Ruthenium-Sulfonamide-Catalyzed Direct Dehydrative Condensation of Benzylic C-H Bonds with Aromatic Aldehydes.

The first catalytic dehydrative condensation of the benzylic C-H bonds of toluene and p-xylene with aromatic aldehydes is reported herein. This protocol provides highly atom-economical access to stilbene and p-distyrylbenzene derivatives, whereby water is the sole byproduct. The reaction is based on the deprotonation-functionalization of benzylic C-H bonds through η6-complexation of the arenes, which is realized for the first time using a catalytic amount of a transition metal activator. The key to the success of this method is the use of a sulfonamide anion as a catalyst component, which appears to facilitate not only the deprotonation of the benzylic C-H bonds but also the formation of a C-C bonds via an electrophilic tosylimine intermediate.

Importance of morphological changes in T-U waves during bepridil therapy as a predictor of ventricular arrhythmic event.

BACKGROUND: Although bepridil is a useful anti-arrhythmic agent for atrial fibrillation, the appearance of serious ventricular arrhythmia, such as torsades de pointes, might be a problem. In this study, T-U wave morphology was evaluated during bepridil therapy and was examined as a predictor of ventricular arrhythmic events. METHODS AND RESULTS: The study population consisted of 113 patients on bepridil therapy. They were divided into 2 groups with and without ventricular arrhythmic events. Morphological changes in T-U waves were analyzed in leads V(2-5). During bepridil treatment, the QTc interval was prolonged from 0.45+/-0.01 to 0.49+/-0.01 s(1/2) in all patients (P<0.0001) and any type of T-U wave change (fused U, slurred, bifid, biphasic or negative) appeared in 73% of event-free and 100% of event groups. In univariate analysis, QTc interval before bepridil (P=0.028), a wide QRS complex (P=0.042) before bepridil, biphasic (P=0.027) or negative (P=0.002) T-U waves in the stable phase, and the new appearance of biphasic (P=0.004) or negative (P<0.0001) T-U waves exhibited significant differences. In multivariate analysis, only newly appeared negative T-U wave exhibited a significant difference (odds ratio 10.13, 95% confidence interval = 0.031-2.302, P=0.041). CONCLUSIONS: In patients with stable bepridil treatment, a change in T-U wave morphology might be a useful predictor of ventricular arrhythmia assisting the QT interval.

Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation.

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

Role of electrophysiologic study (EPS)-guided preventive therapy for the management of ventricular tachyarrhythmias in patients with heart failure.

BACKGROUND: Ventricular tachyarrhythmias (VT/VF) are 1 of the most important factors determining the prognosis of patients with heart failure (HF). Although priority is given to implantable cardioverter defibrillator (ICD) therapy for the prevention of sudden cardiac death, electrophysiologic-study (EPS)-guided preventive therapy could be important for reducing the number of cardiac events. METHODS AND RESULTS: Of 864 patients with a history of HF, an EPS was performed in 168 and 121 had inducible VT/VF. Under the basic therapy of an ICD, additional catheter ablation was attempted for 95 of 124 monomorphic VT foci in 74 patients, and 78 of the VT were successfully ablated. The prognoses were compared among 5 patient groups with different results for the EPS and catheter ablation: (1) success group (n=43), (2) failure group (n=15), (3) not attempted group (n=16), (4) VF group (n=47), and (5) no inducible VT/VF group. During a follow-up period of 31+/-22 months, the incidence of VT/VF was lower in the success and no inducible VT/VF groups than in the other groups (p=0.0018), although a significant difference was not observed for the total deaths. CONCLUSION: EPS-guided preventive therapy using an ICD and catheter ablation can be useful, at least for the reduction of arrhythmic events in patients with HF.

Tumor necrosis factor-alpha downregulates the voltage gated outward K+ current in cultured neonatal rat cardiomyocytes: a possible cause of electrical remodeling in diseased hearts.

BACKGROUND: Inflammatory cytokines have been reported to contribute to the progression of cardiac remodeling in various heart diseases and a remarkable prolongation of the monophasic action potential duration and reductions in the expression of Kv4.2 and K+ channel-interacting protein-2 (KChIP-2) in a rat autoimmune myocarditis model have been documented. In this study, the effect of tumor necrosis factor-alpha (TNF-alpha) on cultured cardiomyocytes was evaluated, focusing on the change in the voltage-gated outward K+ current and expression of related molecules. METHODS AND RESULTS: Cardiomyocytes isolated from 1-day-old Lewis rats were cultured for 72 h and treated with TNF-alpha (50 ng/ml) for an additional 48 h. The myocytes treated with TNF-alpha showed a 22% reduction in the peak K+ current, which consisted of a transient outward K+ current (Ito) and 1.4-fold enhancement of the cell-capacitance in comparison with the control. Among the cardiac ion channel related molecules evaluated in this study, Kv4.2 and KChIP-2 mRNA exhibited remarkable reductions (p < 0.05). CONCLUSIONS: Treatment with TNF-alpha induced reductions in Ito as well as cellular hypertrophy in neonatal cultured myocytes, which indicates that TNF-alpha might play a role in promoting electrical remodeling of cardiomyocytes under inflammatory conditions.

Bepridil block of recombinant human cardiac IKs current shows a time-dependent unblock.

Whole-cell patch-clamp techniques were employed to examine the effects of bepridil, a Ca2+ channel blocker with Vaughan Williams class III action, on a slow component of cardiac delayed rectifier K+ current (IKs), which was reconstituted in HEK293 cells by transfecting KCNQ1 and KCNE1. Micromolar bepridil inhibited tail currents carried by KCNQ1/KCNE1 channels in a concentration-dependent manner (IC50 = 5.3 +/- 0.7 microM at -40 mV from 1000 milliseconds test pulse). When the effect of the drug was examined with a short test pulse protocol (250 milliseconds), IC50 became two-fold smaller than that measured with 1000 milliseconds test pulse (2.5 +/- 0.8 microM). The envelope-of-tails protocol was used to assess how the duration of depolarizing pulse affects the drug action on the outward KCNQ1/KCNE1 channel current. The drug significantly inhibited tail currents more potently during shorter pulses (<600 milliseconds). Bepridil's block was therefore time dependent, and its binding affinity to the channel was greater in the closed state channel, as evidenced by unblocking during prolonged depolarization. These properties of channel blockade appear to underscore the mechanism of bepridil's effect on IKs current.

Monitoring the progression of the atrial electrical remodeling in patients with paroxysmal atrial fibrillation.

It is important to clarify how electrical remodeling develops in clinical cases of paroxysmal atrial fibrillation (PAF), because it has been suggested that this electrophysiological phenomenon promotes an increase in the frequency of PAF. In the present study, the f-f interval during PAF was analyzed from the ambulatory ECG recordings of 21 patients with PAF (total PAF duration >2/24 h with normal atrial size) to monitor the atrial electrophysiological changes. The patients were clinically followed-up for 6 months without any antiarrhythmic drugs. Before and after the follow-up period 24-h Holter monitoring was carried out and the duration of both the PAF and the f-f intervals during the PAF episode were evaluated. In selected cases, the atrial effective refractory period (ERP) was evaluated in an electrophysiologic study before and after the follow-up period. The total PAF duration was prolonged from 187+/-50 to 223+/-79 min (p=0.034) and the f-f interval was shortened from 0.14+/-0.03 to 0.12+/-0.02 ms (p=0.003). There was an inverse relationship between the changes in total PAF duration and f-f interval (p=0.027). The ERP was shortened from 214+/-15 to 194+/-5 ms (n=5, p=0.025) and there was a direct correlation between the changes in ERP and f-f interval (p=0.048). In clinical cases, the prolongation of the PAF was related to the shortening of the f-f interval during the PAF episodes and to the shortening of the atrial ERP. Electrical remodeling plays a role in promoting the development of the atrial fibrillation in patients with PAF.

Electrical remodeling of the ventricular myocardium in myocarditis: studies of rat experimental autoimmune myocarditis.

The purpose of this study was to evaluate the electrical remodeling of the ventricular myocardium in the experimental autoimmune myocarditis (EAM) model in Lewis rats. EAM was induced by immunization with cardiac myosin. During the active myocarditis phase, the effective refractory period (ERP), the duration of the monophasic action potential (MAPD) was extracted from the left ventricular free wall, and the mRNA levels of Kv1.4, 4.2, 4.3 and L type Ca2+ channel were determined by RNase protection assays. The inducibility of ventricular arrhythmia was higher in EAM rats than in the control rat, and the direct relationship between the coupling intervals of the premature stimulus and the ventricular arrhythmia in EAM rats. The ERP was prolonged in EAM rats compared with the control group. The MAPDs determined as 20% and 90% repolarization time, were both longer in EAM rats than in the controls. The level of expression of Kv4.2 mRNA was reduced in EAM rats in comparison with the controls, whereas those of Kv1.4, 4.3 and the L type Ca2+ channel were unchanged. Ventricular vulnerability was higher in EAM rats than in the control rats, and some of the ventricular arrhythmias observed in the EAM group seemed to be based on triggered activity. The level of expression of Kv4.2 mRNA was significantly reduced, and this change was compatible with prolongation of the action potential duration.