Effect of gender difference on platelet reactivity

Background

Previous studies have suggested that women do not accrue equal therapeutic benefit from antiplatelet medication as compared with men. The physiological mechanism and clinical implications behind this gender disparity have yet to be established.

Methods

On-treatment platelet reactivity was determined in 717 men and 234 women on dual antiplatelet therapy, undergoing elective coronary stent implantation. Platelet function testing was performed using arachidonic acid and adenosine diphosphate-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 and Aspirin assays. Also the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke was evaluated.

Results

Women had higher baseline platelet counts than men. Women exhibited a higher magnitude of on-aspirin platelet reactivity using LTA, but not using the VerifyNow Aspirin assay. The magnitude of on-clopidogrel platelet reactivity was significantly higher in women as compared with men with both tests used. The cut-off value to identify patients at risk as well as the incidence of clinical endpoints was similar between women and men (16/234[6.8%] vs. 62/717[8.6%], p = 0.38).

Conclusion

Although the magnitude of platelet reactivity was higher in women, the absolute difference between genders was small and both the cut-off value to identify patients at risk and the incidence of the composite endpoint were similar between genders. Thus, it is unlikely that the difference in platelet reactivity accounts for a worse prognosis in women.     

A constituent-based model of age-related changes in conduit arteries

In the present report, a constituent-based theoretical model of age-related changes in geometry and mechanical properties of conduit arteries is proposed. The model was based on the premise that given the time course of the load on an artery and the accumulation of advanced glycation end-products in the arterial tissue, the initial geometric dimensions and properties of the arterial tissue can be predicted by a solution of a boundary value problem for the governing equations that follow from finite elasticity, structure-based constitutive modeling within the constrained mixture theory, continuum damage theory, and global growth approach for stress-induced structure-based remodeling. An illustrative example of the age-related changes in geometry, structure, composition, and mechanical properties of a human thoracic aorta is considered. Model predictions were in good qualitative agreement with available experimental data in the literature. Limitations and perspectives for refining the model are discussed.     

Differences in nitric oxide production in porcine resistance arteries and epicardial conduit coronary arteries

The purpose of this study was to test the hypothesis that endothelial cells from resistance arteries and epicardial conduit coronary arteries differ in their expression of nitric oxide synthase (NOS) and calcium metabolism, and that these differences contribute to the mechanism underlying disparate physiological vasodilator responses observed between the two populations of vessels. The functional vasodilator responses of isolated resistance arteries and epicardial conduit coronary arteries were compared in vitro using both the receptor-independent agonist A23187 ionophore to increase intracellular calcium and the receptor-dependent agonist bradykinin. Constitutive NOS (cNOS) activity in monocultures of endothelial cells derived from resistance arteries and conduit arteries was assayed using a fibroblast-reporter cell method. Intracellular calcium concentration was assessed using fura-2 microfluorometry. Nitric oxide production was determined using a chemiluminescence technique, while cNOS protein was quantitated by Western blot analysis. A23187 was a less potent vasodilator of resistance arteries studied in vitro, compared to epicardial conduit arteries (EC₅₀ = 1.6 μM, resistance artery vs. EC₅₀ = 0.03 μM, conduit artery); however, bradykinin was more potent in resistance arteries (EC₅₀ = 0.3 nM, resistance artery vs. EC₅₀ = 2 nM, conduit artery). In pure monocultures of endothelium, nitric oxide production measured by chemiluminescence both basally and in response to A23187 was significantly less in resistance arteries (6.1 ± 0.5, basal vs. 10.80 ± 0.55, stimulated nmol/μg protein), compared to conduit arteries (7.7 ± 0.5, basal vs. 17.00 ± 1.52, stimulated nmol/μg protein; P < 0.05 resistance artery endothelium vs. conduit artery endothelium). cNOS enzyme activity assessed by cGMP production in reporter cell fibroblasts was also lower in resistance arteries compared to conduit arteries (0.17 ± 0.03 vs. 0.33 ± 0.05 fmol cGMP/μg protein, respectively; P < 0.05 resistance artery endothelium vs. conduit artery endothelium). Conduit arteries expressed 2.1 × more cNOS protein than resistance arteries, as assessed by Western blotting of cellular homogenates. No significant differences were found with microfluorimetry in either basal or ionophore-stimulated intracellular calcium concentrations. The results signified that porcine resistance arteries expressed less NOS and produced less nitric oxide than epicardial conduit arteries both basally and in response to an increase in intracellular calcium. This difference was reflected functionally as a decreased vasodilatory response to increased intracellular calcium in resistance arteries that could not be explained on the basis of differences in the metabolism of intracellular calcium. In contrast, the functional vasodilator response of intact vessels to a receptor-mediated agonist was enhanced in resistance arteries compared to conduit arteries, suggesting an important role of signal transduction mechanisms in specific physiological responses. Thus, the ability of the endothelium to regulate on a regional basis the expression of NOS and integrate receptor-mediated responses with these differences may provide a mechanism for diverse vasomotor responses in different populations of vessels. © 1996 Wiley-Liss, Inc.     

Effects of longitudinal stretch on VSM tone and distensibility of muscular conduit arteries

With progressing age, large arteries diminish their longitudinal stretch, which in extreme cases results in tortuosity. Increased age is also associated with loss of vessel distensibility. We measured pressure-diameter curves from muscular porcine carotid arteries ex vivo at different longitudinal stretch ratios (lambda(z) = 1.4 and 1.8) and under different vascular smooth muscle (VSM) conditions (fully relaxed, normal VSM tone, and maximally contracted). Distensibility was found to be halved by decreasing longitudinal stretch from lambda(z) = 1.8 to 1.4 at physiological pressures. This counterintuitive observation is possible because highly nonlinear elastic modulus of the artery and anisotropic properties. Furthermore, a significantly larger basal VSM contraction was observed at lambda(z) = 1.8 than 1.4, although this was clearly not related to a myogenic response during inflation. This dependence of VSM tone to longitudinal stretch may have possible implications on the functional characteristics of the arterial wall.     

Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice

The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4(-/-) mice do not have normal endothelial cell responses to flow, such as influx of Ca(2+) and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4(-/-) mice. Furthermore, P2rx4(-/-) mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4(-/-) mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.     

Phosphodiesterase 5 inhibition restores impaired ACh relaxation in hypertensive conduit pulmonary arteries

Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were compared in large (LPA) and small pulmonary artery (SPA) rings from normoxic and chronically hypoxic (CH) rats. In addition, the effects of a selective phosphodiesterase (PDE) 5 inhibitor, E-4021, on ACh-induced relaxation were evaluated. Chronic hypoxia markedly decreased both ACh- and SNP-induced relaxations in LPA but not in SPA rings. Pretreatment with E-4021 caused a much greater leftward shift of the concentration-response curve for ACh in hypoxic than in normoxic LPA rings, eliminating the difference in response to ACh between these two vessels. These results suggest that cGMP-dependent relaxation is impaired in the proximal but not in the distal pulmonary artery of CH rats and that increased PDE5 activity could be a mechanism responsible for this impaired responsiveness.     

Influence of spasmolytic agents on the cumulative calcium dose-effect curve in isolation-perfused peripheral vascular beds]

The influence of verapamil, theophylline, and papaverine on the cumulative calcium dose-effect curve was studied at the isolated perfused rat tail. The results indicate different changes of the contraction and relexation phase respectively. The findings are discussed in connection with the action mechanism of the drugs and the processes of excitation-contraction coupling.     

Remodeling of conduit arteries in hypertension and flow-overload obeys a minimum energy principle

Arterial remodeling is an important process in physiology and pathophysiology. Based on an energy minimization method, Murray's law predicts the optimal inner radius. Application of Darcy's law in the wall results in an optimal outer radius. The average wall stress is computed by the Laplace's law. Using these formulas, a large porcine coronary artery in hypertension is studied. The results reveal how wall thickness and average circumferential stress change after increasing blood pressure and volume flow rate. The theoretical predictions are in good qualitative agreement with experimental observations. The advantage and limitation of the current approach are discussed.     

Differential effects of eNOS uncoupling on conduit and small arteries in GTP-cyclohydrolase I-deficient hph-1 mice

In the present study, we used the hph-1 mouse, which displays GTP-cyclohydrolase I (GTPCH I) deficiency, to test the hypothesis that loss of tetrahydrobiopterin (BH(4)) in conduit and small arteries activates compensatory mechanisms designed to protect vascular wall from oxidative stress induced by uncoupling of endothelial nitric oxide synthase (eNOS). Both GTPCH I activity and BH(4) levels were reduced in the aortas and small mesenteric arteries of hph-1 mice. However, the BH(4)-to-7,8-dihydrobiopterin ratio was significantly reduced only in hph-1 aortas. Furthermore, superoxide anion and 3-nitrotyrosine production were significantly enhanced in aortas but not in small mesenteric arteries of hph-1 mice. In contrast to the aorta, protein expression of copper- and zinc-containing superoxide dismutase (CuZnSOD) was significantly increased in small mesenteric arteries of hph-1 mice. Protein expression of catalase was increased in both aortas and small mesenteric arteries of hph-1 mice. Further analysis of endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) signaling demonstrated that protein expression of phosphorylated Ser(1177)-eNOS as well as basal cGMP levels and hydrogen peroxide was increased in hph-1 aortas. Increased production of hydrogen peroxide in hph-1 mice aortas appears to be the most likely mechanism responsible for phosphorylation of eNOS and elevation of cGMP. In contrast, upregulation of CuZnSOD and catalase in resistance arteries is sufficient to protect vascular tissue from increased production of reactive oxygen species generated by uncoupling of eNOS. The results of our study suggest that anatomical origin determines the ability of vessel wall to cope with oxidative stress induced by uncoupling of eNOS.     

Explaining the gender difference in dream recall frequency.

A recent meta-analysis showed a substantial and robust gender difference in dream recall frequency of medium effect size, that is, women tend to recall their dreams more often than men. The question arises as to what factors might explain this difference. Two previous studies indicate that interest in dreams plays an important role. The present study found a significant effect of frequency of nocturnal awakenings and interest in dreams on the gender difference in dream recall frequency. In addition, neuroticism and depressive mood were associated with the gender difference on the aspects of a dream recall scale and interest in dreams. Longitudinal studies are necessary to validate the present findings, especially regarding their causality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interest in dream interpretation: A gender difference.

Although several studies reported a significant effect with regard to the gender difference in an interest in dreams, the generalizability of these studies is limited because mainly students were recruited as participants. In this study, gender differences with regard to interest in dream interpretation as an indicator of interest in dreams in general have been demonstrated in a representative sample. There was, however, a significant age-gender interaction, indicating that interest in dreams might not be a potent variable for explaining gender differences in dream recall. In future studies, the course of interest in dreams over the life span and any associated gender differences should be investigated using carefully designed scales. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Theoretical study on the effects of pressure-induced remodeling on geometry and mechanical non-homogeneity of conduit arteries

A structure-based mathematical model for the remodeling of arteries in response to sustained hypertension is proposed. The model is based on the concepts of volumetric growth and constitutive modeling of the arterial tissue within the framework of the constrained mixture theory. The major novel result of this study is that remodeling is associated with a local change in the mass fractions of the wall constituents that ultimately leads to mechanical non-homogeneity of the arterial wall. In the new homeostatic state that develops after a sustained increase in arterial pressure, the mass fraction of elastin decreases from the intimal side to the adventitial side of arteries, while the collagen fraction manifests an opposite trend. The results obtained are supported by some experimental observations reported in the literature.     

Blood flow velocity--a constantly acting factor in dilatation of the large arteries

Acute experiments on cats have demonstrated the presence of renal artery sensitivity to the bloodstream velocity; the artery is enlarged with the blood flow increase and is narrowed with its decrease. The dilatation of the artery caused by the double increase of the blood flow (from 20 to 40 ml/min) is 23 +/- 8%. It has been established experimentally that carotid, femoral and renal arteries of cats respond to minor changes (of the order of 1 ml/min) in the volumetric velocity of the bloodstream by changing their diameters. Therefore, the arteries continuously follow the bloodstream velocity changes by changing their diameters. It may thus be concluded that the bloodstream itself is the artery dilatation factor.