Assessment of spatial heterogeneity of ventricular repolarization after multi-channel blocker drugs in healthy subjects.

BACKGROUND AND OBJECTIVES: In contrast to potassium channel blockers, drugs affecting multiple channels seem to reduce torsadogenic risks. However, their effect on spatial heterogeneity of ventricular repolarization (SHVR) is still matter of investigation. Aim of this work is to assess the effect of four drugs blocking the human ether-à-go-go-related gene (hERG) potassium channel, alone or in combination with other ionic channel blocks, on SHVR, as estimated by the V-index on short triplicate 10 s ECG. METHODS: The V-index is an estimate of the standard deviation of the repolarization times of the myocytes across the entire myocardium, obtained from multi-lead surface electrocardiograms. Twenty-two healthy subjects received a pure hERG potassium channel blocker (dofetilide) and 3 other drugs with additional varying degrees of sodium and calcium (L-type) channel block (quinidine, ranolazine, and verapamil), as well as placebo. A one-way repeated-measures Friedman test was performed to compare the V-index over time. RESULTS: Computer simulations and Bland-Altman analysis supported the reliability of the estimates of V-index on triplicate 10 s ECG. Ranolazine, verapamil and placebo did not affect the V-index. On the contrary, after quinidine and dofetilide administration, an increase of V-index from predose to its peak value was observed (ΔΔV-index values were 19 ms and 27 ms, respectively, p < 0.05). CONCLUSIONS: High torsadogenic drugs (dofetilide and quinidine) affected significantly the SHVR, as quantified by the V-index. The metric has therefore a potential in assessing drug arrhythmogenicity.

In silico assessment of drug safety in human heart applied to late sodium current blockers.

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I(NaL)) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K(+) current (I(Kr)). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I(Kr)/I(NaL) ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I(NaL) and I(Kr) were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I(Kr) and I(NaL) of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I(NaL)) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.

BACKGROUND AND PURPOSE: JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. EXPERIMENTAL APPROACH: JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. KEY RESULTS: The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). CONCLUSIONS AND IMPLICATIONS: Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.

Assessment of cardiac structure and function in patients without and with peripheral oedema during rosiglitazone treatment.

BACKGROUND: Thiazolidinediones cause peripheral oedema, the aetiology of which remains poorly understood. METHODS: In a sub-study of a 6-month trial comparing rosiglitazone (Rsg) versus placebo, we compared those with versus without oedema among the 74 subjects treated with Rsg with respect to peak oxygen consumption indexed to fat-free mass (VO(2peak-FFM) ), cardiac MRI and markers of plasma volume expansion. RESULTS: Almost half (49%) of the Rsg-treated patients developed oedema. Baseline VO(2peak-FFM) was not different between those with versus without oedema (25.8 versus 28.2 ml/kg/min; p = 0.22) and declined 5% in the oedema group (Δ -1.3 ml/min/kg; p = 0.005) with no change in those without oedema. Stroke volume increased in both groups (Δ 8.7 and 8.8 ml; p < 0.001 for each); end-diastolic volume increased only in those with oedema (+13.1 ml; p = 0.001). No other cardiac function changes were observed. In both groups, weight increased (3.6 and 2.2 kg) and haematocrit decreased (-3.2% and -2.1%; p < 0.001 for each). In those with oedema, albumin decreased (-0.2 g/dl) and brain natriuretic peptide increased (11.9 pg/ml; p < 0.03 for each). CONCLUSIONS: Oedema was associated with a small decline in VO(2peak FFM), no adverse effects on cardiac function, and changes in selected measures suggesting that volume expansion underpins Rsg oedema.

Effect of Shenmai Injection on ventricular diastolic function in patients with chronic heart failure: An assessment by tissue Doppler imaging.

OBJECTIVE: To assess the effect of Shenmai Injection (SMI) on left ventricular diastolic function (LVDF) in patients with chronic heart failure (CHF) by tissue Doppler imaging (TDI). METHODS: Sixty-four CHF patients were randomly assigned to two groups, the observation group and the control group. Basic treatment including polarized liquid therapy was given to all the patients. In addition, SMI was given to patients of the observation group. The treatment duration was 14 days. TDI was performed in all the patients 3 days prior to the initiation of the treatment and one week after the medication to measure the average movement velocity of the mitral ring of the left ventricle at the early systolic stage and late diastolic stage (Ea and Aa); the outcomes were compared with the corresponding parameters obtained from blood flow Doppler echocardiography, namely, the velocity of the E-wave (E) and A-wave (A). RESULTS: After treatment, Ea and Ea/Aa increased and Aa decreased significantly in the observation group (P<0.05). In the control group, although some improvement was seen, there was no statistically significant change (P>0.05). No statistical significance was shown between groups in these parameters after treatment. CONCLUSION: TDI assessment shows that SMI could effectively improve the LVDF in CHF patients.

Mechanisms of beta-adrenergic modulation of I(Ks) in the guinea-pig ventricle: insights from experimental and model-based analysis.

Detailed understanding of I(Ks) gating complexity may provide clues regarding the mechanisms of repolarization instability and the resulting arrhythmias. We developed and tested a kinetic model to interpret physiologically relevant I(Ks) properties, including pause-dependence and modulation by beta-adrenergic receptors (beta-AR). I(Ks) gating was evaluated in guinea-pig ventricular myocytes at 36 degrees C in control and during beta-AR stimulation (0.1 micromol/L isoprenaline (ISO)). We tested voltage dependence of steady-state conductance (Gss), voltage dependence of activation and deactivation time constants (tau(act), tau(deact)), and pause-dependence of tau(act) during repetitive activations (tau(react)). The I(Ks) model was developed from the Silva and Rudy formulation. Parameters were optimized on control and ISO experimental data, respectively. ISO strongly increased Gss and its voltage dependence, changed the voltage dependence of tau(act) and tau(deact), and modified the pause-dependence of tau(react). A single set of model parameters reproduced all experimental data in control. Modification of only three transition rates led to a second set of parameters suitable to fit all ISO data. Channel unitary conductance and density were unchanged in the model, thus implying increased open probability as the mechanism of ISO-induced Gss enhancement. The new I(Ks) model was applied to analyze ISO effect on repolarization rate-dependence. I(Ks) kinetics and its beta-AR modulation were entirely reproduced by a single Markov chain of transitions (for each channel monomer). Model-based analysis suggests that complete opening of I(Ks) channels within a physiological range of potentials requires concomitant beta-AR stimulation. Transient redistribution of state occupancy, in addition to direct modulation of transition rates, may underlie beta-AR modulation of I(Ks) time dependence.

Validation and application of single breath-hold cine cardiac MR for ventricular function assessment in children with congenital heart disease at rest and during adenosine stress.

PURPOSE: To validate the accuracy of ventricular function analysis using a single breath-hold real-time steady sate free precession (SSFP) cine MR method and demonstrate its application during adenosine stress imaging in children with congenital heart disease. MATERIALS AND METHODS: Twenty-eight subjects with congenital heart disease were studied (mean age 12.4 +/- 2.3 years) with MR imaging at 1.5 T. Short-axis images covering the entirety of both ventricles were acquired at rest, with a conventional segmented SSFP cine sequence acquired over multiple breath-holds and a single breath-hold real-time SSFP sequence. Seventeen subjects were given an infusion of adenosine, and the single breath-hold real-time short-axis stack was repeated during stress. Two independent observers performed the ventricular function analysis. Data was compared between the 2 acquisition methods at rest and between the single breath-hold acquisition at rest and during adenosine stress. RESULTS: There was good agreement between the multiple breath-hold and single breath-hold methods for measurement of end-diastolic volume (r = 0.95 and 0.96, p < .0001) and end-systolic volume (ESV) (r = 0.76 and 0.90, p < .0001) for the left and right ventricles respectively, and the left ventricular mass (r = 0.97, p < .0001). Adenosine was administered safely to all subjects. During stress there were significant changes in the heart rate and ESV, which led to a significant increase in cardiac output (mean 1.5 +/- 1.0 L/min, p < .001). CONCLUSION: Single breath-hold real-time SSFP cine imaging is robust and accurate in assessing cardiac function in children with congenital heart disease. An application of this method is the rapid assessment of cardiac function during adenosine stress.

Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women.

AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.

Cardiovascular assessment of ER-118585, a selective phosphodiesterase 5 inhibitor.

The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC(50) value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 microg/kg/min significantly prolonged the QT interval by 10.5+/-1.6% from 281+/-2 ms to 311+/-6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984+/-78 nM, n=3) and its protein binding fraction (99.0+/-0.1%, n=5), the free plasma concentration was estimated at 9.8+/-0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.

QTc interval in the assessment of cardiac risk.

In the United States alone 300,000-400,000 people die of sudden cardiac death every year. Much of this mortality is assumed to be caused by ventricular tachyarrhythmias. Prolonged QTc reflect cardiac repolarization prolongation and/or increased repolarization inhomogenity known to be associated with increased risk of arrhythmias. The paper gives a review of the possibilities to assess the risk of ventricular arrhythmia and/or cardiac death from QTc. Prolonged QTc may hold independent prognostic importance for mortality in common diseases as ischemic heart disease and diabetes mellitus where as the prognostic importance in heart failure and arterial hypertension is more uncertain. In more rare diseases as the inborn long QT syndrome the QT interval gives not only important hint to the diagnosis but the magnitude also provides information on prognosis. QTc has probably no independent prognostic importance in hypertrophic cardiomyopathy or in the arrhythmogenic right ventricular disease. The degree of QTc prolonging during treatment with QTc prolonging drugs is prognostic for the risk of ventricular arrhythmia in form of torsade de pointes and QTc prolonging drugs should probably not be prescribed for patients with a QTc greater than 460 ms and withdrawn if QTc exceeds 500 ms during treatment. Data from the DIAMOND study suggest that QTc can be used to point out those heart failure patients who will benefit from antiarrhythmic therapy.