physiology. Comparisons were made to coffee as well as water consumption. In Protocol #1 the caffeine content was normalized to body weight to represent a controlled environment. Heart rate, blood pressure and cardiac QTc interval were assessed in 15 participants, on 4 days, prior to and for 6·5 h postconsumption of (i) energy drink (2 mg caffeine per kg body weight; low dose), (ii) energy drink (3 mg caffeine per kg body weight; medium dose), (iii) coffee (2 mg caffeine per kg body weight) and (iv) 250 ml water. In Protocol #2, the beverages were consumed in volumes that they are purchased to represent real-life conditions. The aforementioned measurements were repeated in 15 participants following (i) 1 16 oz can of energy drink (16 oz Monster), (ii) 1 24 oz can of energy drink (24 oz Monster), (iii) 1 packet of Keurig K-Cup Starbucks coffee (coffee) and (iv) 250 ml water. The order of the beverages was performed in a randomized double-blinded fashion. For both protocols, QTc interval, heart rate and systolic blood pressure were unchanged in any condition (P>0·05). Diastolic blood pressure and mean blood pressure were slightly elevated in Protocol #1 (P<0·05, main effect of time) with no difference between beverages (P<0·05, interaction of beverage × time); however, they were unaffected in Protocol #2 (P>0·05). These findings suggest that acute consumption of these commonly consumed beverages has no negative effect on cardiac QTc interval.

Treating arrhythmias with adjunctive magnesium: identifying future research directions.

Magnesium is the fourth most abundant cation in the human body and is the second most prevalent cation in intracellular tissues. Myocardial cell action potentials are mediated by voltage-dependent Na+, K+, and Ca2+ channels which, when their function is altered, can lead to the genesis of cardiac dysrythmias. Magnesium regulates the movement of ions through these channels within myocardial tissues. The potential ability of magnesium supplementation to prevent and/or treat arrhythmias has been recognized in clinical medicine for years. This includes termination of torsade de pointes, prevention of post-operative atrial fibrillation, acute treatment of atrial fibrillation, and improving the efficacy and safety of antiarrhythmic drugs. Despite what is currently known about magnesium's therapeutic potential, a number of limitations and gaps to the literature exist. This includes an unclear link between correction of intracellular magnesium concentrations and both mechanistic and clinical outcomes, small sample sizes, varying routes of administration and doses, as well as short follow-up periods. This review highlights these gaps and recommends areas of need for future research.

Exercise-induced syncope in a 22-year-old man.

CLINICAL INTRODUCTION: A 22-year-old man was referred to us for syncope during a game of Captain's ball. There was no prodrome. His friends did not notice any ictal movements. He was otherwise well prior to passing out. He was not taking any medications or supplements. He was not usually physically active, but was otherwise well with no significant medical history. This is his first episode of syncope. There was no history of cardiac arrest or seizures. There is no family history of premature sudden cardiac death.Physical examination was normal. ECG at rest demonstrated sinus rhythm with corrected QT interval of 400 ms. Echocardiography revealed a structurally normal heart. Holter monitoring was normal. Treadmill exercise stress test demonstrated the following rhythm on figure 1 during stage 4 Bruce protocol. Stress test was terminated in view of sustained arrhythmia as illustrated. He felt light-headed during the period, but otherwise felt that he could carry on with the exercise. ECG during recovery was unremarkable.

Utility of Pre-Induction Ventriculoatrial Response to Adenosine in the Diagnosis of Orthodromic Reciprocating Tachycardia.

OBJECTIVES: This study sought to evaluate the utility of ventriculoatrial (VA) conduction patterns in response to adenosine in predicting inducibility of orthodromic reciprocating tachycardia (ORT). BACKGROUND: Adenosine is known to consistently block atrioventricular (AV) nodal conduction. We hypothesized that persistent VA conduction despite administration of adenosine would have a high predictive value for identifying the presence of a retrograde accessory pathway (AP) and associated ORT. METHODS: A total of 168 patients undergoing electrophysiological study for supraventricular tachycardia (SVT) had assessment of VA conduction during ventricular pacing and adenosine administration. Standard pacing maneuvers were then used for induction and diagnosis of the SVT mechanism. RESULTS: Absence of VA block to adenosine (doses up to 24 mg) had 88% sensitivity and 91% specificity for identifying ORT (positive predictive value 76%, negative predictive value 96%). Four patients with adenosine-induced VA block and inducible ORT had decremental APs. Adenosine caused VA block in 6 patients with eccentric VA activation due to atypical AV nodal conduction, and concentric VA conduction persisted in all 12 patients with a septal AP. Adenosine unmasked free-wall APs in 10 patients by blocking AV nodal conduction, shifting VA activation from concentric to eccentric. CONCLUSIONS: The response of VA conduction to adenosine is a highly sensitive and specific method for detecting retrograde AP conduction and inducible ORT. Adenosine-induced VA block rules out inducible ORT due to a nondecremental AP. In cases of VA fusion, adenosine-induced block of AV nodal conduction can delineate the location of the AP atrial insertion site.

Comparing QT interval variability of semiautomated and high-precision ECG methodologies in seven thorough QT studies-implications for the power of studies intended for definitive evaluation of a drug's QT effect.

BACKGROUND: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects. METHODS: Variability data from investigational, placebo and moxifloxacin treatments from seven thorough QT studies performed by the same sponsor were analyzed with the objective to compare the performance of two commonly used approaches for ECG interval measurements: semiautomated (SA) and the high-precision QT (HPQT) analysis. Five studies were crossover and two parallel. Harmonized procedures were implemented to ensure similar experimental conditions across studies. ECG replicates were extracted serially from continuous 12-lead recordings at predefined time points from subjects supinely resting. The variability estimates were based on the time-point analysis of change-from-baseline QTcF as the dependent variable for the standard primary analysis of previous thorough QT studies. The residual variances were extracted for each study and ECG technique. RESULTS: High-precision QT resulted in a substantial reduction in ∆QTc variability as compared to SA. A reduction in residual variability or approximately 50% was achieved in both crossover and parallel studies, both for the active comparison (drug vs. placebo) and for assay sensitivity (moxifloxacin vs. placebo) data. CONCLUSIONS: High-precision QT technique significantly reduces QT interval variability and thereby the number of subjects needed to exclude small effects in QT studies. Based on this assessment, the sample size required to exclude a QTc effect >10 ms with 90% power is reduced from 35 with SA to 18 with HPQT, if a 3 ms underlying drug effect is assumed.

Effects of therapeutic and supratherapeutic doses of oral tedizolid phosphate on cardiac repolarisation in healthy volunteers: a randomised controlled study.

Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) infrequently results in Torsades de pointes, a potentially fatal arrhythmia. Therefore, thorough QT analysis of new drugs is a regulatory requirement. The objective of this phase 1 study was to assess the effects of oral tedizolid phosphate on the QT interval corrected with Fridericia's formula (QTcF) in healthy adult subjects. A single therapeutic dose (200 mg) and a supratherapeutic dose (1200 mg) of tedizolid phosphate were administered to characterise QTc changes following typical systemic exposure and with markedly higher exposures, respectively. This was a four-way crossover study with 48 subjects randomly assigned to receive therapeutic and supratherapeutic doses of tedizolid phosphate, moxifloxacin (positive control for QT interval prolongation) and placebo (negative control). A continuous 12-lead ECG was recorded from 1 h before drug administration to 23 h after administration. Adverse events, which were generally mild, occurred most frequently with moxifloxacin or with a supratherapeutic dose of tedizolid phosphate; however, all treatments were well tolerated. This study demonstrated that therapeutic or supratherapeutic doses of the antibacterial tedizolid had no clinically significant effect on QT interval in healthy adults [ClinicalTrials.gov registration no.: NCT01461460].

Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetized beagle dogs.

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca(2+) channel but inhibit Na(+) and K(+) channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.