LDL-lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells: mitigation by statin intervention.
ABSTRACT: Elevated low-density lipoprotein (LDL) concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidized LDL (oxLDL) modification and nitration is observed during dementia and hypercholesterolaemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVECs) were maintained in transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naive, normo- and hyper-lipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40 mg of simvastatin intervention/day for 3 months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after 3 months. LDL isolated from statin-naive hyperlipidaemic, AD and AD-plus subjects was more oxidized (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2?) compared with control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 compared with 3.95±0.2 nmol/mg; P<0.001) and 8-isoprostane F2? (30.4±4.0 pg/ml compared with 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids (LDL-L) from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7 nmol/mg of protein) compared with untreated cells (23.8±1.2 compared with nmol/mg of protein). Basolateral interleukin (IL)-6 secretion was increased by LDL-L from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared with healthy subject lipids (18.6±3.6 pg/ml). LDL-L isolated after statin intervention did not affect endothelial function. In summary, LDL-L from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVECs. In vivo intervention with statins reduces the damaging effects of LDL-L on HMVECs.
Project description:Background:Although thyroid hormone (TH) has important effects on lipid metabolism, the relationship between TH and statin responsiveness has never been investigated. We hypothesize that TH plays an important role in statin responsiveness in patients with acute myocardial infarction (AMI). Methods:Consecutive 1091 hospitalized AMI patients in Fuwai hospital (Beijing, China) were enrolled into this current study. The study population was divided into three groups based on the intensity of statin treatment: low-intensity (n = 221), moderate-intensity (n = 712) and high-intensity (n = 158). Lipid levels were measured after statin therapy lasting for 10-14 days. The association between TH, lipid profile levels and achievement of low-density lipoprotein cholesterol (LDL-C) lowering goals was explored in patients with AMI on statin therapy. Results:By general linear analysis, a significant linear trend between free triiodothyronine (FT3) and LDL-C level (linear coefficient r = -0.082, P = 0.001) and FT3 and total cholesterol (TC) level (r = -0.105, P = 0.031) was observed in the moderate-intensity statin group. A more apparent linear trend was detected in the high-intensity statin group (for LDL-C: r = -0.113, P = 0.005; for TC: r = -0.172, P = 0.029, respectively). However, no significant correlation was observed in the low-intensity statin group. Compared with the low-FT3 group (defined as FT3 < 1.79 pg/mL), the OR (95% CI) for attaining a LDL-C < 3.0mmol/L was found to be 2.217 (1.001-4.839) in the higher FT3 group (> 2.95 pg/mL). The OR (95% CI) for attaining the more intensive goal (LDL-C < 1.8mmol/L) was 2.836 (1.014-5.182). Conclusions:Our study reveals that variation in FT3 levels is related to the cholesterol-lowering responsiveness of statins in AMI patients. These findings suggest that low FT3 may be a factor responsible for lack of LDL-C goal attainment and patients' poor responsiveness to statin treatment.
Project description:BACKGROUND:Fractalkine (CX3CL1) promotes migration and adhesion of lymphocytes and monocytes to inflamed tissues. Prior studies show a role for CX3CL1 in atherosclerosis. The relationship between inflammatory cytokines, cholesterol, and CX3CL1 levels in human subjects without known coronary artery disease is not well characterized. The goal of our study was to assess baseline CX3CL1 levels, and after modulation of cholesterol levels by statins to determine if CX3CL1 is linked to cholesterol levels or inflammatory stimuli. METHODS:We performed a blinded, randomized hypothesis generating study in human subjects without known coronary artery disease treated sequentially with three statins of differing potencies. Fractalkine (CX3CL1), GM-CSF, VEGF-A, other chemokines, and lipid levels were measured. Mechanistic studies of CX3CL1 induction by LDL cholesterol and TNF? in cultured human endothelial cells were performed using real-time PCR. RESULTS:Therapy with statins reduced total and LDL cholesterol levels as expected. CX3CL1 levels were significantly reduced from no statin control levels (89.9?±?18.5 pg/mL) after treatment with atorvastatin (60.0?±?7.8 pg/mL), pravastatin (54.2?±?7.0 pg/mL) and rosuvastatin (65.6?±?7.3 pg/mL) (? (2)(2)?=?17.4, p???0.001). Cholesterol is not a known regulator of CX3CL1. We found GM-CSF (r(2)?=?0.524; p?<?0.005) and VEGF-A (r(2)?=?0.4; p?<?0.005) levels were highly and positively correlated with CX3CL1. Total (r(2)?=?0.086) and LDL cholesterol (r(2)?=?0.059) levels weakly correlated with CX3CL1 levels. Finally, we tested whether LDL cholesterol could induce CX3CL1, GM-CSF, and VEGF-A in human endothelial cells, versus TNF?. LDL cholesterol alone resulted in small, non-significant increases in CX3CL1 and GM-CSF, while TNF? resulted in?>?10-fold induction. CONCLUSIONS:Our findings suggest that while statins suppress CX3CL1 levels, inflammatory cytokines may be the major regulator of CX3CL1 levels rather than cholesterol itself. Additional studies in a larger patient population are needed to confirm these findings, determine if CX3CL1 levels reflect inflammation levels, and potentially add to standard risk factors in prediction of atherosclerotic disease events.
Project description:The purpose of the present report was to examine whether proprotein convertase subtilisin/kexin type 9 (PCSK9) levels differ in individuals who do not exhibit expected reductions in low density lipoprotein cholesterol (LDL-C) with statin therapy. Eighteen nonresponder subjects treated with 80?mg atorvastatin treatment for 6 months without substantial reductions in LDL-C (?LDL-C: 2.6 ± 11.4%) were compared to age- and gender-matched atorvastatin responders (?LDL-C: 50.7 ± 8.5%) and placebo-treated subjects (?LDL-C: 9.9 ± 21.5%). Free PCSK9 was marginally higher in nonresponders at baseline (P = 0.07) and significantly higher in atorvastatin responders after 6 months of treatment (P = 0.04). The change in free PCSK9 over 6 months with statin treatment was higher (P < 0.01) in atorvastatin responders (134.2 ± 131.5?ng/mL post- versus prestudy) than in either the nonresponders (39.9 ± 87.8?ng/mL) or placebo subjects (27.8 ± 97.6?ng/mL). Drug compliance was not lower in the nonresponders as assessed by pill counts and poststudy plasma atorvastatin levels. Serum PCSK9 levels, both at baseline and in response to statin therapy, may differentiate individuals who do versus those who do not respond to statin treatment.
Project description:INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-?4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-?4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.
Project description:Introduction:We developed and validated a clinically applicable decision tree for the use of cerebrospinal fluid biomarkers in the diagnosis of Alzheimer's disease (AD). Methods:Subjects with probable AD (n = 1004) and controls (n = 442) were included. A decision tree was modeled using Classification And Regression Tree analysis in a training cohort (AD n = 221; controls n = 221) and validated in an independent cohort (AD n = 783; controls n = 221). Diagnostic performance was compared to previously defined cutoffs (amyloid β 1-42 < 813 pg/ml; tau>375 pg/ml). Results:Two cerebrospinal fluid AD biomarker profiles were revealed: the "classical" AD biomarker profile (amyloid β 1-42: 647-803 pg/ml; tau >374 pg/ml) and an "atypical" AD biomarker profile with strongly decreased amyloid β 1-42 (<647 pg/ml) and normal tau concentrations (<374 pg/ml). Compared to previous cutoffs, the decision tree performed better on diagnostic accuracy (86% [84-88] vs 80% [78-83]). Discussion:Two cerebrospinal fluid AD biomarker profiles were identified and incorporated in a readily applicable decision tree, which improved diagnostic accuracy.
Project description:Experimental studies suggested that statins attenuate vascular AT1 receptor responsiveness. Moreover, the augmented excessive pressor response to systemic angiotensin II infusions in hypercholesterolemic patients was normalized with statin treatment. In 12 hypercholesterolemic patients, we tested the hypothesis that statin treatment attenuates angiotensin II-mediated vasoconstriction in hand veins assessed by a linear variable differential transducer. Subjects ingested daily doses of either atorvastatin (40 mg) or positive control irbesartan (150 mg) for 30 days in a randomized and cross-over fashion. Ang II-induced venoconstriction at minute 4 averaged 59%±10% before and 28%±9% after irbesartan (mean ± SEM; P<0.05) compared to 65%±11% before and 73%±11% after 30 days of atorvastatin treatment. Plasma angiotensin levels increased significantly after irbesartan treatment (Ang II: 17±22 before vs 52±40 pg/mL after [p?=?0.048]; Ang-(1-7): 18±10 before vs 37±14 pg/mL after [p?=?0.002]) compared to atorvastatin treatment (Ang II: 9±4 vs 11±10 pg/mL [p?=?0.40]; Ang-(1-7): 24±9 vs 32±8 pg/mL [p?=?0.023]). Our study suggests that statin treatment does not elicit major changes in angiotensin II-mediated venoconstriction or in circulating angiotensin II levels whereas angiotensin-(1-7) levels increased modestly. The discrepancy between local vascular and systemic angiotensin II responses might suggest that statin treatment interferes with blood pressure buffering reflexes.ClinicalTrials.gov NCT00154024.
Project description:Statins are mainstay anti-lipidaemic treatments for preventing cardiovascular diseases but also known to increase coronary artery calcification (CAC). However, underlying relationship between statin and CAC is still unclear. This study explored the mediating role of five statin-related biochemical factors [i.e., low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, glucose, and high sensitivity C-reactive protein levels]. Seoul Metabolic Syndrome cohort study includes 1370 participants suspected of metabolic syndrome. For causal mediation analysis, the dataset for 2016 including 847 participants with coronary computed tomography without any missing value were analysed using the Mediation package in R software. This study identified a causal mediation mechanism of HDL-cholesterol among the five biochemical factors. It implied that statin treatment increases the HDL-cholesterol level, leading to decreasing the probability of CAC score > 0. Estimated values of interest in HDL-cholesterol mediation were (1) average causal mediation effect, -0.011 with 95% CI [-0.025, -0.003], (2) average direct effect, 0.143 with 95% CI [0.074, 0.219], and total effect, 0.132 with 95% CI [0.063, 0.209]. Its mediation effect was maintained regardless of statin intensity. Sensitivity analysis also provided a robustness of the results under potential existence of a confounder between HDL-cholesterol and CAC. This study suggests a potential causal pathway between statin and CAC (the positive association of statin on CAC) through HDL-cholesterol as an inhibitor.
Project description:BACKGROUND:The well-established benefit of Low-Dense-Lipoprotein-cholesterol (LDL-c) lowering treatments (LLTs) has led clinical guidelines to lower the cardiovascular prevention targets. Despite this, there is a surprising scarcity of real-world studies (RWS) evaluating whether recommendations are applied in the routine clinical management of patients with type 2 diabetes (T2D). We therefore evaluated, in a large RWS, the pattern of LLTs use and the achievement of LDL-c targets in patients with T2D in Italian diabetes specialist clinics. METHODS:We collected data from 46 diabetes outpatient clinics (following 281,381 subjects), including 104,726 T2D patients, for whom use of LLTs between 2015 and 2016 was ascertained. We used the 2016 and 2019 European Atherosclerosis Society and European Society of Cardiology (EAS-ESC) guidelines to define cardiovascular risk categories, LDL-c targets, and the expected LDL-c reduction and cardiovascular benefit achievable with LLT intensification. RESULTS:63,861 patients (61.0%) were on statin therapy, 9.2% of whom were also on ezetimibe. Almost all subjects were at high (29.3%) or very high (70.4%) cardiovascular risk, including 17% being in secondary prevention. Among very high-risk patients, 35% were not on statin despite half of them had LDL-c?>?2.6 mmol/l, and only 15% of those on statins had LDL-c?<?1.4 mmol/l. 83% of subjects in secondary prevention were on a statin, but half of them had LDL-c?>?1.8 mmol/l. Overall, 35% and 14% of subjects achieved the LDL-c targets as suggested by 2016 and 2019 EAS-ESC Guidelines, respectively. Based on anticipated response to treatment, we estimated that 38% of the entire population would require high-intensity-statin (HI-statin), 27% a combination of HI-statin plus ezetimibe, and 27% the addition of proprotein-convertase-subtilisin/kexin-9 (PCSK9) inhibitors. These LLT intensifications would reduce the incidence of cardiovascular events by 32%, from 23.511 to 16.022 events per 100.000 patients/10-years (incidence-rate-ratio 0.68; 95% C.I 0.67-0.70, p?<?0.001). CONCLUSIONS:Despite the increase in use of LLT in T2D over the last decades, a large proportion of subjects with T2D did not achieve their LDL-c targets. Given the very high cardiovascular risk of these patients, improving LLT is expected to have a dramatic impact on cardiovascular event prevention.
Project description:There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.The UMIN Clinical Trials Registry UMIN000002593.
Project description:We investigated (1) the relationship between low-density lipoprotein cholesterol (LDL-C) and vascular function in patients receiving and those not receiving statin therapy and (2) optimal level of LDL-C for maintenance of vascular function. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were inversely correlated with LDL-C in the 957 statin naïve subjects but not in the 392 subjects receiving statin therapy. In statin naïve subjects, non-high LDL-C (?100?mg/dL) was independently associated with a decrease in adjusted odds ratio of the low tertile of FMD (OR: 0.62, 95% CI: 0.45-0.85; P?=?0.003) and NID (OR: 0.69, 95% CI: 0.50-0.96; P?=?0.03). Adjusted odds ratio of the low tertile of FMD was significantly lower in the low LDL-C group (?70?mg/dL) (OR: 0.47, 95% CI, 0.27-0.81; P?=?0.006) and in the moderate LDL-C group (70.1-100?mg/dL) (OR: 0.66, 95% CI, 0.48-0.94; P?=?0.02) than in the high LDL-C group (>100?mg/dL). There was no significant difference in FMD between the low LDL-C group and moderate LDL-C group. There were significant relationships of FMD and NID with LDL-C levels in statin naïve subjects. In a general population, LDL-C of ?100?mg/dL may be the optimal target level for maintenance of endothelial function.