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Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2 -p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1 -p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1 -p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1 -p.A341V hiPSC-CMs or KCNQ1 -p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS. [ABSTRACT FROM AUTHOR]

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1‐63) up‐titrated by 50‐mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo‐moxifloxacin (days −1 and 64); (B) moxifloxacin 400 mg (day −1; positive control), placebo‐cenobamate (days 1‐63), and placebo‐moxifloxacin (day 64); and (C) placebo‐moxifloxacin (day −1), placebo‐cenobamate (days 1‐64), and moxifloxacin 400 mg (day 64). The primary end point was baseline‐adjusted, placebo‐corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, −10.8 milliseconds; day 63, −18.4 milliseconds). Based on concentration‐QTc analysis, ∆∆QTcF effect was predicted as −9.85 and −17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose‐related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc‐prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short‐QT syndrome and caution should be used when coadministering with drugs that shorten QT interval. [ABSTRACT FROM AUTHOR]

Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine‐palmitoyltransferase‐1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch‐clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150‐600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline‐treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel‐designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration‐ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119‐0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration‐JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia, with a lifetime incidence of up to 37%, and is a major contributor to population morbidity and mortality. Important components of AF management include control of cardiac rhythm, rate, and thromboembolic risk. In this narrative review article, we focus on rhythm-control therapy. The available therapies for cardiac rhythm control include antiarrhythmic drugs and catheter-based ablation procedures; both of these are presently neither optimally effective nor safe. In order to develop improved treatment options, it is necessary to use preclinical models, both to identify novel mechanism-based therapeutic targets and to test the effects of putative therapies before initiating clinical trials. Extensive research over the past 30 years has provided many insights into AF mechanisms that can be used to design new rhythm-maintenance approaches. However, it has proven very difficult to translate these mechanistic discoveries into clinically applicable safe and effective new therapies. The aim of this article is to explore the challenges that underlie this phenomenon. We begin by considering the basic problem of AF, including its clinical importance, the current therapeutic landscape, the drug development pipeline, and the notion of upstream therapy. We then discuss the currently available preclinical models of AF and their limitations, and move on to regulatory hurdles and considerations and then review industry concerns and strategies. Finally, we evaluate potential paths forward, attempting to derive insights from the developmental history of currently used approaches and suggesting possible paths for the future. While the introduction of successful conceptually innovative new treatments for AF control is proving extremely difficult, one significant breakthrough is likely to revolutionize both AF management and the therapeutic development landscape. [ABSTRACT FROM AUTHOR]

The article highlights the role of the J-Tpeak Interval in Proarrhythmic Cardiac Safety. Topics discussed the J-Tpeak interval is the time from the end of the QRS complex to the peak of the T-wave; mentions the assessment for unanticipated electrocardiogram (ECG) effects and highlights the use of Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative to impact drug discovery, development, and therapeutic use.

Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐Tpeak (J‐Tpeakc) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐Tpeakc upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔQTc and ΔΔJ‐Tpeakc by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced ΔQTc prolongation, but shortened ΔJ‐Tpeakc and prolonged ΔTpeak‐Tend. Absence of J‐Tpeakc prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases. [ABSTRACT FROM AUTHOR]

Abstract: Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety‐related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration‐response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 “thorough QT/QTc” study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug‐drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health‐care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients’ clinical characteristics and concomitant medications when prescribing and dispensing such drugs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.Methods: In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.Results: A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.Conclusions: Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.Registration: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries. [ABSTRACT FROM AUTHOR]

Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open-label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24-hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose-dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations. [ABSTRACT FROM AUTHOR]

Background: Macrolide antibiotics may cause QT prolongation.Objectives: To study the QT effect of a novel macrolide, solithromycin.Methods: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h.Results: After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) μg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; P = 0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval.Conclusions: The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation. [ABSTRACT FROM AUTHOR]

Background: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the “CiPA” initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results: In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions: Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. Trial Registration: and [ABSTRACT FROM AUTHOR]

Background: Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D. Methods: This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata. Results: The analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all). Conclusions: These results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide. [ABSTRACT FROM AUTHOR]

Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m2 romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8-12 mg/m2 romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m2 over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT-prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate. [ABSTRACT FROM AUTHOR]

Continuous Holter recordings are often used in thorough QT studies (TQTS), with multiple 10-second electrocardiograms (ECGs) visually selected around predesignated time points. The authors hypothesized that computer-automated ECG selection would reduce within-subject variability, improve study data precision, and increase study power. Using the moxifloxacin and placebo arms of a Holter-based crossover TQTS, the authors compared interval duration measurements (IDMs) from manually selected to computer-selected ECGs. All IDMs were made with a fully automated computer algorithm. Moxifloxacin-induced changes in baseline- and placebo-subtracted QT intervals were similar for manual and computer ECG selection. Mean 90% confidence intervals were narrower, and within-subject variability by mixed-model covariance was lower for computer-selected than for manual-selected ECGs. Computer ECG selection reduced the number of subjects needed to achieve 80% power by 40% to 50% over manual. Computer ECG selection returns accurate ddQTcF values with less measurement variability than manual ECG selection by a variety of metrics. This results in increased study power and reduces the number of subjects needed to achieve desired power, which represents a significant potential source cost savings in clinical drug trials. [ABSTRACT FROM PUBLISHER]

Background: Diagnosing obstructive coronary artery disease (CAD) in at-risk patients can be challenging and typically requires both noninvasive imaging methods and coronary angiography, the gold standard. Previous studies have suggested that peripheral blood gene expression can indicate the presence of CAD. Objective: To validate a previously developed 23-gene, expression-based classification test for diagnosis of obstructive CAD in nondiabetic patients. Design: Multicenter prospective trial with blood samples obtained before coronary angiography. (ClinicalTrials.gov registration number: NCT00500617) Setting: 39 centers in the United States. Patients: An independent validation cohort of 526 non-diabetic patients with a clinical indication for coronary angiography. Measurements: Receiver-operating characteristic (ROC) analysis of classifier score measured by real-time polymerase chain reaction, additivity to clinical factors, and reclassification of patient disease likelihood versus disease status defined by quantitative coronary angiography. Obstructive CAD was defined as 50% or greater stenosis in 1 or more major coronary arteries by quantitative coronary angiography. Results: The area under the ROC curve (AUC) was 0.70 ± 0.02 (P < 0.001); the test added to clinical variables (Diamond-Forrester method) (AUC, 0.72 with the test vs. 0.66 without; P < 0.003) and added somewhat to an expanded clinical model (AUC, 0.745 with the test vs. 0.732 without; P < 0.089). The test improved net reclassification over both the Diamond-Forrester method and the expanded clinical model (P < 0.001). At a score threshold that corresponded to a 20% likelihood of obstructive CAD (14.75), the sensitivity and specificity were 85% and 43% (yielding a negative predictive value of 83% and a positive predictive value of 46%), with 33% of patient scores below this threshold. Limitation: Patients with chronic inflammatory disorders, elevated levels of leukocytes or cardiac protein markers, or diabetes were excluded. Conclusion: A noninvasive whole-blood test based on gene expression and demographic characteristics may be useful for assessing obstructive CAD in nondiabetic patients without known CAD. [ABSTRACT FROM AUTHOR]

Proarrhythmias due to drug-induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late-stage development. The studies described in S7B and E14 will contribute to a better understanding of the link between nonclinical assays and QT prolongation in humans. Differences in interpretation among individual regulators in the major regions with respect to measures proposed in the E14 guideline might impact regional regulatory decisions. These differences include the value of nonclinical assays for the subsequent clinical testing and how predictive a negative thorough QT study result is for proarrhythmic risk in patients. [ABSTRACT FROM PUBLISHER]

Outlines the fellowship teaching objectives of clinical cardiac electrophysiology. Historical aspects of electrophysiology; Basic cellular and molecular mechanisms of electrophysiology; Laboratory safety in electrophysiology.

The article focuses on a study which examined the effects of amiodarone and quinidine on myocardial refractoriness in patients diagnosed with intraventricular conduction delay. The study included patients who are undergoing treatment for ventricular arrhythmia. It found that the administration of amiodarone increased the QT interval of the patients and reduced heart rate. Meanwhile, quinidine increased QRS interval more than amiodarone.

Introduction: Frequency-dependent electrophysiologic actions of oral quinidine and oral sotalol may be clinically important, but these properties and their modulation by beta-adrenergic sympathetic stimulation have not been determined. Methods and Results: The frequency-dependent effects of oral quinidine (n = 17) and oral d,l-sotalol (n = 17) were determined at: (1) drug-free baseline; (2) during steady-state drug dosing; and (3) during isoproterenol infusion to patients receiving quinidine or d,l-sotalol. The monophasic APD90 and RVERP were prolonged 12% to 17% (P < 0.001) during pharmacologic therapy, and frequency-dependent effects were only observed for the RVERP during sotalol. In both drug groups, isoproterenol significantly reduced the sinus cycle length and reduced the RVERP to a greater extent at longer than at shorter paced cycle lengths. While isoproterenol fully reversed quinidine's effects on the APD90 and RVERP, sotalol-induced APD90 prolongation was reduced by only 2% to 4%, and the RVERP was unaffected. Isoproterenol attenuated the frequency-dependent effects of quinidine on QRS duration by a relatively fixed amount of 7% to 10%. Isoproterenol fully reversed quinidine-induced, but did not affect sotalol-induced, prolongation in the sustained VT cycle length. Conclusions: (1) Over the range of examined cycle lengths, oral quinidine and d,l-sotalol did not exert frequency-dependent effects on ventricular repolarization. (2) Isoproterenol fully reversed quinidine's effects on refractoriness, repolarization, and prolongation of VT cycle length, whereas d,l-sotalors effects were largely preserved, despite significant reductions in sinus cycle length. (3) These results suggest that beta-blockade is important in preventing reversal of antiarrhythmic drug effects by augmented sympathetic nervous system tone. [ABSTRACT FROM AUTHOR]

Many atrial tachycardias, atrial flutter, and postmyocardial infarction ventricular tachycardias are due to reentry through large "macroreentrant" circuits. These circuits can be difficult to define by catheter mapping of the activation sequence. Entrainment techniques allow the relation of a mapping site to the reentrant circuit to be assessed on a site-by-site basis during catheter mapping. Regions of abnormal conduction that are in the reentrant circuit can be distinguished from bystander sites outside the circuit. A mapping site classification to guide catheter ablation is reviewed. [ABSTRACT FROM AUTHOR]

This study evaluated the role of serial electropharmacological testing on combination therapy with mexiletine and procainamide in 20 patients with inducible sustained ventricular tachycardia (VT) refractory to intravenous procainamide. The clinical arrhythmias were cardiac arrest in five patients, sustained VT in 11 patients, and recurrent syncope of presumably arrhythmic origin in four patients. The mean left ventricular ejection fraction (LVEF) was 0.40 ± 0.12 (mean ± SD). All patients had inducible sustained VT at baseline and after administration of intravenous procainamide. All 20 patients underwent electropharmacological testing on combination therapy with mexiletine and procainamide. The mean cycle length of inducible sustained VT was 251 ± 48 ms at baseline, 324 ± 81 ms on intravenous procainamide (P < 0.014 vs baseline), and 365 ± 82 ms on combination therapy (P < 0.0001 vs baseline, P = NS vs intravenous procainamide). Combination therapy did not suppress VT inducibility, nor did it make VT more difficult to induce in 19 of 20 patients. The remaining one patient had a partial response (runs of nonsustained VT, longest 10 seconds). Furthermore, combination therapy did not significantly prolong the VT cycle length over and above that observed during testing with intravenous procainamide. Therefore, in patients with inducible sustained VT refractory to procainamide during initial electropharmacological testing, mexiletine in combination with procainamide appears to be of little or no value and serial electropharmacological testing on these drugs is of limited usefulness. Early initiation of alternative therapy may be the preferred clinical option. [ABSTRACT FROM AUTHOR]

This case report highlights the feasibility and stability of transvenous placement of a second defibrillation lead in the left subclavian vein from a right cephalic vein approach. This was undertaken in a right-sided implant of an active can cardioverter defibrillator to lower defibrillation thresholds that would have otherwise precluded implant. [ABSTRACT FROM AUTHOR]