Gerasimos Siasos

Diabetes Mellitus-Associated Vascular Impairment: Novel Circulating Biomarkers and Therapeutic Approaches

It is widely accepted that diabetes mellitus (DM) impairs endothelial nitric oxide synthase activity as well as enhances the production of reactive oxygen species, thus resulting in diminished nitric oxide bioavailability and the consequent pro-atherogenetic alterations. Important biomarkers of the vasculature are related to endothelial dysfunction, to inflammatory and coagulation processes, and to oxidative stress in DM. Several therapeutic strategies might exert favorable effects on the vasculature of diabetic patients, such as insulin analogues, antihypertensive agents, statins, and hypoglycemic agents, whereas in spite of the prominent role of oxidative stress in diabetes, antioxidant therapy remains controversial. The use of specific biomarkers related to vascular function could be a useful therapeutic approach in such patients.

Omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect in adults with metabolic syndrome

OBJECTIVES Metabolic syndrome (MetS) is associated with adverse cardiovascular events, and impaired vascular function. In this study we evaluated the effects of omega-3 polyunsaturated fatty acids (PUFAs) supplementation on vascular function, inflammatory and fibrinolytic process in subjects with MetS. METHODS We studied the effect of a 12 weeks oral treatment with 2 g/day of omega-3 PUFAs in 29 (15 male) subjects (mean age 44 ± 12 years) with MetS on three occasions (day0: baseline, day 28 and day 84). The study was carried out on two separate arms (PUFAs and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. The diagnosis of MetS was based on the guidelines of Adult Treatment Panel III definition. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. Serum levels of interleukin-6(IL-6) and plasminogen activator inhibitor-1(PAI-1) were measured by ELISA. RESULTS Treatment with PUFAs resulted in a significant improvement from day 0 to 28 and 84 in FMD and PWV (p < 0.001 for all). Nevertheless, treatment with placebo resulted in no significant changes in FMD (p = 0.63) and PWV (p = 0.17). Moreover, PUFAs treatment, compared to placebo, decreased IL-6 levels (p = 0.03) and increased PAI-1 levels (p = 0.03). Finally, treatment with PUFAs resulted in a significant decrease in fasting triglyceride levels from day 0 to 28 and 84 (p < 0.001) and in serum total cholesterol levels (p < 0.001). CONCLUSIONS In subjects with MetS, treatment with omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect.

Biomarkers of premature atherosclerosis

C-reactive protein (CRP) is an acute phase protein and a biochemical marker with important prognostic value for cardiovascular events. Interleukins IL-1 and IL-6 are implicated in the pathogenesis of atherosclerosis and are associated with CRP. Apolipoproteins ApoA-I and ApoB are the main lipid metabolic markers implicated in the development and progression of atherosclerosis. Fibrinogen has also been proposed to be a major independent risk factor for cardiovascular events. Because premature atherosclerosis precedes the development of cardiovascular disease, identification of the associated biomarkers is of great importance. However, further studies will be needed to determine whether or not these markers are useful predictors of future cardiovascular events. Here, we review the roles of specific biomarkers that have been implicated in premature atherosclerosis.

Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease

BACKGROUND Osteopontin (OPN) and osteoprotegerin (OPG) have recently emerged as key factors in both vascular remodeling and development of atherosclerosis. Arterial stiffness has an independent predictive value for cardiovascular events. We evaluate the relationship between OPG, OPN serum levels and vascular function in coronary artery disease (CAD) patients. METHODS The study population was consisted of 409 subjects (280 with CAD and 129 without CAD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. OPG and OPN levels were measured, as markers of vascular remodeling and calcification, by ELISA. Gensini score was used to evaluate the extent of CAD. RESULTS CAD patients, compared to those without CAD, had higher OPG (3.91 ± 1.87 pmol/l vs. 2.88 ± 1.32 pmol/l, p<0.001) and logOPN levels (1.81 ± 0.18 ng/ml vs. 1.71 ± 0.24 ng/ml, p<0.001) and impaired PWV (8.94 ± 2.21 m/s vs. 8.28 ± 1.91 m/s, p=0.006). Furthermore, PWV was associated with serum OPG levels (r=0.19, p<0.001) and with serum logOPN levels (r=0.10, p=0.049). Multivariate linear regression analysis revealed that increased OPG (p=0.013) and logOPN (p=0.006) levels are associated with 3-vessel CAD and Gensini score (p=0.04 for OPG and p=0.09 for OPN), independently of other known cardiovascular risk factors. CONCLUSION The present study revealed that serum OPG and OPN levels are positively associated with arterial stiffness, and with the extent of CAD. These preliminary results suggest that OPG and OPN levels are significantly correlated with vascular function contributing to the pathogenesis of atherosclerosis in CAD. Further studies are needed to explore the mechanisms of action of OPG and OPN in CAD.

Acute Mental Stress Has a Prolonged Unfavorable Effect on Arterial Stiffness and Wave Reflections

Objective: Large-artery stiffness and arterial wave reflections have been identified as independent markers and prognosticators of cardiovascular risk. Mental stress is a novel risk factor for coronary artery disease and has been associated with left ventricular dysfunction, myocardial ischemia and infarction, and sudden cardiac death. The purpose of this study was to assess the effect of acute mental stress on aortic stiffness and wave reflections. Methods: The effect of a mental arithmetic test was assessed in 19 healthy individuals using a randomized, sham-procedure-controlled, crossover design. Carotid-femoral pulse wave velocity and augmentation index were measured as indices of aortic stiffness and wave reflections, respectively. Results: Mental stress induced a sustained increase in central systolic and pulse pressure throughout the whole study (systolic: by 7.5 mm Hg, p < .05; pulse: by 5.7 mm Hg, p < .01). The increase in peripheral systolic and pulse pressure was not significant throughout the study, but only when their peak values were compared with baseline (systolic: by 6.2 mm Hg, peak at 0 minutes; pulse: by 6.6 mm Hg, peak at 5 minutes, p < .05 for both). There was a sustained increase in pulse wave velocity (by 0.57 m/s, p < .005) throughout the study denoting a sustained increase in aortic stiffness. Similarly, augmentation index showed a sustained increase with mental stress (by 6.16%, p < .05) denoting increased wave reflections from the periphery. Conclusion: Acute mental stress results in a prolonged increase in aortic stiffness and wave reflections. Given the important pathophysiologic and prognostic role of these parameters, our results provide important mechanistic links between acute mental stress and increased cardiovascular risk. Tr = timing of the reflected wave; ANOVA = analysis of variance.

Effects of rosuvastatin and allopurinol on circulating endothelial progenitor cells in patients with congestive heart failure: the impact of inflammatory process and oxidative stress.

OBJECTIVE Endothelial progenitor cells (EPCs) contribute to the maintenance of endothelial integrity and function. We investigated the effects of rosuvastatin and allopurinol on the number of EPCs in patients with heart failure and aimed to provide insight into the molecular inflammatory and oxidative mechanisms that could be responsible for the alterations in EPC levels after treatment. METHODS Sixty patients with systolic heart failure were randomized to receive rosuvastatin 10mg/d, allopurinol 300mg/d or placebo and followed up for 1 month. The number of CD34(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+) EPCs in blood was evaluated by flow cytometry. Endothelial function was assessed by brachial artery flow-mediated dilation. Levels of markers of inflammation and oxidative stress were also determined. RESULTS Circulating EPCs were significantly increased after rosuvastatin treatment (from 230 (170-380) and 10 (8-24) to 390 (230-520) and 19 (8-33) cells/10(6) lymphomonocytes, respectively, p=0.004 and p=0.008), whereas they remained unchanged in the other groups. The increase in EPC levels was not associated with the changes in the levels of the measured inflammatory and oxidative markers. CONCLUSION Short-term treatment with rosuvastatin, but not allopurinol, significantly increases the number of circulating EPCs in patients with heart failure providing further insights into its role in these individuals. The impact of rosuvastatin on EPCs is not mediated by changes in inflammatory and oxidative status.

Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases.

Inflammatory process is essential for the initiation and progression of vascular remodeling, entailing degradation and reorganization of the extra-cellular matrix (ECM) scaffold of the vessel wall, leading to the development of atherosclerotic lesions. Matrix metalloproteinases (MMPs) are zing dependent endo-peptidases found in most living organisms and act mainly by degrading ECM components. Most MMPs are formed as inactive proenzymes and are activated by proteolysis. This process depends and is regulated by other proteases and endogenous MMP inhibitors (TIMPs). MMPs and TIMPs play a major role not only in ECM degradation but also in mediating cell migration, proliferation, tissue remodeling; acting as a signal for the production and secretion of growth factors and cytokines. More importantly MMPs through proteolysis and degradation of ECM contribute in many physiological and pathological processes including organ development, wound healing, tissue support, vascular remodeling and restenosis, atherosclerosis progression, acute coronary syndromes, myocardial infarction, cardiomyopathy, aneurysms remodeling, cancer, arthritis, and chronic inflammatory diseases. A substantial body of evidence support the notion that imbalance between the activity of MMPs and their tissue inhibitors (TIMPs) contribute to the pathogenesis of cardiovascular diseases such as atherosclerosis, vascular remodeling and progression of heart failure. In this review, we will discuss the relationship between MMPs, inflammation and atherosclerosis under the topic of cardiovascular disease.

Mechanisms of Disease: L -arginine in coronary atherosclerosis—a clinical perspective

L-Arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L- Arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin-1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case–control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis.

Interaction between cytokines and sCD40L in patients with stable and unstable coronary syndromes

Background  Evidence suggests that soluble CD40‐ligand (sCD40L) is elevated in coronary artery disease (CAD) and is released from activated platelets during the acute myocardial infarction (AMI). Although sCD40L is part of immune response, the mechanisms regulating its release in different disease states remain unknown.

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.