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Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC., Methods and Results: We recruited children with left ventricular noncompaction from Japanese multi-institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy-associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0-6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate ( P =0.0009)., Conclusions: Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease-causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality-related cardiac phenotypes.

Purpose: This study is to investigate whether angiotensin type 1 receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis) can regress coronary artery aneurysm (CAA) in patients with Kawasaki disease (KD)., Methods: This multicenter, prospective, observational study was conducted at 53 institutions throughout Japan. We enrolled patients who were diagnosed with KD after January 2015 and had a medium or large CAA (maximum luminal diameter ≥ 4 mm or z score ≥  + 5) 30 days or later after KD onset., Results: Of the 209 patients, 47 (22%) were taking ARBs/ ACEis. Compared with those in the non-ARB/ACEi group, the baseline CAA diameter was significantly greater (6.7 mm vs. 5.5 mm, p < 0.01), and bilateral CAA (70% vs. 59%, p = 0.01) and giant CAA (32% vs. 20%, p = 0.08) were more frequently observed in the ARB/ACEi group. Although the overall regression rates did not differ between the groups (67% vs. 65%), the regression rates of giant CAA were approximately 1.6 times greater in the ARB/ACEi group than in the non-ARB/ACEi group (36% vs. 23%). Multivariate Cox regression analysis after adjustment for other clinical variables suggested that ARBs/ACEis may be a factor in CAA regression (hazard ratio [HR]: 1.5, 95% confidence interval [CI]: 0.91-2.46)., Conclusions: Although ARBs/ ACEis were used more frequently in patients with severe CAA, these patients had similar CAA regression rates to patients not taking ARBs/ACEis. ARBs/ACEis may be beneficial agents aimed at inducing CAA regression in KD patients., What Is Known: • Large CAAs are less likely to regress and are always at risk of life-threatening cardiac events. • Moderate CAA, age less than 1 year, and female sex have been reported to be factors that promote the regression of CAA., What Is New: • Although ARBs/ACEis were used more frequently in patients with severe CAA, these patients had a similar rate of CAA regression to patients who did not take ARBs/ACEis. • The regression rates of giant CAA were approximately 1.6 times greater in the ARB/ACEi group than in the non-ARB/ACEi group., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To elucidate epidemiologic and clinical manifestations of Japanese patients with giant cell arteritis (GCA), the first nationwide survey for GCA was conducted in 1998 in Japan., Methods: The first questionnaire on GCA for patients treated in 1997 was sent to 10,717 medical departments in Japan. A total of 177 patients were reported. Among the 177 patients, 66 GCA patients with detailed clinical and epidemiologic features on second survey were analyzed., Results: Prevalence in patients 50 years of age and older in 1997 was 1.47 per 100,000 population in Japan. The average age at onset was 71.5 years old. The male:female ratio was 1:1.7. The association with permanent and complete visual loss (6.5%), jaw claudication (15.2%), and polymyalgia rheumatica (PMR) (30.3%) were low in frequency compared with those reported from other countries. All patients were treated with corticosteroids. Only 3 (4.5%) patients were reported as deceased due to other causes., Conclusion: The prevalence of GCA in Japan was revealed to be extremely low compared with other countries. Clinical findings of permanent and complete visual loss, jaw claudication, and PMR were infrequent among Japanese patients with GCA.

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.

We report a case of scurvy, which is rarely encountered in Japan. A 75-year-old male was hospitalized with diffuse subcutaneous hemorrhaging of both feet, pain on walking, and shortness of breath. A remarkably low serum level of vitamin C was confirmed. Administration of ascorbic acid dramatically improved his clinical symptoms. Improvement paralleled the increase of serum vitamin C level. This case underscores the important role of vitamin C on the integrity function of the vessel wall.

To identify an HLA-linked susceptibility gene to Takayasu's arteritis, comprehensive analysis of HLA genes was performed. By serologic HLA typing, positive associations of Takayasu's 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 Takayasu's arteritis via binding and presenting a yet unknown disease-related antigen.

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.

To analyze the genetic factors involved in the pathogenesis of Buerger's disease, the polymorphisms of HLA class II genes (HLA-DP, -DQ and -DRB) were investigated in 36 patients using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. HLA class I (B54 and B52) and HLA class II (DQ alleles) genes were also typed by polymerase chain reaction-sequence-specific oligonucleotide probe (PCR SSOP) method to confirm alleles. PCR-RFLP typing revealed that the frequencies of HLA class II genes, DRB1*0405, DQB1*0401, DQA1*03 and DPB1*0501, were significantly increased in the patients with Buerger's disease compared with the healthy controls. Further, DNA typing confirmed that HLA-B54 was associated with Buerger's disease. These results suggested that the haplotype of HLA-B54-DRB1*0405-DQB1*0401- DQA1*03-DPB1*0501 was associated with Buerger's disease in Japanese population.

Visceral leishmaniasis is a chronic infectious disease caused by a protozoan parasite of the genus Leishmania, characterized by intermittent fever, monocytosis, hepatosplenomegaly and hypergammaglobulinemia. This morbid condition is rather difficult to diagnose correctly, especially at its early stage, because it is rarely encountered in Japan. Recently we treated a case of visceral leishmaniasis in which the patient was misdiagnosed as malignant lymphoma, and went through splenectomy and steroid administration, which made the diagnosis more difficult.

We studied the thoracic aorta in 42 female patients with Takayasu arteritis by magnetic resonance imaging (MRI) with a 1.5-T superconducting instrument and compared the findings with those in 10 healthy female controls. Images in the transaxial and oblique sagittal planes were acquired by cardiac gating using a spin-echo pulse sequence. Images in the oblique plane were also obtained with cine MRI. Vascular changes were found in 41 (98%) of the patients. Dilatation of the ascending aorta was observed in 20 patients (48%), while stenotic changes were more characteristic in the descending aorta (16 patients, 38%). Moderate signal-intensity masses on the aortic wall were encountered in 21 patients (50%), suggesting mural thrombi. Turbulent blood flow was observed around all masses by cine MRI. HLA analysis revealed that patients carrying HLA-B52 typing showed these masses more frequently than those without this typing (P < 0.05). Cine MRI demonstrated aortic regurgitation in 20 patients (48%), all of whom showed dilated ascending aorta; furthermore, 14 (70%) of them were confirmed as carrying HLA-B52. Thus, MRI was a useful non-invasive tool not only for the evaluation of the morphological changes in the aorta and its branches, and of the hemodynamic disturbance in Takayasu arteritis, but also for follow-up of the morbid condition.

The polymerase chain reaction (PCR) in combination with the sequence-specific oligonucleotide probe (SSOP) was applied to analyze the polymorphism in the exon 2 of the HLA-B gene. In this study, genomic DNAs from 85 B-lymphoblastoid cell lines homozygous for HLA and peripheral blood granulocytes of 156 Japanese individuals were investigated. Two HLA-B-specific 5'-sided primers (CG4 and CG5) and two 3'-sided primers (CG2 and CG3) were designed for specific amplification of the exon. HLA-B alleles were classified into two groups (groups I and II) according to specific amplification with two types of the 3'-sided primers. The amplified DNAs were hybridized with 23 nonradioactively labeled SSOPs. Based on the hybridization patterns with the SSOPs, 34 HLA-B specificities were divided into 26 epitope combination (EC) groups. Fifteen HLA-B specificities were classified into four EC groups and these HLA-B specificities could not be distinguished from one another in the same EC group. Another 16 HLA-B specificities corresponded one by one to 16 distinct EC groups, and two subtypes of HLA-Bw75, B27, and Bw48 were also identified enabling the accurate typing of 22 HLA-B alleles at the DNA level. Single-strand conformation polymorphism (SSCP) of the PCR products from group I HLA-B alleles was also investigated. The HLA-B alleles showed distinct electrophoretic patterns in nondenaturing polyacrylamide gels, depending on the nucleotide sequences of the exon 2, indicating that the SSCP analysis may be an alternative, useful and practical HLA-matching system of HLA-B specificity in tissue transplantation.

Sixty-four patients with Takayasu arteritis and 317 healthy individuals in the Japanese population were examined for HLA-A, -B and -C alleles by serological typing and for HLA-DR, DQ and DP alleles by DNA typing using PCR/SSOP analysis. The frequencies of HLA-Bw52, DRB1*1502, DRB5*0102, DQA1*0103, DQB1*0601 and DPB1*0901 alleles were significantly increased and the frequencies of HLA-Bw54, DRB1*0405, DRB4*0101, DQA1*0301, DQB1*0401 alleles were significantly decreased. Strong linkage disequilibria among the increased alleles and among the decreased alleles were evident in the Japanese population. Therefore, the combination or haplotype of HLA-Bw52-DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0601 -DPA1*02-DPB1*0901 may confer susceptibility to Takayasu arteritis while another combination or haplotype of HLA-Bw54-DRB1*0405-DRB4*0101-DQA1*0301-DQB1++ +*0401 may confer resistance to the disease. Because this is the first evidence for the association between an HLA-DP allele and Takayasu arteritis, we examined the nucleotide sequences of the DPB1*0901 allele from a patient and her healthy relatives and found no difference. The disease is therefore not caused by a mutated DPB1 gene.

In an attempt to provide support for the genetic link theory as related to the etiology of Takayasu's disease, we analyzed simultaneously A, B, and D loci of HLA antigens in 75 Japanese patients with the disease. Serving as control were 128 healthy Japanese. A statistically significant high frequency of BW52 and DHO was confirmed with the levels being 25.6 and 10.4, respectively, in the chi 2 test. A haplotype of A9-BW52-DHO was frequently evident in these patients as compared to the controls, and here also the statistical difference was significant. There appears to be a closer relationship of the gene to BW52 than to DHO. A survey of the homozygote of BW52 revealed 6 of 75 patients with BW52; however, statistically speaking, this rate did not differ from the expected one. Thus, our analysis of HLA illustrates the genetic factors involved in Takayasu's disease. The genes are located between the B and D loci and are closer to BW52 than DHO and these genes have a dominant character.

Takayasu's disease is characterized by a "pulseless" condition which most often occurs in young females from Asian or South American areas. The cause of this disease remains obscure. Recently, we encountered monozygotic, Japanese, identical twin sisters, both of whom were diagnosed as having Takayasu's disease. The parents, two sisters, and one brother are healthy. HL-A typing analyses revealed that one haplotype found in the father had passed only to these twins. Such observations led us to search HL-A typing in Takayasu's disease to determine the possible participation of genetic factors in the pathogenesis of this morbid condition. Ten families, including that of our own patient, have been reported in the literature in Japan, as family cases of Takayasu's disease. HL-A typings in A and B locus analyzed in all family members of six families in attempts to find a common haplotype composed of A9, A10, B5, or BW40 in patients with Takayasu's disease, were confirmed statistically (chi 2 = 7.8, 0.01 less than p less than 0.05). In a population study, HL-A typing analyses of 65 patients with Takayasu's disease also revealed a high frequency of HL-A A10 and HL-A B5 with the level of 15.3 and 17.0 in the chi 2-test (p less than 10(-4)), as compared with the frequency in 128 healthy Japanese. These data strongly suggest that a genetic-related factor has to be given serious consideration.

Human leucocyte antigen analysis of 45 patients with variant angina was performed to determine the presence of causative genetic factor(s). A significantly low frequency of human leucocyte antigen DQ omega 3 was found in these patients, as compared with that in 152 normal Japanese adults. There were no differences in frequencies of antigens between patients with normal and those with atherosclerotic coronaries. These data suggest that some genetic factor(s) may contribute to the pathogenesis of coronary spasm.

Recent studies on the pathogenesis of Takayasu disease have focussed on the participation of genetic factors, and HLA analysis has confirmed the close relationship between Takayasu disease and HLA Bw52. In an attempt to investigate the association of immune response gene with the disease, HLA-DR (DR-1, -2, -3, -4, -5, -w6, -7, -w8, -w9, -w10), MT (-1, -2, -3), MB (-1, -3) antigens were studied in 52 patients with Takayasu disease and the data compared with findings in healthy Japanese. As there were no statistical differences between the two groups in the frequencies of all these antigens, genetic factors in Takayasu disease may be much more closely associated with B than with D loci.

Recent studies have focused on the possible genetic factor(s) in the pathogenesis of Buerger's disease as well as in Takayasu's disease. We investigated HLA-A, B, C, DR, and DQ antigens in 59 patients with Buerger's disease to confirm statistically significant high frequencies of Aw24, Bw40, Bw54, Cw1, and DR2 antigens and a low frequency of DR9 and DRw52 as compared with those in 152 normal Japanese individuals. As the haplotpye Aw24-Bw54-Cw1-DR4 is known to be common among Japanese, a significantly high frequency of haplotype Bw54-DR2 found in cases of Buerger's disease, instead of that of Bw54-DR4, may suggest a possible cross-linkage occurrence in chromosome 6, which could prove to be an important causative phenomenon in the pathophysiology of Buerger's disease.

As HLA studies suggest that the genetic factors contributing to the pathogenesis of Takayasu disease may be polygene, various red blood types, allotypes of serum protein and red blood cell enzyme polymorphisms in eighty-four patients with Takayasu disease were studied and their phenotypes and gene frequencies were compared with those in healthy Japanese. Statistically significant high frequencies of phenotypes and/or gene frequencies were confirmed in MNSs, Rh-Hr, Tf, Gc and Pi in Takayasu disease, as compared with those in controls. These characteristics of gene frequencies were more remarkable in patients who do not carry HLA Bw52. These data suggest that the genetic factors contributing to the pathogenesis of Takayasu disease are polygene and may be located in chromosome No. 1, 4 and 14.