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1.
Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.
Casey, KA, Smith, MA, Sinibaldi, D, Seto, NL, Playford, MP, Wang, X, Carlucci, PM, Wang, L, Illei, G, Yu, B, et al
Arthritis & rheumatology (Hoboken, N.J.). 2021;(3):459-471
Abstract
OBJECTIVE Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
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2.
Comparison of the effectiveness of Martin's equation, Friedewald's equation, and a Novel equation in low-density lipoprotein cholesterol estimation.
Song, Y, Lee, HS, Baik, SJ, Jeon, S, Han, D, Choi, SY, Chun, EJ, Han, HW, Park, SH, Sung, J, et al
Scientific reports. 2021;(1):13545
Abstract
Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500-600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin's equation may be optimal for LDL-C and ASCVD risk estimation.
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3.
Extra Virgin Olive Oil Prevents the Age-Related Shifts of the Distribution of HDL Subclasses and Improves Their Functionality.
Otrante, A, Trigui, A, Walha, R, Berrougui, H, Fulop, T, Khalil, A
Nutrients. 2021;(7)
Abstract
High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in regulating reverse cholesterol transport (RCT), a process by which excess cholesterol is transported back to the liver for elimination. However, RCT can be altered in the presence of cardiovascular risk factors, such as aging, which contributes to the increase in the incidence of cardiovascular diseases (CVD). The present study was aimed at investigating the effect of extra virgin olive oil (EVOO) intake on the cholesterol efflux capacity (CEC) of HDL, and to elucidate on the mechanisms by which EVOO intake improves the anti-atherogenic activity of HDL. A total of 84 healthy women and men were enrolled and were distributed, according to age, into two groups: 27 young (31.81 ± 6.79 years) and 57 elderly (70.72 ± 5.6 years) subjects. The subjects in both groups were given 25 mL/d of extra virgin olive oil (EVOO) for 12 weeks. CEC was measured using J774 macrophages radiolabeled with tritiated cholesterol ((3H) cholesterol). HDL subclass distributions were analyzed using the Quantimetrix Lipoprint® system. The HDL from the elderly subjects exhibited a lower level of CEC, at 11.12% (p < 0.0001), than the HDL from the young subjects. The CEC of the elderly subjects returned to normal levels following 12 weeks of EVOO intake. An analysis of the distribution of HDL subclasses showed that HDL from the elderly subjects were composed of lower levels of large HDL (L-HDL) (p < 0.03) and higher levels of small HDL (S-HDL) (p < 0.002) compared to HDL from the young subjects. A multiple linear regression analysis revealed a positive correlation between CEC and L-HDL levels (r = 0.35 and p < 0.001) as well as an inverse correlation between CEC and S-HDL levels (r = -0.27 and p < 0.01). This correlation remained significant even when several variables, including age, sex, and BMI as well as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and glucose levels (β = 0.28, p < 0.002, and β = 0.24, p = 0.01) were accounted for. Consuming EVOO for 12 weeks modulated the age-related difference in the distribution of HDL subclasses by reducing the level of S-HDL and increasing the level of intermediate-HDL/large-HDL (I-HDL/L-HDL) in the elderly subjects. The age-related alteration of the CEC of HDL was due, in part, to an alteration in the distribution of HDL subclasses. A diet enriched in EVOO improved the functionality of HDL through an increase in I-HDL/L-HDL and a decrease in S-HDL.
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4.
Icosapent ethyl reduces atherogenic markers in high-risk statin-treated patients with stage 3 chronic kidney disease and high triglycerides.
Vijayaraghavan, K, Szerlip, HM, Ballantyne, CM, Bays, HE, Philip, S, Doyle, RT, Juliano, RA, Granowitz, C
Postgraduate medicine. 2019;(6):390-396
Abstract
Objective: Patients with chronic kidney disease (CKD) have increased cardiovascular disease (CVD) risk, likely driven by atherogenic and inflammatory markers beyond low-density lipoprotein cholesterol (LDL-C). The objective of this hypothesis-generating post hoc subgroup analysis was to explore the effects of icosapent ethyl at 2 or 4 g/day (prescription pure ethyl ester of the omega-3 fatty acid eicosapentaenoic acid [EPA]) on atherogenic lipid, apolipoprotein, inflammatory parameters (high-sensitivity C-reactive protein [hsCRP], lipoprotein-associated phospholipase A2 [Lp-PLA2]), and oxidative parameters (oxidized-LDL [ox-LDL]) in statin-treated patients from ANCHOR with stage 3 CKD.Methods: The 12-week ANCHOR study evaluated icosapent ethyl in 702 statin-treated patients at increased CVD risk with triglycerides (TG) 200-499 mg/dL despite controlled LDL-C (40-99 mg/dL). This post-hoc analysis included patients from ANCHOR with stage 3 CKD (estimated glomerular filtration rate [eGFR] ≤60 mL/min/1.73 m2 for ≥3 months) randomized to icosapent ethyl 4 g/day (n = 19), 2 g/day (n = 30), or placebo (n = 36).Results: At the prescription dose of 4 g/day, icosapent ethyl significantly reduced TG (-16.9%; P = 0.0074) and other potentially atherogenic lipids/lipoproteins, ox-LDL, hsCRP, and Lp-PLA2, and increased plasma and red blood cell EPA levels (+879% and +579%, respectively; both P < 0.0001) versus placebo. Icosapent ethyl did not significantly alter eGFR or serum creatinine. Safety and tolerability were similar to placebo.Conclusions: In patients with stage 3 CKD at high CVD risk with persistent high TG despite statins, icosapent ethyl 4 g/day reduced potentially atherogenic and other cardiovascular risk factors without raising LDL-C, with safety similar to placebo. These findings suggest prospective investigation may be warranted.
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5.
Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging.
Tarkin, JM, Joshi, FR, Evans, NR, Chowdhury, MM, Figg, NL, Shah, AV, Starks, LT, Martin-Garrido, A, Manavaki, R, Yu, E, et al
Journal of the American College of Cardiology. 2017;(14):1774-1791
Abstract
BACKGROUND Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. OBJECTIVES This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. METHODS We confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis. RESULTS Target SSTR2 gene expression occurred exclusively in "proinflammatory" M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients. CONCLUSIONS We validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188).
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6.
Clinical Phenotype and Microvascular Dynamics of Subjects with Endothelial Dysfunction as Assessed by Peripheral Tonometry.
Venturi, E, Pinnola, S, Morizzo, C, Boldrini, B, Rossi, M, Trifirò, S, Tricò, D, Natali, A, ,
Microcirculation (New York, N.Y. : 1994). 2016;(3):230-9
Abstract
OBJECTIVE To evaluate the characteristics and the determinants of ED, as measured by PAT. METHODS We measured basal and post-ischemic digital pulse amplitude (EndoPAT(®)) in a mixed outpatient population of 206 diabetic and 101 non-diabetic subjects, of whom 50% with clinically manifest CVD, undergoing to an extensive clinical, biochemical, and vascular phenotype characterization. RESULTS The major characteristics of ED (tertile 1 vs 3), in addition to lower post-ischemic vasodilatory reserve (34 vs 203%), were a 3-fold higher baseline pulse amplitude and a delayed (60 second) peak response. The main determinant of this response was the baseline pulse amplitude (Stβ = -0.59), which in turn was influenced by age (Stβ = 0.13), central obesity (Stβ = 0.27) and inversely by HDL cholesterol (Stβ = -0.17), and systolic blood pressure (Stβ = -0.19). No association was observed with cardiovascular risk factors, previous cardiovascular event or extent of atherosclerosis (ABI and IMT, PWV). Most of the variability in baseline pulse amplitude remained unexplained (r(2) = 0.14). CONCLUSIONS ED, as detected by PAT in a population enriched with subjects at risk for CVD neither reflects the burden of classical risk factors (under treatment) nor the severity of atherosclerosis. Aside from central obesity and HDL cholesterol, most of the factors responsible for this ED remain unknown.
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7.
The association of circulating microRNA-30c with atherogenic lipoprotein subfractions and composition.
Eastwood, J, Caslake, MJ, Sodi, R
Clinica chimica acta; international journal of clinical chemistry. 2016;:135-139
Abstract
Circulating miR-30c has been linked to various aspects of cholesterol homeostasis. The aim of this study was to determine the association of circulating miR-30c with the atherogenic lipoprotein subfractions. Samples from subjects who were given placebo (n=22) in a randomised, double-blind crossover study were used. Subjects were divided into non-atherogenic lipoprotein phenotype (Non-ALP; n=12; triglycerides <2.0mmol/L) and atherogenic lipoprotein phenotype (ALP; n=10; triglycerides ≥2.0mmol/L) groups. All lipid and lipoprotein measurements, RNA extraction and reverse transcription-quantitative real-time polymerase chain reaction were undertaken using standard procedures. Subjects with ALP weighed significantly more than their non-ALP counterparts (p=0.023). In the non-ALP group there was significant correlation between miR-30c and components within VLDL1, namely triglyceride which showed a negative association (p=0.035) whereas phospholipids and cholesterol-ester were both positively correlated (p=0.025 and 0.014, respectively). In contrast, in the ALP group there was a significant correlation between the expression of miR-30c and components within VLDL2, namely triglyceride, which was positively associated (p=0.013). This study reveals specificity with regards to the effect of miR-30c on VLDL subfractions based on the individual's lipoprotein phenotype and implicates roles for microsomal-triglyceride transfer-protein and cholesteryl-ester-transfer-protein in LDL and VLDL metabolism, respectively.
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8.
64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients.
Malmberg, C, Ripa, RS, Johnbeck, CB, Knigge, U, Langer, SW, Mortensen, J, Oturai, P, Loft, A, Hag, AM, Kjær, A
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2015;(12):1895-900
Abstract
UNLABELLED The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers (68)Ga-DOTATOC and (64)Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. METHODS Sixty consecutive patients with neuroendocrine tumors underwent both (68)Ga-DOTATOC and (64)Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool-corrected target-to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. RESULTS We found detectable uptake of both tracers in all arterial segments studied. Uptake of (64)Cu-DOTATATE was significantly higher than (68)Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of (64)Cu-DOTATATE using SUV (r = 0.4; P = 0.004) as well as target-to-background ratio (r = 0.3; P = 0.04), whereas no association was found with (68)Ga-DOTATOC. The association of risk factors and maximum SUV of (64)Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P < 0.001, P = 0.01, P = 0.005, and P = 0.03, respectively). CONCLUSION In a series of oncologic patients, vascular uptake of (68)Ga-DOTATOC and (64)Cu-DOTATATE was found, with highest uptake of the latter. Uptake of (64)Cu-DOTATATE, but not of (68)Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for (64)Cu-DOTATATE in the assessment of atherosclerosis.
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9.
Alogliptin: a new dipeptidyl peptidase-4 inhibitor with potential anti-atherogenic properties.
Kutoh, E, Kaneoka, N, Hirate, M
Endocrine research. 2015;(2):88-96
Abstract
OBJECTIVES The aim of this study is to evaluate the effects of alogliptin on metabolic profiles in relation to those of glycemic control. PATIENTS AND METHODS Treatment naïve subjects with type 2 diabetes received 12.5-25 mg/d alogliptin monotherapy (n = 59). A novel parameter called A1c index was used to assess the glycemic efficacy. The subjects were divided into three groups according to this index; super-responders, average responders and poor-responders. At 3 months, levels of the metabolic parameters were compared with those at baseline between super-responders (n = 20) and poor-responders (n = 21). RESULTS At baseline, total cholesterol, non-high density lipoprotein cholesterol and atherogenic index were significantly higher in super-responders than poor-responders. At 3 months, significant increases of beta-cell function (HOMA-B) and decreases of insulin resistance (HOMA-R) or these atherogenic lipids were observed in super-responders, while significant increases of HOMA-R were observed in poor-responders. Significant correlations were observed between A1c index and the changes of these atherogenic lipids. In super-responders, significant correlations were observed between the changes (Δ) of glycemic parameters (A1c index or fasting blood sugar) and ΔHOMA-R and/or ΔHOMA-B, while in poor-responders, significant correlations were observed between ΔHOMA-R and ΔHOMA-B. Lean subjects gained weight and the changes of body mass index had significant negative correlations with A1c index. CONCLUSIONS These results indicate that (1) glucose lowering efficacy of alogliptin is closely linked to atherogenic lipids. (2) alogliptin can down-regulate atherogenic lipids. (3) glycemic efficacy of alogliptin appears to be determined by the balance of its capacity in modulating insulin resistance and beta-cell function.
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10.
Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study.
Ballantyne, CM, Hoogeveen, RC, Raya, JL, Cain, VA, Palmer, MK, Karlson, BW, ,
Atherosclerosis. 2014;(1):86-93
Abstract
OBJECTIVES Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent. METHODS Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks. RESULTS Significantly greater (p < 0.05) reductions in LDL-C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ∼10-14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced β-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable. CONCLUSION Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe.