Involvement of enhanced expression of classical complement C1q in atherosclerosis progression and plaque instability: C1q as an indicator of clinical outcome.

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.

Decreased serum SIRT6 as a novel predictor of coronary artery disease.

OBJECTIVE: SIRT6 is an NAD-dependent histone deacetylase known to regulate aging, inflammation and energy metabolism, and might play an important role in atherosclerosis. However, whether it also plays a role in coronary artery disease (CAD) remains unclear. PATIENTS AND METHODS: In this study, we detected the expression of SIRT6 in serum by Western blotting. The concentrations of SIRT6 in serum specimens from 69 patients with CAD [30 with stable angina (SA) and 39 with acute coronary syndrome (ACS)] and 16 controls were analysed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Western blotting analysis of the serum samples found that SIRT6 expression was decreased in the SA group (p=0.000) and ACS group (p=0.000) compared with the control group. Significantly lower levels of serum SIRT6 were observed in SA patients (18.80±9.14 ng/mL) and ACS patients (16.85±9.66 ng/mL) than in healthy controls (25.79±14.23 ng/mL). SIRT6 concentrations were positively correlated with other markers of CAD, such as high-density lipoprotein cholesterol (r=0.362, p<0.01) and age (r=0.265, p<0.05), and negatively correlated with blood glucose (r=-0.284, p<0.05). Multivariate logistic regression analysis demonstrated that lower SIRT6 levels were independently associated with the presence of CAD in men (OR=0.817, 95% CI 0.694-0.962, p=0.015). Receiver operating characteristic (ROC) curve analysis showed that lower serum SIRT6 could distinguish CAD patients (AUC, 0.726; 95% CI, 0.508-0.943; p=0.041) from controls. SIRT6 is found downregulated in blood vessels of atherosclerotic APOE-/- mice and human aorta arteries. CONCLUSIONS: We demonstrated that SA and ACS patients had lower serum concentrations of SIRT6. The decreased serum SIRT6 level was independently associated with the diagnosis of CAD. SIRT6 may play a cardioprotective role in CAD patients, and future research is required to address this issue.

Frequency of Lipid-Rich Coronary Plaques in Stable Angina Pectoris versus Acute Coronary Syndrome (from the Lipid Rich Plaque Study).

The multicenter prospective Lipid Rich Plaque (LRP) registry showed that nonculprit (NC) lipid-rich plaques identified by near-infrared spectroscopy (maxLCBI4mm >400) with an intravascular ultrasound plaque burden (PB) >70% and/or minimum lumen area (MLA) <4 mm2 within the maxLCBI4mm segment were more frequently associated with major adverse cardiac events (MACE) within 2 years. The aim of this sub-study was to report the relationship between initial clinical presentation and subsequent NC-MACE. Patients enrolled in the LRP study were stratified post hoc as having a stable angina pectoris or silent ischemia presentation versus acute coronary syndrome, excluding patients presenting with acute ST-elevation myocardial infarction. Among the 1552 patients, 717 presented with stable angina pectoris or silent ischemia. Patients presenting with acute coronary syndrome were more likely to be younger and Black, current smokers, and have less chronic kidney disease. Of the scanned nonculprit vessels, there was no difference between the 2 clinical presentation groups regarding lipidic content, and the rate of lipid-rich plaques (maxLCBI4mm >400) was 31.9% in both groups. Finally, there was no difference in NC-MACE at 2 years' follow-up, although within each group (stable versus acute coronary syndrome), the NC-MACE rate associated with maxLCBI4mm >400 was significantly higher than maxLCBI4mm ≤400 (stable 13.8% vs 6.5%; acute patients 11.6% vs 6.3%, respectively). In conclusion, in patient groups that present with stable angina pectoris or silent ischemia versus acute coronary syndrome, the NC lipidic content was similar, as was NC-MACE, through 2 years of follow-up.

Association of lower vitamin D levels with inflammation and leucocytes parameters in patients with and without diabetes mellitus undergoing coronary angiography.

BACKGROUND: Diabetes mellitus has been associated with a chronic low-grade inflammation and a higher risk of cardiovascular and infectious disease, that could be prevented by the effects of vitamin D. We aimed at evaluating the impact of vitamin D levels on the biomarkers of acute-phase response, inflammation and glucose metabolism in a large cohort of diabetic patients with cardiovascular disease. MATERIALS AND METHODS: Consecutive patients undergoing coronary angiography were included. Diabetes mellitus was defined as previous diagnosis, specific treatment administration (oral drug or insulin), fasting glycaemia >6.99 mmol/L or HbA1c >48 mmol/L. Glucose parameters, white blood cells, Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), C-reactive protein (CRP) and vitamin D were measured at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). RESULTS: We included 1472 diabetic patients and 2499 non-diabetic patients that were divided according to vitamin D tertiles. Among diabetic patients, lower levels of vitamin D were associated with female gender (P = .02), obesity (P = .004), active smoking and acute presentation (P < .001) and with a more atherogenic metabolic profile. The levels of white blood cells, leucocytes subfamilies, and inflammatory parameters significantly correlated with vitamin D levels in both patients with and without diabetes (diabetic: P = .012 for WBC, P = .004 for NLR and P < .001 for MLR and C-reactive protein, non-diabetic: P < .001 for WBC; NLR, MLR and C-reactive protein, respectively). Among diabetic patients, results were confirmed at multivariate analysis with no significant interaction according to glycaemic control. CONCLUSION: The present study demonstrates that, among patients with cardiovascular disease, vitamin D deficiency is associated with metabolic dysregulation and with an elevation of cellular and humoural inflammatory parameters, especially among diabetics, although not being dependent from glycaemic control.

Elevated Plasma Adiponectin Levels Are Associated with Abnormal Corrected QT Interval in Patients with Stable Angina.

Low-circulating levels of adiponectin (ADPN) are associated with obesity, diabetes mellitus, and coronary artery disease. On the contrary, some studies have demonstrated a link between relatively high levels of plasma ADPN and heart failure, atrial fibrillation, and adverse outcome. However, little is known about the relationship between ADPN level and prolonged QT interval. The aim of this study was to investigate the association between plasma ADPN levels and prolonged QT interval in patients with stable angina.In this retrospective study, because the diverse disease severity and condition of the study population may have affected the results, we chose individuals with stable angina. Plasma ADPN concentrations were measured using enzyme-linked immunosorbent assays. A 12-lead ECG recording was obtained from each patient.We enrolled 479 stable-angina patients. Patients with an abnormal corrected QT (QTc) interval had higher median plasma ADPN levels than those with normal QTc intervals. Age- and sex-adjusted ADPN levels were positively associated with heart rate, QTc interval, left ventricular mass index, and creatinine but negatively associated with left ventricular ejection fraction, waist circumference, current smoking, total cholesterol, triglycerides, low-density lipoprotein cholesterol, albumin, and estimated glomerular filtration rate. A multiple logistic regression analysis revealed ADPN as an independent association factor for abnormal QTc interval. Increasing concentrations of sex-specific ADPN were independently and significantly associated with abnormal QTc interval, even after full adjustment of known biomarkers.Our results indicate that ADPN may play a role in the pathogenesis of abnormal QTc interval in patients with stable angina.

Comparing the Diagnostic Value of the C-Reactive Protein to Albumin Ratio With Other Inflammatory Markers in Patients With Stable Angina Pectoris.

Several laboratory parameters have been used to assess inflammatory process and determine cardiovascular risk. The C-reactive protein to albumin ratio (CAR) is a novel marker of inflammation and its clinical importance has not been clearly elucidated in coronary artery disease (CAD). We compared the diagnostic value of CAR with other inflammatory parameters in detecting significant CAD. Patients (n = 421) with stable angina pectoris who underwent coronary angiography for the suspected CAD were included. Neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio, uric acid, monocyte to high-density cholesterol (HDL-C) ratio, mean platelet volume to lymphocyte ratio (MPVLR), and platelet to mean corpuscular volume (MCV) ratio were measured. Patients with significant CAD had a significantly higher NLR (P = .043), MLR (P = .004), uric acid (P < .001), monocyte to HDL-C ratio (P = .004), and CAR (P < .001) compared to patients without significant CAD. However, MPVLR and platelet to MCV ratio weren't different between 2 groups. The area under the curve (AUC) of CAR was the highest AUC among all inflammatory parameters for predicting significant CAD. Multivariate analysis showed that age (odds ratio [OR]: 1.046, 95% confidence interval [CI], 1.020-1.072, P < .001) and CAR (OR: 1.175, 95% CI, 1.126-1.226, P < .001) were the only independent predictors of significant CAD. In conclusion, CAR had the strongest diagnostic value in detecting significant CAD among the inflammatory parameters evaluated in this study.

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.

Impact of periprocedural biomarker elevation on mortality in stable angina pectoris patients undergoing elective coronary intervention: a systematic review and meta-analysis including 24 666 patients.

BACKGROUND: Uncertainty remains regarding the exact prognostic impact of biomarker elevation following percutaneous coronary intervention in patients with stable angina pectoris and the subsequent risk of death. We sought, therefore, to evaluate the effect of periprocedural myocardial infarction on the subsequent mortality risk following percutaneous coronary intervention in patients with stable angina pectoris and normal preprocedural cardiac biomarkers level. METHODS: After a systematic literature search was done in PubMed and EMBASE, we performed a meta-analysis of studies with post-procedural cardiac biomarkers data. All-cause mortality and cardiac death were evaluated in subjects with stable angina pectoris who underwent an elective coronary intervention. RESULTS: Fourteen studies with 24 666 patients were included. The mean age was 64.2 years ± 9.8 with about 3-quarters (74.9%) of these patients being men. The mean duration of follow-up was 18.1 months ± 14.3. Periprocedural myocardial infarction, based on study-specific biomarker criteria, occurred in 14.3% of the patients. Periprocedural myocardial infarction conferred a statistically significant increase in the risk of all-cause mortality (odds ratio, 1.62; 95% confidence interval, 1.30-2.01; P < 0.0001; I = 0%); where reported separately, cardiac death was also significantly increase (odds ratio, 2.77; 95% confidence interval, 1.60-4.80; P = 0.0003; I = 0%). CONCLUSION: The occurrence of periprocedural myocardial infarction after an elective percutaneous coronary intervention in patients with stable angina pectoris is associated with a statistically significant increase in subsequent all-cause mortality and cardiac mortality.

IL-37 Plays a Beneficial Role in Patients with Acute Coronary Syndrome.

BACKGROUND: Interleukin-37 (IL-37) acts as an inhibitor of innate and adaptive immunity. However, the exact role of IL-37 in the patients with acute coronary syndrome (ACS) remains to be elucidated. METHODS: Patients were classified into 4 groups: normal coronary artery (NCA), stable angina (SA), unstable angina (UA), and acute myocardial infarction (AMI). The circulating Treg, Th1, and Th17 frequencies were measured. The effect of IL-37 on stimulated peripheral blood mononuclear cells (PBMCs) and the influence of IL-37 on DCs were explored. In addition, the role of IL-37-treated tDCs on Treg cell expansion and the stability of these tDCs were also tested. RESULTS: Our results showed that the circulating Treg frequencies were decreased, while Th1 and Th17 frequencies were increased in ACS patients, and that IL-37 expanded Tregs but suppressed Th1 and Th17 cells in activated PBMCs derived from ACS patients. Of note, IL-37-treated human DCs obtained a tolerogenic phenotype, and such tDCs promoted expansion of Tregs and decreased the Th1 and Th17 populations when cocultured with CD4+ T cells. Interestingly, IL-37-treated DCs from patients with ACS are phenotypically and functionally comparable to IL-37-treated DCs from NCA patients, and tolerogenic properties of IL-37-treated DCs were highly stable. CONCLUSION: In conclusion, our results reveal a beneficial role of IL-37 in the patients with ACS and suggest that autologous IL-37-treated tDCs may be a novel therapeutic strategy for the patients with ACS.

Sex-specific association of monocyte count to high-density lipoprotein ratio with SYNTAX score in patients with suspected stable coronary artery disease.

Recently, the monocyte count to high-density lipoprotein cholesterol ratio (MHR) was found to be associated with the SYNTAX score in patients with both stable coronary artery disease (CAD) and acute coronary syndrome (ACS). The MHR was significantly higher in male patients. However, the sex-specific association of MHR with SYNTAX score in stable CAD was not well explored. Thus, the present study aimed to investigate the association of MHR and presence and severity of CAD evaluated by coronary angiography and the SYNTAX score in males and females.In total, 873 patients who received selective coronary angiography between March 2017 and July 2018 were included in the present study. Patients were divided into 3 groups according to MHR tertiles. The MHR was calculated by dividing the monocyte count by the high-density lipoprotein cholesterol level. CAD was defined as at least 50% diameter stenosis of a major coronary artery, including the right coronary, left main coronary, left anterior descending, and left circumflex arteries. The SYNTAX score was calculated by 2 experienced interventional cardiologists. SYNTAX score ≥23 was defined as a high SYNTAX score.Males showed a significantly higher MHR (12.2 [8.9-15.5] vs 9.3 [6.2-12.1], P < .001), accompanied by a higher prevalence of CAD (68.1% vs 53.4%, P < .001). Male sex remained an independent predictor of elevated MHR after correction for confounding factors (adjusted odds ratio [OR] 3.102, P = .001). The association between MHR and SYNTAX score was confirmed only in male stable patients with CAD (r = 0.113, P = .036). Multivariate logistic regression analysis showed that MHR was an independent predictor of SYNTAX score ≥23 only in male patients with CAD. The receiver-operating characteristic curve showed a predictive value of MHR for high SYNTAX score only in males.A higher MHR in males and a positive correlation of MHR with SYNTAX score were observed only in male stable patients with CAD. Such an easily obtained index may help interventional cardiologists detect high-risk patients before coronary catheterization, but its application may be restricted to males.

Value of the expression of miR-208, miR-494, miR-499 and miR-1303 in early diagnosis of acute myocardial infarction.

AIMS: This study aims to investigate the value of the expression of miR-208, miR-494, miR-499 and miR-1303 in the early diagnosis of acute myocardial infarction (AMI). MAIN METHODS: Patients were divided into two groups: AMI group (n = 41), and Stable angina pectoris (SAP) group (n = 32). Peripheral venous blood was sampled from these patients at the time of admission (T0), 6 h after onset (T6) and 12 h after onset (T12), while blood was sampled once from healthy subjects who underwent physical examination in the same time period (control group, n = 10). The expression of miR-208, miR-494, miR-499 and miR-1303 in serum were detected by real-time quantitative polymerase chain reaction (qRT-PCR), and differences in miRNA expression among these three groups of patients were analyzed. KEY FINDINGS: Serum miR-208, miR-494, miR-499 and miR-1303 expression levels at different time points were significantly higher in the AMI group than in the SAP group and control group. The differences among these groups were statistically significant (P < 0.05), while the difference between the SAP group and control group was not statistically significant (P > 0.05). Variation trend: The miRNA levels above began to increase at T0 in the AMI group, the peak levels of miR-208, miR-494 and miR-499 appeared before T12, and the peak level of miR-1303 appeared between T6 and T12, or after T12. SIGNIFICANCE: miR-208, miR-494, miR-499 and miR-1303 were not superior to hs-cTnI as myocardial markers in the diagnosis of early acute myocardial infarction.

Loss of Regulatory Immune Function in Coronary Artery Disease Patients from the Indian Population.

The pathogenic roles of inflammatory T cells and monocytes subsets have not been explored in different manifestations of coronary artery disease. We studied the frequency of these cells, their response to autoantigens, regulatory cell functional assay, foam cell formation and macrophage differentiation in 181 patients (stable angina, ST-elevated myocardial infarction (STEMI), NSTEMI, and unstable angina), and 34 controls and in samples collected during recurrent cardiac events and from patients showing clinical improvement. The proportion of Th17 cells and monocytes gradually increased in patients with stable angina at one end of the spectrum followed by NSTEMI, STEMI, and unstable angina at other end. Inflammatory cells were positively and inversely associated with recurrent events and clinical improvement, respectively. Patients showed expansion of Th17 cells in response to autoantigen (HSP60) and compromised Treg function. Our results suggest that stress-induced activation of inflammatory cells expands in the absence of regulatory control in CAD patients.

Targeted metabolomic analysis of plasma metabolites in patients with coronary heart disease in southern China.

Coronary heart disease (CHD), one of the leading causes of death in the world, is a complex metabolic disorder due to genetic and environmental interactions. The potential mechanisms and diagnostic biomarkers for different types of coronary heart disease remain unclear. Metabolomics is increasingly considered to be a promising technology with the potential to identify metabolomic features in an attempt to distinguish the different stages of CHD.We aimed to investigate serum metabolite profiling between CHD patients and normal coronary artery (NCA) subjects and identify metabolic biomarkers associated with CHD progression in an ethnic Hakka population in southern China.Using a novel targeted metabolomics approach, we explored the metabolic characteristics of CHD patients. Blood samples from 302 patients with CHD and 59 NCA subjects were collected that analyses using targeted liquid-chromatography coupled with tandem mass spectrometry (LC-MS).A total of 361 blood samples were determined using targeted LC-MS. Plasma concentrations for trimetlylamine oxide (TMAO), choline, creatinine, and carnitine were significantly higher in patients with CHD compared to the NCA cohort. Further, we observed that the concentration of the 4 metabolites were higher than that of the NCA group in any group of CHD, which including acute myocardial infarction (AMI), unstable angina (UA), and stable angina (SA). In addition, the diagnostic model was constructed based on the metabolites identified and the ROC curve of the NCA subjects and CHD patients were performed. For choline and creatinine, the AUCs ranged from 0.720 to 0.733. For TMAO and carnitine, the AUCs ranged from 0.568 to 0.600.In conclusion, the current study illustrates the distribution of 4 metabolites between CHD patients and NCA subjects. Metabolomics analysis may yield novel predictive biomarkers that will potentially provide value for clinical diagnosis of CHD.

A review of the mechanism of action of Dantonic® for the treatment of chronic stable angina.

Chronic stable angina (CSA) presents as a complication of coronary heart disease, leading to a high incidence and mortality rate worldwide. Dantonic® or Compound Danshen Dripping Pills (CDDP) is a well-known traditional Chinese medicine used for the treatment of myocardial ischemic diseases, such as angina pectoris (AP), myocardial infarction, and sudden death. Dantonic® has been extensively utilized in clinical practice in China for more than 14 years and has proved to be an effective therapy for the treatment of many myocardial ischemic diseases since its approval by CFDA in 1994. Clinical studies in China have shown that Dantonic® is an effective and safe drug for the treatment of angina pectoris manifested with ameliorating anginal symptoms and showing few adverse effects. Nevertheless, the mechanism of Dantonic® for the treatment of angina has been underestimated. Therefore, in this review, we mainly focus on discussing the pharmacological mechanism of action (MoA) of Dantonic® for the treatment of CSA, including the promotion of coronary microcirculation, the optimization of myocardial energy metabolism, and the inhibition of platelet aggregation.

Different network pharmacology mechanisms of Danshen-based Fangjis in the treatment of stable angina.

Danshen (Salvia miltiorrhiza) preparations such as Danhong injection, Danshen injection, Salvianolate injection, compound Danshen injection and Sodium Tanshinone IIA Sulfonate (STS) injection are widely used in China to treat stable angina (angina pectoris) caused by coronary heart disease. In this study we compared the network pharmacological mechanisms of the 5 Danshen preparations. Following a literature search performed in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) database, China Biology Medicine (CBM) database, China Conference Paper Database, Wanfang Database, VIP Database and Conference Proceedings Citation Index (through January 2015), 444 randomized controlled trial publications detailing the use of the 5 Danshen-based injections for treating stable angina were identified, and their combined data were analyzed using a network meta-analysis. All of the 5 Danshen-based preparations were effective in treating stable angina with clinical improvement rates of 72.4%-91.6% and electrocardiogram (ECG) improvement rates of 54.5%-71.6%. According to both clinical improvement and ECG improvement, the 5 Danshen-based preparations were ranked as follows: Danhong injection > Salvianolate injection > STS injection > compound Danshen injection > Danshen injection. There were no significant differences among the safety profiles of the 5 Danshen preparations. The meta-analysis results were further examined using a network pharmacology approach and functional enrichment analysis, which revealed that Danshen and Danhong injections affected 4 and 15 signaling pathways, respectively, and that the 4 signaling pathways affected by Danshen were a subset of those influenced by Danhong. Therefore, Danhong injection affected some unique signaling pathways that might regulate lipoprotein metabolism, oxidation, and inflammation, and protect vascular endothelia, reflecting the multi-component and multi-target characteristics of this traditional formula and its strengths in treating complex diseases.

Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome.

Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.

Cholesterol crystal depth in coronary atherosclerotic plaques: A novel index of plaque vulnerability using optical frequency domain imaging.

BACKGROUND: The involvement of cholesterol crystals (CCs) in plaque progression and destabilization of atherosclerotic plaques has been recently recognized. This study aimed to evaluate the association between the intraplaque localization of CCs and plaque vulnerability. METHODS: We investigated 55 acute coronary syndrome (ACS) and 80 stable angina pectoris (stable AP) lesions using optical frequency domain imaging (OFDI) prior to percutaneous coronary intervention. The distance between CCs and the luminal surface of coronary plaques was defined as CC depth. RESULTS: Although the incidence of CCs had similar frequencies in the ACS and stable AP groups (95% vs. 89%, p = 0.25), CC depth was significantly less in patients with ACS than in those with stable AP (median [25th to 75th percentile]: 68 µm [58 to 92 µm] vs. 152 µm [115 to 218 µm]; p < 0.001). The incidences of plaque rupture, thrombus, lipid-rich plaques, and thin-cap fibroatheroma were significantly greater in patients with ACS than in those with stable AP (62% vs. 18%, p < 0.001; 67% vs. 16%, p < 0.001; 84% vs. 57%, p < 0.01; and 56% vs. 19%, p < 0.001, respectively). CONCLUSION: OFDI analysis revealed that CCs were found in the more superficial layers within the coronary atherosclerotic plaques in patients with ACS than in those with stable AP, suggesting that CC depth is associated with plaque vulnerability. CC depth, a novel OFDI-derived parameter, could be potentially used as an alternative means of evaluating plaque vulnerability in coronary arteries.

Comprehensive metabolomics identified lipid peroxidation as a prominent feature in human plasma of patients with coronary heart diseases.

Coronary heart disease (CHD) is a complex human disease associated with inflammation and oxidative stress. The underlying mechanisms and diagnostic biomarkers for the different types of CHD remain poorly defined. Metabolomics has been increasingly recognized as an enabling technique with the potential to identify key metabolomic features in an attempt to understand the pathophysiology and differentiate different stages of CHD. We performed comprehensive metabolomic analysis in human plasma from 28 human subjects with stable angina (SA), myocardial infarction (MI), and healthy control (HC). Subsequent analysis demonstrated a uniquely altered metabolic profile in these CHD: a total of 18, 37 and 36 differential metabolites were identified to distinguish SA from HC, MI from SA, and MI from HC groups respectively. Among these metabolites, glycerophospholipid (GPL) metabolism emerged as the most significantly disturbed pathway. Next, we used a targeted metabolomic approach to systematically analyze GPL, oxidized phospholipid (oxPL), and downstream metabolites derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid and linoleic acid. Surprisingly, lipids associated with lipid peroxidation (LPO) pathways including oxidized PL and isoprostanes, isomers of prostaglandins, were significantly elevated in plasma of MI patients comparing to HC and SA, consistent with the notion that oxidative stress-induced LPO is a prominent feature in CHD. Our studies using the state-of-the-art metabolomics help to understand the underlying biological mechanisms involved in the pathogenesis of CHD; LPO metabolites may serve as potential biomarkers to differentiation MI from SA and HC.

Differential proteome profile in ischemic heart disease: Prognostic value in chronic angina versus myocardial infarction. A proof of concept.

The initial clinical manifestation of ischemic heart disease (IHD) i.e. unheralded myocardial infarction (MI) versus chronic angina pectoris (AP) is statistically associated with adverse or mild disease progression respectively in the long-term follow-up. Here, we subjected AP and MI patients to blood proteomic analysis by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) in order to investigate putative new prognostic biomarkers of IHD manifestation. We found several differentially expressed peaks but four of them (4176, 4475, 14,158m/z and 8922m/z for AP and MI, respectively) were most reliable. Two of them were identified; 14,158m/z peak was the double-charged form of Apolipoprotein A-I and its vasoprotective action accords with prominence in AP. The 4176m/z peak was related to FAM83C protein, while neither the 4475m/z peak nor the MI-linked 8922m/z peak could be identified. We conclude that SELDI-TOF-MS analysis may yield a panel of molecular signals able to retrospectively classify patients according to their clinical and molecular features, exploitable for predicting the natural course of IHD.

Thrombospondin-1-Derived Peptide RFYVVMWK Improves the Adhesive Phenotype of CD34+ Cells From Atherosclerotic Patients With Type 2 Diabetes.

CD34+ progenitor cells are growing in use for vascular repair. However, in diabetic individuals with cardiovascular diseases, these cells have dysfunctional engraftment capabilities, which compromise their use for autologous cell therapy. The thrombospondin-1-derived peptide RFYVVMWK has previously been reported to stimulate cell adhesiveness through CD47 and integrin activation pathways. Our aim was to test whether RFYVVMWK preconditioning could modulate CD34+ cell phenotype and enhance its proadhesive properties in diabetic patients. Peripheral blood mononuclear CD34+ cells isolated from 40 atherosclerotic patients with type 2 diabetes (T2D; n = 20) or without (non-T2D; n = 20) were preconditioned with 30 µM RFYVVMWK or truncated peptide RFYVVM. CD34+ cell adhesion was assessed on a vitronectin-collagen matrix and on TNF-α or IL-1ß-stimulated HUVEC monolayers. Adhesion receptors, platelet/CD34+ cell conjugates, and cell viability were analyzed by flow cytometry and confocal microscopy. RFYVVMWK increased the adhesion of T2D CD34+ cells by eightfold to the vitronectin-collagen matrix (p < 0.001) corresponding to a threefold increase compared to unstimulated non-T2D CD34+ cells. The peptide induced the formation of platelet/CD34+ conjugates and increased the expression of TSP-1, CD29, CD51/CD61, and CD62P in both T2D and non-T2D cells. However, RFYVVMWK treatment did not affect the viability/apoptosis of CD34+ progenitor cells. In conclusion, priming CD34+ cells with RFYVVMWK may enhance their vascular engraftment during autologous proangiogenic cell therapy.