Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD.

BACKGROUND: Military sexual trauma (MST) is a prevalent issue within the U.S. military. Victims are more likely to develop comorbid diseases such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Nonetheless, not everyone who suffers from MST develops PTSD and/or MDD. DNA methylation, which can regulate gene expression, might give us insight into the molecular mechanisms behind this discrepancy. Therefore, we sought to identify genomic loci and enriched biological pathways that differ between patients with and without MST, PTSD, and MDD. METHODS: Saliva samples were collected from 113 female veterans. Following DNA extraction and processing, DNA methylation levels were measured through the Infinium HumanMethylationEPIC BeadChip array. We used limma and bump hunting methods to generate the differentially methylated positions and differentially methylated regions (DMRs), respectively. Concurrently, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome to find enriched pathways. RESULTS: A DMR close to the transcription start site of ZFP57 was differentially methylated between subjects with and without PTSD, replicating previous findings and emphasizing the potential role of ZFP57 in PTSD susceptibility. In the pathway analyses, none survived multiple correction, although top GO terms included some potentially relevant to MST, PTSD, and MDD etiology. CONCLUSION: We conducted one of the first DNA methylation analyses investigating MST along with PTSD and MDD. In addition, we found one DMR near ZFP57 to be associated with PTSD. The replication of this finding indicates further investigation of ZFP57 in PTSD may be warranted.

A Prospective Randomized Study of the Herbal Medicine Yokukansan for Preventing Delirium After Gastrointestinal Cancer Surgery.

Background: Yokukansan, the Chinese Herbal Medicine, may be effective for treating postoperative delirium. However, there is no sufficient evidence supporting this notion. This study aimed to investigate whether yokukansan was effective for preventing delirium after gastrointestinal cancer surgery by the prospective randomized study. Methods: This was a double-blind, randomized, controlled trial. Patients aged 75 years or older who underwent surgery between May 2017 and December 2019 were randomized to the yokukansan or anchusan (another Herbal Medicine) group. They received treatments with oral intake of assigned medicine from the day before surgery until postoperative day 3. Then, the incidence of postoperative delirium was compared. A psychiatrist diagnosed patients with postoperative delirium. Results: Seventy-seven patients were enrolled in this study, and the full analysis set comprised 68 patients. In total, 25 of 68 (36.8%) patients presented with postoperative delirium. Specifically, 13 (37.1%) patients in the control group and 12 (36.4%) in the yokukansan group were diagnosed with postoperative delirium. However, the results did not differ significantly in both groups. Moreover, there was no remarkable difference in terms of delirium severity, and adverse events correlated with the medications were not observed. Conclusion: Yokukansan was ineffective in preventing delirium after gastrointestinal cancer surgery.

Low Energy Intake Diagnosed Using the Harris-Benedict Equation Is Associated with Poor Prognosis in Elderly Heart Failure Patients.

INTRODUCTION: Insufficient nutrient intake is a strong independent predictor of mortality in elderly patients with heart failure. However, it is unclear to what extent energy intake affects their prognosis. This study investigated the association between patient outcomes and actual measured energy intake in elderly patients (≥65 years) with heart failure. METHODS: This study enrolled 139 elderly patients who were hospitalized with worsening heart failure at Shingu Municipal Medical Center, Shingu, Japan, between May 2017 and April 2018. Energy intake was evaluated for three days (from three days prior to the day of discharge until the day of discharge). Based on basal energy expenditure calculated using the Harris-Benedict equation, the patients were classified into a low-energy group (n = 38) and a high-energy group (n = 101). We assessed the prognosis in terms of both all-cause mortality and readmission due to worsening heart failure as a primary outcome. RESULTS: Compared to the patients in the high-energy group, the patients in the low-energy group were predominantly female, less frequently had smoking habits and ischemic heart diseases, and had a higher left ventricular ejection fraction. The low-energy group had higher mortality than the high-energy group (p = 0.028), although the two groups showed equivalent event rates of the primary outcome (p = 0.569). CONCLUSION: Calculations based on the Harris-Benedict equation revealed no significant difference in the primary outcome between the two groups, with a secondary outcome that showed worse mortality in the low-energy group. Given this result, energy requirement-based assessments using the Harris-Benedict equation might help in the management of elderly heart failure patients in terms of improved life outcomes.

NSAIDs use history: impact on the genome-wide DNA methylation profile and possible mechanisms of action.

BACKGROUND AND OBJECTIVE: NSAIDs inhibit cyclooxygenase, but their role in aging and other diseases is not well understood. Our group previously showed the potential benefit of NSAIDs in decreasing the risk of delirium and mortality. Concurrently, epigenetics signals have also been associated with delirium. Therefore, we sought to find differentially methylated genes and biological pathways related to exposure with NSAIDs by comparing the genome-wide DNA methylation profiles of patients with and without a history of NSAIDs use. METHODS: Whole blood samples were collected from 171 patients at the University of Iowa Hospital and Clinics from November 2017 to March 2020. History of NSAIDs use was assessed through a word-search function in the subjects' electronic medical records. DNA was extracted from the blood samples, processed with bisulfite conversion, and analyzed using Illumina's EPIC array. The analysis of top differentially methylated CpG sites and subsequent enrichment analysis were conducted using an established pipeline using R statistical software. RESULTS: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed several biological pathways relevant to NSAIDs' function. The identified GO terms included "arachidonic acid metabolic process," while KEGG results included "linoleic acid metabolism," "cellular senescence," and "circadian rhythm." Nonetheless, none of the top GO and KEGG pathways and the top differentially methylated CpG sites reached statistical significance. CONCLUSION: Our results suggest a potential role of epigenetics in the mechanisms of the action of NSAIDs. However, the results should be viewed with caution as exploratory and hypothesis-generating given the lack of statistically significant findings.

Prognostic value of Toll-like receptor 4 on human monocyte subsets combined with computed tomography-adapted Leaman score assessing coronary artery disease.

BACKGROUND: Upregulation of Toll-like receptor 4 (TLR-4) is associated with coronary plaque vulnerability assessed by coronary computed tomography angiography (CCTA). Computed tomography-adapted Leaman score (CT-LeSc) is an independent long-term predictor of cardiac events. The relationship between the TLR-4 expression of CD14 ++ CD16 + monocytes and future cardiac events is unknown. We investigated this relationship using CT-LeSc in patients with coronary artery disease (CAD). METHODS: We analyzed 61 patients with CAD who underwent CCTA. Three monocyte subsets (CD14 ++ CD16 - , CD14 ++ CD16 + , and CD14 + CD16 + ) and the expression of TLR-4 were measured by flow cytometry. We divided the patients into two groups according to the best cutoff value of the TLR-4 expression on CD14 + CD16 + which could predict future cardiac events. RESULTS: CT-LeSc was significantly greater in the high TLR-4 group than the low TLR-4 group [9.61 (6.70-13.67) vs. 6.34 (4.27-9.09), P  < 0.01]. The expression of TLR-4 on CD14 ++ CD16 + monocytes was significantly correlated with CT-LeSc ( R2  = 0.13, P  < 0.01). The expression of TLR-4 on CD14 ++ CD16 + monocytes was significantly higher in patients who had future cardiac events than in those who did not [6.8 (4.5-9.1) % vs. 4.2 (2.4-7.6) %, P  = 0.04]. High TLR-4 expression on CD14 ++ CD16 + monocytes was an independent predictor for future cardiac events ( P  = 0.01). CONCLUSION: An increase in the TLR-4 expression on CD14 ++ CD16 + monocytes is related to the development of future cardiac events.

Bispectral EEG (BSEEG) Algorithm Captures High Mortality Risk Among 1,077 Patients: Its Relationship to Delirium Motor Subtype.

OBJECTIVE: Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes. METHODS: We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups. RESULTS: A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16-1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06-1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12-1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05-1.67], which remained significant after adjustment for the same covariates. CONCLUSION: We found that the BSEEG method is capable of capturing patients at high mortality risk.

Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients.

OBJECTIVE: No previous study demonstrates the difference in the genome-wide DNA methylation status of post-operative delirium (POD) using human brain tissue obtained from neurosurgery and multiple peripheral tissues such as blood, saliva, and buccal samples from the same individuals. We aimed to identify epigenetic marks of DNA methylation in the brain and peripheral tissues to elucidate the potential pathophysiological mechanism of POD. METHODS: The four tissue types (brain, blood, saliva, buccal) of DNA samples from up to 40 patients, including 11 POD cases, were analyzed using Illumina EPIC array. DNAm differences between patients with and without POD were examined. We also conducted enrichment analysis based on the top DNAm signals. RESULTS: The most different CpG site between control and POD was found at cg16526133 near the ADAMTS9 gene from the brain tissue(p = 8.66E-08). However, there are no CpG sites to reach the genome-wide significant level. The enrichment analysis based on the 1000 top hit CpG site (p < 0.05) on the four tissues showed several intriguing pathways. In the brain, there are pathways including "positive regulation of glial cell differentiation". Blood samples showed also pathways related to immune function. Besides, both saliva and the buccal sample showed pathways related to circadian rhythm, although these findings were not FDR significant. CONCLUSION: Enrichment analysis found several intriguing pathways related to potential delirium pathophysiology. Present data may further support the role of epigenetics, especially DNA methylation, in the molecular mechanisms of delirium pathogenesis.

Hyperglycemia and intramyocardial hemorrhage in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Hyperglycemia at admission and intramyocardial hemorrhage (IMH) are associated with poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). Little is known about the relationship between glucose levels at admission and IMH. The association between matrix metalloproteinase-9 (MMP-9), which plays an important role in the development of IMH, and hyperglycemia is also unknown. This study aimed to investigate the relationship between hyperglycemia at admission and IMH in patients with STEMI. METHODS: We enrolled 174 patients with first STEMI who underwent primary percutaneous coronary intervention (PCI) and cardiovascular magnetic resonance (CMR) imaging. T2-weighted imaging and late gadolinium enhancement (LGE)-CMR were performed to detect IMH and microvascular obstruction (MVO), respectively. Two patient groups were created: IMH group and non-IMH group. MMP-9 levels were measured in the culprit coronary arteries of 13 patients. RESULTS: Glucose level at admission and the value of glycosylated hemoglobin were higher in the IMH group than in the non-IMH group [IMH group vs. non-IMH group; 208.5 (157.8-300.5) mg/dL vs. 157.0 (128.8-204.3) mg/dL, p < 0.001, and 6.2 (5.7-7.5) % vs. 5.8 (5.4-6.6) %, p = 0.030, respectively]. A multivariable logistic regression analysis revealed that only admission glucose level was an independent predictor of IMH (OR: 1.012; 95 % CI: 1.005-1.020, p = 0.001). The MMP-9 levels in patients with IMH were higher than those in patients without IMH [256.0 (161.0-396.0) ng/mL vs. 73.5 (49.5-131.0) ng/mL, p = 0.040]. There was a moderate positive correlation between glucose levels at admission and MMP-9 levels (r = 0.600, p = 0.030). CONCLUSIONS: Hyperglycemia at admission is associated with the occurrence of IMH in patients with STEMI.

Implications of multiple late gadolinium enhancement lesions on the frequency of left ventricular reverse remodeling and prognosis in patients with non-ischemic cardiomyopathy.

BACKGROUND: Non-ischemic cardiomyopathy (NICM) is a heterogeneous disease, and its prognosis varies. Although late gadolinium enhancement (LGE)-cardiovascular magnetic resonance (CMR) demonstrates a linear pattern in the mid-wall of the septum or multiple LGE lesions in patients with NICM, the therapeutic response and prognosis of multiple LGE lesions have not been elucidated. This study aimed to investigate the frequency of left ventricular (LV) reverse remodeling (LVRR) and prognosis in patients with NICM who have multiple LGE lesions. METHODS: This single-center retrospective study included 101 consecutive patients with NICM who were divided into 3 groups according to LGE-CMR results: patients without LGE (no LGE group = 48 patients), patients with a typical mid-wall LGE pattern (n = 29 patients), and patients with multiple LGE lesions (n = 24 patients). LVRR was defined as an increase in LV ejection fraction (LVEF) ≥ 10 % and a final value of LVEF > 35 %, which was accompanied by a decrease in LV end-systolic volume ≥ 15 % at 12-month follow-up using echocardiography. The frequency of composite cardiac events, defined as sudden cardiac death (SCD), aborted SCD (non-fatal ventricular fibrillation, sustained ventricular tachycardia, or adequate implantable cardioverter-defibrillator therapies), and heart failure death or hospitalization for worsening heart failure, were summarized and compared between the groups. RESULTS: Among the 3 groups, the frequency of LVRR was significantly lower in the multiple lesions group than in the no LGE and mid-wall groups (no LGE vs. mid-wall vs. multiple lesions: 49 % vs. 52 % vs. 19 %, p = 0.03). There were 24 composite cardiac events among the patients: 2 in patients without LGE (hospitalization for worsening heart failure; 2), 7 in patients of the mid-wall group (SCD; 1, aborted SCD; 1 and hospitalization for worsening heart failure; 5), and 15 in patients of the multiple lesions group (SCD; 1, aborted SCD; 8 and hospitalization for worsening heart failure; 6). The multiple LGE lesions was an independent predictor of composite cardiac events (hazard ratio: 11.40 [95 % confidence intervals: 1.49-92.01], p = 0.020). CONCLUSIONS: Patients with multiple LGE lesions have a higher risk of cardiac events and poorer LVRR. The LGE pattern may be useful for an improved risk stratification in patients with NICM.

Stress increases blood beta-hydroxybutyrate levels and prefrontal cortex NLRP3 activity jointly in a rodent model.

AIM: This study aimed to assess the response of endogenous beta-hydroxybutyrate to psychological stress, and its association with nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome, and stress-induced behavior. METHODS: Male C57BL/6J mice were subjected to 1-hour restraint stress to examine changes in the endogenous beta-hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10-day social defeat stress to the male C57BL/6J mice. RESULTS: One-hour restraint stress rapidly increased beta-hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta-hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression- and anxiety-like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta-hydroxybutyrate levels. Among the social defeat model mice, those with high beta-hydroxybutyrate levels tended to have more depression- and anxiety-like behavior. CONCLUSIONS: The increased blood beta-hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta-hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta-hydroxybutyrate levels tend to exhibit increased depression- and anxiety-like behaviors; thus, an increase in blood beta-hydroxybutyrate levels due to stress may indicate stress vulnerability.

Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model.

Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague-Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1ß. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.

Expression of Cyclophilin A in Coronary Artery Plaque with Intraplaque Hemorrhage Is More Frequent in Deceased Patients Who Had Impaired Kidney Function.

Patients with impaired kidney function have a high frequency of intraplaque hemorrhage (IPH) in their coronary arteries. Levels of cyclophilin A (CyPA), an indirect matrix metalloproteinase inducer, are increased in deceased patients who had impaired kidney function. In this study, we have examined the relationship between IPH and CyPA.We examined 47 samples of coronary plaque from 27 cadavers with coronary stenosis. These sections, all with > 50% coronary stenosis, were stained with an antibody against CyPA and the expression of CyPA was semi-quantified. Cadavers and plaques were classified into one of two groups depending on the presence or absence of IPH. IPH was defined as the presence of red blood cells stained with hematoxylin and eosin (HE) indicative of overt acute hemorrhage.In an individual analysis, estimation of glomerular filtration rate (eGFR) in the IPH group was significantly lower than that in the non-IPH group (P = 0.002). In a histological analysis, the percentage of stained area of CyPA in the IPH group was significantly higher than that in the non-IPH group (P < 0.0001).IPH was associated with a significantly higher expression of CyPA in this study. In addition, patients with IPH in their coronary arteries had significantly impaired kidney function.

Increased plaque rupture forms peak incidence of acute myocardial infarction in winter.

BACKGROUND: It has been widely documented that circannual variation has an impact on the incidence and prognosis of cardiovascular diseases. It is unclear why cold ambient temperature increase the incidence of acute myocardial infarction (AMI). We investigated the relationship between the ambient temperature at the onset of AMI, the morphology of the culprit lesion in patients with AMI. METHODS: We investigated 202 consecutive patients with AMI who underwent optical coherence tomography (OCT). The participants were divided into lower (n = 100) and higher (n = 102) temperature groups based on the ambient temperature. The culprit lesion morphology was compared between the two groups. RESULTS: The median temperature at the onset of AMI was 16.6 °C. The prevalence of plaque ruptures was higher at lower temperatures (lower 66% vs. higher 45%, p = .003), whereas OCT-erosion was more frequent in the higher temperature group (lower 13% vs. higher 26%, p = .021). The lower temperature group showed more cholesterol crystals (lower 71% vs. higher 54%, p = .014). CONCLUSION: The peak incidence of AMI in the winter is formed by increased plaque rupture, suggesting environmental temperature has an influence on the pathogenesis of AMI.

Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

AIMS: Neuroinflammation is deeply related to the pathophysiology of depression. Beta-hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti-inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm. METHODS: BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21 days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro-inflammatory cytokines, such as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured. RESULTS: BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF-α in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti-inflammatory mechanisms, and can improve hypothalamus-pituitary-adrenal axis responses. CONCLUSION: BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro-inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.

Lesion characteristics and prognosis of acute coronary syndrome without angiographically significant coronary artery stenosis.

AIMS: While patients with acute coronary syndrome (ACS) presenting with non-obstructive coronary artery disease (CAD) are at high risk for cardiovascular mortality and morbidity, detailed lesion characteristics are unclear. The aim of this study was to investigate the lesion characteristics and prognosis of ACS with non-obstructive CAD. METHODS AND RESULTS: This study consisted of 82 consecutive ACS patients without obstructive CAD who underwent optical coherence tomography (OCT). Based on the presence of high-risk lesions (HL) in the culprit artery, we classified the patients into two groups: HL group and non-high-risk lesions (NHL) group. A systematic clinical follow-up was performed at our outpatient clinic for up to 24 months. Our endpoint was recurrence of ACS with obstructive CAD. OCT revealed that 42 (51.2%) of 82 patients had hidden HL in the culprit artery, including ruptured plaque (15.9%), calcified nodule (11.0%), spontaneous coronary artery dissection (8.5%), lone thrombus (8.5%), thin-cap fibroatheroma (6.1%), and plaque erosion (1.2%). During angiography, 5 (11.9%) HL patients complained of chest pain without ST elevation. Patients in the HL group had poorer prognoses than those in the other groups (P = 0.040). CONCLUSION: Hidden high-risk lesions accompany ACS patients without obstructive CAD, resulting in poorer outcomes. Vascular injury itself might provoke acute chest pain.

Feasibility and Clinical Significance of In Vivo Cholesterol Crystal Detection Using Optical Coherence Tomography.

OBJECTIVE: Cholesterol crystals (CCs) are frequently found at the site of acute myocardial infarctions (AMIs), but the role of CCs in the onset of AMI remains unclear due to the lack of validated in vivo imaging tools. The aim of this study was to validate the ability of optical coherence tomography (OCT) to detect CCs and to compare the prevalence and distribution of CCs in patients with AMIs and stable angina pectoris. Approach and Results: CC assessment using OCT were compared with histopathology results in 45 coronary samples. We investigated 152 consecutive patients with AMIs and 41 patients with single vessel-diseased stable angina pectoris. Based on the presence of plaque ruptures (PR), AMI patients were divided into 2 groups: those with PR (n=112) and those without PR (n=40). CCs invading fibrous caps were defined as superficial-type CCs. A multivariable logistic regression analysis was performed to determine PR predictors. The sensitivity and specificity of OCT for detecting CCs were 68% and 92%, respectively. The prevalence of plaques with CCs was higher in the AMI with PR group (AMI with PR 81%, AMI without PR 48%, stable angina pectoris 39%, P<0.01). A multivariable logistic model showed that superficial-type CCs and thin-cap fibroatheromas were positive predictors for PR. CONCLUSIONS: OCT has a high specificity and modest sensitivity for the detection of CCs. The combination of CCs invading fibrous cap and thin-cap fibroatheromas detected by OCT may better identify rupture-prone plaques.

Combination of Lesion Stenosis and Myocardial Supply Area Assessed by Coronary Computed Tomography Angiography for Prediction of Myocardial Ischemia.

Recent clinical studies revealed that anatomical information assessed by coronary computed tomography angiography (CTA) may be used effectively to diagnose coronary artery disease (CAD). However, a physiological assessment, demonstrating myocardial ischemia, is required to justify a therapeutic strategy for CAD. This study aimed to investigate whether using CTA to assess myocardial supply area can improve the prediction of myocardial ischemia.We analyzed 201 vessels with moderate (luminal narrowing ≥ 50%, < 70%) and severe (luminal narrowing ≥ 70%, < 99%) stenosis on CTA from 174 patients, who were suspected of having stable angina and underwent measurement of fractional flow reserve (FFR). The myocardial area supplied by the coronary artery, distal to the stenosis, was evaluated with CTA, as reported previously (modified Alberta Provincial Project for Outcome Assessment in Coronary Heart score) and was classified into 3 groups (large, medium, and small).Both percentage area stenosis and myocardial supply area were significantly correlated with FFR (r = -0.46, P < 0.01, and r = -0.45, P < 0.01). Among patients who had coronary plaques, with moderate stenosis and a small myocardial supply area, only 3 of 42 lesions (7%) were identified as ischemic; deviation from the ischemic threshold (FFR = 0.80) was P < 0.01. The combined assessment of lesion stenosis and myocardial supply area, using CTA, improved the prediction of myocardial ischemia significantly compared to lesion stenosis alone (77% versus 59%, P < 0.01).Adding the assessment of myocardial supply area to standard CTA might help predict myocardial ischemia in patients with stable angina pectoris.

Prognostic Value of Human Peripheral Monocyte Subsets for Future Coronary Events in Patients Without Significant Coronary Artery Stenosis.

BACKGROUND: Monocytes in human peripheral blood are heterogeneous and can be divided into 2 groups, inflammatory and pro-inflammatory, according to the differential expression of CD14 and CD16. Pro-inflammatory monocytes (CD14+CD16+) seem to contribute to the development of coronary artery disease. This study aimed to investigate the involvement of specific human peripheral monocyte subsets in the development of future coronary events.Methods and Results:We enrolled 271 patients who were suspected to have either stable angina pectoris or silent myocardial ischemia and underwent coronary angiography (CAG). Two monocyte subsets (CD14+CD16-and CD14+CD16+) were measured by flow cytometry. Patients who did not undergo coronary artery revascularization at initial CAG were followed as the medical therapy group, which included 136 patients among whom 15 had future coronary events. The frequency of CD14+CD16+monocytes was significantly higher in patients who had future coronary events than in those who did not (P<0.01). Furthermore, the frequencies of CD14+CD16+monocyte were not significantly different between patients who had future coronary events and those who underwent coronary revascularization at initial CAG (P<0.33). Multivariate analysis revealed that the frequency of CD14+CD16+monocytes was an independent predictor for future coronary events (P<0.01). CONCLUSIONS: An increase in the abundance of human peripheral pro-inflammatory monocytes is related to the development of future coronary events.

Imaging assessment and accuracy in coronary artery autopsy: comparison of frequency-domain optical coherence tomography with intravascular ultrasound and histology.

Optical coherence tomography (OCT) is a coronary artery imaging technique with high resolution. Second-generation frequency-domain OCT (FD-OCT) technology allows safer and faster clinical application compared with first-generation time-domain OCT (TD-OCT). Only limited validation studies compare FD-OCT with other modes of analysis: histology, which is the current gold standard, and intravascular ultrasound (IVUS). This study therefore aims to demonstrate the accuracy of FD-OCT images compared with IVUS and histology. FD-OCT and IVUS images were acquired from 203 segments from 31 coronary arteries obtained at autopsy from 20 cadavers. Of these, 30 randomly-selected pairs were used to create three classifications of plaque type based on morphological features in FD-OCT and IVUS compared with corresponding histopathology. The remaining 173 pairs were used to demonstrate the diagnostic accuracy for classification of coronary plaques by FD-OCT. Plaque type distributions were 27% fibroatheroma, 22% fibrocalcific plaque and 51% fibrous plaque. The diagnostic accuracies of FD-OCT for fibroatheroma, fibrocalcific plaque and fibrous plaque were 90, 95 and 93%, respectively. Those of IVUS were 81, 89 and 84%, respectively. FD-OCT achieved high diagnostic accuracy for the classification of coronary plaques comparable to TD-OCT. Physicians should consider the differences in the ability to classify plaque morphology of OCT of imaging devices when applying their use.

Toll-Like Receptor 9 Plays a Pivotal Role in Angiotensin II-Induced Atherosclerosis.

Background Toll-like receptor ( TLR ) 9 recognizes bacterial DNA , activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR 9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E-deficient ( Apoe -/-) mice. Methods and Results Tlr9-deficient Apoe -/- ( Tlr9 -/- Apoe -/-) mice and Apoe -/- mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR 9, in these mice. Genetic deletion or pharmacologic blockade of TLR 9 in angiotensin II-infused Apoe -/- mice attenuated atherogenesis in the aortic arch ( P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR 9 in bone marrow in Tlr9 -/- Apoe -/- mice promoted atherogenesis in the aortic arch ( P<0.05). A TLR 9 agonist markedly promoted proinflammatory activation of Apoe -/- macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe -/- macrophages than in Tlr9 -/- Apoe -/- macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction ( P<0.05). Conclusions TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR 9 may serve as a potential therapeutic target for atherosclerosis.