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Background The aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters. Methods In this randomized five-way cross-over thorough QT study, 56 healthy subjects were enrolled. Study treatments were administered orally for 3 days in five separate periods in which subjects were dosed with (1) a single dose of 75 mg lomitapide on Day 1 followed by a single dose of 200 mg on Day 3; (2) ketoconazole 200 mg BID; (3) ketoconazole with a single dose of 75 mg lomitapide on Day 3; (4) a single dose of 400 mg moxifloxacin on Day 3 and (5) placebo. Results Single doses of 75 and 200 mg lomitapide alone or in combination with ketoconazole caused minor changes in the change-from-baseline QTcI (ΔQTcI), whereas moxifloxacin and ketoconazole caused an increase of ΔQTcI with a peak effect at 1 and 3 hours postdosing, respectively. The largest mean placebo-corrected ΔQTcI (ΔΔQTcI) for lomitapide did not exceed 3 ms (upper bound of 90% CI: 4.7 ms) at any time points postdosing. Ketoconazole caused mild QT prolongation with mean ΔΔQTcI of 5.9 and 6.5 ms at 2 and 3 hours postdosing, and exposure-response analysis demonstrated a significantly positive slope of 1.3 ms per μg/mL (90% CI: 1.0–1.7). Moxifloxacin met the criteria for assay sensitivity. Conclusions Lomitapide does not have an effect on cardiac repolarization. The study's ability to detect small QTc changes was demonstrated with both moxifloxacin and ketoconazole.

Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose‐HR‐QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations. The final model includes stimulatory drug effects on glucose elimination and HR perturbations. The targeted and constant exenatide plasma concentrations (>200 pg/mL), via intravenous infusions at multiple dose levels, resulted in significant inhibition of glucose concentrations. The exenatide concentration associated with 50% of the stimulation of HR production was 584 pg/mL. After accounting for exenatide effects on glucose and HR, no additional drug effects were required to explain observed changes in the QT interval. Resulting glucose, HR, and QT profiles at all exenatide concentrations were adequately described. For therapeutic agents that alter glycemic conditions, particularly those that alter postprandial glucose, the QT interval cannot be directly compared to that with placebo without first accounting for confounding factors (eg, glucose) either through mathematical modeling or careful consideration of mealtime placement in the study design.

Background: Increases in QT and JT dispersion have been suggested as indicative of a proarrhythmic potential as a result of heterogeneity in myocardial refractoriness, the reduc tion of which by antiarrhythmic agents might be associated with a beneficial effect on the development of serious ventricular arrhythmias. Methods: To test the hypothesis that amiodarone reduces the heter-ogeneity of ventricular refractoriness to a significantly greater extent than quinidine in patients with intraventricu lar conduction defects under treatment for ventricular arrhythmias, the corrected and uncorrected QT and JT intervals and dispersions from 12-lead surface electrocardiograms were determined in 120 patients with intraventricular conduction defects with cardiac arrhythmias before and during treatment with amiodarone (n = 60) and quinidine (n = 60). Rcsults: Amiodarone increased QT from 403 ± 50 ms to 459 ± 47 ms ( P < .001), with a sim ilar increase in the corrected QT interval (QTc) ( P < .001). Amiodarone reduced QT disper sion by 40% ( P < .001), whereas quinidine increased by 18% ( P < .001). The net effects of both drugs were similar for QTc. Amiodarone, but not quinidine, reduced heart rate signifi cantly; amiodarone had no effect on the QRS; but quinidine increased it ( P < .001). Quini dine as well as amiodarone increased the JT and JTc intervals significantly, but the effect of quinidine was quantitatively less striking. Amiodarone decreased the JT dispersion by 33% ( P < .001) and JTc dispersion by 37% ( P < .001). On the other hand, quinidine increased the corresponding values for JT and JTc by 18% ( P < .001) and 21 % ( P < .001), respectively. The overall data on QT and JT dispersions indicate an improvement in the homogeneity of myo cardial refractoriness with amiodarone treatment and the converse with quinidine treatment; this observation is consistent with a lower proarrhythmic propensity and mortality with amio darone than with quinidine. Quinidine increased the QRS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization. Conclusions: Amiodarone and quinidine both increased the corrected and uncorrected QT and JT intervals; amiodarone decreased and quinidine increased the dispersion of these intervals, and these results suggested an improvement in the homogeneity of myocardial refractoriness as a result of amiodarone treatment and the converse as a result of quinidine treatment. Quinidine increased the QTS interval more than amiodarone, and the data indi cate that in patients with intraventricular conduction defects, the monitoring of the JT inter val might more accurately reflect changes in myocardial repolarization.

Aims This double-blind, randomized, parallel, placebo-controlled investigation evaluated the effects of cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). Methods and results The primary endpoint was change in serum potassium over time. Exploratory endpoints included: weight, physician and patient assessment of exertional dyspnoea, effect on N-terminal pro brain natriuretic peptide (NT-proBNP) levels, New York Heart Association (NYHA) classification, 6 min walk test (6MWT), and quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ). Serum potassium was similar in CLP (n =59) and placebo (n =52) groups throughout the 8-week study. Weight loss was greater in the CLP than in the placebo group at Weeks 1 (P =0.014) and 2 (P =0.004), and this trend continued until the end of the study. After 8 weeks, by physician assessment, the percentage of patients experiencing marked or disabling dyspnoea tended to be lower in the CLP than in the placebo group (7.3% vs. 23.9%, P =0.128). Fewer patients in the CLP than in the placebo group had NT-proBNP levels >1000 pg/mL at Week 4 (P =0.039) and Week 8 (P =0.065). The proportion of patients improving by at least one NYHA functional class over the study was higher in the CLP than in the placebo group (48.8% vs. 17.4%; P =0.002). Effects on 6MWT at Week 8 (p =0.072) and quality of life (overall KCCQ score) at Week 4 (p =0.005) and 8 (P =0.062) all favoured the CLP cohort. Four treatment-unrelated deaths occurred in the CLP group and none in the placebo group (P =0.056). Conclusion In advanced, symptomatic HF with CKD, CLP is associated with beneficial clinical effects without significant serum potassium changes. Trial registration: NCT01265524.

In cardiac fibrillation, disorganized waves of electrical activity meander through the heart, and coherent contractile function is lost. We studied fibrillation in three stationary forms: in human chronic atrial fibrillation, in a stabilized form of canine ventricular fibrillation, and in fibrillation-like activity in thin sheets of canine and human ventricular tissue in vitro. We also created a computer model of fibrillation. In all four studies, evidence indicated that fibrillation arose through a quasiperiodic stage of period and amplitude modulation, thus exemplifying the "quasiperiodic transition to chaos" first suggested by Ruelle and Takens. This suggests that fibrillation is a form of spatio-temporal chaos, a finding that implies new therapeutic approaches.

Inter-patient similarities in coronary and ventricular anatomy may cause reentry circuit slow conduction zones (SCZ) to form in certain locations after myocardial infarction (MI). We assessed the location of reentry circuit SCZs identified using entrainment techniques during catheter mapping and ablation in 14 patients with an old inferior wall MI. The inferior wall was divided into 9 regions. Of 34 different ventricular tachycardias (VT) having a mean cycle length of 408 ± 82 msec, SCZs were identified in 21 (62%). At 18 of these 21 sites (86%), the SCZ was in a basal region near the mitral annulus (p l 0.01 vs all other regions). In 6 VTs, the SCZ extended into two regions. IN-SEP INF INF-LAT Total (27) BASAL 3 13 6 22 MID 1 2 0 3 APEX 0 2 0 2 SEP = septum, INF = inferior, LAT = lateral Conclusion The prevalence of SCZs near the base after inferior Mis suggest a possible role olthe mitral annulus in defining the margins olthe reentry circuit.