永井 良三

We evaluated the characteristics of myocardial fatty acid metabolism in patients with left ventricular hypertrophy (LVH). Myocardial imaging with 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) was performed in 28 patients with hypertrophic cardiomyopathy (HCM), 15 patients with hypertensive heart disease (HHD), 13 patients with aortic stenosis (AS) and 8 normal controls (NC). The patients with HCM consisted of 13 patients of asymmetric septal hypertrophy (ASH), 7 patients of diffuse hypertrophy (Diffuse-HCM) and 8 patients of apical hypertrophy (APH). Planar and SPECT images of BMIPP were acquired 15 minutes and 4 hours after tracer injection. Resting 201Tl SPECT images and echocardiography were also performed on other days. We calculated heart/mediastinum count ratio and washout rate of BMIPP by using planar image. In patients with LVH, the incidence of reduced BMIPP uptake was more frequent than that of reduced 201Tl uptake. In delayed images, more than 60% of patients with LVH reduced BMIPP uptake, especially remarkable for patients with ASH and APH. The washout rate of all cardiac hypertrophic disorders was tended to be higher than that of normal subjects. Reduced BMIPP uptake was frequently found in septal portion of anterior and inferior wall in patients with ASH, in inferior wall in patients with Diffuse-HCM and HHD, in apex in patients with APH and AS. These results suggest that BMIPP scintigraphy can differentiate three types of cardiac hypertrophy.

Cardiac sarcoidosis, the main cause of death among patients with sarcoidosis, frequently becomes clinically apparent when the disease is far advanced. To evaluate the usefulness of the 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting cardiac sarcoidosis, 18F-FDG PET was performed in 16 patients with sarcoidosis (13 female, 63 +/- 12 yrs), compared with scintigraphic findings of 99mTc-MIBI and 67Ga. Ten of 16 patients were considered to have cardiac complications on clinical grounds with tissue confirmation such as positive endomyocardial biopsy, severe ventricular arrhythmia, more than second degree atrioventricular block, and echocardiographically proven ventricular dysfunction. Among these patients with cardiac complications, abnormal myocardial uptake of FDG were observed in all (100%), which confirms significantly higher frequency compared to 67Ga scintigraphy (50%) (abnormality of 99mTc-MIBI SPECT were observed in 80%). Although abnormal FDG accumulations were observed in region with decreased uptake of 99mTc-MIBI in many cases, localization of regional abnormality of each tracer was frequently independent. This discrepancy may reflect inflammatory and degenerative process of myocardium in cardiac sarcoidosis. 18F-FDG PET is thought to be a useful noninvasive method in detecting cardiac involvement of sarcoidosis and may provide a useful information on the activity of the disease.

αグルコシダーゼ阻害薬 (α阻薬), インスリン (In) 抵抗性改善薬 (トログリタゾン: TZD), 新型In注入器等, 登場以前の1991年 (前期) に6ヵ月以上通院していた糖尿病外来患者291例と, 登場後の1997年 (後期) の患者394例の血糖コントロール状況を比較した. 全体では前期のHbA1c 7.9±1.7%, 後期7.2±1.5%で, 後期の方が有意に低く (p<0.001) 血糖コントロール良好であった. 前期の経口薬治療138例の内訳は, スルフォニルウレア薬 (SU薬) 97.1%, ビグアナイド薬 (BG薬) 3.6%, 両者併用0.7%であったのに対し, 後期の194例ではSU薬54.1%, BG薬3.6%, α阻薬2.1%, Tr2.1%, 2種以上の薬物併用38.1%と多様化しており, HbA1cは前期8.6±1.7%, 後期7.4±1.3%と有意に低かった (p<0.001). In療法例も前期82例の経口薬併用が6.1%であったのに対し, 後期107例では34.6%と増加し, 注射回数も多く, HbA1cは前期8.6±1.9%, 後期7.9±1.6%と有意に低かった (p<0.01). 治療の多様化で, より良い血糖コントロールが得られていることが判明した.

QT延長症候群は致死性不整脈を呈し突然死の危険性が高い.以前より心臓交感神経系の不均衡が原因の一つとして考えられていた.近年,家族性QT延長症候群の原因として心筋イオンチャネルの遺伝子異常が同定された.遺伝子の同定によりQT延長のメカニズムのみでなく,心筋イオンチャネルの生理機能の解明も進んだ.心筋イオンチャネルの生理機能を解明することにより,不整脈治療への応用も期待される.

大動脈の急性障害は,虚血性心疾患に次ぐ突然死の原因となる循環器疾患である.急性の大動脈疾患は臨床症状が多彩で,診断・治療の進歩が日進月歩の今日でも,見落としや,診断の遅れが小なくない.また,致命的な合併症を併発する可能性が高いため,ハイリスク患者の同定や発症後の早期診断は,予後を決定する重要な要因である.この意味でも疾患の予防・早期発見を目標とした遺伝子・生化学的診断法は,最適な手段であり,開発・確立が急がれている.

This study was designed to assess how the glomerular expression of the nonmuscle-type myosin heavy-chain isoform, SMemb, is regulated in rats with focal glomerulosclerosis induced by puromycin aminonucleoside. SMemb was barely detectable in control glomeruli. On day 48 of focal glomerulosclerosis, SMemb was expressed in mesangial area and glomerular epithelial cells. When glomerulosclerosis became prominent on day 80, SMemb stained immunohistochemically in a focal segmental pattern in the sclerotic glomeruli. SMemb-expressing cells did not always express alpha-smooth muscle actin. In Northern blot analysis, SMemb mRNA was not detected in control glomeruli, whereas it was transiently upregulated in glomeruli on day 48 in rats with focal glomerulosclerosis. The mRNA levels of SMemb were thereafter gradually downregulated by day 80; however, they remained higher than those of control glomeruli. These data suggest that glomerular embryonic nonmuscle-type myosin heavy chain is abnormally regulated in glomerulosclerosis and that glomerulosclerosis may be associated with dedifferentiation of not only the mesangial cells, but also the other resident glomerular cells.

Chronic pressure overload is known to increase cardiac mass and expression levels of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs. Although mechanical stretching of cardiac myocytes could cause these changes, humoral factor(s) secondary to pressure overload may also be involved. To dissociate humoral effects from the effects of mechanical loading on cardiac hypertrophic responses, we examined expression of ANP and BNP at both mRNA and protein levels and proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded under conditions with or without hypertension by aortic coarctation. Seven days after transplantation, cardiac atrophy that usually occurs in transplanted hearts without hypertension by coarctation was prevented in the transplanted hearts with hypertension by coarctation. The levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts with relative to those without hypertension by coarctation. The plasma level of angiotensin II was higher in rats with than without hypertension by coarctation. Plasma endothelin-1 levels were not significantly different between the two groups. In addition, levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts without hypertension relative to those in the in situ hearts. The proportion of the V3 myosin isoform was also increased in the transplanted hearts without hypertension relative to the in situ hearts. These results indicate that humoral factor(s) secondary to the pressure overload produced by aortic coarctation enhanced the cardiac hypertrophic response and elevated the levels of mRNAs encoding these embryonic markers. Moreover, our findings regarding ANP and BNP expression in the transplanted hearts provide additional evidence that the fetal genes are reexpressed during the process of cardiac atrophy as well as in cardiac hypertrophy.

UNLABELLED: We compared myocardial viability evaluated by 18F-deoxyglucose (FDG) SPECT in 14 old myocardial infarction patients with that evaluated by 201TI SPECT and 123I-beta-methyl-iodophenyl pentadecanoic acid SPECT as imaging of fatty acid metabolism. FDG-SPECT was performed after oral administration of glucose. From each SPECT image which was divided into 7 segments, the degree of accumulation of each radioisotope (RI) was visually classified into four grades of defect score (ranging from 0 as normal to 3 as severe defect). The % uptake in the same area was also quantitatively calculated. RESULTS: The degree of accumulation of myocardial Rl relative to regional wall motion. FDG is the most wide for a range of accumulation of Rl of infarct area. Also, at FDG, in the area of wall motion had done a disorder, the degree of accumulation was higher than other two methods. In the infarcted area, the degree of accumulation on FDG-SPECT in the area of decreased wall motion was greater than that on the other two procedures. These results suggest that FDG-SPECT is useful for evaluating myocardial viability.

To evaluate the regional wall motion and the myocardial fatty acid metabolism at hibernating myocardium after revascularization (PTCA or CABG), we performed dual SPECT with 201Tl and 123I-beta-methyliodophenyl-pentadecanoic acid (BMIPP), and left ventriculography (LVG) in 34 patients with coronary artery disease before and 3 to 4 months after revascularization. In the SPECT, regional tracer uptake was estimated qualitatively (visual) and quantitatively (% uptake). Regional wall motion was estimated qualitatively (visual) and quantitatively (shortening fraction). At the 78 hibernating areas, the improvement of regional wall motion was more significantly (p < 0.05) correlated with that of regional tracer uptake of 123I-BMIPP (r = 0.63) than 201Tl (r = 0.39), and also correlated with the improvement of the difference between 201Tl and 123I-BMIPP regional uptake (r = 0.36). These results suggest that the improvement of wall motion at hibernating myocardium is more significantly correlated with the improvement of 123I-BMIPP than 201Tl uptake after revascularization.

We have previously shown that smooth muscle myosin heavy chain isoforms (SMs), including SM1, SM2, and SMemb, are differentially expressed during vascular development, and in vascular lesions, such as atherosclerosis. The SM1/2 gene is expressed exclusively in smooth muscle cells and generates SM1 and SM2 mRNAs by alternative splicing. Whereas SM1 is constitutively expressed from early development, SM2 appears only after birth. In this study, we have isolated and characterized the 5'-flanking region of the mouse SM1/2 gene. Transient transfection assays using a series of promoter-luciferase chimeric constructs demonstrated that tandem elements of the CCTCCC sequence, located at -89 and -61 bp relative to the transcription start site, were essential for transcriptional activity of the SM1/2 gene in primary cultured rabbit aortic smooth muscle cells and smooth muscle cell lines derived from the rabbit aorta but not in non-smooth muscle cells. Gel mobility shift assays indicated that CCTCCC was a binding site for nuclear proteins prepared from smooth muscle cells. Double-stranded oligonucleotides containing either the CACC box or the Sp1 consensus sequence efficiently competed with the CCTCCC elements for binding the nuclear extracts. Site-specific mutations of CCTCCC elements resulted in a significant reduction of the promoter activity. Moreover, CCTCCC elements are evolutionary conserved between mouse and rabbit. In conclusion, the results of this study indicate an important role for the interaction of the CCTCCC sequence with Sp1 or related factors in activating transcription from the SM1/2 gene promoter.

Romano-Ward syndrome, one of familial long QT syndromes, is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. By linkage analyses, three LQT loci were previously mapped: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, LQT3 on 3p21-24. It was recently brought to light that LQT2 and LQT3 were caused by mutations of the gene encoding cardiac ion channels. Mutations in HERG on chromosome 7q35-36, encoding potassium channels (Ikr), cause LQT2, and block of Ikr is a known mechanism for drug-induced prolongation of cardiac action potentials, which provides a mechanistic link between LQT2 and certain forms of acquired LQT. Mutations in SCN5A on chromosome 3p21, encoding the human heart voltage-gated sodium-channel alpha-subunit, cause LQT3. Mutant channels show a sustained inward sodium current during membrane depolarization, which explains prolongation of cardiac action potentials.

Romano-Ward syndrome (RWS) is an autosomal dominant disorder characterized by prolongation of the electrocardiographic QT interval, with clinical manifestations that include recurrent syncope and sudden death from ventricular arrhythmias. In order to find a long QT locus in Japanese patients and to identify DNA markers useful for presymptomatic diagnosis, linkage analyses were undertaken in 13 Japanese families with RWS patients by means of two DNA markers located on 11p15.5. One of these marker loci, HRAS, was previously reported to be tightly linked to the LQT locus in another ethnic group. Our analyses of homogeneity suggest evidence for genetic heterogeneity of RWS with the Japanese population.