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It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P  = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P  = 0.0001 and 8.95% at Day 90, 95% CI 2.06–15.85%, P  = 0.01). We also found that there were no significant differences in new-onset major vascular events ( P  = 0.8502) and serious adverse events ( P  = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Z summary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration ( r 2 : 0.8204, P  = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment. In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (± B6) or placebo (± B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI). Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01). In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.

Background Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility. Methods We used data from stable angina patients reporting ≥3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a ≥20-point improvement in SAQAF score and improving and not improving ≥1 SAQAF classification were compared. Results Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving ≥1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving ≥1 classification (p < 0.001 for both equations). Patients improving ≥20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a ≥20-point improvement (p < 0.001 for both). Conclusions Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility. Clinical trial registration NCT00091429

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.

The relationship between luminal stenosis severity and plaque vulnerability in chronic stable angina (CSA) is not well studied. This study aimed to investigate the link between stenosis severity, plaque characteristics, and thrombus prevalence in CSA patients using optical coherence tomography. The 174 lesions (146 patients) with CSA divided into three groups according to the percentage of area stenosis (AS); group A (AS < 50%), group B (50% ≤ AS < 70%), and group C (AS ≥ 70%). Twenty-four lesions of group A, 51 lesions of group B, and 99 lesions from group C were studied. The prevalence of thrombus was 19.0% and it was significantly different among the three groups (none in group A vs. 17.6% in group B vs. 24.2% in group C; P  = 0.024). The more severe the luminal narrowing, the more thrombus occurred, with a higher prevalence at the minimal lumen area site. Additionally greater the area stenosis, the higher the prevalence of lipid-rich plaque, thin cap plaque, macrophage infiltration, and ruptured plaque. In the multivariate analysis, thrombus was independently associated with ruptured plaque (OR = 20.96, CI 8.40–57.69, P  < 0.001), macrophage infiltration (OR = 3.77, CI 1.53–10.72, P  = 0.007), lipid angle (OR = 1.01, CI 1.00–1.01, P  = 0.004), and area stenosis (OR = 1.05, CI 1.02–1.10, P  = 0.002). In patients with CSA, the prevalence of thrombus, as assessed by OCT, is not uncommon. Plaque vulnerability, including thrombus occurrence, increased with the severity of area stenosis and was more prevalent at the minimal lumen site exposed to high shear stress.

The current standard biomarker for myocardial infarction (MI) is high‐sensitive troponin. Although powerful in clinical setting, search for new markers is warranted as early diagnosis of MI is associated with improved outcomes. Extracellular vesicles (EVs) attracted considerable interest as new blood biomarkers. A training cohort used for diagnostic modelling included 30 patients with STEMI, 38 with stable angina (SA) and 30 matched‐controls. Extracellular vesicle concentration was assessed by nanoparticle tracking analysis. Extracellular vesicle surface‐epitopes were measured by flow cytometry. Diagnostic models were developed using machine learning algorithms and validated on an independent cohort of 80 patients. Serum EV concentration from STEMI patients was increased as compared to controls and SA. EV levels of CD62P, CD42a, CD41b, CD31 and CD40 increased in STEMI, and to a lesser extent in SA patients. An aggregate marker including EV concentration and CD62P/CD42a levels achieved non‐inferiority to troponin, discriminating STEMI from controls (AUC = 0.969). A random forest model based on EV biomarkers discriminated the two groups with 100% accuracy. EV markers and RF model confirmed high diagnostic performance at validation. In conclusion, patients with acute MI or SA exhibit characteristic EV biomarker profiles. EV biomarkers hold great potential as early markers for the management of patients with MI.

Background Plaque healing may serve a vital function in the natural progression of atherosclerotic disease. This study sought to investigate predictors and morphological characteristics of healed plaque (HP) among angina pectoris (AP) patients. Methods Patients who presented with AP and received preintervention optical coherence tomography (OCT) imaging were consecutively selected for this single‐center retrospective observational study. Patient's demographic and clinical information was collected from the hospital's electronic medical records. Coronary angiograms and OCT images were compared via offline software. Results A total of 390 patients were chosen as the final study population. HP was identified in 186 patients (47.7%) and was relatively less in cases of unstable angina pectoris (UAP) than in stable angina pectoris (SAP) (89/233 [38.2%] vs. 97/157[61.8%]). The HP group had greater prevalence rates of previous myocardial infarction and SAP and higher levels of triglycerides and uremia (median, 1.67 vs. 1.31 mmol/L [p = .01] and 364.22 ± 91.80 vs. 341.53 ± 77.64 µmol/L [p = .01], respectively). Using multivariate analysis, SAP and long lesion length were shown to be stand‐alone indicators of HP. HP presented with more severe stenosis as well as a longer lesion length and had more vulnerable and more complex features. In HP lesions, UAP patients had more plaque ruptures and thrombosis, whereas SAP patients had lower uric acid levels and more multiple HPs(≥3 HPs). Conclusion Clinical presentation of SAP and long lesion length were strong predictors for HP in patients with AP. Patients with HP presented with more severe stenosis, longer lesion lengths, greater inflammation, and vulnerability.

Nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in a series of physiological and pathological processes. However, its correlation in coronary heart disease (CHD) still remains to be elucidated. The present study aimed to determine the expression of NLRP3 inflammasome in peripheral blood monocytes (PBMCs) of stable angina pectoris (SAP) and acute myocardial infarction (AMI) patients. In addition, the effect of rosuvastatin on their activities was analyzed in vitro. A total of 60 participants with SAP (n=20), AMI (n=20) and non-CHD controls (n=20) were enrolled. Fluorescence-activated cell sorting, real-time PCR, western blotting and enzyme-linked immunosorbent assay were performed to reveal the role of NLRP3 inflammasome. NLRP3 inflammasome was expressed in the PBMCs, and revealed an increased expression along the downstream interleukin (IL)-1β and IL-18 in both SAP and AMI groups, compared to the control group. Moreover, there was a more marked increase in the expression of these indicators in AMI patients when compared to SAP patients. Interference with rosuvastatin in vitro revealed that the expression of NLRP3 inflammasome and its downstream cytokines were significantly downregulated in both SAP and AMI groups in a time-dependent manner. The activation of NLRP3 inflammasome may be involved in the development of CHD, and rosuvastatin could attenuate the inflammatory process of atherosclerosis by downregulating NLRP3 expression and its downstream mediators. These findings indicated a potential role of NLRP3 in the pathogenesis and management of CHD, and also provided new insights into the mechanistic framework of rosuvastatin activity.

Purpose The aim of this study was to investigate the relationship between monocyte count/high density lipoprotein cholesterol (HDL-C) ratio (MHR) and the severity of coronary atherosclerosis, as assessed by the SYNTAX score (SXscore), in patients with stable coronary artery disease (CAD) undergoing coronary angiography. Materials and methods A total of 428 patients were included in the study between March 2012 and February 2015. The SXscore was determined with baseline coronary angiography. An SXscore ≥ 23 was regarded as severe CAD by definition, and the patients were divided into two groups: those with low SXscores (< 23) and those with high SXscores (≥ 23). Results MHR and C-reactive protein (CRP) were significantly higher in patients with high SXscores ( p  < 0.001 and p  < 0.001, respectively). Left ventricular ejection fraction (LVEF) was lower in the group with high MHR and high SXscores. The cutoff value of MHR that predicted a high SXscore was 24, with a sensitivity of 66 % and a specificity of 65.1 %. Conclusion To the best of our knowledge, this is the first study in the literature showing that MHR is significantly associated with SXscores. Our results suggest that MHR can be used as a prognostic marker in patients with stable CAD, since it is an easily available and inexpensive test.

Layered plaque, a signature of previous plaque destabilization and healing, is a known predictor for rapid plaque progression; however, the mechanism of which is unknown. The aim of the current study was to compare the level of vascular inflammation and plaque vulnerability in layered plaques to investigate possible mechanisms of rapid plaque progression. This is a retrospective, observational, single-center cohort study. Patients who underwent both coronary computed tomography angiography (CTA) and optical coherence tomography (OCT) for stable angina pectoris (SAP) were selected. Plaques were defined as any tissue (noncalcified, calcified, or mixed) within or adjacent to the lumen. Perivascular inflammation was measured by pericoronary adipose tissue (PCAT) attenuation at the plaque levels on CTA. Features of plaque vulnerability were assessed by OCT. Layered plaques were defined as plaques presenting one or more layers of different optical densities and a clear demarcation from underlying components on OCT. A total of 475 plaques from 195 patients who presented with SAP were included. Layered plaques (n = 241), compared with non-layered plaques (n = 234), had a higher level of vascular inflammation (-71.47 ± 10.74 HU vs. -73.69 ± 10.91 HU, P = 0.026) as well as a higher prevalence of the OCT features of plaque vulnerability, including lipid-rich plaque (83.8% vs. 66.7%, P < 0.001), thin-cap fibroatheroma (26.1% vs. 17.5%, P = 0.026), microvessels (61.8% vs. 34.6%, P < 0.001), and cholesterol crystals (38.6% vs. 25.6%, P = 0.003). Layered plaque was associated with a higher level of vascular inflammation and a higher prevalence of plaque vulnerability, which might play an important role in rapid plaque progression.Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04523194.Level of vascular inflammation and plaque vulnerability in patients with versus without layered plaque phenotype. In patients with stable angina pectoris, layered plaques had a higher level of pericoronary adipose tissue attenuation indicating a higher level of perivascular inflammation and a higher prevalence of optical coherence tomography features of plaque vulnerability