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Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease: A single lipid center real-world experience.
Scicali, R, Di Pino, A, Urbano, F, Ferrara, V, Marchisello, S, Di Mauro, S, Scamporrino, A, Filippello, A, Rabuazzo, AM, Purrello, F, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(3):869-879
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) may be crucial in subjects with familial hypercholesterolemia (FH). We aimed to evaluate the effect of the inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9-i) on steatosis biomarkers such as triglyceride-glucose index (TyG) and hepatic steatosis index (HSI) and analyse the role of TG/HDL in this population before and after adding-on PCSK9-i. METHODS AND RESULTS In this observational study, we evaluated 26 genetically confirmed FH patients with NAFLD and an LDL-C off-target despite high-intensity statins plus ezetimibe. All patients added PCSK9-i treatment and obtained biochemical analysis and TyG and HSI evaluation at baseline and after six months of PCSK9-i. No difference of steatosis biomarkers was found after adding-on PCSK9-i therapy. In a secondary analysis, we divided the study population in two groups according to TG/HDL median value: high TG/HDL group (H-TG/HDL) and low TG/HDL group (L-TG/HDL). TyG and HSI were significantly lower in the L-TG/HDL than H-TG/HDL group (for TyG 9.05 ± 0.34 vs 9.51 ± 0.32; for HSI 38.43 ± 1.35 vs 41.35 ± 1.83, p value for both < 0.05). After six months of PCSK9-i therapy, TyG and HSI were significantly reduced in the L-TG/HDL group after PCSK9-i therapy (-7.5% and -8.4% respectively, p value for both < 0.05) and these biomarkers were lower compared to H-TG/HDL group (for TyG 8.37 ± 0.14 vs 9.19 ± 0.12; for HSI 35.19 ± 1.32 vs 39.48 ± 1.33, p value for both < 0.05). CONCLUSION In conclusion, PCSK9-i therapy significantly ameliorate steatosis biomarkers in FH patients with low TG/HDL; our results appear to be consistent with a beneficial role of PCSK9-i on steatosis biomarkers in FH subjects with NAFLD.
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Inflammation Alters Relationship Between High-Density Lipoprotein Cholesterol and Cardiovascular Risk in Patients With Chronic Kidney Disease: Results From KNOW-CKD.
Kim, JY, Park, JT, Kim, HW, Chang, TI, Kang, EW, Ahn, C, Oh, KH, Lee, J, Chung, W, Kim, YS, et al
Journal of the American Heart Association. 2021;(16):e021731
Abstract
Background The function of high-density lipoprotein can change from protective to proatherosclerotic under inflammatory conditions. Herein, we studied whether inflammation could modify the relationship between high-density lipoprotein level and risk of adverse outcomes in patients with chronic kidney disease . Methods and Results In total, 1864 patients from the prospective KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were enrolled. The main predictor was high-density lipoprotein cholesterol (HDL-C) level. Presence of inflammation was defined by hs-CRP (high-sensitivity C-reactive protein) level of ≥1.0 mg/L. The primary outcome was extended major adverse cardiovascular events. During 9231.2 person-years of follow-up, overall incidence of the primary outcome was 15.8 per 1000 person-years. In multivariable Cox analysis after adjusting for confounders, HDL-C level was not associated with the primary outcome. There was a significant interaction between the inflammatory status and HDL-C for risk of extended major adverse cardiovascular events (P=0.003). In patients without inflammation, the hazard ratios (HRs) (95% CIs) for HDL-C levels <40, 50 to 59, and ≥60 mg/dL were 1.10 (0.50-1.82), 0.95 (0.50-1.82), and 0.42 (0.19-0.95), respectively, compared with HDL-C of 40 to 49 mg/dL. However, the significant association for HDL-C ≥60 mg/dL was not seen after Bonferroni correction. In patients with inflammation, we observed a trend toward increased risk of extended major adverse cardiovascular events in higher HDL-C groups (HRs [95% CIs], 0.73 [0.37-1.43], 1.24 [0.59-2.61], and 1.56 [0.71-3.45], respectively), but without statistical significance. Conclusions The association between HDL-C level and adverse cardiovascular outcomes showed reverse trends based on inflammation status in Korean patients with chronic kidney disease. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.
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Longitudinal Changes of Cytokines and Appetite in Older Hospitalized Patients.
Pourhassan, M, Babel, N, Sieske, L, Westhoff, TH, Wirth, R
Nutrients. 2021;(8)
Abstract
There are few data on the longitudinal association of cytokine and appetite among older hospitalized patients. We aimed to investigate the impact of the changes of inflammatory cytokines on appetite in older hospitalized patients. A total of 191 patients (mean age 81.3 ± 6.6 years, 64% women) participated in this prospective longitudinal observational study. Appetite was evaluated using the Edmonton Symptom Assessment System on admission and after seven days. Serum cytokines such as IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17, IL-18, IL-23 and IL-33, IFN-α2, IFN-γ, TNF-α and MCP-1 were measured both times. No significant differences in the mean serum levels of all the cytokines could be detected overtime in relation to appetite changes, except for IL-18. Appetite significantly deteriorated overtime in patients with increasing IL-18 levels and improved in those without significant changes in IL-18 levels. In a stepwise regression analysis, changes of IL-18 levels were the major independent predictor for the changes of patients' appetite and explained 4% of the variance, whereas other cytokines and variables, such as age, sex, infection and disease, did not show any impact on appetite changes. We conclude that IL-18 seems to exert a significant impact on appetite in acutely ill older hospitalized patients and should, therefore, be considered as a potential target in the diagnosis, prevention and treatment of malnutrition.
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Dietary Inflammatory Potential and Risk of Cardiovascular Disease Among Men and Women in the U.S.
Li, J, Lee, DH, Hu, J, Tabung, FK, Li, Y, Bhupathiraju, SN, Rimm, EB, Rexrode, KM, Manson, JE, Willett, WC, et al
Journal of the American College of Cardiology. 2020;(19):2181-2193
Abstract
BACKGROUND Inflammation plays an important role in cardiovascular disease (CVD) development. Diet modulates inflammation; however, it remains unknown whether dietary patterns with higher inflammatory potential are associated with long-term CVD risk. OBJECTIVES This study sought to examine whether proinflammatory diets are associated with increased CVD risk. METHODS We prospectively followed 74,578 women from the Nurses' Health Study (NHS) (1984-2016), 91,656 women from the NHSII (1991-2015), and 43,911 men from the Health Professionals Follow-up Study (1986-2016) who were free of CVD and cancer at baseline. Diet was assessed by food frequency questionnaires every 4 years. The inflammatory potential of diet was evaluated using a food-based empirical dietary inflammatory pattern (EDIP) score that was pre-defined based on levels of 3 systemic inflammatory biomarkers. RESULTS During 5,291,518 person-years of follow-up, we documented 15,837 incident CVD cases, including 9,794 coronary heart disease (CHD) cases and 6,174 strokes. In pooled analyses of the 3 cohorts, after adjustment for use of anti-inflammatory medications and CVD risk factors including body mass index, a higher dietary inflammatory potential, as indicated by higher EDIP scores, was associated with an increased risk of CVD (hazard ratio [HR] comparing the highest to lowest quintiles: 1.38; 95% confidence interval [CI]: 1.31 to 1.46; p for trend <0.001), CHD (HR: 1.46; 95% CI: 1.36 to 1.56; p for trend <0.001), and stroke (HR: 1.28; 95% CI: 1.17- to 1.39; p for trend <0.001). These associations were consistent across cohorts and between sexes, and they remained significant after further adjustment for other dietary quality indices. In a subset of study participants (n = 33,719), a higher EDIP was associated with a higher circulating profile of proinflammatory biomarkers, lower levels of adiponectin, and an unfavorable blood lipid profile (p < 0.001). CONCLUSIONS Dietary patterns with a higher proinflammatory potential were associated with higher CVD risk. Reducing the inflammatory potential of the diet may potentially provide an effective strategy for CVD prevention.
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High-Sensitivity C-Reactive Protein Discordance With Atherogenic Lipid Measures and Incidence of Atherosclerotic Cardiovascular Disease in Primary Prevention: The ARIC Study.
Quispe, R, Michos, ED, Martin, SS, Puri, R, Toth, PP, Al Suwaidi, J, Banach, M, Virani, SS, Blumenthal, RS, Jones, SR, et al
Journal of the American Heart Association. 2020;(3):e013600
Abstract
Background Inflammation is an independent causal risk factor for atherosclerotic cardiovascular diseases (ASCVDs). However, whether hsCRP (high-sensitivity C-reactive protein) is prognostic across various levels of atherogenic lipid measures such as low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B and total cholesterol/high-density lipoprotein cholesterol in primary prevention is unknown. Methods and Results We studied 9748 ARIC (Atherosclerosis Risk in Communities) study participants who were free of ASCVD at baseline (visit 4, 1996-1998) and had measurements of lipids, apolipoprotein B, and hsCRP. We used multivariable adjusted Cox models to estimate the risk of incident ASCVD events associated with hsCRP levels (less than/greater than or equal to median) in individuals where triple lipid measures combined (low-density lipoprotein cholesterol + non-high-density lipoprotein cholesterol + apolipoprotein B) or quadruple measures combined [triple + total cholesterol/high-density lipoprotein cholesterol] were less than versus greater than or equal to median cut points. Mean age of participants was 62.6±5.6 years; 59% women, 22% black. There were 1574 ASCVD events over median (interquartile range) follow-up of 18.4 (12.8-19.5) years, and discordance between hsCRP and lipid measures was prevalent in 50% of the population. hsCRP greater than or equal to median (2.4 mg/L), compared with less than median, was associated with an increased risk of ASCVD in individuals with less than median levels of the triple (adjusted hazard ratio, 1.33; 95% CI, 1.09-1.60) and quadruple (adjusted hazard ratio,1.47; 95% CI, 1.18-1.85) lipid measures. Such increased risk was consistent among individuals with low (<7.5%) or high (≥7.5%) estimated risk by the pooled cohort equation. There were no interactions by sex, diabetes mellitus, or statin use. Conclusions Our findings suggest that inflammation is independently associated with ASCVD regardless of atherogenic lipid levels and pooled cohort equation risk score in individuals without known ASCVD.
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A Pilot Study Assessing the Impact of rs174537 on Circulating Polyunsaturated Fatty Acids and the Inflammatory Response in Patients with Traumatic Brain Injury.
Waits, CMK, Bower, A, Simms, KN, Feldman, BC, Kim, N, Sergeant, S, Chilton, FH, VandeVord, PJ, Langefeld, CD, Rahbar, E
Journal of neurotrauma. 2020;(17):1880-1891
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Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in persons under age 45. The hallmark secondary injury profile after TBI involves dynamic interactions between inflammatory and metabolic pathways including fatty acids. Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) have been shown to provide neuroprotective benefits by minimizing neuroinflammation in rodents. These effects have been less conclusive in humans, however. We postulate genetic variants influencing PUFA metabolism in humans could contribute to these disparate findings. Therefore, we sought to (1) characterize the circulating PUFA response and (2) evaluate the impact of rs174537 on inflammation after TBI. A prospective, single-center, observational pilot study was conducted to collect blood samples from Level-1 trauma patients (N = 130) on admission and 24 h post-admission. Plasma was used to quantify PUFA levels and inflammatory cytokines. Deoxyribonucleic acid was extracted and genotyped at rs174537. Associations between PUFAs and inflammatory cytokines were analyzed for all trauma cases and stratified by race (Caucasians only), TBI (TBI: N = 47; non-TBI = 83) and rs174537 genotype (GG: N = 33, GT/TT: N = 44). Patients with TBI had higher plasma DHA levels compared with non-TBI at 24 h post-injury (p = 0.013). The SNP rs174537 was associated with both PUFA levels and inflammatory cytokines (p < 0.05). Specifically, TBI patients with GG genotype exhibited the highest plasma levels of DHA (1.33%) and interleukin-8 (121.5 ± 43.3 pg/mL), which were in turn associated with poorer outcomes. These data illustrate the impact of rs174537 on the post-TBI response. Further work is needed to ascertain how this genetic variant directly influences inflammation after trauma.
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Modified Glasgow Prognostic Score is a novel predictor of clinical outcome in heart failure with preserved ejection fraction.
Bolat, I, Biteker, M
Scandinavian cardiovascular journal : SCJ. 2020;(3):174-178
Abstract
Objectives. Although the modified Glasgow Prognostic Score (mGPS) has been reported to have prognostic value in patients with various cancers, the association between mGPS and prognosis in patients with heart diseases have not been well studied. The aim of this study was to evaluate the predictive value of mGPS in outcomes of patients with heart failure and preserved ejection fraction (HFpEF). Design. We prospectively followed consecutive adult patients with HFpEF admitted to the cardiology outpatient unit. Echocardiographic and laboratory data were recorded at enrolment. mGPS was scored as 0, 1, or 2 based on C-reactive protein (CRP) and albumin levels. Patients with both elevated CRP (>1 mg/dL) and hypoalbuminemia (<3.5 g/dL) are given mGPS of 2, patients with serum CRP ≤ 1 g/dL with or without hypoalbuminemia received scores of 0. Patients with only elevated CRP levels received mGPS of 1. The primary composite endpoint of the study was all-cause mortality or heart failure hospitalization through one year. Results. A total of 315 HFpEF outpatients were included, and 42 (13.3%) reached the primary endpoint at one year of follow-up. Compared to patients without mortality or heart failure-related hospitalization, patients who reached the primary endpoint during follow-up were older, were more likely be symptomatic, had higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and mGPS levels at study entry. Multivariate analysis showed that both NT-proBNP and mGPS were independent predictors of primary composite endpoint. Combining NT-proBNP with mGPS improved its prognostic value with an increase of area under the receiver operating characteristic curve from 0.759 to 0.822 (p = .001). Conclusion. This is the first study which demonstrates that mGPS is a predictor of outcomes in patients with HFpEF.
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Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.
Ter Horst, R, van den Munckhof, ICL, Schraa, K, Aguirre-Gamboa, R, Jaeger, M, Smeekens, SP, Brand, T, Lemmers, H, Dijkstra, H, Galesloot, TE, et al
Arteriosclerosis, thrombosis, and vascular biology. 2020;(7):1787-1800
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Abstract
OBJECTIVE Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.
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Is the prevalence of anemia in children living at high altitudes real? An observational study in Peru.
Choque-Quispe, BM, Alarcón-Yaquetto, DE, Paredes-Ugarte, W, Zaira, A, Ochoa, A, Gonzales, GF
Annals of the New York Academy of Sciences. 2020;(1):35-47
Abstract
Anemia diagnosis in populations residing at high altitude (HA) involves an adjustment of hemoglobin (Hb) values owing to the increase in its concentration with altitude. The suitability of the adjustment has been questioned since Hb concentrations depend on how adapted a population is to HA. In Peru, anemia in preschool children (PSC) is a matter of severe public concern for its high rates; in the city of Puno (∼3800 MASL), for example, 67.7% of children under 3 years are diagnosed with anemia. Here, we conducted an observational study in PSC living at different altitudes in Puno to assess Hb, iron status, and the suitability of altitude-adjusted Hb values in defining iron deficiency anemia. After adjusting Hb, 65.66% of the population had anemia, while only 4.8% of PSC had anemia when using unadjusted Hb. Receiver-operating characteristic curves using total body iron (TBI) as a marker of iron status are presented. In the 36- to 59-month age group, unadjusted Hb performed better than altitude-adjusted Hb. In the 6- to 35-month age group, anemia (adjusted or unadjusted) was not associated with TBI. We conclude that Hb adjustment by altitude is not appropriate. Anemia at an early age is not entirely attributable to iron deficiency.
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Evaluation of serum sST2 and sCD40L values in patients with microvascular angina.
Aslan, G, Polat, V, Bozcali, E, Opan, S, Çetin, N, Ural, D
Microvascular research. 2019;:85-93
Abstract
OBJECTIVES Coronary microvascular dysfunction plays a major role in the pathogenesis of microvascular angina (MVA). Along with endothelial dysfunction, microvascular atherosclerosis and inflammation seem to contribute to the development of coronary microvascular dysfunction. Serum soluble ST2 (sST2) and serum soluble CD40 ligand (sCD40L) are two biomarkers associated with inflammation and atherosclerosis. The aim of this study was to investigate the role of these biomarkers in the pathogenesis of MVA and determine their possible association with coronary microvascular dysfunction. METHODS A total of 152 patients were included in the study. Ninety-one patients with MVA {median age 56 years (40-79), of which 55 are women} and sixty-one controls {median age 52 (38-76), of which 29 are women} were included in the study. Serum concentration of sST2 and sCD40L were measured with a commercially available ELISA kit. RESULTS Serum sST2 (median 13.6 ng/ml; interquartile range (IQR), 3.5-63.8 ng/ml vs median 10.6 ng/ml; IQR, 2.9-34.2 ng/ml, p < 0.0005) and sCD40L (median 5.3 ng/ml; IQR, 0.5-20.6 ng/ml vs median 2.2 ng/ml; IQR, 0.7-10.8 ng/ml, p < 0.0005) were significantly higher in patients with MVA compared to controls. Analysis of the associations between these biomarkers and potential contributors of MVA revealed that serum sST2 showed a positive correlation with LDL-cholesterol (r = 0.19, p = 0.016) and serum sCD40L concentrations correlated positively with hs-CRP (r = 0.22, p = 0.005). In logistic regression analysis, sCD40L and hs-CRP but not sST2 were found to be significantly associated with MVA. CONCLUSION Higher serum concentrations of sST2 and sCD40L in MVA patients may be associated with inflammatory activation and coronary microvascular dysfunction. Larger studies are required for understanding their role in the pathogenesis of inflammatory and possibly fibrotic process in MVA patients.