Familial risk assessment for early-onset coronary heart disease.

PURPOSE: We examined the performance of a familial risk assessment method that stratifies risk for early-onset coronary heart disease by considering the number of relatives with coronary disease, degree of relationship, lineage, and age at diagnosis. METHODS: By using data from the HealthStyles 2003 survey, we assessed the associations between familial risk and early-onset coronary heart disease, diabetes, hypercholesterolemia, hypertension, and obesity. By using area under the curve statistics, we evaluated the discriminatory ability of various risk assessment models. RESULTS: Of 4,035 respondents, 60% were female and 72% were white, with a mean age of 48.8 years. After adjustment for demographics, strong and moderate risk were significantly associated with approximately a five- and twofold risk of early-onset coronary disease, respectively. After adjustment for demographics and personal history of cardiovascular disease, strong familial risk was also significantly associated with diabetes, hypercholesterolemia, hypertension, and obesity. A risk assessment model that included familial risk, demographics, and personal history of diabetes, hypercholesterolemia, hypertension, and obesity was most optimal with an area under the curve statistic of 87.2% CONCLUSIONS: Familial risk assessment can stratify risk for early-onset coronary heart disease. Several conditions associated with increased familial risk can be prevented. These results have important implications for risk assessment and risk-reducing interventions.     

Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells

Both the rate of overall translation and the specific acceleration of proinsulin synthesis are known to be glucose-regulated processes in the beta-cell. In this study, we propose that glucose-induced stimulation of overall translation in beta-cells depends on a protein phosphatase-1-mediated decrease in serine-51 phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), a pivotal translation initiation factor. The decrease was rapid and detectable within 15 min and proportional to the range of glucose concentrations that also stimulate translation. Lowered net eIF2alpha phosphorylation was not associated with a detectable decrease in activity of any eIF2alpha kinase. Moreover, okadaic acid blocked glucose-induced eIF2alpha dephosphorylation, suggesting that the net effect was mediated by a protein phosphatase. Experiments with salubrinal on intact cells and nuclear inhibitor of protein phosphatase-1 (PP1) on cell extracts suggested that this phosphatase was PP1. The net effect contained, however, a component of glucose-induced folding load in the endoplasmic reticulum because coincubation with cycloheximide further amplified the effect of glucose on eIF2alpha dephosphorylation. Thus, the steady-state level of eIF2alpha phosphorylation in beta-cells is the result of a balance between folding-load-induced phosphorylation and PP1-dependent dephosphorylation. Because defects in the pancreatic endoplasmic reticulum kinase-eIF2alpha signaling system lead to beta-cell failure and diabetes, deregulation of the PP1 system could likewise lead to cellular dysfunction and disease.     

Genetic predisposition to coronary artery disease

Understanding the genetic basis of coronary artery disease (CAD) can improve management and prevention. Family and twin studies, animal models and gene association studies support a genetic basis for CAD. Genes contribute to CAD development and progression, and response to risk factor modification and lifestyle choices. Family history is the best indicator of a predisposition to CAD and further refinement is possible with biochemical and DNA testing. Many inherited cardiovascular risk factors can be modified, such as LDL cholesterol, homocysteine and lipoprotein(a). Early detection of CAD might lead to earlier intervention for genetically susceptible individuals. However, data are lacking regarding the efficacy of this approach in preventing clinical events. Despite this lack of evidence, knowledge of genetic CAD susceptibility has value in providing risk information and guiding decision making. Further research that investigates outcomes regarding genetic risk assessment for CAD is necessary.     

A graphical method for assessing risk factor threshold values using the generalized additive model: the multi-ethnic study of atherosclerosis

Continuous variable dichotomization is a popular technique used in the estimation of the effect of risk factors on health outcomes in multivariate regression settings. Researchers follow this practice in order to simplify data analysis, which it unquestionably does. However thresholds used to dichotomize those variables are usually ad-hoc, based on expert opinions, or mean, median or quantile splits and can add bias to the effect of the risk factors on specific outcomes and underestimate such effect. In this paper, we suggest the use of a semi-parametric method and visualization for improvement of the threshold selection in variable dichotomization while accounting for mixture distributions in the outcome of interest and adjusting for covariates. For clinicians, these empirically based thresholds of risk factors, if they exist, could be informative in terms of the highest or lowest point of a risk factor beyond which no additional impact on the outcome should be expected.     

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in h<Emphasis Type="Italic">IAPP</Emphasis> transgenic mice

Aims/hypothesis

Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.

Methods

Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid.

Results

In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475?±?5581 vs 5762?±?575 density/unit area, p?<?0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83?±?2.22 vs 29.34?±?2.03 standardised uptake value × min, p?<?0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r?=?0.74, p?<?0.001).

Conclusions/interpretation

Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.