Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Adsorption of Biomineralization Protein Mms6 on Magnetite (Fe3O4) Nanoparticles.

Biomineralization is an elaborate process that controls the deposition of inorganic materials in living organisms with the aid of associated proteins. Magnetotactic bacteria mineralize magnetite (Fe3O4) nanoparticles with finely tuned morphologies in their cells. Mms6, a magnetosome membrane specific (Mms) protein isolated from the surfaces of bacterial magnetite nanoparticles, plays an important role in regulating the magnetite crystal morphology. Although the binding ability of Mms6 to magnetite nanoparticles has been speculated, the interactions between Mms6 and magnetite crystals have not been elucidated thus far. Here, we show a direct adsorption ability of Mms6 on magnetite nanoparticles in vitro. An adsorption isotherm indicates that Mms6 has a high adsorption affinity (Kd = 9.52 µM) to magnetite nanoparticles. In addition, Mms6 also demonstrated adsorption on other inorganic nanoparticles such as titanium oxide, zinc oxide, and hydroxyapatite. Therefore, Mms6 can potentially be utilized for the bioconjugation of functional proteins to inorganic material surfaces to modulate inorganic nanoparticles for biomedical and medicinal applications.

[Successful treatment of pure red cell aplasia complicated by multicentric Castleman disease with prednisolone].

A 76-year-old man presented with shortness of breath and the laboratory tests suggested anemia and reticulocytopenia. CBC showed only anemia, and the bone marrow aspiration smear demonstrated absence of erythroid hematopoietic cells. Consequently, pure red cell aplasia (PRCA) was diagnosed. Computed tomography (CT) showed mediastinal multiple lymph node enlargement and ground-glass opacity in both the lung fields. Biopsy specimens of the mediastinal lymph node showed mild follicular hyperplasia and polyclonal plasma cells proliferation in the interfollicular area. These findings suggest idiopathic multicentric Castleman disease plasma cell type (iMCD PC type). Ciclosporin (CyA) was administered but there was no clinical improvement after 6 weeks of therapy. Therefore, prednisolone (PSL) was started at 0.5 mg/kg/day and was very effective for the PRCA and MCD. A total of 3 cases of CD (2 cases of MCD PC type and 1 case of CD HV type) with PRCA have been previously reported. In the 2 cases of MCD PC type, anemia was improved using PSL combination therapy. However, in the single case of CD HV type, PSL was not effective and anemia was improved with CyA treatment. This case suggests the possibility of using PSL as the first-line drug for MCD PC type with PRCA.

[Impaired hematopoiesis due to copper deficiency in a hemodialysis patient supplemented with zinc].

This is a case of a 75-year-old man who was on maintenance hemodialysis for 10 years due to diabetic nephropathy and was prescribed polaprezinc due to a low serum zinc level (55 µg/dl) and dysgeusia. Three months after the polaprezinc treatment was initiated, the patient developed pancytopenia, which persisted even after the serum zinc level was normalized and medication was discontinued. He was referred to our institute so that the progression of pancytopenia could be assessed. A blood biochemical examination revealed a WBC count of 1,700/µl, Hb level of 8.9 g/dl, and Plt count of 9.5×104/µl. A bone marrow aspirate smear showed slight megaloblastic changes and ringed sideroblasts in addition to an elevated WT1 mRNA level (76 copies/µg RNA) in the peripheral blood. Although these findings mimicked those of myelodysplasia, low serum copper (<2 µg/dl) and ceruloplasmin levels (3 mg/dl) were suggestive of hematopoietic abnormalities due to zinc-induced copper deficiency. Treatment with cocoa, a compound generally known to be rich in copper, gradually improved the pancytopenia and dysplastic bone marrow histology. This case indicates that clinicians should consider the risk of zinc-induced copper deficiency and its complications when zinc supplementation is administered to patients with chronic kidney disease, particularly those undergoing hemodialysis.

[Chronic myeloid leukemia harboring T315I and F317L mutations successfully treated with interferon-α and ponatinib].

Our patient was diagnosed with chronic myeloid leukemia (CML) in chronic phase (CP) when he was 40 years old. Although dasatinib (DAS) was prescribed during his clinical course, he was poorly compliant with the treatment. In November 20XX, at 65 years of age, he visited our hospital with leukocytosis. He was diagnosed with CML in CP and recommenced DAS at 50 mg/day, achieving a complete hematological response after 2 months. However, DAS was increased to 100 mg/day because only minimum cytogenetic response was evident even after 9 months, but CML progressed to the accelerated phase after 18 months. The ABL kinase domain mutations T315I and F317L were detected. Ponatinib (PON) was not yet approved, and he declined allogeneic stem cell transplantation therapy. He commenced interferon-α (IFN-α) in addition to DAS, and the F317L mutation (only) disappeared after 7 months; the patient achieved a major cytogenetic response. In January 20XX＋4, he commenced PON monotherapy (the drug was approved by this time) and achieved a major molecular response after 8 months. The T315I mutation disappeared during PON therapy. Although IFN-α is rarely used in the treatment of CML, this case suggests that IFN-α should be re-considered in patients with CML who exhibit tyrosine kinase inhibitor resistance.

[Acquisition of IgH/CCND1 translocation during the natural disease course in a patient with chronic lymphocytic leukemia].

A 69-year-old man visited a doctor because of systemic lymphadenopathy. Peripheral blood examination revealed leukocytosis, anemia, and decreased platelet count (WBC, 103,060/µl; lymph, 92.2%; Hb, 8.9 g/dl; and Plt, 4.1×104/µl). Bone marrow biopsy revealed that approximately 70% of nucleated cells were small, mature lymphoid cells with positive immunostaining for CD5, CD20, and CD23. He was diagnosed with chronic lymphocytic leukemia (CLL). The IgH/CCND1 translocation and ATM locus loss in 20% and 95% peripheral cells, respectively, were detected by fluorescence in situ hybridization. Immunostaining revealed that cyclin D1 was positive in approximately 30% bone marrow cells. As the positive rate of CCND1 fusion signal was low, the diagnosis of mantle cell lymphoma was excluded. In contrast, signals of ATM locus deletion were detected in most tumor cells. Therefore, we assessed that IgH/CCND1 translocations occurred during the natural clinical course of CLL with ATM locus deletion from the onset of disease. The secondary IgH/CCND1 translocation in CLL is rare, and all reported cases with such translocations received treatments with alkylating agents. This is the first report regarding secondary IgH/CCND1 translocation during the natural clinical course of CLL and may provide insights into CLL pathogenesis.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Metabolic flux determination in perfused livers by mass balance analysis: effect of fasting.

Isolated perfused livers from fasted rats have been extensively studied to understand the underlying mechanisms of injury-induced acute and chronic changes in liver metabolism. In this study, we investigated the impact of fasting on perfused liver metabolism. The methodology we used combines a flux variability approach, sampling analysis and singular value decomposition (SVD) to analyze the data using the same metabolic reaction network for both fed and fasted livers. Considering both experimental observations and mathematical analysis, the results show that 24 h fasting results in a limited glucose production from glycogen and up-regulation of gluconeogenic pathway. Glutamate metabolism and fatty acid oxidation are also slightly up-regulated whereas aspartate metabolism is down-regulated after fasting. Moreover, SVD analysis elucidates that glycogen breakdown mainly affects the pentose phosphate pathway in fasted state whereas co-occurrence pattern associated with glycogen breakdown and glycolysis observed in flux samples of fed state is dominant. In conclusion, this analysis provides a detailed description of the metabolic changes in two different states, considering the entire steady state flux space and dominant flux patterns that capture the system variations within the flux space.

Impact of renal function on coronary plaque composition.

BACKGROUND: Recent studies have demonstrated that patients with chronic kidney disease are at high risk of atherosclerosis. Recently it has been found that coronary plaque components can be evaluated by integrated backscatter intravascular ultrasound (IB-IVUS), and lipid-rich plaque is associated with vulnerable plaque. The aim of the study was to investigate the relationship between renal function and tissue characterization of coronary plaque composition at the target stenotic site for percutaneous coronary intervention (PCI). METHODS: We prospectively performed IB-IVUS before elective PCI in 89 consecutive patients with stable angina. According to estimated glomerular filtration rate (eGFR), they were divided into two groups (eGFR <60 ml/min/ 1.73 m(2) or eGFR > or =60 ml/min/1.73 m(2)). The tissue characteristics of the coronary plaque at each target stenotic site were evaluated by three-dimensional (3D) IB-IVUS just before PCI procedure. RESULTS: The patients with eGFR <60 ml/min/1.73 m(2) had higher percentage of lipid volume and lower percentage of fibrous volume compared to the patients with eGFR > or = 60 ml/min/1.73 m(2) on the 3D IB-IVUS images (36.7 +/- 10.6% versus 28.7 +/- 9.3%, P < 0.001 and 59.1 +/- 8.7% versus 66.3 +/- 8.3%, P < 0.001, respectively). eGFR showed a significant negative correlation with lipid volume and had a significant positive correlation with fibrous volume in coronary plaques (r = -0.44, P < 0.0001, and r = 0.46, P < 0.0001, respectively). CONCLUSIONS: Impaired renal function was related to higher percentage of lipid volume and lower percentage of fibrous volume in coronary plaque. Our findings may explain the increasing risk of cardiovascular events in patients with renal dysfunction.

Volumetric analysis of coronary plaque characterization in patients with metabolic syndrome using 64-slice multi-detector computed tomography.

BACKGROUND: Metabolic syndrome (MetS) is associated with adverse cardiovascular events and mortality, where acute coronary syndrome significantly impacts on mortality and morbidity. In contrast, evidences have accumulated that the lipid-rich plaque might play a critical role in acute coronary syndrome. METHODS AND RESULTS: The study population consisted of 94 patients with suspected angina pectoris who underwent multi-detector computed tomography (MDCT). Of those, we identified 41 with MetS. In MDCT analysis, low-density plaque volume (LDPV) (42 ± 28 vs 24 ± 18 mm(3), P=0.0003), moderate-density plaque volume (105 ± 41 vs 82 ± 33 mm(3), P=0.003), total plaque volume (164 ± 70 vs 118 ± 59 mm(3), P=0.0008) and %LDPV (24.2 ± 10.0 vs 18.3 ± 7.1%, P=0.01) were significantly increased in the MetS group compared to the non-MetS group. Multivariate linear regression analysis after adjusting for confounding variables revealed that MetS was significantly correlated with an increase in %LDPV (ß=0.48, P=0.0001). Multivariate logistic regression analysis for lipid-rich plaque after adjusting for confounding variables indicated that MetS was significantly associated with lipid-rich plaque (odds ratio: 5.99, 95% confidence intervals: 1.94-18.6, P=0.002). CONCLUSIONS: Patients with MetS were strongly related to having a lipid-rich composition in their coronary plaque, as detected by MDCT.

Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics.

Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.

Impact of long-term statin treatment on coronary plaque composition at angiographically severe lesions: a nonrandomized study of the history of long-term statin treatment before coronary angioplasty.

BACKGROUND: Studies have found an association between treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") and reductions in procedure-related complications in percutaneous coronary intervention (PCI). OBJECTIVE: This study investigated the effects of long-term statin treatment before elective PCI on coronary plaque composition at the angiographically severe target stenotic lesions. METHODS: This nonrandomized, observational study was conducted at Nagoya University Hospital, Nagoya, Japan. Data were collected from the electronic medical records of patients with stable angina pectoris who underwent PCI guided by intravascular ultrasound (IVUS). Patients were stratified into 2 groups: those who received long-term statin treatment for > or =6 months before PCI (statin group) and those who did not (nonstatin group). The tissue characteristics of the coronary plaque at each target stenotic site were analyzed using 3-dimensional integrated backscatter IVUS immediately before PCI. RESULTS: Data from 100 patients were included (91 men, 9 women; mean [SD] age, 67 [10] years; statin group, 44 patients; nonstatin group, 56). The clinical characteristics of the 2 groups were not significantly different, with the exception of the prevalence of hyperlipidemia (statin vs nonstatin, 100% vs 51.8%; P < 0.001). There were no significant between-group differences in serum lipid profiles. The statin group had a significantly greater mean (SD) percentage decrease in lipid volume (28.7% [10.0%] vs 34.7% [9.8%]; P = 0.003) and a significantly greater increase in fibrous volume (66.5% [8.5%] vs 60.9% [8.6%]; P = 0.001) compared with the nonstatin group. CONCLUSION: This study found a significant difference in lipid and fibrous volumes in angiographically severe coronary stenotic lesions in these patients with stable angina who received long-term statin treatment before PCI versus those who did not.

The correlation between lipid volume in the target lesion, measured by integrated backscatter intravascular ultrasound, and post-procedural myocardial infarction in patients with elective stent implantation.

AIMS: The aim of this study was to perform quantitative analysis of the plaques of target lesions by integrated backscatter intravascular ultrasound (IB-IVUS) and to investigate the association between these data and the risk of post-procedural myocardial injury after stenting. METHODS AND RESULTS: One hundred and fourteen consecutive patients who received elective stent implantations following IB-IVUS analysis were enrolled. The volume of each plaque component (lipid, fibrous, and calcified) was calculated for the target lesion. Creatine kinase-MB (CK-MB) and troponin-T (TnT) were also evaluated 18 h after procedure. We defined a post-procedural TnT level higher than three times the normal limit as a post-procedural myocardial injury. Lipid, fibrous, and calcified volumes were greater in patients with myocardial injury than in those without myocardial injury. Lipid and fibrous volumes correlated with post-procedural cardiac biomarkers, and the lipid volume fraction (lipid volume/total plaque volume) also correlated with post-procedural TnT and CK-MB. The fibrous volume fraction for plaques was found to be inversely correlated with post-procedural TnT and CK-MB. Hence, lipid volume and volume fraction were concluded to be independent predictors of post-procedural myocardial injury. CONCLUSION: A larger plaque volume and lipid-rich plaque may be indicative of embolic events after stent implantation, resulting in myocardial injury.

Dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis.

A 64-year-old man was diagnosed with limited cutaneous systemic sclerosis 5 years prior to this report. His sclerotic skin symptoms did not respond to oral low-dose prednisone (5-10 mg/day). Five years after the diagnosis, the patient presented with leukocytosis 3.8 × 109/L in a routine blood test, and was finally diagnosed with chronic-phase chronic myelogenous leukemia (CML). The leukemia responded optimally to initial dasatinib, and a complete cytogenetic response was achieved after 6 months of therapy. His skin symptoms dramatically improved in parallel with dasatinib therapy, as indicated by a decrease in the modified Rodnan skin score, from 12 points at diagnosis to 2 after 9 months. It has been reported that imatinib, a first-generation tyrosine kinase inhibitor, improves skin sclerosis in some patients with systemic sclerosis. To the best of our knowledge, this is the first report of simultaneous improvement of CML and limited cutaneous systemic sclerosis in response to dasatinib. Further study of the mechanism of action of dasatinib is crucial.

Epicardial fat volume correlates with severity of coronary artery disease in nonobese patients.

OBJECTIVE: It has been reported that epicardial adipose tissue could locally modulate the coronary artery functions through secretion of proinflammatory and anti-inflammatory cytokines. Epicardial fat tissue is further implicated in the pathogenesis of coronary artery disease (CAD) because of its proximity to the adventitia of the major epicardial coronary arteries. We investigated the relationship between epicardial fat volume (EFV) and severity of CAD in nonobese patients using 64-slice multidetector computed tomography (MDCT). METHODS: One hundred and forty nonobese patients (BMI <25 kg/m2) were enrolled. EFV and visceral fat area were measured by MDCT. Patients were classified according to the plaque components (noncalcified, mixed and calcified) and severity of CAD. Inflammatory biomarkers were also measured, and compared with each CT parameter. RESULTS: EFV was significantly correlated with the extent or severity of CAD. Patients with noncalcified or mixed plaque had a greater EFV than those with calcified plaque. Log-transferred high sensitivity C-reactive protein (CRP) was significantly correlated with EFV (r = 0.24, P = 0.04). Adiponectin level was significantly inversely correlated with visceral fat area (r = 0.38, P = 0.0001). CONCLUSION: Increased EFV is associated with more severe CAD and noncalcified or mixed coronary plaques in nonobese patients.

Accuracy of 64-slice multidetector computed tomography for classification and quantitation of coronary plaque: comparison with integrated backscatter intravascular ultrasound.

BACKGROUND: Noninvasive assessment of coronary plaque is important for coronary risk stratification. Whereas integrated backscatter intravascular ultrasound (IB-IVUS) has proven effective for analysis of the tissue components of coronary plaque, plaque assessment by 64-slice multidetector computed tomography (MDCT) has not been established. We therefore evaluated the accuracy of MDCT compared with IB-IVUS for identification of coronary plaque components and determination of plaque volume. METHODS: Thirty-one sites in 17 coronary vessels (7 left anterior descending, 5 left circumflex, and 5 right coronary arteries) with substantial stenosis were visualized by both 64-slice MDCT and IB-IVUS. Coronary plaque was evaluated by MDCT and the findings were compared with those of IB-IVUS at the same sites and for the same vessel lengths. Plaque was classified as low-attenuated, fibrous, or calcified, and the volume of each plaque component and total plaque volume were calculated. RESULTS: Total plaque volume per vessel determined by MDCT was significantly correlated with that determined by IB-IVUS (r=0.704, P<0.05, n=17). However, the volumes of individual plaque components determined by the two approaches were not correlated. The predominant plaque morphology as determined by the two approaches was consistent in 12 of the 17 vessels (70.6%), whereas calcified and low-attenuated plaques were overestimated by MDCT in the remaining vessels. CONCLUSIONS: MDCT is a promising approach for noninvasive detection of different types of coronary plaque and may therefore contribute to coronary risk stratification. The ability of MDCT to determine the volume of individual plaque components, however, is limited.

Abnormal glucose regulation is associated with lipid-rich coronary plaque: relationship to insulin resistance.

OBJECTIVES: This study sought to determine lipid and fibrous volume of coronary atherosclerotic plaques in subjects with abnormal glucose regulation (AGR) by integrated backscatter (IB) intravascular ultrasound (IVUS) during percutaneous coronary intervention. BACKGROUND: Abnormal glucose regulation, including impaired glucose regulation (IGR) and diabetes mellitus (DM), has emerged as an important determinant of cardiovascular risk. We hypothesized that AGR would be associated with coronary plaque instability. METHODS: Conventional intravascular ultrasound and IB-IVUS using a 40-MHz (motorized pullback 1 mm/s) intravascular catheter was performed in 172 consecutive patients. The percentage of fibrous area and the percentage of lipid area were automatically calculated by IB-IVUS. Three-dimensional analysis of IB-IVUS images was performed to determine the percentage of lipid volume (%LV) and fibrous volume (%FV). Following the World Health Organization criteria, the subjects were classified into the DM group, the IGR group, and the normal glucose regulation group. The cutoff point for the lipid-rich plaque was defined as %LV >44% or %FV <52%, which was the 75th percentile of %LV or the 25th percentile of %FV in this study population. Insulin resistance (IR) was defined as the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: There were no significant differences in the baseline characteristics except for glucometabolic parameters. The conventional IVUS analysis indicated that the DM group had a significantly increased plaque volume (and percent plaque volume). In the IB-IVUS analysis, as compared with the normal glucose regulation group, the DM and the IGR groups showed a significant increase in %LV (36 +/- 14% and 37 +/- 13% vs. 29 +/- 14%, p = 0.02) and a significant decrease in %FV (59 +/- 11% and 58 +/- 11% vs. 64 +/- 11%, p = 0.03). The lipid-rich plaque rate was significantly associated with an increasing HOMA-IR in the tertile (p = 0.008). On logistic regression analysis after adjusting for confounding and coronary risk factors, the DM group (odds ratio 3.52, 95% confidence interval 1.13 to 11.0, p = 0.03) and the IGR group (odds ratio 3.92, 95% confidence interval 1.13 to 13.6, p = 0.03) were significantly associated with the lipid-rich plaque. CONCLUSIONS: Coronary lesions in patients with AGR are associated with more lipid-rich plaque content, which may be related to the increased IR in these patients.

Impact of metabolic syndrome on tissue characteristics of angiographically mild to moderate coronary lesions integrated backscatter intravascular ultrasound study.

OBJECTIVES: We assessed the impact of metabolic syndrome (MetS) on the tissue characteristics of coronary plaques using integrated backscatter intravascular ultrasound (IB-IVUS). BACKGROUND: Metabolic syndrome is associated with the increasing risk of cardiovascular disease. METHODS: We identified MetS by the definition of the National Cholesterol Education Program in Adult Treatment Panel III criterion. Non-target coronary lesions with mild to moderate stenosis were measured by conventional and IB-IVUS parameters using 40-MHz (motorized pullback 0.5 mm/s) intravascular catheter. A total of 20 IB-IVUS images were recorded at an interval of 0.5 mm for 10 mm length in each plaque. The 3-dimensional analyses were performed using commercially available software. RESULTS: The prevalence of MetS was 61 patients (50%) with 73 lesions (49%) among 122 patients with 148 lesions. Patients with MetS showed a significant increase in percentage lipid area (38 +/- 19% vs. 30 +/- 19%, p = 0.02) and percentage lipid volume (39 +/- 17% vs. 33 +/- 17%, p = 0.03), and they also showed a significant decrease in percentage of fibrous volume (57 +/- 14% vs. 61 +/- 13%, p = 0.03). Multivariate regression analysis after adjustment for potentially confounding risk factors showed that MetS remains correlated independently with the percentage of lipid volume (r = 0.223, p = 0.01). Logistic regression analysis after adjusting for confounding and non-MetS coronary risk factors showed that MetS (odds ratio 4.00, 95% confidence interval 1.33 to 12.0, p = 0.01) is proved to be an independent predictor of the lipid-rich plaque. CONCLUSIONS: Metabolic syndrome is associated with lipid-rich plaques, contributing to the increasing risk of plaque vulnerability.

Insulin resistance and fasting hyperinsulinemia are risk factors for new cardiovascular events in patients with prior coronary artery disease and normal glucose tolerance.

BACKGROUND: Insulin resistance and hyperinsulinemia are important risk factors for coronary artery disease (CAD) and cardiovascular event (CVE). However, their independent relationship to new CVE in patients with normal glucose tolerance (NGT) and CAD is not known. METHODS AND RESULTS: Subjects of this 3-year observational study were 102 patients with CAD. Plasma glucose and insulin concentrations were determined at 2 time points (baseline and post oral glucose tolerance test [OGTT]. The fasting plasma glucose <110 mg/dl and post-OGTT <140 mg/dl was diagnosed as NGT (World Health Organization criteria). Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). Of the 102 patients, 23 had onset of new CVE, including 19 with new CAD. They had significantly higher fasting and post-OGTT insulin levels and HOMA-IR than those without new CVE (P<0.01, 0.031 and <0.01, respectively). Using the univariate Cox proportional hazards model, fasting and post-OGTT insulin values, HOMA-IR and high density lipoprotein (HDL) cholesterol differed significantly between the 2 groups. The multivariate Cox model showed that the effect of fasting plasma insulin and HOMA-IR remained significant and independent of HDL cholesterol. CONCLUSION: Fasting hyperinsulinemia and high insulin resistance increased the risk of new CVE in patients with NGT and CAD.