Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.

Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC.

PURPOSE: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. METHODS: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. RESULTS: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. CONCLUSIONS: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC.

Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Amongst inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a seven-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. Methods: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. Results: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of three months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+ 131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. Conclusions: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

A complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis.

Advances in next-generation sequencing technology have identified many genes responsible for inborn errors of immunity (IEI). However, there is still room for improvement in the efficiency of genetic diagnosis. Recently, RNA sequencing and proteomics using peripheral blood mononuclear cells (PBMCs) have gained attention, but only some studies have integrated these analyses in IEI. Moreover, previous proteomic studies for PBMCs have achieved limited coverage (approximately 3000 proteins). More comprehensive data are needed to gain valuable insights into the molecular mechanisms underlying IEI. Here, we propose a state-of-the-art method for diagnosing IEI using PBMCs proteomics integrated with targeted RNA sequencing (T-RNA-seq), providing unique insights into the pathogenesis of IEI. This study analyzed 70 IEI patients whose genetic etiology had not been identified by genetic analysis. In-depth proteomics identified 6498 proteins, which covered 63% of 527 genes identified in T-RNA-seq, allowing us to examine the molecular cause of IEI and immune cell defects. This integrated analysis identified the disease-causing genes in four cases undiagnosed in previous genetic studies. Three of them could be diagnosed by T-RNA-seq, while the other could only be diagnosed by proteomics. Moreover, this integrated analysis showed high protein-mRNA correlations in B- and T-cell-specific genes, and their expression profiles identified patients with immune cell dysfunction. These results indicate that integrated analysis improves the efficiency of genetic diagnosis and provides a deep understanding of the immune cell dysfunction underlying the etiology of IEI. Our novel approach demonstrates the complementary role of proteogenomic analysis in the genetic diagnosis and characterization of IEI.

Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Therapeutic options for CTLA-4 insufficiency.

BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.

Enhanced osteoclastogenesis in patients with MSMD due to impaired response to IFN-γ.

BACKGROUND: Patients with Mendelian susceptibility to mycobacterial disease (MSMD) experience recurrent and/or persistent infectious diseases associated with poorly virulent mycobacteria. Multifocal osteomyelitis is among the representative manifestations of MSMD. The frequency of multifocal osteomyelitis is especially high in patients with MSMD etiologies that impair cellular response to IFN-γ, such as IFN-γR1, IFN-γR2, or STAT1 deficiency. OBJECTIVES: This study sought to characterize the mechanism underlying multifocal osteomyelitis in MSMD. METHODS: GM colonies prepared from bone marrow mononuclear cells from patients with autosomal dominant (AD) IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 gain of function (GOF) and from healthy controls were differentiated into osteoclasts in the presence or absence of IFN-γ. The inhibitory effect of IFN-γ on osteoclastogenesis was investigated by quantitative PCR, immunoblotting, tartrate-resistant acid phosphatase staining, and pit formation assays. RESULTS: Increased osteoclast numbers were identified by examining the histopathology of osteomyelitis in patients with AD IFN-γR1 deficiency or AD STAT1 deficiency. In the presence of receptor activator of nuclear factor kappa-B ligand and M-CSF, GM colonies from patients with AD IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-γ concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-γR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF. CONCLUSIONS: Osteoclast differentiation is increased in AD IFN-γR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-γ, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis.

Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice.

Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with 'normal' or 'high' level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ stimulation, the 'normal' level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the 'high' level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer.

Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.

Association of cardiorespiratory fitness with characteristics of coronary plaque: assessment using integrated backscatter intravascular ultrasound and optical coherence tomography.

BACKGROUND: Cardiorespiratory fitness (CRF) can predict future cardiovascular disease. Rupture of vulnerable plaque which often has a large lipid core with a thin fibrous cap causes acute coronary syndrome including sudden cardiac death. We tested our hypothesis that preserved CRF is associated with low lipid composition and thick fibrous cap thickness of coronary lesions. METHODS: We prospectively performed both integrated backscatter intravascular ultrasound (IB-IVUS) and optical coherence tomography (OCT) for 77 non-culprit coronary lesions in 77 consecutive angina pectoris patients who underwent percutaneous coronary intervention (PCI). Percentage of achieved of predicted peak oxygen consumption (%PPeak Vo(2)) calculated based on measured peak Vo(2) using a cardiopulmonary exercise test performed post PCI was adapted as an indicator of patient CRF. RESULTS: Patients were divided into two groups [those with preserved CRF (%PPeak Vo(2) >82%) (Group I) or others (Group II)]. Coronary plaques of Group I patients had significantly smaller lipid volume, greater fibrous volume, and thicker fibrous cap thickness than those of Group II (32 ± 14% vs. 45 ± 13%, p<0.001; 57 ± 11% vs. 49 ± 11%, p<0.001; and 177.7 ± 20.9 µm vs. 143.7 ± 36.9 µm, p<0.001). In multivariate linear regression analysis, %PPeak Vo(2) showed a significantly negative correlation with lipid volume and a positive correlation with fibrous volume and fibrous cap thickness (ß=-0.418, p=0.001; ß=0.361, p=0.006; and ß=0.339, p=0.008). CONCLUSIONS: High %PPeak Vo(2) was associated with low lipid volume, high fibrous volume and thick fibrous cap thickness in coronary lesions. These results may well suggest an attenuated risk of cardiovascular events in patients with preserved CRF.

Morphologic characterization and quantification of superficial calcifications of the coronary artery--in vivo assessment using optical coherence tomography.

Coronary calcification is proportional to the extent and severity of atherosclerotic disease, and is a predictor of cardiac events. Furthermore, coronary calcification protruding into the lumen is considered as one type of vulnerable plaque. Optical coherence tomography (OCT) can provide in vivo imaging of the detailed vessel wall structure of the coronary artery with high resolution, as in the histological approach. We analyzed coronary calcification in that fashion using OCT in vivo. This study consisted of 70 superficial coronary calcifications of 39 consecutive patients who underwent percutaneous coronary intervention. After revascularization, OCT was performed in the treated vessel. We analyzed morphologic characteristics and the quantification of OCT-determined coronary calcification. Superficial coronary calcifications were classified into two groups depending on whether they did not intrude the lumen (type I) or did (type II). The distance from the lumen and the volume of each calcification were then measured. Superficial coronary calcifications were classified into two groups; type I, n = 39 (56%) and type II, n = 31 (44%). Type II calcifications were located significantly closer to the lumen [80 microm (60-130) vs.130 microm (90-260), p = 0.015], and tended to be smaller, but did not show a significant difference [0.65 (0.2631.3) mm3 vs. 1.2 (0.47-1.9) mm3, p = 0.153] compared to those of type I. In conclusion, OCT could visualize superficial coronary calcifications in detail and enable us to evaluate in vivo morphologic characterizations and quantify them.

Impact of the first-generation drug-eluting stent implantation on periprocedural myocardial injury in patients with stable angina pectoris.

BACKGROUND AND PURPOSE: Percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) is one of the standard treatments for patients with stable angina pectoris (AP). In spite of a notable effect in preventing restenosis after PCI, DES cannot improve the mortality of patients compared to a bare-metal stent (BMS). On the other hand, periprocedural myocardial injury (PMI) is related to poor prognosis in patients undergoing PCI. We compared DES to BMS in the incidence of PMI in patients with stable AP. METHODS AND SUBJECTS: We enrolled 265 consecutive patients with AP undergoing successful stent implantation. A blood sample was obtained from all patients immediately before and 24h after PCI. PMI was defined as an increase in creatine kinase-myocardial band isozyme fraction (CK-MB) greater than the upper limit of reference range 24h after PCI. During the study period, sirolimus- and paclitaxel-eluting stents were used as DES. The strategy of PCI including the type of stent to implant was left to the discretion of the operator. RESULTS: Patients were divided into two groups (DES group, n=136 and BMS group, n=129). The incidence of PMI was significantly higher in the DES group than in the BMS group (24% vs. 12%, p=0.015). Use of DES remained an independent predictor of PMI on multivariate logistic regression analysis after adjustment for confounding factors (odds ratio 2.20, 95% CI, 1.07-4.51, p=0.032). CONCLUSIONS: Implantation of the first-generation DES including sirolimus- and paclitaxel-eluting stents was associated with a higher incidence of PMI in patients with AP compared to BMS.

Association of plasma ω-3 to ω-6 polyunsaturated fatty acid ratio with complexity of coronary artery lesion.

OBJECTIVE: Eicosapentaenoic acid (EPA) of the omega-3 polyunsaturated fatty acids (ω-3 PUFA) family plays important roles in the prevention of cardiovascular disease (CVD), while, arachidonic acid (AA) of the ω-6 PUFA family promotes inflammatory and prothrombotic influences. The complexity of coronary lesions represents the vulnerability of patients. The aim of this study was to investigate the association between the plasma EPA/AA ratio and the prevalence of complex coronary lesion morphology. METHODS: This study consisted of 206 consecutive patients with stable angina pectoris (sAP). Each coronary lesion was determined either as complex or simple based on angiographic findings. To examine the plasma fatty acid level, blood samples were obtained. Patients were divided into three groups according to the obtained plasma EPA/AA ratio: the highest tertile, n=67, the 2nd tertile, n=70, or the lowest tertile, n=69. RESULTS: A higher incidence of complex coronary lesion was obtained from patients with a lower plasma EPA/AA ratio [43 (62%) vs. 31 (44%) vs. 25 (37%), p=0.011]. High-sensitivity CRP levels and a low plasma EPA/AA ratio could independently predict the prevalence of complex coronary lesions on multivariate logistic regression analysis [odds ratio 1.83 (95%CI 1.03-3.25), p=0.038 and odds ratio 2.10 (95%CI 1.11-3.94), p=0.02)]. CONCLUSION: In patients with sAP, a low plasma EPA/AA ratio was significantly associated with a high prevalence of complex coronary lesions.

Transient pseudothrombocytopenia in a neonate: transmission of a maternal EDTA-dependent anticoagulant.

EDTA-dependent pseudothrombocytopenia (PTCP) is characterised by a low platelet count caused by autoantibodies in the serum reacting with EDTA-anticoagulated blood. EDTA-dependent PTCP is caused by a factor that retains EDTA anticoagulation activity in the serum. We report here that a neonate from a mother with PTCP presented with transient low platelet counts when EDTA was used as an anticoagulant. To confirm the transmission of a maternal serum factor to the neonate, we examined to add the maternal serum into the normal blood. Platelet count decreased significantly after adding maternal serum. Clumped platelets were also observed in the smears of mixed samples.

Impact of the low- to high-density lipoprotein cholesterol ratio on composition of angiographically ambiguous left main coronary artery plaque.

BACKGROUND: A high low-density lipoprotein cholesterol (LDL-C) to a high-density lipoprotein cholesterol (HDL-C) ratio is associated with cardiac events, while the left main coronary artery (LMCA) is considered to be an important target of atherosclerotic plaque accumulation. This aim of the present study was to investigate the relationship between a LDL-C/HDL-C ratio and the characteristics of tissue components of LMCA plaque. METHODS AND RESULTS: One-hundred-twenty consecutive patients with stable angina pectoris who received chronic statin treatment underwent percutaneous coronary intervention for the left coronary artery. We prospectively performed integrated backscatter (IB) intravascular ultrasound (IVUS) to their LMCAs and evaluated the tissue characteristics. According to the median value of their LDL-C/HDL-C ratios (2.4), they were divided into 2 groups [high LDL-C/HDL-C ratio (>2.4) (n=60) or low LDL-C/HDL-C ratio (≤ 2.4) (n=60)]. There was no significant difference in the data analyzed using conventional IVUS between the 2 groups. In the IB-IVUS analysis, patients with a high LDL-C/HDL-C ratio had a larger lipid volume and a smaller fibrous volume compared to patients with a low LDL-C/HDL-C ratio (52 ± 10% vs. 48 ± 10%, P=0.014 and 45 ± 9% vs. 50 ± 10%, P=0.010). CONCLUSIONS: A high LDL-C/HDL-C ratio was associated with a high percentage of lipid volume and a low percentage of fibrous volume in LMCA lesions. Our findings might well suggest the increased risk of cardiovascular events in patients with a high LDL-C/HDL-C ratio.