Fujio Numano

Angiographic findings of Takayasu arteritis: New classification

Having proposed a new classification on angiographic findings of patients with Takayasu arteritis, we evaluated the angiographic findings of 80 Japanese patients and 102 Indian patients according to this classification. Japanese patients showed a higher frequency of involvement of the ascending aorta, aortic arch and its branches than did the Indians (P < 0.01). On the other hand, the frequency of involvement of the abdominal aorta and/or renal arteries was higher in Indian patients (P < 0.01). Type III cases of the new classification which involves the thoracic descending aorta, abdominal aorta and/or renal arteries were observed in 3% of the Indian patients, but not at all in the Japanese. In conclusion, in Japanese patients, vascular lesions tend to occur primarily in the ascending aorta, aortic arch and/or its branches and extend into the abdominal aorta. On the other hand, in Indian patients, the tendency is primarily in the abdominal aorta including renal arteries and extending into the thoracic aorta.

Clinical Manifestations of Takayasu Arteritis in India and Japan— New Classification of Angiographic Findings:

In this retrospective review 102 Indian and 80 Japanese patients with Takayasu arteritis were compared in regard to their clinical manifestations and angiographic findings. Regardless of nationality, most patients were initially affected in their teens or twenties. Japanese patients were female in a larger ratio compared with the ratio in India. Clinically, the two groups exhibited several different features. More Japanese patients were found to be pulseless (P<0.01) whereas many Indian patients were hypertensive (P<0.01). Inflammatory conditions in Japanese patients were more severe (P<0.01) and tended to be more prolonged than those in the Indians. More Japanese patients suffered from aortic regurgitation (P<0.01), but Indians suffered from hypertension (P<0.01). Angiographic findings revealed that the aortic arch and its branches were mainly involved in Japanese patients (type I, IIa) whereas the abdominal aorta and its branches were mainly involved in Indian patients (type IV). However, the diffusely involved type (type V) was the one most commonly found in both countries. From the analyses of vascular lesions in both Indian and Japanese patients, 510 and 396, respectively, different progressions of vasculitis are speculated. In Japanese patients, vasculitis generally occurs in the ascending aorta, the aortic arch, and/or its branches and extends into the thoracic and abdominal aorta, subsequently forming various complicated lesions with prolonged inflammatory activity. On the other hand, in Indian patients, vasculitis generally occurs in the abdominal aorta involving renal arteries, subsequently extending into the thoracic aorta within one or two decades, simple vascular lesions being formed. Data analysis suggests that this morbid condition progresses differently in India and Japan, in spite of some common etiologic factor(s).

Diagnostic criteria for Takayasu arteritis

Diagnosis of Takayasu arteritis (TA) is often delayed because of a non-specific clinical presentation. Ishikawas criteria (1988) has been widely used for the diagnosis of this disease. Few modifications have been proposed in Ishikawas criteria for the diagnosis of TA. The proposed modifications include: (a) removal of the obligatory criteria of age less than 40 years; (b) inclusion of characteristic signs and symptoms as a major criteria; (c) removal of age in defining hypertension; (d) deletion of the absence of aorto-iliac lesion, in defining abdominal aortic lesion; and (e) an addition of coronary artery lesion in absence of risk factors. The criteria proposed consists of three major criteria including left and right mid subclavian artery lesions and characteristic signs and symptoms of at least one month duration and ten minor criteria-a high erythrocyte sedimentation rate, carotid artery tenderness, hypertension, aortic regurgitation or annuloaortic ectasia, pulmonary artery lesion, left mid common carotid lesion, distal brachiocephalic trunk lesion, descending thoracic aorta lesion, abdominal aorta lesion and coronary artery lesion. Presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of TA. When applied to 106 Indian patients of angiographically proven TA and 20 control subjects, it had a sensitivity of 92.5% and specificity of 95% that was higher than that of Ishikawas criteria (sensitivity 60.4%, specificity 95%) and American college of Rheumatology criteria (sensitivity 77.4%, specificity 95%). Similarly, this criteria had a 96% sensitivity and 96% specificity in 79 Japanese patients of TA and 79 control subjects. Adoption of these criteria is expected to prevent the possibility of an under diagnosis of TA.

Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three-dimensional MR angiography.

The purpose of the study was to determine the diagnostic accuracy of breath‐hold contrast‐enhanced three‐dimensional (3D) magnetic resonance (MR) angiography in Takayasu arteritis. Thirty patients suspected of having Takayasu arteritis were examined with MR angiography and conventional angiography. Takayasu arteritis was diagnosed in 20 of these patients. MR angiography was performed using a 1.5‐T system after bolus injection of 0.1 mmol/kg of gadodiamide. MR angiography clearly depicted various vascular lesions in the aorta and its major branches in all 20 patients with Takayasu arteritis. It also depicted pulmonary artery lesions in 10 (50%) of the 20 patients. MR angiography accurately depicted 323 (98%) of 330 arteries, but 7 (2%) stenotic arteries were overestimated as occluded. The sensitivity and specificity of MR angiography for the diagnosis of Takayasu arteritis were both 100%. Breath‐hold contrast‐enhanced 3D MR angiography clearly depicts various vascular lesions in both the systemic and pulmonary arteries in Takayasu arteritis, thus allowing a definitive diagnosis of Takayasu arteritis. J. Magn. Reson. Imaging 2000;11:481–487.

Comprehensive analysis of HLA genes in Takayasu arteritis in Japan

To identify an HLA-linked susceptibility gene to Takayasus arteritis, comprehensive analysis of HLA genes was performed. By serologic HLA typing, positive associations of Takayasus arteritis with HLA-B52 and B39 were observed. The DNA typing of HLA-B gene and class II genes (DRB1, DQA1, DPB1) showed positive associations of the disease with HLA-B52, B39.2, DRB1 * 1502 and DPB1 * 0901, confirming in part the serologic observations. Comparison of odds ratio for the risk of disease revealed that HLA-B52 and B39.2 were primarily involved in the susceptibility, while the associations with DRB1 * 1502 and DPB1 * 0901 were suggested to reflect a strong linkage disequilibrium of these class II alleles with HLA-B52 in the Japanese population. Sequencing analyses of HLA-B52 and B39.2 from patients confirmed that they were B 5201 and B 3902, respectively. Comparison of amino acid sequences of these disease-associated HLA-B alleles identified critical amino acid residues of the HLA-B molecule, Glu and Ser at 63rd and 67th positions, respectively, which may determine the susceptibility to Takayasus arteritis via binding and presenting a yet unknown disease-related antigen.

The Effect of Glucose and Advanced Glycosylation End Products on IL‐6 Production by Human Monocytes

To clarify the mechanism that causes elevation of plasma fibrinogen levels in diabetes, we examined the effect of high concentration of glucose and/or advanced glycosylation end products (AGEs) on the production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by human monocytes. Monocytes isolated from nine healthy volunteers were incubated with glucose, glucose with mannitol, or glucose with AGE-BSA for 24 or 48 h, respectively. IL-6 and TNF-alpha levels of culture supernatants were measured by ELISA methods. IL-6 and TNF-alpha levels of culture supernatants incubated with 22 mM or 33 mM glucose showed considerable increase over basal levels incubated with 11 mM glucose, whereas those levels incubated with high concentration of mannitol showed no increase. These two cytokine levels of culture supernatants, especially IL-6 level, showed synergistic elevation with AGE-BSA concentration. Our serial observation with treatment for lowering glucose levels showed that the diabetics with decreasing plasma fibrinogen levels also showed decrease in plasma IL-6 levels. In this study, we revealed the effect of glucose and AGEs on the production of IL-6 or TNF-alpha by human monocytes. These results suggest that hyperglycemia and AGEs will cause disregulated production of IL-6 and hyperfibrinogenemia in diabetics.

Vasa vasoritis, vascu1itis and atherosclerosis

Abstract Takayasu arteritis, Buergers diseases, temporal arteritis, vascular Bechet disease and inflammatory abdominal aortic aneurysm are classified in Japan as intractable vasculitides involving mainly large vessels, because their etiologies are not yet elucidated and, therefore, treatments for them were not yet established. Recent experimental and vascular biological studies, however, have focussed on the roles of virus infection in vasa vasorum (vasa vasoritis) and on the subsequent inflammatory vascular changes through HLA and/or other autoimmune mechanisms. Several studies including ours have demonstrated that these vascular inflammatory changes progress from the adventitial side to the intimal side of the vessel, finally complicating atherosclerotic changes in the intima. These vascular inflammatory changes are also recognized during progression of atherosclerosis and these observations strongly suggest that inflammation is a serious risk factor of atherosclerosis.

Increased QT dispersion in patients with vasospastic angina.

BACKGROUND The risk factors for ventricular arrhythmias in patients with coronary vasospasm have not been identified. We evaluated QT dispersion in patients with vasospastic angina and its relation to susceptibility to ventricular arrhythmias during myocardial ischemia and reperfusion. METHODS AND RESULTS We assessed the corrected QT (QTc) dispersion before induction of coronary artery spasm by intracoronary injection of acetylcholine (baseline) and 30 minutes after administration of isosorbide dinitrate in 50 patients with vasospastic angina and 50 patients with atypical chest pain. The baseline QTc dispersion was significantly greater in patients with vasospastic angina than in patients with atypical chest pain (mean+/-SD: 69+/-24 versus 44+/-19 ms, 95% confidence interval of mean difference [CI]: 16 to 33 ms; P<0.001). QTc dispersion decreased significantly, to 48+/-15 ms (CI: 15 to 26 ms; P<0.001 versus baseline), after administration of isosorbide dinitrate in patients with vasospastic angina but did not change significantly in patients with atypical chest pain (mean+/-SD: 41+/-17 ms, CI: -3 to 9 ms). During the provocation test, 24 of 50 patients with vasospastic angina experienced ventricular arrhythmias. The baseline QTc dispersion was significantly greater in patients with than without ventricular arrhythmias (mean+/-SD: 77+/-23 versus 61+/-19 ms, CI: 4 to 26 ms; P<0.05). CONCLUSIONS Patients with vasospastic angina exhibited an increased baseline QTc dispersion compared with patients with atypical chest pain, which suggests that inhomogeneity of repolarization and susceptibility to ventricular arrhythmias are increased in patients with vasospastic angina, even when asymptomatic. The association between increased QTc dispersion and ventricular arrhythmias during the provocation test suggests that measurement of QT dispersion may help predict which patients with vasospastic angina are at high risk for ventricular arrhythmias during ischemia.

Coronary artery lesions in Takayasu arteritis: Pathological considerations

SummaryThis communication reviews the clinical and pathological features of coronary artery lesions in Takayasu arteritis. The incidence of coronary artery involvement has been reported to be 9% to 10%, and is observed mainly in autopsy cases because coronary artery disease is usually not evident until the occurrence of angina pectoris or myocardial infarction, or after the onset of congestive heart failure. On the basis of pathological features, the following three types of coronary artery lesions can be distinguished: type 1, stenosis or occlusion of the coronary ostia and the proximal segments of the coronary arteries; type 2, diffuse or focal coronary arteritis, which may extend diffusely to all epicardial branches or may involve focal segments, so-called skip lesions; and type 3, coronary aneurysm. Most of the coronary artery lesions in Takayasu arteritis are of type 1. Narrowing of the coronary arteries is mainly due to the extension of the inflammatory processes of proliferation of the intima and contraction of the fibrotic media and adventitia from the ascending aorta. In some cases, coronary stenosis may be caused by coronary arteritis as skip lesions in Takayasu arteritis, but even in these cases the lesions have been reported to affect mainly the proximal segments of the coronary arteries. Diffuse lesions of the coronary artery and coronary artery aneurysm seem to be very rare in Takayasu arteritis. Other causes of coronary ostial stenosis, coronary arteritis and coronary artery aneurysm are also discussed.

Takayasu's disease in twin sisters. Possible genetic factors.

Takayasus disease is well-known for its characteristic clinical features and its elusive etiology. Recently, we encountered twin Japanese sisters, both of whom were diagnosed as having Takayasus disease. The parents, two sisters, and one brother are healthy. Family history revealed the parents are first cousins. Analyses of serveral blood types and HLA typing were performed on all members of the family, and it was confirmed that these twins are monozygotic. Moreover, HLA typing analyses revealed that one haplotype found in the father was passed only to these twins. The history of consanguinity of the parents, the occurrence in twins, and the results of HLA typing suggest a genetic factor in the etiology of Takayasus disease.