Vascular Disease Prevention (Discontinued) - Volume 2, Issue 3, 2005

An acceptable concept is that the acute coronary syndrome (ACS) is related to erosion or rupture of vulnerable plaques leading to intracoronary thrombosis as a result of the activation of the coagulation cascade and platelet aggregation. Clinical trials and animal models suggest an inflammatory etiology in ACS. This concept is supported by evidence showing that a reduction in serum inflammatory marker levels significantly decreased coronary events in patients with ACS. Statins can lower the circulating levels of inflammatory markers and rapidly improve endothelial function with a concurrent decrease in vascular events. This may explain the accumulating evidence indicating that statins, like aspirin, should be given intensively and early in patients with ACS. Long-term statin therapy will also decrease subsequent coronary events. Our recent findings show that simvastatin induced significant reductions in C-reactive protein (CRP) levels and endothelin-1 (ET-1) on day 14. A rapid reduction in CRP could even be achieved within 24 h following a single, high dose of simvastatin (80 mg) which also positively influenced short-term clinical outcomes. In addition, our in vitro data demonstrated that simvastatin could significantly inhibit the release of interleukin-6 (IL-6) in cultured blood monocytes induced by CRP as well as lipopolysaccharide (LPS) in dose-dependent manner. We also showed that fluvastatin significantly inhibited the induction of tumor necrosis factor-α (TNF-α), and activation of nuclear factor-kappa B (NF-kB) in cultured human vascular endothelial cells stimulated by CRP. These findings provide an insight into the antiinflammatory and anti-atherosclerotic actions of statins. Based on available evidence and in the light of the understanding that statins have potential pleiotropic effects, especially as anti-inflammatory agents, early, intensive and long-term statin therapy has become accepted in patients with ACS.

Objective: To investigate the function of vascular endothelial cells (EC) and the plasma levels of nitric oxide (NO) and endothelin (ET) in elderly Chinese patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and its association with coronary heart disease (CHD). Methods: Elderly simple snorers (n = 31) with neither OSAHS nor CHD were randomly selected as the control group; 45 elderly patients with moderate or severe degree of OSAHS were recruited as the OSAHS group, which were further divided into two subgroups, CHD subgroup (16 patients) and non-CHD subgroup (29 patients). The changes of plasma concentrations of NO and ET were compared between the groups. Results: Compared with the control group, in the OSAHS group there was a significantly lower NO level (27.7 ± 9.2 μmol/L vs 61.9 ±13.5 μmol/L, P<0.01), higher ET level (58.1 ± 14.2 ng/ml vs 34.8 ± 8.2 ng/ml, P<0.01), and lower NO/ET ratio (0.47 ± 0.18 vs 1.72 ± 0.97, P<0.01). The incidence of CHD in the OSAHS group was 35.6%. Comparison between the control group and non-CHD OSAHS subgroup showed that the decreased NO level (35.5 ± 9.4μmol/L), increased ET level (47.5 ± 11.1 ng/ml) and declined the NO/ET ratio (0.75 ± 0.13) in non-CHD subgroup were statistically significant (P<0.05). This difference was more significant between the control group and CHD OSAHS subgroup (P<0.01). Comparison between the two OSAHS subgroups indicated that there was a significantly lower NO level, higher ET level and more declined NO/ET ratio in those with OSAHS and CHD than in the OSAHS without CHD subgroup (all P<0.05). Conclusion: Vascular endothelial function was significantly impaired in elderly Chinese patients with OSAHS, especially in those with both OSAHS and CHD. Dysfunction of the vascular EC may be one of the causes of CHD in OSAHS patients.

The pathogenesis of cardiovascular disease involves a complex and multifactorial process. Accumulating evidence indicates that inflammation and endothelial dysfunction may play a fundamental role in the initiation, progression and ultimately in the clinical manifestation of progressive vascular diseases. The vasodilator, anti-inflammatory and antithrombotic properties of the endothelium are dynamically regulated and are severely compromised by a variety of injuries, including atherosclerosis and inflammation. Endothelial dysfunction can occur well before the structural manifestation of atherosclerosis. It is therefore of great importance to develop non-invasive means of evaluating a broader array of endothelial function in vivo, to identify arteries at risk for atherothrombosis and its consequences, and to predict prognosis in patients with vascular disease. Recent studies identified novel biomarkers of vascular disease that would serve as indicators of widespread vascular inflammation or as surrogates for endothelial dysfunction. This review will focus on Creactive protein, serum amyloid A protein, myeloperoxidase, the cytokines interleukin-8 and interleukin-18, the CD40/CD40 ligand system, platelet-activating factor acetylhydrolase, lectin-like oxidized low-density lipoprotein receptor- 1 and gelatinolytic matrix metalloproteinases. Identifying biomarkers with sensitivity and specificity for detection of inflammation underlying endothelial dysfunction will increase our understanding of disease mechanisms, may allow early and more accurate prediction and diagnosis of disease progression, and ultimately may guide the development of novel therapeutic approaches directed towards prevention of vascular disease progression.

Blood vessels are continuously subjected to the action of mechanical forces in the form of shear stress and strain associated with stretch of the vessel wall. Shear stress results from the friction of blood against the lumen of the vessel and is sensed by endothelial cells. Strain is the major determinant of vessel stretch, to which a cyclic quantity is added stemming from the pulsatile nature of blood pressure. The mechanical stretch affects endothelial cells, smooth muscle cells and cells in the outer adventitial layer of the blood vessel. These mechanical forces are detected by mechanosensors which initiate a variety of signaling system cascades responsible for triggering functional responses unique for a particular cell type. Although many of the pathophysiological effects resulting from mechanical stimulation have been described for vascular cells, identity of the mechanosensor and associated transduction mechanisms remain to be determined. The cellular reaction to shear stress and circumferential stretching also depends on other factors, such as stretch-induced secretion of humoral growth factors and effects on cell-cell junctions, some of which might be triggered directly while others are secondary to the adhesion-mediated response. This article discusses key aspects of mechanical signaling and how these mechanisms may regulate and cross-talk with humoral systems in the development of vascular disease. This includes the potential role of integrinextracellular matrix interactions, focal adhesions, ion-channels, the cytoskeleton, mitogen-activated protein kinases, GTP-binding proteins and interaction of these components to form various signaling complexes. Although the vascular system is emphasized, the signal transduction systems presented have similar functions in other tissues. Future progress in the cardiovascular field will require identification of the mechanosensor(s) and associated signaling cascades which synergize with humoral systems that ultimately lead to structural and functional abnormalities.

Central retinal vein occlusion (CRVO) is a common visually disabling disease. Although CRVO is among the most common vascular disorders affecting the retina, second in prevalence only to diabetic retinopathy, there is a great deal of confusion regarding its management. The pathogenesis of CRVO is multifactorial with both local factors and systemic diseases being etiologically important. Various therapeutic regimens advocated include fibrinolytic or thrombolytic agents administered by various routes, anticoagulants, hemodilution, corticosteroids, acetazolamide, hyperbaric oxygen, complex medical therapy and other treatment modalities. The objective of this review is to evaluate the treatments commonly advocated, in the light of our current knowledge of CRVO.

Atherosclerosis is strongly modulated by inflammatory components. Furthermore, arterial blood flow is an important modulator of plaque location and plaque progression. The connection between blood flow and plaque progression is found in shear stress, i.e. the frictional force induced by the blood flow, exerted on the endothelium. If shear stress and inflammation play an important role in atherosclerosis, both factors may influence each other. In this review, the role of shear stress on inflammation is evaluated. Because low shear stress has been associated with plaque formation, we specifically sought how low shear stress affects inflammation. By reviewing the literature, we were able to formulate important mechanisms in which low shear stress might interfere with monocyte accumulation. These mechanisms will be discussed in details in the present review.

OBJECTIVE: An epidemiological study to explore the relationship between proinsulin and cardiovascular risk factor clustering. METHODS: 1196 subjects (533 men, 663 women; average age was 46.7 years) aged 35-59 in Pizhou city in Jiangsu province were randomly recruited. Fasting serum proinsulin was measured by a high sensitivity specific monoclonal antibody-based two-site enzyme immunoassay. RESULTS: The mean cardiovascular risk factor score was 0.97, 1.15, 1.53, and 2.04 (p = 0.000), and the rates of clustering of cardiovascular risk factors were 25.8%, 30.8%, 45.8% and 58.5% (p = 0.000) from the lowest to the highest quartile of proinsulin level, respectively. The Spearman correlation coefficient between proinsulin level and cardiovascular risk factors score was 0.308 (p = 0.000). By partial correlate analysis after adjusting for age, sex, body mass index and waist circumference the correlation was 0.2095 (p = 0.000). The results of non-conditional univariate logistic regression and multivariate stepwise logistic regression indicated that the concentration of proinsulin was associated with cardiovascular risk factor clustering (independent of age, sex, body mass index and waist circumference) and the odds ratio (95% confidence interval) was 1.656 (1.483∼1.851) and 1.381 (1.206∼1.582), respectively. CONCLUSIONS: There was a dose-response relationship independent of age, sex, body mass index and waist circumference between proinsulin and the clustering of cardiovascular risk factors in this Chinese middle-aged population.

protein Z (PZ) is a vitamin K-dependent plasma glycoprotein synthesized by the liver. Its structure is similar to other vitamin K-dependent coagulation factors. PZ plays an important role in mediating thrombosis and may be an independent risk factor for ischemic strokes. PZ mainly promotes the assembly of thrombus with phospholipids surfaces in a Ca2+-dependent fashion, thus enhancing coagulation. On the other hand, PZ binds with a specific PZ-dependent protease inhibitor (ZPI) to factor Xa and therefore indirectly acts as a natural anticoagulant. Therefore, PZ plays two paradoxical roles in vivo. It is connected with coagulation and anticoagulation and ischemic stroke. More research is needed to improve our understanding of PZ's role in preventing and treating thrombosis.

Lysophosphatidic acid (LPA) is one of the simplest phospholipids. LPA is a potent bioactive lipid with specific and multiple effects on cells of the vessel wall and blood platelets via G protein-coupled receptors (GPCR). LPA is present in serum, induces platelet aggregation, and can be generated by thrombin-stimulated platelets. Blood plasma contains physiologically relevant levels of LPA. Because of the multiple actions of LPA on cells of the vasculature, a growing body of evidence suggests that LPA plays an important role in blood clotting, wound healing, and tissue regeneration. LPA is involved in atherogenesis, pathological vasoconstriction, plaque rupture and intravascular thrombus formation. Recently many showed that LPA levels are higher in ischemic stroke samples than in matched plasma samples. Elevated plasma levels of LPA have been associated with ischemic cerebrovascular diseases. Furthermore elevated plasma levels of LPA occur in acute ischemic samples. We suggest that LPA could be an early diagnostic biomarker, a prognostic indicator that can be used to test acute ischemic cerebrovascular diseases and cardiovascular diseases or an indicator of response to therapy. This leads us to propose new strategies for the prevention and therapy of cerebrovascular diseases.

The last ten years focused on the relevance of the endothelium in the onset and progression of atherosclerosis. It has been established that the impact of a recognized risk factor such as low-density lipoproteins (LDL) begins on the endothelial surface by impairing endothelial function. The relevance of lipid metabolism in atherosclerosis is complex and extends to other lipid subfractions such as triglycerides, high-density lipoproteins (HDL) and postprandial lipaemia. All these variables can influence endothelial function. Triglyceride levels are associated with altered endothelial function in healthy subjects probably via an oxidative mechanism. HDL exerts a protective action on endothelial reactivity via antioxidant and anti-inflammatory properties attenuating the damage produced by LDL. Postprandial lipaemia may impair endothelial reactivity; this transient injury of the endothelium favours atherosclerotic lesions. Several reports suggested that endothelial dysfunction represents a reversible phase of atherosclerosis; this consideration underlines the significance of dietary and lipid-lowering treatment in the prevention of atherosclerosis. However, additional strategies are needed to treat the cluster of risk factors in high-risk patients.