Case report: alternating exit sites in reentry circuit of ventricular tachycardia with nonischemic cardiomyopathy - relationship between ablation site and inner loop.

We present a patient with nonischemic cardiomyopathy who had ventricular tachycardia (VT) with QRS morphology alternans. VTs of two QRS morphologies (VT1 and VT2) exhibiting a right bundle branch block pattern with inferior axis was induced by ventricular pacing. The morphology of the QRS complex during VT1 exhibited more distinctively inferior axis than those during VT2. Induced VTs had similar morphologies to clinically the documented VTs. Pacemapping at anterolateral site of the left ventricle during sinus rhythm produced the same QRS complex of VT1 in a surface 12-lead electrocardiogram. A mapping study was performed with an electrode catheter located at the same site of LV during sustained VT1. The analysis of the local electrograms and postpacing interval during concealed entrainment at the catheter mapping revealed this pacing site was at the inner loop of the reentry circuit. Radiofrequency catheter ablation was performed at this site. The morphology of VT1 changed to different QRS morphology (VT2) during the first delivery of radiofrequency energy and was terminated after 20 seconds of the application. Then VT with alternans of QRS morphology and cycle length of VT1 and VT2 was induced by ventricular pacing, and was abolished by the second application of radiofrequency energy at this same site, suggesting that this site was located in the exit site close to inner loop of the reentry circuit and the alternans of QRS morphology was linked to the change of exit site.

Recombinant annexin II modulates impaired fibrinolytic activity in vitro and in rat carotid artery.

Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. The effect of rAN II on human umbilical vein endothelial cells (HUVECs) was measured. Addition of a fluorescent plasmin substrate revealed that HUVECs treated with rAN II exhibited significantly more plasmin generation than those treated with BSA. Moreover, rAN II treatment of HUVECs restored plasmin generation impaired by plasminogen activator inhibitor-1 or homocysteine pretreatment. In a rat carotid artery thrombus model, the patency of thrombosed carotid arteries was significantly enhanced by rAN II injection, in contrast to BSA injection, without systemic blood coagulation dysregulation. We found that rAN II enhanced plasmin generation on vascular endothelium in vitro and reduced thrombus formation in vivo, and concluded that enhancement of endothelial fibrinolytic activity by annexin II could modulate the hypercoagulable state of atherosclerosis. Further study of rAN II in vitro and in vivo may lead to the establishment of novel therapeutic approaches to thrombogenic vascular disease.

Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes.

OBJECTIVES: The goal of this study was to evaluate the relative effects of hyperglycemia and hyperinsulinemia on postprandial remnant lipoprotein (RLP) concentrations in newly diagnosed type 2 diabetics. BACKGROUND: Increases in fasting RLP concentration have been described in type 2 diabetics, as well as in insulin-resistant nondiabetics. Given the atherogenicity of RLPs, we have extended these observations by assessing postprandial RLP concentrations and observing that hyperglycemia was necessary for the increase in RLP concentrations. METHODS: Patients with type 2 diabetes were subdivided on the basis of their plasma insulin response to oral glucose into hyperinsulinemic (H-DM) and normoinsulinemic (N-DM) groups of 15 patients each. Plasma triglyceride (TG), RLP-TG and RLP cholesterol (RLP-C) concentrations were determined before and 2 and 4 h after an oral fat load in these patients and 10 control (CTL) subjects. RESULTS: Plasma TG, RLP-TG and RLP-C concentrations peaked 2 h after the fat load in the CTL group, returning to baseline within 4 h. In contrast, concentrations of these variables increased throughout the 4-h study in both groups of patients with type 2 diabetes. Total integrated plasma RLP-TG and RLP-C responses above baseline after the oral fat load were significantly higher in the H-DM group compared with the CTL (p = 0.019 and 0.009, respectively) or N-DM (p = 0.026 and 0.029, respectively) groups. Post-heparin lipoprotein lipase activities and apo E phenotypes were similar in the H-DM and N-DM groups. CONCLUSIONS: Remnant lipoprotein response to an oral fat load is significantly increased in hyperinsulinemic patients with type 2 diabetes. These changes may increase the risk of coronary heart disease in these individuals.

Fluid shear stress suppresses interleukin 8 production by vascular endothelial cells.

The effects of shear stress on interleukin 8 (IL-8) production by human umbilical vein endothelial cells (HUVEC) were studied by subjecting the HUVEC to a steady flow laminar shear stress of up to 0.7 N/m(2) in a parallel plate flow chamber. Shear stress decreased IL-8 mRNA expression in a dose and time-dependent fashion. High glucose concentrations increased IL-8 mRNA levels in a MAPK-p38-dependent manner, which was suppressed by shear stress. Measurement of IL-8 protein in HUVEC culture media by ELISA demonstrated that IL-8 secretion was also increased by high glucose and suppressed by shear stress. These results suggest that the anti-atherogenic effect of shear stress arises partly from the suppression of the production of IL-8 which has been shown to trigger the adhesion of monocytes to a vascular endothelium and also acts as a mitogen and chemoattractant for vascular smooth muscle cells.

Enhanced platelet sensitivity to prostacyclin in patients in an active stage of Takayasu arteritis.

Patients in an active stage of Takayasu arteritis are often complicated with thrombosis in the affected vessels. We investigated whether alteration of platelet sensitivity to prostacyclin is involved in platelet function in these patients. Twelve female patients in an active stage (48.3+/-11.8 years, mean+/-S.D.), diagnosed clinically by a persistently elevated erythrocyte sedimentation rate (>40 mm/h) with typical symptoms, along with 10 gender- and age-matched patients in an inactive stage and 12 control subjects were enrolled. Half-maximal concentration (EC(50)) for platelet aggregation to collagen was determined in the presence and absence of 1 nM iloprost, a stable prostacyclin analog. Sensitivity of platelets to prostacyclin was quantified by the ratio of EC(50) (R) in the presence of iloprost to that in its absence. Patients in an active stage exhibited enhanced platelet aggregation, as demonstrated by significantly lower EC(50) to collagen and increased plasma thromboxane B(2) concentration. However, R values in these patients were significantly higher (4.00+/-1.05; P<.001) than those in the inactive patients or controls (2.58+/-0.62 and 2.43+/-0.68, respectively), suggesting enhanced sensitivity to prostacyclin in patients with active disease. Plasma 6-keto-PGF1 alpha levels were lower in the active patients than those in other groups of subjects. We conclude that platelets in an active stage of TA may be sensitive not only to collagen but also to prostacyclin. The increase in sensitivity of the platelets to prostacyclin could be a compensatory mechanism against a decrease in the prostanoid production, presumably associated with endothelial dysfunction.

Triglyceride-rich lipoprotein cholesterol exceeds low-density lipoprotein cholesterol in hypertriglyceridemia patients.

The atherogenicity of triglyceride-rich lipoprotein has been revealed. This study was performed to explore the clinical importance of triglyceride-rich lipoprotein by measuring its cholesterol content and comparing it with other lipoprotein fractions. Blood samples were obtained from 103 patients whose fasting plasma triglyceride concentration exceeded 300 mg/dl. The cholesterol monitor using the technique of high-performance liquid chromatography was used for the measurement of their plasma cholesterol concentrations and the determination of cholesterol distribution among lipoprotein fractions. This monitor showed 4 peaks: large-triglyceride-rich lipoprotein, small-triglyceride-rich lipoprotein, low-density lipoprotein, and high-density lipoprotein. Total cholesterol increased with increasing triglyceride. The increment of total cholesterol was nearly equal to that of small-triglyceride-rich lipoprotein cholesterol. Small-triglyceride-rich lipoprotein cholesterol exceeded low-density lipoprotein cholesterol where plasma triglyceride concentration was over 500 mg/dl. In conclusion, triglyceride-rich lipoprotein may be clinically important for hypertriglyceridemic patients as a source of cholesteryl ester in arteriosclerotic plaques, and increased triglyceride-rich lipoprotein cholesterol may be used as a basis for hypertriglyceridemia atherogenicity. Our study suggests that hypertriglyceridemia should be treated to prevent arteriosclerotic disease.

Identification of MICA alleles with a long Leu-repeat in the transmembrane region and no cytoplasmic tail due to a frameshift-deletion in exon 4.

MHC class I chain-related gene A (MICA) is located close to HLA-B gene and expressed in epithelial cells. The MICA gene is reported to be highly polymorphic as are the classical class I genes. To further assess the polymorphism in the MICA gene, we analyzed a total of 60 HLA-homozygous cells for the sequences spanning exons 2-6. In the analysis, four new MICA alleles were identified and six variations were recognized in exon 6. MICA*017, which was identified in three HLA-B57 homozygous cells (DBB, DEM and WIN), differed from MICA*002 in exon 3 and had a guanine deletion at the 3' end of exon 4. MICA*015 identified in an HLA-B45 homozygous cell (OMW) also had the same deletion that causes a frameshift mutation resulting in complete change of the transmembrane region and premature termination in the cytoplasmic tail; these alleles have a long hydrophobic leucine-rich region instead of the alanine repeat in the transmembrane region and terminate at the second position in the cytoplasmic domain. The frameshift deletion was found only in HLA-B45- or -B57-positive panels tested, suggesting a strong linkage disequilibrium between the deletion and B45 or B57. MICA*048, which was different in exon 5 from MICA*008, was identified in an HLA-B61 homozygous cell (TA21), while MICA*00901 identified in HLA-B51 homozygous cells (LUY and KT2) was distinguished from MICA*009 by exon 6.

Colon cancer cell adhesion to endothelial E-selectin inhibits detachment of endothelial cells through activation of beta(1)-integrin.

Previous studies have implicated a role for E-selectin in carcinoma cell adhesion to vascular endothelium. We examined the role of colon cancer cell adhesion to vascular endothelium via E-selectin using adenoviral vector-mediated transfection in human umbilical vein endothelial cells (HUVECs). We found that the amount of HUVEC detachment from the gelatin matrix 24 h after LS-180 cell adhesion was inhibited only when the HUVECs were transduced with wild-type E-selectin, but not with a cytoplasmic domain truncated mutant E-selectin or the control Lac-Z vector. We also found that the adhesion of LS-180 cells to wild-type E-selectin transduced HUVEC-induced activation of beta(1)-integrin receptors without affecting MMP activity. These results indicate that colon cancer cell adhesion via E-selectin inhibits HUVEC detachment from the monolayer, at least in part by modulating beta(1)-integrin activity in HUVECs. In addition, they indicate the importance of the cytoplasmic domain of E-selectin with this phenomenon.

Spontaneous regression over a 16-year period of tachyarrhythmias to sick sinus syndrome and complete atrioventricular block in a young patient with Ebstein's anomaly.

A 25-year-old man with Ebstein's anomaly showed spontaneous regression of tachyarrhythmias to sick sinus syndrome and complete atrioventricular block over a 16-year period. This is the first clinical report supporting the hypothesis that abnormal cell death might contribute to the disturbance of the heart conduction system in Ebstein's anomaly.

Hmg-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been reported to exert actions independent of their lipid-lowering effects. To critically assess the effects of statins on monocyte-endothelial cell interactions, we used an in vitro model that mimicked physiological flow conditions. Monocytic U937 cells were incubated in the presence of cerivastatin for 48 hours. Adhesive interactions of statin-treated U937 cells were then analyzed by use of activated (interleukin-1beta 10 U/mL, 4 hours) human umbilical vein endothelial cells in an in vitro flow apparatus. Flow cytometric analysis of adhesion molecules and measurement of F-actin content in U937 cells were performed before and after statin treatment. Preincubation with cerivastatin significantly decreased U937 firm adhesion to activated human umbilical vein endothelial cells, whereas U937 rolling was not decreased. Fluorescence-activated cell sorter analysis revealed downregulation of U937 surface expression of CD11a, CD18, and VLA4 after statin treatment. Cerivastatin significantly reduced F-actin content in U937 cells and inhibited RhoA translocation, whereas preincubation with C3 exoenzyme reduced U937 adhesion under flow. Cerivastatin reduces monocyte adhesion to vascular endothelium under physiological flow conditions via downregulation of integrin adhesion molecules and inhibition of actin polymerization via RhoA inactivation. Our findings have important implications for the lipid-independent effects of statins.

Left ventricular apical aneurysm in cardiac sarcoidosis.

A 53-year-old woman was hospitalized for general fatigue and palpitations. An electrocardiogram showed ST elevation and T wave inversion in leads II, III, aVF, and V4-6. Cardiac catheterization was performed since the echocardiogram demonstrated the existence of a left ventricular apical aneurysm. Left ventriculography showed an aneurysm of the apex. An endomyocardial biopsy specimen from the left ventricular apical wall demonstrated typical noncaseating granulomas with giant cells. The patient was diagnosed as having cardiac sarcoidosis. There was no evidence suggesting involvement of other systemic organs. Cardiac sarcoidosis should be considered within a spectrum of diseases that cause left ventricular aneurysm.

Polymorphic ventricular tachycardia in patients with vasospastic angina--clinical and electrocardiographic characteristics and long-term outcome.

There have been few clinical studies exploring the characteristics of spontaneous polymorphic ventricular tachycardia (VT) during a vasospastic angina attack. During a 4-year recruitment period, Holter ECG recordings were monitored for 42+/-24 h during a drug-free period in 60 consecutive patients with vasospastic angina (VSA) and of these, 8 patients had at least one episode of polymorphic VT during monitoring. Ischemic ST segment elevation was immediately preceded the spontaneous polymorphic VT in all 8 patients, 4 of whom had silent coronary vasospasm. Immediately before the onset of polymorphic VT, both R-on-T and long-short sequences were observed in 4 of the 8 patients and ST wave alternans were recorded in 2 patients. VT exhibited a pattern of torsade de pointes in 4 of the 8 patients. Five patients underwent electrophysiologic testing during a drug-free asymptomatic phase, and polymorphic VT was induced in 2 of the 5 patients, with one developing ventricular fibrillation. During a follow-up period of 73+/-17 months, there was a significant difference in the incidence of sudden death between patients with and without VT (2/8 cases [25%] vs 0/52 [0%]; p<0.01). Thus, vasospastic attacks, even if asymptomatic, that immediately precede the development of polymorphic VT may be associated with a repolarization abnormality and an increased risk of sudden death.

Stimulation of arterial smooth muscle cell proliferation by remnant lipoprotein particles isolated by immuno-affinity chromatography with anti-apo A-I and anti-apo B-100.

Postprandial lipidemia, characterized by high plasma triglyceride-rich lipoprotein remnants, is associated with atherosclerosis. It has also been known that proliferation of vascular smooth muscle cells is crucial for the development of atherosclerosis. In this study, we investigated the direct effect of remnant lipoprotein particles, which consist of chylomicron remnants and very low density lipoprotein remnants, on vascular smooth muscle cell proliferation. Blood was collected from six patients with postprandial lipidemia two hours after their usual meal. Remnant lipoprotein particles were isolated from plasma by immuno-affinity chromatography containing two monoclonal antibodies, anti-apo A-I (H-12) and anti-apo B-100 (JI-H). Remnant lipoprotein particles, as well as betaVLDL, significantly stimulated the proliferation of porcine coronary artery smooth muscle cells in a concentration-dependent manner, whereas very low density lipoprotein (d < 1.006) was virtually ineffective. These observations are consistent with recent reports that triglyceride-rich lipoprotein remnants, which are rich in apo E as well, are atherogenic.

Lack of association between the Met196Arg polymorphism in the TNFR2 gene and autoimmune diseases accompanied by vasculitis including SLE in Japanese.

A polymorphism in high-affinity receptor of TNF (TNFR2) gene, Met196Arg, was reported to be associated with systemic lupus erythematosus (SLE) in Japanese, whereas the association could not be found in Europeans at all and this represents an apparent discrepancy. The association, then, should be tested in other populations to clarify the possible involvement, if any, of the TNFR2 polymorphism in SLE or other related autoimmune diseases. The purposes of this study were to examine the TNFR2 polymorphism in Japanese patients with SLE and to investigate its association with other autoimmune diseases accompanied by vasculitis, mixed connective tissue disease, Buerger's disease, and Takayasu's arteritis. We found no association at all between the TNFR2 polymorphism and any autoimmune diseases including SLE in Japanese.

Regional wall motion abnormalities during early diastole in patients with hypertensive left ventricular hypertrophy: a Doppler tissue echocardiographic study.

To investigate left ventricular wall motion asynchrony in patients with hypertensive heart disease, we measured regional myocardial velocity in hypertensive patients with left ventricular hypertrophy and in normotensive individuals using tissue Doppler imaging. The endocardial velocity and the myocardial velocity gradient were measured in the basal and mid segments of the septal and posterior walls. The dilating velocity of the left ventricular cavity were determined for the basal and mid ventricular segments of left ventricle. The peak myocardial velocity gradient was significantly lower in the hypertensive group than in the control group for all regions. The peak endocardial velocity during early diastole in the mid ventricular septum was significantly lower in the hypertensive group (Hypertensive vs Controls; 3.8 +/- 1.3 vs 5.1 +/1.6 cm/s, P < 0.05), whereas the peak endocardial velocity at the other three sites were similar in the two groups. The peak dilating velocity was significantly lower in the hypertensive group only in the mid portion of the left ventricle (Hypertensive vs Controls; 7.2 +/- 2.4 vs 9.8 +/- 1.3 s(-1), P < 0.005). These results suggest that there were regional wall motion abnormalities and nonuniformity during the early diastolic phase in the hypertensive hearts with left ventricular hypertrophy.

Metabolism of triglyceride-rich lipoproteins and their role in atherosclerosis.

Recent large-scale clinical trials indicate that hypertriglyceridemia is a risk factor in coronary artery disease; however, the mechanism has not yet been completely clarified. We are currently studying the metabolism of triglyceride-rich lipoproteins and their role in atherosclerosis. Remnants, one of atherogenic lipoproteins, showed a marked increase and remained high even 8 hours after fat loading, especially in patients with coronary artery disease or diabetes mellitus. This shows that the postprandial state persists almost the whole day in these patients. Accordingly, it may be important to assess post-prandial remnant concentrations when evaluating risk factors for atherosclerosis. We identified apo B100 expression in the epithelial cells of the small intestine by immunoblotting with anti-apo B100 monoclonal antibody and dot-blotting of PCR-amplified cDNA. This indicates that not only apo B48, but also apo B100 is expressed in human small intestinal epithelium. The expression of apo B100 suggests that dietary VLDL may be synthesized in human small intestinal epithelium and converted into LDL, which may play an important role in atherosclerosis. A new receptor, apo B48, which binds and internalizes triglyceride-rich lipoproteins via a domain in apo B48, was identified in human monocyte-macrophages. The receptor differs from the scavenger receptor family and LDL receptor family because it does not bind acetyl LDL and it does bind VLDL devoid of apo E. Immunohistochemical studies indicate colocalization of anti-apo B48 receptor antibody in human atherosclerotic lesion foam cells, suggesting that apo B48 receptor may contribute to foam cell formation and atherosclerosis.

Potential role of recombinant annexin II in diabetic vascular injury.

Hyperinsulinemia and hyperglycemia have been associated with vascular injury such as atherosclerosis in diabetes mellitus. Recently, annexin II, a member of annexin family proteins, has been found to work as co-receptor on endothelial cells for plasminogen and tissue plasminogen activator, facilitating plasmin generation on the surface of vascular endothelium. In this review, we overviewed the effect of glucose and insulin on plasmin generation in endothelial cells and its potential modulation by recombinant annexin II (rAN II) based on our data.