Independent Risk Factor For Atherosclerosis Research Articles

The regulation of Ero1-alpha in homocysteine-induced macrophage apoptosis and vulnerable plaque formation in atherosclerosis

Background and aimsHyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. Macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesized that Ero1α may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy. MethodsApoe−/− mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1α in atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe−/− mice with or without silence or overexpression of Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α on ER stress dependent apoptosis in the presence of HHcy. ResultsAtherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe−/− mice by high Hcy diet, accompanied by the upregulation of Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression. ConclusionsHcy, via upregulation of Ero1α expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.

Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries

Increased Homocysteine Levels (HHcy) is an independent risk factor for atherosclerosis. On the other hand, hydrogen sulfide (H2S) exerts a protection against cardiovascular injuries. On the contrary, accumulating evidences showed that downregulation of defective catabolism of HHcy, with reduced H2S synthesis, is involved in the pathogenesis of a variety of cardiovascular diseases. In that occurrence, the detrimental actions on cardiovascular structures performed by HHcy are added to the negative consequences of reduced H2S (in part unlike each HHcy) on cardiovascular system. Therefore, when the reduced re-methylation pathway of Hcy towards Met (resulting in HHcy) is contemporarily added to the decreased trans-sulfuration pathway (inducing a reduction of H2S synthesis) cardiovascular impairment significantly increases.

Elevated homocysteine induces atherosclerosis-related changes in aortic rabbit walls in the absence of hypercholesterolemia

Background and Aims: Cardiovascular disease, the leading cause of death worldwide, is in the majority of cases a result of atherosclerosis. However, only half of all cases of atherosclerosis incidence can be explained by established risk factors including hypercholesterolemia (HCL). Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and strongly correlates with cardiovascular mortality. HHcy is found in 5-10% of the general population and up to 30% of the elderly, and is due to genetic defects or vitamin deficiency related to homocysteine (Hcy) degradation.

Relationships of Thyroid Hormones in the Normal Range to Coronary Artery Disease in Different Age Groups

Background: The change of thyroid hormones with age may partially explain the effect of age on coronary artery disease (CAD). However, the effects of thyroid hormones within the normal range on CAD in different age were unkown. Aims: To evaluate the relationships between thyroid hormones within the normal range and CAD in different age groups. Methods: 769 individuals were enrolled. Individuals were divided into two groups according to their age: ＜ 60 years and ≥ 60 years. Free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH)were compared between CAD and non-CAD group. The associations of FT3, FT4 and TSH with CAD in different age groups were evaluated by logistic regression analyses. Results: The levels of FT4 were significantly higher in CAD than non-CAD group of total (13.75 ± 2.46 vs. 12.90 ± 1.58 pmol/l, p = 0.003) and ≥ 60Y (13.83 ± 2.73 vs. 12.69 ± 1.47 pmol/l, p = 0.041). The incidences of CAD were significantly higher in the fourth quartile than the first quartile of FT4 in total (7.2% vs. 2.1%, p = 0.017) and ≥ 60Y (14.5% vs. 4.3%, p = 0.041). FT4was the independent risk factor for CAD in ≥ 60Y and total people by univariate and multivariate analyses (all p ＜ 0.05). No associations were found between FT3, TSH and CAD in different age groups. Conclusions: FT4 within the normal range was associated with CAD in ≥ 60Y and total people, but not FT3 and TSH. The relationship between FT4 within the normal range and CAD may be affected by age.

Gene polymorphism and serum levels of interleukin-18 in patients with coronary artery disease and type 2 diabetes mellitus

Background Circulating concentrations of interleukin-18 (IL-18) were shown to be correlated with the vascular events in patients with coronary artery disease (CAD). Objectives To assess the serum levels of IL-18 and its gene polymorphism in CAD and diabetic patients and correlate these findings with clinical, echocardiographic, laboratory, and coronary angiographic findings. Patients and methods This cross-sectional observational study included 180 patients, who were divided according to presence or absence of CAD and type 2 diabetes mellitus into four groups: group I (41 patients), nondiabetic patients without CAD; group II (51 patients), nondiabetic patients with CAD; group III (40 patients), diabetic patients without CAD; and group IV (48 patients), diabetic patients with CAD. Serum levels of IL-18 and its genotyping distributions were measured in all groups and correlated with the angiographic coronary scoring systems. Results Serum IL-18 level was higher significantly in patients with CAD (groups II and IV) than in patients without CAD (groups I and III) (P Conclusion IL-18 is a novel and independent risk factor for CAD, and it is associated with its extent and severity. IL-18 gene polymorphism at 137 G/C site could be a risk factor for development of CAD, presumably by increasing serum IL-18 levels. Individuals carrying the G allele and the G/G genotype of IL-18 have an increased risk to develop CAD.

Mirabegron Ameliorated Atherosclerosis of ApoE-/- Mice in Chronic Intermittent Hypoxia but Not in Normoxia.

It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates β3 adrenergic receptor (β3 AR). However, the effect of selective β3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. We generated a CIH-induced atherosclerosis model through exposing ApoE-/- mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5-21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective β3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. The expression of β3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE-/- mice in CIH but not in normoxia. Mechanistically, mirabegron activated β3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, β3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via β3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.

Lack of Association of LPA Gene Polymorphisms with Coronary Artery Disease in Pakistani Subjects.

Coronary artery disease (CAD) is the leading cause of death worldwide. Pakistan faces a high epidemic of CAD, and the disease burden is increasing with the passage of time. Several genetic markers have been reported to be significantly associated with CAD; one of them is the lipoprotein A gene. The aim of the current investigation was to genotype the LPA gene SNPs, rs3798220 and rs10455872, in Pakistani subjects with CAD in a case control study design. The genotyping was done by TaqMan allelic discrimination assay. The results showed that the cases had significantly higher prevalence of diabetes (64.6%), hypertension (62.1%), and smoking habits (29.5%). The level of cholesterol in cases was higher than in controls (208.25 ± 54.11 vs. 175.34 ± 43.51, p ≤ 0.0001). The LDL-C was higher in cases than in controls (104.62 ± 37.94 vs. 77.05 ± 21.17, p ≤ 0.0001). Similarly, triglycerides were also higher in cases than in controls (214.51 ± 74.60 vs. 190.54 ± 70.26, p ≤ 0.0001), whereas HDL-C was lower in cases than in controls (45.13 ± 11.63 vs. 67.9 ± 17.57, p ≤ 0.0001). For rs3798220, the risk allele (C) frequency was 0.005 in cases and 0.002 in controls. For rs10455872, the risk allele (G) frequency was 0.017 in cases and 0.014 in controls. The risk allele frequencies were not significantly different between cases and controls (p > 0.05). In conclusion, these two LPA SNPs do not contribute significantly to CAD progression and cannot be used as independent risk factors for CAD in Pakistani population.

Metformin alleviates choline diet-induced TMAO elevation in C57BL/6J mice by influencing gut-microbiota composition and functionality

Trimethylamine-N-oxide (TMAO), a gut-microbiota-dependent metabolite generated from its dietary precursors such as choline, has been identified as an independent risk factor for atherosclerosis. Metformin is the most widely used drug for the treatment of type 2 diabetes (T2D), which has therapeutic effects on hyperglycemia accelerated atherosclerosis. A growing body of evidence suggest that metformin plays a therapeutic role by regulating the structure and metabolic function of gut microbiota. However, whether metformin has an impact on gut-microbiota-mediated TMAO production from choline remains obscure. In this study, the oral administration of metformin significantly reduced choline diet-increased serum TMAO in choline diet-fed C57BL/6J mice. The diversity analysis based on 16S rRNA gene sequencing of C57BL/6J mice fecal samples indicated that metformin markedly changed the gut-microbiota composition. Metformin was positively correlated with the enrichment of different intestinal bacteria such as Bifidobacterium and Akkermansia and a lower cutC (a choline utilization gene) abundance. Furthermore, the ex vivo and in vitro inhibitory effects of metformin on choline metabolism of TMA-producing bacteria were confirmed under anaerobic condition. The results suggested that metformin suppresses serum TMAO level by remodeling gut microbiota involved in TMA generation from choline.

Heart failure in patients with high homocysteine levels

Increased levels of homocysteine (HHcy) can induce both systolic and diastolic left ventricular (LV) dysfunction that may evolve until chronic heart failure (HF). It is known that HHcy acts as an independent risk factor for atherosclerosis and hypercoagulation. This condition may cause coronary artery disease (CAD. Chronic reduction of oxygen supply to the myocardium can induce a reduction in LV contractility. These conditions can further evolve towards HF with reduced ejection fraction (HFrEF). But, HHcy can be also responsible for adverse cardiac remodeling for accumulation and proliferation of interstitial collagen, increased fibrosis and myocardial stiffness and preserved LV ejection fraction (HFpEF). Both HF can be further favoured by the advanced age, hypertension, diabetes and others. The administration of some nutrients, such as folic acid and B12 vitamin can delay or avoid these cardiac complications. However, the cellular mechanisms behind the adverse effects of Hcy on cardiac remodeling and pump function are not understood.

Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRSLDLC) using a genome-wide association study summary statistic from the BioBank Japan Project. We assessed the association of PRSLDLC with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRSLDLC was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10-13). PRSLDLC was also significantly linked to LDL-C in controls (p trend = 3.6 × 10-4) but not in FH patients. Moreover, we could not detect any association between PRSLDLC and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRSLDLC than controls. However, PRSLDLC may have little additional effect on LDL-C and CAD among FH patients.

Effect of Antiviral Agents on Atherosclerosis in Patients with Chronic Hepatitis C

Chronic hepatitis C is an independent risk factor for atherosclerosis and is associated with cardiovascular events. Mechanisms include inflammatory cytokines, endothelial dysfunction, and increased oxidative stress. The objective was to evaluate the response of carotid atherosclerosis to treatment with direct-antiviral agents. We developed a prospective cohort study that included patients with chronic hepatitis C treated with direct-acting antiviral agents (DAAs), without cardiovascular disease, diabetes mellitus, significative chronic kidney disease or coinfections. Clinical characteristics, laboratory values and carotid ultrasound to measure carotid intima-media thickness (CIMT) and look for established atherosclerosis were performed at baseline and 3 months after completing treatment with DAAs. A total of 24 patients were included. The mean age was 60 years and 79% were women. The prevalence of smoking was 41.7%, obesity 25% and hypertension 20.8%. Age, arterial hypertension, genotype, AST, glomerular filtration rate and cirrhosis were significantly associated with established carotid atherosclerosis. After treatment with DAAs, an overall significant reduction of C-reactive protein (CRP) levels was found (p = 0.004). A trend towards reduction of significant CIMT (>0.9 mm) (20.8 vs. 8.3%, RR 1.18, IC 95% 0.75-1.86, p = 0.29) and a statistically significant resolution of atherosclerotic plaque (45.8 vs. 41.7% RR 0.09, IC 95% 0.01-0.63, p = 0.001) was found. Treatment of chronic hepatitis C with DAAs decrease carotid thickening, atheromatous plaques, and inflammatory markers like CRP. More studies are needed to confirm this finding and its impact on long-term cardiovascular outcomes.

The Atherogenic Index of Plasma: A Powerful and Reliable Predictor for Coronary Artery Disease in Patients With Type 2 Diabetes.

We evaluated the predictive power of the atherogenic index of plasma (AIP) for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). A total of 3278 patients who underwent coronary angiography were consecutively enrolled, including 2052 patients with CAD and 1226 patients with T2DM but without CAD. Patients in the CAD group had higher levels of triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, AIP and a lower level of high-density lipoprotein cholesterol (HDL-C). In correlation analyses, AIP correlated positively with body mass index, log (homeostasis model assessment of insulin resistance), TG, remnant lipoprotein cholesterol, non-HDL-C, but negatively with age and HDL-C. Multivariate logistic regression analyses demonstrated that AIP was an independent risk factor for CAD in diabetic patients and was validated by multiple models. Furthermore, the ORs for CAD risk were raised with increasing AIP quartiles; ORs of AIP quartiles Q2-Q4 compared with Q1 were 1.56, 1.70, and 2.22, respectively (Ps < .001), which suggested AIP was the lipid parameter that most strongly associated with incident CAD. In conclusion, AIP is a powerful and reliable biomarker for predicting CAD risk beyond individual lipid profiles in patients with T2DM.

Elevation of homocysteine levels in the plasma leads to deregulation of lipid metabolism in a rabbit model of atherosclerosis

Cardiovascular disease, the leading cause of death worldwide, is in the majority of cases a result of atherosclerosis, which can be only to 50% explained by established risk factors including hypercholesterolemia (HCL). Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. It is linked to numerous human diseases, strongly correlates with cardiovascular and all-cause mortality, and is associated with deregulation of lipid metabolism. HHcy is found in 5-10% of the general population and up to 30% of the elderly, and is mainly due to genetic defects or vitamin deficiency resulting in blocking of homocysteine (Hcy) degradation. We induced HHcy by dietary partial blocking of Hcy degradation and intravenous injections of Hcy into a rabbit model of atherosclerosis in the presence or absence of HCL. Deficiency of vitamins and choline required for Hcy degradation in the absence of HCL leads to an accumulation of lipid droplets in cells of the aorta including endothelial cells, smooth muscle cells, and fibroblasts, an accumulation of dilated ER in fibroblasts of the aorta as well as decreased LPC18:1 and 18:2 levels in muscles. In addition, while dietary blocking of Hcy degradation results in increased triacylglycerol (TAG) concentrations in blood cells, further elevation of Hcy levels leads to their decrease, but also to ceramide, lyso-phosphatidylcholine (LPC), phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin accumulation in blood cells, compared to the diet blocking Hcy degradation alone. A decrease of TAG levels was also observed in the liver, in response to intravenous injections of Hcy and in rabbits receiving a combined diet that blocked Hcy degradation and induced HCL. In conclusion our data suggest that dietary blocking of Hcy degradation as well as Hcy itself may contribute to different human pathologies by deregulation of lipid metabolism in different tissues.

SNF5 promotes IL-1β expression via H3K4me1 in atherosclerosis induced by homocysteine

Homocysteine (Hcy) is a strong and independent risk factor of atherosclerosis. It can accelerate atherosclerosis through increased production of inflammatory factors, especially interleukin-1 β (IL-1β), while the precise mechanisms remain to be well elucidated. In this study, we investigated the role of the tumor suppressor gene SNF5 related to switch/sucrose non-fermentable complex (SWI/SNF) in the occurrence and development of atherosclerosis induced by Hcy. Using Hyperhomocysteinemia (HHcy) atherosclerotic model with apolipoprotein E knockout (ApoE−/−) mice fed with high-methionine diet, we showed that Hcy aggravates inflammation in macrophages during the atherosclerotic plaque formation. Further analysis showed that SNF5 promotes IL-1β expression and secretion. In addition, due to the existence of H3K4 methylation signals in the vicinity of IL-1β, we found that Hcy significantly promotes the expression of H3K4me1, and lysine-specific histone demethylase 1A (KDM1A) acts as a transcriptional repressor to regulate the expression of H3K4me1 by demethylating H3K4me1. In summary, our results demonstrated that Hcy up-regulates the expression of SNF5 through KDM1A, resulting in an increased level of H3K4me1 modification and IL-1β in macrophages, which in turn promotes the formation of atherosclerosis. Our study will provide more evidence for further revealing the specific mechanism of Hcy-induced inflammation and the diagnosis, prevention, and treatment of atherosclerosis.

Association between triglyceride glucose index and coronary artery disease with type 2 diabetes mellitus in middle-aged and elderly people.

This study aimed to investigate the correlation between triglyceride glucose (TyG) index and coronary artery disease (CAD) with type 2 diabetes mellitus (T2DM) and identify the risk associated TyG index in different subgroups.A total of 1665 eligible inpatients (CAD with T2DM group [n = 680], non-coronary artery disease without T2DM [n = 985]) were consecutively enrolled in this study. They were assigned into 4 subgroups: middle-aged, elderly, male, and female subgroups. Receiver operating characteristic curve diagnostic test and a logistic regression model was established to analyze the risk factors for CAD with T2DM.TyG index is an independent risk factor for patients with CAD with T2DM. The risk of increased TyG index is greater in the middle-aged and male subgroups than in the elderly and female subgroups, respectively (all P < .05). The specificity and the positive predictive value of the TyG index is greater than the sensitivity and the negative predictive value, respectively (all P < .05).Increased TyG index is a new independent risk factor for CAD with T2DM, and its risk is higher in the middle-aged and male subgroups than in the elderly and female subgroups, respectively. TyG index may be used as a clinical predictor of CAD with T2DM.

Association between insulin resistance and post-ischaemic stroke outcome in patients without diabetes: protocol for a systematic review and meta-analysis

IntroductionInsulin resistance is an independent risk factor for atherosclerosis, coronary artery disease and ischaemic stroke. Currently, insulin resistance is not usually included in post-stroke risk stratification. This systematic review and...

Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice.

Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue-derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.

Hawthorn fruit extract reduced trimethylamine-N-oxide (TMAO)-exacerbated atherogenesis in mice via anti-inflammation and anti-oxidation

BackgroundTrimethylamine-N-oxide (TMAO) is an independent risk factor for atherosclerosis. Consumption of hawthorn fruit is believed to be cardio-protective, yet whether it is able to suppress the TMAO-induced atherosclerosis remains unexplored. The present study was to investigate the effects of hawthorn fruit extract (HFE) on TMAO-exacerbated atherogenesis.MethodsFive groups of male Apolipoprotein E knock-out (ApoE−/−) mice were fed a low-fat diet (LFD), a Western high-fat diet (WD), or one of the three WDs containing 0.2% TMAO (WD + TMAO), 0.2% TMAO plus 1% HFE (WD + TMAO + L-HFE), or 0.2% TMAO plus 2% HFE (WD + TMAO + H-HFE), respectively. After 12-weeks of intervention, plasma levels of TMAO, lipid profile, inflammatory biomarkers, and antioxidant enzyme activities were measured. Atherosclerotic lesions in the thoracic aorta and aortic sinus were evaluated. The sterols and fatty acids in the liver and feces were extracted and measured. Hepatic expressions of inflammatory biomarkers and antioxidant enzymes were analyzed.ResultsDietary TMAO accelerated atherogenesis, exacerbated inflammation, and reduced antioxidant capacities in the plasma and the liver. TMAO promoted hepatic cholesterol accumulation by inhibiting fecal excretion of acidic sterols. HFE could dose-dependently reduce the TMAO-aggravated atherosclerosis and inflammation. HFE was also able to reverse the TMAO-induced reduction in antioxidant capacity by up-regulating the expression of antioxidant enzymes including superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase 3 (GSH-Px3), and catalase (CAT) in the liver. Moreover, the hepatic cholesterol content was lowered by HFE via enhanced fecal excretion of neutral and acidic sterols.ConclusionsThe present results indicated that HFE was able to reduce the TMAO-exacerbated atherogenesis by attenuating inflammation and improving antioxidant capacity at least in mice.Graphic abstract

Nomograms Based on the Advanced Lung Cancer Inflammation Index for the Prediction of Coronary Artery Disease and Calcification.

AimTo develop and validate 3 nomograms incorporating the advanced lung cancer inflammation index (ALI) that can aid in predicting the risk of coronary artery disease (CAD) and coronary artery calcification (CAC).MethodsThe study enrolled 562 consecutive patients with suspected CAD who underwent coronary computed tomographic angiography between September 2015 and June 2017. Independent risk factors for CAD, CAC, and CAD with CAC were identified via univariate and multivariate analysis, and nomograms were established based on the independent predictors identified. The area under the curve (AUC), calibration curve, and decision curve analysis were used to evaluate the nomograms. Correlations between ALI and other clinical indicators were examined via Spearman correlation analysis.ResultsIn total, 549 patients with suspected CAD who underwent coronary computed tomographic angiography were included. Male sex, hypertension, diabetes, dyslipidemia, ischemic stroke, and ALI were independent predictors of both CAD and CAC. Male sex, hypertension, diabetes, dyslipidemia, and ALI were also identified as independent predictors of CAD with CAC. The AUC values for the nomograms developed using these risk factors were 0.739 (95% confidence interval [CI], 0.693-0.785), 0.728 (95% CI, 0.684-0.772), and 0.717 (95% CI 0.673-0.761), respectively. ALI was negatively correlated with neutrophil-to-lymphocyte ratio and CAC score and positively correlated with serum albumin levels and body mass index (all P < .05).ConclusionsALI is an independent predictor of CAD, CAC, and CAD with CAC. Our ALI-based nomograms can provide accurate and individualized risk predictions for patients with suspected CAD.

Probucol decreases homocysteine-stimulated CRP production in rat aortic smooth muscle cells via regulating HO-1/NADPH oxidase/ROS/p38 pathway.

The elevated homocysteine level is an independent risk factor for atherosclerosis, which is characterized as a chronic inflammatory disease associated with oxidative stress. We have confirmed that homocysteine can stimulate the production of C-reactive protein (CRP) in rat aortic smooth muscle cells (RASMCs). In the present study, we investigated the role of probucol in homocysteine-induced CRP expression in cultured RASMCs and high-methionine-diet-induced hyperhomocysteinemic rats. The results showed that probucol decreased homocysteine-induced CRP mRNA and protein expression in RASMCs in a concentration-dependent manner. In addition, the animal experiment showed that probucol not only inhibited CRP expression in the vessel wall but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further investigations revealed that probucol markedly increased heme oxygenase-1 activity, suppressed nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, diminished superoxide anion generation, and decreased p38 phosphorylation in RASMCs and hyperhomocysteinemic rat aorta. These data demonstrate that probucol can inhibit homocysteine-induced CRP generation by interfering with the NADPH oxidase/p38 signal pathway in RASMCs, which will provide new evidence for the anti-inflammatory and anti-atherosclerotic effects of probucol.