Abstract: BACKGROUND: Premature ventricular contractions (PVCs) do not occur frequently but can induce ventricular fibrillation (VF) in patients with Brugada syndrome. The effect of SCN5A mutation on the onset of ventricular arrhythmias is unknown. OBJECTIVE: The purpose of this study was to evaluate PVC morphology and onset of VF in patients with Brugada syndrome. METHODS: Morphology of PVCs was evaluated by 12-lead ECG in 32 patients with Brugada syndrome. Patients had spontaneous ventricular arrhythmia (n = 17) or sodium channel blocker-induced ventricular arrhythmia (n = 19). Patients were classified into two groups according to the existence of SCN5A mutation (22 mutation negative, 10 mutation positive). RESULTS: Patients without mutation often had PVCs of left bundle branch block (LBBB) morphology (82%), especially with inferior axis (77%). Patients with mutation had PVCs of both right bundle branch block (36%) and LBBB (64%) morphologies. Only two patients with mutation had PVCs of LBBB, inferior-axis morphology. CONCLUSION: Patients without SCN5A mutation often had PVCs of LBBB, inferior-axis morphology, suggesting a right ventricular outflow tract origin. Patients with SCN5A mutations had PVCs that originated from both the right and left ventricles.

Abstract: Angiotensin II type I receptor blocker (ARB) or statin has been reported to be effective in preventing stent restenosis, but little is known about the combined effect on stent restenosis. The objective of this study was to determine the effect of combination therapy with ARB and statin on restenosis rate after coronary stenting and on proliferation and migration of and reactive oxygen species (ROS) production by human coronary artery smooth muscle cells (SMCs) in vitro. Clinical data were collected from 330 consecutive patients who underwent coronary stenting for de novo lesions. Six months after stenting, quantitative coronary angiography was performed. Combined therapy with the ARB and statin significantly inhibited stent restenosis (P < 0.05) compared with the effect of the ARB or statin alone. In an in vitro study, platelet-derived growth factor (PDGF)-induced proliferation was significantly inhibited by combined treatment with CV11974, an ARB, and simvastatin (P < 0.01), but the inhibitory effect was not significantly greater than that of simvastatin alone. Migration of human coronary artery SMCs was significantly inhibited by the ARB + statin compared with the effect of the ARB or statin alone (P < 0.01). PDGF-induced production of ROS was also inhibited significantly by the ARB + statin compared with the effect of the ARB or statin alone (P < 0.01). These results indicate that inhibitory effects of combined therapy on PDGF-induced migration of and ROS production by SMCs play an important role in reduction of restenosis rate. Combined treatment with ARB and statin after stenting is useful for preventing stent restenosis.

Abstract: BACKGROUND: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction. METHODS: Circulating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60+/-2 years old) and 20 control subjects (57+/-2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization. RESULTS: HCM patients had significantly elevated levels of MCP-1 (HCM: 309+/-30 vs. control: 178+/-8 pg/ml, P<.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<.05) and were also significantly higher than those in patients with outflow obstruction (P<.05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=-.401, P<.05) and correlated with left ventricular end-diastolic pressure (r=-.579, P<.01). CONCLUSION: These results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM.

Abstract: OBJECTIVES: We examined the relationship between repolarization abnormality and coved-type ST-segment elevation with terminal inverted T-wave (type 1 electrocardiogram [ECG]) in patients with Brugada syndrome (BrS). BACKGROUND: Recent experimental studies have suggested that accentuation of the right ventricular action potential (AP) notch preferentially prolongs epicardial AP causing inversion of the T-wave. METHODS: In 19 patients with BrS and 3 control subjects, activation-recovery intervals (ARIs) and repolarization times (RTs) in the epicardium and endocardium were directly examined with the use of local unipolar electrograms at the right ventricular outflow tract. Surface ECG, ARI, and RT were examined before and after administration of pilsicainide. RESULTS: Type 1 ECG was observed in 10 of the 19 BrS patients before the administration of pilsicainide and in all of the 19 patients after the administration of pilsicainide. We found that ARI and RT in the epicardium were shorter than those in the endocardium in all 9 BrS patients without type 1 ECG under baseline conditions and in all control subjects regardless of pilsicainide administration. However, longer epicardial ARI than endocardial ARI was observed in 8 of the 10 BrS patients manifesting type 1 ECG under baseline conditions and in all of the BrS patients after the administration of pilsicainide. Also, epicardial RT was longer than endocardial RT in all patients manifesting type 1 ECG regardless of pilsicainide administration. CONCLUSIONS: Our data provide support for the hypothesis that the negative T-wave associated with type 1 BrS ECG is due to a preferential prolongation of the epicardial AP secondary to accentuation of the AP notch in the region of the right ventricular outflow tract.

Abstract: Brain natriuretic peptide (BNP) level has been used as a marker of left ventricular (LV) systolic dysfunction (LVSD), even though some patients with atherosclerosis have a high BNP level irrespective of LV function. In this study, we investigate whether augmentation index (AI), which is an index of wave reflection, is involved in increasing BNP level in hypertensive patients without LVSD. Sixty treated hypertensive patients were enrolled in this study. Radial AI (r-AI) was measured in all patients. The patients were classified into tertiles on the basis of r-AI to identify the characteristics of the patients with a high r-AI. BNP level was significantly higher in the patients classified into the highest tertile of r-AI. In echocardiography, e', which is index of left ventricular (LV) diastolic function, decreased and LV mass index (LVMI) increased gradually with r-AI, whereas there was no difference in LV ejection fraction (LVEF). r-AI significantly correlated with LVMI (r=0.35, p<0.01) and e' (r=-0.30, p<0.05). In univariate analysis, age, heart rate, r-AI, LVEF, e' and LVMI were significantly correlated with BNP level, whereas multivariate analysis demonstrated that only r-AI and LVEF correlated with BNP level. In conclusion, an increase in r-AI was significantly associated with an increase in BNP level in hypertensive patients without LVSD. LV hypertrophy and diastolic dysfunction associated with increase in r-AI may be involved in increase in BNP level.

Abstract: OBJECTIVES: The goal of our work was to examine the relationships of atrial fibrillation (AF) with genetic, clinical, and electrophysiological backgrounds in Brugada syndrome (BrS). BACKGROUND: Atrial fibrillation is often observed in patients with BrS and indicates that electrical abnormality might exist in the atrium as well as in the ventricle. SCN5A, a gene encoding the cardiac sodium channel, has been reported to be causally related to BrS. However, little is known about the relationships of atrial arrhythmias with genetic, clinical, and electrophysiological backgrounds of BrS. METHODS: Seventy-three BrS patients (49 +/- 12 years of age, men/women = 72/1) were studied. The existence of SCN5A mutation and clinical variables (syncopal episode, documented ventricular fibrillation [VF], and family history of sudden death) were compared with spontaneous AF episodes. Genetic and clinical variables were also compared with electrophysiologic (EP) parameters: atrial refractory period, interatrial conduction time (CT), repetitive atrial firing, and AF induction by atrial extra-stimulus testing. RESULTS: Spontaneous AF occurred in 10 (13.7%) of the BrS patients and SCN5A mutation was detected in 15 patients. Spontaneous AF was associated with higher incidence of syncopal episodes (60.0% vs. 22.2%, p < 0.03) and documented VF (40.0% vs. 14.3%, p < 0.05). SCN5A mutation was associated with prolonged CT (p < 0.03) and AF induction (p < 0.05) in EP study, but not related to the spontaneous AF episode and other clinical variables. In patients with documented VF, higher incidence of spontaneous AF (30.8% vs. 10.0%, p < 0.05), AF induction (53.8% vs. 20.0%, p < 0.03), and prolonged CT was observed. CONCLUSIONS: Spontaneous AF and VF are closely linked clinically and electrophysiologically in BrS patients. Patients with spontaneous AF have more severe clinical backgrounds in BrS. SCN5A mutation is associated with electrical abnormality but not disease severity.

Abstract: INTRODUCTION: Macroscopic T-wave alternans (TWA) is sometimes observed after sodium channel blocker administration in patients with Brugada syndrome (BS), but little is known about the association between occurrence of TWA and clinical characteristics in BS patients. We investigated the association between spontaneous ventricular fibrillation (VF) occurrence and TWA after pilsicainide, a sodium channel blocker administration in BS patients. METHODS AND RESULTS: We administered pilsicainide at a dose of 1 mg/kg to 77 BS patients (76 males and one female; mean age, 48.4 years) and examined the association between TWA after pilsicainide administration and clinical characteristics, including age, spontaneous VF, syncope, family history of sudden death, spontaneous coved ST elevation, late potentials (LP), induction of VF by programmed electrical stimulation, and SCN5A mutation. None of the patients had TWA before pilsicainide administration, but TWA became apparent in 17 (22.1%) of the patients after pilsicainide administration. Patients with TWA had a significantly higher incidence of spontaneous VF (52.9% vs 8.3%, P < 0.001) and syncope (58.8% vs 26.7%, P < 0.05) than did patients without TWA. Then, we focused on the association between spontaneous VF and clinical characteristics. Patients with spontaneous VF had a significantly higher incidence of TWA (64.3% vs 12.7%, P < 0.001) and LP positive (92.9% vs 56.5%, P < 0.01) than did patients without spontaneous VF. In multivariate analysis, TWA (P = 0.001) and LP (P = 0.047) appeared as the independent predictor for spontaneous VF. CONCLUSION: TWA after pilsicainide administration is associated with a high risk of clinical VF in patients with BS.

Abstract: BACKGROUND: Pacing at the right atrial septum (RAS) appears to be superior to that performed at the right atrial appendage for preventing paroxysmal atrial fibrillation and for reducing complications. However, atrial lead insertion at the RAS is difficult and time-consuming. Although a few useful devices have been reported, handling of the atrial lead around the RAS is sometimes difficult even with those devices. Therefore, in the present study a long-straight sheath (LSS) was used in an attempt to secure sufficient space for handling the atrial lead around the RAS. METHODS AND RESULTS: Seventy-six consecutive patients who underwent insertion of an atrial lead at the RAS from a left-sided approach were examined. The non-LSS group comprised 24 patients and the LSS group had 52. The success rate of atrial lead insertion was significantly higher in the LSS group than in the non-LSS group [50/52 (96.1%) vs 13/24 (54.2%); p<0.01]. The operation time was significantly shorter in the LSS group (13.6+/-9.1 min vs 32.7+/-11.1 min, p<0.01). P wave duration was significantly shorter during RAS pacing than during normal sinus rhythm. CONCLUSION: The LSS technique is useful for atrial lead insertion at the RAS because it enables sufficient space to be secured for lead handling.

Abstract: Immunological factors have been involved in the pathogenesis of dilated cardiomyopathy (DCM). The cytotoxic action of macrophages is one of the main factors causing cardiac myocyte damage. Monocyte chemoattractant protein-1 (MCP-1) is a major signal for the accumulation of monocytes/macrophages. We examined whether MCP-1 was expressed in the myocardium of DCM patients and whether the expression level was correlated with the degree of impairment of cardiac function. The expression of MCP-1 in the myocardium was determined by immunohistochemistry in endomyocardial biopsy samples from 13 patients. The expression of MCP-1 was found in all myocardial samples from DCM patients but not in those from control subjects. Positive staining for MCP-1 was distinct in cardiac myocytes, interstitium and infiltrating cells. Semi-quantitative analysis revealed that the expression of MCP-1 was inversely correlated with left ventricular ejection fraction. In conclusion, the expression level of MCP-1 in the myocardium was correlated with the degree of impairment of cardiac function in patients with DCM.

Abstract: BACKGROUND: Brugada syndrome (BrS) is characterized by repolarization abnormality with ST-segment elevation in the right ventricular outflow tract (RVOT). OBJECTIVE: Although action potential (AP) heterogeneity is associated with induction of ventricular arrhythmias (VA) in BrS, clinical evidence and its experimental correlations are still absent and are the focus of this study. METHODS: We evaluated repolarization heterogeneity in 15 patients with BrS using body surface mapping and in 8 pairs of isolated canine RVOT and right ventricular anteroinferior (RVAI) preparations having drug-induced BrS using optical mapping. RESULTS: Patients had large J-ST-segment elevation and long QT interval in the RVOT at baseline. Administration of pilsicainide (1 mg/kg) exaggerated J-ST-segment elevation, caused simultaneous long and short QT intervals in the RVOT, and induced polymorphic ventricular tachycardia (VT) and T wave alternans (TWA). Dispersion of QT within the RVOT after pilsicainide was greater in patients that had syncope or ventricular fibrillation than those that did not. Ventricular arrhythmias originated from the RVOT along with local electrocardiogram changes and TWA. Repolarization heterogeneity was much less in areas outside the RVOT. Inducing BrS increased AP heterogeneity (with and without spike-and-dome) within the RVOT epicardium. Phase 2 reentry and TWA originated from the epicardium in 88% and 50% of RVOT preparations, respectively. In contrast, the RVOT endocardium and RVAI had little AP heterogeneity, with neither reentry nor TWA. CONCLUSION: The instability and heterogeneity of repolarization within the epicardium of the RVOT seem to be associated with arrhythmogenesis in both patients and in the in vitro tissue models of BrS.

Abstract: BACKGROUND: Amiodarone (AMD) is a strong antiarrhythmic drug but has severe side effects such as pulmonary toxicity. There are no indicators or drugs that can prevent the development of amiodarone-induced pulmonary toxicity (AIPT). METHODS: We collected data for 96 consecutive patients treated with AMD and analyzed clinical factors related to AIPT. In addition, we examined the effect of AMD and angiotensin II (Ang II) on human lung alveolar epithelial cells (AEC) and verified the protective efficacy of an Ang II type 1 receptor blocker (ARB) in vitro. RESULTS: During a follow-up period of 33.8+/-34.6 months, AIPT developed in 11 patients (11.5%). There were no differences in the dose of AMD, left ventricular ejection fraction, serum KL-6 and %DLCO level before starting AMD between patients with and those without AIPT. However, repeated episodes of congestive heart failure (CHF) were observed more frequently in patients with AIPT than in patients without AIPT (81.8% vs. 41.2%, P<0.011). In vitro examination, AMD progressively increased apoptosis of AEC and Ang II enhanced this effect of AMD (P<0.001). However, ARB inhibited the enhancement by Ang II of the AMD-induced apoptosis effect (P<0.001). Furthermore, patients with AIPT were administrated a lower dose of angiotensin system antagonists than were those without AIPT (P<0.05). CONCLUSIONS: The results indicate that Ang II induced by CHF increases the risk of AMD-induced pulmonary toxicity. An angiotensin-converting enzyme inhibitor or ARB should be given at a sufficient dose during AMD treatment.

Abstract: A 19-year-old man was transferred to hospital because of myocarditis with cardiogenic shock. Echocardiography showed a left ventricular ejection fraction of 23.8% and an intermediate amount of pericardial effusion. The patient immediately received an intra-aortic balloon pump and percutaneous cardiopulmonary support. Right ventricular endomyocardial biopsy was performed in the acute phase and showed extensive eosinophilic inflammatory cell infiltration, severe interstitial edema and moderate myocardial necrosis. High-dose corticosteroids were administered. Because the patient's antibody titer against Toxocara canis was high and his symptoms had appeared after eating raw deer meat, the diagnosis was fulminant eosinophilic myocarditis caused by a hypersensitivity reaction to visceral larval migrans. After starting high-dose corticosteroids, the ejectionfraction dramatically improved, the eosinophilia decreased and the patient made a full recovery.

Abstract: BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a disease characterized by progressively increased resistance of pulmonary arteries. In this study, we evaluated the mechanical property of single pulmonary artery smooth muscles cells (PASMC) from patients with IPAH and tested whether the PASMC showed abnormal response to a vasodilator by use of an atomic force microscope (AFM). METHODS: PASMC were isolated and cultured from explanted lungs of 7 patients with IPAH (IPAH-PASMC). Normal vascular specimens from 3 patients with bronchogenic carcinoma were used as normal controls (normal PASMC). The nano/micro-order elasticity of five to ten living PASMC in each sample was measured by parabolic force curves of cantilever deflection/indentation obtained by using an AFM. The elasticity measurements were performed under control conditions and under condition of nitric oxide (NO) treatment (190 and 380 nmol/L). RESULTS: There was no significant difference between nano/micro-order elasticity of normal PASMC and that of IPAH-PASMC under the control conditions. In normal PASMC, NO (190 and 380 nmol/L) significantly reduced (i.e., softened) the nano/micro-order elasticity. However, NO did not reduce elasticity in IPAH-PASMC, indicating higher vasodilator-resistive nano/micro-order rigidity in IPAH-PASMC. CONCLUSION: Nano/micro-order elasticity change in PASMC in response to vasodilation induced by NO is reduced in patients with IPAH.

Abstract:

Abstract: 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.

Abstract: BACKGROUND: Conduction abnormalities serve as a substrate for ventricular fibrillation (VF) in patients with Brugada syndrome (BS). Signal-averaged electrograms can detect late potentials, but the significance of conduction abnormalities within the QRS complex is still unknown. The latter can present as multiple spikes within the QRS complex (fragmented QRS [f-QRS]). We hypothesized that f-QRS could indicate a substrate for VF and might predict a high risk of VF for patients with BS. METHODS AND RESULTS: In study 1, we analyzed the incidence of f-QRS in 115 patients with BS (13 resuscitated from VF, 28 with syncope, and 74 asymptomatic). f-QRS was observed in 43% of patients, more often in the VF group (incidence of f-QRS: VF 85%, syncope 50%, and asymptomatic 34%, P<0.01). SCN5A mutations occurred more often in patients with f-QRS (33%) than in patients without f-QRS (5%). In patients with syncope or VF, only 6% without f-QRS experienced VF during follow-up (43+/-25 months), but 58% of patients with f-QRS had recurrent syncope due to VF (P<0.01). In study 2, to investigate the mechanism of f-QRS, we studied in vitro models of BS in canine right ventricular tissues (n=4) and optically mapped multisite action potentials. In the experimental model of BS, ST elevation resulted from a large phase 1 notch of the action potential in the epicardium, and local epicardial activation delay reproduced f-QRS in the transmural ECG. CONCLUSIONS: f-QRS appears to be a marker for the substrate for spontaneous VF in BS and predicts patients at high risk of syncope.

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Abstract: BACKGROUND: Bepridil has multiple ion-channel blocking effects and is expected to be useful for managing atrial fibrillation (AF). The purpose of this study was to clarify the efficacy and safety of additional treatment with bepridil in patients with AF who had been treated with class I antiarrhythmic drugs (AADs). METHODS AND RESULTS: Bepridil (50-200 mg/day) was given to 76 patients with either paroxysmal (n=49) or persistent AF (n=27). All patients had been treated with class I AADs (1.9+/-0.9 drugs/patient) that failed to control the AF. With the addition of bepridil, the frequency of symptomatic AF episodes decreased to less than 10% in 38 (78%) patients with paroxysmal AF, and sinus rhythm was restored within 3 months and maintained during the follow-up in 20 (74%) patients with persistent AF. Efficacy was usually obtained with a small to moderate dose (50-150 mg/day) of bepridil. During a mean follow-up period of 27+/-22 months, no potential complications occurred in any of the patients. CONCLUSIONS: The addition of bepridil to class I AADs is effective and safe for AF, but careful observation using periodic ECG recordings is essential for avoiding torsades de pointes caused by QT prolongation.

Abstract:

Abstract: Andersen-Tawil syndrome (ATS) is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features. In this study, we characterized the KCNJ2 channels with an ATS mutation (T75M) which is associated with cardiac phenotypes of bi-directional ventricular tachycardia, syncope, and QT(c) prolongation. Confocal imaging of GFP-KCNJ2 fusion proteins showed that the T75M mutation impaired membrane localization of the channel protein, which was restored by co-expression of WT channels with T75M channels. Whole-cell patch-clamp experiments in CHO-K1 cells showed that the T75M mutation produced a loss-of-function of the channel. When both WT and the T75M were co-expressed, the T75M mutation showed dominant-negative effects on inward rectifier K+ current densities, with prominent suppression of outward currents at potentials between 0 mV and +80 mV over the E(K). Inside-out patch experiments in HEK293T cells revealed that co-expression of WT and the T75M channels enhanced voltage-dependent block of the channels by internal Mg2+, resulting in enhanced inward rectification at potentials 50 mV more positive than the E(K). We suggest that the T75M mutation causes dominant-negative suppression of the co-expressed WT KCNJ2 channels. In addition, the T75M mutation caused alteration of gating kinetics of the mutated KCNJ2 channels, i.e., increased sensitivity to intracellular Mg2+ and resultant enhancement of inward rectification. The data presented suggest that the mutation may influence clinical features, but it does not directly show this.

Abstract: BACKGROUND: In patients with cardiac sarcoidosis, ventricular arrhythmias and/or conduction disturbances are frequently observed and sometimes fatal. However, few reports on disease activity and arrhythmic events in cardiac sarcoidosis are available. OBJECTIVE: The purpose of this study was to investigate the relationship between disease activity and arrhythmic events in cardiac sarcoidosis and the effect of corticosteroid therapy. METHODS: The study population consisted of 15 cardiac sarcoidosis patients with new-onset symptomatic arrhythmia, including eight patients admitted once for complete atrioventricular block (CAVB), five patients admitted once for sustained ventricular tachycardia (VT), and two patients admitted twice for two arrhythmic events (one for CAVB and the other for sustained VT). Disease activity was evaluated by gallium-67 citrate (Ga) scintigraphy. All patients with positive Ga uptake were treated with corticosteroids, and arrhythmic events were evaluated by repeat Holter recordings. RESULTS: Positive uptake of Ga was observed in 8 (80%) of the 10 CAVB events and in 1 (14%) of the 7 sustained VT events (80% vs 14%, P = .02). Corticosteroids abolished myocardial Ga uptake in all nine patients with positive Ga uptake. After corticosteroid therapy was started, AV conduction improved in 5 of 9 CAVB patients (including 8 patients with new-onset CAVB and one patient with history of CAVB). However, ventricular arrhythmias were not improved after corticosteroid therapy. CONCLUSION: In cardiac sarcoidosis patients, CAVB develops mainly during the active phase of the disease. Early treatment with corticosteroids might improve AV conduction disturbance. However, sustained VT is not closely linked with disease activity and frequently develops in the advanced stage of disease.

Abstract:

Abstract: Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. Inhibition of proliferation of pulmonary artery smooth muscle cells (PASMCs) may be an effective treatment of patients with idiopathic pulmonary arterial hypertension. Recent studies have shown that carvedilol, an alpha- and beta-blocker with antioxidant and calcium channel blocking properties, inhibits the proliferation of cultured normal human pulmonary artery smooth muscle cells. In this study, we tested the hypothesis that carvedilol has antiproliferative effects on pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. Pulmonary artery smooth muscle cells from six idiopathic pulmonary arterial hypertension patients who had undergone lung transplantation were cultured. To determine cell proliferation, H-thymidine incorporation was measured. Platelet-derived growth factor-induced proliferation of IPAH-PASMCs was significantly greater than that of normal control pulmonary artery smooth muscle cells. Carvedilol (0.1 microM to 10 microM) inhibited the proliferation of idiopathic pulmonary arterial hypertension-pulmonary artery smooth muscle cells in a concentration-dependent manner. Prazosin (an alpha-blocker) and N-acetyl L cysteine (an antioxidant agent) (0.1 microM to 10 microM) did not inhibit their proliferation, but the high concentration of propranolol (a beta-blocker) and nifedipine (a calcium channel blocker) (10 microM) inhibited the proliferation. The combination of propranolol and nifedipine inhibited the proliferation but only at a high concentration (10 microM) combination. Cell cycle analysis revealed that carvedilol (10 microM) significantly decreased the number of cells in S and G2/M phases. These results indicate that carvedilol inhibits the exaggerated proliferation of pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension partially via its beta-blocking [corrected] and calcium channel blocking effects in vitro.

Abstract: AIMS: Arrhythmic storm or repetitive ventricular arrhythmia (VA) has been occasionally observed in Brugada syndrome (BS). A beta-adrenergic stimulator [isoproterenol (ISP)] has been reported to suppress this arrhythmic storm in sporadic cases. Accordingly, we investigated the antiarrhythmic effects of ISP infusion in consecutive BS patients with arrhythmic storm or repetitive VA. METHODS AND RESULTS: Seven BS patients with arrhythmic storm were studied. Intravenous ISP was administered as a bolus injection (1-2 microg), followed by continuous infusion (0.15 microg/min). Arrhythmic storm or repetitive VA was suppressed immediately after the bolus administration of ISP, which was followed by continuous infusion of low-dose ISP for 1-3 days. In all patients, ST-elevation decreased in right precordial leads. In six of the seven patients, VA subsided after the discontinuance of ISP. RR interval was shortened and ST-elevation in right precordial leads was decreased after ISP bolus injection. ST-elevation in right precordial leads remained decreased during continuous ISP infusion, whereas the RR interval returned to the control level. CONCLUSION: Continuous administration of low-dose ISP may be effective for the suppression of repetitive VA occurrence in patients with BS.

Abstract: Previously, we reported that spironolactone reduced cytokine production in cultured human peripheral blood mononuclear cells (PBMCs) with angiotensin (Ang) II stimulation. To address the mechanisms underlying this effect, we examined the contribution of aldosterone to cytokine production in cultured human PBMCs with Ang II stimulation. PBMCs expressed the messenger RNA (mRNA) of Ang II type 1 receptor (AT1R) and mineralocorticoid receptor (MR) both spontaneously and after Ang II stimulation, but expressed Ang II type 2 receptor (AT2R) under neither condition. After 24 h of incubation, exogenous Ang II induced the expression of CYP11B2 (a key enzyme of aldosterone synthesis) mRNA and caused aldosterone synthesis. CV-11974 (an AT1R antagonist) reduced Ang II-induced aldosterone synthesis, whereas PD-123319 (an AT2R antagonist) had no effect. The concentration of aldosterone peaked earlier than those of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha). After 48 h of incubation (under the influence of synthesized aldosterone), CV-11974 and spironolactone significantly reduced the Ang II-enhanced production of MCP-1 and TNF-alpha, whereas PD-123319 also had no effect. In conclusion, Ang II induces aldosterone synthesis through AT1R and enhances cytokine production through an AT1R-dependent mechanism and, at least partly, through a MR-dependent mechanism in human PBMCs.

Abstract: BACKGROUND: Oxidative stress has been implicated in the pathogenesis of chronic heart failure. The present study investigated whether the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were elevated in the serum and myocardium of patients with dilated cardiomyopathy (DCM), and furthermore whether carvedilol, a vasodilating beta-blocker with antioxidant activity, could reduce the levels. METHODS AND RESULTS: Serum levels of 8-OHdG were measured by enzyme immunoassay in 56 patients with DCM and in 20 control subjects. DCM patients had significantly elevated serum levels of 8-OHdG compared with control subjects. Endomyocardial biopsy samples obtained from 12 DCM patients and 5 control subjects with normal cardiac function were studied immunohistochemically for the expression of 8-OHdG. Positive 8-OHdG staining was found in the nuclei of cardiomyocytes from DCM patients but not in those from control subjects. After treatment with carvedilol, the serum levels of 8-OHdG in DCM patients significantly decreased by 19%, together with amelioration of heart failure. CONCLUSIONS: Levels of 8-OHdG are elevated in the serum and myocardium of patients with heart failure. Treatment with carvedilol might be effective for decreasing the oxidative DNA damage.

Abstract: We evaluated the effect of alacepril, CV-11974, and spironolactone on the production of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in cultured human peripheral blood mononuclear cells stimulated with angiotensin (Ang) II. Alacepril, CV-11974, and spironolactone significantly reduced the enhanced production of MCP-1 and TNF-alpha induced by exogenous Ang II. Specifically, 10 muM of spironolactone significantly reduced cytokine production, compared to the same dose of alacepril or CV-11974. These findings indicate that spironolactone may contribute to ameliorate the prognosis of patients with cardiovascular diseases by reducing Ang II-induced inflammation, although further exploration including determining the mechanisms would be required.

Abstract: Several proven medical therapies such as beta-blockers and angiotensin converting enzyme inhibitors play important roles in preventing sudden death of patients with heart failure. Therapy with amiodarone and therapy with implantable cardioverter defibrillator (ICD) have developed specifically to prevent sudden death by life-threatening arrhythmias. But recently many large-scale clinical trials have proved that ICD therapy improves prognosis of patients with heart failure better than amiodarone therapy. Because ICD is not a treatment to prevent the occurrence of ventricular arrhythmias, it may not necessarily improve quality of life of patients. In that respect catheter ablation may play a role in preventing life-threatening arrhythmias.

Abstract: The long QT syndrome (LQTS) is characterized by prolongation of the QT interval, causing torsade de pointes and sudden cardiac death. This syndrome can be divided into idiopathic (congenital) and acquired forms. The idiopathic form is a familial disorder that can be associated with sensorineural deafness (Jervell and Lange--Nielsen syndrome, autosomal recessive) or normal hearing (Romano--Ward syndrome, autosomal dominant). The acquired form has a long QT interval caused by various drugs such as quinidine sotalol and dofetilide, also by noncardiovascular drugs such as antihistamine, antibiotics, antipsychotics and others. Also, the QT interval is prolonged by electrolyte abnormalities such as hypokalemia and hypomagnesemia, central nervous system lesions, significant bradyarrhythmias, cardiac ganglionitis, mitral valve prolapse and probucol. DNA variants appearing to predispose to drug-associated acquired long QT syndrome have been reported in congenital long QT.

Abstract: BACKGROUND: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism is not known. We examined whether oxidative stress was elevated in myocardia of HCM patients and whether the levels were correlated with left ventricular dilatation and systolic dysfunction. METHODS AND RESULTS: Endomyocardial biopsy samples obtained from the right ventricular side of the septum of 31 patients with HCM, and 10 control subjects were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with HCM. Expression was distinct in the cytosol of cardiomyocytes. The expression levels in patients with HCM were significantly increased compared with those in control subjects (P = .0005). The expression levels in patients with HCM were correlated with left ventricular end-diastolic diameter (r = 0.483, P = .0053) and end-systolic diameter (r = 0.500, P = .0037) determined by echocardiography. The expression levels were inversely correlated with left ventricular ejection fraction determined by left ventriculography (r = -0.640, P = .0001). CONCLUSION: Oxidative stress was elevated in myocardia of HCM patients and the levels were correlated with left ventricular dilatation and systolic dysfunction. Oxidative stress is involved in the pathogenesis of heart failure in patients with HCM.

Abstract: BACKGROUND: Intraoperative transesophageal echocardiography (TEE) during lung transplantation is useful for monitoring cardiac condition and pulmonary vascular anastomoses to detect vascular complications, but the parameters for evaluation by TEE during lung transplantation have not been established. METHODS: We performed intraoperative TEE on 17 patients during living-donor lobar lung transplantation (LDLLT) and investigated the usefulness of measurement of peak flow velocities through bilateral pulmonary vein (PV) anastomoses and evaluation of the equivalence. RESULTS: The peak flow velocities through bilateral PV anastomoses were almost equivalent in 14 patients without complications and were not equivalent in 3 patients with complications such as vascular stenosis and peripheral atelectasis. CONCLUSIONS: The flow velocities through the bilateral PV anastomoses are shown to be nearly equivalent during bilateral LDLLT, and the equivalence may be one factor for predicting the success of LDLLT.

Abstract: BACKGROUND: Anticoagulation therapy and continuous intravenous infusion of epoprostenol are the standard treatment for primary pulmonary hypertension (PPH). Because epoprostenol has an antiplatelet effect, concomitant use of an anticoagulant could increase the likelihood of hemorrhagic complications. METHODS AND RESULTS: In the present study, 31 consecutive patients with PPH (10 men, 21 women, mean +/- SD age, 28.5+/-10.1 years) treated with anticoagulation and epoprostenol between April 1999 and December 2003 were retrospectively evaluated. Clinical and hematological data at the time of the bleeding episode were retrieved from the medical records. Nine patients (22.6%) experienced 11 bleeding episodes: 9 episodes (81.8%) were alveolar hemorrhage and 2 patients were in severe respiratory distress. The mean dose of epoprostenol at the time of the first bleeding episode was 89.0 +/-40.5 ng.kg(-1).min(-1) (range, 28.1-164.0). More of the patients who did not have a bleeding episode remain alive than did patients with bleeding episodes (59% vs 33%) nor did they require lung transplantation. CONCLUSIONS: A considerable number of patients with PPH who received combined anticoagulant and high-dose epoprostenol therapy developed alveolar hemorrhage, which can be fatal.

Abstract: Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of "idiopathic" cardiomyopathy. Recent molecular genetic analyses have now revealed that "idiopathic" cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy-associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.

Abstract: BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. There is no therapy that specifically inhibits SMC proliferation. Recent studies reported that prednisolone (PSL) inhibits the postangioplasty proliferation of SMCs in atherosclerotic arteries. In this study, we tested the hypothesis that PSL has antiproliferative effects on pulmonary artery SMCs of patients with IPAH. METHODS AND RESULTS: Pulmonary artery SMCs were harvested from the pulmonary arteries of 6 patients with IPAH who underwent lung transplantation. Control SMCs were obtained from 5 patients with bronchogenic carcinoma who underwent lung lobectomy. After incubation in the presence of platelet-derived growth factor (PDGF), PSL was added at different concentrations and cell proliferation was assessed by 3H-thymidine incorporation. PSL (2x10(-4) and 2x10(-3) mol/L) significantly inhibited PDGF-stimulated proliferation (P<0.05) of SMCs from patients with IPAH but did not affect cell viability of SMCs, as confirmed by trypan blue staining. In cell cycle analysis using a microscope-based multiparameter laser scanning cytometer, PSL inhibited the progression of SMCs from G(0)/G1 to the S phase. This inhibition was associated with increased p27 expression level. PSL (2x10(-4) mol/L) also inhibited PDGF-induced SMC migration. CONCLUSIONS: Our results indicate that PSL has an antiproliferative effect on cultured SMCs of pulmonary arteries from patients with IPAH and suggest that PSL may be potentially useful therapeutically in patients with IPAH.

Abstract: It was recently reported that gene therapy using hepatocyte growth factor (HGF) has the potential to preserve cardiac function after myocardial ischemia. We speculated that this HGF gene therapy could also prevent ventricular arrhythmia. To investigate this possibility, we examined the antiarrhythmic effect of HGF gene therapy in rat acute and old myocardial infarction models. Myocardial ischemia was induced by ligation of the left descending coronary artery. Hemagglutinating virus of Japan (HVJ)-coated liposome containing HGF genes were injected directly into the myocardium fourteen days before programmed pacing. Ventricular fibrillation (VF)was induced by programmed pacing. The VF duration was reduced and the VF threshold increased after HGF gene therapy ( p< 0.01). Histological analyses revealed that the number of vessels in the ischemic border zone was greatly increased after HGF gene injection. These findings revealed that HGF gene therapy has an anti-arrhythmic effect after myocardial ischemia.

Abstract: The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

Abstract: We attempted to determine the usefulness of body surface mapping (BSM) for differentiating patients with Brugada syndrome (BS) from patients with asymptomatic Brugada syndrome (ABS). Electrocardiograms (ECG) and BSM were recorded in 7 patients with BS and 35 patients with ABS. Following the administration of Ic antiarrhythmic drugs, BSM was recorded in 5 patients with BS and 16 patients with ABS. The maximum amplitudes at J0, J20, J40 and J60 were compared between the 2 groups, as were 3-dimensional maps. The maximum amplitudes at J0, J20 and J60 under control conditions were larger in patients with BS than in patients with ABS (P < 0.05). A three-dimensional map of the ST segments under control conditions in patients with BS showed a higher peak of ST elevation in the median precordium compared to that for patients with ABS. Increases in ST elevation at J20, J40 and J60 following drug administration were greater in patients with BS than in patients with ABS (P < 0.05). Evaluation of the change in amplitude of the ST segment at E5 caused by Ic drug administration was also useful for differentiating between the 2 groups. In conclusion, BSM was useful for differentiating patients with BS from those with ABS.

Abstract: BACKGROUND: Some studies have shown that patients with Brugada syndrome (BS) have atrioventricular conduction disturbance, but their sinus node function has not been evaluated. METHODS AND RESULTS: The patients group consisted of 59 male patients and 1 female patient with BS. Supraventricular and ventricular programmed electrical stimulation (PES) was performed. Ventricular fibrillation (VF) or sustained polymorphic ventricular tachycardia was induced by ventricular PES in 26 patients with BS (VF group), but was not induced in the other 34 patients (non-VF group). Sinus node function and conduction of the atrioventricular (AV) node in the control group, non-VF group and VF group were evaluated. Sinus node function was attenuated and the His - ventricle interval was prolonged in the VF group (corrected sinus node recovery time: 452+/-126 ms (VF group), 324+/-146 ms (non-VF group), Sino-atrial conduction time: 179+/-60 ms (VF group), 127+/-60 ms (non-VF group), His-ventricle interval: 41+/-9 ms (VF group), 35+/-8 ms (non-VF group)). CONCLUSION: The function of both the sinus node and AV node are attenuated in patients with PES-induced VF.

Abstract: BACKGROUND: It has been reported that recording electrocardiograms (ECGs) in the 3rd intercostal space (ICS) is one method that can be used for detecting Brugada syndrome; however, the prevalence of Brugada-type ECGs recorded in the 3rd ICS and the usefulness of recording the ECG in the 3rd ICS in accordance with recently established electrocardiographic criteria is unknown. METHODS AND RESULTS: ECGs were recorded in both the 4th and 3rd ICS in 17 Brugada-type ECG patients (group A) and in 206 consecutive male subjects (group B). Brugada-type ECGs were divided into 3 types. In group A, the prevalence of type 1 ECG, which is a coved-type ECG with ST-segment elevation of >/=2 mm, increased from 23.5% to 64.7% when ECG was recorded in the 3rd ICS. The conversion to type 1 ECG was found to be related to induction of ventricular arrhythmia. In group B, the prevalence of Brugada-type ECG increased from 1.5% to 5.8% when the ECG was recorded in the 3rd ICS. CONCLUSIONS: Recording the ECG in the 3rd ICS is useful for identifying high-risk patients with Brugada-type ECG and for detecting concealed Brugada-type ECG.

Abstract: BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. METHODS AND RESULTS: The serum MCP-1 concentrations and the intimal - medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemically in radial arterial tissues obtained from the HD patients. IMT and the serum concentration of MCP-1 in the HD patients were both significantly greater than in controls. Multiple regression analysis revealed that the serum concentration of MCP-1 was an independent factor influencing IMT. Tissue immunostaining showed that MCP-1 is expressed in both endothelial and smooth muscle cells and that its level of expression correlates with the serum concentration of MCP-1. CONCLUSIONS: An increase in MCP-1 may be an important factor in the progression of atherosclerosis in non-diabetic HD patients.

Abstract: Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.

Abstract: INTRODUCTION: Repolarization and depolarization abnormalities have been reported to be related to Brugada syndrome. METHODS AND RESULTS: We evaluated the relationships between repolarization abnormality and depolarization abnormality using 48-lead unipolar signal-averaged electrocardiograms and 87-lead unipolar body surface maps in 15 patients with Brugada-type ECGs. Data were compared with those from healthy control subjects (n = 5) and within subgroups of Brugada syndrome with (n = 8) and without (n = 7) ventricular arrhythmias (VA) induced by programmed electrical stimulation (PES). Eighty-seven-lead body surface maps were recorded, and potential maps were constructed to evaluate elevation of the ST segment 20 ms after the J point. Forty-eight-lead signal-averaged ECGs were recorded, and isochronal maps of duration of the delayed potential (dDP) were constructed to evaluate the dDP in each lead. Potential maps showed that patients with Brugada-type ECG, especially those with VA induced by programmed electrical stimulation, had greater elevation of the ST segment in the right ventricular outflow tract, especially at E5. Isochronal maps of dDP in the Brugada-type ECG group showed that maximum dDP was located at E5 and that the area with long dDP was larger than that in the control subjects. The dDPs at E7, E5, F7, and F5 in the VA-inducible group were significantly longer than those in the VA-noninducible group. These results showed that the location of greater elevation in the ST segment coincided with the location of longer dDP. CONCLUSION: Repolarization abnormality and depolarization abnormality in the walls of both ventricles, especially in the right ventricular outflow tract, are related to the VA of Brugada syndrome.

Abstract: Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as beta-blockers, are more effective for relief of RVOTO.

Abstract: OBJECTIVES: The aim of this study was to test the hypothesis that epinephrine test may have diagnostic value for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome (LQTS). BACKGROUND: A differential response of dynamic QT interval to epinephrine infusion between LQT1, LQT2, and LQT3 syndromes has been reported, indicating the potential diagnostic value of the epinephrine test for genotyping the three forms. METHODS: The responses of 12-lead ECG parameters to epinephrine were retrospectively examined in 15 LQT1, 10 LQT2, 8 LQT3, and 10 healthy volunteers to select the best ECG criteria for separating the four groups. The epinephrine test then was prospectively conducted in 42 probands clinically affected with LQTS, their 67 family members, and 10 new volunteers. The best criteria were applied in a blinded fashion to prospectively separate a different group of 31 LQT1, 23 LQT2, 6 LQT3, and 30 Control patients (10 genotype-negative LQT1, 10 genotype-negative LQT2 family members, and 10 volunteers). RESULTS: The sensitivity (penetrance) by ECG diagnostic criteria was lower in LQT1 (68%) than in LQT2 (83%) or LQT3 (83%) before epinephrine and was improved with steady-state epinephrine in LQT1 (87%) and LQT2 (91%) but not in LQT3 (83%), without the expense of specificity (100%). The sensitivity and specificity to differentiate LQT1 from LQT2 were 97% and 96%, those from LQT3 were 97% and 100%, and those from Control were 97% and 100%, respectively, when Delta mean corrected Q-Tend >/=35 ms at steady state was used. The sensitivity and specificity to differentiate LQT2 from LQT3 or Control were 100% and 100%, respectively, when Delta mean corrected Q-Tend >/=80 ms at peak was used. CONCLUSIONS: Epinephrine infusion is a powerful test to predict the genotype of LQT1, LQT2, and LQT3 syndromes as well as to improve the clinical diagnosis of genotype-positive patients, especially those with LQT1 syndrome.

Abstract: OBJECTIVES: We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS). BACKGROUND: The LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms. METHODS: Sixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes. RESULTS: Patients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005). CONCLUSIONS: In this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations.

Abstract: BACKGROUND: Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors. HYPOTHESIS: The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors. METHODS: Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration. RESULTS: Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups. CONCLUSIONS: Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.

Abstract: Intraoperative transesophageal echocardiography is generally performed to detect vascular complications during lung transplantation. We report a case with a kink in pulmonary artery (PA) anastomosis suggested by an abnormal flow profile of pulmonary vein (PV) anastomoses during living-donor lobar lung transplantation. During the transplantation, velocity of blood flow through the right PV anastomosis showed abnormal elevation. Then, the patient's PA pressure elevated abnormally and a kink in the left PA anastomosis was found. Careful monitoring of PV anastomoses may enable detection of not only an abnormality of PV anastomoses but also that of PA anastomoses, especially in living-donor lobar lung transplantation.

Abstract: We report two cases of peripheral atelectasis during cadaveric and living-donor lobar lung transplantation, which had different effects on the flow profile of pulmonary vein (PV) anastomoses. In the patient who underwent living-donor lobar lung transplantation, we detected the increase in the velocity of blood flow through the left PV anastomosis by intraoperative transesophageal echocardiography. Then peripheral atelectasis occurred in the transplanted left lung lobe. On the other hand, in the patient who underwent cadaveric bilateral lung transplantation, peripheral atelectasis occurred, but no changes in velocities of blood flow through PV anastomoses were detected by intraoperative transesophageal echocardiography. This difference may have been caused by the difference in sizes of pulmonary beds of transplanted grafts. These findings indicate the necessity of careful monitoring of PV anastomoses, especially in cases of living-donor lobar lung transplantation.

Abstract: Ventricular fibrillation (VF) is induced in some asymptomatic patients with Brugada syndrome (BS), but the prognostic value of programmed electrical stimulation (PES) in such patients is controversial. The clinical characteristics of 41 asymptomatic BS patients, divided into 2 groups according to whether VF was induced by PES (inducible VF group: n=13, non-inducible VF group: n=28) were evaluated. ST levels in the right precordial leads were measured before and after administration of pilsicainide and the abnormal late potential (LP) was evaluated on the signal-averaged electrogram. The ST level at V(2) at baseline in the inducible VF group was significantly higher than that in the non-inducible VF group (p<0.05). Pilsicainide induced significant ST segment elevation in both groups and the ST level after pilsicainide in the inducible VF group was higher than that in the non-inducible VF group (p<0.01). LP was more frequent in the inducible VF group than in the non-inducible VF group. The criterion of ST level >0.15 mV at baseline with pilsicainide-induced additional ST elevation >0.10 mV and positive LP showed high sensitivity (92%) and specificity (89%) for detection of PES-induced VF in asymptomatic BS patients.

Abstract: OBJECTIVES: This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation carriers. BACKGROUND: The LQT1 form of congenital long QT syndrome is associated with high vulnerability to sympathetic stimulation and appears with incomplete penetrance. METHODS: The 12-lead electrocardiographic parameters before and after epinephrine infusion were compared among 19 mutation carriers with a baseline corrected QT interval (QTc) of > or =460 ms (Group I), 15 mutation carriers with a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls (Group IV). RESULTS: The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak-end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger in Group I than in the other three groups. Epinephrine (0.1 microg/kg/min) increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in Groups I and II, but not in Groups III and IV. The sensitivity and specificity of QTce measurements to identify mutation carriers were 59% (20/34) and 100% (27/27), respectively, before epinephrine, and the sensitivity was substantially improved to 91% (31/34) without the expense of specificity (100%, 27/27) after epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers in Groups I and II, and the prolongation of the mean QTce with epinephrine was significantly larger in symptomatic patients. CONCLUSIONS: Epinephrine challenge is a powerful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death.

Abstract: INTRODUCTION: It has been believed that electrophysiologic abnormality of the epicardial region of the right ventricular free wall may play an important role in arrhythmogenesis of phase 2 reentry in Brugada syndrome, but clinical evidence of the occurrence of ventricular arrhythmias at the right ventricular free wall has not been evaluated. In this study, we evaluated the site-specific inducibility of ventricular fibrillation (VF) and the origin of spontaneous premature ventricular contractions (PVCs) in patients with Brugada syndrome. METHODS AND RESULTS: Forty-five patients with Brugada-type ECG were enrolled in this study. Spontaneous PVCs were recorded in 9 patients. Programmed electrical stimulation (PES) was performed at the right ventricular apex (RVA), the free wall and septal region of the right ventricular outflow tract (RVOT), and the left ventricle (LV). The inducibility of PVT/VF was evaluated at each ventricular site, and the origin of PVC was determined by pace mapping. Sustained VF was induced in 17 patients. VF was induced in all 17 patients by PES at RVOT. Although PES at the septal region of the RVOT induced VF in only 5 patients (29%), PES at the free-wall region of the RVOT induced PVT/VF in 13 patients (76%). PES at RVA induced VF in only 2 patients (12%), and PES at LV failed to induce any arrhythmic events. Ventricular pace mapping showed that 64% of PVCs occurred at the free-wall region of the RVOT, 18% at the septal region of the RVOT, 9% at RVA, and 9% at LV. CONCLUSION: VF in patients with Brugada syndrome frequently is induced at the free-wall region of the RVOT area. The origin of PVC appears to be related to the site of PVT/VF induction by PES.

Abstract: OBJECTIVES: We administered pilsicainide chloride, a class Ic pure sodium channel blocker, to patients with Brugada syndrome (BS) and evaluated the occurrence of ventricular arrhythmia (VA) and T-wave alternans (TWA). BACKGROUND: Ventricular arrhythmia and TWA are sometimes induced by a sodium channel blocker challenge test in BS patients, but the significance of the induced VA and TWA is not known. METHODS: Pilsicainide was administered to 65 patients with BS (10 symptomatic and 55 asymptomatic patients), and the occurrence of VA, TWA, and change of electrocardiogram were evaluated. Electrophysiologic study was performed in 57 patients, and the induction of VA by programmed electrical stimulation (PES) was evaluated. RESULTS: Ventricular arrhythmia was not induced by administration of pilsicainide in 55 patients (no-VA group). Administration of pilsicainide-induced VA in 10 patients (Pil-VA group) and polymorphic ventricular tachycardia in four patients. Pilsicainide-induced VA in 60% of the symptomatic patients but in only 7% of asymptomatic patients (p < 0.01). ST level, QTc, and indexes of cardiac conduction in the Pil-VA group were not different from those in the no-VA group. Ventricular fibrillation was induced by PES in 67% of the patients in the Pil-VA group and in 33% of the patients in the no-VA group. In six cases, macroscopic TWA occurred in association with pilsicainide-induced VA, but TWA occurred in only one patient without pilsicainide-induced arrhythmia. CONCLUSIONS: Administration of a sodium channel blocker results in induction of not only ST-elevation but also VA and TWA in patients with BS.

Abstract: Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin II-induced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild-type and angiotensin II type-1a receptor knockout mice for 2 weeks. The angiotensin II treatment increased blood pressure and heart weight/body weight ratio in wild-type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alpha-phenyl-N-tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2-fold (p < 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type-1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.

Abstract: INTRODUCTION: Tissue factor plays a key role in the extrinsic coagulation pathway and is induced by inflammatory cytokines. Atrial myocarditis has been detected recently in some patients with lone atrial fibrillation. Virchow's triad of low blood flow, hypercoagulability, and endothelial dysfunction, enhances thrombus formation. The present study was designed to elucidate the role of endothelial dysfunction in thrombogenesis associated with nonvalvular atrial fibrillation. MATERIAL AND METHODS: We investigated tissue factor expression in the endothelia of left atrial appendages obtained from seven patients with nonvalvular atrial fibrillation and cardiogenic thromboembolism. Tissues were divided into 7-13 sections and compared with control specimens from four patients who died of noncardiac events. Expression of tissue factor, von Willebrand factor and tissue factor pathway inhibitor was evaluated by immunohistochemistry. RESULTS: Histopathologically, inflammatory cells infiltrated the endocardium and all seven patients showed features of persistent myocarditis. Activated T cells [15.3+/-9.4 cells/high power field (HPF, mean+/-S.D.) vs. control 2.2+/-4.4/HPF (P=0.0294)] and a few macrophages [5.1+/-8.4 cells/HPF vs. control 2.4+/-3.5 cells/HPF (P=NS)] infiltrated the endocardium. Tissue factor was overexpressed in the endothelia particularly in tissues containing inflammatory cells and denuded matrix of the endocardium, compared with the control group. Von Willebrand factor, but not tissue factor pathway inhibitor, was also overexpressed in these tissues. CONCLUSION: Tissue factor expression induced by local inflammation is involved in the pathogenesis of thrombosis in patients with nonvalvular atrial fibrillation.

Abstract: AIMS: Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome. METHODS AND RESULTS: We recorded a 12-lead electrocardiogram continuously before and after bolus injection (0.1 microg x kg(-1)) of epinephrine followed by continuous infusion (0.1 microg x kg(-1) min(-1)) in 12 LQT1, 10 LQT2, 6 LQT3, and 13 control patients. The QT intervals and previous RR intervals of all beats were measured semi-automatically, and the QTc intervals of all beats were calculated by Bazett's method. The dynamic response of the RR interval to epinephrine was no different between the four groups. The QTc was prolonged remarkably (477+/-42 to 631+/- 59 ms; P<0.0005, % delta prolongation =+32%) as the RR was maximally decreased (at peak of epinephrine), and remained prolonged at steady state conditions of epinephrine (556+/-56 ms; P<0.0005 vs baseline, +17%) in LQT1 patients. Epinephrine also prolonged the QTc dramatically (502+/-23 to 620+/-39 ms; P<0.0005, +24%) at peak of epinephrine in LQT2 patients, but this shortened to baseline levels at steady state (531+/-25 ms; P=ns vs baseline, +6%). The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state. CONCLUSION: Our data suggest that the dynamic response of ventricular repolarization to sympathetic stimulation differs between LQT1, LQT2 and LQT3 syndromes, and may explain why the trigger of cardiac events differs between the genotypes.

Abstract: BACKGROUND: Tissue factor pathway inhibitor (TFPI) has anti-proliferative and anti-migratory effects on cultured smooth muscle cells (SMC) in addition to its anti-thrombotic activity. Here, we assess how long locally delivered recombinant TFPI (rTFPI) remains detectable at the delivery sites and clarify the main mechanism by which rTFPI blocks neointimal growth in vivo. METHODS: The iliac arteries of 85 Japanese white rabbits were injured using a Cutting Balloon. First, to establish the efficacy of local delivery of rTFPI, 5 groups of 3 rabbits each were examined immediately or 1, 2, 4 or 7 days after delivery. They were treated locally with a total amount of 200 microg of rTFPI given at 40 microg per pulse per minute by means of a Pulse Spray catheter. Thereafter, 34 rabbits which had received 200 microg of rTFPI after cutting angioplasty were compared to the same number of controls regarding thrombosis, inhibition of neointimal proliferation and inflammation. RESULTS: A total of 2.6+/-1.6 ng rTFPI persisted on the injured vessel 4 days after delivery. rTFPI was still present on 48 % of the cut sites 7 days after delivery, despite its short half-life in plasma. Thrombosis in the rTFPI-treated group was significantly reduced compared to the controls. The number of macrophages present within the media and intima was significantly decreased at day 7 after delivery of rTFPI. Furthermore, the number of Ki-67-positive cells 14 days after rTFPI delivery was significantly lower than in controls although there were no significant differences between them after 2 days. CONCLUSIONS: Local delivery of rTFPI decreased the degree of neointimal formation 4 weeks after TFPI delivery because of anti-inflammatory and anti-proliferative effects in addition to, or rather than, via anti-thrombosis.

Abstract: BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure. CONCLUSIONS: Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

Abstract: OBJECTIVES: We tried to record an epicardial electrogram directly, and we examined local electrograms before and after administration of a class IC anti-arrhythmic drug in patients with the Brugada syndrome. BACKGROUND: Electrical heterogeneity of the epicardium in the right ventricular outflow tract (RVOT) has been thought to be related to the Brugada syndrome. However, an epicardial abnormality has not been demonstrated in patients with the Brugada syndrome. METHODS: In five patients with a Brugada-type electrocardiogram (ECG), local unipolar electrograms were recorded at the epicardium and endocardium of the RVOT. To record the epicardial electrogram directly, we introduced an electrical guidewire into the conus branch (CB) of the right coronary artery. The duration of the local electrogram after termination of the QRS complex (DP) was measured before and after class IC anti-arrhythmic drug administration. The signal-averaged electrocardiogram (SAECG) was also obtained in all patients. RESULTS: A definite DP was observed at the epicardium, but not at the endocardium. After administration of a class IC anti-arrhythmic drug, the DP at the epicardium was prolonged from 38 +/- 10 ms to 67 +/- 24 ms. The late potential corresponding to the DP at the epicardium was observed in all patients on the SAECG. CONCLUSIONS: An epicardial electrogram can be recorded from the CB. Recording from the CB enables identification of an epicardial abnormality in patients with the Brugada syndrome. These abnormal electrograms may be related to a myocardial abnormality in the epicardium of patients with the Brugada syndrome.

Abstract: OBJECTIVES: This study compared the effects of beta-blockade on transmural and spatial dispersion of repolarization (TDR and SDR, respectively) between the LQT1 and LQT2 forms of congenital long QT syndrome (LQTS). BACKGROUND: The LQT1 form is more sensitive to sympathetic stimulation and more responsive to beta-blockers than either the LQT2 or LQT3 forms. METHODS: Eighty-seven-lead, body-surface electrocardiograms (ECGs) were recorded before and after epinephrine infusion (0.1 microg/kg body weight per min) in the absence and presence of oral propranolol (0.5-2.0 mg/kg per day) in 11 LQT1 patients and 11 LQT2 patients. The Q-T(end) interval, the Q-T(peak) interval and the interval between T(peak) and T(end) (T(p-e)), representing TDR, were measured and averaged from 87-lead ECGs and corrected by Bazett's method (corrected Q-T(end) interval [cQT(e)], corrected Q-T(peak) interval [cQT(p)] and corrected interval between T(peak) and T(end) [cT(p-e)]). The dispersion of cQT(e) (cQT(e)-D) was obtained among 87 leads and was defined as the interval between the maximum and minimum values of cQT(e). RESULTS: Propranolol in the absence of epinephrine significantly prolonged the mean cQT(p) value but not the mean cQT(e) value, thus decreasing the mean cT(p-e) value in both LQT1 and LQT2 patients; the differences with propranolol were significantly larger in LQT1 than in LQT2 (p < 0.05). The maximum cQT(e), minimum cQT(e) and cQT(e)-D were not changed with propranolol. Propranolol completely suppressed the influence of epinephrine in prolonging the mean cQT(e), maximum cQT(e) and minimum cQT(e) values, as well as increasing the mean cT(p-e) and cQT(e)-D values in both groups. CONCLUSIONS: Beta-blockade under normal sympathetic tone produces a greater decrease in TDR in the LQT1 form than in the LQT2 form, explaining the superior effectiveness of beta-blockers in LQT1 versus LQT2. Beta-blockers also suppress the influence of sympathetic stimulation in increasing TDR and SDR equally in LQT1 and LQT2 syndrome.

Abstract: OBJECTIVES: We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND: Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS: The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS: Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS: Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Abstract: INTRODUCTION: The incidence of sudden death or ventricular fibrillation (VF) in asymptomatic Brugada syndrome patients with a family history of sudden death is reported to be very high. However, there are few reports on the prognosis of asymptomatic Brugada syndrome patients without a family history of sudden death. METHODS AND RESULTS: Eleven patients (all male; mean age 40.5 +/- 9.6 years, range 26 to 56) with asymptomatic Brugada-type ECG who had no family history of sudden death were evaluated. The degrees of ST segment elevation and conduction delay on signal-averaged ECG (SAECG) before and after pilsicainide were evaluated in all 11 patients. VF inducibility by ventricular electrical stimulation also was evaluated in 8 of 11 patients. Patients were followed for a period of 9 to 84 months (mean 42.5 +/- 21.6). The J point level was increased (V1: 0.19 +/- 0.09 mV to 0.36 +/- 0.23 mV; V2: 0.31 +/- 0.12 mV to 0.67 +/- 0.35 mV) by pilsicainide. Conduction delay was increased (total QRS: 112.2 +/- 6.3 msec to 131.7 +/- 6.3 msec; under 40 microV: 42.0 +/- 8.5 msec to 52.7 +/- 12.7 msec; last 40 msec: 17.4 +/- 5.9 microV to 10.4 +/- 6.1 microV) on SAECG by pilsicainide. VF was induced in only 1 of 8 patients. None of the patients had syncope or sudden death during a mean follow-up of 42.5 +/- 21.6 months. CONCLUSION: This study suggests that asymptomatic patients with Brugada-type ECG who have no family history of sudden death have a relatively benign clinical course.

Abstract: OBJECTIVES: The study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT sYndrome (LQTS). BACKGROUND: Cardiac events are more associated with sympathetic stimulation in LQT1 than in LQT2 or LQT3 syndrome. Experimental studies have suggested that the interval between Tpeak and Tend (Tp-e) in the electrocardiogram (ECG) reflects transmural dispersion of repolarization across the ventricular wall. METHODS: We recorded 87-lead body-surface ECGs before and after epinephrine infusion (0.1 microg/kg/min) in 13 LQT1, 6 LQT2, and 7 control patients. The Q-Tend (QT-e), Q-Tpeak (QT-p), and Tp-e were measured automatically from 87-lead ECGs, corrected by Bazett's method (QTc-e, QTc-p, Tcp-e), and averaged among all 87-leads and among 24-leads, which reflect the potential from the left ventricular free wall. As an index of spatial dispersion of repolarization, the dispersion of QTc-e (QTc-eD) and QTc-p (QTc-pD) were obtained among 87-leads and among 24-leads, and were defined as the interval between the maximum and the minimum of the QTc-e and the QTc-p, respectively. RESULTS: Epinephrine significantly increased the mean QTc-e but not the mean QTc-p, resulting in a significant increase in the mean Tcp-e in both LQT1 and LQT2, but not in control patients. The epinephrine-induced increases in the mean QTc-e and Tcp-e were larger in LQT1 than in LQT2, and were more pronounced when the averaged data were obtained from 24-leads than from 87-leads. Epinephrine increased the maximum QTc-e but not the minimum QTc-e, producing a significant increase in the QTc-eD in both LQT1 and LQT2 patients, but not in control patients. The increase in the QTc-eD was larger in LQT1 than in LQT2 patients. CONCLUSIONS: Our data suggest that sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than in LQT2 syndrome, and this may explain why LQT1 patients are more sensitive to sympathetic stimulation.

Abstract: BACKGROUND: It has been reported that administration of low-dose aspirin significantly reduces the frequency of major cardiovascular events in patients with hypertension and coronary artery disease. It is generally considered that the preventative effects of long-term aspirin administration on major cardiovascular events are due to the inhibition of platelet aggregation. HYPOTHESIS: It is not known whether administration of low-dose aspirin restores endothelium-dependent vasodilatation, and this study was undertaken to prove or disprove this question in patients with hypertension. METHODS: Flow-mediated endothelium-dependent dilatation and glyceryl trinitrate-induced endothelium-independent dilatation were investigated in 18 hypertensive patients and 10 normotensive control subjects. In the hypertensive patients, flow-mediated dilatation was investigated and cyclic guanosine monophosphate plasma (cGMP) was measured before and at 8 weeks after the administration of 162 mg of aspirin. RESULTS: Flow-mediated dilatation before aspirin administration was more reduced in the hypertensive patients than in the control subjects (6.4+/-2.0% vs. 11.3+/-2.3%, p <0.0001). Glyceryl trinitrate-induced dilatation before aspirin administration was similar in hypertensive patients and control subjects. Flow-mediated dilatation after aspirin administration was improved compared with that before aspirin administration (10.4+/-3.5% vs. 6.4+/-2.0%, p<0.0004). The cGMP product after aspirin administration was significantly higher than that before aspirin administration. CONCLUSIONS: Administration of low-dose aspirin may restore the endothelium-dependent vasodilatation in hypertensive patients. Furthermore, increased nitric oxide production may play a partial role in the improvement in endothelial function induced by administration of low-dose aspirin.

Abstract: We investigated the relationship between the effects of ischemic preconditioning (IPC) and Ca(2+) preconditioning (CPC) on reperfusion-induced arrhythmias. In the control group (noPC), Langendorff-perfused rat hearts were subjected to 5-min zero-flow global ischemia (I) followed by 15-min reperfusion (I/R). In ischemic preconditioning groups (IPC), the hearts were subjected to three cycles of 3-min global ischemia and 5-min reperfusion. In the CPC group, the hearts were exposed to three cycles of 3-min perfusion of higher Ca(2+) (2.3 mmol/l Ca(2+)) followed by 5-min perfusion of normal 1.3 mmol/l Ca(2+), and the hearts were then subjected to I/R. Verapamil was administered in several hearts of the IPC group (VR+IPC). Ventricular arrhythmias upon reperfusion were less frequently seen in the IPC and CPC groups than in the noPC and VR+IPC groups. IPC and CPC could attenuate conduction delay and enhance shortening of the monophasic action potential duration during ischemia. The ventricular fibrillation threshold measured at 1-min reperfusion was significantly higher in the IPC and CPC groups than in the noPC and VR+IPC groups. Verapamil completely abolished the salutary effects of IPC. These results demonstrate that Ca(2+) plays an important role in the antiarrhythmic effect of IPC during reperfusion.

Abstract: Hepatitis C virus (HCV) infection is frequently associated with autoimmune disease. We present here a case of dermatomyositis manifested as heart failure in which HCV was detected from an endomyocardial biopsy sample. HCV infection may have contributed to the left ventricular dysfunction in this patient with dermatomyositis.

Abstract: Drinking alcohol sometimes causes cardiac arrhythmia, but the precise mechanism remains unknown. To study the mechanism, we investigated the effects of ethanol exposure on the beating rate of cultured chick cardiac myocytes. Primary cultures of cardiac myocytes were prepared from the ventricles of 14-day-old chick embryos and then treated with ethanol which, in the range of 0.3 to 1.5 vol%, increased the beating rate in a dose-dependent manner. Ethanol (0.6 vol%) caused an increase in the beating rate, but disopyramide (5 microg/ml) and procainamide (10 microg/ml), Na+ and K+ channel blockers, inhibited the increase in the beating rate significantly. Neither lidocaine (5 microg/ml) nor mexiletine (2 microg/ml), Na+ channel blockers, nor calcium antagonist verapamil (5 ng/ml) inhibited the increase. However, tetraethylammonium chloride (ranging from 15 to 30 mmol/l), a K+ channel blocker, inhibited the increase. These findings indicate that ethanol increases the beating rate of cultured chick cardiac myocytes via the activation of the K+ channel. This experimental model may be useful in studying the effect of ethanol on the K+ channel.

Abstract:

Abstract: Restenosis after angioplasty is thought to be caused by proliferation and migration of vascular smooth muscle cells (VSMCs), and it is a most serious problem in medical treatment. A low dose (50 ng/ml) of manumycin A, an inhibitor of p21(ras) (ras) farnesylation, significantly inhibited proliferation of rat VSMCs stimulated by the platelet-derived growth factor (PDGF). The mitoinhibitory effect of manumycin A was dose- and time-dependent but was independent of cell density. Western blot analysis showed that manumycin A reduced the amount of functional ras localized at the cytoplasmic membrane and inhibited the phosphorylation of p42/44 mitogen-activated protein kinase (MAPK). Manumycin A also inhibited VSMC migration and disorganized alpha actin fibers, as shown by immnofluorecence staining. These results indicate that the interruption of the ras/MAPK signal transduction pathway and the disorganization of alpha actin fibers are the main cause of manumycin A inhibition of VSMC proliferation and migration induced by PDGF.

Abstract: To evaluate the relationship between the distribution of hypertrophy and the electrocardiographic findings in patients with hypertrophic cardiomyopathy (HCM), 54 HCM patients were studied using magnetic resonance imaging. The patients were divided into 4 groups according to hypertrophic patterns: (i) hypertrophy only at the apex (group I, n=12); (ii) hypertrophy in both the apex and base (group II, n=20); (iii) hypertrophy only at the base with asymmetric septal hypertrophy (ASH) (group IIIa, n=17); and (iv) hypertrophy only at the base without ASH (group IIIb, n=5). Abnormal Q waves in leads II, III and aVF were found in 1/12, 3/20, 10/17 and 0/5, respectively, and in leads I and aVL they were found in 1/12, 8/20, 4/17 and 1/5, respectively. The largest negative T waves (mm) were found in group I (group I vs group II vs group IIIa vs group IIIb: 15.2+/-5.3, 8.2+/-6.1, 1.6+/-2.0, 0.8+/-1.3, respectively). The largest positive T waves (mm) were identified in group IIIb (3.8+/-3.0, 6.8+/-3.2, 5.8+/-3.6, 9.3+/-2.1, respectively). The presence of abnormal Q waves reflected regional hypertrophy in HCM patients but the configuration of T waves represented the difference in the localization of hypertrophy between the basal and apical segments.

Abstract: BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF-alpha and Ang II might cause myocyte hypertrophy via the generation of ROIs. METHODS AND RESULTS: To test the hypothesis, we tested whether TNF-alpha and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2',7'-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-alpha and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-alpha (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [3H]leucine uptake, and BHA (10 micromol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 microg/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-alpha. CONCLUSIONS: These results indicate that TNF-alpha and Ang II cause hypertrophy in part via the generation of ROIs in cardiac myocytes.

Abstract: In patients with hypertrophic cardiomyopathy (HCM), we conducted cine magnetic resonance imaging (MRI) studies in which our objectives were to quantify the regional early diastolic function of the left ventricle and to evaluate the relationship between regional diastolic function and hypertrophy. Short-axis images of the left ventricle were recorded by cine MRI in 8 control patients and 24 patients with HCM. The images were then divided into 10 blocks to evaluate regional early diastolic function. The regional wall-thickness-time curve, the radius-time curve, and their first-derivative curves were computed for each of the 10 blocks. There was no difference between the time-to-peak-radius-increasing ratio and the time-to-peak-wall-thickness-thinning ratio in the 10 blocks in the control patients. These 2 parameters in the patients with HCM were significantly longer than those in the control patients. There was also a significant linear correlation between the time-to-peak-wall-thickness-thinning ratio and regional wall thickness. Cine MRI was useful for evaluating regional early diastolic function, which is apparently related to regional hypertrophy, in patients with HCM.

Abstract: A 53-year-old man who had no chest pain and no family history of heart disease demonstrated a rapid T wave change on an electrocardiogram, from a positive T wave to a giant negative T wave, within 1 year. Echocardiography showed no left ventricular hypertrophy before or after the T wave change. Cine-magnetic resonance imaging revealed focal apical hypertrophy after the appearance of the giant negative T wave. Although T wave inversions sometimes develop within a short period in patients with hypertrophic cardiomyopathy, they are rare in a patient without hypertension or chest pain.