The Relationship between the complement system and subclinical carotid atherosclerosis in patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) events and CV mortality. Subclinical carotid atherosclerosis is independently associated with rates of incident CV events among patients with RA. The complement system has been related to both the etiopathogenesis of RA and CV disease. In this study, we aimed to evaluate the association between a comprehensive assessment of the complement system and carotid intima media thickness and carotid plaque in patients with RA. METHODS: 430 patients with RA were recruited. Functional assays of the three pathways of the complement system, utilizing new-generation techniques, were assessed. Additionally, serum levels of individual components of the complement system belonging to the three pathways were measured: C1q (classical), lectin (lectin), C2, C4, and C4b (classical and lectin), factor D and properdin (alternative), C3 and C3a (common), C5, C5a, and C9 (terminal), as well as regulators factor I and C1-inhibitor. Subclinical carotid atherosclerosis was evaluated by ultrasonography. Multivariable linear regression analysis was conducted to investigate the association between the complement system and carotid intima media thickness and carotid plaque. RESULTS: After multivariable adjustment, which included traditional CV risk factors and disease-related data, C3a and C5a exhibited significant positive correlations with carotid intima media thickness. Additionally, higher values of C1-inhibitor, properdin, C3, C5, and C5a were independently associated with the presence of carotid plaque. CONCLUSION: The complement system and subclinical carotid atherosclerosis are linked in patients with RA.

Association between augmented levels of the gut pro-hormone Proneurotensin and subclinical vascular damage.

Elevated levels of the gut pro-hormone Proneurotensin (proNT) have been found to predict development of cardiovascular disease. However, it is still unknown whether higher proNT levels are associated with subclinical vascular damage. Herein, we investigated the relationship between higher proNT concentrations and augmented pulse pressure (PP) and carotid intima-media thickness (cIMT), indicators of increased arterial stiffness and subclinical atherosclerosis, respectively. Clinical characteristics, PP and cIMT were evaluated in 154 non-diabetic individuals stratified into tertiles according to fasting serum proNT concentrations. We found that, subjects with higher proNT levels exhibited a worse lipid profile and insulin sensitivity, increased C-reactive protein levels, along with higher values of PP and cIMT as compared to the lowest proNT tertile. Prevalence of elevated PP (≥ 60 mmHg) and subclinical carotid atherosclerosis (IMT > 0.9 mm) was increased in the highest tertile of proNT. In a logistic regression analysis adjusted for several confounders, subjects with higher proNT levels displayed a fivefold raised risk of having elevated PP values (OR 5.36; 95%CI 1.04-27.28; P = 0.05) and early carotid atherosclerosis (OR 4.81; 95%CI 1.39-16.57; P = 0.01) as compared to the lowest proNT tertile. In conclusion, higher circulating levels of proNT are a biomarker of subclinical vascular damage independent of other atherosclerotic risk factors.

The association of cumulative low-density lipoprotein cholesterol exposure and carotid intima-media thickness in a young adulthood population.

OBJECTIVE: To investigate the association between cumulative exposure to low-density lipoprotein cholesterol (LDL-C) and carotid intima-media thickness (IMT) in the young adulthood population. METHODS: Young adult subject (18-45 year old) from the Kailuan Study group who participated in the same period of follow-up and received carotid artery ultrasound were selected as the observation subjects. Among them, 3651 cases met the inclusion criteria, which required that carotid artery color ultrasound examinations be completed from 2010 to 2016, with complete IMT measurements, LDL-C data collected at least twice before carotid ultrasound, and participants' age to be ≤ 45 years at the time of carotid artery color ultrasound examination. Linear regression was used to analyze the correlation between time-weighted average (TWA) to LDL-C cumulative exposure and IMT the young population. Logistic regression was used to analyze the effects of different TWA groups on IMT thickening. Considering that the use of anti hypertensive drugs and lipid-lowering drugs may affect TWA LDL-C, this study excluded people taking antihypertensive drugs and lipid-lowering drugs, and conducted a repeat analysis of the main results. RESULTS: There was a positive correlation between TWA LDL-C and IMT, with IMT increasing by 0.017 mm when TWA LDL-C increased by 1 mmol/L * year. The TWA LDL-C in the highest group was identified as a risk factor for IMT thickening, with odds ratio (OR) values of 1.812(1.027 ~ 3.200) in the T3 group. After excluding patients taking antihypertensive drugs and lipid-lowering drugs, the results still showed that the T3 group with the highest TWA LDL-C was a risk factor for IMT thickening, with an OR value of 1.850(0.988-3.464), P for trend is 0.043. CONCLUSION: This cohort study revealed that TWA LDL-C is positively correlated with IMT in young adulthood for risk stratification, and control LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic disease. TRIAL REGISTRATION: ChiCTR-TNC-11001489.

Association of Blood Copper With the Subclinical Carotid Atherosclerosis: An Observational Study.

BACKGROUND: Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear. METHODS AND RESULTS: This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty-five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal-progressively-adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021-1.238], relative risk according to per interquartile increment was 1.039 [1.008-1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper-cadmium-lead mixture on subclinical carotid plaque presence. CONCLUSIONS: Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.

Insulin resistance in the adipose tissue predicts future vascular resistance: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases.

BACKGROUND AND AIMS: Diameter, plaque score, and resistance index (RI) in the common carotid artery (CCA) are indicators of arterial remodeling, atherosclerosis, and vascular resistance, respectively. This study investigated the longitudinal association between adipose tissue insulin resistance or serum free fatty acid (FFA) levels and the CCA parameters. METHODS: This retrospective cohort analysis included 1089 participants (mean age 57.6 years; 40.0 % women) with data on health checkups from January 1982 to March 2003 and carotid artery ultrasonography from January 2015 to June 2019. Baseline serum FFA and immunoreactive insulin levels were assessed before and 30, 60, and 120 min after glucose ingestion. Adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and FFA levels. An RI value >0.75 was defined as high RI. RESULTS: A significant association was found between Adipo-IR and RI; however, Adipo-IR showed no association with CCA diameter or plaque score. The incidence of high RI increased with Adipo-IR quartile (Q) groups (47.3 % in Q1, 52.8 % in Q2, 53.3 % in Q3, 62.4 % in Q4; Cochrane-Armitage test for trend, p < 0.001). In multivariate analysis, Adipo-IR levels (Q4 vs. Q1 odds ratio: 1.67, 95 % confidence interval: 1.12-2.51) were positively associated with high RI incidence. Moreover, a significant association was found between RI and serum FFA levels after glucose intake, but not fasting FFA levels. CONCLUSIONS: Future vascular resistance was predicted by insulin resistance in the adipose tissue. After glucose intake, serum FFA levels may significantly impact vascular resistance development.

Plasma lipidome differences in patients with and without significant carotid plaque.

BACKGROUND: Atherosclerosis is a major cause of ischemic stroke, and early detection of advanced atherosclerosis in the carotid artery is important for reducing morbidity and mortality. What is even more important is not only detection of atherosclerosis but early determination whether the patients are at high risk of an event with adverse effects as the size of the plaque does not necessarily reflect its potential to trigger such events. AIM: We studied whether plasma lipidomics profile can be used as a diagnostic tool for stratification of stable or unstable plaques without the need of removing the carotid plaque. METHODS: This study used liquid chromatography high-resolution tandem mass spectrometry lipidomics to characterize lipid profiles in patients' plasma and found that patients with significant and complicated (vulnerable) atherosclerotic plaque had distinct lipid profiles compared to those with insignificant plaques. RESULTS: The lipid classes that were most predictive of vulnerable plaque were lysophosphoethanolamines, fatty acyl esters of hydroxy fatty acids, free fatty acids, plasmalogens, and triacylglycerols. Most of these compounds were found decreased in plasma of patients with unstable plaques which enabled sufficient performance of a statistical model used for patient stratification. CONCLUSIONS: Plasma lipidomes measured by liquid chromatography-mass spectrometry show differences in patients with stable and unstable carotid plaques, therefore these compounds could potentially be used as biomarkers for unstable plaque in future clinical diagnosis.

Correlation between novel inflammatory markers and carotid atherosclerosis: A retrospective case-control study.

OBJECTIVE: Carotid atherosclerosis is a chronic inflammatory disease, which is a major cause of ischemic stroke. The purpose of this study was to analyze the relationship between carotid atherosclerosis and novel inflammatory markers, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to neutrophil ratio (PNR), neutrophil to lymphocyte platelet ratio (NLPR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), in order to find the best inflammatory predictor of carotid atherosclerosis. METHOD: We included 10015 patients who underwent routine physical examinations at the physical examination center of our hospital from January 2016 to December 2019, among whom 1910 were diagnosed with carotid atherosclerosis. The relationship between novel inflammatory markers and carotid atherosclerosis was analyzed by logistic regression, and the effectiveness of each factor in predicting carotid atherosclerosis was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULT: The level of PLR, LMR and PNR in the carotid atherosclerosis group were lower than those in the non-carotid atherosclerosis group, while NLR, NLPR, SII, SIRI and AISI in the carotid atherosclerosis group were significantly higher than those in the non-carotid atherosclerosis group. Logistic regression analysis showed that PLR, NLR, LMR, PNR, NLPR, SII, SIRI, AISI were all correlated with carotid atherosclerosis. The AUC value of NLPR was the highest, which was 0.67, the cut-off value was 0.78, the sensitivity was 65.8%, and the specificity was 57.3%. The prevalence rate of carotid atherosclerosis was 12.4% below the cut-off, 26.6% higher than the cut-off, and the prevalence rate increased by 114.5%. CONCLUSION: New inflammatory markers were significantly correlated with carotid atherosclerosis, among which NLPR was the optimum inflammatory marker to predict the risk of carotid atherosclerosis.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.

BACKGROUND AND AIMS: Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis. METHODS: The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model. RESULTS: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (ß = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways. CONCLUSIONS: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

Correlation between blood inflammatory indices and carotid intima-media thickness in the middle-aged and elderly adults.

OBJECTIVES: This study aimed to investigate the correlations between carotid intima-media thickness (IMT) and systemic immune inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte (NLR) ratio. MATERIALS AND METHODS: This was a cross-sectional study enrolling a total of 582 middle-aged and elderly patients. The correlations between SII, PLR, and NLR with IMT were assessed using logistic regression models, which were subsequently incorporated into the underlying models with traditional risk factors and their predictive values for IMT. RESULTS: NLR exhibited a significant correlation with IMT in the simple regression analysis (ß = 0.01, 95 %CI= 0.00-0.02, p < 0.05). After controlling for potential confounding variables in the multivariate analysis, the association between NLR and both Maximum IMT [ß = 0.04, 95 %CI = 0.02-0.07, p = 0.0006] and Mean IMT [ß = 0.05, 95 %CI = 0.02-0.07, p = 0.0001] remained statistically significant. Additionally, PLR was found to be a significant independent predictor of Maximum IMT [ß = 0.04, 95 % CI =0.00-0.07, p = 0.0242] and Mean IMT [ß = 0.04, 95 % CI = 0.01-0.07, p = 0.0061]. Similarly, SII was identified as an independent predictor of Maximum IMT [ß = 1.87, 95 % CI =1.24, p = 0.0003]. The study found a significant positive correlation between Maximum IMT and the levels NLR, PLR, and SII. Specifically, in the Maximum IMT group, higher quartiles of NLR, PLR, and SII were associated with increased odds ratios (OR) for elevated IMT levels, with statistically significant results for NLR (Q4vsQ1: OR 3.87, 95 % CI 1.81-8.29), PLR (Q4vsQ1: OR 2.84, 95 % CI 1.36-5.95), and SII (Q4vsQ1: OR 2.64, 95 % CI 1.30-5.37). Finally, the inclusion of NLR, PLR, and NLR+PLR+SII in the initial model with traditional risk factors resulted in a marginal improvement in the predictive ability for Maximum IMT, as evidenced by the net reclassification index (p < 0.05). CONCLUSIONS: This study discovered a positive correlation between SII, PLR, NLR, and IMT, which are likely to emerge as new predictors for IMT thickening. These findings lay a theoretical reference for future predictive research and pathophysiological research on carotid intima-media thickening.

Independent Relationship of Lipoprotein(a) and Carotid Atherosclerosis With Long-Term Risk of Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) (Lp(a)) is considered to be a causal risk factor of atherosclerotic cardiovascular disease (ASCVD), but whether there is an independent or joint association of Lp(a) and atherosclerotic plaque with ASCVD risk remains uncertain. This study aims to assess ASCVD risk independently or jointly conferred by Lp(a) and carotid atherosclerotic plaque. METHODS AND RESULTS: A total of 5471 participants with no history of cardiovascular disease at baseline were recruited and followed up for ASCVD events (all fatal and nonfatal acute coronary and ischemic stroke events) over a median of 11.5 years. Independent association of Lp(a), or the joint association of Lp(a) and carotid plaque with ASCVD risk, was explored using Cox proportional hazards models. Overall, 7.6% of the participants (60.0±7.9 years of age; 2649 [48.4%] men) had Lp(a) ≥50 mg/dL, and 539 (8.4/1000 person-years) incident ASCVD events occurred. Lp(a) concentrations were independently associated with long-term risk of total ASCVD events, as well as coronary events and ischemic stroke events. Participants with Lp(a) ≥50 mg/dL had a 62% higher risk of ASCVD incidence (95% CI, 1.19-2.21) than those with Lp(a) <10 mg/dL, and they exhibited a 10-year ASCVD incidence of 11.7%. This association exists even after adjusting for prevalent plaque. Moreover, participants with Lp(a) ≥30 mg/dL and prevalent plaque had a significant 4.18 times higher ASCVD risk than those with Lp(a) <30 mg/dL and no plaque. CONCLUSIONS: Higher Lp(a) concentrations are independently associated with long-term ASCVD risk and may exaggerate cardiovascular risk when concomitant with atherosclerotic plaque.

Impact of optimal cholesterol levels on subclinical atherosclerosis in the absence of risk factors in young adults.

BACKGROUND AND AIMS: We aimed to assess the association of blood lipids with the prevalence, incidence, and progression of subclinical atherosclerosis among young individuals without dyslipidemia and other traditional cardiovascular risk factors (CVRFs). METHODS: A total of 1270 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study aged 32-46 years free of cardiovascular disease, diabetes, hypertension, current smoking, and dyslipidemia (total cholesterol [TC] ≥ 240 mg/dL, triglycerides [TG] ≥ 150 mg/dL, low-density lipoprotein cholesterol [LDL-C] ≥ 160 mg/dL, high-density lipoprotein cholesterol [HDL-C] < 40 mg/dL, or taking lipid-lowering medications) were included. A subgroup with optimal lipids within the low-CVRF group was defined with TC < 200 mg/dL, LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL, and women with HDL-C ≥ 50 mg/dL. RESULTS: 1-SD higher TC (25.9 mg/dL), LDL-C (24.7 mg/dL), and non-HDL-C (26.6 mg/dL) were associated with a greater risk of presence (hazard ratios: 1.30-1.36), incidence (1.30-1.32), and progression (1.31-1.35) of coronary artery calcium (CAC) and a 42-44% greater odds of composite mean carotid intima-media thickness (CIMT) ≥ 75th percentile [780 µm] (p < 0.05). Repeating the analyses in a subset of participants with a CAC score of zero did not alter the association of TC, LDL-C, and non-HDL-C with CIMT. In the subgroup with optimal lipids, these lipid indices remained associated with an increased risk of presence and incidence of CAC and greater CIMT measures. CONCLUSIONS: Among adults aged 32-46 years, in the absence of traditional CVRFs, elevated cholesterol levels, even within what is considered optimal, are associated with atherosclerosis and arteriopathy.

Association of the trimethylamine N-oxide with cardiovascular risk and vascular alterations in middle-aged patients with risk factors for cardiovascular diseases.

BACKGROUND: Trimethylamine N-oxide (TMAO) is synthesized by the intestinal microbiota and is an independent predictor of cardiovascular disease (CVD). However, its underlying mechanisms remain unclear. We investigated TMAO levels across different CVD-risk patient groups, and evaluated associations between TMAO and vascular alterations (e.g., arterial stiffness, intima-media thickness [IMT], and the presence and grade of carotid artery plaques [CAPs]). METHODS: We examined 95 patients (58.5 ± 7.3 years): 40 with clinical atherosclerotic cardiovascular disease (ASCVD), 40 with atherosclerosis risk factors (RF), and 15 controls. Arterial stiffness was measured by Carotid-Femoral Pulse Wave Velocity (C-F PWV). B-mode ultrasound was used to evaluate the presence and grade of CAPs and carotid IMT (CIMT). TMAO was measured by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and results were presented as the median (interquartile range). RESULTS: TMAO levels were higher in patients with ASCVD (251.5 [164.5] µg/l) when compared with patients with RFs (194.0 [174] µg/l, P=0.04) and controls (122.0 (77) µg/l, P<0.001). A significant correlation was observed between TMAO and PWV (r = 0.31, P=0.003), which was not confirmed after adjustment for RFs. TMAO levels were significantly correlated with plaque score (r = 0.46, P<0.001) and plaque height (r=0.41, P=0.003), and were independent predictors for grade III plaques (odds ratio [OR] = 1.002, confidence interval (CI) 95%: 1.000047-1.003, P=0.044). CONCLUSIONS: TMAO levels are increased with expanded CVD risk. Across different types of vascular damage, TMAO is associated with atherosclerotic changes.

Homocysteine Facilitates the Formation of Carotid Atherosclerotic Plaque Through Inflammatory and Noninflammatory Mechanisms.

Background: Elevated homocysteine (Hcy) was considered a significant risk factor in the development and progression of carotid atherosclerosis (CAS), which involves a combination of inflammatory and noninflammatory mechanisms. However, epidemiological surveys have presented conflicting results. In this study, we aim to offer an epidemiological viewpoint on how elevated Hcy impacts CAS and its potential mechanisms. Methods: Levels of high-sensitivity C-reactive protein (hsCRP) were measured to assess the inflammatory status. The estimation of CAS events was performed by assessing carotid intima-media thickness using Doppler ultrasonography. Univariate analysis was conducted to investigate the variations in biochemical parameters among three groups: normal, carotid atherosclerotic thickening (CAT), and carotid atherosclerotic plaque (CAP) formation. Logistic regression analysis was conducted to identify the risk factors associated with the progression of CAT and CAP. In addition, multivariate linear regression analysis was conducted to identify the independent factors that correlated with hsCRP levels. Results: The study encompassed 3897 participants, with 2992 (76.8%) being males and 905 (23.2%) being females. The incidence of CAT and CAP rose with higher Hcy levels, with an overall odds ratio (OR) of 2.04 [95% confidence intervals (CI) 1.69-2.40] for CAT and 2.68 (95% CI 2.32-3.05) for CAP. After adjusting for gender, age, and blood markers, the OR for CAT and CAP decreased, with an overall OR of 1.05 (95% CI 0.81-1.28) and OR of 1.24 (95% CI 1.02-1.46), respectively. CAP risk independently increased when Hcy level exceeded 19.7 µmol/L (P = 0.030), but not CAT risk (P = 0.299). The impact of hsCRP on CAS events is similar to that of Hcy, and a multiple linear analysis found a significant independent correlation between hsCRP and Hcy (P = 0.001). Conclusions: Elevated Hcy levels can facilitate the formation of CAP through both inflammatory and noninflammatory processes, but it does not independently influence CAT.

Additive effect between homocysteine and low-density-lipoprotein cholesterol upon incidence of novel carotid plaque formation: data from a Chinese community-based cohort.

OBJECTIVE: Homocysteine (HCY) has been associated with carotid plaque in cross-sectional studies, but the prospective relationship between HCY and incident carotid plaque has not been well established. The purpose of this study was to investigate the association between HCY and incidence of novel carotid plaque in a Chinese community-based population without pre-existing carotid atherosclerosis and to assess the additive effect of HCY and low-density lipoprotein cholesterol (LDL-C) on the incidence of novel plaque. METHODS: At baseline, we measured HCY and other risk factors in subjects aged ≥ 40 years. All participants underwent carotid ultrasound examinations at baseline and after an average of 6.8 years of follow-up. Incidence of plaque was identified if plaque was absent at baseline, but plaque was detected at the end of follow-up. A total of 474 subjects were included in the analysis. RESULTS: The incidence of novel carotid plaque was 24.47%. Multivariate regression analyses showed that HCY was independently associated with a 1.05-fold-higher likelihood for incident novel plaque (adjusted odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.01-1.09, P = 0.008). Using tertile 1 and tertile 2 for reference, the top HCY tertile (T3) showed a 2.28-fold-higher likelihood for incident plaque (adjusted OR = 2.28, 95%CI: 1.33-3.93, P = 0.002). The combination of HCY T3 and LDL-C ≥ 3.4 mmol/L had the highest risk for novel plaque formation (adjusted OR = 3.63, 95%CI: 1.67-7.85, P = 0.001) compared to those without either condition. In the LDL-C ≥ 3.4 mmol/L subgroup, HCY was significantly associated with incidence of plaque (adjusted OR = 1.16, 95%CI: 1.04-1.28, P = 0.005, P-interaction = 0.023). CONCLUSION: In the Chinese community-based population, HCY was independently associated with the incidence of novel carotid plaque. There were additive effect between HCY and LDL-C on the incidence of plaque, the highest risk was observed in individuals with both high HCY levels and LDL-C ≥ 3.4 mmol/L. Our findings suggest that HCY may be a potential target for preventing the incidence of carotid plaque, particularly in individuals with elevated LDL-C levels.

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis.

BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

Association between Triglyceride-Glucose Index and carotid plaque in Japanese population: a cross-sectional study.

OBJECTIVE: Previous studies linking Triglyceride Glucose (TyG) Index to carotid plaque have yielded inconsistent results. Moreover, related studies on the population of Japan are rare. This study aims to provide further results. DESIGN: A hospital-based cross-sectional study. SETTING: The Shin Takeo Hospital. PARTICIPANTS: We assessed 1904 Japanese participants (988 men and 916 women) whose mean age was 57±11.9 years, and those participants underwent health check-ups at Shinbuf Hospital at Shin Takeo Hospital from 1 April 2016 to 31 October 2017. METHODOLOGY: Carotid plaque, triglyceride and fasting glucose and other relevant indicators were collected. We used ultrasonography to evaluate carotid plaque. A multivariable logistic regression model and generalised additive model were used to evaluate the association between the TyG Index and carotid plaque. Subgroup and interaction analyses were validated for the consistency of these correlations. RESULTS: Following the adjustment of traditional carotid plaque risk factors, the non-linear relationship between the TyG Index and carotid plaque was investigated. Using a two-piecewise regression model, we calculated the inflection point to be 9.06. The OR and 95% CIs for the inflection points on the left and right sides were 1.70 (1.27 to 2.29) and 0.88 (0.52 to 1.47), respectively. According to the variables tested, the interactions between the TyG Index and all subgroup factors were analysed and significant interactions were not observed. CONCLUSION: In individuals who underwent a comprehensive check-up in Japan, the relationship between the TyG Index and carotid plaque is non-linear. When the TyG Index is less than 9.06, it is associated with carotid plaque.

Transforming growth factor beta 1 is associated with subclinical carotid atherosclerosis in patients with systemic lupus erythematosus.

BACKGROUND: Transforming growth factor beta (TGF-ß1) is a multifunctional cytokine that has anti-inflammatory and immunosuppressive effects. TGF-ß1 has been linked to cardiovascular disease in the general population. The immunosuppressive effect of TGF-ß1 is believed to be dysregulated in patients with systemic lupus erythematosus (SLE). In the present work, we aimed to study the relationship of serum levels of TGF-ß1 with subclinical carotid atherosclerosis in patients with SLE. METHODS: The study included 284 patients with SLE. Serum levels of TGF-ß1 and subclinical carotid atherosclerosis (by carotid ultrasonography) were evaluated. In addition, the complete lipid profile and insulin resistance were analyzed. Multivariable linear and logistic regression analysis was performed to establish the relationship of TGF-ß1 with carotid subclinical atherosclerosis adjusting for traditional cardiovascular risk factors that included lipid profile and insulin resistance. RESULTS: Circulating TGF-ß1 was positively and significantly associated with higher levels of LDL:HDL cholesterol ratio and atherogenic index. TGF-ß1 was also associated with significantly lower levels of HDL cholesterol and apolipoprotein A1. Remarkably, TGF-ß1 was associated with the presence of carotid plaque not only after adjustment for demographics (age, sex, body mass index, diabetes, hypertension, and aspirin use) but also after adjustment for relationships of TGF-ß1 with lipid profile molecules, insulin resistance, and SLEDAI disease score (odds ratio 1.14 [95% confidence interval 1.003-1.30], p = 0.045). CONCLUSION: TGF-ß1 serum levels are positively and independently associated with the presence of subclinical atherosclerosis disease in patients with SLE.

The impact of cumulative exposure to diverse lipid profiles on carotid intima-media thickness among an asymptomatic population.

BACKGROUND AND AIMS: We aimed to investigate the relationship between the cumulative exposure to different lipid parameters and carotid intima-media thickness(CIMT), which is considered a marker for the early stage of atherosclerosis. This is due to the shift in research focus from assessing individual lipoproteins to considering their cumulative exposure. METHODS AND RESULTS: The study included 2,348 participants who had their lipid parameters measured biennially since 2006.To calculate the cumulative lipid burden, the weighted sum of the difference between the measured value and the cutoff value of each parameter, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and non-HDLC, was added. Carotid ultrasound was used to detect CIMT. The association between cumulative lipid burden and CIMT was evaluated using linear and logistic analyses. TC and LDLC burden were significantly associated with thickening CIMT (p<0.05). A 2.65-fold, 1.67-fold increased risk of abnormal CIMT was documented in the highest quartile of these two lipid burdens. Notably, a dose-dependent relationship was observed in the overall population when taking non-HDLC burden as a continuous variable (fully-adjusted ß coefficient=0.0013, 95%CI 0.0004-0.0022). CONCLUSIONS: Out of the five lipid parameters, TC and LDLC burden showed independent associations with abnormal CIMT. it is crucial to attain optimal lipid levels for the prevention and treatment of subclinical atherosclerosis.

The Relationship between Serum TWEAK Levels and Carotid Intima-media Thickness in Patients with Fabry Disease.

Fabry disease (FD) is associated with inflammation, proteinuria, and chronic kidney disease. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) plays an important role in inflammation in diabetic nephropathy and lupus nephritis. Since there is a close relationship linking serum TWEAK (sTWEAK), inflammation, and carotid intima-media thickness (CIMT) in various kidney diseases, we aimed to determine the relationship between sTWEAK levels and CIMT in subjects with and without proteinuria in a cross-sectional study involving 15 FD patients (seven females, eight males) and seven healthy controls (four females, three males). There were no differences in age, sex, estimated glomerular filtration rate, and biochemical parameters (serum glucose, albumin, creatinine, uric acid, C-reactive protein (CRP), low-density lipoprotein, and high-density lipoprotein) between FD patients and healthy controls. The spot urine protein-creatinine ratios of healthy controls and FD patients were 90 mg/g and 185 mg/g, respectively (P = 0.022). STWEAK levels were higher in FD patients than in healthy controls (P = 0.007). The CIMT of FD patients and healthy controls was 0.55 ± 0.14 mm and 0.42 ± 0.04 mm, respectively (P = 0.007). STWEAK was positively correlated with CRP and CIMT, and negatively with proteinuria (P = 0.005, P = 0.013, and P = 0.018, respectively). In the multivariate analysis, only sTWEAK was an independent variable of increased CIMT. We demonstrated that sTWEAK and CIMT were increased in FD patients. STWEAK might have a role in the pathogenesis of subclinical atherosclerosis in FD.

Monomeric form of C-reactive protein in the assessment of the residual inflammatory cardiovascular risk in patients with subclinical carotid atherosclerosis.

Aim      To study the relationship between monomeric C-reactive protein (mCRP) and the progression of asymptomatic carotid atherosclerosis in patients with a moderate risk for cardiovascular diseases (CVD) as assessed with the SCORE model.Material and methods  The study included 80 men and women aged 53.1±5.8 years assigned to the category of a moderate risk for CVDs by the SCORE model with a low-density lipoprotein cholesterol (LDL-C) level of 2.7-4.8 mmol/l and asymptomatic, hemodynamically insignificant (<50% luminal narrowing) carotid atherosclerosis according to ultrasonic data. All patients were prescribed atorvastatin to achieve a LDL-C level <2.6 mmol/l. After 7 years of follow-up, ultrasonic examination of carotid arteries was performed, and concentrations of high-sensitivity C-reactive protein (hsCRP) and mCRP were measured.Results A concentration of LDL-C <2.6 mmol/l was achieved in all patients. The progression of atherosclerosis as determined by an increased number of atherosclerotic plaques (ASPs), was observed in 45 (56 %) patients. At 7 months of follow-up, concentrations of cCRP were higher in the group of patients with progressive carotid atherosclerosis, while the levels of hsCRP did not differ between the groups. Increased mCRP concentrations were associated with changes in variables of the "atherosclerotic load", including the number of ASPs, total ASP height, and the intima-media thickness (IMT). In patients with a median mCRP concentration of 5.2 [3.3; 7.1] µg/l and more, the increases in mean ACP number and total ASP height were considerably higher than in patients with mCRP concentrations lower than the median (3.9 and 2.7 times, respectively), whereas the odds ratio for the progression of asymptomatic carotid atherosclerosis was 5.5 (95 % confidence interval, CI: 2.1-14.6; p=0.001). ROC analysis showed that the concentration of hsCRP had no predictive value for prognosis of asymptomatic carotid atherosclerosis (p=0.16), while the area under the ROC curve (AUC) for mCRP was 0.75±0.056 (95 % CI: 0.64-0.86; p=0.001).Conclusion      According to the results of 7-year follow-up, the plasma concentration of mCRP was significantly higher in patients with an increased number of ASPs than in patients without this increase. An increased level of mCRP may indicate a higher inflammatory risk of CVD.