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Background: Previous studies revealed a linear relationship between body mass index (BMI) and repeat coronary revascularization rate in patients who underwent percutaneous coronary intervention (PCI). However, this relationship has not been demonstrated in Korean patients who meet old and new target low-density lipoprotein cholesterol (LDL-C) levels of Korean dyslipidemia guidelines. Therefore, we conducted this study to find out the effect of BMI on repeat coronary revascularization rate in patients with LDL-C <55 mg/dL and patients with LDL-C <70 mg/dL. Methods: This cohort study was followed for 42 months in Daegu Catholic Medical Center, Korea. We included 429 patients with LDL-C <70 mg/dL 1 year after PCI. We compared repeat revascularization rates using Kaplan-Meier survival curves between the normal weight group (18.5 kg/m2 ≤ BMI < 23 kg/m2) and the pre-obesity and obesity group (23 kg/m2 ≤ BMI) in patients with LDL-C <55 mg/dL and patients with LDL-C <70 mg/dL. Results: During a follow-up period, there was no significant difference in repeat coronary revascularization-free survival between a group with LDL-C <55 mg/dL and a group with LDL-C <70 mg/dL (79.6% vs. 76.2%, P=0.32). In normal weight patients, LDL-C <55 mg/dL group showed higher repeat coronary revascularization-free survival than LDL-C <70 mg/dL group (89.3% vs. 77.1%, P=0.05). There was no significant difference in repeat revascularization-free survival between the normal weight group and the pre-obesity and obesity group in patients with LDL-C <70 mg/dL (77.1% vs. 75.7%, P=0.67). However, the normal weight group showed significantly higher repeat revascularization-free survival compared to the pre-obesity and obesity group in patients with LDL-C <55 mg/dL (89.3% vs. 74.3%, P=0.03). Normal body weight and LDL-C <55 mg/dL [hazard ratio (HR): 0.421, 95% confidence interval (CI): 0.193-0.916, P=0.02] was the only independent predictor for repeat revascularization. Conclusions: In Korean PCI patients with normal body weight whose LDL-C level is less than 70 mg/dL, but more than 55 mg/dL, should be treated with more intensive therapy to lower LDL-C to less than 55 mg/dL. For obese patients who have succeeded in reducing LDL-C below 55 mg/dL, it seems that weight loss should be attempted to a normal body weight level.
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AIMS: Elevated lipoprotein (a) (Lp[a]), predominantly determined by genetic variability, causes atherosclerotic cardiovascular disease (ASCVD), particularly in patients with familial hypercholesterolemia (FH). We aimed to elucidate the clinical impact of Lp(a) and cumulative exposure to low-density lipoprotein cholesterol (LDL-C) on CAD in patients with FH. METHODS: One hundred forty-seven patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) were retrospectively investigated. Patients were divided into 2 groups according to the presence of CAD. Their clinical characteristics and lipid profiles were evaluated. RESULTS: There were no significant differences in untreated LDL-C levels between the 2 groups (p=0.4), whereas the cumulative exposure to LDL-C and Lp(a) concentration were significantly higher in patients with CAD (11956 vs. 8824 mg-year/dL, pï¼0.01; 40 vs. 14 mg/dL, pï¼0.001, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated that the cutoff values of Lp(a) and cumulative LDL-C exposure to predict CAD in patients with FH were 28 mg/dL (AUC 0.71) and 10600 mg-year/dL (AUC 0.77), respectively. A multivariate analysis revealed that cumulative LDL-C exposure ≥ 10600 mg-year/dL (pï¼0.0001) and Lp(a) level ≥ 28 mg/dL (pï¼0.001) were independent predictors of CAD. Notably, the risk of CAD remarkably increased to 85.7% with smoking, Lp(a) ≥ 28 mg/dL, and cumulative LDL-C exposure ≥ 10600 mg-year/dL (odds ratio: 46.5, 95%CI: 5.3-411.4, pï¼0.001). CONCLUSIONS: This study demonstrated an additive effect of Lp(a) and cumulative LDL-C exposure on CAD in patients with HeFH. Interaction with traditional risk factors, particularly smoking and cumulative LDL-C exposure, enormously enhances the cardiovascular risk in this population.
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BACKGROUND: Cerebrovascular accident (CVA), also commonly known as stroke, is an acute condition characterized by jeopardized perfusion of the brain tissue. Atherosclerosis is a common converging point for the various risk factors for CVA. It is a chronic, evolving condition of the vessel wall characterized by peculiar lesions known as atheromas. Low-density lipoprotein cholesterol (LDL-C) has been one of the established and traditional risk factors for the development of plaques in atherosclerosis. Small dense LDL-C (sdLDL-C) is a subclass of LDL-C that is considered more atherogenic, and its role in atherosclerotic plaque formation has been very well established. Hence, in this study, we aimed to find the association between calculated sdLDL-C and atherosclerotic carotid plaque (including various plaque characteristics). MATERIALS AND METHODS: This retrospective cross-sectional study was conducted at Sri Ramachandra Medical College and Research Institute between December 2022 and December 2023 after getting ethics approval from the Institutional Ethics Committee. Patients who underwent CT angiogram (312) were included in the study, and their lipid profile data were collected from the Laboratory Information System. Participants were divided into groups depending on the presence or absence of carotid plaque, the characteristics of the plaque, and the narrowing caused by the plaque. sdLDL-C was calculated using Sampson formula from the lipid parameters in these groups. Statistical analysis was done using SPSS Statistics version 16.0 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). A p-value of <0.05 was considered significant. RESULTS: sdLDL-C was significantly higher in the plaque group (37.25 ± 13.69 mg/dL) when compared to the group without plaques on CT angiogram (34.09 ± 11.64 mg/dL) (p<0.05), wherein the LDL-C wasn't significantly different between the two groups. sdLDL-C was also elevated in the soft plaque sub-group (39.46 ± 13.63 mg/dL) when compared to the calcific plaque sub-group (35.41 ± 13.05 mg/dL), which was statistically significant (p<0.05). CONCLUSION: sdLDL-C is associated with atherosclerotic carotid plaques, especially the soft plaques on CT angiogram, which are considered to be vulnerable plaques. Thus, calculated sdLDL-C can be utilized as a cost-effective tool to assess plaque vulnerability and monitor hypolipidemic treatment in addition to LDL-C.
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Per- and polyfluoroalkyl substances (PFAS) are artificial chemicals extensively utilized in everyday products, and numerous cross-sectional epidemiological studies consistently link PFAS exposure with lipid profiles across diverse populations and age groups. In longitudinal studies, the findings also indicate a positive correlation between PFAS and lipid profiles; however, this association remains unexplored in adolescents and young adults. Notably, previous research has predominantly focused on conventional lipid biomarkers, with limited exploration of the relationship between PFAS and diverse lipoprotein subfractions. Furthermore, there is a lack of comprehensive investigation into the temporal trends in PFAS concentrations in Taiwan. To address this research gap, we conducted a prospective study following 592 adolescents and young adults (12-30 years old at enrollment) from the YOung TAiwanese Cohort (YOTA) over a duration of 10 years. During the follow-up period, we measured 11 types of PFAS and various lipid profile biomarkers (low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein triglyceride (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL3-C, lipoprotein(a), triglyceride). Our results revealed a general decline in PFAS concentrations in the study population. Regarding the correlation between the average levels (averaged across the initial and second tracking periods) of PFAS and lipid profiles (during the second tracking period), we observed positive correlations with total cholesterol and LDL-C for perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), N-methylperfluorooctane sulfonamide acetic acid (N-MeFOSAA), and the sum of PFAS (sum of the 11 kinds of PFAS). Additionally, average levels of PFUdA, N-MeFOSAA, and the sum of PFAS exhibited positive associations with sdLDL-C. This study unveiled an overall decrease in PFAS concentrations and underscores a potential link between PFAS exposure and adverse changes in lipid profiles among young populations, emphasizing the need for further exploration into the mechanisms of PFAS on lipid metabolism and atherosclerosis.
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Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death globally despite advances in preventive therapies. Understanding of the initiation and progression of atherosclerosis, the interplay between lipoproteins, endothelial dysfunction, inflammation, and immune responses is critical to treating this disease. The development of vulnerable coronary plaques prone to thrombosis, can lead to acute coronary syndromes, for these reasons, the potential plaque stabilization and regression through pharmacological interventions, particularly lipid-lowering agents like statins and PCSK9 inhibitors is crucial. The imaging techniques such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) play a key role in assessing plaque composition and guiding interventional therapeutic strategies. Clinical evidence supports the efficacy of intensive lipid-lowering therapy in inducing plaque regression, with studies demonstrating reductions in plaque volume and improvements in plaque morphology assessed by IVUS, OCT and NIRS. While pharmacological interventions show promise in promoting plaque regression and stabilization, their impact on long-term cardiovascular events requires further investigation. Multimodality imaging and comprehensive outcome trials are proposed as essential tools for elucidating the relationship between plaque modification and clinical benefit in coronary atherosclerosis. The stabilization or regression of atherosclerotic plaque might serve as the phenomenon linking the reduction in LDL-C levels to the decrease in cardiovascular events. Overall, this review emphasizes the ongoing efforts to advance our understanding of ASCVD pathophysiology and optimize therapeutic approaches for improving patient outcomes.
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Purpose: Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design. Methods: We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis. Results: In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002). Conclusions: Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.
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LDL-Colesterol , Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular Isquémico , Análisis de la Aleatorización Mendeliana , Humanos , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/sangre , LDL-Colesterol/sangre , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Femenino , Factores de Riesgo , MasculinoRESUMEN
Anomalies in lipid metabolism involve multifactorial pathogenesis, among other factors, being associated with an inflammatory state and disturbances in vitamin D status. The literature has focused on the binary relationships between inflammation and dyslipidemia, vitamin D and dyslipidemia, or vitamin D and inflammation. Our study aimed to explore the link between all these three factors: 25-OH vitamin D serum levels, the presence of inflammation assessed through serum C-reactive protein (CRP), and serum lipid profile in 2747 hospitalized patients. Our results showed a positive correlation of HDL-C with 25 (OH) vitamin D and a negative correlation of HDL-C with CRP. This relationship had different patterns in the statistical network analysis. The network analysis patterns are preserved for males and females, except for the relationship between CRP and vitamin D, which is present in male cases and absent in females. The same triangular relationship between all three-CRP, vitamin D, and HDL-C was found with different strengths of partial correlation in obese and non-obese patients. This pattern was similar in patients with and without fatty liver. A shifted pattern was found in the network analysis of hypertensive patients. The CRP was negatively correlated with vitamin D and HDL-C, and vitamin D was positively correlated with HDL-C in non-hypertensive patients. Castelli's Risk indexes I and II were positively associated with CRP, suggesting that increased cardiovascular risk is proportional to an inflammatory state. The triad formed by altered serum lipid levels, inflammation, and vitamin D represents a complex relationship marked by specific dynamics between lipidic fractions such as HDL-C and C-reactive protein and vitamin D.
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Background: The relationship between circulating lipid levels and the risk for heart failure (HF) is controversial. We aimed to examine this association, and whether it is modified by the duration of diabetes or treatment regimens in people with type 2 diabetes mellitus. Methods: Individuals (n=2,439,978) who underwent health examinations in 2015 to 2016 were identified from the Korean National Health Information Database. Subjects were categorized according to the duration of diabetes (new-onset, <5, 5-10, or ≥10 years) and number of antidiabetic medications. Incident HF was defined according to the International Classification of Diseases, 10th Revision (ICD-10) code I50 as the primary diagnosis during hospitalization. The risk for HF was estimated using multivariate Cox proportional hazard analysis. Results: During a median follow-up of 4.0 years, 151,624 cases of HF occurred. An inverse association between low-density lipoprotein cholesterol (LDL-C) levels and incident HF was observed in the new-onset diabetes group, with an approximately 25% lower risk in those with LDL-C levels of 100-129, 130-159, and ≥160 mg/dL, compared to those with levels <70 mg/dL. However, J-shaped associations were noted in the long-standing diabetes group, with a 16% higher risk in those with LDL-C level ≥160 mg/dL, compared to those with levels <70 mg/dL. Similar patterns were observed in the relationship between total cholesterol or non-high-density lipoprotein cholesterol and the risk for HF, and when subjects were grouped according to the number of antidiabetic medications instead of diabetes duration. Conclusion: Different associations between lipid levels and the risk for HF were noted according to disease progression status among individuals with diabetes.
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PURPOSE: Nut-enriched diets are related to improve lipid and inflammatory biomarkers in meta-analyses in the context of primary cardiovascular prevention. However, primary studies on secondary cardiovascular prevention are scarce and controversial. This systematic review and meta-analysis aimed to evaluate the effect of nut supplementation on lipid and inflammatory profiles in individuals with atherosclerotic cardiovascular disease, and the frequency of adverse events. METHODS: Six databases were used for research: PubMed, EMBASE, BVS, Cochrane Library, Web of Science, and ClinicalTrials.gov, until February 2023, with no language restrictions. We performed random-effects meta-analyses to compare nut-enriched diets vs. control diets for pre-post intervention changes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system assessed the evidence's certainty. RESULTS: From the 5187 records identified, eight publications containing data referring to five randomized clinical trials involving 439 participants were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with doses ranging between 5 g and 85 g (median: 30 g/day). The intervention time varied between 6 and 12 weeks. Compared to nut-free diets, nut intake did not have a statistically significant effect on lipid profile biomarkers, except on the atherogenic index (MD: -0.32 [95% CI -0.58 to -0.06], I2 = 0% - moderate certainty of the evidence). Similarly, there was no effect of nuts on inflammatory profile biomarkers. It was not possible to aggregate data on adverse events. CONCLUSIONS: Nut supplementation did not change lipid and inflammatory profiles in the secondary cardiovascular prevention setting.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.
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Enfermedades Neurodegenerativas , Estrés Oxidativo , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Proproteína Convertasa 9/metabolismo , Fármacos Neuroprotectores/farmacologíaRESUMEN
BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.
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Cirugía Bariátrica , Obesidad , Inhibidor 1 de Activador Plasminogénico , Proproteína Convertasa 9 , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proproteína Convertasa 9/sangre , Proproteína Convertasa 9/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Obesidad/cirugía , Obesidad/metabolismo , Obesidad/sangre , Estudios Longitudinales , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.
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BACKGROUND: Defining lipid goals solely on low-density lipoprotein-cholesterol (LDL-C) levels in Indian population may cause misclassification due to high prevalence of hypertriglyceridemia and small dense LDL-C particles. International guidelines now recommend Apoliporotein-B (Apo-B) and non-high-density lipoprotein-cholesterol (non-HDL-C) levels as alternative targets. In this study, we used a cross-sectional representative population database to determine Apo-B and non-HDL-C cut-offs corresponding to identified LDL-C targets and compared them to international guidelines. METHODS: A community-based survey carried out in urban Delhi and adjacent rural Ballabhgarh provided lipid values for 3047 individuals. The Spearman correlation coefficient was used to evaluate the degree of relationship between Apo-B and LDL-C and non-HDL-C. Cut-off values for Apo-B and non-HDL-C were established using receiver operator curve analysis correlating with guideline-recommended LDL-C targets. RESULTS: Spearman's rank correlations between Apo-B and LDL-C (0.82) and non-HDL-C and LDL-C (0.93) were significant (p < 0.05). Proposed corresponding cut-off values for LDL-C of 55, 70,100,130 and 160 mg/dl for Apo-B and non-HDL-C in our population were 75.3, 75.5, 91.3, 107.6, 119.4 mg/dL and 92.5,96.5, 123.5, 154.5, 179.5 mg/dL respectively. However, in those with triglycerides >150 mg/dl the corresponding Apo-B and non-HDL-C values were 85.1, 92.7, 103.5, 117.5 and 135 mg/dL and 124.5, 126.5, 147.5, 167.5 and 190.5 mg/L respectively. CONCLUSION: Based on this study we provide Apo-B and non-HDL cut-offs corresponding to target LDL-C values in Indian patients with and without high triglycerides. It is noted that in individuals with triglycerides ≥ 150 mg/dl, the Apo-B levels are much higher than the values recommended by guidelines.
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Apolipoproteínas B , LDL-Colesterol , Humanos , Estudios Transversales , India/epidemiología , Masculino , Femenino , Persona de Mediana Edad , LDL-Colesterol/sangre , Adulto , Apolipoproteínas B/sangre , Biomarcadores/sangre , HDL-Colesterol/sangre , PrevalenciaRESUMEN
BACKGROUND: Presently, the majority of investigations primarily evaluate the association between lipid profiles and asthma. However, few investigations explore the connection between lipids and mortality related to the disease. This study aims to explore the association of serum lipids with all-cause mortality within asthmatic adults. METHODS: The investigation included 3233 eligible patients with asthma from the NHANES (2011-2018). The potential associations were explored using three Cox proportional hazards models, restricted cubic splines (RCS), threshold effect models, and CoxBoost models. In addition, subgroup analyses were conducted to investigate these associations within distinct populations. RESULTS: After controlling all covariables, the Cox proportional hazards model proved a 17% decrease in the probability of death for each increased unit of low-density lipoprotein-cholesterol (LDL-C) (mmol/L). Yet, there was no association seen between blood high-density lipoprotein cholesterol (HDL-C), total cholesterol, or triglyceride and all-cause mortality in asthmatics. The application of RCS and threshold effect models verified an inverse and linear association of LDL-C with all-cause mortality. According to the results from the CoxBoost model, LDL-C exhibited the most substantial impact on the follow-up status of asthmatics among the serum lipids. CONCLUSION: Our investigation concluded that in American asthmatic populations, LDL-C levels were inversely and linearly correlated with mortality. However, no independent relationship was found between triglycerides, total cholesterol, or HDL-C and mortality.
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Asma , HDL-Colesterol , LDL-Colesterol , Modelos de Riesgos Proporcionales , Triglicéridos , Humanos , Asma/sangre , Asma/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Adulto , LDL-Colesterol/sangre , HDL-Colesterol/sangre , Triglicéridos/sangre , Estudios de Cohortes , Lípidos/sangre , Anciano , Factores de RiesgoRESUMEN
BACKGROUND: Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types such as macrophages. METHODS: We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis-the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo. RESULTS: We identified 18â 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-ß in the causal mechanisms at this locus. CONCLUSIONS: Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.
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Enfermedad de la Arteria Coronaria , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Macrófagos , Humanos , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Macrófagos/metabolismo , Factores de Riesgo , Análisis de la Célula Individual , Redes Reguladoras de Genes , Masculino , Polimorfismo de Nucleótido Simple , FemeninoRESUMEN
The Shiga Epidemiological Study of Subclinical Atherosclerosis was conducted in Kusatsu City, Shiga, Japan, from 2006 to 2008. Participants were measured for LDL-p through nuclear magnetic resonance technology. 740 men participated in follow-up and underwent 1.5 T brain magnetic resonance angiography from 2012 to 2015. Participants were categorized as no-ICAS, and ICAS consisted of mild-ICAS (1 to < 50%) and severe-ICAS (≥ 50%) in any of the arteries examined. After exclusion criteria, 711 men left for analysis, we used multiple logistic regression to examine the association between lipid profiles and ICAS prevalence. Among the study participants, 205 individuals (28.8%) had ICAS, while 144 individuals (20.3%) demonstrated discordance between LDL-c and LDL-p levels. The discordance "low LDL-c-high LDL-p" group had the highest ICAS risk with an adjusted OR (95% CI) of 2.78 (1.55-5.00) in the reference of the concordance "low LDL-c-low LDL-p" group. This was followed by the concordance "high LDL-c-high LDL-p" group of 2.56 (1.69-3.85) and the discordance "high LDL-c-low LDL-p" group of 2.40 (1.29-4.46). These findings suggest that evaluating LDL-p levels alongside LDL-c may aid in identifying adults at a higher risk for ICAS.
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Lipoproteínas LDL , Humanos , Masculino , Persona de Mediana Edad , Lipoproteínas LDL/sangre , Anciano , Japón/epidemiología , Angiografía por Resonancia Magnética/métodos , Constricción Patológica/sangre , LDL-Colesterol/sangre , Lípidos/sangre , Factores de Riesgo , Adulto , FemeninoRESUMEN
BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.
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LDL-Colesterol , Enfermedad de la Arteria Coronaria , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hiperlipoproteinemia Tipo II , Lipoproteína(a) , Herencia Multifactorial , Fenotipo , Sistema de Registros , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Femenino , Masculino , Persona de Mediana Edad , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Medición de Riesgo , Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Adulto , Anciano , Canadá/epidemiología , Reino Unido/epidemiología , Índice de Severidad de la Enfermedad , Factores de Riesgo , Estudios de Casos y Controles , Biomarcadores/sangre , IncidenciaRESUMEN
INTRODUCTION: Several observational studies have been conducted to assess the prevalence of cardiovascular risk factors in hypertensive patients; however, none has yet investigated prevalence, clustering, and current management of cardiovascular risk factors upon first referral to hypertension specialists, which is the aim of the present study. METHODS: Consecutive adult outpatients with essential/secondary hypertension were included at the time of their first referral to hypertension specialists at 13 Italian centers in the period April 2022-2023 if they had at least one additional major cardiovascular risk factor among LDL-hypercholesterolemia, type 2 diabetes, and cigarette smoking. Prevalence, degree of control, and current management strategies of cardiovascular risk factors were assessed. RESULTS: A total of 255 individuals were included, 40.2% women and 98.4% Caucasian. Mean age was 60.3±13.3 years and mean blood pressure [BP] was 140.3±17.9/84.8±12.3 mmHg). Most participants were smokers (55.3%), had a sedentary lifestyle (75.7%), suffered from overweight/obesity (51%) or high LDL-cholesterol (41.6%), had never adopted strategies to lose weight (55.7%), and were not on a low-salt diet (57.4%). Only a minority of patients reported receiving specialist counseling, and 27.9% had never received recommendations to correct unhealthy lifestyle habits. Nearly 90% of individuals with an estimated high/very high cardiovascular risk profile did not achieve recommended LDL-cholesterol targets. CONCLUSIONS: In patients with hypertension, both pharmacological and lifestyle therapeutic advice are yet to improve before referral to hypertension specialists. This should be considered in the primary care setting in order to optimize cardiovascular risk management strategies.