Objectives:The study assessed the relationship between atherogenic index of plasma(AIP)and the rapid progression of coronary non-target lesions.Methods:A total of 1 247 patients with coronary artery disease who underwent two coronary angiography examinations at Fuwai Hospital,Chinese Academy of Medical Sciences between January 2010 and September 2014 were enrolled in this retrospective study.The AIP is defined as the base 10 logarithm of the ratio of the concentrations of triglyceride to high-density lipoprotein cholesterol.Patients were divided into the high AIP group(n=623)and the low AIP group(n=624)based on the median value of AIP.Lesion rapid progression is defined as an increase of more than 10%in the lumen stenosis of the lesion with a stenosis rate of more than 50%,or an increase of more than 30%in the lumen stenosis rate of the lesion with a stenosis rate of less than 50%,or a progression to total occlusion within 2 years.Results:Median AIP was 0.39(0.23-0.56)in this patient cohort.Rapid progression of non-target lesions occurred in 65(5.21%),including 42(6.74%)in the high AIP group.The Kaplan-Meier curve showed that the cumulative incidence of rapid progression of non-target lesions was higher in the high AIP group than in the low AIP group(HR=1.751,95%CI:1.053-2.912,log-rank P=0.028).In univariate cox analysis,the AIP and high AIP correlated with rapid progression of non-target lesions.After multivariate adjustment,AIP was an independent risk factor for rapid progression of non-target lesions(adjusted HR=2.731,95%CI:1.090-6.844,P=0.032).Conclusions:AIP is an independent risk factor for rapid progression of non-target lesions.AIP should be considered as a biomarker for estimating the risk of cardiovascular disease,along with other traditional risk factors.

Objective To investigate the role and molecular mechanism of ginsenoside Rb1(Rb1)in regulating neutrophil extracellular trapping networks(NETs)to intervene in atherosclerosis(AS).Methods In vivo:an AS model was constructed with ApoE knockout mice superimposed on a high-fat diet.The pathological and morphological changes of aortic root plaques were observed by HE staining and oil red O staining;Immunofluorescence labelling of neutrophils citrullinated histones(Cit-H3)and macrophages as well as IL-1β at the aortic root plaque site were used to assess the inflammatory infiltration.In vitro:NETs induced by PMA and cholesterol crystals were taken as models respectively.Direct effect of Rb1 against NETs formation assessed by Sytox staining and immunofluorescence staining with Cit-H3 and myeloperoxidase.Rb1 on ROS levels was assessed by DCFH-DA.Rb1 on histone H3 citrulline modification was assessed by Western blotting.Results In vivo:Rb1 significantly inhibited plaque formation,lipid deposition(P<0.05)and intra-plaque inflammatory infiltration(P<0.05).In vitro:Rb1 significantly inhibited NETs formation(P<0.05),neutrophil ROS levels(P<0.05),and Cit-H3 levels(P<0.05).Conclusions Rb1 significantly inhibited AS progression by inhibiting plaque NETs formation,which may be partly through the inhibition of histone H3 citrullination resulting from activation of the neutrophil oxidative stress pathway.

Objective To investigate the role and molecular mechanism of ginsenoside Rb1(Rb1)in regulating neutrophil extracellular trapping networks(NETs)to intervene in atherosclerosis(AS).Methods In vivo:an AS model was constructed with ApoE knockout mice superimposed on a high-fat diet.The pathological and morphological changes of aortic root plaques were observed by HE staining and oil red O staining;Immunofluorescence labelling of neutrophils citrullinated histones(Cit-H3)and macrophages as well as IL-1β at the aortic root plaque site were used to assess the inflammatory infiltration.In vitro:NETs induced by PMA and cholesterol crystals were taken as models respectively.Direct effect of Rb1 against NETs formation assessed by Sytox staining and immunofluorescence staining with Cit-H3 and myeloperoxidase.Rb1 on ROS levels was assessed by DCFH-DA.Rb1 on histone H3 citrulline modification was assessed by Western blotting.Results In vivo:Rb1 significantly inhibited plaque formation,lipid deposition(P<0.05)and intra-plaque inflammatory infiltration(P<0.05).In vitro:Rb1 significantly inhibited NETs formation(P<0.05),neutrophil ROS levels(P<0.05),and Cit-H3 levels(P<0.05).Conclusions Rb1 significantly inhibited AS progression by inhibiting plaque NETs formation,which may be partly through the inhibition of histone H3 citrullination resulting from activation of the neutrophil oxidative stress pathway.

Objectives:The study assessed the relationship between atherogenic index of plasma(AIP)and the rapid progression of coronary non-target lesions.Methods:A total of 1 247 patients with coronary artery disease who underwent two coronary angiography examinations at Fuwai Hospital,Chinese Academy of Medical Sciences between January 2010 and September 2014 were enrolled in this retrospective study.The AIP is defined as the base 10 logarithm of the ratio of the concentrations of triglyceride to high-density lipoprotein cholesterol.Patients were divided into the high AIP group(n=623)and the low AIP group(n=624)based on the median value of AIP.Lesion rapid progression is defined as an increase of more than 10%in the lumen stenosis of the lesion with a stenosis rate of more than 50%,or an increase of more than 30%in the lumen stenosis rate of the lesion with a stenosis rate of less than 50%,or a progression to total occlusion within 2 years.Results:Median AIP was 0.39(0.23-0.56)in this patient cohort.Rapid progression of non-target lesions occurred in 65(5.21%),including 42(6.74%)in the high AIP group.The Kaplan-Meier curve showed that the cumulative incidence of rapid progression of non-target lesions was higher in the high AIP group than in the low AIP group(HR=1.751,95%CI:1.053-2.912,log-rank P=0.028).In univariate cox analysis,the AIP and high AIP correlated with rapid progression of non-target lesions.After multivariate adjustment,AIP was an independent risk factor for rapid progression of non-target lesions(adjusted HR=2.731,95%CI:1.090-6.844,P=0.032).Conclusions:AIP is an independent risk factor for rapid progression of non-target lesions.AIP should be considered as a biomarker for estimating the risk of cardiovascular disease,along with other traditional risk factors.

Objective:Investigate the impact of calcification on the long-term outcomes of patients with coronary chronic total occlusion (CTO) after percutaneous coronary intervention (PCI).Methods:A retrospective cohort study was conducted. Patients who underwent PCI and had at least one CTO lesion at Fuwai Hospital between January 2010 and December 2013 were consecutively enrolled. Calcification was evaluated by coronary angiography, and patients were divided into two groups: moderate/severe calcification group and non/mild calcification group. Clinical follow-up was completed up to 5 years. Incidence of PCI-related complications and immediate procedural outcomes were compared between two groups, and the primary endpoint was the target lesion failure (TLF) at 5 years after PCI. Clinical follow-up endpoint events were analyzed using Kaplan-Meier survival analysis with log-rank test, and Cox multivariate regression model was used to evaluate the relationship between calcification and TLF.Results:The study included 2 659 CTO patients with an age of (57.2±10.5) years, of whom 442 (16.6%) were female, and among whom 13.5% (360/2 659) had moderate/severe calcification. Compared with the non/mild calcification group, the moderate/severe calcification group had a higher incidence of PCI-related complications (43.2% (156/361) vs. 32.5% (772/2 374), P<0.001) and procedural failure (34.3% (124/361) vs. 24.3% (577/2 374), P<0.001). Additionally, the moderate/severe calcification group showed a higher risk of the primary endpoint event (TLF) during the 5-year follow-up (19.8% vs. 15.3%, log-rank P=0.028). Higher incidence of cardiac death was observed in moderate/severe calcification group (5.7% vs. 2.7%, log-rank P=0.003). Cox multivariate regression analysis revealed that moderate/severe calcified plaques remained an independent risk factor for 5-year TLF after CTO-PCI ( HR=1.34, 95% CI: 1.01-1.79, P=0.043). Conclusion:Compared with CTO patients with non/mild calcification, those with moderate/severe calcification have higher procedural failure and complication rates, as well as poorer long-term prognosis, mainly due to an increase in cardiac death.

Objective:To investigate the effect of CT-derived fractional flow reserve (CT-FFR) measurement sites on the values and the diagnostic performance, and to determine the optimal measurement site for CT-FFR using invasive FFR as the reference standard.Methods:This study was part of the CT-FFR CHINA clinical trial. Patients with suspected coronary artery disease who were scheduled for invasive coronary angiography (ICA) were prospectively recruited from five clinical centers across the country from November 2018 to March 2020. Each enrolled patient underwent coronary CT angiography (CCTA), CT-FFR, ICA, and invasive pressure wire-based FFR assessments sequentially within one week. Four groups of CT-FFR values were obtained on each enrolled target vessels according to different CT-FFR measurement locations: 1, 2, 3 cm distal to the target lesion, and terminal vessel groups. Spearman and Bland-Altman analyses were used to explore the correlation and consistency of CT-FFR values and FFR values at different measurement sites. The measurement deviation of CT-FFR was also compared. Diagnostic accuracy and performance of CT-FFR, including sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC), in discriminating myocardial ischemia were analyzed across all measurement site groups on a per-vessel level, using FFR as the reference standard.Results:A total of 289 patients with 345 target lesion vessels were included. According to CCTA, there were 51 target vessels (14.8%) with<50% stenosis, 106 vessels (30.7%) with 50%-69% stenosis, and 188 vessels (54.5%) with stenosis≥70%. At per-vessel level, CT-FFR and FFR values at each measurement position group were highly positively correlated: 1 cm distal to target lesion group, r=0.734 ( P<0.001); 2 cm distal to target lesion group, r=0.732 ( P<0.001); 3 cm distal to target lesion group, r=0.737 ( P<0.001); terminal vessel group was 0.719 ( P<0.001). At per-vessel level, CT-FFR and FFR values of all measurement sites were in good agreement (Bland-Altman analysis results): 1 cm distal to target lesion group, 0.014 (95% LoA 0.002-0.026); 2 cm distal to target lesion group, 0.026 (95% LoA 0.015-0.038); 3 cm distal to target lesion group, 0.040 (95% LoA 0.039-0.051); terminal vessel group, 0.075 (95% LoA 0.064-0.087). And at per-vessel level, the accuracy of diagnosing myocardial ischemia with CT-FFR at 1 cm was highest [84.6% (95% CI 80.4%-88.3%)], and the lowest accuracy in the terminal vessel group [67.0% (95% CI 61.7%-72.0%)]. However, there was no significant difference in the diagnostic accuracy of CT-FFR at 1 cm, 2 cm [80.6% (95% CI 76.1%-84.6%)] and 3 cm [77.5% (95% CI 72.6%-81.7%)]. AUC of CT-FFR at 1 cm distal to the lesion were both highest for global level and moderately stenosis (50%-69%) lesions [0.85 (95% CI 0.81-0.89), 0.84 (95% CI 0.77-0.90)]. And the differences were statistically significant among the four measurement location groups (all P<0.05). Conclusions:The deviation of CT-FFR increases with measurement site distance distal to target lesions. One centimeter distal to the target lesion is the optimal measurement site, and the CT-FFR value here shows the highest diagnostic performance for myocardial ischemic lesions, especially for moderate stenosis.

Objective:Investigate the impact of calcification on the long-term outcomes of patients with coronary chronic total occlusion (CTO) after percutaneous coronary intervention (PCI).Methods:A retrospective cohort study was conducted. Patients who underwent PCI and had at least one CTO lesion at Fuwai Hospital between January 2010 and December 2013 were consecutively enrolled. Calcification was evaluated by coronary angiography, and patients were divided into two groups: moderate/severe calcification group and non/mild calcification group. Clinical follow-up was completed up to 5 years. Incidence of PCI-related complications and immediate procedural outcomes were compared between two groups, and the primary endpoint was the target lesion failure (TLF) at 5 years after PCI. Clinical follow-up endpoint events were analyzed using Kaplan-Meier survival analysis with log-rank test, and Cox multivariate regression model was used to evaluate the relationship between calcification and TLF.Results:The study included 2 659 CTO patients with an age of (57.2±10.5) years, of whom 442 (16.6%) were female, and among whom 13.5% (360/2 659) had moderate/severe calcification. Compared with the non/mild calcification group, the moderate/severe calcification group had a higher incidence of PCI-related complications (43.2% (156/361) vs. 32.5% (772/2 374), P<0.001) and procedural failure (34.3% (124/361) vs. 24.3% (577/2 374), P<0.001). Additionally, the moderate/severe calcification group showed a higher risk of the primary endpoint event (TLF) during the 5-year follow-up (19.8% vs. 15.3%, log-rank P=0.028). Higher incidence of cardiac death was observed in moderate/severe calcification group (5.7% vs. 2.7%, log-rank P=0.003). Cox multivariate regression analysis revealed that moderate/severe calcified plaques remained an independent risk factor for 5-year TLF after CTO-PCI ( HR=1.34, 95% CI: 1.01-1.79, P=0.043). Conclusion:Compared with CTO patients with non/mild calcification, those with moderate/severe calcification have higher procedural failure and complication rates, as well as poorer long-term prognosis, mainly due to an increase in cardiac death.

Objective:To investigate the effect of CT-derived fractional flow reserve (CT-FFR) measurement sites on the values and the diagnostic performance, and to determine the optimal measurement site for CT-FFR using invasive FFR as the reference standard.Methods:This study was part of the CT-FFR CHINA clinical trial. Patients with suspected coronary artery disease who were scheduled for invasive coronary angiography (ICA) were prospectively recruited from five clinical centers across the country from November 2018 to March 2020. Each enrolled patient underwent coronary CT angiography (CCTA), CT-FFR, ICA, and invasive pressure wire-based FFR assessments sequentially within one week. Four groups of CT-FFR values were obtained on each enrolled target vessels according to different CT-FFR measurement locations: 1, 2, 3 cm distal to the target lesion, and terminal vessel groups. Spearman and Bland-Altman analyses were used to explore the correlation and consistency of CT-FFR values and FFR values at different measurement sites. The measurement deviation of CT-FFR was also compared. Diagnostic accuracy and performance of CT-FFR, including sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC), in discriminating myocardial ischemia were analyzed across all measurement site groups on a per-vessel level, using FFR as the reference standard.Results:A total of 289 patients with 345 target lesion vessels were included. According to CCTA, there were 51 target vessels (14.8%) with<50% stenosis, 106 vessels (30.7%) with 50%-69% stenosis, and 188 vessels (54.5%) with stenosis≥70%. At per-vessel level, CT-FFR and FFR values at each measurement position group were highly positively correlated: 1 cm distal to target lesion group, r=0.734 ( P<0.001); 2 cm distal to target lesion group, r=0.732 ( P<0.001); 3 cm distal to target lesion group, r=0.737 ( P<0.001); terminal vessel group was 0.719 ( P<0.001). At per-vessel level, CT-FFR and FFR values of all measurement sites were in good agreement (Bland-Altman analysis results): 1 cm distal to target lesion group, 0.014 (95% LoA 0.002-0.026); 2 cm distal to target lesion group, 0.026 (95% LoA 0.015-0.038); 3 cm distal to target lesion group, 0.040 (95% LoA 0.039-0.051); terminal vessel group, 0.075 (95% LoA 0.064-0.087). And at per-vessel level, the accuracy of diagnosing myocardial ischemia with CT-FFR at 1 cm was highest [84.6% (95% CI 80.4%-88.3%)], and the lowest accuracy in the terminal vessel group [67.0% (95% CI 61.7%-72.0%)]. However, there was no significant difference in the diagnostic accuracy of CT-FFR at 1 cm, 2 cm [80.6% (95% CI 76.1%-84.6%)] and 3 cm [77.5% (95% CI 72.6%-81.7%)]. AUC of CT-FFR at 1 cm distal to the lesion were both highest for global level and moderately stenosis (50%-69%) lesions [0.85 (95% CI 0.81-0.89), 0.84 (95% CI 0.77-0.90)]. And the differences were statistically significant among the four measurement location groups (all P<0.05). Conclusions:The deviation of CT-FFR increases with measurement site distance distal to target lesions. One centimeter distal to the target lesion is the optimal measurement site, and the CT-FFR value here shows the highest diagnostic performance for myocardial ischemic lesions, especially for moderate stenosis.

Objectives:To investigate the impacts of American College of Cardiology/American Heart Association (ACC/AHA) coronary artery classification on the progression of coronary non-target lesions and revascularization in patients with coronary heart disease.Methods:From January 2010 to September 2014,1255 patients who underwent two consecutive coronary angiographies at Fuwai Hospital and had coronary non-target lesions were retrospectively analyzed.Lesion characteristics of all coronary non-target lesions were recorded at both procedures.All non-target lesions were divided into A,B1,B2 and C lesion group according to ACC/AHA coronary artery classification.Patients were divided into non-B2/C lesion group (noncomplex lesion group) and B2/C lesion group (complex lesion group) according to whether the non-target lesion had B2/C lesion The characteristics of all non-target coronary artery lesions and quantitative coronary angiography results were recorded.Lesion progression and revascularization were compared between different groups.Results:There were 1003 (79.9％) male patients,mean age was (58.0±9.7) years old,and 853 patients had B2/C lesions.There were 1670 non-target lesions,including 619 A/B1 lesions (214 A lesions and 405 B1 lesions) and 1051 B2/C lesions (796 B2 lesions and 255 C lesions).Follow-up time was (14.8±4.5) months.Compared with the patients in noncomplex lesion group,patients in complex lesion group were older,had lower proportion of family history of coronary heart disease and stroke (all P<0.05).The baseline levels of leukocytes,C-reactive protein,erythrocyte sedimentation rate (ESR),triglyceride and HbA1c were higher in complex lesion group than those in noncomplex lesion group.Complex lesion group had higher risk of lesion progression (21.8％ vs.13.2％,P<0.001) compared with noncomplex lesion group,similar results were observed in revascularization (16.5％ vs.11.2％,P=0.013),and there was no statistically difference in non-target lesion related myocardial infarction (P>0.05).At the lesion level,compared with A/B1 lesion,B2/C lesion was associated with a higher rate of lesion progression (17.4％ vs.11.0％,P<0.001),and a higher rate of revascularization (13.0％ vs.9.2％,P=0.018).Multivariate Cox regression analysis showed that lesion classification (B2/C) was an independent risk factor for non-target lesion progression (HR=1.732,95％CI:1.275-2.351,P<0.001) and non-target lesion revascularization (HR=1.477,95％CI:1.053-2.070,P=0.024).Conclusions:The risk of non-target lesion progression and revascularization is higher in complex groups compared with noncomplex groups according to ACC/AHA classification.So patients with complex lesions should receive more strict medical care to control related risk factors and improve their outcome.

Objective The current study aims to investigate the protective effect and mechanisms of baicalin on pathological left ventricular remodeling.Methods Angiotensin Ⅱ(Ang Ⅱ)infusion mouse model was adopted to evaluate the impact of baicalin on pathological left ventricular remodeling in vivo.C57BL/6J mice were randomly allocated to 5 experimental groups,including sham controls,model group(Ang Ⅱ-infusion controls),as well as low-,medium-,and high-dose baicalin treatment groups.Except for the sham controls,C57/BL6 mice were subjected to AngⅡ infusion for 2 weeks.The mice from the baicalin treatment groups received baicalin via gavage at the indicated doses for 2 weeks.The blood pressure,body weight,heart weight and tibia length were measured at the end of the indicated treatments.Immunohistochemistry of wheat germ agglutinin(WGA)was performed to examine the cross-sectional area of cardiomyocytes.Immunohistochemistry was also performed to assess the expression of atrial natriuretic peptide(ANP)in cardiomyocytes.Hematoxylin/eosin(HE)staining and Masson's trichrome staining were performed to evaluate the cardiac pathologies.In vitro experiments were as follows.Ang Ⅱ was adopted to induce cardiomyocyte hypertrophy in H9C2 cells in order to determine if baicalin is able to directly suppress cardiomyocyte hypertrophy.H9C2 cells were divided into vehicle control group(VC group),model group(Ang Ⅱ group)and baicalin group(Bai group).The morphology and size of cardiomyocytes were examined by rhodamine phalloidin staining.The intracellular level of ANP was analyze by immunofluorescence staining.Mitochondrial superoxide(Mito-SOX)was assessed to evaluate oxidative stress.The mitochondrial membrane potential(ΔΨm)was analyzed by JC-1 staining.The opening of mitochondrial permeability transition pore(mPTP)was evaluated by calcein acetyl methyl ester(Calcein AM)staining.Results The in vivo findings:Baicalin significantly antagonized Ang Ⅱ-induced elevation of systolic blood pressure(P<0.05)when administered at the medium and high doses.Meanwhile,baicalin treatment resulted in lower ratios of heart weight to tibia length(HW/TL)and heart weight to body weight(HW/BW)in Ang Ⅱ-infused mice.Baicalin treatment mitigated cardiomyocyte hypertrophy(P<0.05)and lowered the level of cardiomyocyte ANP(P<0.05)in Ang Ⅱ-infused mice.Furthermore,baicalin treatment significantly alleviated cardiac inflammation and fibrosis in Ang Ⅱ-infused mice(P<0.05).In vitro findings:Baicalin suppressed Ang Ⅱ-stimulated enlargement of cardiomyocytes and elevation of the intracellular ANP in H9C2 cells.Moreover,baicalin alleviated Ang Ⅱ-induced mitochondrial oxidative stress,mitochondrial ΔΨm impairment and mPTP opening(P<0.05).Conclusion Our current findings demonstrate that baicalin is effective at mitigating Ang Ⅱ-mediated left ventricular pathological remodeling.Baicalin is pharmacologically active at antagonizing Ang Ⅱ-induced hypertrophic responses and mitochondrial dysfunction in cardiomyocytes,which may in part account for its therapeutic effects against pathological left ventricular remodeling.