Biomedical subjects

N Rifai

Publications and source records attributed to N Rifai.

At least 37 records · Page 2Linked to original sources

PubMed2001

Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.

CONTEXT: Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers. OBJECTIVE: To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD). DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status-matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls. MAIN OUTCOME MEASURE: Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol-HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100. RESULTS: In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P =.001), triglycerides (P =.001), apo B-100 (P =.001), fibrinogen (P =.02), CRP (P =.006), and the total cholesterol-HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P =.009) and apo A-I (P =.05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P =.40) and homocysteine (P =.90) were observed. In multivariable analyses, the total cholesterol-HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001). CONCLUSIONS: Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol-HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures.

Adult↗

PubMed2001

Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia.

BACKGROUND: Long-term therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce levels of C-reactive protein (CRP). However, the generalizability, speed of onset, and dose-response characteristics of this effect are uncertain. METHODS AND RESULTS: We measured CRP, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels among 785 patients with primary hypercholesterolemia at baseline and after 8 weeks of therapy with either 0.4 or 0.8 mg of cerivastatin. Overall, cerivastatin resulted in a 13.3% reduction in median CRP levels (P:<0.001) and a 24.5% reduction in mean CRP levels (P:<0.001). Although LDL-C promptly decreased in a dose-dependent manner (mean LDL-C reduction, 37.3% for 0.4 mg and 42.2% for 0.8 mg of cerivastatin), no clear dose-response effect of cerivastatin on CRP was observed, nor was there any substantive correlation between the magnitude of change in CRP and the magnitude of change in LDL-C (r=-0.08) or the magnitude of change in HDL-C (r=-0.04). Thus, <2% of the variance in the percent change in CRP over 8 weeks could be attributed to the percent change in either of these lipid parameters. Further, there was no evidence of correlation between baseline CRP levels and baseline lipid levels or between end-of-study CRP levels and end-of-study lipid levels. CONCLUSIONS: Among 785 patients with primary hypercholesterolemia, CRP levels were significantly reduced within 8 weeks of initiating cerivastatin therapy in a lipid-independent manner.

Administration, Oral↗

PubMed2001

Soluble P-selectin and the risk of future cardiovascular events.

BACKGROUND: P-selectin, a cell-surface adhesion molecule involved in leukocyte rolling and attachment, has been hypothesized to play a role in the initiation of atherosclerosis. However, little clinical data are available evaluating the role of soluble P-selectin in determining vascular risk. METHODS AND RESULTS: In a large-scale prospective study of apparently healthy women, we measured baseline plasma concentration of soluble P-selectin among 115 participants who subsequently developed cardiovascular events and among 230 age- and smoking-matched participants who remained free of disease during 3.5 years of follow-up. Overall, mean levels of soluble P-selectin were significantly higher at baseline among women who subsequently experienced cardiovascular events compared with those who did not (83.2 versus 69.3 ng/mL; P:=0.003). The risk of future cardiovascular events increased with increasing quartiles of soluble P-selectin (P:=0.02), such that women in the highest quartile at study entry had an age- and smoking-matched relative risk 2.2 times higher than those in the lowest quartile (95% confidence interval, 1.2 to 4.2; P:=0.01). This effect was independent of traditional risk factors. For each quartile increase in soluble P-selectin, the risk of future cardiovascular events increased 28% (P:=0.03) after additional adjustment for obesity, hypertension, hyperlipidemia, diabetes, and exercise frequency. The highest risks were observed among women with the very highest levels of P-selectin (>137.3 ng/mL, the 95th percentile cut point of the control distribution). CONCLUSIONS: Soluble P-selectin levels are elevated among apparently healthy women at risk for future vascular events.

Age Factors↗

PubMed2001

The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity.

PURPOSE: To compare the protective effect of dexrazoxane (DRZ) against cardiotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX). METHODS: Adult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DXR (i.v.) or 0.5 mg/kg MTX (i.v.), either alone or 30 min after 25 mg/kg DRZ (i.p.) weekly for up to 12 weeks. Animals treated with DXR alone either died (n = 2) or were killed (n = 3) at a cumulative dose of 10 mg/kg. The severity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3. RESULTS: Cardiac lesions were observed in all SHR given DXR or MTX alone, and were attenuated in those given DRZ prior to either DXR (mean lesion scores 2.7 vs 1.5; P < 0.05) or MTX (mean lesion scores 2.0 vs 1.25; P < 0.05). Cardioprotection was also demonstrated by monitoring serum levels of cardiac troponin T (cTnT), which were elevated in all animals receiving DXR or MTX alone. These elevations were attenuated in SHR given the combination of DXR and DRZ (mean values 0.79 ng/ml vs 0.24 ng/ml; P < 0.05) and MTX and DRZ (mean values 0.19 ng/ml vs 0.04 ng/ ml; P < 0.05). Biochemical studies have shown that both DXR and MTX form potentially cardiotoxic complexes with iron. ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA, diethylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR. CONCLUSIONS: The present study showed that DRZ significantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of cardiac tissues and by monitoring the concentrations of cTnT in serum.

Animals↗

PubMed2001

Gender differences in exercise-induced changes in sex hormone levels and lipid peroxidation in athletes participating in the Hawaii Ironman triathlon. Ginsburg-gender and exercise-induced lipid peroxidation.

BACKGROUND: Exercise reduces the risk of coronary heart disease in men and women but paradoxically, may promote free-radical formation, lipid peroxidation and vascular tissue injury. In this study, we assessed whether exercise-induced oxidative stress similarly affected men and women who participated in the Hawaii Ironman triathlon. METHODS AND RESULTS: Fifty-seven athletes (38 males) who completed the triathlon (3.9 km swim, 180.2 km bike, 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the measurement of lipids, antioxidants and sex hormones and for the assessment of the susceptibility of plasma lipids to peroxidation. Lipid changes after exercise were similar for men and women. However, the susceptibility of plasma lipids to peroxidation was reduced by 61% (P < 0.001) in men and only 14% (P = NS) in women postrace. These changes were not associated with the supplemental use or levels of antioxidants. In addition, in men there was an increase of 58% in the antioxidant sex hormone estradiol and a decrease of 58% in testosterone (P < 0.001) postrace. No significant changes were noted for these two hormones in women. CONCLUSIONS: There are significant gender-specific differences in the susceptibility of lipids to peroxidation and in changes in estradiol and testosterone levels as a result of ultra-endurance exercise. These changes may in part explain the salutary effect of exercise on the development of vascular disease.

Adult↗

PubMed2001

Performance characteristics of a point of care C-reactive protein assay.

BACKGROUND: C-reactive protein (CRP) is a non-specific marker of inflammation that can be used for atherosclerotic risk assessment. This application requires increased precision at low CRP concentrations compared to traditional assays. METHODS: The Micros CRP analyzer (ABX Diagnostics) is a small bench top device. Its limit of detection, limit of quantitation, linearity and imprecision were assessed. Method comparison studies were performed using samples both inside and outside the reference interval. Anticoagulant effects and the prozone effect were also evaluated. RESULTS: The limit of detection was 0.1 mg/l. The method was linear from 2 to 60 and 0.3 to 60 mg/l using systematic error limits of 10% and 20%, respectively. The total imprecision was <8% for CRP concentrations from 0.7 to 9.1 mg/l. A prozone effect was seen at CRP concentrations >500 mg/l. Using samples from 120 apparently healthy adults, the Micros CRP method demonstrated excellent concordance with the BN II high sensitivity CRP (hs-CRP) method. The Micros CRP method compared well with a nephelometric method using samples with elevated CRP concentrations. CONCLUSIONS: The Micros CRP method is adequate for atherosclerotic risk prediction in clinical practice but does not have adequate accuracy at CRP concentrations <2 mg/l for epidemiological studies.

Adult↗

PubMed2001

Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men.

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-alpha), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47--83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m(2)) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.

Adult↗

PubMed2001

Dietary and lifestyle factors in relation to plasma leptin concentrations among normal weight and overweight men.

OBJECTIVE: Leptin, the product of the obesity (ob) gene, is a multi-functional polypeptide that is important in energy metabolism, which is strongly correlated with body fat mass and body mass index (BMI). In a recent prospective study, we found that leptin was positively associated with 4 y weight gain among overweight and obese men. This suggests that leptin resistance, marked by hyperleptinemia among obese subjects, may be an important marker for weight gain. The purpose of this study is to evaluate whether modifiable dietary and lifestyle factors are associated with plasma leptin concentrations among US men. METHODS: We included 268 men aged 47--83 y (who were free of cardiovascular disease, diabetes mellitus and cancer, except nonmelanoma skin cancer) from the ongoing Health Professionals Follow-up Study. These subjects completed a detailed dietary and lifestyle questionnaire (including cigarette smoking, alcohol drinking and physical activity) and provided a fasting venous blood sample in 1994. All blood samples were stored in a deep freeze (-70 degrees C) for 4--5 y before being analyzed. Plasma leptin concentrations were measured by radioimmunoassay. RESULTS: Men in the highest quintile of plasma leptin (mean=14.4 ng/ml) weighed more, were less physically active, and had higher total and saturated fat and cholesterol intake than men in the lowest quintile (mean=3.0 ng/ml). Physical activity and current smoking were inversely associated with plasma leptin concentrations (P<0.001). A 20 MET difference in physical activity per week (equivalent to approximately 3 h of jogging) was associated with 0.38--0.58 ng/ml lower plasma leptin concentrations for normal weight and overweight men after adjusting for total energy and fat intake, BMI and other confounding variables. Total fat and monounsaturated fat intakes were positively associated with plasma leptin concentrations even after adjusting for BMI and other confounding variables; however, this association was limited to men of normal weight (BMI<25 kg/m(2)). CONCLUSION: These data suggest that physical activity may be a significant determinant of plasma leptin concentrations in men. Increasing physical activity is associated with lower plasma leptin concentrations even after adjusting for BMI. Physical activity may lower leptin concentrations not only due to decreased body fat mass, but potentially through an increase in leptin sensitivity. International Journal of Obesity (2001) 25, 106-114

Aged↗

PubMed2001

Plasma leptin concentrations and four-year weight gain among US men.

OBJECTIVE: Leptin, a primarily adipose tissue-derived protein product of the obesity (ob) gene, is an important regulator of energy metabolism. The strong association between body fat mass and elevated circulating leptin levels in humans suggests that leptin resistance, rather than leptin production, may contribute to the development of obesity and associated disorders. The purpose of this study is to evaluate the relationship between circulating plasma leptin levels and regulation of body weight over time among US men. DESIGN: Four-year prospective study. SUBJECTS: A total of 247 men from the Health Professionals Follow-up Study, who at baseline (1994), were 47-64 y of age, were free of cardiovascular diseases, diabetes mellitus and malignant neoplasmas, and completed a detailed lifestyle questionnaire. In addition, all participants completed a follow-up questionnaire in 1998. MEASUREMENTS: Baseline plasma leptin levels and 4-y weight change. RESULTS: At the start of follow-up, men in the highest quintile for plasma leptin (mean=12.1 ng/ml) weighed more, were less physically active, and had higher circulating insulin levels than men in the lowest quintile (mean=2.7 ng/ml). After adjustments for baseline age, weight, height, smoking status, alcohol intake, and physical activity, each 10 ng/ml increase in plasma leptin concentration was associated with a 1.68 kg (95% CI 0.14-3.18 kg) weight gain over the 4-y follow-up period. The observed association between leptin level and weight gain was limited to men with a baseline body mass index (BMI) of > or =25 kg/m2, in whom a 10 ng/ml higher baseline leptin was associated with a 2.45 kg (95% CI 0.73-4.18-kg) weight gain. Further adjustments for baseline total energy intake, plasma insulin and soluble tumor necrosis factor receptors levels did not appreciably alter these results. Plasma insulin level was not independently associated with subsequent weight gain. CONCLUSION: These results suggest that elevated plasma leptin concentrations among overweight men may be a marker of leptin resistance and subsequent weight gain.

Anthropometry↗

PubMed2001

Association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk.

BACKGROUND: Although the effects of individual foods or nutrients on the development of diseases and their risk factors have been investigated in many studies, little attention has been given to the effect of overall dietary patterns. OBJECTIVE: Our objective was to examine the associations of 2 major dietary patterns, Western and prudent, with biomarkers of obesity and cardiovascular disease (CVD) risk. DESIGN: We used factor analysis to define major dietary patterns for a subsample of men (n = 466) from the Health Professionals Follow-up Study by using dietary information collected from food-frequency questionnaires (FFQs) in 1994. We calculated partial correlation coefficients between pattern scores and biomarker values adjusted for age, smoking status, energy and alcohol intake, physical activity, hours of television watching, and body mass index. RESULTS: We derived 2 major dietary patterns that were generally reproducible over time. The first pattern (prudent) was characterized by higher intakes of fruit, vegetables, whole grains, and poultry. The second pattern (Western) was characterized by higher intakes of red meats, high-fat dairy products, and refined grains. Using pattern scores from 1994 and adjusting for potential confounders, we found significant positive correlations between the Western pattern and insulin, C-peptide, leptin, and homocysteine concentrations, and an inverse correlation with plasma folate concentrations. The prudent pattern was positively correlated with plasma folate and inversely correlated with insulin and homocysteine concentrations. CONCLUSION: Major dietary patterns are predictors of plasma biomarkers of CVD and obesity risk, suggesting that the effect of overall diet on CVD risk may be mediated through these biomarkers.

Adult↗

PubMed2001

The pharmacokinetics of epidural ropivacaine in infants and young children.

UNLABELLED: The pharmacokinetic variables of ropivacaine were characterized after epidural bolus injection in pediatric patients. The subjects, 7 infants (aged 3-11 mo) and 11 young children (aged 12-48 mo), received 1.7 mg/kg of ropivacaine via a lumbar epidural catheter. Total plasma concentrations of ropivacaine measured over 24 h were assayed by high-pressure liquid chromatography, and pharmacokinetic modeling was performed by Nonlinear Mixed Effects Modeling analysis. The median peak venous plasma concentrations (C(max)) in infants and young children were 610 microg/L (interquartile range [IQR], 550-725 microg/L) and 640 microg/L (IQR, 540-750 microg/L), respectively. The median times to maximum plasma ropivacaine concentration (T(max)) were 60 min (IQR, 60-120 min) in infants and 60 min (IQR, 30-90 min) in young children. There were no statistical differences between median values of C(max) and T(max) between infants and young children. The calculated clearance (CL) in infants was 4.26 mL x min(-1) x kg(-1) (9% coefficient of variation), and in young children it was 6.15 mL x min(-1) x kg(-1) (11% coefficient of variation). The CL for infants was significantly less than the CL for young children (P < 0.01). The volume of distribution was estimated to be 2370 mL/kg (9% coefficient of variation) for both young children and infants. No systemic toxicity was observed in either group. IMPLICATIONS: This study revealed that the pharmacokinetic variables of lumbar epidural bolus ropivacaine in pediatric patients aged 3 to 48 mo are similar to those of adults, except that drug clearance was less in infants compared with older children.

Algorithms↗

PubMed2001

Simultaneous measurement of plasma ropivacaine and bupivacaine concentrations by HPLC with UV detection.

The authors developed a high-performance liquid chromatography (HPLC) assay for the simultaneous determination of plasma ropivacaine and bupivacaine concentrations using ultraviolet (UV) detection and a simple solid-phase extraction procedure. The absolute retention times of ropivacaine, bupivacaine, and the internal standard pentycaine were 1.9, 3.0, and 5.6 minutes, respectively. The assay had a linearity of 2000 ng/mL, a sensitivity of 5 ng/mL, an average recovery of 98%, and an average day-to-day imprecision of <10% for both drugs. A patient correlation study (n = 23) using this HPLC method and an established gas chromatographic assay revealed a slope of 1.01, an intercept of -10.6 ng/mL, and a correlation coefficient of 0.99 for ropivacaine; and a slope of 0.96, an intercept of 14.7 ng/mL, and a correlation coefficient of 0.99 for bupivacaine. Of the 60 different drugs tested, only quinidine and lidocaine extracted but did not interfere with the measurement of the drugs of interest. The authors conclude that the method described here is ideally suited for the therapeutic monitoring of plasma ropivacaine and bupivacaine concentrations.

Amides↗

PubMed2001

Blood pressure and inflammation in apparently healthy men.

Inflammation plays an important role in the development of atherosclerosis, but the specific stimuli governing cytokine release in atherogenesis are unknown. We examined the hypothesis that hypertension may increase the risk of atherosclerosis via proinflammatory effects. In a cross-sectional study involving 508 apparently healthy men, we studied the association between blood pressure and baseline plasma concentrations of 2 inflammatory markers, intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6). Increase in systolic blood pressure (SBP) (P=0.003), pulse pressure (PP) (P=0.019), and mean arterial pressure (P=0.014) was significantly associated with levels of sICAM-1. All of these measures of blood pressure, as well as diastolic blood pressure (DBP), were significantly associated with levels of IL-6 (all, P</=0.001). In multiple linear regression models controlled for age and other cardiac risk factors, SBP (7.6 ng/mL per 10 mm Hg, P=0.016) and PP (8.13 ng/mL per 10 mm Hg, P=0.038) were significantly associated with sICAM-1 levels, whereas SBP (0.11 pg/mL per 10 mm Hg, P<0.001), DBP (0.11 pg/mL per 10 mm Hg, P=0.008), PP (0.10 pg/mL per 10 mm Hg, P=0.009), and mean arterial pressure (0.15 pg/mL per 10 mm Hg, P<0.001) had similar strong relationships with log-transformed IL-6 levels. Therefore, in apparently healthy men, we observed significant graded relationships between blood pressure and levels of sICAM-1 as well as IL-6. These data suggest that increased blood pressure may be a stimulus for inflammation and that this is a possible mechanism underlying the well-established role of hypertension as a risk factor for atherosclerotic disease.

Blood Pressure↗

PubMed2001

Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis.

Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. Prospective data evaluating whether levels of these proteins are associated with incident cardiovascular disease are sparse. Employing a prospective, nested, case-control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age- and smoking-matched controls who remained free of reported vascular disease during 5 years of follow-up. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83 mg/l, p = 0.84), whereas median baseline levels of mannose binding protein among cases and controls were 2.32 mg/l and 2.20 mg/l respectively (p = 0.69). No evidence of association was found between either cystatin-C or mannose binding protein and the development of peripheral arterial disease in analyses evaluating for linear trends or for threshold effects (all p-values > 0.05). In contrast with prior retrospective and cross-sectional studies, no evidence was found that baseline levels of cystatin-C or mannose binding protein are associated with an increased risk of future arterial disease.

Adult↗

PubMed2001

Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial.

GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.

Adult↗

PubMed2001

Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women.

Although increased levels of C-reactive protein have been linked to E therapy, the significance of this finding and whether it occurs with the selective ER modulators are unknown. Thirty-five healthy postmenopausal women were enrolled in a placebo-controlled, two-period cross-over design trial to evaluate the effects of 0.625 mg oral conjugated E and 60 mg droloxifene, a structural analog of tamoxifen, on serum levels of C-reactive protein, IL-6, and endothelial cell adhesion molecules. E treatment resulted in 65.8% higher levels of C-reactive protein (P = 0.0002) and 48.1% higher levels of IL-6 (P < 0.001), but also resulted in a 10.9% reduction in soluble E-selectin (P = 0.002) and borderline reductions in vascular cell adhesion molecule-1. In contrast, droloxifene had no effect on C-reactive protein and IL-6, but did produce a significant 11% reduction in E-selectin (P < 0.00001). However, droloxifene also resulted in an 11.6% increase in vascular cell adhesion molecule-1 (P < 0.007). These data provide additional evidence of a proinflammatory effect of E that may have adverse cardiovascular consequences. However, these changes were also accompanied by a reduction in E-selectin, suggesting an antiinflammatory effect at the level of the endothelium. The net clinical impact of these changes is not yet well established. In contrast, droloxifene had little or no proinflammatory effects on C-reactive protein and IL-6 and had mixed effects on endothelial adhesion molecules. This observation provides additional rationale for continuing to evaluate the potential cardiovascular benefits of selective ER modulators.

Acute-Phase Proteins↗

PubMed2001

C-reactive protein and coronary heart disease: diagnostic and therapeutic implications for primary prevention.

Coronary heart disease (CHD) is the leading cause of death in the industrialized world. Recent laboratory and clinical studies have shown that inflammation plays a pivotal role in the inception, progression, and destabilization of atheromas. The acute-phase reactant C-reactive protein (CRP) has been shown to reflect systemic and, perhaps, vascular inflammation and to predict future cardiovascular events in asymptomatic individuals. The relative risk associated with CRP is independent of other cardiovascular disease risk factors. High-sensitivity assays (hs-CRP) are needed for the measurement of CRP concentration for the purpose of predicting the risk of future coronary events. Available assays must be standardized because patients' results will be interpreted using population-based cutpoints. An algorithm for risk stratification incorporating hs-CRP and total cholesterol to high-density lipoprotein cholesterol ratio has been developed. Statin class drugs and aspirin appear to modulate CHD risk in those with increased hs-CRP concentration. Several prospective studies are now underway to specifically develop novel clinical utilities and therapeutic strategies for hs-CRP.

C-Reactive Protein↗

PubMed2001

Markers of the acute phase response in cardiovascular disease: an update.

There is now widespread agreement that inflammation is a key component in the progression of atheromatous lesions. Inflammatory cells are present at all stages in the development of the atheromatous plaque, and gene knockout experiments in mice show that atheroma is largely prevented in the absence of the normal inflammatory mediators. In humans reduction of inflammation accompanies successful treatment strategies for atheroma. An increasing number of studies suggest that the acute phase protein, C-reactive protein, provides increased prognostic information over and above existing markers of atheroma severity or progression in healthy individuals and in the acute coronary syndromes. Recent advances in our knowledge of the normal variability of C-reactive protein levels and in precise and sensitive measurements strengthen the arguments for adding this marker to the repertoire of the routine laboratory assessment of cardiovascular disease.

Acute-Phase Reaction↗