Vascular Disease Prevention (Discontinued) - Volume 3, Issue 4, 2006

The well-being of an entire organism is dependent upon its vascular system, which transports oxygen, nutrients and hormones, and removes carbon-dioxide and other metabolic end products from tissues. The basement membrane of the arterial wall is composed mainly of extracellular matrix (ECM) molecules. By interacting with a family of cell adhesion receptors called integrins, ECM molecules provide structural support, and stimulate both physical and chemical signaling. Integrin-mediated signaling in either direction can regulate various aspects of vascular cell behavior, including their migratory ability, proliferation and wound repair. Extensive injury or inflammation to the vascular endothelium can compromise the ability of vascular cells to repair a wound. For example, injured endothelium could expose cell-binding epitopes that can promote adhesion of monocytes. Attached monocytes migrate through the endothelial cell (EC) junctions, into the sub-endothelial space via a complex mechanism and differentiate into macrophages. Moreover, specific ECM molecules encountered by vascular smooth muscle cells (vSMCs) following vascular wall injury could transform these cells to either “contractile” or “synthetic” phenotypes. Advances made in our understanding of integrin signaling that regulates contractile versus synthetic phenotypes of vSMC will be the subject of this review.

The implantation of coronary stents for coronary artery diseases is one of the most common percutaneous procedures. Among them, drug-eluting stents have been widely used for more than 3 years to overcome in-stent restenosis (ISR), the Achilles heel of angioplasty. Numerous trials have shown the remarkable efficiency of rapamycin (sirolimus)- eluting stents for the prevention of ISR. ISR is mostly due to hyperplasia of smooth muscle cells in the intimal layer of the vessel wall (so-called neointima hyperplasia). The cellular mechanism of rapamycin is mediated by binding to the FK506 binding protein, followed by inhibiting a kinase known as the target of rapamycin. Cell cycle genes and their products, such as cyclin, cyclin dependent kinases (Cdks), and Cdk inhibitors (CKIs), are the molecules to conserve the cell cycle progression and checkpoint traverse. While Cdks act as an accelerator, CKIs are brakes for cell cycle and these molecules affect each other. Inhibiting the target of rapamycin results in an elevation of CKI, p27Kip1. This inhibition possesses antiproliferative effects on smooth muscle cells by blocking cell-cycle progression at the G1/S transition. This review will focus on the current status of our knowledge regarding rapamycin in the era of the drug-eluting stent.

Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with cardiovascular risk factors including hypertension, diabetes and chronic kidney disease. Plasma ADMA levels are one of the useful biomarkers of future cardiovascular events in apparent healthy subjects as well as high-risk patients. In this review, we first discuss the synthesis and metabolism of ADMA and then consider the molecular mechanisms for the elevation of ADMA levels in various disorders.

We evaluated the effect of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor, on vasomotor responses in diabetic patients with peripheral arterial disease (PAD). The subjects were 10 type 2 diabetes patients with PAD who received 600 mg daily of naftidrofuryl, orally for 12 weeks. Another study group included 10 type 2 diabetes patients with PAD who did not receive naftidrofuryl (W); 10 healthy subjects were selected as controls (C). The patient groups were matched for age, sex and body mass index. All patients had a decreased ankle brachial index (ABI) in both legs (0.73 ± 0.17). We recorded changes in laser Doppler flux (LDF; PeriFlux 4001, Perimed). Basal LDF (b-LDF), vasoconstrictor response (v-LDF) to deep inspiration, postocclusive hyperaemia (m 1-LDF) on the pulp of the toe (in apical skin), and heat (+44°C; PeriTemp 4005)-induced hyperaemia (m 2-LDF) on the dorsum of the foot (non-apical skin) were estimated using PeriSoft software. After treatment, the following indices improved (mean ± SD): b-LDF at both locations (apical skin: 48 ± 34 vs. 78 ± 42 PU, p<0.01; non-apical skin: 14 ± 9 vs. 27 ± 24 PU, p<0.05), v-LDF (13.5 ± 12.4 vs. 26.7 ± 15.5%, p<0.001), m1-LDF (100 ± 54 vs. 133 ± 60 PU, p<0.01) and m2-LDF (61 ± 31 vs. 95 ± 49 PU, p<0.01). Treatment also increased local skin temperature at both measured places (pulp: p<0.001; dorsum, p<0.01). After 12 weeks no significant changes of LDF indexes were observed in the patients without naftidrofuryl therapy (p>0.05). In both patient groups ABI was not significantly changed after 12 weeks and there was no close correlation between ABI and LDF indexes. Our results suggest that 12 weeks of naftidrofuryl therapy improves the cutaneous vasomotor response in diabetic patients with PAD.

Dysfunction of the vascular endothelium is considered to be a major risk factor associated with cardiovascular complications in patients with diabetes types I and II. Furthermore, vascular complications are the leading cause of mortality in diabetic patients. However, the mechanism by which endothelial dysfunction occurs remains obscure. Two systems have been implicated in the pathogenesis of endothelial dysfunction, including a decrease in the availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties and/or enhanced action of vasoconstrictors such as endothelin-1. Chronic hyperglycemia is a major initiator of diabetic vascular complications. The mechanisms by which hyperglycemia causes vascular dysfunction are probably multiple. Such mechanisms include non-enzymatic glycosylation, oxidative stress, alteration of polyol-myoinositols, and activation of diacylglycerol (DAG) and protein kinase C (PKC) pathways. The initial studies of PKC activation in diabetes focused on microvascular complications, but there is accumulating evidence that PKC plays a role in several mechanisms promoting atherosclerosis. This review summarizes the current data that implicate PKC in promoting endothelial dysfunction mechanisms and microand macrovascular disease in diabetic patients.

Elevated levels of plasma homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), appear to be associated with higher risks of occlusive vascular disease and various clinical conditions ranging from the fetus to the elderly and from cardiovascular and neuro-degenerative diseases to neuropsychiatric disorders, rheumatoid arthritis and osteoporosis. The exact mechanism(s) involved is not fully understood. Current interest is focused upon modulating the levels of Hcy and/or their negative impacts through natural preventive strategies. In this regard, we recently showed that the Black seed (Nigella sativa), its oil, and its active ingredient Thymoquinone impart high protection (72-100%) against the induced rise of HHcy in rats. In this investigation, the ability of natural honey to protect against HHcy in rats was investigated. The results show that honey administered to rats at 1% in water significantly improved growth and imparted a protective effect against HHcy (54.5 ± 8.0%) induced by feeding the animals a diet enriched in methionine and deficient in Bvitamins (M+B- diet) for two months. This protection was not accompanied by a decrease in concentration of ADMA (asymmetrical dimethylarginine), which may indicate that ADMA concentrations may not be related to the pathophysiology of HHcy. On the other hand, HHcy induced a 30.7 ± 0.8% drop in the antioxidant enzyme superoxidase dismutase (SOD) activity. Honey treatment recovered an 8.8 ± 1.7 % of the decrease in SOD activity. Furthermore, treatment with honey in the HHcy state decreased catalase antioxidant activity by 47.8 ± 3.9%, while it did not cause any effect on the honey-treated control rats fed a standard methionine and B-vitamin diet, indicating that honey which can release H2O2 can compromise the H2O2-neutralizing activity of the catalase enzyme under excess methionine and deficient B-vitamin conditions. Honey treatment on the other hand, did not significantly affect glutathione peroxidase activity and total antioxidant status in the control and the M+B--fed rats, while in the same rats it significantly increased the antioxidant agent uric acid by 41.5 ± 3.0 % and 33.4 ± 2.0 %, respectively. These results indicate an overall beneficial role of honey under conditions favoring HHcy, and the important role of B-vitamins in the defense against oxidative parameters such as H2O2 and superoxide anion.

Acute coronary syndrome (ACS) is caused by the disruption of vulnerable plaque and subsequent thrombosis. Coronary angioscopy is thought to be an effective modality for detecting not only the ruptured plaque but also the vulnerable plaques and patients. Previously, we reported that the extent of yellow-plaque formation evaluated by angioscopy reflects the risk of secondary coronary event in ACS patients. On the other hand, multi-detector row computed tomography (MDCT) can detect not only the coronary stenosis but also the outward remodeling and calcified spot in coronary arteries. Recently, some reports indicated that MDCT was useful for the non-invasive characterization of coronary plaques. MDCT can classify coronary plaques into soft, intermediate and calcified plaques by the CT number. We developed a new plaque-detecting system Plaque Map, which analyzes short-axis coronary CT images, and reported good correlation between yellow plaques (detected by angioscopy) and soft plaques (detected by Plaque Map) in patients with ACS. Quantitative and qualitative analysis of coronary plaques by Plaque Map might potentially be useful for the evaluation of plaque progression or regression. Analysis of MDCT would be improved by the validation of the analyzed results with angioscopy.

Chronic kidney disease (CKD) is a new cardiovascular disease risk factor. However, few epidemiological studies examined the relationship between CKD and the risk of developing cardiovascular disease (CVD) in a general population. We evaluated the significance of CKD on the incidence of CVD by using a large community-based mass screening registries in Okinawa, Japan. Screenees of the 1983 Okinawa General Health Maintenance Association were investigated whether they also registered in the hospital-based stroke and acute myocardial infarction registry and the dialysis program. All relative risks of CVD and dialysis were adjusted for sex, blood pressure, and the presence of CKD at the time of screening. CKD was defined as the presence of proteinuria or estimated creatinine clearance of less than 60 ml/min. Among the 13,983 screenees, 7,477 subjects were grouped into CKD. We identified 121 CVD and 116 dialysis patients. Presence of CKD was a significant predictor of CVD; the adjusted hazard ratio 2.650 and the 95% confidence interval of 1.693-4.148, P<0.0001. Results support the notion that the presence of CKD is an important predictor of CVD.

Type 2 diabetes (DM) increases the risk of coronary heart disease (CHD) by a factor of 2 to 4. In the Scandinavian Simvastatin Survival Study, 483 of the enrolled 4444 patients with CHD also had type 2 DM. Simvastatin (20-40 mg/day) decreased low density lipoprotein (LDL) cholesterol by 35% and triglycerides by 15% while raising high density lipoprotein (HDL) cholesterol by 8%. In the patients with DM, over 5.4 years, simvastatin significantly reduced the number of major coronary events, revascularizations and coronary mortality. Pravastatin also reduces the risk of coronary events in diabetic patients with coronary syndromes, and atorvastatin reduced cardiac events in patients with type 2 DM and dyslipidemia. CARDS (Collaborative Atorvastatin Diabetes Study) was the first study of a statin set up solely in patients with DM. In CARDS, the 2838 enrolled patients with type 2 DM had no documented previous history of CHD but did have one of retinopathy, albuminuria, current smoking or hypertension. In CARDS, atorvastatin (10 mg daily) lowered LDL-cholesterol levels by 34% and triglycerides by 18%, but had no effect on HDL-cholesterol. Associated with these changes, after a follow-up of nearly 4 years, less patients in the atorvastatin group (83 of 1428 patients) had had a major cardiovascular event than in the placebo group (127 of 1410 patients). After 4 years, there were reductions with atorvastatin in acute coronary heart disease events (50 vs. 74), coronary revascularizations (12 vs. 18) and stroke (21 vs. 35). Recently, evidence has shown that better outcomes can be achieved with intensive lipid lowering (atorvastatin 80 mg) than with moderate lipid lowering (pravastatin 40 mg) in patients hospitalized for an acute coronary syndrome. In the 734 patients with DM, the composite primary endpoint (death, myocardial infarction, unstable angina requiring rehospitalization, revascularization and stroke) occurred in 34.6% of patients treated with pravastatin compared to 28.8% of patients treated with atorvastatin. DM is commonly associated with low HDL cholesterol and high triglyceride levels. This dyslipidemia can be reversed by fibrates or nicotinic acid. The Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) was the first large clinical trial to show that a fibrate reduced the risk of major cardiovascular events in diabetic men with established CHD and low HDL cholesterol. In VA-HIT, 769 patients had DM, and 1425 had normal fasting glucose. Gemfibrozil caused a lesser increase in HDL cholesterol in diabetic (5%) than in normal subjects (8%) and also caused a lesser decrease in triglycerides in diabetic (20%) than in normal subjects (29%). Despite this, gemfibrozil had a greater ability to reduce the primary combined end point in the diabetic (32% risk reduction) than in those without DM (18%); this was due to a greater reduction for death from CHD and stroke in the patients with type 2 DM. Fenofibrate reduces the angiographic progression of coronary artery disease. Nicotinic acid is a possible alternative to fibrates in patients who do not tolerate fibrates but has the disadvantage of reducing glucose control. Obesity is associated with insulin resistance and is a major risk factor for type 2 DM. Agents that inhibit cholesterol absorption (orlistat, ezetimibe, plant sterols) have small beneficial effects on lipids in patients with type 2 DM, but it is not known whether this translates into a reduction in CHD.

Inflammation plays a central role in the pathogenesis of atherosclerosis and restenosis following intra-arterial intervention. The ubiquitin-proteasome pathway is crucial for the control of biological processes involving inflammation, cell proliferation and apoptosis that contribute to atherogenesis and neointima formation. Accordingly, it is reasonable to postulate that inhibition of the proteasome could have a major role in prevention and treatment of atherosclerosis and restenosis. In eukaryotes, the ubiquitin-proteasome system is responsible for degradation of most intracellular proteins. Among the diverse substrates of the system are the cell cycle regulators (cyclin A, B, D, and E), mediators of apoptosis (p53, c-myc, and bcl2) and IkB, the major inhibitory protein of nuclear factor (NF)-κB. Natural and synthetic proteasomal inhibitors have been developed and evaluated in preclinical studies of reperfusion and vascular injury. Additionally, a metabolic pathway, reversible modification of the proteasome by addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues (O-glycosylation), has been shown to decrease proteasomal function, is inducible by various forms of stress and may be protective in the cardiovascular system. This article reviews the current data available on the ubiquitinproteasome system, its inhibition by specific pharmaceutical inhibitors and by O-glycosylation, and their possible therapeutic implications in the prevention of cardiovascular disease.

Vascular disease is a common cause of dementia. The early diagnosis as well as the differential diagnosis of Vascular Dementia (VD) and its subtypes from other neurodegenerative causes of dementia (the most common being Alzheimer Disease) is important since they affect the therapeutic management and the outcome of patients with cognitive impairment. Functional brain imaging with Nuclear Medicine techniques, Single Photon Emission Computed Tomog raphy (SPECT) and Positron Emission Tomography (PET) play an important role in the investigation of VD. Many studies support the usefulness of these methods in the initial diagnosis, the differential diagnosis and the follow-up of VD patients. SPECT and PET are non-invasive Nuclear Medicine techniques that allow in vivo estimation of brain functions and also quantification of cerebral blood flow, cerebral blood volume, cerebral glucose metabolism and cerebral oxygen metabolism. The characteristic patterns of radiotracer distribution abnormalities as well as functional tests with the use of drugs that alter the regional Cerebral Blood Flow (rCBF) offer additional information to the other clinical, biochemical and structural imaging findings making the diagnosis of VD more accurate. The multi-infarct type of VD is characterized by multiple, asymmetric perfusion defects on brain perfusion studies. Subcortical VD is characterized by reduced perfusion but preserved oxygen extraction fraction. Bilateral temporoparietal hypoperfusion and hypometabolism characterize Alzheimer Disease. In the future, new developments will increase the sensitivity and specificity of Nuclear Medicine techniques for the detection and management of VD patients.

Background. Helicobacter pylori (Hp) infection has frequently been detected in dialysis patients. Chronic infection induces cytokine production which is poorly cleared by inefficient kidneys. These cytokines have systemic and catabolic effects. We studied the effects of Hp infection-eradication on serum cytokine levels, nutrition and endothelial function (EF) markers in peritoneal dialysis (PD) patients. Methods. Hp-infection was diagnosed by breath test. Prior and post eradication we measured, nutritional markers: biochemical, daily food-intake and appetite modulator (orexigen neuropeptide-Y, NPY, anorexigen cholecystokinin, CCK). Stomach acid secretion: pepsinogen-I and II, and inflammatory markers: C-reactive protein (CRP), plasma TNF-α and IL-6. And EF markers which were taken pre- and post-venous occlusion test (VOT) in the right-arm for 10 min: tissue-type plasminogen activator (tPA), NO3 (representing nitric oxide) and plasminogen activator inhibitor (PAI). Forty-eight clinically stable PD patients divided into four groups according to Hp- infection and food intake werestudied: I, Hp(+) and low food-intake (<30 kcal/kg/day, DOQI-guidelines), n=12; II, Hp(+) and normal food intake,n=4, III Hp(-) and low food intake, n=5, IV, Hp(-) and normal food intake, n=27. Group-I showed the highest cytokines and the lowest residual renal function (RRF). TNF-α: group-I 127±85.5*pg/ml; group-II 70.5±25; group-III 60.5±10* and group-IV 43.4±5.4*, *p<0.05. IL-6: group-I 34.2±18* pg/ml,group-II 3.4±7*, *p<0.05, group-III 11.1±7.9*, *p<0.05 and group-IV 1.02±0.65*, *p<0.05. RRF was significantlyhigher in group-IV (4.8±1.6 ml/min*) than group-I (2.7±2.3*, *p<0.05). After Hp-eradication in group-I, nutritionalmarkers and NPY increased. Inflammatory, gastric acid-secretion parameters decreased. EF markers also improved.Control group included 10 volunteers, non-renal subjects infected by Hp who followed similar process, includingeradication treatment. Hp-eradication was associated to improvement in inflammatory and stomach acid-secretionmarkers

Suppression of cell proliferation and macrophage accumulation by endothelium is believed to play a role in preventing the development of atherosclerosis. We have previously shown that tibolone administration in cholesterol-fed rabbits resulted in reduced extension of lesional areas and that cyproterone acetate induced a greater atheromatosis. Material & Methods: A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. The rabbits were allocated into 6 groups of 8 animals each receiving mixed with the rabbit chow, tibolone (Group T), raloxifene (R), estradiol valerate (E), estradiol valerate plus cyproterone acetate (EC), and no treatment for the control and sham group (C and S). Aorta sections were stained using haematoxylin/eosin (HE) and by an avidin-biotin complex method for smooth muscle cells (SMC) and macrophages (α-actin antibodies and anti-macrophages antibodies RAM 11). For detection of apoptosis and cellular replication BAX and MIB1 antibodies were used. Results: After 12 weeks of atherogenic diet, the extension and thickness of the lesions assessed by HE were greater ingroups C, S, and EC. In these groups, SMC were found in the surface and in the edges, macrophages in the middle and thecells labelled for apoptosis in the deepest lesional zones. In contrast, in groups T and E the lesions showed a more uniformdistribution of macrophages and SMC, nearly without apoptosis and with a smaller degree of replication Conclusion: Tibolone, a compound with androgenic proprieties, may have a preventive action on the genesis of atheromalesions whereas cyproterone acetate an antiandrogenic substance may enhance the progression of atherosclerosis. Theseresults illustrate how difficult it is to predict the effects on atheroma plaque of different drugs based on the characteristicsof the original molecule.

Atherosclerosis is the primary cause for the global burden of disease accounting for the number one and two causes of death and disability in the world, namely, coronary artery disease and strokes. Multiple processes such as endothelial dysfunction, inflammation, vascular proliferation, and modulation of matrix are linked to the development of atherosclerosis. Vascular smooth muscle cell (VSMC) proliferation is the key etiological factor in primary atherosclerosis and in the pathophysiology of post-intervention restenosis, transplant vasculapothy, and vein bypass graft failure. VSMC proliferation is linked to other cellular processes such as inflammation, apoptosis and matrix modification that contribute to atherosclerosis. Consequently, suitable therapeutic approach is to inhibit or block the pathological processes of VSMC proliferation by targeting cell cycle regulation. Pathogenesis of atherosclerosis is very complex and involves interplay of both genetic and environmental factors. The major risk factors for atherosclerosis are hypertension, hyperlipidemia, diabetes, obesity, smoking, xenobiotics, and viral and bacterial infection. Controlling these risk factors is as critical as is an understanding of atherosclerosis' pathogenesis. Clinical advances for the treatment of many of these major risk factors have been huge and effective in the past two decades such as for the hypertension, hyperlipidemia, diabetes, and smoking. However, antiproliferative therapeutic strategies targeting the cell cycle regulation are still in their infancy. In this article, the current understanding of the pathogenesis of atherosclerosis will be reviewed along with the clinical advances in the treatment of vascular proliferative diseases and the status of molecular and gene therapeutic approaches in disease prevention.

Background: Spontaneous isolated dissection of the iliac artery without involvement of the aorta is extremely rare, and has unique etiological backgrounds. The purpose of this study was to review 34 patients reported in the literature and to discuss etiological and therapeutic considerations. Methods and Results: Patients (21 male, 13 female) were identified in a PUBMED search since 1966. Median age was 45 years old (rage, 25 to 65 years). The patients were divided into five categories; 1) dissection associated with fibromuscular dysplasia (n=10), 2) associated with Marfan's syndrome or other systemic disorders (n=6), 3) associated with atherosclerosis (n=10), 4) associated with pregnancy (n=2), and 5) associated with exercise (n=6). Four patients went into shock at presentation. Site of dissection was in the common iliac artery in 16 patients, and in the external iliac artery in 18 patients. Bypass surgery was performed in 20 patients, and an endovascular stent was placed in 5 patients. Seven patients had conservative therapy. There were two (6%) hospital deaths. Two patients developed another dissection shortly after treatment. There was no late death related to dissection. One patient had recurrent dissection in the contralateral iliac artery during the median follow-up of 12 months. Conclusions: Spontaneous isolated dissection of the iliac artery occurred resulting from various etiologies categorizedinto five subgroups. This vascular event is strongly associated with systemic disorders or certain physical conditions asso-ciated with hemodynamic, mechanical and/or hormonal stresses. Despite favorable outcomes, fatal dissection could occur,and awareness of this vascular event, careful follow-up and expeditious diagnosis and management are of great impor-tance to prevent catastrophic consequences.