Electrophysiological characteristics of idiopathic ventricular tachycardia in children.

BACKGROUND: Idiopathic ventricular tachycardia (VT) has been reported to have a good prognosis, but there still might be the potential risk of sudden death. METHODS AND RESULTS: The 46 consecutive children (mean age 11.7 ± 3.4 years) with idiopathic VT were enrolled in this study. Monomorphic VT was detected in 39 patients and polymorphic VT in 7 patients. The VT originated from the right ventricle (RV) in 22 patients, and left ventricle (LV) in 17 patients. The VT was induced by exercise in 68% of the RVVT, 41% of the LVVT, and 100% of the polymorphic VT. The VT was induced by programmed ventricular stimulation in 41% of the RVVT, 35% of the LVVT, and none of the polymorphic VT. Adenosine tri-phosphate terminated the VT in 9 of 15 patients (60%). The mechanism of the VT was suspected to be triggered by activity in 36.4%, automaticity in 40.9%, and re-entry in 22.7% of the RVVT, whereas it was 52.9%, 5.9%, and 41.2% of the LVVT, respectively. CONCLUSIONS: The exercise inducibility was higher in polymorphic VT than the RVVT and LVVT, but no difference in the programmed stimulation. The sensitivity to adenosine tri-phosphate was not different between the RVVT and LVVT. In some patients with idiopathic VT, a non-verapamil sensitive re-entry was documented, which was more common in patients with ischemic heart disease or cardiomyopathy.

Excitation energy dependence for the Li 1s X-ray photoelectron spectra of LiMn2O4.

The Li 1s XPS (X-ray Photoelectron Spectroscopy) spectra of LiMn2O4, which is one of the major positive-electrode materials in lithium-ion rechargeable batteries, and MnO2 as a reference material, were measured by a laboratory-type XPS spectrometer. The Li 1s peak was not observed in the spectra excited by the Mg Kalpha line (1253.6 eV), because the Li 1s peak overlapped the background of the Mn 3p peak of LiMn2O4. The photoionization cross section of Mn 3p was larger than that of Li 1s for Mg Kalpha excitation. Therefore, the XPS measurement of LiMn2O4 by soft X-ray synchrotron excitation was carried out at beamline BL-7B on NewSUBARU synchrotron facility. Excitation energies of 110, 120, 130, 140, 150 and 151.4 eV were selected. The Li 1s peak was clearly observed in these XPS spectra. In order to investigate the excitation energy dependence, the area ratio of the Li 1s and Mn 3p peaks in the XPS spectra was plotted against the excitation energy. As a result, when the excitation energy was 110 eV, the area ratio had the maximum value.

Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.

In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.

Detection of myocardial contractile reserve by low-dose dobutamine quantitative gated single-photon emission computed tomography in patients with Kawasaki disease and severe coronary artery lesions.

We studied 24 patients with severe coronary artery lesions to assess myocardial perfusion and left ventricular contractile reserve simultaneously using low-dose dobutamine quantitative electrocardiographically gated single-photon emission computed tomography in patients with Kawasaki disease. Low-dose dobutamine infusion was started after an injection of technetium-99m tetrofosmin at rest. Myocardial contractile reserve was evaluated using the post-stress and low-dose dobutamine images, and myocardial perfusion was evaluated using the stress and rest images. Quantitative electrocardiographically gated single-photon emission computed tomography during low-dose dobutamine infusion is a useful and safe method for the combined evaluation of myocardial contractile reserve and myocardial perfusion.

The role of histidine residues conserved in the putative ATP-binding region of macrolide 2'-phosphotransferase II.

Macrolide 2'-phosphotransferase (MPH(2')) catalyzes the transfer of the gamma-phosphate of ATP to the 2'-hydroxyl group of macrolide antibiotics. In this study, H198 and H205, conserved in the ATP-binding region motif 1 in the putative amino acid sequence of MPH(2')II, were replaced by Ala to investigate their role. H205 was also subsequently replaced by Asn. H198A and H205N mutant enzymes retained more than 50% of the specific activity of the original enzyme to substrate oleandomycin. On the other hand, the specific activity of the H205A mutant enzyme was reduced to less than 1% of that of the wild enzyme. The results suggested that H205 is crucial for maintaining the catalytic activity of MPH(2')II, and Asn can substitute for His at this position.

Combination of TS-021 with metformin improves hyperglycemia and synergistically increases pancreatic ß-cell mass in a mouse model of type 2 diabetes.

AIMS: The objectives of this study were to elucidate the effects of a potent dipeptidyl peptidase (DPP)-IV inhibitor, TS-021, combined with/without metformin on glycemic control and pathological changes in pancreatic islets in high-fat diet and streptozotocin-induced (HFD-STZ) diabetic mice. MAIN METHODS: The anti-diabetic effects of TS-021 and/or metformin in HFD-STZ mice were examined in both acute and chronic treatment studies. In addition, we performed immunohistochemical analysis after repeated administration of TS-021 and/or metformin to HFD-STZ mice twice a day for 5 weeks. KEY FINDINGS: In the acute treatment study, TS-021 and/or metformin significantly improved glucose tolerance and glucagon-like peptide-1 (GLP-1) level, and TS-021 alone or in combination with metformin significantly increased the plasma insulin level after nutrient ingestion. In the chronic treatment study, TS-021 in combination with metformin significantly lowered the glycosylated hemoglobin level, plasma insulin level, and α-cell-to-ß-cell area ratio in pancreatic islets. In particular, the combined treatment synergistically increased the insulin-positive area in pancreatic islets from 32.3% in diabetic mice treated with the vehicle to 51.1% (TS-021 alone, 35.3%; metformin alone, 30.6%). SIGNIFICANCE: The present study demonstrated that the coadministration of TS-021 and metformin synergistically improved the islet morphology by increasing the circulating level of biologically active GLP-1, which is thought to result from two different mechanisms (namely, an increase in GLP-1 secretion and DPP-IV inhibition). These findings strongly support the rationale for combined treatment with DPP-IV inhibitors plus metformin in clinical practice by clearly demonstrating an anti-diabetic effect associated with the remarkable improvement in pancreatic ß-cell morphology.

Quantitative evaluation of coronary artery wall echogenicity by integrated backscatter analysis in Kawasaki disease.

BACKGROUND: Coronary artery wall echogenicity increases on echocardiograms during the acute phase of Kawasaki disease (KD). According to this background, echogenicity of the coronary artery wall in patients with KD is quantified by using integrated backscatter (IB) analysis. METHODS: IB analysis is a quantitative method for evaluating echogenicity. We examined the value of IB in the wall of the left anterior descending coronary artery and compared it with that in adjacent intracardiac blood as a measure of background. The difference between these values is represented as corrected IB for the coronary artery wall. RESULTS: Corrected IB for the coronary artery wall was higher in patients with KD than in controls (KD with pre-immunoglobulin therapy vs. controls: 27.4 +/- 5.3 dB vs. 22.0 +/- 3.5 dB, P < .05) and in patients with coronary enlargement after intravenous immunoglobulin (with vs. without coronary enlargement, 29.2 +/- 5.2 dB vs. 24.1 +/- 5.5 dB, P < .05). CONCLUSION: The magnitude of IB from the coronary artery wall reflects the effectiveness of immunoglobulin therapy. Furthermore, this method and its value might be useful to predict the occurrence of coronary enlargement in patients with KD.

Development of a microfocus x-ray tube with multiple excitation sources.

A microfocus x-ray tube with multiple targets and an electron gun with a focal spot size of 10 microm in diameter has been developed. The electron gun contains a LaB(6) cathode and an Einzel lens. The x-ray tube can be operated at 50 W (50 kV, 1 mA) and has three targets, namely, Cr, W, and Rh on the anode that can be selected completely by moving the anode position. A focal spot size of 10 microm in diameter can be achieved at 0.5 mA current. As demonstration of the usability of a multiexcitation x-ray tube, the fluorescence x-rays have been measured using a powder specimen mixed of TiO(2), Co, and Zr of the same quantity. The differences of excitation efficiency have clearly appeared according to the change in excitation source. From the results discussed here, it can be expected that the presented x-ray tube will be a powerful tool in microx-ray fluorescence spectrometers and various x-ray instruments.

Dual myocardial scintigraphy mismatch in an infant with Bland-White-Garland syndrome.

Bland-White-Garland syndrome (BWG) is a rare disorder that includes abnormalities of the coronary arteries that cause severe myocardial ischemia or infarction in infancy. In this case report, we describe an infant with BWG evaluated by dual single photon emission computed tomography using thallium-201 and I-123 beta-methyl-p-iodophenyl-pentadecanoic acid before and after surgery.

Association of sinus node dysfunction, atrioventricular node conduction abnormality and ventricular arrhythmia in patients with Kawasaki disease and coronary involvement.

BACKGROUND: This study was performed to investigate the incidence of arrhythmias in patients with Kawasaki disease (KD). METHODS AND RESULTS: Electrophysiologic studies (EPS) were performed in 40 patients (mean age: 10.3+/-5.1 years; 30 males, 10 females) with KD who had severe to moderate coronary artery disease. Clinical arrhythmias were documented in 4 patients (premature ventricular contractions, ventricular tachycardia, atrioventricular block, and ventricular fibrillation). Dual atrioventricular nodal pathways were demonstrated in 3 patients. Nonsustained atrial fibrillation was induced in 1 patient. The AH interval was prolonged in 2 patients. The Wenckebach rate was 164+/-37 beats/min, and 4 of the patients had a decreased Wenckebach rate. The maximum and corrected sinus node recovery times were 997+/-257 ms and 281+/-130 ms, respectively, and 7 patients were thought to be abnormal. The sino-atrial conduction time was 108+/-64 ms, and 2 patients had prolonged conduction times. CONCLUSIONS: Although there was no relationship between coronary stenosis or obstruction and the EPS parameters, the incidence of abnormal sinus node and atrioventricular node function is apparently higher in KD patients than in the normal population. These functional abnormalities may possibly be caused by myocarditis or an abnormal microcirculation in the sinus node and atrioventricular node artery. In some patients, myocardial ischemia may provoke malignant ventricular arrhythmia.

Usefulness of real-time 3-dimensional echocardiography for the evaluation of coronary artery morphology in patients with Kawasaki disease.

OBJECTIVES: This study was designed to evaluate the usefulness of real-time 3-dimensional echocardiography (RT-3DE) for evaluating coronary artery morphology in patients with Kawasaki disease. BACKGROUND: The diagnosis of coronary artery morphology in the acute phase of the disease is of prime importance for evaluating the likelihood of cardiovascular sequelae. Occasionally, visualization of the right coronary artery and bifurcated regions, including the circumflex artery, has proved challenging with traditional echocardiographic methods. METHODS: A total of 111 patients with Kawasaki disease were studied. Coronary aneurysms were detected in 8 patients (4 had giant aneurysms), and coronary dilation was found in 11 patients. Coronary artery visualization was evaluated and scored as 1 of 4 grades, 0 to 3 points, for both 2-dimensional echocardiography (2DE) and RT-3DE. Evaluation criteria for each coronary artery were defined according to the American Heart Association classification of coronary angiographic features. Total scores for each patient and for individual coronary branches were compared between 2DE and RT-3DE. RESULTS: The total scores for coronary artery visualization were, respectively, showing a significantly higher score for RT-3DE than for 2DE (P < .01). A mural thrombus could be clearly delineated in the giant coronary aneurysms by RT-3DE. CONCLUSIONS: RT-3DE is superior to 2DE for coronary artery visualization. This diagnostic system is expected to improve the screening of coronary artery abnormalities in Kawasaki disease.

[Advantages of multislice spiral computed tomography for evaluation of serious coronary complications after Kawasaki disease].

OBJECTIVES: Novel multislice spiral computed tomography (MSCT) findings were identified in patients after Kawasaki disease that could not be detected by coronary angiography (CAG). METHODS: Eighteen patients had suffered from serious coronary arterial lesions after Kawasaki disease (mean age 21.7 years, range 13-34 years). Seventeen patients had stenotic lesions, and all of them had coronary aneurysms. MSCT was performed using a Siemens SOMATOM Volume Zoom (4-detector row) or a Toshiba Aquillion 16 (16-detector row). Findings of coronary calcification, stenotic lesion, and intimal hypertrophy in all coronary arteries were compared to those of CAG. RESULTS: Eleven of the 18 patients (61%) had novel findings detected by MSCT. Coronary calcifications were found in 11 of the 18 patients (61%). Five patients had concentric calcified aneurysms, four had eccentric calcified aneurysms, and two had mixed calcified aneurysms. Coronary stenotic lesions were present in 6 of the 18 patients (33%) with calcified aneurysms. Two patients had intimal hypertrophy (11%). One patient had intimal hypertrophy along the left main trunk with a giant calcified aneurysm along the left anterior descending artery. Two patients had severe stenoses just distal to giant calcified aneurysms that were regarded as false positive findings, and were identified as mild stenoses by CAG. CONCLUSIONS: MSCT offers advantages over CAG in the evaluation of calcified aneurysms and intimal hypertrophy, and is a potential diagnostic modality for coronary intervention in patients after Kawasaki disease.

Clinical importance of Koch's triangle size in children: a study using 3-dimensional electroanatomical mapping.

BACKGROUND: Catheter ablation inside the Koch's triangle has a risk for complete atrioventricular block. METHODS AND RESULTS: The anatomic size of the coronary sinus (CS) and His bundle (HB) in children and the distance between them was studied using a 3-dimensional electroanatomical mapping system (CARTO). Fifty-three children (mean age, 11.8+/-3.7 years) without congenital heart disease (ie, 24 with atrioventricular re-entrant tachycardia, 18 with atrioventricular nodal re-entrant tachycardia, 7 with atrial tachycardia, 2 with ventricular tachycardia and 2 with atrial flutter) were studied. The size of the HB recording area was 148+/-97 mm2 and the size of the CS was 66+/-44 mm2. The size of the CS and the distance between the HB and CS (18+/-7 mm) were proportional to body weight, body length and body surface area. All patients underwent catheter ablation, including 25 ablations inside Koch's triangle. Catheter ablation was successful in 52 patients without any atrioventricular nodal injury. CONCLUSIONS: The CS size and the distance between the HB and CS increased proportionally with children's growth. To know the distance from the HB to the ablation point is useful in avoiding atrioventricular node injury, and information about the length of Koch's triangle may provide supportive information when applying radiofrequency energy inside Koch's triangle without needing to use the CARTO system in children, but this merits further investigation.

Association of atrial arrhythmia and sinus node dysfunction in patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: This study was performed to investigate the frequency and importance of supraventricular arrhythmia and sinus node (SN) dysfunction in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). METHODS AND RESULTS: Eight patients with CPVT (mean age: 16.8+/-8.1 years) underwent an electrophysiological study. SN recovery time (1,389+/-394 ms) was slightly prolonged, and 4 of 8 patients had abnormal values. Atrial flutter (AF) was induced by low-rate atrial pacing in 2 patients and by isoproterenol infusion in 1 patient. Atrial fibrillation (Af) was induced by isoproterenol infusion in 2 patients. One patient presented with Af during the follow-up period, and 2 of 4 patients with AF/Af presented with increased SN recovery time. CONCLUSIONS: Patients with CPVT frequently have associated with SN dysfunction, and inducible atrial tachyarrhythmias, which indicate that the pathogenesis of CPVT is limited not only to the ventricular myocardium, but also to broad regions of the heart, including the SN and atrial muscle.

Increased excretion of urinary 20-HETE in rats with cyclosporine-induced nephrotoxicity.

The present study examined the contribution of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in cyclosporine A (CsA)-induced renal nephrotoxicity. Treatment of rats with CsA (50 mg/kg) for 9 days induced renal damage as indicated by marked increase in urine flow (from 9.0 +/- 0.3 ml/day to 46.6 +/- 7.1 ml/day) and a 3 - 5-fold rise in blood urea nitrogen (BUN) levels. The urinary excretion of 20-HETE increased from 164 +/- 5 ng/day (N = 5) to 2432 +/- 290 ng/day (N = 5, P<0.01) after 9 days of CsA treatment. The increase in the urinary excretion of 20-HETE in the CsA treated rats was highly correlated with the increase in BUN levels (r = 0.819, P<0.001) and urine volume (r = 0.832, P<0.001). Immunohistochemical examination of kidney revealed that expression of cytochrome P450 4A (CYP4A) protein was markedly enhanced in the proximal tubules of CsA-treated rats. These results indicate that CsA-induced nephrotoxicity in rats is associated with a marked elevation in the renal production of 20-HETE and that 20-HETE may contribute to the pathophysiological condition of CsA-induced nephrotoxicity.

Beneficial effects of a new 20-hydroxyeicosatetraenoic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], on hemorrhagic and ischemic stroke.

The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 microM. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.

Pyrazole derivatives as new potent and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.

Improvement of the physical properties of pyrazole derivative 1, which we reported previously as a potent and selective 20-HETE synthase inhibitor (IC(50) 5.7 nM), is described. Introduction of a sufficient substituted-amino group on the side chain enhanced the water-solubility of 1 (0.014 mg/mL at pH 6.8). Among the products, 2-piperazinoethoxy derivatives 3e and 6b showed solubility suitable for injection and potent inhibitory activity toward 20-HETE synthase (IC(50) 21.2 and 14.0 nM, respectively).

Design and synthesis of 1-(4-benzoylphenyl)imidazole derivatives as new potent 20-HETE synthase inhibitors.

Structural modification of the novel 20-HETE synthase inhibitor 1 (IC(50) 310nM) is described. Introduction of a side chain with a carboxylic acid at the terminal position to 1 resulted in increased ability to inhibit human renal microsomal production of 20-HETE (7c: IC(50) 7.9nM), with good selectivity toward CYP2D6 and cyclooxygenases (COX)-1 and -2.

Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors.

In a previous paper, we reported that an imidazole derivative 1 exhibited a potent inhibitory activity of 20-HETE synthase (1; IC(50) value of 5.7 nM), but this compound also exhibited little selectivity for cytochrome P450s (CYPs). We examined some derivatives of imidazole 1 which had an amino group on the side chain, and found that a dimethylaminohexyloxy derivative (3g; IC(50) value of 8.8 nM) showed potent and selective inhibitory activity.