Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

Platelets at the Vessel Wall in Non-Thrombotic Disease.

Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.

Comparison of body fatness measurements by near-infrared reactance and dual-energy X-ray absorptiometry in normal-weight and obese black and white women.

The aim of the present study was to compare body fat percent (BF %) using single-site near-IR reactance (NIR) and dual-energy X-ray absorptiometry (DXA) in a cohort of normal-weight (BMI < 25 kg/m2) black (n 102) and white (n 71); and obese (BMI > or = 30 kg/m2) black (n 117) and white (n 41) South African women (18-45 years). NIR-derived BF % was significantly correlated with DXA-derived BF % in all groups: normal-weight black (r 0.55, 95 % CI: 0.40, 0.67, P < 0.001) and white (r 0.69, 95 % CI: 0.53, 0.79, P < 0.001) women; obese black (r 0.59, 95 % CI: 0.46, 0.70, P < 0.001) and white (r 0.56, 95 % CI: 0.30, 0.74, P < 0.001) women. NIR under-predicted BF% compared to DXA in black women (normal-weight, - 4.36 (sd 4.13) % and obese, - 3.41 (sd 3.72) %), while smaller mean differences were observed in white women (normal-weight, - 0.29 (sd 4.19) % and obese, - 0.81 (sd 3.09) %), irrespective of normal-weight or obese status (P < 0.001). In obese subjects, NIR-derived BF % did not measure values greater than approximately 45 %, while the maximum DXA-derived measure was 58 %. In conclusion, although there was a significant relationship between NIR- and DXA-derived BF %, NIR under-predicted BF % in normal-weight and obese black South African women compared to DXA, but to a greater extent in subjects with very high levels of adiposity (>45 %). The results of single-site NIR as a measure of BF % should therefore be interpreted with caution, particularly in women of African descent and in those with very high levels of adiposity.

The atypical presentation of the metabolic syndrome components in black African women: the relationship with insulin resistance and the influence of regional adipose tissue distribution.

The appropriateness of the metabolic syndrome criteria as an indicator of cardiovascular disease risk has been challenged in black Africans. Hence, the aims of this study were (1) to examine the level of agreement between the International Diabetes Federation (IDF) and the National Cholesterol Education Program Adult Treatment Panel III (ATP III) metabolic syndrome criteria, which differ in their emphasis on central obesity; (2) to investigate the degree to which these criteria predict insulin resistance, as estimated by the homeostasis model assessment of insulin resistance (HOMA-IR); and (3) to investigate the extent to which a diagnosis of the metabolic syndrome and insulin resistance may be explained by body fat and its distribution. In 103 normal-weight (body mass index or=30 kg/m(2), mean: 33.9 +/- 5.5 kg/m(2)) urbanized black South African women (27 +/- 7 years old), body composition (dual-energy x-ray absorptiometry), fat distribution (waist and computed tomography), blood pressure, fasting glucose, HOMA-IR, and lipid profiles were measured. Insulin resistance was defined as the upper tertile of HOMA-IR. The overall proportion of individuals who met the IDF and ATP III metabolic syndrome criteria were 13% and 10%, respectively. Agreement was high between the IDF and ATP III metabolic syndrome criteria (kappa = 0.87); however, neither criteria predicted HOMA-IR (kappa = 0.16, 95% confidence interval: 0.05-0.27 and 0.14, 95% confidence interval: 0.05-0.27, respectively). Visceral adipose tissue was the largest contributor to diagnosis of the metabolic syndrome, and waist alone (>80 cm or >88 cm) had an improved specificity (21% or 18% higher, respectively) and positive predictive value (64% or 57% higher, respectively) for identifying insulin resistance compared with the metabolic syndrome criteria. Waist circumference was a better predictor of HOMA-IR than the IDF or ATP III metabolic syndrome criteria in young black African women without known disease. The measurement of waist circumference, as an indicator of disease risk, should therefore be encouraged in the public health setting.

Association between the 4 bp proinsulin gene insertion polymorphism (IVS-69) and body composition in black South African women.

The objective of the study was to examine the association between a functional 4 bp proinsulin gene insertion polymorphism (IVS-69), fasting insulin concentrations, and body composition in black South African women. Body composition, body fat distribution, fasting glucose and insulin concentrations, and IVS-69 genotype were measured in 115 normal-weight (BMI<25 kg/m2) and 138 obese (BMI>or=30 kg/m2) premenopausal women. The frequency of the insertion allele was significantly higher in the class 2 obese (BMI>or=35 kg/m2) compared with the normal-weight group (P=0.029). Obese subjects with the insertion allele had greater fat mass (42.3+/-0.9 vs. 38.9+/-0.9 kg, P=0.034) and fat-free soft tissue mass (47.4+/-0.6 vs. 45.1+/-0.6 kg, P=0.014), and more abdominal subcutaneous adipose tissue (SAT, 595+/-17 vs. 531+/-17 cm2, P=0.025) but not visceral fat (P=0.739), than obese homozygotes for the wild-type allele. Only SAT was greater in normal-weight subjects with the insertion allele (P=0.048). There were no differences in fasting insulin or glucose levels between subjects with the insertion allele or homozygotes for the wild-type allele in the normal-weight or obese groups. In conclusion, the 4 bp proinsulin gene insertion allele is associated with extreme obesity, reflected by greater fat-free soft tissue mass and fat mass, particularly SAT, in obese black South African women.

Determinants of insulin-resistant phenotypes in normal-weight and obese Black African women.

OBJECTIVE: Subsets of metabolically "healthy obese" and "at-risk" normal-weight individuals have been previously identified. The aim of this study was to explore the determinants of these phenotypes in black South African (SA) women. METHODS AND PROCEDURES: From a total of 103 normal-weight (BMI or= 30 kg/m(2)) black SA women, body composition, fat distribution, blood pressure, fasting glucose levels, insulin resistance, and lipid profiles were measured. Questionnaires relating to family history, physical activity energy expenditure (PAEE), and socio-demographic variables were administered. The subjects were classified as insulin sensitive or insulin resistant according to the homeostasis model assessment of insulin resistance (HOMA-IR) (>or=1.95 insulin resistant). RESULTS: Our study showed that 22% of the normal-weight women were insulin resistant and 38% of the obese women were insulin sensitive. Increased visceral adipose tissue (VAT) (P=0.001) and decreased VAT/leg fat mass (P

The reliability of the FitroDyne as a measure of muscle power.

The FitroDyne is a device that attaches to conventional resistance-training equipment to measure speed of movement, from which muscle power is calculated. The aim of this study was to quantify the repeatability of the measurement of muscle power with the FitroDyne during squat jump and biceps curl exercises. Thirty male subjects completed 3 trials, each consisting of 6 squat jumps and 6 biceps curls of increasing loads. Upper body and lower body maximum power was predicted from the force-velocity curves derived from the range of weights used for each trial. Maximum power measurements of a squat jump (range, 911- 1,673 W) and biceps curl (range, 45-110 W) had intraclass correlation coefficients (ICC) of R = 0.97 (95% CI, 0.95-0.98) and R = 0.97 (95% CI, 0.95-0.98), respectively. The limits of agreement for the squat jump and biceps curl trials were -17 +/- 96 W and 0.11 +/- 13.90 W, respectively. It may be concluded that muscle power can be measured with a high degree of reliability with the FitroDyne. The limits of agreement need to be considered when data are interpreted.