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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.

Drug-induced arrhythmias or QT interval prolongation is one of the two most common reasons for drugs to be denied regulatory approval or to have warnings imposed on their clinical labelling. The assessment of torsades de pointes (TdP) risk during clinical development of a new pharmaceutical compound has been an issue of debate since the original description of drug-induced proarrhythmia. TdP risk assessment is complicated by the very low incidence (e.g.

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.

198 Background: VT-464 is a dual selective inhibitor of CYP17,20 lyase and an androgen receptor antagonist in development for the treatment of CRPC. In early clinical testing, several pts receiving VT-464 in 28-day cycles were noted to have syncopal, pre-syncopal or vaso-vagal episodes with typical prodromes. To further evaluate these events, Holter monitoring (HM) was performed in pts enrolled in two clinical studies. Methods: Continuous HM was performed at Screening, after the first dose of VT-464 C1D8, and C2D1 for study INO-VT-464-CL-001; and at Screening, after the first dose of VT-464, and C2D1 for study INO-VT-464-CL-004. The Screening visit HM data was considered the baseline. Plasma levels of VT-464 (in selected pts) and 12-lead ECGs of 10-seconds duration were extracted in triplicate for each pt from the HM data at Baseline, Day 1 and C2D1 at multiple time points. Results: 57 pt screened for VT-464 treatment, underwent HM. Nonsustained ventricular tachycardia (NSVT) was seen in 6 pts (11%) prior to VT-464, providing a background estimate in this population. 37 pts were treated with VT-464 and had > 1 post-screen HM; 4 pts (11%; all with cardiac disorders) had post-treatment NSVT (all < 5 beats); no episodes of sustained VT were seen. 28 pts had ECG data extracted from HMs that coincided with peak plasma levels of VT-464. There was no QTcF or QRS prolongation; increases in the HR (mean 13.1-19.5 BPM but with a non-significant VT-464 concentration/HR relationship) and small PR increases (mean 32.9 ms; partially driven by several pts) without second degree AV block were observed. Conclusions: VT -464 did not prolong QTcF or QRS intervals and the lack of a significant exposure response HR analysis suggests that the HR increases may not be drug related. The PR prolongation is unlikely to be clinical significance. HM showed a frequency of NSVT consistent with background frequency for this pt population.A detailed examination of study pts experiencing syncope or presyncope revealed these to likely be vasovagal in nature, consistent with the increased vagal tone observed in nonclinical testing. There does not appear to be a pro-arrhythmogenic potential of VT-464 based on data from both nonclinical and clinical assessments. Clinical trial information: NCT02361086.

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.

Because the burden of sudden cardiac death (SCD) is substantial, it is important to use all guideline-driven therapies to prevent SCD. Among those therapies is the implantable cardioverter defibrillator (ICD). When indicated, ICD use is beneficial and cost-effective. Unfortunately, studies suggest that most patients who have indications for this therapy for primary or secondary prevention of SCD are not receiving it. To explore potential reasons for this underuse and to propose potential facilitators for ICD dissemination, the Duke Center for the Prevention of SCD at the Duke Clinical Research Institute (Durham, NC) organized a think tank meeting of experts on this issue. The meeting took place on December 12 and 13, 2007, and it included representatives of clinical cardiology, cardiac electrophysiology, general internal medicine, economics, health policy, the US Food and Drug Administration, the Centers for Medicare and Medicaid Services, the Agency for Health care Research and Quality, and the device and pharmaceutical industry. Although the meeting was funded by industry participants, this article summarizing the presentations and discussions that occurred at the meeting presents the expert opinion of the authors.

The goal of this double-blind, randomized, placebo-controlled trial was to evaluate the effects of a cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). The pre-specified primary endpoint was change in serumK+ over time, with an associated goal of facilitating the initiation of aldosterone blockers in patients at risk for hyperkalemia. Since CLP also removes fluid through the GI tract, we also hypothesized that this intervention would ameliorate congestion as assessed by serial weights and its associated symptoms, as assessed by NYHA class, quality of life (assessed by the KansasCityCardiomyopathyQuestionnaire (KCCQ), and 6minutewalk test (6MWT) after 8 weeks of CLP treatment. Results: 111 patients (mean age 69; 59% men) were randomized to CLP or placebo. Unexpectedly, CLP did not have a significant effect on serum K+, and there was no significant difference in the number of patients who could be titrated to a 50 mg spironolactone dose. However, as shown in Figure 1 below, weight loss was significantly greater in the CLP group at week 1 (-0,716 1.5 vs. -0.11 6 2.0 Kg, p50.014, and week 2 (-0.83 6 1.8 kg vs. -0.29 6 2.3 kg, p50.004). In addition, the proportion of subjects with marked or disabling dyspnea on exertion was lower in the CLP group and this difference increased over time (Figure 2). A highly significant (p50.005) improvement in the KCCQ was also observed after 4 weeks of treatment in the CLP group, with a somewhat lesser change at week 8. Safety evaluation: CLP was generally well tolerated, with 21 active patients and 16 placebo patients reporting adverse events, the majority of which were gastrointesFigure 1. Change in weight. tinal (abdominal discomfort (7 vs. 2), distension (3 vs. 1) or nausea (3 vs. 0). There were 4 deaths, all of which were in the CLP group. One occurred at Week 3 in a 70 year old man with NYHA class IV ischemic heart failure (LVEF520%). The second occurred at Week 4 in a 60 year old diabetic man with NYHA class III ischemic heart failure (LVEF 520%). The third death occurred at Week 6 in a 63 year old man with ischemic HF, worsening fluid retention, and progressive CKD. The fourth death Figure 2. Improvement in dyspnea. Figure 3. Improvement in KCCQ. SAEs (Events/Patient Year) Selected Adverse Events CircuLite (n514)*

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.

In patients with history of sustained ventricular tachycarrhythmias, the efficacy and safety of moricizine have not been systematically evaluated by electrophysiological studies. We performed electrophysiological testing in these patients in the drug-free state and then after moricizine loading, and evaluated the safety profile of moricizine during in-hospital loading and follow-up. The study population comprised of 31 patients with clinically sustained ventricular tachyarrhythmia. The underlying heart disease was coronary in 25 patients, cardiomyopathy in 5 patients, and none in 1 patient. The left ventricular (LV) ejection fraction ranged from 15%-69% (mean 39 +/- 15%). During the baseline drug-free electrophysiological testing, sustained ventricular tachycardia was inducible in 27 patients, ventricular fibrillation in 1 patient, and reproducible, nonsustained ventricular tachycardia (15-25 sec) in 3 patients. All 31 patients received moricizine to the maximum tolerated dose (851 +/- 185 mg) over a period of 2-7 days. Six patients developed ventricular proarrhythmia within the first 4 days. Proarrhythmia required multiple cardioversions in three patients, was not associated with QT prolongation, and spontaneously resolved 6-24 hours after withdrawal of moricizine. Of the remaining 25 patients, 24 underwent electrophysiological testing on moricizine and 4 patients (16%) were rendered noninducible. The VT cycle length in the other 20 patients slowed from 243 +/- 30 msec to 299 +/- 60 msec (P < 0.09). Four noninducible patients, two patients with inducible but slowed VT and one patient who had refused further testing were discharged on moricizine.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

We report the results of 50 angioplasty procedures via the popliteal artery. A 3-year follow-up including control of blood pressures at ankle and toe levels show results comparable to reports in the literature. This new approach for angioplasty of the superficial femoral artery and eventually of coexisting iliac lesions enables treatment of previously inaccessible lesions. The technique is especially suited for lesions close to the takeoff of the superficial femoral artery.