Biomarkers associated with coronary high-risk plaques.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

Skin Autofluorescence and Clinical Outcomes in Patients with Coronary Artery Disease.

AIM: This study aimed to investigate whether skin autofluorescence (SAF) is associated with clinical outcomes in patients with coronary artery disease. Advanced glycation end products (AGE) play a crucial role in atherosclerosis. Accumulation of AGE can be measured non-invasively by SAF. METHODS: We performed a single-center prospective study of 896 patients with coronary artery disease treated with percutaneous coronary intervention (PCI) between January 2014 and December 2015. SAF was measured before the PCI procedure. The primary endpoint was patient-oriented composite endpoints (POCE) defined as a composite of all-cause death, any myocardial infarction, any stroke, and any revascularization. RESULTS: Patients were significantly older and suffered higher rates of chronic kidney disease (CKD) in the high SAF group. A higher SAF was associated with an increased risk for POCE (HR 1.43; 95% CI 1.19-1.71, p＜0.001) that was mainly driven by any coronary revascularization (HR 1.33; 95% CI 1.08-1.65, p=0.01) including target lesion revascularization (HR 1.41; 95% CI 1.02-1.94, p=0.04). The higher SAF group also experienced worse outcomes in stroke (HR 2.08; 95% CI 1.38-3.15, p=0.001). Multivariate analyses indicated that SAF was an independent predictor of POCE (HR 1.36; 95% CI 1.13-1.63, p=0.001). CONCLUSIONS: SAF as a measure of AGE deposition is independently associated with cardiovascular events amongst patients with coronary artery disease treated with PCI. SAF also predicts the incidence of restenosis and stroke.

Gut Microbiota and Coronary Plaque Characteristics.

Background The relationship between gut microbiota and in vivo coronary plaque characteristics has not been reported. This study was conducted to investigate the relationship between gut microbiota and coronary plaque characteristics in patients with coronary artery disease. Methods and Results Patients who underwent both optical coherence tomography and intravascular ultrasound imaging and provided stool and blood specimens were included. The composition of gut microbiota was evaluated using 16S rRNA sequencing. A total of 55 patients were included. At the genus level, 2 bacteria were associated with the presence of thin-cap fibroatheroma, and 9 bacteria were associated with smaller fibrous cap thickness. Among them, some bacteria had significant associations with inflammatory/prothrombotic biomarkers. Dysgonomonas had a positive correlation with interleukin-6, Paraprevotella had a positive correlation with fibrinogen and negative correlation with high-density lipoprotein cholesterol, Succinatimonas had positive correlations with fibrinogen and homocysteine, and Bacillus had positive correlations with fibrinogen and high-sensitivity C-reactive protein. In addition, Paraprevotella, Succinatimonas, and Bacillus were also associated with greater plaque volume. Ten bacteria were associated with larger fibrous cap thickness. Some were associated with protective biomarker changes; Anaerostipes had negative correlations with trimethylamine N-oxide, tumor necrosis factor α, and interleukin-6, and Dielma had negative correlations with trimethylamine N-oxide, white blood cells, plasminogen activator inhibitor-1, and homocysteine, and a positive correlation with high-density lipoprotein cholesterol. Conclusions Bacteria that were associated with vulnerable coronary plaque phenotype and greater plaque burden were identified. These bacteria were also associated with elevated inflammatory or prothrombotic biomarkers. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000041692.

Non-mercaptalbumin is significantly associated with the coronary plaque burden and the severity of coronary artery disease.

Human non-mercaptalbumin (HNA), oxidized form of serum albumin, has been reported as a useful marker in oxidative stress-related diseases; however, few reports have examined the association between HNA and the severity of coronary artery disease (CAD). The present study evaluated whether the HNA fraction is correlated with coronary artery stenosis in 140 patients considered to have a high risk of CAD or who were suspected of having acute coronary syndrome. The severity of CAD was defined by the number of stenotic coronary vessels and a severity score system (the Gensini score). HNA measurements were performed using our newly established high-performance liquid chromatography methodology. The results had shown that HNA was significantly increased in patients with three-vessel disease, compared with those without CAD or with single-vessel disease (p = 0.025), and was positively correlated with the Gensini score (ρ = 0.421, p < 0.001). A multivariate analysis showed that the number of stenotic vessels was an independent and significant factor associated with HNA (ρ = 1.246, p = 0.012). A logistic regression analysis showed that HNA was a strong predictor of multivessel CAD (odds ratio, 1.12; 95% confidence interval, 1.020-1.229; p = 0.017). These findings indicate that the measurement of HNA could be clinically practical for predicting the severity of coronary artery stenosis.

Impact of Abnormal Remote Stress Myocardial Blood Flow by Dynamic CT Perfusion on Clinical Outcomes.

The objective of this study was to investigate the incremental prognostic value for adverse events of myocardial blood flow (MBF) derived from stress computed tomography perfusion (CTP) at remote myocardium over cardiac risk factors and ischemia. We prospectively analyzed 242 patients who underwent dynamic CTP and CT angiography. Adverse events were defined as a composite of all-cause mortality, non-fatal myocardial infarction, unstable angina, heart failure requiring hospitalization, peripheral artery disease, and stroke. MBF value was calculated in each myocardial segment and ischemia was defined as mild decrease in MBF in two consecutive segments or moderate decrease in a single segment accompanied with a coronary stenosis ≥50%. The mean MBF of the non-ischemic segments was defined as remote MBF. We divided the patients into two groups by median MBF value of 1.15 ml/min/g. During a median follow-up of 18 months, 18 patients had adverse events. Annual event rate showed a significant difference between patients with low (≤1.15 ml/min/g) and high (>1.15 ml/min/g) MBF (6.1% vs 1.8%, p = 0.02). Univariate analysis showed that low MBF was a significant predictor of events (hazard ratio (HR): 3.4; 95% confidence interval (CI): 1.2 to 12.0; p = 0.02). This relationship maintained significant after adjusted for the presence of ischemia and cardiac risk factors (HR: 3.0; 95%CI: 1.1 to 11.1; p = 0.04). In conclusion, MBF value ≤1.15 ml/min/g derived from dynamic CTP in remote myocardium is significantly related with poor outcome and this relationship was independent of myocardial ischemia and cardiac risk factors.

Feasibility of dynamic myocardial CT perfusion using single-source 64-row CT.

BACKGROUND: Dynamic myocardial computed tomography perfusion (CTP) is an emerging technique to diagnose significant coronary stenosis. However, this procedure has not been reported using single-source 64-row CT. OBJECTIVE: To investigate the radiation dose and the diagnostic performance of dynamic CTP to diagnose significant stenosis by catheter exam. METHODS: We prospectively included 165 patients who underwent CTP exam under adenosine stress using a single-source 64-row CT. MBF was calculated using the deconvolution technique. Quantitative perfusion ratio (QPR) was defined as the myocardial blood flow (MBF) of the myocardium with coronary stenosis divided by the MBF of the myocardium without significant stenosis or infarct. Of the 44 patients who underwent subsequent coronary angiography, we assessed the diagnostic performance to diagnose ≥50% stenosis by quantitative coronary analysis (QCA). RESULTS: The average effective dose of dynamic CTP and the entire scans were 2.5 ±â€¯0.7 and 7.3 ±â€¯1.8 mSv, respectively. The MBF of the myocardium without significant stenosis was 1.20 ±â€¯0.32 ml/min/g, which significantly decreased to 0.98 ±â€¯0.24 ml/min/g (p < 0.01) in the area with ≥50% stenosis by CT angiography. The QPR of the myocardium with QCA ≥50% stenosis was significantly lower than 1 (0.84 ±â€¯0.32, 95% confidence interval (CI), 0.77-0.90, p < 0.001). The accuracy to detect QCA ≥50% stenosis was 82% (95%CI, 74-88%) using CT angiography alone and significantly increased to 87% (95%CI, 80-92%, p < 0.05) including QPR. CONCLUSION: Dynamic myocardial CTP could be performed using 64-row CT with a low radiation dose and would improve the diagnostic performance to detect QCA ≥50% stenosis than CT angiography alone.

Longer diabetes duration reduces myocardial blood flow in remote myocardium assessed by dynamic myocardial CT perfusion.

AIMS: To investigate the relationship of type 2 diabetes duration and myocardial blood flow (MBF) assessed by myocardial CT perfusion. MATERIALS AND METHODS: We prospectively included 140 patients with type 2 diabetes who underwent dynamic myocardial CT perfusion exam. MBF of the remote myocardium was calculated using the deconvolution technique and the Voronoi method. The relationships of MBF and diabetic duration, diabetic complications, conventional risk factors, coronary calcium, and coronary stenosis were assessed by logistic regression analysis. RESULTS: A weak but significantly negative relationship was present between diabetes duration and MBF (R2 = 0.05, p < 0.01). The average MBF of patients with a duration of >8 years was 13% lower than that of the remaining patients (1.11 ±â€¯0.35 vs 1.28 ±â€¯0.27 ml min-1 g-1, p < 0.01). Duration of one year was associated with a 6% increased risk for low MBF (<1.18 ml min-1 g-1) (odds ratio 1.06, 95% confidence interval 1.01-1.12, p < 0.05). Calcium score was also a significant factor for low MBF (odds ratio 1.08 (per 100 Agatston units), 95% confidence interval 1.01-1.17, p < 0.05). CONCLUSION: Longer diabetes duration is associated with lower MBF independent of conventional cardiac risk factors or the presence of coronary stenosis.

Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.

Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A.

Data for comparison of computed tomography angiography and dynamic myocardial perfusion to detect significant stenosis by coronary angiography.

This article describes data related to a research article titled "Feasibility of dynamic myocardial CT perfusion using single-source 64-row CT", Tomizawa et al. (in press) [1]. Decrease in the myocardial blood flow could be calculated by performing stress dynamic computed tomography perfusion. This article compares the receiver operating characteristics curve of computed tomography angiography and dynamic myocardial perfusion to diagnose significant stenosis by invasive coronary angiography.

Myocardial Injury without Electrocardiographic Changes after a Suicide Attempt by an Overdose of Glimepiride and Zolpidem: A Case Report and Literature Review.

A 40-year-old diabetic man was admitted to our hospital for poor glycemic control. During hospitalization, he took 42 mg glimepiride and 50 mg zolpidem as a suicide attempt. The following day, the creatine kinase-MB fraction and troponin I levels were elevated to 112 IU/L and 8.77 ng/mL, respectively, without any electrocardiographic abnormalities. The patient recovered completely without any complications. Four weeks later, coronary computed tomography angiography and myocardial perfusion scintigraphy revealed moderate one-vessel coronary disease without the evidence of myocardial ischemia or old infarction. Cardiac-specific markers must be considered in sulfonylurea-induced hypoglycemic patients, particularly when the patient is unconscious and does not exhibit any clinical manifestations.