Cardiovascular disease risk profiles among 'healthy' siblings of patients with early-onset cardiovascular disease:Application of the new SCORE system

BACKGROUND: Cardiovascular disease (CVD) occurs more frequently in individuals with a family history of premature CVD. Within families the demographics of CVD are poorly described. DESIGN: We examined the risk estimation based on the Systematic Coronary Risk Evaluation (SCORE) system and the Joint British Guidelines (JBG) for older unaffected siblings of patients with premature CVD (onset ≤55 years for men and ≤60 years for women). METHODS: Between August 1999 and November 2003 laboratory and demographic details were collected on probands with early-onset CVD and their older unaffected siblings. Siblings were screened for clinically overt CVD by a standard questionnaire and 12-lead electrocardiogram (ECG). RESULTS: A total of 790 siblings was identified and full demographic details were available for 645. The following siblings were excluded: 41 with known diabetes mellitus; seven with random plasma glucose of 11.1 mmol/l or greater; and eight with ischaemic ECG. Data were analysed for 589 siblings from 405 families. The mean age was 55.0 years, 43.1% were men and 28.7% were smokers. The mean total serum cholesterol was 5.8 mmol/l and hypertension was present in 49.4%. Using the SCORE system, when projected to age 60 years, 181 men (71.3%) and 67 women (20.0%) would be eligible for risk factor modification. Using JBG with a 10-year risk of 20% or greater, 42 men (16.5%) and four women (1.2%) would be targeted. CONCLUSIONS: Large numbers of these asymptomatic individuals meet both European and British guidelines for the primary prevention of CVD and should be targeted for risk factor modification. The prevalence of individuals defined as eligible for treatment is much higher when using the SCORE system. © 2007 European Society of Cardiology.

Selective Targeting of Glucagon-Like Peptide-1 Signalling As a Novel Therapeutic Approach for Cardiovascular Disease in Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the cardiovascular system where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting are limited although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1 based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting, and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.

Low alanine aminotransferase levels and higher number of cardiovascular events in people with Type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

<p>AIMS: To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with Type 2 diabetes.</p><p>METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years.</p><p>RESULTS: Alanine aminotransferase level had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase value (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P=0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P=0.001). No relationship was found for gamma-glutamyltransferase.</p><p>CONCLUSIONS: The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health. This article is protected by copyright. All rights reserved.</p>

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (&gt;10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation.

AIMS/HYPOTHESIS: To determine if vaccinations and infections are associated with the subsequent risk of Type I (insulin-dependent) diabetes mellitus in childhood. METHOD: Seven centres in Europe with access to population-based registers of children with Type I diabetes diagnosed under 15 years of age participated in a case-control study of environmental risk factors. Control children were chosen at random in each centre either from population registers or from schools and policlinics. Data on maternal and neonatal infections, common childhood infections and vaccinations were obtained for 900 cases and 2302 control children from hospital and clinic records and from parental responses to a questionnaire or interview. RESULTS: Infections early in the child's life noted in the hospital record were found to be associated with an increased risk of diabetes, although the odds ratio of 1.61 (95% confidence limits 1.11, 2.33) was significant only after adjustment for confounding variables. None of the common childhood infectious diseases was found to be associated with diabetes and neither was there evidence that any common childhood vaccination modified the risk of diabetes. Pre-school day-care attendance, a proxy measure for total infectious disease exposure in early childhood, was found, however, to be inversely associated with diabetes, with a pooled odds ratio of 0.59 (95% confidence limits 0.46, 0.76) after adjustment for confounding variables. CONCLUSION/INTERPRETATION: It seems likely that the explanation for these contrasting findings of an increased risk associated with perinatal infections coupled with a protective effect of pre-school day care lies in the age-dependent modifying influence of infections on the developing immune system.

Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes

An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q(84)-M(86)-K(88), W(108)-M(112)-R(116), and L(144)-M(148)-R(149). These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met(86), Met(112), and Met(148)) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N(epsilon)-malondialdehyde-lysine or N(epsilon)-(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.

Apolipoprotein C-III protein concentrations and gene polymorphisms in type 1 diabetes:associations with lipoprotein subclasses

Serum apolipoprotein C-III (apoCIII) concentration and apoCIII gene polymorphisms have been shown to be a risk factor for cardiovascular disease; however, the underlying mechanisms remain unclear. In addition, no studies have been performed that address these issues in type 1 diabetes. The current study investigated apoCIII protein and apoCIII gene variation in a normotriglyceridemic (82 +/- 57 mg/dL) population of patients with type 1 diabetes, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort. Blood samples were obtained in 409 patients after an overnight fast. Serum apoCIII concentration was highly correlated with multiple changes in lipids and lipoproteins that resulted in an adverse cardiovascular disease risk profile. Higher apoCIII concentrations were associated (P &lt;.0001) with increased triglycerides (r = 0.78), total (r = 0.61) and low-density lipoprotein (LDL) (r = 0.40) cholesterol, apoA-I (r = 0.26), and apoB (r = 0.50), and these relationships persisted after controlling for age, gender, body mass index (BMI), and hemoglobin A1c (HbA1c). Nuclear magnetic resonance (NMR) lipoprotein subclass analyses demonstrated that apoCIII was correlated with an increase in very-low-density lipoprotein (VLDL) subclasses (P = .0001). There also was a highly significant positive relationship between serum apoCIII concentration and the LDL particle concentration in both men (r = 0.49, P = .001) and women (r = 0.40, P = .001), and a highly significant negative relationship between serum apoCIII levels and average LDL particle size in both men (r = -0.37, P = .001) and women (r = -0.22, P = .001) due primarily to an augmentation in the small L1 subclass (r = 0.42, P = .0001). Neither the T(-455) --&gt; C polymorphism affecting an insulin response element in the apoCIII gene promoter nor a SacI polymorphism in the 3'UTR were associated with any alterations in circulating apoCIII concentrations, serum lipids, apolipoprotein concentrations, lipoprotein composition, or parameters measured by NMR lipoprotein subclass analyses. In summary, elevated apoCIII concentration was associated with risk factors for cardiovascular disease in normolipidemic type 1 diabetic patients through associated changes in lipoprotein subfraction distributions, which were independent of apoCIII genotype.

Dose-response effect of fruit and vegetables on insulin resistance in people at high risk of cardiovascular disease:a randomized controlled trial

The purpose of this randomized controlled trial was to investigate the dose-response effect of fruit and vegetable (F&amp;V) intake on insulin resistance (IR) in people who are overweight and at high risk of cardiovascular disease (CVD).

Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes

Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes.

Fruit and vegetable intake and risk of cardiovascular disease

A high intake of fruit and vegetables (FV) has been shown to be associated with reduced risk of a number of chronic diseases, including CVD. This review aims to provide an overview of the evidence that increased FV intake reduces risk of CVD, focusing on studies examining total FV intake. This evidence so far available is largely based on prospective cohort studies, with meta-analyses demonstrating an association between increased FV intake and reduced risk of both CHD and stroke. Controlled intervention trials examining either clinical or cardiovascular risk factor endpoints are scarce. However, such trials have shown that an increase in FV consumption can lower blood pressure and also improve microvascular function, both of which are commensurate with a reduced risk of CVD. The effects of increased FV consumption on plasma lipid levels, risk of diabetes and body weight have yet to be firmly established. In conclusion, evidence that FV consumption reduces the risk of CVD is so far largely confined to observational epidemiology, with further intervention studies required.

Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization.

Purpose: To investigate the association of cardiovascular risk factors and inflammatory markers with neovascular age-related macular degeneration (AMD). Design: Cross-sectional case-control study. Participants: Of the 410 of the =65-year-old community sample invited to attend, 205 participated (50% response rate). Of the 215 clinic attendees who were invited to participate, 212 agreed to take part (98% response rate). A diagnosis of neovascular AMD in at least one eye was made in 193 clinic attendees and 2 of the community sample. Methods: Clinic and community participants underwent a detailed ophthalmic examination with fundus imaging, were interviewed for assessment of putative risk factors, and provided a blood sample. Analysis included levels of serum lipids, intercellular adhesion molecule 1 (ICAM), vascular cellular adhesion molecule (VCAM), and C-reactive protein (CRP). All participants were classified by fundus image grading on the basis of the eye with more severe AMD features. Main Outcome Measure: Neovascular AMD. Results: There were 195 participants with choroidal neovascularization in at least one eye, 97 nonneovascular AMD participants, and 115 controls (no drusen or pigmentary irregularities in either eye). In confounder-adjusted logistic regression, a history of cardiovascular disease was strongly associated with neovascular AMD (odds ratio [OR], 7.53; 95% confidence interval [CI], 2.78-20.41). Cigarette smoking (OR, 3.71; 95% CI, 1.25-11.06), being in the highest quartile of body mass index (OR, 3.82; 95% CI, 1.22-12.01), stage 2 hypertension (OR, 3.21; 95% CI, 1.14-8.98), and being in the highest quartile of serum cholesterol (OR, 4.66; 95% CI, 1.35-16.13) were positively associated with neovascular AMD. There was no association between AMD status and serum CRP, ICAM, or VCAM. Conclusions: Our results suggest that cardiovascular disease plays an etiological role in the development of choroidal neovascularization in a proportion of older adults and highlight the importance of control of blood pressure and cholesterol, avoidance of smoking, and maintenance of a normal body weight. © 2008 American Academy of Ophthalmology.<br/>