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Biomedical subjects

Naveed Sattar

Publications and source records attributed to Naveed Sattar.

At least 55 records · Page 3Linked to original sources
PubMed2005

Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.

Animals↗
PubMed2005

Metformin reduces serum mullerian-inhibiting substance levels in women with polycystic ovary syndrome after protracted treatment.

OBJECTIVE: Assessment of ovarian responses to metformin treatment in obese women with polycystic ovary syndrome (PCOS). DESIGN: Prospective treatment with randomization to two doses of metformin. SETTING: University teaching hospital. PATIENT(S): Obese women (n = 82) with PCOS. INTERVENTION(S): Markers of ovarian function were assessed after 4 and 8 months. MAIN OUTCOME MEASURE(S): Hormone (androgens and mullerian-inhibiting substance [MIS]) changes over time. RESULT(S): There was no difference in the reproductive hormone changes between the doses of metformin, and data were combined for further analyses. Significant responses to treatment were recorded for menstrual frequency and androstenedione (A) (reduction) within the first 4 months of treatment. However, suppression of the elevated circulating MIS concentrations required protracted treatment, because no change was observed in the first 4 months-only in the second 4-month assessment period. CONCLUSION(S): Metformin treatment of PCOS leads to rapid suppression of A and improved menstrual frequency. Suppression of MIS is a delayed response that may be secondary to the development of a cohort of follicles that underwent initial recruitment in an environment of reduced insulin stimulation.

Adult↗
PubMed2005

Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction.

OBJECTIVES: Human and animal studies have demonstrated that peroxisome proliferator-activated receptors (PPARs) are important in placental development and play key roles in metabolism and inflammation. We studied placental PPARdelta, PPARgamma, and retinoid X receptor alpha (RXRalpha) expression in healthy pregnancy and in preeclampsia (PET) and intrauterine growth restriction (IUGR). METHODS AND RESULTS: Using immunocytochemistry, PPARdelta, PPARgamma, and RXRalpha were localized to the cyto- and syncytiotrophoblast and invading trophoblast columns in first and second trimester placentas. Third trimester placentas from healthy pregnancy, and in PET and IUGR, demonstrated PPARdelta, PPARgamma, and RXRalpha staining within the syncytium, and localization within isolated cells in the stroma. In uncomplicated pregnancies, PPARdelta mRNA expression (PPARdelta:18s ratio, third trimester median 0.43 [interquartile (IQ) range 0.26-0.52] vs first trimester 0.20 [0.00-0.26], P = .03) and PPARdelta protein expression (third trimester 3.94 [2.45-4.68] vs first trimester 1.29 [0.78-2.29] optical densitometry [OD] mm(2), P = .04) were higher in the third trimester than in the first trimester. There were no consistent differences in PPARdelta, PPARgamma, or RXRalpha mRNA and protein expression among PET or IUGR placentas and controls. CONCLUSION: PPARdelta expression is up-regulated between the first and third trimester, indicating a role for this nuclear receptor in placental function. We found no evidence that placental PPARdelta, PPARgamma, and RXRalpha expression is changed in PET or IUGR. This suggests that changes in total placental PPAR expression are not involved in the pathophysiology of these conditions.

Case-Control Studies↗
PubMed2005

Cardiovascular risk parameters in men with ankylosing spondylitis in comparison with non-inflammatory control subjects: relevance of systemic inflammation.

Men with AS (ankylosing spondylitis) are at elevated risk for CHD (coronary heart disease) but information on risk factors is sparse. We compared a range of conventional and novel risk factors in men with AS in comparison with healthy controls and, in particular, determined the influence of systemic inflammation. Twenty-seven men with confirmed AS and 19 controls matched for age were recruited. None of the men was taking lipid-lowering therapy. Risk factors inclusive of plasma lipids, IL-6 (interleukin-6), CRP (C-reactive protein), vWF (von Willebrand factor), fibrin D-dimer, ICAM-1 (intercellular cell-adhesion molecule-1) and fibrinogen were measured, and blood pressure and BMI (body mass index) were determined by standard techniques. A high proportion (70%) of men with AS were smokers compared with 37% of controls (P = 0.024). The AS patients also had a higher BMI. In analyses adjusted for BMI and smoking, men with AS had significantly higher IL-6 and CRP (approx. 9- and 6-fold elevated respectively; P < 0.001), fibrinogen (P = 0.013) and vWF (P = 0.008). Total cholesterol and HDL-C (high-density lipoprotein cholesterol) were lower (P < 0.05 and P = 0.073 respectively) in AS and thus the ratio was not different. Pulse pressure was also significantly higher in AS (P = 0.007). Notably, adjustment for IL-6 and CRP levels rendered all case-control risk factor differences, except pulse pressure, non-significant. In accordance with this finding, IL-6 correlated positively (r = 0.74, P < 0.001) with fibrinogen, but negatively (r = -0.46, P = 0.016) with total cholesterol concentration. In conclusion, men with AS have perturbances in several CHD risk factors, which appear to be driven principally by systemic inflammatory mediators. Inflammation-driven atherogenesis potentially contributes to the excess CHD risk in AS.

Adult↗
PubMed2005

Vascular comorbidity in rheumatoid arthritis: potential mechanisms and solutions.

PURPOSE OF REVIEW: To summarise recent evidence for elevated risk of coronary heart disease (CHD) in rheumatoid arthritis (RA) and explore explanatory mechanisms and modalities that may lessen such risk. RECENT FINDINGS: Evidence for elevated CHD risk in RA is convincing. On current estimates, individuals who have had RA for several years have around a twofold higher risk for CHD compared with non-RA persons after taking account of most traditional risk factors. Such excess risk appears to be driven by systemic inflammation both directly via its deleterious effects on blood vessels (endothelial dysfunction inclusive of myocardial microvascular abnormalities) and indirectly by its accentuation of multiple risk pathways including lipid abnormalities. Established therapies that lessen RA disease activity and systemic inflammation will likely lessen CHD risk, although there remains considerable scope for more robust studies employing better measures of vascular disease (e.g., carotid intima-media thickening). Other emerging evidence indicates statins may have dual effects in RA, with a modest disease-modifying effect (requiring confirmation) and significant lipid-lowering action. The latter finding is particularly important because extrapolation of data from all statin endpoint trials suggests that the extent of low-density lipoprotein cholesterol reduction may account for most statin clinical benefit. SUMMARY: Systemic inflammation is the major driver for excess vascular comorbidity in RA. Controlling systemic inflammation should lessen vascular risk but complete, long-term suppression of articular inflammation is rarely achieved. Thus, the use of conventional CHD risk reduction strategies, in particular statins, should be considered in patients with RA with prevalent CHD or at elevated risk.

Arthritis, Rheumatoid↗
PubMed2005

Genetic determinants of metabolic syndrome components in the stroke-prone spontaneously hypertensive rat.

OBJECTIVE: The metabolic syndrome is a complex multifactorial disease, which results from interactions between genes on multiple chromosomes and environmental factors. Animal models may facilitate genetic analysis of complex phenotypes by allowing complete control of environmental conditions and the ability to produce designer strains. METHODS: Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rat strains were used to construct congenic (SP.WKYGla2a), consomic (SP.WKYGlaYw, WKY.SPGlaYs) and double-introgressed (SP.WKYGla2aYw) strains, which were characterized for metabolic syndrome phenotypes (systolic blood pressure, glucose tolerance and lipid profile) after feeding a 60% fructose diet for 14 days. RESULTS: The Y consomic strain (SP.WKYGlaYw) demonstrated that the WKY Y chromosome significantly lowered triglyceride levels (3.77 +/- 0.60 versus 9.09 +/- 1.47 mmol/l; P < 0.001) and improved glucose tolerance [area under the curve (AUC): 26.93 +/- 0.81 versus 31.47 +/- 0.89; P < 0.05] compared with SHRSP. The chromosome 2 congenic strain (SP.WKYGla2a) exhibited significantly improved glucose tolerance (AUC: 28.19 +/- 1.17 versus 31.47 +/- 0.89; P < 0.05) and lower systolic blood pressure (161.2 +/- 6.2 versus 179.7 +/- 3.9 mmHg; P < 0.05) compared with SHRSP. 2 x 2 factorial ANOVA identified a significant interaction for glucose metabolism (P = 0.004) in the double-introgressed strain (SP.WKYGla2aYw) between chromosome 2 and Y. CONCLUSIONS: These results identify novel interacting regions on chromosome 2 and the Y chromosome influencing a cluster of metabolic and cardiovascular phenotypes. Translation to clinical studies will facilitate genetic dissection of human metabolic syndrome.

Animals↗
PubMed2005

Growth hormone replacement reduces C-reactive protein and large-artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency.

Hypopituitary patients have an increased risk of vascular mortality that may relate to growth hormone deficiency (GHD). We investigated the effects of 6 months of GH therapy on large- and small-artery function and high-sensitivity C-reactive protein (hsCRP) in a cohort of GH-deficient patients. Sixteen hypopituitary patients were randomized to 6 months of GH therapy or no treatment, then vice versa. hsCRP, 24-h blood pressure (BP) and pulse wave velocity (PWV) were measured and resistance arteries were used to construct concentration-response curves to endothelium-dependent and -independent agents. GH therapy increased IGF-1 from 60 +/- 7.2 to 167 +/- 16.2 microg/l [confidence interval (CI) 94.9, 138.8, P < 0.001]. hsCRP declined after 6 months of GH from 3.8 +/- 0.88 to 2.0 +/- 0.49 mg/l (CI 0.73, 3.57, P = 0.006). Mean arterial BP fell from 91.7 +/- 1.5 to 89.3 +/- 1.2 mmHg (CI 0.81, 4.07, P = 0.005), as did PWV (8.1 +/- 0.4 to 6.7 +/- 0.5 m/s). The decline in PWV correlated with the decline in hsCRP (r = 0.68, P = 0.01). Resistance artery function was unchanged after GH therapy. GH replacement may lead to differentially altered production of vasorelaxant agents from the endothelium of large and small arteries. Reduction in vascular inflammation may be associated with reduced vascular risk.

Adult↗
PubMed2005

Changes in booking body mass index over a decade: retrospective analysis from a Glasgow Maternity Hospital.

Whether booking body mass index (BMI) in the UK is increasing is unknown but is of clinical interest since overweight or obese pregnant women face far greater risks of pregnancy complications including pre-eclampsia and gestational diabetes. We examined booking BMI in 1990 and 2002/2004, of women with singleton pregnancies. Our analyses indicate an increase of 1 U in mean BMI over this period despite lower parity in recent years. When the model was adjusted for maternal age, parity, smoking status and deprivation category the mean BMI was 1.37 U higher in 2002/2004 than in 1990. More striking was the significant increase in the proportion of women who were obese (BMI > or = 30 kg/m2) at booking--more than twofold higher in unadjusted analysis (18.9% vs 9.4%) rising to greater than threefold higher in multivariate analysis. These findings suggest that obesity-related pregnancy complications are likely to increase with implications for both mother and child.

Adult↗
PubMed2005

The systemic inflammatory response predicts overall and cancer specific survival in patients with malignant lymphoma.

BACKGROUND: The value of C-reactive protein concentrations in the assessment of prognosis in patients with advanced lymphoma has not been clearly defined. MATERIAL/METHODS: Patients with a diagnosis of non-Hodgkin's lymphoma (n = 108) and Hodgkin's lymphoma, (n = 39) and who had measurements of C-reactive protein were studied retrospectively and the data was reviewed over 8 years. RESULTS: Median survival, from the time of sampling, was 7.4 months. On univariate analysis there was a significant relationship between the duration of cancer specific survival and tumour type (p < 0.05), circulating concentrations of albumin (p < 0.001) and C-reactive protein (p < 0.001). In contrast, only C-reactive protein concentration was a predictor of death from intercurrent disease (p < 0.05). On multivariate analysis, C-reactive protein concentration remained a strong independent predictor of both death from cancer and intercurrent disease (p < 0.001). The hazard ratio associated with a unit increase in stratified C-reactive protein concentration was 8.18 (95% CI 4.80 - 13.95) for cancer specific death and 2.11 (95% CI 1.22 - 3.64) for intercurrent death. CONCLUSIONS: The results of the present study demonstrate that patients with advanced lymphoma have evidence of a systemic inflammatory response and the magnitude of the C-reactive protein response predicts the duration of overall and cancer specific survival.

C-Reactive Protein↗
PubMed2004

Effects of prior moderate exercise on postprandial metabolism and vascular function in lean and centrally obese men.

OBJECTIVES: We investigated whether a session of prior exercise could ameliorate postprandial endothelial dysfunction. BACKGROUND: Endothelial function is impaired after fat ingestion, and this may be related to rises in triglyceride concentrations. Exercise reduces postprandial triglyceride concentrations. METHODS: Ten lean (waist <90 cm) and 10 centrally obese (waist >100 cm) middle-aged men each underwent two oral fat tolerance tests (blood taken fasting and for 8 h after a high-fat meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Endothelium-dependent and -independent microvascular function was assessed using laser Doppler imaging in the fasted state and at two hourly intervals during the 8-h postprandial period. RESULTS: Exercise reduced both fasting and postprandial triglyceride concentrations by 25% in both the lean and centrally obese groups (p < 0.0005). For all subjects taken together, exercise improved fasting endothelium-dependent function by 25% (p < 0.05), and, although there was a significant postprandial decrease in both endothelium-dependent and -independent function in both the control and exercise trials (p < 0.01), postprandial endothelium-dependent and -independent function were 15% and 20% higher, respectively, in the exercise trial than the control trial (both p < 0.05). CONCLUSIONS: A session of prior exercise improves fasting and postprandial vascular function in middle-aged men. This may be one mechanism by which exercise influences cardiovascular risk.

Acetylcholine↗
PubMed2004

Comparison of the associations of apolipoprotein B and non-high-density lipoprotein cholesterol with other cardiovascular risk factors in patients with the metabolic syndrome in the Insulin Resistance Atherosclerosis Study.

BACKGROUND: The metabolic syndrome (MetS) as defined by the National Cholesterol Education Panel definition has been proposed as an indicator of cardiovascular disease risk. Both apolipoprotein (apo)B and non-HDL cholesterol (NHDLC) have been proposed as an additional indicator to identify patients at higher risk in MetS patients. METHODS AND RESULTS: We studied 1522 individuals in the Insulin Resistance Atherosclerosis Study (IRAS) who were 40 to 69 years of age and from 3 ethnic groups. Their anthropometric measures, lipids, apoB, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1, fasting and post-glucose load glucose, and insulin concentrations were measured, and insulin sensitivity was determined by intravenous glucose tolerance test. Differences in risk parameters in individuals with hyper-apoB/normo-NHDLC, and normo-apoB/hyper-NHDLC were compared in all IRAS subjects and again in those with MetS. In both cases, despite anticipated lower LDL cholesterol, the hyper-apoB/normo-NHDLC group had elevated risk indicated by greater waist circumference (both P<0.05) and fasting insulin (P<0.01) and lower insulin sensitivity (P<0.001). They also had higher C-reactive protein (P<0.05). Moreover, the Spearman correlation of apoB was significantly stronger (P<0.05) in the direction of greater associated risk than that of NHDLC with body mass index, waist circumference, systolic blood pressure, 2-hour glucose, fasting glucose, fasting insulin, 2-hour insulin, insulin sensitivity, C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1. CONCLUSIONS: In conclusion, apoB is more closely associated with central adiposity, insulin resistance, thrombosis, and inflammation than NHDLC. Our data suggest that apoB is a better candidate risk parameter than NHDLC for identifying a subgroup of individuals with or without MetS with elevated cardiovascular risk.

Adult↗
PubMed2004

Short- and long-term changes in plasma inflammatory markers associated with preeclampsia.

Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor-alpha (TNF-alpha) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF-alpha rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 [2.04] to 2.94 [2.47] pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 [6.07] versus 2.12 [1.89]; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1beta (C-511T), IL-6 (G-174C), TNF-alpha (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.

Adult↗
PubMed2004

Women with polycystic ovary syndrome (PCOS) often undergo protracted treatment with metformin and are disinclined to stop: indications for a change in licensing arrangements?

Women with polycystic ovary syndrome (PCOS) are increasingly being treated with metformin as an insulin sensitizing agent to reduce symptoms of hyperandrogenism and promote fertility. Indications such as hirsutism and cycle regulation require long term treatment. The drug is also being used through pregnancy. It is not licensed for any indication specific to PCOS, which means that much of this prescribing is taking place in an environment short of reliable information concerning safety. We describe the failure of recruitment to a study undertaken to explore the effects of metformin treatment discontinuation in women with PCOS, to provide both clinical and aetiological information. The study failed because the patients did not wish to stop treatment, and it illustrates the problems facing doctors working in this area. To achieve a safer prescribing environment, we recommend that action be taken by the manufacturer of metformin to work with regulatory agencies on a European base to extend prescribing indications for metformin to women with PCOS.

Clinical Trials as Topic↗
PubMed2004

Serum C-reactive protein and lipids in ultra-Marathon runners.

In this investigation, we compared lipid and inflammatory parameters in regular long distance runners with matched sedentary controls. Long distance runners had significantly lower low-density lipoprotein cholesterol and C-reactive protein levels than the control group. This exercise-induced reduction in low-density lipoprotein cholesterol was independent of the decrease in C-reactive protein levels.

Adult↗
PubMed2004

Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial.

BACKGROUND: Rheumatoid arthritis is characterised by inflammatory synovitis, articular destruction, and accelerated atherogenesis. HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) mediate clinically significant vascular risk reduction in patients without inflammatory disease and might have immunomodulatory function. We postulated that statins might reduce inflammatory factors in rheumatoid arthritis and modify surrogates for vascular risk. METHODS: 116 patients with rheumatoid arthritis were randomised in a double-blind placebo-controlled trial to receive 40 mg atorvastatin or placebo as an adjunct to existing disease-modifying antirheumatic drug therapy. Patients were followed up over 6 months and disease activity variables and circulating vascular risk factors were measured. Coprimary outcomes were change in disease activity score (DAS28) and proportion meeting EULAR (European League Against Rheumatism) response criteria. Analysis was by intention to treat. FINDINGS: At 6 months, DAS28 improved significantly on atorvastatin (-0.5, 95% CI -0.75 to -0.25) compared with placebo (0.03, -0.23 to 0.28; difference between groups -0.52, 95% CI -0.87 to -0.17, p=0.004). DAS28 EULAR response was achieved in 18 of 58 (31%) patients allocated atorvastatin compared with six of 58 (10%) allocated placebo (odds ratio 3.9, 95% CI 1.42-10.72, p=0.006). C-reactive protein and erythrocyte sedimentation rate declined by 50% and 28%, respectively, relative to placebo (p<0.0001, p=0.005, respectively). Swollen joint count also fell (-2.69 vs -0.53; mean difference -2.16, 95% CI -3.67 to -0.64, p=0.0058). Adverse events occurred with similar frequency in patients allocated atorvastatin and placebo. INTERPRETATION: These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.

Aged↗
PubMed2004

Inverse association between birth weight and C-reactive protein concentrations in the MIDSPAN Family Study.

OBJECTIVE: Inflammation markers and low birth weight each predict elevated risk of cardiovascular events and type 2 diabetes. However, potential associations between the low-grade inflammatory response as represented by C-reactive protein (CRP) concentrations and low birth weight have been sparsely examined. METHODS AND RESULTS: In the MIDSPAN Family Study, 1663 individuals had birth weight data and CRP concentrations measured as adults (age 30 to 59). The relationship between these parameters was examined after adjusting for factors known to influence CRP concentrations inclusive of age, body mass index, smoking, socio-economic deprivation, and hormone use in women. After adjusting for potential confounders, there was a negative association between birth weight and CRP, whereby a 1-kg increase in birth weight is associated with a 10.7% decrease in CRP (95% CI: 3.0% to 17.8% decrease). There was no strong evidence that the effects differed in men and women (P=0.32). CONCLUSIONS: Low birth weight contributes to elevated CRP concentration in adult life. Future studies are required to determine to what extent this association reflects catch-up centile crossing, in utero programming, or genetic factors.

Adult↗