RESUMEN
Apolipoproteins are associated with survival among patients on hemodialysis (HD), but these associations might be influenced by dysfunctional (oxidized) high-density lipoprotein (HDL). We assessed associations among apolipoproteins and oxidized HDL, mortality and cardiovascular disease (CVD) events in patients on HD. This prospective observational study examined 412 patients on prevalent HD. Blood samples were obtained before dialysis at baseline to measure lipids, apolipoproteins, oxidized LDL, oxidized HDL, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 at baseline, and HDL-C and hs-CRP were measured 12 months later. Patients were then prospectively followed-up (mean, 40 months) and all-cause mortality and composite CVD events were analyzed. Associations between variables at baseline and clinical outcome were assessed by Cox proportional hazards modeling (n = 412) and Cox hazards modeling with a time-varying covariate with HDL-C and hs-CRP (n = 369). Quartiles of apolipoproteins and oxidized HDL were not associated with all-cause mortality. However, Cox proportional hazards models with quartiles of each variable adjusted for confounders and hs-CRP or IL-6 identified apolipoprotein (apo)B-to-apoA-I ratio (apoB/apoA-I) and oxidized HDL, but not apoA-I or apoA-II, as independent risk factors for composite CVD events. These associations were confirmed by Cox proportional hazards modeling with time-varying covariates for hs-CRP. ApoB/apoA-I was independently associated with composite CVD events in 1-standard deviation (SD) increase-of-variables models adjusted for the confounders, oxidized HDL and hs-CRP. However, these associations disappeared from the model adjusted with IL-6 instead of hs-CRP, and oxidized HDL and IL-6 were independently associated with composite CVD events. Findings resembled those from Cox proportional hazards modeling using time-varying covariates with HDL-C adjusted with IL-6. In conclusion, both oxidized HDL and apoB/apoA-I might be associated with CVD events in patients on prevalent HD, while associations of apoB/apoA-I with CVD events differed between models of apoB/apoA-I quartiles and 1-SD increases, and were influenced by IL-6.
Asunto(s)
Apolipoproteínas/sangre , Enfermedades Cardiovasculares/sangre , Lipoproteínas HDL/sangre , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Interleucina-6/sangre , Lípidos/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
AIM: Chronic kidney disease (CKD) may lead to reduced concentrations of high-density lipoprotein (HDL) and its subfractions (HDL2 and HDL3), and damage them via inflammation and oxidative stress. The present study aimed to determine the contribution of such changes to cardiovascular disease (CVD) in patients with CKD. METHODS: The levels of total cholesterol, low-density lipoprotein cholesterol, HDL-C, HDL2, HDL3, apolipoproteins, malondialdehyde-modified LDL (MDA-LDL), oxidized (ox) HDL, oxHDL2, and oxHDL3 were measured in blood samples from patients with CKD (stages 2-5, n=86) who were not on dialysis and from patients undergoing hemodialysis (CKD stage 5D, n=25). The patients were followed up for 28±9 months after baseline examinations and CVD events were recorded. RESULT: The levels of HDL3 and ApoA1 in HDL3 fraction decreased according to CKD severity, whereas those of HDL2 and ApoA1 in HDL2 fraction did not differ. The levels of oxHDL were similar across CKD stages. The levels of oxHDL3 and MDA-LDL were decreased, whereas those of oxHDL2 increased according to CKD severity. Multivariate analyses using the Cox proportional hazards model selected high levels of oxHDL and its subfractions, and those adjusted with HDL-C and HDL subfractions or ApoA1 in HDL fractions respectively, compared with HDL-C and HDL subfractions or ApoA1 in HDL fractions alone as independent risk factors for CVD events. CONCLUSION: The levels of HDL subfractions and their oxidized subfraction particles differed among patients with CKD. The increasing levels of oxHDL subfractions might cause a high frequency of CVD events in such patients.
Asunto(s)
Lipoproteínas HDL/sangre , Oxígeno/química , Insuficiencia Renal Crónica/sangre , Anciano , Apolipoproteína A-I/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Inflamación , Masculino , Malondialdehído/química , Persona de Mediana Edad , Análisis Multivariante , Estrés Oxidativo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVES: Here, we assessed the impact of oxidized high-density lipoprotein (oxHDL), dysfunctional HDL, on mortality and cardiovascular disease (CVD) events in prevalent HD patients and compared oxHDL to interleukin-6 (IL-6), a strong predictor of CVD events in HD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This prospective study examined a cohort of prevalent HD patients (n=412). Blood samples were obtained at baseline to measure lipids, high-sensitive C-reactive protein (hsCRP), IL-6, oxidized low-density lipoprotein, N-terminal pro B-type natriuretic peptide, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase, adiponectin, and oxHDL. Carotid intima-media thickness (CIMT) was assessed at baseline and 3-year follow-up. Nutritional status was assessed by subjective global assessment (SGA), body mass index, and geriatric nutritional risk index (GNRI). After the baseline assessment, study patients were prospectively followed up (mean observational period, 40 months). RESULTS: At baseline, patients with high oxHDL had a worse nutritional state and higher HDL-cholesterol (HDL-chol), ICAM-1, and adiponectin levels and a higher oxHDL/HDL-chol ratio than low oxHDL patients. A combination of high oxHDL and high IL-6 was significantly associated with increased CIMT at baseline and a larger increase in CIMT at 3-year follow-up. High oxHDL did not predict all-cause mortality; however, it was significantly associated with CVD-related mortality and composite CVD events, particularly with concomitant high IL-6. These associations were confirmed in multivariate Cox hazard models adjusted with confounding variables. CONCLUSIONS: High oxHDL, particularly with concomitant high IL-6, may be associated with an increased risk of CVD events and CVD-related mortality in prevalent HD patients.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Fallo Renal Crónico/terapia , Lipoproteínas LDL/sangre , Diálisis Renal/efectos adversos , Anciano , Análisis de Varianza , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/mortalidad , Grosor Intima-Media Carotídeo , Distribución de Chi-Cuadrado , Femenino , Evaluación Geriátrica , Humanos , Interleucina-6/sangre , Japón , Estimación de Kaplan-Meier , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Evaluación Nutricional , Estado Nutricional , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Diálisis Renal/mortalidad , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
OBJECTIVE: The benefits of fenofibrate, a peroxisome proliferator-activated receptor α agonist, against cardiovascular risk factors have been established. To clarify the underlying mechanisms of these benefits, we examined the effects of fenofibrate on insulin resistance, hypertension, inflammation, oxidative stress and coagulation markers in patients with metabolic syndrome. METHODS: Eleven Japanese patients with metabolic syndrome underwent physical examinations and blood tests before and after treatment with fenofibrate 200 mg daily for 8 weeks. RESULTS: Fenofibrate significantly decreased systolic blood pressure, pulse wave velocity, serum insulin, insulin resistance (calculated from the homeostasis model assessment), total cholesterol, triglyceride, remnant-like particles cholesterol, uric acid, D-dimer, fibrinogen, serum amyloid A/low-density lipoprotein (LDL) and apoA1/LDL levels. It also significantly increased levels of high molecular weight adiponectin, thrombomodulin and high-density lipoprotein cholesterol in these patients. Plasminogen activator inhibitor-1, C-reactive protein, fasting plasma glucose and thrombin-antithrombin complex levels did not change. LIMITATION: Small sample size. CONCLUSION: Short-term fenofibrate administration not only improved lipid profiles, but also ameliorated insulin resistance, hypertension and oxidative stress markers in patients with metabolic syndrome, suggesting that fenofibrate can decrease the risk of arteriosclerosis through various pathways.
RESUMEN
BACKGROUND: Serum cystatin C is not only a marker of renal function but also acts as an independent risk factor for cardiovascular damage, heart failure, and death. It is known that the initiation and progression of these cardiovascular events contributes to renal dysfunction and chronic inflammation. In this study, we investigated the relationship between cystatin C and proinflammatory cytokines. METHODS: Eighty-eight patients with essential hypertension participated in the study, which involved measuring proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP). RESULTS: Positive correlations were detected between cystatin C and estimated glomerular filtration rate (eGFR) (r = -0.503, p < 0.001), systolic blood pressure (r = -0.246, p = 0.034), and pulse pressure (r = -0.295, p = 0.010). In contrast, serum creatinine correlated only with eGFR (r = -0.755, p < 0.001) and eGFR correlated only with age (r = -0.339, p = 0.001) and not with the other clinical parameters, whereas cystatin C also correlated with log natural (ln) IL-6 (r = -0.247, p = 0.033) and ln TNF-α (r = -0.405, p < 0.001) but not with CRP (r = -0.188, p = 0.108). In contrast, plasma creatinine and eGFR did not correlate with any of these proinflammatory cytokines. Stepwise regression analysis showed that ln TNF-α, eGFR and pulse pressure were independent determinants of serum cystatin C concentration. CONCLUSION: This study showed that cystatin C is a marker of inflammation as well as renal function.
Asunto(s)
Biomarcadores/sangre , Inflamación/sangre , Anciano , Presión Sanguínea , Proteína C-Reactiva/análisis , Creatinina/sangre , Estudios Transversales , Cistatina C , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Hipertensión/sangre , Inflamación/fisiopatología , Interleucina-6/sangre , Riñón/fisiología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Oxidized HDL (oxHDL) may behave as proinflammatory HDL because of reduced anti-inflammatory capacity and is considered a risk factor for mortality in patients on maintenance hemodialysis (MHD). The study presented here assessed the effect of oxHDL on protein-energy wasting (PEW) in MHD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective study examined a cohort of MHD patients (n = 176) who were not taking lipid-lowering drugs. Blood samples were obtained to measure albumin, lipids, high-sensitivity C-reactive protein (hsCRP), oxidized LDL (oxLDL), and oxHDL. PEW was assessed by subjective global assessment (SGA) and geriatric nutritional risk index (GNRI). Measurements and assessment of nutritional status were followed up 1 year later. RESULTS: OxHDL was significantly increased in patients with PEW at baseline. High oxHDL and high hsCRP were significantly associated with PEW, and receiver operating characteristic curves for oxHDL and hsCRP showed statistically similar accuracy for predicting SGA-positive status. According to multivariate regression models, high oxHDL had a significant influence on PEW in patients, particularly those with high hsCRP. Decreased changes in GNRI and high prevalence of SGA-positive status at 1 year were more common in patients with high oxHDL at baseline and 1 year later than in patients with low oxHDL at both time points. CONCLUSIONS: A high oxHDL state may be associated with PEW estimated by GNRI and SGA, particularly concomitant with inflammation in MHD patients.
Asunto(s)
Mediadores de Inflamación/sangre , Lipoproteínas HDL/sangre , Desnutrición Proteico-Calórica/sangre , Diálisis Renal/efectos adversos , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Distribución de Chi-Cuadrado , Femenino , Humanos , Japón , Modelos Lineales , Lipoproteínas LDL/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estado Nutricional , Oportunidad Relativa , Oxidación-Reducción , Estudios Prospectivos , Desnutrición Proteico-Calórica/etiología , Curva ROC , Medición de Riesgo , Factores de Riesgo , Albúmina Sérica/metabolismo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
AIM: In patients with essential hypertension (EHT), the intrarenal resistance index (RI) has been shown to be related to the severity of target organ damage (TOD). Cystatin C is has been reported to be related to TOD in EHT. The aim of the present study was to clarify whether the RI predicts future renal function assessed by cystatin C levels in EHT. METHODS: One-hundred and twelve patients participated. RI and cystatin C were measured at baseline, and 12 months later, cystatin C was measured again. RESULTS: The patients were divided into 2 groups according to RI value: the low RI group (RI<0.7) and the high RI group (RI> or =0.7). After 12 months, cystatin C levels were significantly elevated in the high RI group, whereas the levels remained unchanged in the low RI group. Stepwise regression analysis using the baseline values of RI, age, pulse pressure, HbA1c, cystatin C, log-transformed (ln) C-reactive protein and ln urinary albumin/creatinine as covariates, showed baseline RI was the only independent determinant of the time-related changes in cystatin C levels. CONCLUSION: This finding suggests that the renal RI may be a marker of future renal dysfunction in EHT.
Asunto(s)
Hipertensión/fisiopatología , Enfermedades Renales/etiología , Riñón/irrigación sanguínea , Circulación Renal , Resistencia Vascular , Factores de Edad , Anciano , Albuminuria/etiología , Albuminuria/fisiopatología , Biomarcadores/sangre , Biomarcadores/orina , Presión Sanguínea , Creatinina/sangre , Cistatina C/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Hemoglobina Glucada/metabolismo , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Hipertensión/diagnóstico por imagen , Enfermedades Renales/sangre , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Análisis de Regresión , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Ultrasonografía Doppler DúplexRESUMEN
BACKGROUND AND OBJECTIVES: The present study assesses the effects of the oxidative stress marker, myeloperoxidase (MPO), and the possible MPO-related oxidative stress marker, oxidative alpha(1)-antitrypsin (oxAT), on carotid intima-media thickness (CIMT) and protein-energy wasting (PEW) in patients on hemodialysis (HD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Blood samples were obtained from 383 patients before HD to measure WBC count, serum albumin, lipids, high-sensitivity C-reactive protein (CRP), alpha(1)-antitrypsin (AT), interleukin-6, oxidative LDL-C, MPO, and oxAT. We assessed both CIMT and the geriatric nutritional risk index (GNRI) in this cross-sectional competitive study. RESULTS: Levels of MPO and oxAT correlated. Myeloperoxidase was associated with max-CIMT, and oxAT correlated with max-CIMT and GNRI. Multivariate linear regression models showed that MPO and oxAT were independent predictors of increasing max-CIMT, whereas oxAT, but not MPO, independently correlated with GNRI. In four combined MPO and oxAT groups classified according to median values, a multinomial logistic regression model showed that high MPO together with high oxAT was independently associated with increased max-CIMT. Moreover, the OR for max-CIMT with positive PEW and high MPO was significantly increased in the four groups with combined MPO and PEW. CONCLUSIONS: High MPO with high oxAT and high MPO with PEW seem to contribute to plaque formation in patients on HD, whereas elevated MPO or oxAT alone might not predict increasing CIMT. In contrast, a high oxAT value seems to be an independent predictor of PEW in patients on HD.
Asunto(s)
Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/etiología , Fallo Renal Crónico/terapia , Peroxidasa/sangre , Desnutrición Proteico-Calórica/etiología , Diálisis Renal , alfa 1-Antitripsina/sangre , Anciano , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estado Nutricional , Estrés Oxidativo , Valor Predictivo de las Pruebas , Desnutrición Proteico-Calórica/sangre , Medición de Riesgo , Factores de Riesgo , Túnica Íntima/diagnóstico por imagen , Túnica Media/diagnóstico por imagen , Ultrasonografía , Regulación hacia ArribaRESUMEN
BACKGROUND: Serum low-density lipoprotein (LDL), which includes apolipoprotein A-I (apoAI-LDL) may be generated by oxidization in the serum of patients with coronary artery disease (CAD). We determine the utility of the serum apoAI-LDL level as a novel coronary risk factor. METHODS: We measured serum apoAI-LDL in 473 consecutive patients who underwent diagnostic coronary angiography. Serum levels of apoAI-LDL were assayed by a newly developed ELISA. RESULTS: The patients consisted of 84 with unstable angina (UA), 259 with stable CAD, and 130 without CAD (control). The serum level of apoAI-LDL was higher in CAD patients than in the control group (31.4 (22.1-41.4) microg/ml vs. 24.6 (18.4-29.2) microg/ml, respectively, p<0.001), as well as in patients with UA compared to those with stable CAD 44.5 (35.8-51.9) microg/ml vs. 27.1 (19.5-35.6) microg/ml, respectively, p<0.0001) (data are expressed as the median (25th-75th percentiles)). By logistic regression analysis, only apoAI-LDL was independent, being significantly able to predict CAD (odds ratio: 1.50, 95% CI: 1.23-1.82, p<0.001), and differentiate unstable angina (odds ratio: 1.80, 95% CI: 1.48-2.17, p<0.001) after controlling for classical risk factors. CONCLUSION: The serum level of apoAI-LDL, a newly identified component of oxidized LDL, may be a more sensitive marker of CAD and acute coronary syndrome than CRP.
Asunto(s)
Apolipoproteína A-I/sangre , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Anciano , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
In recent years, it has been reported that the acute-phase proteins C-reactive protein(CRP) and serum amyloid A(SAA), the sera levels of which are elevated in inflammation, are also elevated in coronary artery disease such as acute myocardial infarction. Also, high-sensitivity CRP assay is thought to be useful in predicting the prognosis of coronary heart disease. While investigating complexes of acute-phase proteins and low-density lipoprotein(LDL), we found a complex of LDL and SAA(SAA/LDL complex). The SAA/LDL complex in blood are formed from LDL and HDL by an oxidation reaction. Therefore, we developed an ELISA using anti-human SAA antibody and anti-human apoB, and determined a new method for measuring SAA/LDL complex in sera. We evaluated SAA/LDL complex as a new marker for prediction of prognosis in addition to the ordinary markers in consecutive 140 patients with stable coronary heart disease who had at least 1 coronary artery stenosis more than 50% in diameter at the diagnostic coronary angiography. Of these 140 patients, 2 developed fatal myocardial infarction, 2 cerebral infarction, and 17 angina pectoris requiring coronary revascularization therapy during 1 year and 6 months after blood examinations. The SAA/LDL complex value in this EVENT group of 21 patients was significantly higher than that in the control group of 119 individuals. High-sensitivity CRP (hs-CRP) assay and SAA measurement showed no significant difference between the 2 groups. The SAA/LDL complex reflects intravascular inflammation directly and can be a new marker more sensitive than hs-CRP or SAA for prediction of prognosis in patients with stable coronary artery disease.