Biomedical subjects

Naveed Sattar

Publications and source records attributed to Naveed Sattar.

At least 73 records · Page 4Linked to original sources

PubMed2004

Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy?

Complications of pregnancy, particularly pre-eclampsia (PET) and intra-uterine growth restriction (IUGR) have been associated with future maternal cardiovascular disease (CVD). Pre-eclampsia, characterised by insulin resistance, widespread endothelial damage and dysfunction, coagulation defects and increased systemic inflammatory response, shares many risk factors with CVD. This review describes the pathology of PET and the maternal metabolic response and discusses the possible underlying mechanisms common to CVD and PET. The contributions of pre-existing risk factors and of the exaggerated atherogenic-like response seen in PET persisting post-partum to future CVD are considered. The potential for interventions based on early assessment of cardiovascular risk is addressed. We conclude that despite the low immediate cardiovascular risk in a population of young women, a pregnancy with multiple complications including PET, premature delivery and IUGR, carries a seven-fold additive risk of future disease. These women may be an appropriate cohort for CVD risk screening and for possible intervention.

Cardiovascular Diseases↗

PubMed2004

Do pregnancy complications and CVD share common antecedents?

Considerable data link low birth weight, due to intrauterine growth restriction, to increased offspring risk of vascular disease in later adult life. This is considered to be the result, in part, of programming through fetal nutrition. These data support the hypothesis that pregnancy outcome in terms of birth weight is linked to the infant's subsequent health. In contrast, much less attention has been focused on the relationship between adverse pregnancy outcomes, such as pre-eclampsia, gestational diabetes, pre-term delivery and intrauterine growth restriction, and the mother's subsequent health. Interesting data have accumulated linking the maternal vascular, metabolic and inflammatory complications of pregnancy to an increased risk of vascular disease in later life (Table 1). This paper reviews the emerging evidence to support this fascinating concept, addresses potential mechanisms and discusses potential clinical implications.

Cardiovascular Diseases↗

PubMed2004

Insights from apoB: from better diagnosis & therapy to the Medusa Hypothesis.

This article will review six of the most important insights that have come from the measurement of apolipoprotein B (apoB). Amongst these are critical clinical advances, which include better definition of those at high risk of vascular disease and better definition of the adequacy of statin therapy. There are also major advances in our understanding of the fundamental processes that interact to cause vascular disease. These include a more precise understanding of the determinants of lipoprotein levels and lipoprotein composition in plasma and, even more importantly, an appreciation of the pivotal role excess fatty acid intake and impaired fatty acid trapping by adipose tissue play in the generation of the complex risk profile that is so common in patients with coronary disease. We have designated the constellation of hypertriglyceridemic (hyperTg) hyperapoB, dysglycemia, and elevated levels of markers of prothrombosis and inflammation--all of which are traceable to adipose tissue dysfunction--as the Medusa Hypothesis. The Medusa Hypothesis puts forward a common pathophysiology for the complex and biologically diverse array of factors that have been associated with vascular disease.

Adipocytes↗

PubMed2004

Inflammation and endothelial dysfunction: intimate companions in the pathogenesis of vascular disease?

There is increasing evidence to implicate inflammation as an important precursor of endothelial dysfunction. This mechanistic link is apparent across the entire spectrum of inflammatory status, i.e. endothelial function is apparent following acute infection, and in subjects with chronic high-grade inflammation and, perhaps most importantly, persistent low-grade inflammation. The recognition of this relationship has present therapeutic ramifications, but also requires that future longitudinal studies determining the predictive ability of endothelial function measures for vascular events should incorporate markers of inflammation as potential confounders. In this issue of Clinical Science, Fichtlscherer and co-workers describe a link between endothelial function and sPLA(2) (secretory non-pancreatic type II phospholipase A(2)) serum activity.

C-Reactive Protein↗

PubMed2004

Non-esterified fatty acids impair endothelium-dependent vasodilation in rat mesenteric resistance vessels.

Elevated circulating levels of NEFAs (non-esterified fatty acids) are associated with states of insulin resistance and increased risk of vascular disease. Previous animal and human studies have demonstrated NEFA-induced endothelial dysfunction of large conduit arteries, reversible by the antioxidant ascorbic acid. We therefore investigated the effect of NEFAs on carbachol-induced endothelium-dependent vasodilation of rat resistance arteries in vitro using the technique of wire myography. In addition, we investigated the effect of co-incubation of NEFAs and ascorbic acid. Cumulative concentration-response curves to carbachol (endothelium-dependent vasodilation) and SNAP (S-nitroso-N-acetyl-DL-penicillamine; endothelium-independent vasodilation) were constructed. Those to carbachol were repeated following a 30 min incubation with either oleic acid (10(-4) M) or palmitic acid (10(-4) M), demonstrating significant impairment of endothelium-dependent vasodilation with both [P<0.05, comparison of pD2 values (the negative log concentration of agonist required to effect a 50% response)]. A cumulative concentration-response curve to carbachol was repeated following co-incubation with palmitic acid (10(-4) M) and the antioxidant ascorbic acid (10(-5) M), demonstrating an abolition of the previously observed endothelial dysfunction induced by palmitic acid. There was no impairment of vasodilation to SNAP following NEFA incubation. We conclude that NEFAs directly impair endothelial function in rat resistance arteries via an increase in oxidative stress at the vascular endothelium.

Animals↗

PubMed2004

Dietary lipids and vascular function: UK Food Standards Agency workshop report.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating the effect of dietary lipids on vascular function. The workshop highlighted the need for intervention studies to be sufficiently powered for these measures and that they should be corroborated with other, more validated, risk factors for CVD. Work presented at the workshop suggested a beneficial effect of long-chain n-3 PUFA and a detrimental effect of trans fatty acids. The workshop also considered the importance of the choice of study population in dietary intervention studies and that "at risk" subgroups within the general population may be more appropriate than subjects that are unrepresentatively healthy.

Cardiovascular Diseases↗

PubMed2004

Divergent metabolic and vascular phenotypes in pre-eclampsia and intrauterine growth restriction: relevance of adiposity.

OBJECTIVE: Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) may both arise secondary to inadequate trophoblast invasion. Maternal vascular disease is evident only in PE. Little mechanistic evidence exists to explain this dichotomy. METHODS: We employed laser Doppler imaging (LDI) to examine microvascular function in 15 women with PE and 30 healthy pregnant women matched for body mass index (BMI). We also examined 16 women with IUGR. Other factors examined included indices of inflammation, lipoproteins, leptin and insulin concentrations. RESULTS: Women with PE had double the concentration of leptin and 30% higher triglyceride than controls. Vascular cell adhesion molecule (VCAM)-1 and interleukin (IL)-6 were also higher in women with PE, with both factors correlating with leptin independently of BMI. No difference in microvascular reactivity was observed between controls and women with PE. Women with IUGR had a four-unit smaller BMI than women with PE. When compared with controls, they also had lower low-density lipoprotein cholesterol (LDL-C) concentrations and systemic inflammatory measures were not elevated. CONCLUSIONS: The technique of LDI is not sensitive to the vascular dysfunction of PE. However, circulating endothelial-derived factors are elevated in association with markedly elevated leptin levels. Therefore, women with IUGR may demonstrate a protective role for their 'leanness' with regard to maternal systemic inflammatory effect.

Adipose Tissue↗

PubMed2004

Score based on hypoalbuminemia and elevated C-reactive protein predicts survival in patients with advanced gastrointestinal cancer.

The presence of a systemic inflammatory response (as evidenced by elevated C-reactive protein concentrations) has been shown to be associated with loss of lean body mass and poor survival in cancer patients. The aim of this study is to assess the value of the combination of hypoalbuminemia and an elevated circulating concentration of C-reactive protein as a prognostic score in patients with advanced gastrointestinal cancer. Patients with advanced colorectal (n = 99) and gastric (n = 66) cancer and who had measurements of albumin and C-reactive protein were identified. Hypoalbuminemia (< 35 g/l/ > or = 35 g/l) and an elevated C-reactive protein (< or = 10 mg/l/ > 10 mg/l) were combined to form a prognostic score (0, 1, and 2). In patients with colorectal cancer, median survival was 12.1, 6.1, and 1.7 m (P < 0.001) for scores of 0, 1, and 2, respectively. In patients with gastric cancer the corresponding median survival was 6.1, 3.1, and 1.6 m, respectively (P < 0.01). The results of the present study suggest that, in patients with advanced gastrointestinal cancer, a cumulative score based on hypoalbuminemia and an elevated C-reactive protein may be useful. It has the advantage that it is based on routinely available well-standardized measurements and is simple to use.

Aged↗

PubMed2004

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study.

We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men in the West of Scotland Coronary Prevention Study. A total of 139 men developed new diabetes over 4.9 years of follow-up. ALT, but not aspartate aminotransferase, levels increased progressively with the increasing number of metabolic syndrome abnormalities from (means +/- SD) 20.9 +/- 7.6 units/l in those with none to 28.1 +/- 10.1 units/l in those with four or more (P < 0.001). In a univariate analysis, men with ALT in the top quartile (ALT >/=29 units/l) had an elevated risk for diabetes (hazard ratio 3.38 [95% CI 1.99-5.73]) versus those in the bottom quartile (<17 units/l). ALT remained a predictor with adjustment for age, BMI, triglycerides, HDL cholesterol, systolic blood pressure, glucose, and alcohol intake (2.04 [1.16-3.58] for the fourth versus first quartile). In stepwise regression, incorporating ALT and C-reactive protein (CRP) together with metabolic syndrome criteria, elevated ALT (>/=29 units/l), and CRP (>/=3 mg/l) predicted incident diabetes, but low HDL cholesterol and hypertension did not. Thus, elevated ALT levels within the "normal" range predict incident diabetes. The simplicity of ALT measurement and its availability in routine clinical practice suggest that this enzyme activity could be included in future diabetes prediction algorithms.

Alanine Transaminase↗

PubMed2004

Effects of low-dose continuous combined HRT on vascular function in women with type 2 diabetes.

BACKGROUND: Improvement in vascular endothelial function is widley cited as a beneficial effect of hormone replacement therapy (HRT). Women with type 2 diabetes (T2DM) are at increased cardiovascular risk and have impaired endothelial function. Any benefits of HRT on endothelial function in this group are of particular interest. OBJECTIVES: We assessed effects on vascular function of oral 17beta oestradiol (1 mg) and norethisterone (0.5 mg) in postmenopausal women with T2DM. DESIGN: Double-blind, randomised, placebo-controlled trial. ASSESSMENTS: Twenty-eight women had pulse wave velocity (PWV) and adhesion molecules VCAM-1 and ICAM-1 assessed before and after three months' treatment. Twenty-four women also had gluteal fat biopsy for assessment of resistance vessel function (using wire myography). RESULTS: HRT did not affect PWV, VCAM-1, ICAM-1 or carbachol response. Effects of L-NAME and indomethacin on carbachol sensitivity were similar in both groups. CONCLUSIONS: This HRT preparation had no detectable effect on these measures of endothelial function in women with T2DM.

Arteries↗

PubMed2003

Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis.

There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

Arthritis, Rheumatoid↗

PubMed2003

Comparison of the associations of apolipoprotein B and low-density lipoprotein cholesterol with other cardiovascular risk factors in the Insulin Resistance Atherosclerosis Study (IRAS).

BACKGROUND: Risk factors for vascular disease include obesity, dyslipidemia, hypertension, dysglycemia, insulin resistance, inflammation, thrombosis, and subclinical atherosclerosis. This study compares the associations of apolipoprotein B (apoB) and LDL cholesterol (LDLC) with a wide array of measures of these risk factors. METHODS AND RESULTS: In 1522 individuals in the Insulin Resistance Atherosclerosis Study, anthropometric measures and measures of lipids, apoB, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), fasting and postglucose load glucose and insulin concentrations, and carotid artery intima-media thickness (IMT) were taken and insulin sensitivity was determined by frequently sampled intravenous glucose tolerance test. There were significant differences in measures of abdominal obesity, dyslipidemia, hyperinsulinemia, and thrombosis between subjects with elevated apoB but normal LDLC versus those with elevated LDLC but normal apoB. In each statistically significant comparison, the elevated-apoB group had higher associated risk than the elevated-LDLC group. Moreover, apoB is highly significantly (P<0.0001) correlated with each measure in the direction of higher risk, whereas LDLC was significantly correlated (P<0.05) only with blood pressure, triglyceride, fibrinogen, and C-reactive protein. After further adjustment for LDLC, apoB correlations remained significant, whereas several LDLC correlations adjusted for apoB became significant in the direction of lower risk. CONCLUSIONS: Elevated apoB is more strongly associated than LDLC with other risk factors, including measures in the National Cholesterol Education Program guidelines for lipid treatment and other more recently established risk factors. This may provide new insight into why apoB is a better predictor of vascular risk than LDLC.

Adult↗

PubMed2003

Paradoxical elevation in adiponectin concentrations in women with preeclampsia.

Adiponectin is a recently identified, insulin-sensitizing and anti-inflammatory protein released by adipocytes, which is paradoxically reduced in obesity. It suppresses endothelial activation. Physiological insulin resistance occurs in normal pregnancy and is exaggerated in women with preeclampsia (PE), together with enhanced inflammatory and endothelial activation. Women with increased body mass index (BMI) and insulin resistance are predisposed to PE. We hypothesized that adiponectin concentrations are reduced in normal pregnancy compared with postpartum values and further reduced in women with PE. Fifteen women with PE and 30 control subjects with similar first trimester BMI had adiponectin concentrations measured in the third trimester; postpartum measurements were repeated in 16 control subjects. Adiponectin concentration in healthy pregnant women correlated inversely with early pregnancy BMI (r=-0.47, P=0.01) and fasting insulin concentrations (r=-0.58, P=0.001). However, adiponectin concentrations did not differ significantly in pregnancy and postpartum samples (mean change, -0.15 microg/mL; 95% CI, -2.28 to 1.98, P=0.88). Plasma adiponectin concentrations were markedly elevated (P=0.01) in women with PE (mean, 21.6; SD, 8.18 microg/mL) compared with control subjects (mean, 14.7; SD, 7.06 microg/mL). Moreover, in PE, adiponectin concentrations did not correlate with first trimester BMI or insulin or with serum urate or creatinine concentrations or urinary protein levels. We conclude that plasma adiponectin concentrations are not elevated in normal human pregnancy and paradoxically elevated (by 47%) in women with PE. This may be secondary to exaggerated nonspecific adipocyte lipolysis or as a physiological response to enhance fat utilization and attenuate endothelial damage. Future studies should determine whether adiponectin concentrations help improve prediction of PE.

Adiponectin↗

PubMed2003

Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity: how low can you go?

OBJECTIVE: This study was undertaken to evaluate to what extent C-reactive protein (CRP) can be reduced by exercise by examining its circulating concentrations in male ultramarathon runners and to determine if low leptin as a robust circulating marker of fat mass could account for low CRP in such men. METHODS AND RESULTS: Sixty-seven male ultramarathon runners and 63 sedentary male controls of similar age and body mass index were recruited. CRP and leptin were measured by ELISA and radioimmunoassay, respectively. Median CRP concentration in lean (body mass index <25 kg/m2) marathon runners was less than half control median (0.4 [0.2 to 0.9] mg/L versus 0.9 [0.5 to 2.7] mg/L, P=0.0013) and, more strikingly, in nonlean runners was approximately 26% of control median (0.4 [0.3 to 0.8] mg/L versus 1.5 [0.9 to 2.5] mg/L, P=0.0002). Circulating leptin levels were also substantially lower in lean (45% less) and nonlean (63% less, both P<0.0001) ultramarathon runners. However, interleukin-6 levels were not different. Furthermore, leptin adjustment only minimally attenuated the case-control difference in CRP, suggesting that mechanisms other than fat mass reduction contribute to low concentrations of CRP in marathon runners. CONCLUSIONS: This study suggests that circulating CRP concentrations can be markedly suppressed, independently of total adiposity or indeed fat mass, by intense regular physical exercise.

Adult↗

PubMed2003

Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study.

BACKGROUND: The National Cholesterol Education Program (NCEP) recently proposed a simple definition for metabolic syndrome. Information on the prospective association of this definition for coronary heart disease (CHD) and type 2 diabetes is currently limited. METHODS AND RESULTS: We used a modified NCEP definition with body mass index in place of waist circumference. Baseline assessments in the West of Scotland Coronary Prevention Study were available for 6447 men to predict CHD risk and for 5974 men to predict incident diabetes over 4.9 years of follow-up. Mean LDL cholesterol was similar but C-reactive protein was higher (P<0.0001) in the 26% of men with the syndrome compared with those without. Metabolic syndrome increased the risk for a CHD event [univariate hazard ratio (HR)=1.76 (95% CI, 1.44 to 2.15)] and for diabetes [univariate HR=3.50 (95% CI 2.51 to 4.90)]. Metabolic syndrome continued to predict CHD events (HR=1.30, 95% CI, 1.00 to 1.67, P=0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both P<0.0001). C-reactive protein enhanced prognostic information for both outcomes. With pravastatin, men with the syndrome had similar risk reduction for CHD as compared with those without (HR, 0.73 and 0.69; pravastatin versus placebo). CONCLUSIONS: A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.

Body Mass Index↗

PubMed2003

Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome.

Use of metformin in polycystic ovary syndrome (PCOS) is becoming increasingly accepted and widespread, but clinical practice is ahead of the evidence. Although a wide range of benefits in metabolic, reproductive, and clinical measures have been reported from non-randomised trials with metformin, close inspection of results from the adequately controlled studies shows that the benefits are modest. Our aim in this descriptive review is not to define practice guidelines but to improve clinicians' knowledge of the available published clinical evidence, concentrating on the few randomised controlled trials. We also highlight other issues, including hirsutism, acne, pregnancy, and neonatal outcome, that require more attention before clinical recommendations for the use of metformin in PCOS can be formalised. The potentially greater benefits achievable by lifestyle changes alone are also emphasised. We hope that the review will lead to more judicious use of metformin in PCOS and a more structured approach to research.

Cardiovascular Diseases↗

PubMed2003

Classic and novel risk factor parameters in women with a history of preeclampsia.

Epidemiological studies demonstrate a relation between preeclampsia (PE) and an increased risk of maternal coronary heart disease (CHD) in later life. However, there are few data available to explain any underlying mechanism. We recruited 40 primigravid women with a history of proteinuric PE delivering between 1975 and 1985 and 40 controls, matched as a group for time of index pregnancy, smoking, and current body mass index to assess classic (lipids, blood pressure) and novel (adhesion molecules, insulin, leptin) risk factor pathways. Women with a history of PE had higher diastolic blood pressure compared with controls (83 vs 76 mm Hg, P<0.05), but there were no significant differences in fasting lipoprotein concentrations (P>0.20). However, concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) in particular were higher in the PE group by 14% (P=0.038) and 44% (P=0.002), respectively. The cases also demonstrated a tendency toward higher fasting insulin (P=0.08) concentrations and had higher glycosylated hemoglobin levels (P=0.004). Leptin concentrations were not significantly elevated. Interestingly, significantly more of the women with history of PE were classified as menopausal (37.55% vs 17.5%, P=0.045). The differences in ICAM-1 concentration persisted (P=0.010) after adjustment for potential confounders, including hormonal use/menopausal status, antihypertensive or lipid-lowering therapy, and social class. We conclude that classic risk factors alone cannot fully explain the elevated CHD risk in women with a history of PE. Rather markedly elevated ICAM-1 concentrations and specific but subtle features of the metabolic syndrome (glucose, blood pressure) are likely to be involved.

Adult↗

PubMed2003

A novel anti-inflammatory role for simvastatin in inflammatory arthritis.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

Animals↗