Vascular Disease Prevention (Discontinued) - Volume 4, Issue 3, 2007

Cardiopulmonary bypass (CPB) is widely used to maintain systemic perfusion and oxygenation during cardiac surgery. Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury. Thus, it follows that inhibition of glycogenolysis could be cardioprotective. Therefore, we assessed glycogen phosphorylase (GP) and creatine kinase-MB (CK-MB) activity in 120 patients during CPB. Arterial blood samples were collected at different stages of CPB. CK MB and GP activity were significantly increased at all the stages of CPB (P<0.001). Maximum Peak of GP activity was measured at rewarming (at 35°C) (T3) during surgery as compared to that of CK MB 24 h after surgery. In conclusion, GP activity was increased during CPB. The early GP release is a marker of ischemic myocardial damage. This may be part of the response to the increased reactive oxygen species produced during reperfusion.

Excessive calorie intake induces metabolic dysfunction and obesity, leading to the development of type 2 diabetes. Diabetic macroangiopathy is one of the most important complications of type 2 diabetes and it increases the risk of vascular events. Recent clinical studies suggest that impaired insulin signaling rather than hyperglycemia itself is involved in the pathogenesis of diabetes, but the mechanisms underlying the development of diabetic vasculopathy are still largely unknown. Restriction of calorie intake can extend the longevity of organisms ranging from yeast to mice and to prevent age-related conditions such as cancer, deterioration of immune function and increased inflammation. Calorie restriction decreases the plasma levels of glucose, insulin and insulin-like growth factor-1 (IGF-1). Recent genetic studies demonstrated that reduction-of-function mutations affecting insulin/IGF-1/phosphatidylinositol-3 kinase/Akt also extend the lifespan of many organisms, suggesting that these pathways may underlie the mechanism of longevity related to calorie restriction. We recently demonstrated that insulin increases the expression of negative regulators of the cell cycle, such as p53 and p21, and that it promotes endothelial cell senescence in an Akt-dependent manner. We found that the introduction of a dominant-negative Akt mutant decreased the insulin-induced activation of p53 and thus prolonged the lifespan of endothelial cells. Conversely, constitutive activation of Akt promoted senescence-like arrest of cell growth via a p53/p21- dependent pathway. Moreover, it has been shown that senescence of vascular cells is associated with the upregulation of insulin/Akt signaling in patients with type 2 diabetes. Accordingly, we propose that type 2 diabetes can be regarded as a type of premature aging syndrome in which the dysregulation of insulin/Akt signaling promotes cellular senescence, leading to various complications that include macroangiopathy. This concept suggests that anti-senescence therapy might be effective for the treatment of diabetic complications.

Objective: We assessed the radial distribution of elasticity in healthy porcine thoracic aorta. Methods: Cylindrical aortic specimens (n=24) were tested in a uniaxial tension device so that their Stiffness Modulus (SM) could be determined. The specimens were divided into three groups: Group A, radial stretching at zero degrees; Group B, radial stretching at forty five degrees; and Group C, radial stretching at ninety degrees. Results: Stress-Strain analysis showed that (SM-A) vs. (SM-B) and (SM-A vs. SM-C) and (SM-B vs. SM-C) were not statistically different for all strain levels (e=0.5, 1, 1.5, 2.3). Conclusions: In vitro, the radial expansion of aortic tissue appears to be uniform.Thus, diminished elastic properties of the aorta in cases of atheromatosis, would appear in these radial directions where the tissue is atheromatic. So, a useful site prediction could be made for future development of vessel abnormalities (i.e. aneurysm rupture) and the necessary vascular prosthesis might be applied more effectively.

The leading cause of the high morbidity and mortality in hemodialysis (HD) patients is cardiovascular disease (CVD), followed by infections. A combination of patho-physiological processes is involved in the development and progression of vascular disease in HD patients including volume-overload/hypertension, atherosclerosis, calcification and thrombosis. A vicious circle of inflammation and oxidative stress, augmented by iatrogenic effects of HD lines, dialyzers and water contribute to the severity of atherosclerosis and possibly of vascular calcification. Specific metabolic risk factors include increased homocysteine levels, abnormal lipid profile and insulin resistance. The iatrogenic effect of associated therapy such as intravenous (IV) iron administration, active vitamin D derivatives, calcium containing phosphate binders, high dialysate Na concentration and possibly heparin, may add to the detrimental effects of uremia and co-morbid diseases. Potential mechanisms for iatrogenic processes may include effects of IV iron on protein oxidation and leucocyte adhesion to endothelial cells, as well as adverse effects of anticoagulation such as sub-clinical heparin induced thrombocytopenia (HIT). Preventive measures require a multidirectional approach to improve dialysis delivery and volume/blood pressure control, and to minimize adverse effects of current common essential therapies.

Recent clinical trials show that atorvastatin, an inhibitor of 3-hydroxy-methylglutaryl coenzyme A, reduces the risk of cardiovascular events and slows the progression of atherosclerosis in patients with coronary artery diseases. Several clinical studies have suggested that atorvastatin has pleiotropic effects. Indeed, atorvastatin reduces C-reactive protein (CRP), an inflammatory biomarker and a powerful predictor of cardiovascular events. However, the molecular mechanism for the anti-inflammatory effect of atorvastatin is not fully understood. Since advanced glycation end products (AGE), the senescent macroprotein derivatives, have been involved in diabetic or non-diabetic atherosclerosis, we investigated here whether and how atorvastatin could inhibit the AGE-induced CRP expression in human cultured hepatoma cells. Atorvastatin dose-dependently inhibited the AGE-induced ROS generation in Hep3B cells. Furthermore, atorvastatin as well as an anti-oxidant N-acetylcysteine, was found to suppress CRP expression in AGE-exposed Hep3B cells at both mRNA and protein levels. These results demonstrate that atorvastatin could block the AGE-signaling to CRP expression through its anti-oxidative property. Our study suggests that atorvastatin may have atheroprotective properties by working as an antiinflammatory agent against AGE in the liver.

Background. Endothelial dysfunction (ED) with atherosclerosis is a recognized complication of uremic patients. The importance of inflammation in ED pathophysiology has recently been proposed. The aim of this study was to analyze the role played by inflammation on ED in peritoneal dialysis (PD) patients. Methods: During 15 months, all the patients from our PD unit were followed-up. We determined nutritional, inflammatory (C-reactive protein (CRP), TNF-α and Vascular cell adhesion molecule-1 (VCAM)) and endothelial function markers at baseline and during systemic inflammation (SI). Seventeen patients were finally included due to elevation of CRP by various etiologies (4 suffered silent infection by Helicobacter pylori, 4 upper respiratory infections and 2 intestinal bacterial over-growth). They were compared with a control group (CG) with 12 PD patients who did not suffer SI. A venous occlusion test (VOT) was performed to stimulate the endothelium. Endothelial function was assessed by measuring: endothelial fibrinolytic capacity: tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI); endothelial damage markers: von Willebrand factor (vWF), thrombomodulin (TM) and nitric oxide (NO); cardiovascular (CV) risk markers: fibrinogen, lipoprotein(a) and homocysteine (Hcy); growth factors: VCAM-1, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF). After variable of follow-up time, CRP and TNF-α plasma levels increased. Results: We found a decrease in albumin, tPA ratio (post VOT/pre-VOT) and nitrate (NO3)-ratio. PAI, TM, Lp(a) and TGF-β Increase. A positive linear correlation between Hcy and PDGF was found, suggesting a pro-atherogenic environment. The CG did not show changes in the studied parameters. Conclusions: In PD patients, systemic inflammation induces endothelial dysfunction estimated by elevation of endothelial damage markers. Pro-inflammatory cytokines are associated with elevations in procoagulable and proatherosclerotic mediators in plasma.

The total white blood cell count, and in particular, the neutrophil count, has been reported to be positively associated with the risk of cardiovascular disease. The aim of this study is to clarify the association between hypertension and peripheral blood neutrophil count as an inflammatory marker in the occupational setting. 1,244 Japanese men and women were examined controlling for confounding factors. In men, the age, the product of the daily amount of liquor consumed and the weekly drinking frequency, current history of diabetes mellitus, Body Mass Index, and the peripheral blood neutrophil count were associated with an increased odds ratio for hypertension (1.08, 1.06, 1.89, 2.94 and 1.21, respectively); in contrast, a current history of smoking was inversely related to the risk of hypertension (odds ratio 0.53). In women, a current history of diabetes mellitus and the peripheral blood neutrophil count were associated with an increased odds ratio for hypertension (8.29 and 1.93, respectively). The peripheral blood neutrophil count was positively associated with the risk of hypertension in both men and women, independent of age, alcohol consumption, smoking status, history of diabetes mellitus and Body Mass Index. Follow-up studies and further research are needed to confirm this association.

Familial Combined Hyperlipidemia (FCH) is a common metabolic disorder characterized by: a) increase in cholesterolemia and/or triglyceridemia in at least two members of the same family, b) intraindividual and intrafamilial variability of the lipid phenotype, and, c) increased risk of premature coronary heart disease (CHD). FCH is one of the most common genetic hyperlipidemias in the general population (prevalence estimated: 0.5-2.0%), being the most frequent one in patients affected by CHD (10%) and among acute myocardial infarction survivors aged less than 60 years (11.3%). This percentage increases to 40% when all the myocardial infarction survivors are considered without age limits. However, because of the peculiar variability of laboratory parameters, and because of the frequent overlapping with the features of the metabolic syndrome, FCH is often not recognised and therefore, treated late. Some algorithms and guidelines exist, aimed at improving the detection of FCH in a specialist setting. The aim of this review is to define the main characteristics of FCH in order to simplify its detection and early treatment by non-specialists by using practical guidelines.

In type 1 diabetes a main burden of complications is related to presence of nephropathy. A generalised vascular damage in patients with nephropathy has been proposed to explain this relation. A procoagulant state in type 1 diabetes patients can be related to the transcapillary escape rate of albumin in patients without nephropathy. There is however to date, no consistently demonstrated further procoagulant derangement in patients with nephropathy, but this may be due to a methodological shortcoming caused by urinary loss of the coagulation marker measured. A significant heparin-induced vitronectin release in patients with nephropathy can reflect procoagulant activity in these patients. The procoagulant state in normoalbuminuric type 1 diabetes is followed by an increased activity of tissue- type plasminogen activator, and this potential compensation of the procoagulant state is absent in nephropathy. Haemostatic balance could be achieved at a higher level of fibrin accumulation or a higher activity of a fibrin surface exposed to the circulation. Data from a venous occlusion study indicate that plasminogen activator inhibitor 1 (PAI 1), fibronectin and von Willebrand factor were significantly captured by the subendothelial matrix in patients with nephropathy. Antithrombin with specific affinity for heparan sulphate was not significantly captured and this could be a consequence of a deficiency of heparan sulphate in the subendothelial matrix. Heparin is able to reduce urinary albumin excretion in patients with incipient nephropathy, and although the mechanism for this effect is unknown, it is theoretically in accordance with the hypothesis that heparan sulphate is a key in the development of diabetic nephropathy. Future long-term studies, perhaps with oral heparins, should be performed to investigate whether such treatment, added to the current treatment set in guidelines, could further protect patients from progression in diabetic nephropathy. Such studies could also address whether generalised vascular damage can be modified.

Objective: To study the impact of pressure drop (PD) which was developed along experimental stenoses on Pulse Wave Velocity (PWV). Methods: Eight, healthy, Landrace pigs were subjected to thoracotomy. In the upper segment of descending thoracic aorta a circumferential symmetric constriction 5 mm in length, was imposed and stabilized so that a pressure drop of 0 (DP-0, control group) 10 (DP-10), 20 (DP-20) and 30 mmHg (DP-30) could be created. respectively. Via catheterization of the vessel with pressure tip catheters, PD could be monitored. Pulse Wave Velocity (PWV) was measured via simultaneous recordings of Electrocardiogram and Doppler pressure waveforms which were received from right carotid and femoral artery. Then the recordings were fed to a computer for analytical estimation of PWV on several occasions: PWV-DP-0=8.27 +/- 0.12 m/sec, PWV-DP-10=8.68 +/- 0.13 m/sec, PWV-DP-20=9.19 +/- 0.13 m/sec and PWV-DP-30=9.51+/-0.14. Results: Significant increase in PWV estimated for all pressure drops compared to the control group. Thus, PWV-DP-0 vs. PWV-DP-10 or PWV-DP-20 or PWV-DP-30 were found to be statistical different (p<0.05). Conclusions: The observed increase in PWV is proportional to the developed PD along the experimental stenoses. The higher the pressure drop the higher the arterial stenosis and the higher the PWV-increase. The present outcome should be taken into account in patients with atherosclerosis because minor stenoses in the aorta may produce cumulative PWV elevation which undermines coronary flow reserve.

Asian Indians constitute almost one-fifth of the world population. A high prevalence of cardiovascular disease (CVD) and diabetes has been observed in this ethnic group in most of the studies conducted worldwide. It has been documented that migrant Indians have 3-4 times higher risk for CVD compared with Caucasians, 6 times higher than Chinese and 20 times higher than Japanese. Further, the incidence of CVD appears to be rising at an alarming rate in the Indian population in contrast to the decrease in incidence occurring in the developed countries. This predilection to CVD among Indians has been attributed to the so called “Asian Indian or South Asian Phenotype” which comprises of increased central obesity despite lower body mass index, increased insulin resistance, a characteristic dyslipdemia with low HDL-C (High Density Lipoprotein Cholesterol), increased triglycerides and excess of small dense LDL-C (Low Density Lipoprotein Cholesterol), decreased adiponectin and increased high sensitivity C-reactive protein levels. Clustering of metabolic abnormalities and high prevalence of metabolic syndrome and diabetes has also been reported among Indians. This review discusses the role of several vascular risk factors in contributing to the excess of CVD in Asian Indians with a focus on some of the recent studies from the Indian subcontinent.