今井 靖

Recently, variants in ATP-binding cassette transporter Al (ABCA1) were demonstrated to be associated with increased level of high density lipoprotein cholesterol (HDL-C) and decreased risk of coronary artery disease (CAD) in Caucasians. However, this is not universally applicable due to the ethnic or environmental differences. In this context, to clarify the effect of ABCAI in Japanese, we evaluated the phenotypic effects of I/M 823 and R/K 219 variants on the plasma level of HDL-C in 410 patients recruited in our hospital. Subjects with M 823 allele had significantly higher level of HDL-C than those without M823 allele (49.0 +/- 15.1 vs. 44.9 +/- 11.5 mg/dl, respectively, P < 0.05). This statistical significance did not change even after multiple regression analysis. In contrast, there was no difference in HDL-C level among the genotypes in R/K 219 polymorphism. Further, in our study population an inverse relationship was shown to exist between HDL-C level and incidence of CAD. However, no positive association was observed between those variants and susceptibility to CAD. In this study, we provide evidence that I/M 823 variant, not R/K 219 variant, in ABCA1 is one of the determinants of HDL-C level, suggesting the importance of this gene on lipid metabolism in Japanese. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Deficiency of protein S causes potential problems of thrombosis. Cases of familial venous thrombosis due to deficiency of protein S were presented. First, an 85-year-old woman had pulmonary thromboembolism due to left deep femoral venous thrombosis, which might be triggered by leg fracture and the long-term treatment with a plaster cast. Next, her 29-year-old granddaughter had episodes of recurrent venous thrombosis in her legs and arms, which might be triggered by the treatment with a plaster cast and abortion. In the latter part, the aspects of risks for thromboembolism, potential problems in gestational period, and an advisability of thromboprophylaxis in patients with deficiency of protein S are described.

The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and beta-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved. in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor alpha. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.

As the number of the genetic studies has rapidly increased in recent years, there has been growing concern that the privacy of the participants in such studies can be invaded unless effective measures are adopted to protect confidentiality. It is crucial for the scientific community to establish a method to anonymize DNA samples so that the public will trust genetic researchers. Here, we present a reliable and practical method of making DNA samples used in the genetic research anonymous. It assures complete anonymity by coding samples and personal information twice. Since it does not require equipment, such as bar-code readers or a software package, its cost is nominal compared with the laboratory costs. All institutions engaged in genetic research may wish to take measures such as the one described here to ensure the privacy and confidentiality of the participants in their genetic studies.

Objective-Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). Methods and Results-Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively, P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N-w-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%. respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. Conclusions-Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.

alpha -Calcitonin gene-related peptide (alpha CGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of alpha CGRP, we developed an alpha CGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained alpha CGRP-null mice than in corresponding wild-type mice. The elevated MAP in alpha CGRP-null mice was shown to be the result of elevated peripheral vascular resistance by alpha -adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between alpha CGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in alpha CGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that alpha CGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.

Genetically modified mice serve as a powerful tool to determine the role of specific molecules in a wide variety of biological phenomena including vascular remodeling. Several models of arterial injury have been proposed to analyze transgenic/knock-out mice, but many questions have been raised about: their reproducibility and physiological significance. Here, we report a new mouse model of vascular injury that resembles balloon-angioplasty. A straight spring wire was inserted into the femoral artery via arterioctomy in a small muscular branch. The wire was left in place for one minute to denude and dilate the artery. After the wire was removed, the muscular branch was tied off and the blood flow of the femoral artery was restored. The lumen was enlarged with rapid onset of medial cell apoptosis. While the circumference of the external elastic lamina remained enlarged, the lumen was gradually narrowed by neointimal hyperplasia composed of smooth muscle cells. At 4 weeks, a concentric and homogeneous neointimal lesion was formed reproducibly in the region where the wire had been inserted. Similar exuberant hyperplasia could be induced in all strains examined (C57BL/6J, C3H/HeJ, BALB/c, and 129/SVi). This model may be widely used to study the molecular mechanism of postangioplasty restenosis at the genetic level. (C) 2000 Academic Press.

症例:48歳男.小児時から胸部X線写真で左上部縦隔の異常陰影と左胸部上方に異常雑音があり,30歳時に高血圧を指摘された.頭痛のため来診し,上下肢間に血圧の差があることが明らかになった(上肢172/100mmHg,100/62mmHg)左胸部上方に連続雑音を聴取した.MRI血管造影及びDSAにより診断を確定,人工血管による再建術を行った

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P < 0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Coronary artery aneurysm (CAA) occurs in 6-12% of lesions after directional coronary atherectomy (DCA). The prognosis and the optimal treatment for DCA-related CAAs have not been well known. Therefore, we reviewed the clinical course of 214 consecutive patients with DCA-related CAAs who underwent DCA in our hospital. Follow-up coronary angiography 6 months after DCA was completed in 193 patients (212 lesions)and 14 lesions with CAAs (14 patients) were detected. We evaluated these 14 lesions by repeat coronary angiography at an average of 32 months after DCA in comparison with the adjacent reference vessel. Twelve of the 14 patients have been uneventful but 2 suffered from de novo angina due to new stenotic lesion unrelated to the DCA procedures. We compared the preprocedual angiographic characteristics and periprocedural parameters between the 14 lesions with CAAs [CAA (+) group] and the 198 without CAAs [CAA (-) group], but found no significant differences. Histological examination of specimens retrieved during atherectomy demonstrated that subintimal resection was more frequent in the CAA(+)group(57%) than the CAA (-)group (31%). The diameter of the aneurysm divided by the reference diameter was significantly larger at 6 months immediately after DCA (1.71 ± 0.21 vs 1.31 ± 0.18, p &lt 0.05) but did not change subsequently (1.68 ± 0.23). Our retrospective analysis revealed a good mid-term (an average of 32 months) prognosis for CAAs found by routine follow-up coronary angiography and also demonstrated that the depth of resection was significantly associated with aneurysm formation.

1. Vascular endothelial growth factor, a potent angiogenic mitogen, is known to be induced in response to ischaemia as well as being secreted from tumour cells. However, the precise mechanism of vascular endothelial growth factor release in acute myocardial infarction and the effects of coronary reperfusion on the circulating levels of vascular endothelial growth factor are still unknown. 2. Nineteen patients with acute myocardial infarction who underwent early reperfusion therapy were studied. Serum levels of vascular endothelial growth factor before reperfusion were markedly increased as compared with those in 19 healthy control subjects [252.4 +/- 158.1 pg/ml (mean +/- SD) compared with undetectable]. After reperfusion, the serum vascular endothelial growth factor levels rapidly returned almost completely to the normal control range. 4. These data strongly suggest that the serum level of vascular endothelial growth factor is one of the most sensitive indicators of myocardial ischaemia.