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Chen H, Wang D, Shen J, Guo B, Song C, Ma D, Wu Y, Liu G, Chen G, Ni Y, Kong T, Wang F. Predicting peripartum depression using elastic net regression and machine learning: the role of remnant cholesterol. BMC Pregnancy Childbirth 2025; 25:544. [PMID: 40340559 PMCID: PMC12060319 DOI: 10.1186/s12884-025-07656-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 04/25/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Traditional statistical methods have dominated research on peripartum depression (PPD), but innovative approaches may provide deeper insights. This study aims to predict the impact factors of PPD using elastic net regression (ENR) combined with machine learning (ML) model. METHODS This longitudinal study was conducted from June 2020 to May 2023, involving healthy pregnant women in the first trimester, followed up until the completion of the assessment in the second trimester. PPD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Features with p <.05 from logistic regression were selected and refined using ENR. These features were then used to build six ML models to identify the best-performing one. SHapley Additive exPlanations (SHAP) analysis was employed to enhance model interpretability by visualizing its decision-making process. RESULTS A total of 608 participants were followed, resulting in 384 valid questionnaires. After excluding incomplete or incorrect baseline data, 325 participants were ultimately included in the study. Among these, 130 were classified as having mild depression, and 32 were classified with major depression. Nineteen features were initially identified as being associated with PPD, with 14 retained after ENR refinement. The random forest (RF) model outperformed the other ML models. SHAP analysis identified the top five predictors of PPD: magnesium (Mg), remnant cholesterol (RC), calcium (Ca), mean corpuscular hemoglobin concentration (MCHc), and potassium (K). Mg, Ca, MCHc, and K were negatively correlated with PPD, while RC showed a positive correlation. CONCLUSIONS The RF model effectively identified associations between exposure factors and PPD. Mg, Ca, MCHc, and K were found to be protective factors, while RC emerged as a potential risk factor, highlighting its potential as a novel biomarker for PPD.
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Affiliation(s)
- Hongxu Chen
- School of Public Health, Xinjiang Medical University, Urumqi, 830063, China
| | - Denglan Wang
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China
| | - Juanjuan Shen
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China
| | - Baoyan Guo
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China
| | - Chun Song
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China
| | - Duo Ma
- Department of Ultrasonography, The Second Afffliated Hospital of Xiamen Medical College, Xiamen, China
| | - Yan Wu
- Beijing Hui-Long-Guan Hospital, Peking University, Beijing, 100096, China
| | - Guohui Liu
- Inner Mongolia Maternity and Child Health Care Hospital, Huhhot, 010020, China
| | - Guangxue Chen
- Department of Gynaecology and Obstetrics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Yan Ni
- Department of Women Health Care, Quzhou Maternal and Child Health Care Hospital, Quzhou, 324000, China
| | - Tiantian Kong
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China.
| | - Fan Wang
- Beijing Hui-Long-Guan Hospital, Peking University, Beijing, 100096, China.
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Xu P, Fan C, Yan M, Liu J, Zhang X. Remnant cholesterol and suicide attempts in untreated first-episode major depressive disorder. Front Psychiatry 2025; 16:1493509. [PMID: 40104336 PMCID: PMC11913861 DOI: 10.3389/fpsyt.2025.1493509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
Objective The objective of this research was to investigate the relationship between remnant cholesterol (RC) levels and suicide attempts (SA) made by Chinese patients with untreated first-episode major depressive disorder (UFE MDD). Methods This study included 1718 patients with UFE MDD. Demographic, clinical characteristics, and blood lipid parameters were collected. The 17-item Hamilton Depression Rating Scale (HAMD), the 14-item Hamilton Anxiety Rating Scale (HAMA), and the positive subscale of the Positive and Negative Syndrome Scale (PANSS) were used to assess their depression, anxiety, and psychotic symptoms, respectively. Multivariable binary logistic regression analysis was used to estimate the association between RC and the risk of SA. A two-piecewise linear regression model was used to investigate the threshold effects if non-linear associations existed. Results Univariate logistic regression analysis showed a significant positive correlation between RC and SA, but after controlling for confounding factors, the association between them was not statistically significant. After dividing the RC into quartiles, only the RC in the Q4 group was significantly positively correlated with suicide attempts (OR = 1.73, 95% CI: 1.13-2.65, P = 0.012, vs. Q1) in a fully adjusted model. Curve fitting analysis also showed a nonlinear relationship between RC and suicide attempts with an inflection point at 1.99 mmol/L in RC. On the left of the inflection point, a significant positive correlation was observed between RC and SA (OR: 1.36, 95% CI: 1.09-1.69, p=0.006). However, on the right of the inflection point, no significant correlation was found (OR: 0.79, 95% CI: 0.55-1.14, p=0.214). Conclusion This study demonstrates a non-linear association between RC levels and SA in patients with untreated first-episode major depressive disorder. When RC was less than 1.99 mmol/L, they showed a significant positive correlation.
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Affiliation(s)
- Ping Xu
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Cheng Fan
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Mingxing Yan
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Junjun Liu
- Department of Psychiatry, Nanjing Meishan Hospital, Nanjing, China
- Medical College of Soochow University, Suzhou, China
- Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Xiangyang Zhang
- Chinese Academy of Sciences (CAS) Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
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Yu P, Yuan Q, Huang L, Tao L, Peng Z, Pu J. The prognostic value of remnant cholesterol to adverse renal outcomes in patients with type 2 diabetes. Diabetol Metab Syndr 2025; 17:52. [PMID: 39940009 PMCID: PMC11823253 DOI: 10.1186/s13098-025-01617-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Type 2 diabetes (T2DM) is known to have detrimental effects on renal health. Our study aimed to investigate the relationship between remnant cholesterol (remnant-C) and adverse renal outcomes in patients with T2DM. METHODS We utilized data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which included 10,196 participants with T2DM to investigate the relationship between remnant-C and adverse renal outcomes by performing Kaplan-Meier survival analysis, Cox proportional regression and Restricted cubic spline (RCS) analysis. Finally, several sensitivity analyses were conducted to assess the robustness of our findings. RESULTS Over a 7-year follow-up period, 2039 patients (23.2%) developed albuminuria, 5824 patients (57.1%) experienced worsening renal function, and 280 patients (2.7%) progressed to renal failure. After adjusting for multiple confounding factors, we found that remnant-C was significantly associated with the development of albuminuria (P = 0.007) and worsening renal function (P = 0.002). However, there was no discernible connection between remnant-C and renal faiure (P = 0.621). In sensitivity analyses, the association between remnant-C and the risk of adverse renal outcomes remained robust. CONCLUSION Our findings highlight the association between remnant-C and the risk of adverse renal outcomes in patients with T2DM. This easily calculable index can provide valuable information to physicians for predicting the risk of adverse renal outcomes in patients with T2DM.
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Affiliation(s)
- Pan Yu
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China
| | - Qiongjing Yuan
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China
- Hunan Key Lab of Organ Fibrosis, Changsha, China
- Xiangya Hospital, National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, China
| | - Ling Huang
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China
- Hunan Key Lab of Organ Fibrosis, Changsha, China
- Xiangya Hospital, National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, China
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China
- Hunan Key Lab of Organ Fibrosis, Changsha, China
- Xiangya Hospital, National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, China
| | - Zhangzhe Peng
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China
- Hunan Key Lab of Organ Fibrosis, Changsha, China
- Xiangya Hospital, National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, China
| | - Jiaxi Pu
- Department of Nephrology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, China.
- Hunan Key Lab of Organ Fibrosis, Changsha, China.
- Xiangya Hospital, National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, China.
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Zhou Y, Lin Y, Yang Y, Lei W, Xu J, Zhu Y. Association between remnant cholesterol and depression in middle-aged and older Chinese adults: a population-based cohort study. Front Endocrinol (Lausanne) 2025; 16:1456370. [PMID: 39963278 PMCID: PMC11830595 DOI: 10.3389/fendo.2025.1456370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Background The focus on remnant cholesterol (RC) has intensified because of its association with various diseases. In this study, we investigated the association between RC and depression in middle-aged and older adults. Methods The study involved 7,305 participants from the 2015 and 2018 waves of the China Health and Retirement Longitudinal Study. Based on the 10-item Center for Epidemiological Studies Depression Scale (CESD-10), depression was indicated by scores ≥ 12. To assess the correlation between RC levels and depression, a logistic regression model that incorporated restricted cubic spline techniques was used. Results Of the study population, (mean age: 60.0 ± 9.5 years), 50.3% were female. From 2015 to 2018, the mean CESD-10 score increased from 6.31 ± 3.56 to 7.85 ± 5.23. Following adjustment for confounding factors, individuals in the higher RC level quartile exhibited a higher depression risk (Q3: odds ratio [OR]: 1.75, 95% confidence intervals [CI]: 1.29-2.39; Q4: OR: 2.68, 95% CI: 1.96-3.68, P for trend < 0.001), with a linear correlation between RC levels and depression (P for nonlinearity = 0.108). And the subgroup analysis yielded results consistent with the primary findings. Conclusion This study revealed that in China, in middle-aged and older individuals, elevated RC levels were associated with a higher depression risk, suggesting RC is a promising target for depression prevention and treatment.
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Affiliation(s)
- Yang Zhou
- Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China
| | - Yan Lin
- Department of Endocrinology, The People’s Hospital of Danyang, Danyang Hospital of Nantong University, Danyang, Jiangsu, China
| | - Yanhui Yang
- Department of Cardiology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wang Lei
- Department of Breast Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China
| | - Juan Xu
- Department of General Surgery, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Yuanzeng Zhu
- Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China
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Ma Y, Wu S, Lai J, Wan Q, Hu J, Liu Y, Zhou Z, Wu J. Exploring the comorbidity mechanisms between atherosclerosis and hashimoto's thyroiditis based on microarray and single-cell sequencing analysis. Sci Rep 2025; 15:1792. [PMID: 39805933 PMCID: PMC11730997 DOI: 10.1038/s41598-025-85112-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025] Open
Abstract
Atherosclerosis (AS) is a chronic vascular disease characterized by inflammation of the arterial wall and the formation of cholesterol plaques. Hashimoto's thyroiditis (HT) is an autoimmune disorder marked by chronic inflammation and destruction of thyroid tissue. Although previous studies have identified common risk factors between AS and HT, the specific etiology and pathogenic mechanisms underlying these associations remain unclear. We obtained relevant datasets for AS and HT from the Gene Expression Omnibus (GEO). By employing the Limma package, we pinpointed common differentially expressed genes (DEGs) and discerned co-expression modules linked to AS and HT via Weighted Gene Co-expression Network Analysis (WGCNA). We elucidated gene functions and regulatory networks across various biological scenarios through enrichment and pathway analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Core genes were identified using Cytoscape software and further validated with external datasets. We also conducted immune infiltration analysis on these core genes utilizing the CIBERSORT method. Lastly, Single-cell analysis was instrumental in uncovering common diagnostic markers. Based on differential analysis and WGCNA, we identified 119 candidate genes within the cohorts for AS and HT. KEGG and GO enrichment analyses indicate that these genes are significantly involved in antigen processing and presentation, along with various immune-inflammatory pathways. Two pivotal genes, PTPRC and TYROBP, were identified using five algorithms from the cytoHubba plugin. Validation through external datasets confirmed their substantial diagnostic value for AS and HT. Moreover, the results of Gene Set Enrichment Analysis (GSEA) indicated that these core genes are significantly enriched in various receptor interactions and signaling pathways. Immune infiltration analysis revealed a strong association of lymphocytes and macrophages with the pathogenesis of AS and HT. Single-cell analysis demonstrated predominant expression of the core genes in macrophages, monocytes, T cells and Common Myeloid Progenitor (CMP). This study proposes that an aberrant immune response might represent a shared pathogenic mechanism in AS and HT. The genes PTPRC and TYROBP are identified as critical potential biomarkers and therapeutic targets for these comorbid conditions. Furthermore, the core genes and their interactions with immune cells could serve as promising targets for future diagnostic and therapeutic strategies.
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Affiliation(s)
- Yirong Ma
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Shuguang Wu
- Neurology Department, Jiangxi Province Hospital of Integrated Chinese & Western Medicine, Nanchang, China
| | - Junyu Lai
- Cardiology Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Qiang Wan
- Cardiology Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jingxuan Hu
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yanhong Liu
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Ziyi Zhou
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jianguang Wu
- Cardiology Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China.
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Karpouzas GA, Papotti B, Ormseth SR, Palumbo M, Hernandez E, Adorni MP, Zimetti F, Ronda N. Changes in serum cholesterol loading capacity are linked to coronary atherosclerosis progression in rheumatoid arthritis. RMD Open 2024; 10:e004991. [PMID: 39719397 PMCID: PMC11683967 DOI: 10.1136/rmdopen-2024-004991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/19/2024] [Indexed: 12/26/2024] Open
Abstract
OBJECTIVE Excess cholesterol loading on arterial macrophages is linked to foam cell formation, atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). However, the effect of changes in cholesterol loading on coronary plaque trajectory and the impact of RA therapies on this relationship are unknown. We investigated the association between variations in cholesterol loading capacity (CLC) over time and atherosclerosis progression. METHODS In a prospective observational cohort study, coronary CT angiography evaluated atherosclerosis (non-calcified, partially calcified or fully calcified plaques and coronary artery calcium (CAC) score) in 100 patients with RA without cardiovascular disease at baseline and 6.9±0.4 years later. The presence of ≥5 plaques and lesions rendering >50% stenosis was considered an extensive and obstructive disease, respectively. Serum CLC was measured on human THP-1 monocyte-derived macrophages with a fluorometric assay. RESULTS Mean CLC change (follow-up CLC-baseline CLC) was 1.54 (SD 3.69) μg cholesterol/mg protein. In models adjusting for atherosclerotic cardiovascular disease risk score, baseline plaque and other relevant covariates, CLC change (per SD unit increase) is associated with a higher likelihood of progression of non-calcified (OR 2.55, 95% CI 1.22 to 5.35), fully calcified plaque (OR 3.10, 95% CI 1.67 to 5.76), CAC (OR 1.80, 95% CI 1.18 to 2.74) and new extensive or obstructive disease (OR 2.43, 95% CI 1.11 to 5.34). Exposure to prednisone unfavourably influenced, while biologics and statins favourably affected the relationship between CLC change and atherosclerosis progression (all p-for-interactions ≤0.048). CONCLUSION CLC change is associated with atherosclerosis progression in a dose-dependent manner, including lipid-rich non-calcified plaques and extensive or obstructive disease that yield the greatest cardiovascular risk.
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Affiliation(s)
- George Athanasios Karpouzas
- Internal Medicine- Rheumatology, The Lundquist Institute, Torrance, California, USA
- Department of Rheumatology, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Bianca Papotti
- Department of Food and Drug, University of Parma, Parma, Italy
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Dai Y, Sheng Y, Zheng Z, Di W. Cumulative remnant cholesterol exposure during young adulthood and middle age and risk of cardiovascular events: A 30-year population-based cohort study. Int J Cardiol 2024; 414:132435. [PMID: 39121920 DOI: 10.1016/j.ijcard.2024.132435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/22/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Remnant cholesterol (RC) is recognized as a residual risk factor for cardiovascular diseases (CVD). Most studies on the association between RC and CVD have focused on RC level at a single time point, typically during middle or older age. Limited data have characterized long-term RC exposures among young adult. Here we aimed to investigate the association of cumulative RC exposure during young adulthood and middle age with incident CVD later in life. METHODS This cohort study enrolled 3416 CARDIA (Coronary Artery Risk Development in Young Adults) participants aged 18-30 years. Cumulative RC exposure was determined as cumulative RC and time-weighted average (TWA) RC during young adulthood and middle age. Multivariable Cox proportional hazards models were employed to examine the association between cumulative RC exposure and incident CVD. RESULTS Of the 3416 included participants, 193 (5.6%) primary CVD outcomes occurred with a median 30.4-year follow-up. In multivariable Cox proportional hazards regression models that adjusted for LDL-C level, the most recent RC level and other CVD risk factors, the hazard ratios for primary CVD ourtcomes were as follows: 2.01 (95% CI, 1.23-3.27; P for trend = 0.021) for cumulative RC, and 2.11 (95% CI, 1.28-3.47; P for trend = 0.011) for TWA RC. Similar results were observed in other secondary outcomes. CONCLUSIONS Greater exposures to cumulative RC and TWA RC during young adulthood and middle age were independently associated with an increased risk of cardiovascular events, suggesting that maintaining low RC levels early in life may reduce the lifetime CVD risk.
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Affiliation(s)
- Yongbin Dai
- Department of Cardiology, Shenzhen Third People's Hospital, Shenzhen 518000, China
| | - Yanhua Sheng
- Department of Cardiology, Shenzhen Third People's Hospital, Shenzhen 518000, China
| | - Zhenzhong Zheng
- Department of Cardiology, Shenzhen Third People's Hospital, Shenzhen 518000, China.
| | - Wencheng Di
- Department of Cardiology, Shenzhen Third People's Hospital, Shenzhen 518000, China.
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Chang CK, Li YC, Chen PK, Chang SH, Chen DY. Elevated remnant cholesterol as a potential predictor for cardiovascular events in rheumatoid arthritis patients. Front Cardiovasc Med 2024; 11:1449219. [PMID: 39323754 PMCID: PMC11423425 DOI: 10.3389/fcvm.2024.1449219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/27/2024] [Indexed: 09/27/2024] Open
Abstract
Objective The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) remains inadequately defined. Consequently, this study aims to evaluate the predictive value of remnant cholesterol (RC) for assessing CVD risk in RA patients. Methods Plasma RC levels were measured in 114 RA patients and 41 healthy controls, calculated as total cholesterol minus HDL-C and LDL-C. These levels were further analyzed using 1H-NMR lipid/metabolomics. Meanwhile, the 28-joint Disease Activity Score (DAS28) assessed RA activity. Results RC levels were significantly elevated in RA patients (19.0 mg/dl, p < 0.001) compared to healthy controls (14.5 mg/dl). Furthermore, RC levels were significantly elevated at 37.4 mg/dl in patients who experienced cardiovascular event (CVE) compared to 17.4 mg/dl in those without CVE (p < 0.001). To enhance the precision and reliability of RC measurements, RC concentrations were further validated using 1H-NMR spectroscopy. Additionally, a positive correlation was observed between RC levels and DAS28. Multivariate analysis identified RC as a significant predictor of CVE (odds ratio = 1.82, p = 0.013). ROC curve analysis revealed superior predictive capability of RC for CVE (AUC = 0.919, p < 0.001) compared to LDL-C (AUC = 0.669, p = 0.018), with a high sensitivity of 94.7% and a specificity of 82.1%. Conclusion Elevated RC levels demonstrate greater accuracy in predicting CVE occurrence in RA patients compared to traditional measures such as LDL-C. These findings suggest that elevated RC levels may serve as a novel predictor for occurrence of CVE in RA patients, facilitating early intervention strategies based on the risk stratification.
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Affiliation(s)
- Ching-Kun Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- Organ-on-a Chip Fabrication and Verification Division, Taiwan Instrument Research Institute, National Applied Research Laboratories, Hsinchu, Taiwan
| | - Yi-Chen Li
- Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan
- Center of Cell Therapy, National Cheng Kung University Hospital, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Ku Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
| | - Shih-Hsin Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Der-Yuan Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Jiang X, Zhuang J, Juan Y, Zheng X, Zhang H. Association between remnant cholesterol and the risk of cardiovascular disease in Chinese population. J Stroke Cerebrovasc Dis 2024; 33:107825. [PMID: 38914356 DOI: 10.1016/j.jstrokecerebrovasdis.2024.107825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 05/09/2024] [Accepted: 06/15/2024] [Indexed: 06/26/2024] Open
Abstract
OBJECTIVES Previous genetic, observational, and clinical intervention studies reported that circulating levels of remnant cholesterol was associated with cardiovascular disease (CVD). However, whether remnant cholesterol can predict CVD events in Chinese population was not well characterized. STUDY DESIGN This was a prospective cohort study. METHODS We used the data of 9456 Chinese adults aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS). Estimated remnant cholesterol was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol. Cox proportional hazard models and restricted cubic spline models were used to assess the relationships between remnant cholesterol levels and CVD, stroke and cardiac events. RESULTS During 7 years of follow-up, a total of 886 (9.37 %) respondents experienced CVD, 392 (4.15 %) experienced stroke and 544 (5.75 %) experienced cardiac events. In multivariable-adjusted analyses, the adjusted hazard ratios (95 % confidence interval) for the highest versus lowest quartile of remnant cholesterol were 1.14 (1.02-1.32) for CVD and 1.43 (1.12-1.82) for stroke, and each 1-SD increase of log-transformed remnant cholesterol (2.93 mg/dl) was associated with 5 % and 11 % increased risk of the CVD and stroke, respectively. Remnant cholesterol was not associated with increased risk of cardiac events. CONCLUSION Elevated remnant cholesterol levels were positively associated with CVD and stroke in Chinese adult population, suggesting that remnant cholesterol could be considered as a preferential predictor and treatment target of CVD in Chinese population.
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Affiliation(s)
- Xinye Jiang
- Department of Child Health Care, Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, 214002, China
| | - Jielian Zhuang
- Department of Child Health Care, Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, 214002, China
| | - Yin Juan
- Department of Child Health Care, Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, 214002, China
| | - Xiaowei Zheng
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214002, China; Public Health Research Center and Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Heng Zhang
- Department of Child Health Care, Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, 214002, China; Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214002, China.
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Zou YW, Wu T, Li QH, Ma JD, Pan J, Lu Y, Lin JZ, Jia PW, Zheng HW, Gao JW, Dai W, Mo YQ, Dai J, Dai L. Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022. Int J Cardiol 2024; 405:131947. [PMID: 38458390 DOI: 10.1016/j.ijcard.2024.131947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/05/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.
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Affiliation(s)
- Yao-Wei Zou
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Tao Wu
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Qian-Hua Li
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Jian-Da Ma
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Jie Pan
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Ye Lu
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Jian-Zi Lin
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Pei-Wen Jia
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Hu-Wei Zheng
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Jing-Wei Gao
- Department of Cardiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Wei Dai
- Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA
| | - Ying-Qian Mo
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China
| | - Jun Dai
- Department of Public Health, College of Health Sciences, Des Moines University, 8025 Grand Ave., West Des Moines, IA 50266, USA.
| | - Lie Dai
- Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, China.
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Zhou ZY, Wu L, Liu YF, Tang MY, Tang JY, Deng YQ, Liu L, Nie BB, Zou ZK, Huang L. IRE1α: from the function to the potential therapeutic target in atherosclerosis. Mol Cell Biochem 2024; 479:1079-1092. [PMID: 37310588 DOI: 10.1007/s11010-023-04780-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/03/2023] [Indexed: 06/14/2023]
Abstract
Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1β, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1β is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1β-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.
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Affiliation(s)
- Zheng-Yang Zhou
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Li Wu
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Yi-Fan Liu
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Mu-Yao Tang
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Jing-Yi Tang
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Anaesthesiology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Ya-Qian Deng
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Lei Liu
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Bin-Bin Nie
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Zi-Kai Zou
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Liang Huang
- The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
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Wu S, Su X, Zuo Y, Chen S, Tian X, Xu Q, Zhang Y, Zhang X, Wang P, He Y, Wang A. Discordance between remnant cholesterol and low-density lipoprotein cholesterol predicts arterial stiffness progression. Hellenic J Cardiol 2023; 74:24-31. [PMID: 37245643 DOI: 10.1016/j.hjc.2023.05.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/18/2023] [Accepted: 05/23/2023] [Indexed: 05/30/2023] Open
Abstract
BACKGROUND Cross-sectional studies have shown that remnant cholesterol (RC) was associated with arterial stiffness. The present study evaluated the association of RC and the discordance between RC and low-density lipoprotein cholesterol (LDL-C) with arterial stiffness progression. METHODS Data were derived from the Kailuan study. RC was calculated as total cholesterol - high-density lipoprotein cholesterol - LDL-C. Discordant RC with LDL-C were defined by residuals, cutoff points, and median values. Arterial stiffness progression was assessed by the brachial-ankle pulse wave velocity (baPWV) change, baPWV change rate, and increase/persistently high baPWV. Multivariable linear regression models and logistic regression models were used to explore the association of RC and discordant RC versus LDL-C with the arterial stiffness progression. RESULTS A total of 10,507 participants were enrolled in this study, with the mean age of 50.8 ± 11.8 years, 60.9% (6,396) of male. Multivariable regression analyses showed that, each 1 mmol/L increase in the RC level was associated with a 12.80 cm/s increase in baPWV change, a 3.08 cm/s/year increase in the baPWV change rate, and 13% (95% CI, 1.05-1.21) of increase in the risk for increase in/persistently high baPWV. Discordant high RC was associated with a 13.65 cm/s increase in baPWV change and 19% (95% CI, 1.06-1.33) of increase in the risk for increase in/persistently high baPWV compared to those with concordant group. CONCLUSION Discordantly high RC with LDL-C was associated with an increased risk of arterial stiffness progression. The findings demonstrated that RC may be an important marker of future coronary artery disease risk.
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Affiliation(s)
- Shouling Wu
- Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China
| | - Xin Su
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China
| | - Yingting Zuo
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shuohua Chen
- Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China
| | - Xue Tian
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qin Xu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yijun Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Penglian Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yan He
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China; Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China.
| | - Anxin Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China; Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China.
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13
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Zhu X, Zhao Y, Li L, Liu J, Huang Q, Wang S, Shu Y. Association of non-HDL-C and depression: a cross-sectional analysis of the NHANES data. Front Psychiatry 2023; 14:1274648. [PMID: 37928909 PMCID: PMC10623352 DOI: 10.3389/fpsyt.2023.1274648] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/26/2023] [Indexed: 11/07/2023] Open
Abstract
Objectives Non-high-density lipoprotein cholesterol (non-HDL-C) has attracted attention because it is associated with a variety of diseases and is easy to measure. However, the relationship between non-HDL-C and depression is still unclear. Our aim was to assess the relationship between non-HDL-C and depression using the cross-sectional NHANES survey from 2005 to 2018. Methods We examined the association between non-HDL-C and depression using weighted multivariable logistic regression models and subgroup analysis. Sensitivity analysis demonstrated the robustness of the results. Results There were 42,143 participants in this study and 8.6% had depression (weighted 7.53%). Non-HDL-C was higher in participants with depression compared to those without depression (weighted mean 3.64 vs. 3.73, p < 0.01). There was a positive association between non-HDL-C and depression with a 95% OR of 1.22 adjusted for multifactorial (95% CI,1.03-1.45). In subgroup analyses, non-HDL-C was positively associated with depression in men (OR, 1.31; 95% CI, 1.01-1.70), normal BMI (OR: 0.93; 95% CI: 0.66-1.32) and in participants without hypertension (OR, 1.29; 95% CI, 1.01-1.66). Conclusion Non-HDL-C positively correlated with depression, and further research may be better for clinical service.
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Affiliation(s)
- Xianlin Zhu
- Department of Clinical Psychology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yiwen Zhao
- Department of Psychiatry, Linhai Kangning Hospital, Linhai, China
| | - Lu Li
- Department of Psychiatry, Linhai Kangning Hospital, Linhai, China
| | - Jiaoying Liu
- Graduate School of Zunyi Medical University, Zunyi Medical University, Zunyi, China
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guivang, China
| | - Qiankun Huang
- Department of Psychology, Yichang Mental Health Center, Yichang, China
| | - Suhong Wang
- Department of Clinical Psychology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yanping Shu
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guivang, China
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14
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Wang B, Liang B, Huang Y, Li Z, Zhang B, Du J, Ye R, Xian H, Deng Y, Xiu J, Yang X, Ichihara S, Ichihara G, Zhong Y, Huang Z. Long-Chain Acyl Carnitines Aggravate Polystyrene Nanoplastics-Induced Atherosclerosis by Upregulating MARCO. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205876. [PMID: 37144527 PMCID: PMC10323628 DOI: 10.1002/advs.202205876] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 04/10/2023] [Indexed: 05/06/2023]
Abstract
Exposure to micro- and nanoplastics (MNPs) is common because of their omnipresence in environment. Recent studies have revealed that MNPs may cause atherosclerosis, but the underlying mechanism remains unclear. To address this bottleneck, ApoE-/- mice are exposed to 2.5-250 mg kg-1 polystyrene nanoplastics (PS-NPs, 50 nm) by oral gavage with a high-fat diet for 19 weeks. It is found that PS-NPs in blood and aorta of mouse exacerbate the artery stiffness and promote atherosclerotic plaque formation. PS-NPs activate phagocytosis of M1-macrophage in the aorta, manifesting as upregulation of macrophage receptor with collagenous structure (MARCO). Moreover, PS-NPs disrupt lipid metabolism and increase long-chain acyl carnitines (LCACs). LCAC accumulation is attributed to the PS-NP-inhibited hepatic carnitine palmitoyltransferase 2. PS-NPs, as well as LCACs alone, aggravate lipid accumulation via upregulating MARCO in the oxidized low-density lipoprotein-activated foam cells. Finally, synergistic effects of PS-NPs and LCACs on increasing total cholesterol in foam cells are found. Overall, this study indicates that LCACs aggravate PS-NP-induced atherosclerosis by upregulating MARCO. This study offers new insight into the mechanisms underlying MNP-induced cardiovascular toxicity, and highlights the combined effects of MNPs with endogenous metabolites on the cardiovascular system, which warrant further study.
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Affiliation(s)
- Bo Wang
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Boxuan Liang
- Affiliated Dongguan People's HospitalSouthern Medical UniversityDongguan523059China
| | - Yuji Huang
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Zhiming Li
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Bingli Zhang
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Jiaxin Du
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Rongyi Ye
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Hongyi Xian
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Yanhong Deng
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Jiancheng Xiu
- State Key Laboratory of Organ Failure ResearchDepartment of CardiologyNanfang HospitalSouthern Medical UniversityGuangzhou510515China
| | - Xingfen Yang
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Sahoko Ichihara
- Department of Environmental and Preventive MedicineSchool of MedicineJichi Medical UniversityTochigi329‐0498Japan
| | - Gaku Ichihara
- Department of Occupational and Environmental HealthFaculty of Pharmaceutical SciencesTokyo University of ScienceNoda278‐8510Japan
| | - Yizhou Zhong
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
| | - Zhenlie Huang
- NMPA Key Laboratory for Safety Evaluation of CosmeticsGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou510515China
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German CA, Liao JK. Understanding the molecular mechanisms of statin pleiotropic effects. Arch Toxicol 2023; 97:1529-1545. [PMID: 37084080 PMCID: PMC10119541 DOI: 10.1007/s00204-023-03492-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023]
Abstract
Statins represent the cornerstone of pharmacotherapy for the prevention of atherosclerotic cardiovascular disease. These medications not only reduce low-density lipoprotein cholesterol (LDL-C) via inhibition of 3-hydroxy-3-methylglutarate attached to CoA reductase, the key rate-limiting step in the cholesterol biosynthetic pathway, but also upregulate expression of the low-density lipoprotein receptor, improving serum clearance. Given LDL-C is a causal risk factor for the development of atherosclerosis, these complementary mechanisms largely explain why statin therapy leads to reductions in major adverse cardiovascular events. However, decades of basic and clinical research have suggested that statins may exert other effects independent of LDL-C lowering, termed pleiotropic effects, which have become a topic of debate among the scientific community. While some literature suggests statins may improve plaque stability, reduce inflammation and thrombosis, decrease oxidative stress, and improve endothelial function and vascular tone, other studies have suggested potential harmful pleiotropic effects related to increased risk of muscle-related side effects, diabetes, hemorrhagic stroke, and cognitive decline. Furthermore, the introduction of newer, non-statin LDL-C lowering therapies, including ezetimibe, proprotein convertase subtilisin/Kexin Type 9, and bempedoic acid, have challenged the statin pleiotropy theory. This review aims to provide a historical background on the development of statins, explore the mechanistic underpinnings of statin pleiotropy, review the available literature, and provide up to date examples that suggest statins may exert effects outside of LDL-C lowering and the cardiovascular system.
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Affiliation(s)
- Charles A German
- Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.
| | - James K Liao
- Department of Medicine, University of Arizona, Tucson, AZ, USA
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Caiati C, Stanca A, Lepera ME. Free Radicals and Obesity-Related Chronic Inflammation Contrasted by Antioxidants: A New Perspective in Coronary Artery Disease. Metabolites 2023; 13:712. [PMID: 37367870 PMCID: PMC10302379 DOI: 10.3390/metabo13060712] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/28/2023] [Accepted: 05/29/2023] [Indexed: 06/28/2023] Open
Abstract
We are surrounded by factors called free radicals (FR), which attach to the molecules our body is made of, first among them the endothelium. Even though FR are to a certain extent a normal factor, nowadays we face an escalating increase in these biologically aggressive molecules. The escalating formation of FR is linked to the increased usage of man-made chemicals for personal care (toothpaste, shampoo, bubble bath, etc.), domestic laundry and dish-washer detergents, and also an ever wider usage of drugs (both prescription and over the counter), especially if they are to be used long-term (years). In addition, tobacco smoking, processed foods, pesticides, various chronic infectious microbes, nutritional deficiencies, lack of sun exposure, and, finally, with a markedly increasing impact, electromagnetic pollution (a terribly destructive factor), can increase the risk of cancer, as well as endothelial dysfunction, owing to the increased production of FR that they cause. All these factors create endothelial damage, but the organism may be able to repair such damage thanks to the intervention of the immune system supported by antioxidants. However, one other factor can perpetuate the state of inflammation, namely obesity and metabolic syndrome with associated hyperinsulinemia. In this review, the role of FR, with a special emphasis on their origin, and of antioxidants, is explored from the perspective of their role in causing atherosclerosis, in particular at the coronary level.
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Affiliation(s)
- Carlo Caiati
- Unit of Cardiovascular Diseases, Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.S.); (M.E.L.)
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Li H, Miao S, Chen L, Liu B, Li YB, Duan RS. Association and mediating mechanism between remnant cholesterol and first-ever stroke among the Chinese general population. Front Neurosci 2023; 17:1161367. [PMID: 37304024 PMCID: PMC10247974 DOI: 10.3389/fnins.2023.1161367] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/13/2023] [Indexed: 06/13/2023] Open
Abstract
Background Remnant cholesterol (RC) has been suggested to be implicated in atherosclerosis. The objective of the study was to evaluate the association between RC and first-ever stroke in the Chinese general population and to investigate whether the association is mediated via hypertension or diabetes. Methods This study is a retrospective cohort analysis of participants from the China Health and Nutrition Survey. Participants without previous stroke and myocardial infarction in 2009 were enrolled and followed up in 2011 and 2015. Logistic regression analyses were adopted to explore the association of RC with stroke risk. Propensity score methods and doubly robust estimation method were used to ensure the robustness of our findings. Potential mediators were identified by mediation analyses. Results A total of 7,035 participants were involved, and during 6 years of follow-up, 78 (1.1%) participants experienced a first-ever stroke. Participants with high RC had a significantly higher incidence of stroke (1.4% versus 0.8%; p = 0.007). High RC was associated with 74% higher stroke risk after adjusting for multiple relevant variables (odds ratio [OR], 1.74; 95% CI, 1.06-2.85). The association was consistent in analyses using propensity score methods and doubly robust estimation method. Hypertension showed a significant mediating effect on the association between RC and stroke, while the mediating effect of diabetes was not significant. Conclusion High RC increased the risk of first-ever stroke in the Chinese general population without previous stroke and myocardial infarction, partially through the pathway of hypertension. RC might be a potential target for the primary prevention of stroke.
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Affiliation(s)
- Heng Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Shuai Miao
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lu Chen
- Department of Neurology, ZiBo Central Hospital, Zibo, China
| | - Bin Liu
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
- Shandong Institute of Neuroimmunology, Jinan, China
| | - Yan-Bin Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
- Shandong Institute of Neuroimmunology, Jinan, China
| | - Rui-Sheng Duan
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
- Shandong Institute of Neuroimmunology, Jinan, China
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Wang Y, Shen R. Association of remnant cholesterol with depression among US adults. BMC Psychiatry 2023; 23:259. [PMID: 37069633 PMCID: PMC10108798 DOI: 10.1186/s12888-023-04770-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/11/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND Remnant cholesterol is receiving increasing attention because of its association with various diseases. However, there have been no studies on remnant cholesterol levels and depression. METHODS A cross-sectional analysis was performed based on the National Health and Nutrition Examination Survey (NHANES) 2005-2016. Depression was assessed using a Patient Health Questionnaire (PHQ-9). Fasting remnant cholesterol was calculated as the total cholesterol minus high-density lipoprotein cholesterol (HDL-C) minus low-density lipoprotein cholesterol (LDL-C). Logistic regression analysis with sampling weights was used to examine the association between remnant cholesterol concentration and depression. RESULTS Among 8,263 adults enrolled in this study (weighted mean age, 45.65 years), 5.88% (weighted percentage) had depression. Compared to the participants without depression, those with depression had higher concentration of remnant cholesterol (weighted mean, 26.13 vs. 23.05, P < 0.001). There was a significant positive relationship between remnant cholesterol concentration and depression and multivariable-adjusted OR with 95% CI was 1.49 (1.02-2.17). Among the subgroup analyses, remnant cholesterol concentration was positively associated with depression among participants less than 60 years (OR, 1.62; 95% CI, 1.09-2.42), male (OR, 2.02; 95% CI, 1.01-4.05), BMI under 30 (OR, 1.83; 95% CI, 1.14-2.96), and those with diabetes (OR, 3.88; 95% CI, 1.43-10.49). CONCLUSIONS Remnant cholesterol concentration positively correlated with depression, suggesting that a focus on remnant cholesterol may be useful in the study of depression.
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Affiliation(s)
- Yang Wang
- Department of Cardiovascular Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Ruhua Shen
- Department of Cardiovascular Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, 230001, China.
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19
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Karpouzas GA, Papotti B, Ormseth SR, Palumbo M, Hernandez E, Marchi C, Zimetti F, Budoff MJ, Ronda N. Serum cholesterol loading capacity of macrophages is regulated by seropositivity and C-reactive protein in rheumatoid arthritis patients. Rheumatology (Oxford) 2023; 62:1254-1263. [PMID: 35809057 DOI: 10.1093/rheumatology/keac394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages. METHODS In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. RESULTS OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)]. CONCLUSION Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.
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Affiliation(s)
- George A Karpouzas
- Division of Rheumatology, Harbor-UCLA Medical Center, The Lundquist Institute, Torrance, CA, USA
| | - Bianca Papotti
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Sarah R Ormseth
- Division of Rheumatology, Harbor-UCLA Medical Center, The Lundquist Institute, Torrance, CA, USA
| | | | - Elizabeth Hernandez
- Division of Rheumatology, Harbor-UCLA Medical Center, The Lundquist Institute, Torrance, CA, USA
| | - Cinzia Marchi
- Department of Food and Drug, University of Parma, Parma, Italy
| | | | - Matthew J Budoff
- Division of Cardiology, Harbor-UCLA Medical Center and The Lundquist Institute, Torrance, CA, USA
| | - Nicoletta Ronda
- Department of Food and Drug, University of Parma, Parma, Italy
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20
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Wu Z, Wang J, Zhang H, Pan H, Li Z, Liu Y, Miao X, Han Z, Kang X, Li X, Guo X, Tao L, Wang W. Longitudinal association of remnant cholesterol with joint arteriosclerosis and atherosclerosis progression beyond LDL cholesterol. BMC Med 2023; 21:42. [PMID: 36747220 PMCID: PMC9903550 DOI: 10.1186/s12916-023-02733-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 01/11/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Arteriosclerosis and atherosclerosis are closely related with cardiovascular disease (CVD) risk. Remnant cholesterol (RC) could predict CVD. However, its effect on joint arteriosclerosis and atherosclerosis progression remains unclear. This study aims to evaluate the association of RC with joint arteriosclerosis and atherosclerosis progression trajectories in the general population. METHODS This study collected data across five biennial surveys of the Beijing Health Management Cohort from 2010 to 2019. Multi-trajectory model was used to determine the joint arteriosclerosis and atherosclerosis progression patterns by brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). We also performed discordance analyses for RC vs. low density lipoprotein cholesterol (LDL-C) using ordinal logistics model. RESULTS A total of 3186 participants were included, with three clusters following distinct arteriosclerosis and atherosclerosis progression patterns identified using a multi-trajectory model. In the multivariable-adjusted ordinal logistics analyses, RC was significantly associated with baPWV and ABI progression (OR: 1.20; 95% CI: 1.13-1.28, per 10 mg/dL). For the discordance analyses, the discordant low RC group was associated with decreased risk compared to the concordant group (OR: 0.73; 95% CI: 0.60-0.89). People with a high RC level were at an increased risk of joint arteriosclerosis and atherosclerosis progression, even with optimal LDL-C. CONCLUSIONS RC is independently associated with joint arteriosclerosis and atherosclerosis progression beyond LDL-C. RC could be an earlier risk factor than LDL-C of arteriosclerosis and atherosclerosis in the general population.
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Affiliation(s)
- Zhiyuan Wu
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China.,Centre for Precision Health, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia
| | - Jinqi Wang
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Haiping Zhang
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Huiying Pan
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Zhiwei Li
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Yue Liu
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Xinlei Miao
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | - Ze Han
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China
| | | | - Xia Li
- Department of Mathematics and Statistics, La Trobe University, Melbourne, Australia
| | - Xiuhua Guo
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China. .,Centre for Precision Health, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia.
| | - Lixin Tao
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmen Street, Beijing, 100069, China.
| | - Wei Wang
- Centre for Precision Health, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia.
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21
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Song Y, Yang J, Zhao Q, Bai Y, Ruan L. Remnant Cholesterol and Common Carotid Artery Intima-Media Thickness in Community Population with Normal Low-Density Lipoprotein Cholesterol. Cerebrovasc Dis 2023; 52:487-494. [PMID: 36746129 DOI: 10.1159/000527704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 10/07/2022] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Remnant cholesterol is a risk factor for cardiovascular disease, especially when low-density lipoprotein cholesterol (LDL-C) levels are normal. However, there are few studies on the relationship between remnant cholesterol and subclinical atherosclerosis. Common carotid artery intima-media thickness (cIMT) is an imaging marker of subclinical atherosclerosis. This study aimed to investigate the relationship between remnant cholesterol and cIMT in a community population with normal LDL-C. METHODS This study is a retrospective analysis; 1,101 community population with available carotid artery imaging and fasting lipid data with LDL-C <4.1 mmol/L were included in this analysis. Remnant cholesterol was calculated as total cholesterol minus LDL-C minus high-density lipoprotein cholesterol. Abnormal cIMT was defined as maximum cIMT value ≥1 mm. Logistic regression was used to assess the relationships between remnant cholesterol levels and abnormal cIMT. RESULTS As the remnant cholesterol level increased from the lowest to the highest quartile, the rate of abnormal cIMT increased from 24.5% to 38.6% (p trend <0.001) in the community population with normal LDL-C level. In the unadjusted model, the odds ratios (ORs, 95% confidence intervals) in the highest quartile group were 1.937 (1.338-2.803) for abnormal cIMT compared with the lowest quartile. The multivariable-adjusted ORs (95% confidence intervals) for the highest versus lowest quartile of remnant cholesterol were 2.132 (1.420-3.202) for abnormal cIMT. CONCLUSION Elevated fasting remnant cholesterol levels were positively associated with abnormal cIMT in community population with normal LDL-C levels. Remnant cholesterol may be an important indicator of risk stratification in community population with normal LDL-C level.
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Affiliation(s)
- Yan Song
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jinru Yang
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiaoling Zhao
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yunfei Bai
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Litao Ruan
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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22
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Tian Y, Wu W, Qin L, Yu X, Cai L, Wang H, Zhang Z. Prognostic value of remnant cholesterol in patients with coronary heart disease: A systematic review and meta-analysis of cohort studies. Front Cardiovasc Med 2023; 9:951523. [PMID: 36741830 PMCID: PMC9892060 DOI: 10.3389/fcvm.2022.951523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 12/30/2022] [Indexed: 01/20/2023] Open
Abstract
Background The relationship between abnormal lipid levels and atherosclerotic cardiovascular diseases is well established, but the association between remnant cholesterol (RC) and coronary heart disease (CHD) remains uncertain. The aim of this meta-analysis is to systematically evaluate the prognostic value of RC concentration in patients with CHD. Methods PubMed, EMBASE, Cochrane, and Web of Science databases were reviewed to identify relevant observational cohort studies published in English up to December 2021. Random-effects meta-analysis compared the highest and lowest RC concentration. The primary outcome was a composite of major adverse cardiovascular events (MACEs) and all-cause mortality in patients with CHD. Results A total of 10 studies recruiting 30,605 patients with CHD were selected to be included in this meta-analysis. Patients with CHD with elevated RC concentration had an increased risk of the composite endpoint events (RR = 1.54, 95% CI: 1.26-1.87) and MACEs (RR = 1.70, 95% CI: 1.54-1.88), but the risk of all-cause mortality was not statistically significant (RR = 1.16, 95% CI: 0.79-1.69, P = 0.44). Subgroup analysis showed consistent results. Conclusion Our results suggest that elevated concentration RC may independently predict MACEs in patients with CHD. Determination of RC concentration may improve risk stratification of prognosis in patients with CHD. However, more high-quality studies are necessary to confirm this association.
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23
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Zheng X, Jiang M, Ren X, Han L. The longitudinal association of remnant cholesterol with diabetes in middle-aged and elderly Chinese: A nationwide population-based cohort study. J Diabetes Complications 2023; 37:108360. [PMID: 36459863 DOI: 10.1016/j.jdiacomp.2022.108360] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND AIMS The association between remnant cholesterol (RC) and diabetes remains unclear in Chinese. METHODS AND RESULTS We used the data of 9464 Chinese adults aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS). Estimated RC level was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol. Cox proportional hazard models and restricted cubic spline models were used to assess the relationships between RC and diabetes. RESULTS After 6 years of follow-up, a total of 777 respondents experienced new-onset diabetes. In multivariable-adjusted analyses, the adjusted hazard ratios (95 % confidence intervals) for the highest versus lowest quartile of RC was 1.45 (1.19-1.75) for risk of diabetes, and each 1-SD increase of RC (19.52 mg/dl) was associated with 9 % (HRs = 1.09; 1.03-1.15) increased risk of diabetes. There were also significant linear associations between RC level and diabetes (P for linearity <0.001). CONCLUSION Elevated RC levels were positively associated with increased risk of diabetes in Chinese adult population, suggesting that RC could be considered as a preferential predictor and treatment target of diabetes in Chinese population. Future prospective studies are needed to verify our findings and to assess the effect of RC-lowering interventions in diabetes prevention.
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Affiliation(s)
- Xiaowei Zheng
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Minglan Jiang
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xiao Ren
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Longyang Han
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
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24
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Zheng X, Han L, Shen S. Hypertension, remnant cholesterol and cardiovascular disease: evidence from the China health and retirement longitudinal study. J Hypertens 2022; 40:2292-2298. [PMID: 35950988 DOI: 10.1097/hjh.0000000000003259] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Previous studies had reported the significant association between hypertension, remnant cholesterol (RC) and risk of cardiovascular disease (CVD). The aim of present study was to evaluate the combined effect of hypertension and RC on the risk of CVD. METHODS A total of 9456 participants from the China Health and Retirement Longitudinal Study were included. Multivariate Cox proportional hazards regression model was used to explore the associations between hypertension, RC and new-onset CVD, stroke and cardiac events. RESULTS During the follow-up period, 1702 CVD events (including 563 stroke and 1282 cardiac events) were recorded. Compared to those without hypertension and low RC level, the adjusted hazard ratios (95% confidence intervals) were 1.09 (0.95-1.24) for individuals with high RC alone, 1.27 (1.10-1.46) for individuals with hypertension alone and 1.32 (1.15-1.51) for individuals with comorbid hypertension and high RC. Individuals with co-existence of hypertension and high RC also had the highest risks of stroke and cardiac events. CONCLUSION Our study indicated that there was a combined effect of hypertension and RC on the risk of CVD, stroke and cardiac events. Larger-sample prospective cohort studies are still required to test the potential application of combination of hypertension and RC as a screening method to identify individuals at risk of CVD.
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Affiliation(s)
- Xiaowei Zheng
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine Jiangnan University
| | - Longyang Han
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine Jiangnan University
| | - Suwen Shen
- Wuxi Municipal Center for Disease Control and Prevention, Wuxi, Jiangsu, China
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25
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Tan L, Lu J, Zhang C, Meng L, Zhu Q. The proatherosclerotic function of BCAT1 in atherosclerosis development of aged-apolipoprotein E-deficient mice. Biochem Biophys Res Commun 2022; 631:93-101. [DOI: 10.1016/j.bbrc.2022.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/10/2022] [Indexed: 11/29/2022]
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Zhang K, Qi X, Zhu F, Dong Q, Gou Z, Wang F, Xiao L, Li M, Chen L, Wang Y, Zhang H, Sheng Y, Kong X. Remnant cholesterol is associated with cardiovascular mortality. Front Cardiovasc Med 2022; 9:984711. [PMID: 36204586 PMCID: PMC9530659 DOI: 10.3389/fcvm.2022.984711] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Genetic, observational, and clinical intervention studies indicate that circulating levels of remnant cholesterol (RC) are associated with cardiovascular diseases. However, the predictive value of RC for cardiovascular mortality in the general population remains unclear. METHODS Our study population comprised 19,650 adults in the United States from the National Health and Nutrition Examination Survey (NHANES) (1999-2014). RC was calculated from non-high-density lipoprotein cholesterol (non-HDL-C) minus low-density lipoprotein cholesterol (LDL-C) determined by the Sampson formula. Multivariate Cox regression, restricted cubic spline analysis, and subgroup analysis were applied to explore the relationship of RC with cardiovascular mortality. RESULTS The mean age of the study cohort was 46.4 ± 19.2 years, and 48.7% of participants were male. During a median follow-up of 93 months, 382 (1.9%) cardiovascular deaths occurred. In a fully adjusted Cox regression model, log RC was significantly associated with cardiovascular mortality [hazard ratio (HR) 2.82; 95% confidence interval (CI) 1.17-6.81]. The restricted cubic spline curve indicated that log RC had a linear association with cardiovascular mortality (p for non-linearity = 0.899). People with higher LDL-C (≥130 mg/dL), higher RC [≥25.7/23.7 mg/dL in males/females corresponding to the LDL-C clinical cutoff point (130 mg/dL)] and abnormal HDL-C (<40/50 mg/dL in males/females) levels had a higher risk of cardiovascular mortality (HR 2.18; 95% CI 1.13-4.21 in males and HR 2.19; 95% CI 1.24-3.88 in females) than the reference group (lower LDL-C, lower RC and normal HDL-C levels). CONCLUSIONS Elevated RC levels were associated with cardiovascular mortality independent of traditional risk factors.
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Affiliation(s)
- Kerui Zhang
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Xiangyun Qi
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Fuyu Zhu
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Quanbin Dong
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Zhongshan Gou
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Fang Wang
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Li Xiao
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Menghuan Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Lianmin Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yifeng Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Haifeng Zhang
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Yanhui Sheng
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Xiangqing Kong
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
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Karpouzas GA, Papotti B, Ormseth S, Palumbo M, Hernandez E, Adorni MP, Zimetti F, Budoff M, Ronda N. Serum cholesterol loading capacity on macrophages is linked to coronary atherosclerosis and cardiovascular event risk in rheumatoid arthritis. RMD Open 2022; 8:rmdopen-2022-002411. [PMID: 36113961 PMCID: PMC9486392 DOI: 10.1136/rmdopen-2022-002411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 08/03/2022] [Indexed: 11/05/2022] Open
Abstract
Objectives Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA). Methods Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum. Results CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users. Conclusion CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.
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Affiliation(s)
- George Athanasios Karpouzas
- Internal Medicine-Rheumatology, Lundquist Institute, Torrance, California, USA .,Department of Rheumatology, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Bianca Papotti
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Sarah Ormseth
- Internal Medicine-Rheumatology, Lundquist Institute, Torrance, California, USA
| | | | | | | | - Francesca Zimetti
- Department of Pharmacy, University of Parma, Parma, Emilia-Romagna, Italy
| | - Matthew Budoff
- Internal Medicine, Lundquist Institute, Torrance, California, USA
| | - Nicoletta Ronda
- Department of Pharmacy, University of Parma, Parma, Emilia-Romagna, Italy
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Fu L, Tai S, Sun J, Zhang N, Zhou Y, Xing Z, Wang Y, Zhou S. Remnant Cholesterol and Its Visit-to-Visit Variability Predict Cardiovascular Outcomes in Patients With Type 2 Diabetes: Findings From the ACCORD Cohort. Diabetes Care 2022; 45:2136-2143. [PMID: 35834242 PMCID: PMC9472497 DOI: 10.2337/dc21-2511] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 05/31/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Remnant cholesterol (remnant-C) predicts atherosclerotic cardiovascular disease, regardless of LDL-cholesterol (LDL-C) levels. This study assessed the associations between remnant-C and cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS This post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial used patient (type 2 diabetes >3 months) remnant-C and major adverse cardiovascular event (MACE) data from the study database. The associations between remnant-C and MACEs were evaluated using Cox proportional hazards regression analyses. We examined the relative MACE risk in remnant-C versus LDL-C discordant/concordant groups using clinically relevant LDL-C targets by discordance analyses. RESULTS The baseline analysis included 10,196 participants, with further visit-to-visit variability analysis including 9,650 participants. During follow-up (median, 8.8 years), 1,815 patients (17.8%) developed MACEs. After adjusting for traditional cardiovascular risk factors, each 1-SD increase in remnant-C was associated with a 7% higher MACE risk (hazard ratio [HR] 1.07, 95% CI 1.02-1.12, P = 0.004). In the fully adjusted model, the visit-to-visit remnant-C variability calculated using logSD (HR 1.41, 95% CI 1.18-1.69, P < 0.001) and logARV (HR 1.45, 95% CI 1.22-1.73, P < 0.001) was associated with MACEs. Residual lipid risk (remnant-C ≥31 mg/dL) recognized individuals at a higher MACE risk, regardless of LDL-C concentrations. Within each LDL-C subgroup (>100 or ≤100 mg/dL), high baseline remnant-C was associated with a higher MACE risk (HR 1.37, 95% CI 1.09-1.73, P = 0.007; HR 1.22, 95% CI 1.04-1.41, P = 0.015, respectively). CONCLUSIONS Remnant-C levels were associated with MACEs in patients with type 2 diabetes independent of LDL-C, and visit-to-visit remnant-C variability helped identify those with higher cardiovascular risk.
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Affiliation(s)
- Liyao Fu
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shi Tai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jiaxing Sun
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ningjie Zhang
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ying Zhou
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhenhua Xing
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yongjun Wang
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shenghua Zhou
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
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Hsa_circ_0007478 aggravates NLRP3 inflammasome activation and lipid metabolism imbalance in ox-LDL-stimulated macrophage via miR-765/EFNA3 axis. Chem Biol Interact 2022; 368:110195. [DOI: 10.1016/j.cbi.2022.110195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 11/20/2022]
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Wasim R, Ansari TM, Ahsan F, Siddiqui MH, Singh A, Shariq M, Parveen S. Pleiotropic Benefits of Statins in Cardiovascular Diseases. Drug Res (Stuttg) 2022; 72:477-486. [PMID: 35868336 DOI: 10.1055/a-1873-1978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In 1976, Japanese microbiologist Akira Endo discovered the first statin as a product of the fungus Penicillium citrinum that inhibited the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Their primary mode of action is to lower the blood cholesterol by decreasing hepatic cholesterol production, which upregulates hepatic low-density lipoprotein (LDL) receptors and increases LDL-cholesterol clearance. In addition to cholesterol lowering, statins inhibit other downstream products of the mevalonate pathway, causing the so-called pleiotropic effects. As a result of their pleiotropic effects statins modulate virtually all known processes of atherosclerosis and have beneficial effects outside the cardiovascular system Statins inhibit the post-translational prenylation of small GTP-binding proteins such as Rho, Rac, as well as their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases since they suppress the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway altering the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, production of proinflammatory cytokines, reactive oxygen species, platelet reactivity, development of cardiac hypertrophy and fibrosis in cell culture and animal experiments. Inhibition of Rho and Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. However, the relative contributions of statin pleiotropy to clinical outcomes are debatable and difficult to measure because the amount of isoprenoid inhibition by statins corresponds to some extent with the amount of LDL-cholesterol decrease. This article examines some of the existing molecular explanations underlying statin pleiotropy and discusses if they have clinical relevance in cardiovascular diseases.
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Affiliation(s)
- Rufaida Wasim
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | | | - Farogh Ahsan
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | | | - Aditya Singh
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Mohammad Shariq
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Saba Parveen
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
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Yang Z, Yang K, Shi J, Yang Q, Zhang Y, Gao J, Shi D, Qu H. The Association Between Remnant Cholesterol and the Estimated 10-Year Risk of a First Hard Cardiovascular Event. Front Cardiovasc Med 2022; 9:913977. [PMID: 35783820 PMCID: PMC9247399 DOI: 10.3389/fcvm.2022.913977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundRemnant cholesterol (Remnant-C), rather than TG, is believed to increase the risk of atherosclerotic cardiovascular disease. We evaluated whether Remnant-C is associated with an estimated 10-year risk of a first hard atherosclerotic cardiovascular disease event.MethodsThis cross-sectional study was performed on 2,048 participants (1,130 men and 918 women), aged 40 to 79 years, from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. The independent variable was Remnant-C; the dependent variable was the 10-year risk of a first hard atherosclerotic cardiovascular disease event (defined as non-fatal myocardial infarction, coronary heart disease death, or stroke, over a 10-year period among people free from atherosclerotic cardiovascular disease at the beginning of the period). The other variables, such as smoking behavior, hypertension, diabetes etc., were considered as the potential effect modifiers. Multivariate linear regression models and smooth curve fittings were used to evaluate the association between Remnant-C and the 10-year risk of a first hard atherosclerotic cardiovascular disease event. Subgroup analyses stratified by gender and race were also performed.ResultsA positive association between Remnant-C and the 10-year risk of a first hard atherosclerotic cardiovascular disease event was demonstrated in the fully adjusted model (β = 0.078, [95%CI: 0.061–0.094], P < 0.001). The 10-year risk was increased by 0.078% for each 1 mg/dl increase in Remnant-C. In the subgroup analysis for gender, this association remained in both men (β = 0.128, [95%CI: 0.108–0.148], P < 0.001) and women (β = 0.043, [95%CI: 0.016–0.070], P = 0.00179). However, in the subgroup analysis for race, the association between Remnant-C and the 10-year risk reached an inflection point at remnant-C 38 mg/dL, where a positive association was not as obvious for the non-Hispanic Black population as for other racial groups.ConclusionsRemnant-C positively correlates with a 10-year risk of a first hard atherosclerotic cardiovascular disease event.
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Affiliation(s)
- Zhen Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Cardiovascular Department, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
- Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Kuo Yang
- School of Computer and Information Technology, Beijing Jiaotong University, Beijing, China
| | - Junhe Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
- National Medical Products Administration, Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Beijing, China
| | - Qiaoning Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
- National Medical Products Administration, Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Beijing, China
| | - Ying Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dazhuo Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Cardiovascular Department, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
- Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
- *Correspondence: Dazhuo Shi
| | - Hua Qu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
- National Medical Products Administration, Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Beijing, China
- Hua Qu
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Wang W, Zhang J, Li Z, Gu J, Qin J, Li J, Zhang X, Ru S. Bisphenol S exposure accelerates the progression of atherosclerosis in zebrafish embryo-larvae. JOURNAL OF HAZARDOUS MATERIALS 2022; 426:128042. [PMID: 34942454 DOI: 10.1016/j.jhazmat.2021.128042] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/30/2021] [Accepted: 12/06/2021] [Indexed: 06/14/2023]
Abstract
Bisphenol S (BPS), widely utilized in manufacturing of daily necessities, is a toxicant with potential to induce atherosclerotic cardiovascular disease (ASCVD). However, the mode of action by which BPS exposure induces ASCVD remains unknown. Here, macrophages that were exposed to BPS in combination with oxidized low-density lipoprotein (oxLDL) exhibited enhanced formation of foam cells, a hallmark of ASCVD. Furthermore, zebrafish embryo-larvae were exposed to BPS (0, 1, 10 and 100 μg/L) for 15 days (d) and the characteristic symptoms of ASCVD including an inflammatory response, macrophage recruitment around blood vessels, and accumulation of oxLDL on vascular endothelium, were induced in 15-d larvae. After zebrafish were exposed to BPS for 45 d, BPS mobilized fatty acid metabolism and activated peroxisome proliferator-activated receptor signaling in larval liver, the hub of endogenous lipid metabolism, causing an increase in plasma LDL. Driven by high plasma LDL levels, the caudal artery of zebrafish larvae exhibited lipid accumulation and a thickened area with a large number of collagen fibers, accompanied by characteristic lesions, as well as hyperlipidemia, erythrocyte aggregation, thinner blood vessel walls and increased levels of leukocytes and thromboocytes in plasma. Our data demonstrate that BPS accelerates the progression of ASCVD using zebrafish embryo-larvae as a model.
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Affiliation(s)
- Weiwei Wang
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China
| | - Jie Zhang
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China
| | - Ze Li
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China
| | - Jie Gu
- Nanjing Institute of Environmental Sciences, Nanjing 210000, China
| | - Jingyu Qin
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China
| | - Jiali Li
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China
| | - Xiaona Zhang
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
| | - Shaoguo Ru
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
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Hussain A, Sun C, Selvin E, Nambi V, Coresh J, Jia X, Ballantyne CM, Hoogeveen RC. Triglyceride-rich lipoproteins, apolipoprotein C-III, angiopoietin-like protein 3, and cardiovascular events in older adults: Atherosclerosis Risk in Communities (ARIC) study. Eur J Prev Cardiol 2022; 29:e53-e64. [PMID: 33580780 PMCID: PMC8277878 DOI: 10.1093/eurjpc/zwaa152] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/03/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022]
Abstract
AIMS Despite statin and antihypertensive therapies, older Americans have high atherosclerotic cardiovascular disease (ASCVD) risk. Novel measures of triglyceride-rich lipoproteins, low-density lipoprotein triglycerides (LDL-TG), and remnant-like particle cholesterol (RLP-C), are associated with ASCVD in middle-aged adults. Polymorphisms in genes encoding angiopoietin-related protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III), two proteins involved in triglyceride catabolism, are associated with increased risk for hypertriglyceridaemia and ASCVD and are potential therapeutic targets. We examined associations of LDL-TG, RLP-C, apoC-III, and ANGPTL3 levels with ASCVD events in older adults in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS In 6359 participants (mean age 75.8 ± 5.3 years) followed for ASCVD events [coronary heart disease (CHD) or ischaemic stroke] up to 6 years, associations between LDL-TG, RLP-C, apoC-III, and ANGPTL3 and ASCVD events were assessed using Cox regression. With adjustment for age, sex, and race, RLP-C, LDL-TG, apoC-III, and ANGPTL3 (as continuous variables) were significantly associated with CHD. However, after adjustment for traditional risk factors and lipid-lowering medications, only LDL-TG and ANGPTL3 were significantly associated with ASCVD events [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.25-2.37 per log unit increase in LDL-TG; HR 1.63, 95% CI 1.17-2.28 per log unit increase in ANGPTL3]. CONCLUSIONS In older adults, LDL-TG, RLP-C, apoC-III, and ANGPTL3 were associated with CHD events in minimally adjusted models; LDL-TG and ANGPTL3 remained independent predictors of ASCVD events with further adjustment. Future studies should assess potential benefit of lowering hepatic apoC-III or ANGPTL3 expression in patients with elevated triglyceride-rich lipoproteins.
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Affiliation(s)
- Aliza Hussain
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
| | - Caroline Sun
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
| | - Elizabeth Selvin
- Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Baltimore, Maryland (MD), 21287, Baltimore, MD, USA
| | - Vijay Nambi
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, Texas (TX), 77030, USA
| | - Josef Coresh
- Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Baltimore, Maryland (MD), 21287, Baltimore, MD, USA
| | - Xiaoming Jia
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
| | - Christie M Ballantyne
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
| | - Ron C Hoogeveen
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
- Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, TX 77030, USA
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Targeting Reactive Oxygen Species in Atherosclerosis via Chinese Herbal Medicines. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1852330. [PMID: 35047104 PMCID: PMC8763505 DOI: 10.1155/2022/1852330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022]
Abstract
Cardio-cerebrovascular disease (CCVD) has become the leading cause of human mortality with the coming acceleration of global population aging. Atherosclerosis is among the most common pathological changes in CCVDs. It is also a multifactorial disorder; oxidative stress caused by excessive production of reactive oxygen species (ROS) has become an important mechanism of atherosclerosis. Chinese herbal medicine (CHM) is a major type of natural medicine that has made great contributions to human health. CHMs are increasingly used in the auxiliary clinical treatment of atherosclerosis. Although their mechanism of action is unclear, CHMs can exert a variety of antiatherosclerosis effects by regulating intracellular ROS. In this review, we discussed the mechanism of ROS regulation in atherosclerosis and analyzed the role of CHMs in the treatment of atherosclerosis via ROS.
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Lorey MB, Öörni K, Kovanen PT. Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis. Front Cardiovasc Med 2022; 9:841545. [PMID: 35310965 PMCID: PMC8927694 DOI: 10.3389/fcvm.2022.841545] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/26/2022] [Indexed: 12/15/2022] Open
Abstract
Circulating apolipoprotein B-containing lipoproteins, notably the low-density lipoproteins, enter the inner layer of the arterial wall, the intima, where a fraction of them is retained and modified by proteases, lipases, and oxidizing agents and enzymes. The modified lipoproteins and various modification products, such as fatty acids, ceramides, lysophospholipids, and oxidized lipids induce inflammatory reactions in the macrophages and the covering endothelial cells, initiating an increased leukocyte diapedesis. Lipolysis of the lipoproteins also induces the formation of cholesterol crystals with strong proinflammatory properties. Modified and aggregated lipoproteins, cholesterol crystals, and lipoproteins isolated from human atherosclerotic lesions, all can activate macrophages and thereby induce the secretion of proinflammatory cytokines, chemokines, and enzymes. The extent of lipoprotein retention, modification, and aggregation have been shown to depend largely on differences in the composition of the circulating lipoprotein particles. These properties can be modified by pharmacological means, and thereby provide opportunities for clinical interventions regarding the prevention and treatment of atherosclerotic vascular diseases.
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Affiliation(s)
- Martina B. Lorey
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Katariina Öörni
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
- *Correspondence: Katariina Öörni
| | - Petri T. Kovanen
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
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Yu D, Wang Z, Zhang X, Qu B, Cai Y, Ma S, Zhao Z, Simmons D. Remnant Cholesterol and Cardiovascular Mortality in Patients With Type 2 Diabetes and Incident Diabetic Nephropathy. J Clin Endocrinol Metab 2021; 106:3546-3554. [PMID: 34291804 DOI: 10.1210/clinem/dgab533] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT The association between remnant cholesterol (remnant-C) and cardiovascular mortality in patients with type 2 diabetes (T2D) and incident diabetic nephropathy remains unclear. OBJECTIVE To examinie the association between remnant-C and cardiovascular mortality in patients with T2D, chronic kidney disease (CKD) stages 3 to 5, and newly diagnosed DN. METHODS This study determined the baseline lipid profile and searched for deaths with cardiovascular disease (CVD) within 2 years of baseline among 2282 adults enrolled between January 1, 2015 and December 31, 2016, who had T2D, CKD stages 3 to 5, and newly diagnosed DN. Adjusted logistic regression models were used to assess the associations between lipid, especially remnant-C concentration (either as continuous or categorical variables), and risk of cardiovascular mortality. RESULTS In multivariable-adjusted analyses, low-density lipoprotein cholesterol (LDL-C) (odds ratio [OR], 1.022; 95% CI, 1.017-1.026, per 10 mg/dL), high-density lipoprotein cholesterol (HDL-C) (OR, 0.929; 95% CI, 0.922-0.936, per 5 mg/dL), non-HDL-C (OR, 1.024; 95% CI, 1.021-1.028, per 10 mg/dL), and remnant-C (OR, 1.115; 95% CI, 1.103-1.127, per 10 mg/dL), but not triglycerides were associated with cardiovascular mortality. Atherogenic dyslipidemia (triglycerides > 150 mg/dL [1.69 mmol/L] and HDL-C < 40 mg/dL in men or < 50 mg/dL in women) was also associated with cardiovascular mortality (OR, 1.073; 95% CI, 1.031-1.116). Remnant-C greater than or equal to 30 mg/dL differentiated patients at a higher risk of cardiovascular mortality from those with lower concentrations, especially with interaction with LDL-C level greater than 100 mg/dL: The highest risk was found in patients with higher levels both of remnant-C and LDL-C (OR, 1.696; 95% CI, 1.613-1.783). CONCLUSION In patients with T2D, CKD stages 3 to 5, and incident DN, remnant-C was associated with a higher risk of death with CVD. Different from the general population, the interaction of remnant-C and LDL-C was associated with the highest risk of cardiovascular mortality.
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Affiliation(s)
- Dahai Yu
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Keele ST5 5BG, UK
| | - Zheng Wang
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Xiaoxue Zhang
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Bingjie Qu
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Yamei Cai
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Shuang Ma
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - David Simmons
- Department of Nephrology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
- Macarthur Clinical School, Western Sydney University, Campbelltown, Sydney NSW 2751, Australia
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Human Angiopoietin-like Protein 3/ANGPTL3 Antibodies: Adding to the Armamentarium in the Management of Dyslipidemia. J Cardiovasc Pharmacol 2021; 78:e631-e640. [PMID: 34738550 DOI: 10.1097/fjc.0000000000001132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 08/08/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Cardiovascular (CV) disease remains the leading cause of death in the United States. In addition to lifestyle modifications, current guidelines primarily focus on lowering low-density lipoprotein cholesterol (LDL-C) to reduce atherosclerotic CV disease risk. However, despite aggressive management, a degree of residual risk remains, suggesting that focusing on lowering LDL-C alone may be inadequate and that other lipid parameters may need to be targeted. In patients who remain at high risk despite current pharmacologic options either because of inadequate response, elevated levels of other lipoproteins, or those who have genetic variants predisposing them to atherosclerotic CV disease, additional treatment strategies continue to be sought. One such group is the homozygous familial hypercholesterolemia population, especially those patients carrying the null low-density lipoprotein receptor mutation as they often fail to derive the same benefit from traditional LDL-C lower strategies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitors that work by upregulating the LDL receptor. Emerging data also suggest that patients with increased levels of triglyceride-rich lipoproteins are also at increased risk as elevated levels are proposed to have a role in various pathways promoting atherogenesis. Angiopoietin-life protein 3 (ANGLTPL3) has recently become a target of interest because of the discovery that inhibiting its action leads to reductions in lipid parameters. Although the mechanism of action of ANGLTPL3 inhibitors is independent of the LDL receptor, their ability to significantly lower triglycerides and LDL-C make them an attractive option particularly in patients with homozygous familial hypercholesterolemia and hypertriglyceridemia. The efficacy and safety of 2 ANGLTPL3 inhibitor agents have been evaluated in clinical trials. In this review, the lipid lowering, metabolic effects, and safety are reported. Ongoing trials assessing CV outcomes as well as long-term safety data are still needed to provide a more definitive role for these agents in the overall management in these populations.
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Malekmohammad K, Bezsonov EE, Rafieian-Kopaei M. Role of Lipid Accumulation and Inflammation in Atherosclerosis: Focus on Molecular and Cellular Mechanisms. Front Cardiovasc Med 2021; 8:707529. [PMID: 34552965 PMCID: PMC8450356 DOI: 10.3389/fcvm.2021.707529] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis is a chronic lipid-driven and maladaptive inflammatory disease of arterial intima. It is characterized by the dysfunction of lipid homeostasis and signaling pathways that control the inflammation. This article reviews the role of inflammation and lipid accumulation, especially low-density lipoprotein (LDL), in the pathogenesis of atherosclerosis, with more emphasis on cellular mechanisms. Furthermore, this review will briefly highlight the role of medicinal plants, long non-coding RNA (lncRNA), and microRNAs in the pathophysiology, treatment, and prevention of atherosclerosis. Lipid homeostasis at various levels, including receptor-mediated uptake, synthesis, storage, metabolism, efflux, and its impairments are important for the development of atherosclerosis. The major source of cholesterol and lipid accumulation in the arterial wall is proatherogenic modified low-density lipoprotein (mLDL). Modified lipoproteins, such as oxidized low-density lipoprotein (ox-LDL) and LDL binding with proteoglycans of the extracellular matrix in the intima of blood vessels, cause aggregation of lipoprotein particles, endothelial damage, leukocyte recruitment, foam cell formation, and inflammation. Inflammation is the key contributor to atherosclerosis and participates in all phases of atherosclerosis. Also, several studies have shown that microRNAs and lncRNAs have appeared as key regulators of several physiological and pathophysiological processes in atherosclerosis, including regulation of HDL biogenesis, cholesterol efflux, lipid metabolism, regulating of smooth muscle proliferation, and controlling of inflammation. Thus, both lipid homeostasis and the inflammatory immune response are closely linked, and their cellular and molecular pathways interact with each other.
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Affiliation(s)
| | - Evgeny E. Bezsonov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, Moscow, Russia
- Institute for Atherosclerosis Research, Moscow, Russia
- Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions. Sci Rep 2021; 11:10548. [PMID: 34006929 PMCID: PMC8131603 DOI: 10.1038/s41598-021-89981-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 05/05/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs have emerged as key regulators in vascular diseases and are involved in the formation of atherosclerotic lesions. However, the atherosclerotic-specific MicroRNAs and their functional roles in atherosclerosis are unclear. Here, we report that miR-378c protects against atherosclerosis by directly targeting Sterile Alpha Motif Domain Containing 1 (Samd1), a predicted transcriptional repressor. miR-378c was strikingly reduced in atherosclerotic plaques and blood of acute coronary syndrome (ACS) patients relative to healthy controls. Suppression of miR-378c promoted vascular smooth muscle cells (VSMCs) phenotypic transition during atherosclerosis. We also reported for the first time that Samd1 prolonged immobilization of LDL on the VSMCs, thus facilitated LDL oxidation and subsequently foam cell formation. Further, we found that Samd1 contains predicted DNA binding domain and directly binds to DNA regions as a transcriptional repressor. Together, we uncovered a novel mechanism whereby miR-378c-Samd1 circuit participates in two key elements of atherosclerosis, VSMCs phenotypic transition and LDL oxidation. Our results provided a better understanding of atherosclerosis pathophysiology and potential therapeutic management by targeting miR-378c-Samd1 circuit.
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Di Costanzo A, Perla FM, D'Erasmo L, Arca M, Chiesa C, Pacifico L. Elevated Serum Concentrations of Remnant Cholesterol Associate with Increased Carotid Intima-Media Thickness in Children and Adolescents. J Pediatr 2021; 232:133-139.e1. [PMID: 33476608 DOI: 10.1016/j.jpeds.2021.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the relationship between remnant cholesterol and carotid intima-media thickness (cIMT), a surrogate marker for atherosclerosis, in children and adolescents. STUDY DESIGN Anthropometric, laboratory, liver, and carotid ultrasonographic data were obtained from 767 youths (594, overweight/obese; 173, normal weight). Fasting remnant cholesterol was calculated from the standard lipid profile. cIMT ≥0.56 mm (corresponding to the 90th percentile of values observed in normal-weight children) was chosen to define elevated cIMT. Logistic regression analysis was used to estimate the risk of elevated cIMT according to tertiles of remnant cholesterol levels. RESULTS In the entire cohort, the mean concentration of remnant cholesterol was 17.9 ± 10.3 mg/dL and mean cIMT value was 0.51 ± 0.8 mm. Remnant cholesterol significantly correlated with age, sex, body mass index, waist circumference, blood pressure, lipids, liver enzymes, and insulin resistance. cIMT value increased progressively with rising remnant cholesterol tertiles (Pfor trend < .001). Compared with subjects in the lowest remnant cholesterol tertile, those in the middle and highest remnant cholesterol tertiles had a 2.3- and 2.4-fold increased risk of elevated cIMT, independently of age, sex, pubertal stage, body mass index, and apolipoprotein B (all Padj ≤ .003). When the effects of overweight/obesity on the association between remnant cholesterol and cIMT were determined, normal-weight as well as overweight/obese subjects in the highest remnant cholesterol tertile had a 3.8- and 2.3-fold increased risk to have elevated cIMT compared with the respective study groups in the lowest tertile, after adjustment for conventional risk factors (Padj = .038 and Padj = .003, respectively). CONCLUSIONS In youths, elevated levels of remnant cholesterol might represent a marker of early atherosclerotic damage.
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Affiliation(s)
| | | | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Rome, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Rome, Italy
| | - Claudio Chiesa
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Lucia Pacifico
- Department of Maternal and Child Health, Sapienza University of Rome, Rome, Italy
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Zinöcker MK, Svendsen K, Dankel SN. The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk. Am J Clin Nutr 2021; 113:277-289. [PMID: 33471045 DOI: 10.1093/ajcn/nqaa322] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
SFAs play the leading role in 1 of the greatest controversies in nutrition science. Relative to PUFAs, SFAs generally increase circulating concentrations of LDL cholesterol, a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, the purpose of regulatory mechanisms that control the diet-induced lipoprotein cholesterol dynamics is rarely discussed in the context of human adaptive biology. We argue that better mechanistic explanations can help resolve lingering controversies, with the potential to redefine aspects of research, clinical practice, dietary advice, public health management, and food policy. In this paper we propose a novel model, the homeoviscous adaptation to dietary lipids (HADL) model, which explains changes in lipoprotein cholesterol as adaptive homeostatic adjustments that serve to maintain cell membrane fluidity and hence optimal cell function. Due to the highly variable intake of fatty acids in humans and other omnivore species, we propose that circulating lipoproteins serve as a buffer to enable the rapid redistribution of cholesterol molecules between specific cells and tissues that is necessary with changes in dietary fatty acid supply. Hence, circulating levels of LDL cholesterol may change for nonpathological reasons. Accordingly, an SFA-induced raise in LDL cholesterol in healthy individuals could represent a normal rather than a pathologic response. These regulatory mechanisms may become disrupted secondarily to pathogenic processes in association with insulin resistance and the presence of other ASCVD risk factors, as supported by evidence showing diverging lipoprotein responses in healthy individuals as opposed to those with metabolic disorders such as insulin resistance and obesity. Corresponding with the model, we suggest alternative contributing factors to the association between elevated LDL cholesterol concentrations and ASCVD, involving dietary factors beyond SFAs, such as an increased endotoxin load from diet-gut microbiome interactions and subsequent chronic low-grade inflammation that interferes with fine-tuned signaling pathways.
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Affiliation(s)
| | - Karianne Svendsen
- Department of Nutrition, University of Oslo, Oslo, Norway.,The Lipid Clinic, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Simon Nitter Dankel
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
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Gianazza E, Brioschi M, Martinez Fernandez A, Casalnuovo F, Altomare A, Aldini G, Banfi C. Lipid Peroxidation in Atherosclerotic Cardiovascular Diseases. Antioxid Redox Signal 2021; 34:49-98. [PMID: 32640910 DOI: 10.1089/ars.2019.7955] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Atherosclerotic cardiovascular diseases (ACVDs) continue to be a primary cause of mortality worldwide in adults aged 35-70 years, occurring more often in countries with lower economic development, and they constitute an ever-growing global burden that has a considerable socioeconomic impact on society. The ACVDs encompass diverse pathologies such as coronary artery disease and heart failure (HF), among others. Recent Advances: It is known that oxidative stress plays a relevant role in ACVDs and some of its effects are mediated by lipid oxidation. In particular, lipid peroxidation (LPO) is a process under which oxidants such as reactive oxygen species attack unsaturated lipids, generating a wide array of oxidation products. These molecules can interact with circulating lipoproteins, to diffuse inside the cell and even to cross biological membranes, modifying target nucleophilic sites within biomolecules such as DNA, lipids, and proteins, and resulting in a plethora of biological effects. Critical Issues: This review summarizes the evidence of the effect of LPO in the development and progression of atherosclerosis-based diseases, HF, and other cardiovascular diseases, highlighting the role of protein adduct formation. Moreover, potential therapeutic strategies targeted at lipoxidation in ACVDs are also discussed. Future Directions: The identification of valid biomarkers for the detection of lipoxidation products and adducts may provide insights into the improvement of the cardiovascular risk stratification of patients and the development of therapeutic strategies against the oxidative effects that can then be applied within a clinical setting.
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Affiliation(s)
- Erica Gianazza
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | - Maura Brioschi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | | | | | | | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Cristina Banfi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
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Castañer O, Pintó X, Subirana I, Amor AJ, Ros E, Hernáez Á, Martínez-González MÁ, Corella D, Salas-Salvadó J, Estruch R, Lapetra J, Gómez-Gracia E, Alonso-Gomez AM, Fiol M, Serra-Majem L, Corbella E, Benaiges D, Sorli JV, Ruiz-Canela M, Babió N, Sierra LT, Ortega E, Fitó M. Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease. J Am Coll Cardiol 2020; 76:2712-2724. [PMID: 33272365 DOI: 10.1016/j.jacc.2020.10.008] [Citation(s) in RCA: 301] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/08/2020] [Accepted: 10/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Genetic, observational, and clinical intervention studies indicate that circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol) can predict cardiovascular events. OBJECTIVES This study evaluated the association of triglycerides and remnant cholesterol (remnant-C) with major cardiovascular events in a cohort of older individuals at high cardiovascular risk. METHODS This study determined the baseline lipid profile and searched for major adverse cardiovascular events (MACEs) in the high-risk primary prevention PREDIMED (Prevención con Dieta Mediterránea) trial population (mean age: 67 years; body mass index: 30 kg/m2; 43% men; 48% with diabetes) after a median follow-up of 4.8 years. Unadjusted and adjusted Cox proportional hazard models were used to assess the association between lipid concentrations (either as continuous or categorical variables) and incident MACEs (N = 6,901; n cases = 263). RESULTS In multivariable-adjusted analyses, triglycerides (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.06, per 10 mg/dl [0.11 mmol/l]; p < 0.001), non-high-density lipoprotein cholesterol (HDL-C) (HR: 1.05; 95% CI: 1.01 to 1.10, per 10 mg/dl [0.26 mmol/l]; p = 0.026), and remnant-C (HR: 1.21; 95% CI: 1.10 to 1.33, per 10 mg/dl [0.26 mmol/l]; p < 0.001), but not low-density lipoprotein cholesterol (LDL-C) or HDL-C, were associated with MACEs. Atherogenic dyslipidemia (triglycerides >150 mg/dl [1.69 mmol/l] and HDL-C <40 mg/dl [1.03 mmol/l] in men or <50 mg/dl [1.29 mmol/l] in women) was also associated with MACEs (HR: 1.44; 95% CI: 1.04 to 2.00; p = 0.030). Remnant-C ≥30 mg/dl (0.78 mmol/l) differentiated subjects at a higher risk of MACEs compared with those at lower concentrations, regardless of whether LDL-C levels were on target at ≤100 mg/dl (2.59 mmol/l). CONCLUSIONS In overweight or obese subjects at high cardiovascular risk, levels of triglycerides and remnant-C, but not LDL-C, were associated with cardiovascular outcomes independent of other risk factors.
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Affiliation(s)
- Olga Castañer
- Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Xavier Pintó
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge-Idibell, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Isaac Subirana
- CIBER of Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio J Amor
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Lipid and Vascular Risk Clinic, Endocrinology and Nutrition Department, Hospital Clínic, Barcelona, Spain
| | - Emilio Ros
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Lipid and Vascular Risk Clinic, Endocrinology and Nutrition Department, Hospital Clínic, Barcelona, Spain; Cardiovascular Risk, Nutrition, and Aging Research Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Álvaro Hernáez
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Cardiovascular Risk, Nutrition, and Aging Research Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Miguel Ángel Martínez-González
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine and Public Health, Universidad de Navarra, Pamplona, Spain; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts
| | - Dolores Corella
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine, Universidad de Valencia, Valencia, Spain
| | - Jordi Salas-Salvadó
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Unitat de Nutrició Humana, Hospital Universitari San Joan de Reus, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Ramón Estruch
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - José Lapetra
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Internal Medicine Service, Hospital Clínic, Barcelona, Spain
| | - Enrique Gómez-Gracia
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain
| | - Angel M Alonso-Gomez
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine and Public Health, Universidad de Málaga, Málaga, Spain
| | - Miquel Fiol
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain Health Research Institute of the Balearic Islands (IdISBa), Hospital Son Espases Palma de Mallorca, Mallorca, Spain
| | - Lluís Serra-Majem
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Instituto de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain; Centro Hospitalario Universitario Insular Materno Infantil (CHUIMI), Servicio Canario de Salud, Las Palmas, Spain
| | - Emili Corbella
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge-Idibell, L'Hospitalet de Llobregat, Barcelona, Spain
| | - David Benaiges
- Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Endocrinology Service, Parc de Salut Mar, Barcelona, Spain
| | - Jose V Sorli
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine, Universidad de Valencia, Valencia, Spain
| | - Miguel Ruiz-Canela
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine and Public Health, Universidad de Navarra, Pamplona, Spain; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts
| | - Nancy Babió
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Unitat de Nutrició Humana, Hospital Universitari San Joan de Reus, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Lucas Tojal Sierra
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Preventive Medicine and Public Health, Universidad de Málaga, Málaga, Spain
| | - Emilio Ortega
- Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Lipid and Vascular Risk Clinic, Endocrinology and Nutrition Department, Hospital Clínic, Barcelona, Spain.
| | - Montserrat Fitó
- Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Barreto J, Karathanasis SK, Remaley A, Sposito AC. Role of LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1) as a Cardiovascular Risk Predictor: Mechanistic Insight and Potential Clinical Use. Arterioscler Thromb Vasc Biol 2020; 41:153-166. [PMID: 33176449 DOI: 10.1161/atvbaha.120.315421] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.
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Affiliation(s)
- Joaquim Barreto
- Atherosclerosis and Vascular Biology Lab (Atherolab), Clinical Research Center, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Brazil (J.B., A.C.S.)
| | - Sotirios K Karathanasis
- National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (S.K.K., A.R.)
- NeoProgen, Baltimore, MD (S.K.K.)
| | - Alan Remaley
- National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (S.K.K., A.R.)
| | - Andrei C Sposito
- Atherosclerosis and Vascular Biology Lab (Atherolab), Clinical Research Center, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Brazil (J.B., A.C.S.)
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Abstract
Hypertriglyceridemia is one of the most common lipid abnormalities encountered in clinical practice. Many monogenic disorders causing severe hypertriglyceridemia have been identified, but in most patients triglyceride elevations result from a combination of multiple genetic variations with small effects and environmental factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol misuse, and various commonly used drugs. Correcting these factors and optimizing lifestyle choices, including dietary modification, is important before starting drug treatment. The goal of drug treatment is to reduce the risk of pancreatitis in patients with severe hypertriglyceridemia and cardiovascular disease in those with moderate hypertriglyceridemia. This review discusses the various genetic and acquired causes of hypertriglyceridemia, as well as current management strategies. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented.
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Affiliation(s)
- Vinaya Simha
- Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA
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Sukhorukov VN, Khotina VA, Chegodaev YS, Ivanova E, Sobenin IA, Orekhov AN. Lipid Metabolism in Macrophages: Focus on Atherosclerosis. Biomedicines 2020; 8:biomedicines8080262. [PMID: 32752275 PMCID: PMC7459513 DOI: 10.3390/biomedicines8080262] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/26/2020] [Accepted: 07/27/2020] [Indexed: 12/18/2022] Open
Abstract
Mechanisms of lipid homeostasis and its impairment are of crucial importance for atherogenesis, and their understanding is necessary for successful development of new therapeutic approaches. In the arterial wall, macrophages play a prominent role in intracellular lipid accumulation, giving rise to foam cells that populate growing atherosclerotic plaques. Under normal conditions, macrophages are able to process substantial amounts of lipids and cholesterol without critical overload of the catabolic processes. However, in atherosclerosis, these pathways become inefficient, leading to imbalance in cholesterol and lipid metabolism and disruption of cellular functions. In this review, we summarize the existing knowledge on the involvement of macrophage lipid metabolism in atherosclerosis development, including both the results of recent studies and classical concepts, and provide a detailed description of these processes from the moment of lipid uptake with lipoproteins to cholesterol efflux.
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Affiliation(s)
- Vasily N. Sukhorukov
- Research Institute of Human Morphology, Laboratory of Cellular and Molecular Pathology of Cardiovascular System, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (I.A.S.); (A.N.O.)
- Russian Medical Research Center of Cardiology, Institute of Experimental Cardiology, Laboratory of Medical Genetics, 15-a 3-rd Cherepkovskaya Str., 121552 Moscow, Russia
- Correspondence: ; Tel.: +7-915-393-3263
| | - Victoria A. Khotina
- Research Institute of Human Morphology, Laboratory of Cellular and Molecular Pathology of Cardiovascular System, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (I.A.S.); (A.N.O.)
- Institute of General Pathology and Pathophysiology, Laboratory of Angiopathology, 8 Baltiyskaya Str., 125315 Moscow, Russia
| | | | - Ekaterina Ivanova
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia;
| | - Igor A. Sobenin
- Research Institute of Human Morphology, Laboratory of Cellular and Molecular Pathology of Cardiovascular System, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (I.A.S.); (A.N.O.)
- Russian Medical Research Center of Cardiology, Institute of Experimental Cardiology, Laboratory of Medical Genetics, 15-a 3-rd Cherepkovskaya Str., 121552 Moscow, Russia
| | - Alexander N. Orekhov
- Research Institute of Human Morphology, Laboratory of Cellular and Molecular Pathology of Cardiovascular System, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (I.A.S.); (A.N.O.)
- Institute of General Pathology and Pathophysiology, Laboratory of Angiopathology, 8 Baltiyskaya Str., 125315 Moscow, Russia
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Poznyak AV, Zhang D, Grechko AV, Wu WK, Orekhov AN. The role of sialic acids in the initiation of atherosclerosis. Minerva Cardioangiol 2020; 68:359-364. [PMID: 32472985 DOI: 10.23736/s0026-4725.20.05145-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Atherosclerosis is a major cause of disease-related mortality around the globe. The main characteristic of the disease is an accumulation of plaque on the arterial wall and subsequent erosion or rupture of some plaques. Atherosclerosis often leads to cardiovascular disease and such acute complications as myocardial infarction or ischemic stroke due to thrombus formation. Most recent advances in atherosclerotic research state that the modifications of low-density lipoprotein (LDL) are one of the most significant stages in the disease initiation, and among these modifications desialylation is of particular interest. Sialic acids are widely expressed on all types of cells of many organisms and participate in numerous biological processes. Regarding atherosclerosis, sialidases that are responsible for the regulation of the sialic component of different molecules, are probably one of the most crucial enzymatic families. Sufficient sialylation of vascular endothelium defines its susceptibility to an atherogenic plaque formation. Moreover, the desialylation of LDL provokes an accumulation of cholesterol and lipids in the arterial walls. According to the multiple involvements of sialic acids and related enzymes, sialidases, in the initiation and development of atherosclerosis, the deeper understanding of their exact role, as well as cellular and molecular mechanisms, will allow creating more targeted and effective therapeutic and diagnostic approaches.
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Affiliation(s)
- Anastasia V Poznyak
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
| | - Dongwei Zhang
- Diabetes Research Center, Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Andrey V Grechko
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitation, Moscow, Russia
| | - Wei-Kai Wu
- Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Alexander N Orekhov
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia - .,Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia.,Institute of Human Morphology, Moscow, Russia
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48
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Dhindsa DS, Sandesara PB, Shapiro MD, Wong ND. The Evolving Understanding and Approach to Residual Cardiovascular Risk Management. Front Cardiovasc Med 2020; 7:88. [PMID: 32478100 PMCID: PMC7237700 DOI: 10.3389/fcvm.2020.00088] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/22/2020] [Indexed: 12/21/2022] Open
Abstract
Despite unprecedented advances in treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death and disability worldwide. Treatment of major traditional risk factors, including low-density lipoprotein-cholesterol, serves as the foundation of atherosclerotic risk reduction. However, there remains a significant residual risk of cardiovascular events despite optimal risk factor management. Beyond traditional risk factors, other drivers of residual risk have come to the forefront, including inflammatory, pro-thrombotic, and metabolic pathways that contribute to recurrent events and are often unrecognized and not addressed in clinical practice. This review will explore the evidence linking these pathways to atherosclerotic cardiovascular disease and potential future therapeutic options to attenuate residual cardiovascular risk conferred by these pathways.
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Affiliation(s)
- Devinder S. Dhindsa
- Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Atlanta, GA, United States
| | - Pratik B. Sandesara
- Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Atlanta, GA, United States
| | - Michael D. Shapiro
- Section on Cardiovascular Medicine, Center for the Prevention of Cardiovascular Disease, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States
| | - Nathan D. Wong
- Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, Irvine, CA, United States
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Oesterle A, Liao JK. The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia. Curr Vasc Pharmacol 2020; 17:222-232. [PMID: 30124154 DOI: 10.2174/1570161116666180817155058] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 04/06/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
Abstract
Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed "pleiotropic" effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.
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Affiliation(s)
- Adam Oesterle
- The Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, IL 60637, United States
| | - James K Liao
- The Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, IL 60637, United States
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50
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Oxidative Stress and Antioxidants in Atherosclerosis Development and Treatment. BIOLOGY 2020; 9:biology9030060. [PMID: 32245238 PMCID: PMC7150948 DOI: 10.3390/biology9030060] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/10/2020] [Accepted: 03/18/2020] [Indexed: 02/07/2023]
Abstract
Atherosclerosis can be regarded as chronic inflammatory disease affecting the arterial wall. Despite the recent progress in studying the pathogenesis of atherosclerosis, some of the pathogenic mechanisms remain to be fully understood. Among these mechanisms is oxidative stress, which is closely linked to foam cells formation and other key events in atherosclerosis development. Two groups of enzymes are involved in the emergence of oxidative stress: Pro-oxidant (including NADPH oxidases, xanthine oxidases, and endothelial nitric oxide synthase) and antioxidant (such as superoxide dismutase, catalases, and thioredoxins). Pro-oxidant enzymes in normal conditions produce moderate concentrations of reactive oxidant species that play an important role in cell functioning and can be fully utilized by antioxidant enzymes. Under pathological conditions, activities of both pro-oxidant and antioxidant enzymes can be modified by numerous factors that can be relevant for developing novel therapies. Recent studies have explored potential therapeutic properties of antioxidant molecules that are capable to eliminate oxidative damage. However, the results of these studies remain controversial. Other perspective approach is to inhibit the activity of pro-oxidant enzymes and thus to slow down the progression of atherosclerosis. In this review we summarized the current knowledge on oxidative stress in atherosclerosis and potential antioxidant approaches. We discuss several important antioxidant molecules of plant origin that appear to be promising for treatment of atherosclerosis.
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