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Background Accelerated intermediate inactivation, which is caused by mutations in the cardiac voltage-gated sodium channel α-subunit gene ( SCN5A ), is one of the molecular mechanisms underlying Brugada syndrome. The N406S mutation associated with Brugada syndrome results in the accelerated intermediate inactivation, in addition to unique pharmacological characteristics. Methods Functional sodium channels were expressed transiently in HEK293 cells by transfecting equally the α- and β-subunit plasmids (1 μg/ml) and the sodium current were measured in whole-cell mode of patch-clamp recording. Results Since the N406S mutant channel has a greatly reduced use-dependent block of lidocaine, we took the advantage of the mutant channel to examine the effect of lidocaine on intermediate inactivation using wild-type (WT) and N406S mutant channels recombinantly expressed in HEK293 cells. Lidocaine (100 μM) slowed the recovery from the fast inactivation similarly for WT and N406S. On the other hand, whereas lidocaine slowed the recovery from the intermediate inactivation for WT, lidocaine accelerated the recovery for N406S. Activity-dependent loss of channel availability by repetitive 500-ms pulses was more strongly enhanced and accelerated by lidocaine for WT, but lidocaine exerted little effect on the N406S channel. Conclusion We demonstrate that lidocaine may suppress Brugada syndrome associated with the N406S mutation by preventing the sodium channel from accumulating in the intermediate inactivation state.

本研究では肺静脈隔離術 (PVI) 後に再発する心房細動 (AF) の検出において, 携帯型心電計によるイベント心電図記録の有用性を検証した.対象は発作性AFに対しPVIを施行した連続27症例.PVI後2～3週間にわたり, 朝夕定時および有症候時にイベント心電図記録 (1139記録) と自覚症状の記載をしてもらったところ, 次の結果を得た, (1) 再発群でAF初検出まで6.0±6.6日, AF検出率は20.6%. (2) PVI後経過は非再発型55, 6%, 緩徐抑制型18.5%, 緩徐再発型14.8%, 汎再発型11.1%の4つに分類. (3) 有症候時記録のうちAFは16.8%のみで, 心房期外収縮 (PAC) が403%も占めた, (4) AF検出における自覚症状の感度73%, 特異度79%, 陽性適中率78%, 陰性適中率75%. (5) AF心拍数が低いと無症候性になりやすかった.以上より, PVI後のAF検出には, ボルター心電図だけでは不十分で, 患者の自覚症状にも頼れないため, 携帯型心電計による間欠的なイベント心電図記録が有用と示唆された.

To obtain insights into the mechanisms underlying the membrane excitation and contraction of cardiac myocytes, we developed a computer model of excitation-contraction coupling (Kyoto model: Jpn. J. Physiol. 53 (2003) 105). This model was further expanded by incorporating pivotal reactions of ATP metabolism; the model of mitochondrial oxidative phosphorylation by Korzeniewski and Zoladz (Biophys. Chem. 92 (2001) 17). The ATP-dependence of contraction, and creatine kinase and adenylate kinase were also incorporated. After minor modifications, the steady-state condition was well established for all the variables, including the membrane potential, contraction, and the ion and metabolite concentrations in sarcoplasmic reticulum, mitochondria and cytoplasm. Concentrations of major metabolites were close to the experimental data. Responses of the new model to anoxia were similar to experimental results of the P-31 NMR study in whole heart. This model serves as a prototype for developing a more comprehensive model of excitation-contraction-metabolism coupling.

The heart produces and uses ATP at a high rate. Each step involved in ATP metabolism has been extensively studied. However, functional coupling between ATP production and membrane excitation-contraction coupling, which is the main ATP consumption process, is not yet fully understood because of complicated interactions and the lack of quantitative data obtained in vivo. Computer simulation is a powerful tool for integrating experimental data and for solving their complicated interactions. To investigate the mechanisms underlying cardiac excitation-contraction-energy metabolism coupling, we have developed a computer model of cardiac excitation-contraction coupling (Kyoto model) that includes the major processes of ATP production, such as oxidative phosphorylation that was originally developed for skeletal muscle by Korzeniewski and Zoladz [Biophys Chem 92: 17-34, 2001], creatine kinase, and adenylate kinase. In this review, we briefly summarize cardiac energy metabolism and discuss the regulation of mitochondrial ATP synthesis, using the Kyoto model.

We herein describe two patients with Brugada syndrome in whom J-waves were successfully modified by drugs. Case 1 was a 54-year-old man who presented with repeated ventricular fibrillations (VF) and J-point elevation in the right precordial and lateral leads. After administration of cilostazol (200 mg/d), J-waves disappeared and coved-type ST-segment elevation changed to a saddleback-type for 25 months. Case 2 was a 31-year-old man who presented with a VF storm and J-point elevation in the lateral leads. After administration of quinidine (300 mg/d), J-waves and coved-type ST-segment elevation disappeared for 20 months. J-wave disappearance and coved-type ST-segment elevation were followed by VF suppression, probably due to transient outward potassium current (Ito) suppression.

In a 34-year-old man showing short QT interval (QTc 329 ms), we identified a novel C-terminal KCNH2 mutation, R1135H. Using a heterologous expression system with CHO cells, the mutant channels were found to display a significantly slow deactivation, which resulted in a gain-of-function for reconstituted 'I(Kr)' channels. This mutation could modify clinical phenotypes for this patient.

Background— Drugs with I Kr -blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results— Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P =0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions— dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I Kr -blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Background: The present study investigated whether administration of controlled release matrix metalloproteinase-1 (MMP-1) plasmid DNA prevents left ventricular (LV) remodeling in a rat chronic myocardial infarction (MI) model. Methods and Results: Rats with a moderate-sized MI were randomized to 2 groups: injection of phosphate buffered saline (PBS) containing microspheres into the peri-infarct area (MI group, n=14) and injection of cationized gelatin microspheres incorporating MMP-1 plasmid DNA (MI+MMP-1 group, 50 μg MMP-1/20 μl; n=14). As a control group (n=14), rats received neither the coronary artery ligation nor the injection of PBS. Echocardiography, cardiac catheterization and histological studies were performed. At 2 and 4 weeks after the treatment, the MI+MMP-1 group had smaller LV end-diastolic and end-systolic dimensions, better fractional area change and smaller akinetic areas than the MI group. The LV end-systolic elastance and time constant of isovolumic relaxation were also better in the MI+MMP-1 group compared with the MI group 4 weeks after the treatment. Fibrosis evaluated with Masson's trichrome staining was less in the MI+MMP-1 group than the MI group. Conclusions: Gelatin microspheres for the controlled release of MMP-1 plasmid DNA are promising for improving cardiac remodeling and function when they are administered during the chronic phase of MI. (Circ J 2009; 73: 2315-2321)

We measured mitochondrial NADH autofluorescence or Ca 2+ using Rhod-2, simultaneously with cell shortening in isolated guinea-pig ventricular myocytes. When both frequency and amplitude of twitch shortening (work intensity) were increased by raising stimulus frequency in incremental steps from 0.1 to 3.3 Hz, the steady level of NADH signal increased in a frequency-dependent manner. Mitochondrial Ca 2+ also increased with increasing work intensity. Applying Ru360, an inhibitor of mitochondrial Ca 2+ uniporter, largely attenuated the response of both NADH fluorescence and mitochondrial Ca 2+ . The increase in mitochondrial Ca 2+ was slow with t 1/2 = ~12 s and no obvious cyclic changes were observed in the NADH signal. When a step change from 0.1 to 3.3 Hz stimulation was applied, the NADH signal first decreased to 83% and then increased to 155% of the control level. Upon returning to 0.1 Hz, the NADH signal showed an overshoot before declining to the control level. The biphasic onset time course was well explained by the delayed Ca 2+ activation of the substrate dehydrogenation superimposed on the feedback control of the ATP synthesis, while the offset time course with a delayed deactivation of dehydrogenation. A computer simulation using an oxidative phosphorylation linked to the cardiac excitation contraction model well reconstructed the response of NADH. This model simulation predicts that the activation of substrate dehydrogenation provides ~23% of driving force of the ATP synthesis to meet the increased workload induced by the jump of stimulus from 0.1 to 3.3 Hz, and remaining ~77% is supplied by the feedback control.

The heart produces and uses ATP at a high rate. Each step involved in ATP metabolism has been extensively studied. However, functional coupling between ATP production and membrane excitation-contraction coupling, which is the main ATP consumption process, is not yet fully understood because of complicated interactions and the lack of quantitative data obtained in vivo. Computer simulation is a powerful tool for integrating experimental data and for solving their complicated interactions. To investigate the mechanisms underlying cardiac excitation-contraction-energy metabolism coupling, we have developed a computer model of cardiac excitation-contraction coupling (Kyoto model) that includes the major processes of ATP production, such as oxidative phosphorylation that was originally developed for skeletal muscle by Korzeniewski and Zoladz [Biophys Chem 92: 17-34, 2001], creatine kinase, and adenylate kinase. In this review, we briefly summarize cardiac energy metabolism and discuss the regulation of mitochondrial ATP synthesis, using the Kyoto model.

The reentry circuit of Fast/Slow atrioventricular nodal reentrant tachycardia (AVNRT) is not well understood. We experienced two cases of AVNRT where Fast/Slow and Slow/Slow AVNRT shifted to each other. In the first case, anterograde conduction over the fast pathway and retrograde conduction over one of the two slow pathways was considered as the reentrant circuit of Fast/Slow AVNRT. The transition from Fast/Slow to Slow/Slow AVNRT was caused by the shift of the anterograde pathway from the fast pathway to the other slow pathway. In the second case, anterograde conduction over the one slow pathway and retrograde conduction over the other slow pathway was considered as the circuit of Fast/Slow AVNRT. Fast pathway activated His bundle but did not participate in the reentrant circuit. The transition from Fast/Slow to Slow/Slow AVNRT was caused by the conduction block of the fast pathway. These two cases with the transition from Fast/Slow to Slow/Slow AVNRT show that two different circuits may underlie Fast/Slow AVNRT.