Improvement Of Endothelial Dysfunction Research Articles

Hypertension and Endothelial Dysfunction: Therapeutic Approach

A large body of evidence indicates that patients with essential hypertension are characterized by endothelial dysfunction mediated by an impaired NO availability secondary to oxidative stress production. A dysfunctioning endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. In the last two decades, many studies have evaluated the endothelium in hypertensive patients, using different techniques. Several methodologies were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries), both in coronary and peripheral vascular districts. This review will describe the most relevant available techniques in the research on endothelial dysfunction in essential hypertension, their advantages and limitations, focusing on available data on endothelial dysfunction and on the effect of treatment. Endothelial dysfunction in the coronary and peripheral circulation of hypertensive patients are associated with hypertensive target organ damage and it is predictive of cardiovascular events. Several non-pharmacological approaches, including physical exercise and dietary interventions, can ameliorate endothelial function in hypertensive patients. Despite blood pressure reduction per se is not effective, some antihypertensive drugs can improve endothelial dysfunction, particularly calcium channel antagonist in the microcirculation, ACE-inhibitors and AT1-receptor antagonists mostly in conduit arteries. Some beneficial effects were also exerted by nebivolol and statins. Future studies are needed to confirm whether the improvement in endothelial dysfunction is associated to better cardiovascular prognosis in hypertension.

Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus

Background Controversies exist among trials reporting the effects of statins on endothelial dysfunction in patients with diabetes mellitus (DM). Therefore, we performed a meta-analysis to determine whether statin therapy could improve endothelial dysfunction in patients with DM. Methods PubMed, Cochrane and Embase were searched for randomized controlled trials of statins. Only trials reporting changes in flow-mediated dilatation (FMD) were included in this analysis. A meta-analysis was performed to assess the relationship between statin therapy and improvements in endothelial dysfunction. Meta-regression and subgroup analyses were done to identify sources of heterogeneity. Results Ten statin studies (845 patients) were included in this analysis. Statin therapy significantly improved FMD in patients with DM [weighted mean difference (WMD): 0.94%; 95% CI: 0.38%, 1.5%; P < 0.001]. Although heterogeneity among trials was found ( I 2 : 67%), no significant publication bias was detected. Subgroup analyses showed that patients did not benefit from statin therapy if their body mass index (BMI) was > 27.6 kg/m 2 (four trials; I 2 : 0%; WMD: 0.11%; 95% CI:–0.47%, 0.70%; P = 0.70). However, FMD was significantly improved among patients with BMI ≤ 27.6 kg/m 2 (five trials; I 2 : 14%; WMD: 1.52%; 95% CI: 1.19%, 1.85%; P< 0.001). Type 1 diabetes, younger age, lower baseline blood lipid levels and blood pressure were all associated with improvements in FMD. The meta-regression analysis yielded similar results. Conclusion Statins significantly improved the FMD only in patients with better endothelial functions. The use of FMD in evaluating therapeutic outcomes should be careful in populations at high risk.

Estatinas: efeitos pleiotrópicos. Statins: pleiotropic effects

Since the discovery of the fi rst statin in 1971, studies of this class of drugs have been constantly evolving with interesting results that go beyond their primary pharmacological action. Statins are shown to have an intriguing range of pharmacological actions, the so-called pleiotropic effects, including anti-infl ammatory, antidiabetic, improvement in Alzheimer disease, improvement in endothelial dysfunction, antioxidant, among others. The purpose of this literature review is to demonstrate the amount of studies about this class of drugs and confi rm the relevance of pleiotropic effects.

Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: Role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction

The 2 kidney, 1-clip (2K, 1C) model of hypertension was used to investigate the potential antihypertensive effect of a standardized leaf extract of Ginkgo biloba (EGb 761). Clipping of the renal artery resulted in gradual elevation of the systolic blood pressure (SBP) reaching a plateau after 4 weeks of surgery. Treatment of hypertensive rats with EGb 761 (60, 90, 180 mg/kg/day orally) was therefore started 4 weeks after surgery and continued for 3 weeks. This led to a dose-dependent reduction in SBP with no significant change in heart rate. Control hypertensive rats showed a significant elevation of total protein thiols (Pr-SHs level) in both clipped and non-clipped kidneys as well as in the serum. However, glutathione peroxidase (GSH-Px) activity was decreased in the clipped kidneys but elevated in the non-clipped ones and in the blood. The malondialdehyde (MDA) level was raised in clipped kidneys but not in non-clipped ones nor in the serum. Nitric oxide (NO level) and angiotensin converting enzyme (ACE) activity were increased in both clipped and non-clipped kidneys but not in the serum. Endothelium-dependent and -independent relaxation of aortic rings towards acetylcholine (Ach) and sodium nitroprusside (SNP) were impaired. Treatment with EGb 761 (180 mg/kg/day for 3 weeks) was associated with recovery of GSH-Px activity in clipped kidneys, inhibition of ACE activity in both kidneys and a reduction in the elevated NO level of the non-clipped kidneys, decreased responsiveness to the vasoconstrictor NE and improvement of endothelial function as evidenced by restoration of endothelium-dependent vasorelaxation induced by Ach. The observed beneficial effects of the EGb 761 may be attributed to different factors, including ACE inhibition and maintenance of cellular antioxidant capacity as well as preserving vascular reactivity towards endothelium-dependent and -independent vasodilators while inhibiting responses to vasoconstrictors.

Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin

Objective:To study the effects of N-acetylcysteine (NAC) and atorvastatin on endothelial dysfunction in patients with systemic lupus erythematosus (SLE).Materials and Methods:Thirty-two SLE patients and age, sex-matched 10 healthy control subjects were studied. The patients were between 17 and 65 years of age and positive for diagnostic tests, such as antinuclear antibodies (ANA). Photoplethysmogram (PPG) detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in the blood volume. Pulse wave analysis was performed at rest, 30 s, 90 s after shear stress, and 10 min after 300 μm of salbutamol inhalation.Results:Stiffness index (SI) of patients before the treatment was 8.46±2.78 cm/s and of controls was 6.07±1.4 cm/s (P = 0.002) and that of reflection index (RI) was 73±13 for patients and 65±7 for controls (P = 0.001). The percentage change in RI after salbutamol inhalation for controls and patients were -16±6 and -7±4 (P = 0.001), respectively, indicating the presence of endothelial dysfunction. The percentage decrease in RI after salbutamol inhalation was from -2.36±0.76 to ?7.92±1.46 in patients treated with N-acetylcysteine (NAC, P = 0.007). The percentage decrease in RI after salbutamol inhalation was from ?6.36΁1.21 to -9.92±1.21 in patients treated with atorvastatin (P = 0.05). This indicated the improvement in endothelial function. There was decrease in C-reactive protein (CRP) from 1.03±0.72 mg/dL to 0.52±0.22 mg/dL and that of malondialdehyde (MDA) from 11.20±4.07 nmol/mL to 8.81±2.79 nmol/mL with N-acetylcysteine treatment (P < 0.05). The CRP was decreased from 1.11±0.92 mg/dL to 0.440.16 mg/dL (P = 0.05) and that of MDA was decreased from 9.37±3.29 nmol/mL to 8.51±3.27 nmol/mL after treatment with atorvastatin. It showed improvement in oxidative stress with these treatments.Conclusion:The presence of arterial stiffness indicated endothelial dysfunction. There was reduction in RI and SI with treatment of N-acetylcysteine and atorvastatin suggesting improvement in endothelial dysfunction. There was decrease in CRP (a marker of inflammation) and MDA after treatment with N-acetylcysteine suggesting improvement in endothelial dysfunction. There was reduction in CRP after treatment with atorvastatin, suggesting improvement in endothelial function. Improvement in endothelial dysfunction is associated with decreased incidence of cardiovascular and cerebrovascular accidents.

Cardiovascular Risk-Benefit Profile of Sibutramine

Sibutramine is a combined norepinephrine and serotonin reuptake inhibitor used as an antiobesity agent to reduce appetite and promote weight loss in combination with diet and exercise. At a daily dose of 10-20 mg, it was initially considered to have a good safety profile, as it does not induce primary pulmonary hypertension or adverse effects on cardiac valves, in contrast to previous reports relating to some other antiobesity agents. However, it exerts disparate effects on cardiovascular risk factors. On the one hand, sibutramine may have antiatherogenic activities, as it improves insulin resistance, glucose metabolism, dyslipidemia, and inflammatory markers, with most of these effects resulting from weight loss rather than from an intrinsic effect of the drug. On the other hand, because of its specific mode of action, sibutramine exerts a peripheral sympathomimetic effect, which induces a moderate increase in heart rate and attenuates the reduction in BP attributable to weight loss or even slightly increases BP. It may also prolong the QT interval, an effect that could induce arrhythmias. Because of these complex effects, it is difficult to conclude what the final impact of sibutramine on cardiovascular outcomes might be. Sibutramine has been shown to exert favorable effects on some surrogate cardiovascular endpoints such as reduction of left ventricular hypertrophy and improvement of endothelial dysfunction. A good cardiovascular safety profile was demonstrated in numerous 1- to 2-year controlled trials, in both diabetic and nondiabetic well selected patients, as well as in several observational studies. However, since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, and myocardial infarction) have been reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. SCOUT (Sibutramine Cardiovascular and Diabetes Outcome Study) was designed to prospectively evaluate the efficacy/safety ratio of sibutramine in a high-risk population. The efficacy/safety results of the first 6-week lead-in open period of treatment with sibutramine 10 mg/day were reassuring in 10 742 overweight/obese high-risk subjects (97% had cardiovascular disease, 88% had hypertension, and 84% had type 2 diabetes mellitus). However, the final results of SCOUT showed that long-term (5 years') treatment with sibutramine (10-15 mg/day) exposed subjects with pre-existing cardiovascular disease to a significantly increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality. Because the benefit of sibutramine as a weight-loss aid seems not to outweigh the cardiovascular risks, the European Medicines Agency recommended the suspension of marketing authorizations for sibutramine across the EU. The US FDA stated that the drug should carry a 'black box' warning due to an increased risk of stroke and heart attack in patients with a history of cardiovascular disease. In conclusion, concern still persists about the safety profile of sibutramine regarding cardiovascular outcomes, and the drug should not be prescribed for overweight/obese patients with a high cardiovascular risk profile.

The Acute Effect of Acupuncture on Endothelial Dysfunction in Patients with Hypertension: A Pilot, Randomized, Double-Blind, Placebo-Controlled Crossover Trial

The objective of the study was to test whether acupuncture improves endothelial dysfunction in patients with hypertension and compare the effects of different acupoints to find out which one is the most suitable for the long-term follow-up study. This study is a pilot, randomized, double-blind, placebo-controlled crossover trial. Subjects were randomly assigned to a sequence of four acupuncture treatment phases, each for 15 minutes with a 7-day washout period in between. Acupuncture needles were inserted at bilateral ST 36; PC 6; ST 36 plus PC 6; and placebo points. Fifteen (15) patients with essential hypertension were the subjects. Flow-mediated dilation (FMD) and blood pressure were assessed before and after acupuncture treatment. FMD significantly improved with the acupuncture treatment at ST 36 (0.266 +/- 0.078 mm to 0.306 +/- 0.077 mm, p = 0.003) and ST 36 plus PC 6 (0.284 +/- 0.098 mm to 0.332 +/- 0.103 mm, p < 0.001). In contrast, FMD was unchanged after the acupuncture treatment at PC 6 or the placebo treatment. The FMD response to the acupuncture treatment at ST 36 plus PC 6 was significantly different from the response to the acupuncture treatment at PC 6 and the placebo treatment (p < 0.05, p < 0.01, respectively). The acupuncture treatment at ST 36 significantly increased FMD compared to the placebo treatment (p < 0.05). This study demonstrates that the acute treatment of acupuncture in hypertensive patients improves endothelial dysfunction. The beneficial effect of acupuncture could be of clinical importance to prevent the progression of cardiovascular diseases in hypertensive patients. However, the potential role of acupuncture treatment for long-term therapy has not been examined. Further studies will be necessary to demonstrate whether long-term acupuncture treatment can sustain the improvement in endothelial dysfunction.

Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease

In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs). Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function. In a randomized, controlled, double-masked, cross-over trial, 16 CAD patients (64+/-3 years of age) received a dietary high-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily in random order over 30 days. Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: -4.2+/-2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74+/-32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs. Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs. (Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients: Interaction Between Endothelial Progenitor Cells, Reactivity of Micro- and Macrocirculation; NCT00553774).

Gene therapy for dysfunctional endothelium: Is dimethylarginine dimethylaminohydrolase-2 a therapeutic target?

In this issue of IJC, Feng et al [ [1] Feng M. He Z.M. Zhu Y.X. Liu L.H. Lu C.W. Xiong Y. Improvement of endothelial dysfunction in atherosclerotic rabbit aortas by ex vivo gene transferring of dimethylarginine dimethylaminohydrolase-2. Int J Cardiol. 2009; ([Electronic publication ahead of print]) PubMed Google Scholar ] demonstrate that ex vivo transfer of dimethylarginine dimethylaminohydrolase-2 (DDAH-2) gene to atherosclerotic rabbit aortas leads to a significant improvement of nitric oxide (NO) bioavailability in vascular endothelium. This is one of the first studies demonstrating a causal association between DDAH-2 and endothelial dysfunction, under conditions of ongoing atherogenesis, providing a novel target for therapeutic gene delivery.

Improvement of endothelial dysfunction in atherosclerotic rabbit aortas by ex vivo gene transferring of dimethylarginine dimethylaminohydrolase-2

Elevated endogenous asymmetric dimethylarginine (ADMA) is an independent risk factor for atherosclerosis, and dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme responsible for the metabolism of ADMA. This study was to determine whether reduced vascular DDAH activity was implicated in endothelial dysfunction of atherosclerosis and whether ex vivo gene transferring of DDAH2 could upregulate vascular DDAH activity and improve endothelial dysfunction associated with atherosclerosis. Recombinant adenovirus encoding human DDAH2 gene driven by a cytomegalovirus (CMV) promoter was constructed and used to infect thoracic aortic rings from hyperlipidemic rabbits. Vascular hDDAH2 transcription, DDAH activity and endothelium-dependent relaxation were measured in thoracic aortas of hyperlipidemic and control rabbits. Vascular DDAH activity was distinctly reduced (0.048±0.002 vs 0.095 ± 0.007U/g protein, n=5, P<0.01) in atherosclerotic aortas in accompany with impaired endothelium-dependent relaxation, whereas serum ADMA levels were markedly elevated in hyperlipidemic rabbits (2.24 ± 0.12 vs 1.22 ± 0.12µmol/L, n=5, P<0.01) compared to control rabbits. Ex vivo gene transferring of hDDAH2 to atherosclerotic aortas not only increased the functional expression of hDDAH2 as shown by presenting hDDAH2 mRNA and enhancing DDAH activity (0.112 ± 0.008 U/g protein, n=5) but also markedly improved the impaired endothelium-dependent relaxation in atherosclerotic arteries. Reduced vascular DDAH activity contributes to endothelial dysfunction in hyperlipidemic rabbits. Ex vivo gene transferring of hDDAH2 can improve the endothelial dysfunction and inhibited DDAH activity, indicating that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for treatment of endothelial dysfunction in atherosclerosis.

Atorvastatin Causes Insulin Resistance and Increases Ambient Glycemia in Hypercholesterolemic Patients

We investigated whether atorvastatin might decrease insulin sensitivity and increase ambient glycemia in hypercholesterolemic patients. Clinical trials suggest that some statin treatments might increase the incidence of diabetes despite reductions in low-density lipoprotein (LDL) cholesterol and improvement in endothelial dysfunction. A randomized, single-blind, placebo-controlled parallel study was conducted in 44 patients taking placebo and in 42, 44, 43, and 40 patients given daily atorvastatin 10, 20, 40, and 80 mg, respectively, during a 2-month treatment period. Atorvastatin 10, 20, 40, and 80 mg significantly reduced LDL cholesterol (39%, 47%, 52%, and 56%, respectively) and apolipoprotein B levels (33%, 37%, 42%, and 46%, respectively) after 2 months of therapy when compared with either baseline (all p < 0.001 by paired t test) or placebo (p < 0.001 by analysis of variance [ANOVA]). Atorvastatin 10, 20, 40, and 80 mg significantly increased fasting plasma insulin (mean changes: 25%, 42%, 31%, and 45%, respectively) and glycated hemoglobin levels (2%, 5%, 5%, and 5%, respectively) when compared with either baseline (all p < 0.05 by paired t test) or placebo (p = 0.009 for insulin and p = 0.008 for glycated hemoglobin by ANOVA). Atorvastatin 10, 20, 40, and 80 mg decreased insulin sensitivity (1%, 3%, 3%, and 4%, respectively) when compared with either baseline (p = 0.312, p = 0.008, p < 0.001, and p = 0.008, respectively, by paired t test) or placebo (p = 0.033 by ANOVA). Despite beneficial reductions in LDL cholesterol and apolipoprotein B, atorvastatin treatment resulted in significant increases in fasting insulin and glycated hemoglobin levels consistent with insulin resistance and increased ambient glycemia in hypercholesterolemic patients. (Effects of Atorvastatin on Adiponectin Levels and Insulin Sensitivity In Hypercholesterolemic Patients; NCT00745836).

Effect of telmisartan on vascular endothelium in hypertensive and type 2 diabetic hypertensive patients

Hypertension and type 2 diabetes mellitus (DM) cause endothelial dysfunction and may result in cardiovascular disease. The aim of this study was to assess endothelial dysfunction in essential hypertensives, and normotensive and hypertensive type 2 diabetics and to evaluate the effect of telmisartan on endothelium in hypertensives. Materials and methods: Eighteen essential hypertensives (group 1), 16 type 2 diabetic hypertensives (group 2), 10 type 2 diabetic normotensives (group 3), and 10 control subjects (group 4) were included in this study. Groups 1 and 2 received 40 mg/day telmisartan for 12 weeks and were evaluated at the beginning and end. Groups 3 and 4 were evaluated once by serum nitrate (NO), vascular cell adhesion molecule-1 (VCAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), thrombomodulin (TM), plasminogen activator inhibitor-1 (PAI-1), paraoxonase (PON1), urine microalbumin (MAU), and endothelium dependent flow mediated dilation (FMD). Results: In groups 1, 2, and 3, PAI-1 (P < 0.001, for all) and MAU (P = 0.012, P = 0.006, P = 0.004, respectively) were significantly higher than they were in group 4. In group 2, PON1 was significantly lower than it was in groups 4 and 1 (P = 0.028, P < 0.001 respectively), and NO was significantly lower than it was in groups 1, 3, and 4 (P < 0.001, for all). Brachial artery FMD was significantly lower in groups 1 and 2 than it was in group 4 and FMD in group 2 was lower than it was in group 3. After telmisartan treatment there were significant increases in PON1 in groups 1 and 2, and in TM in group 2. Conclusion: Type 2 DM and essential hypertension result in endothelial dysfunction. Telmisartan decreases blood pressure to normal ranges in hypertensives, but it has a minimal role in improvement of endothelial dysfunction.

Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease

We hypothesized that granulocyte macrophage colony-stimulating factor (GM-CSF) administration will be safe and will improve endothelial dysfunction and exercise capacity by mobilizing progenitor cells in patients with peripheral arterial disease (PAD). Forty-five patients with PAD received thrice-weekly injections for 2 weeks of 3, 6, or 10 microg/kg per day of GM-CSF or placebo in successive cohorts of 15 subjects randomized 2:1 to drug or placebo. CD34+ mononuclear cell subsets and colony formation assay, endothelial function, ankle-brachial index, and walking capacity were measured. Granulocyte macrophage colony-stimulating factor administration was safe. After pooling data from GM-CSF cohorts, at 2 weeks, there was a significant increase in total leukocytes (43%, P < .0001), CD34+ cells (46%, P = .035), and colony-forming units (31%, P = .026, week 1). At 12 weeks, endothelial function improved with GM-CSF (flow-mediated vasodilation increased by 59%, P < .01) as did pain-free treadmill walking time (38 seconds, P = .008) and total treadmill walking time (55 seconds, P = .016). Corresponding changes were not observed in the placebo group. Granulocyte macrophage colony-stimulating factor therapy in patients with PAD was associated with mobilization of progenitor cells, improvement of endothelial dysfunction, and exercise capacity. The efficacy of strategies designed to mobilize bone marrow progenitors warrants further study in patients with PAD.

Periodontitis and risk for atherosclerosis: an update on intervention trials

Periodontitis has been associated with an increased risk of cardiovascular events. The nature of the association is unclear because both periodontitis and cardiovascular disease (CVD) share a host of risk factors. Intervention trials are critical to explore the relationship. If the association were causal, successful periodontal therapy will lead to an attenuation of the effect - CVD. The paper reviewed the design and the results of intervention trials aimed at improving systemic inflammation, endothelial dysfunction, carotid atherosclerosis and cardiovascular events. Early systematic reviews and a definitive controlled clinical trial indicate that intensive periodontal therapy results in a decrease in systemic inflammation and an improvement of endothelial dysfunction in systemically healthy subjects. A pilot trial has indicated the feasibility to assess the impact of periodontal therapy on carotid atherosclerosis in a primary cardiac prevention design. Efforts to test causality in the relationship between periodontitis and CVD are ongoing. Evidence to date is consistent with the notion that severe generalized periodontitis causes systemic inflammation and endothelial dysfunction. Periodontitis has effects that go beyond the oral cavity and its treatment and prevention may contribute to the prevention of atherosclerosis.

Anti-inflammatory strategies for homocysteine-related cardiovascular disease

Homocysteine may induce vascular damage for atherosclerosis. Vitamin/folate supplementation has been proposed to reduce the cardiovascular disease risk. Nevertheless, there is no randomized clinical trial clearly proving the efficacy of reducing the homocysteine as a means of lowering the incidence of cardiovascular disease. Homocysteine induces oxidative stress leading to endothelial dysfunction. In addition, homocysteine-induced oxidative stress favors lipid peroxidation and induces production of inflammatory factors, thus accelerating atherosclerosis. In this paper, we reviewed the available evidence concerning the association between homocysteine and cardiovascular disease, with the objective of discussing the pertinence of screening, treatment, and prevention of hyperhomocysteinemia-related cardiovascular disease. Our previous findings also indicated the significant role of mononuclear cells activation in homocysteine-induced endothelial dysfunction; treatment with statins attenuated homocysteine-induced endothelial adhesiveness, indicating the novel endothelial protection effects of statins in the presence of homocysteine. Since inflammation and oxidative stress are critical to homocysteine-induced vascular damage, the improvement of endothelial dysfunction and the inhibition of mononuclear cell activation by anti-inflammatory and/or antioxidative drugs/agents may serve as the potential therapeutic strategy for hyperhomocysteinemia-related cardiovascular disease.

Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima‐media thickness

Several cohort studies reported a relation of cardiovascular events and periodontal disease. In particular, Porphyromonas gingivalis is associated with the development of atherosclerotic plaques. We verified in a longitudinal study whether inflammation biomarkers, endothelial adhesion molecules, leukocyte activation markers, and intima-media thickness could be beneficially modified by periodontal treatment alone. Thirty-five otherwise healthy individuals affected by mild to moderate parodontopathy were enrolled in the study. Echo-Doppler cardiography of the carotid artery, fluorescence-activated cell sorting analyses on lymphocytes and monocytes, and plasma inflammatory indices were evaluated at baseline and at multiple time points after the periodontal treatment. Results showed that inflammation biomarkers were abnormally increased at baseline. Periodontal treatment resulted in a significant reduction of the total oral bacterial load that was associated with a significant amelioration of inflammation biomarkers and of adhesion and activation proteins. Notably, intima-media thickness was significantly diminished after treatment. Inflammatory alterations associated with the genesis of atherosclerotic plaques are detected in otherwise healthy individuals affected by parodontopathy and are positively influenced by periodontal treatment. Reduction of oral bacterial load results in a modification of an anatomical parameter directly responsible for atherosclerosis. These results shed light on the pathogenesis of atherosclerosis and could have practical implications for public health.

Statins for heart failure: still caught in no man's land?

Statins are well-known for their ability to lower serum cholesterol levels, but have properties beyond mere cholesterol reduction, including an improvement in endothelial dysfunction, release of endothelial progenitor cells, anti-inflammatory properties and a number of antitumour activities. In the present issue of Clinical Science, Stumpf et al. show that a 4-week treatment course with the lipophilic statin atorvastatin ameliorates left ventricular remodelling and function, reduces serum levels of TNF-alpha (tumour necrosis factor-alpha), IL (interleukin)-6 and MCP-1 (monocyte chemoattractant protein-1), and increases both serum and myocardial levels of IL-10. The authors hypothesize that this shift from a pro- to an anti-inflammatory response might be beneficial in the clinical setting, because patients with low levels of IL-10 may fare worse than those with higher levels. In light of the recent setbacks with rosuvastatin in large-scale clinical trials, this notion requires further investigation, but highlights the need to identify those patients with heart failure who are likely to benefit from statin therapy.

Comparison of vasculoprotective effects of benidipine and losartan in a rat model of metabolic syndrome

Although antihypertensive drugs confer improvement in endothelial dysfunction and protection from atherogenesis in hypertension, different classes of antihypertensive drugs may elicit different degrees of vasculoprotective effects. We have investigated the effects of a long-acting calcium antagonist, benidipine, and an angiotensin AT 1 receptor antagonist, losartan, on the vascular damage observed in OLETF rats, an animal model of metabolic syndrome. At 34 weeks of age, OLETF rats were treated with either benidipine (3 mg/kg/day, per os) or losartan (25 mg/kg/day, per os) for 8 weeks. The extent of blood pressure reduction, restoration endothelium-dependent aortic relaxation, and elevation of serum nitrite/nitrate concentration did not differ significantly between benidipine- and losartan-treated OLETF rats. Benidipine and losartan also reduced the aortic expression of transforming growth factor-β1 mRNA and thickening of the vascular wall to a similar extent. Increased cardiac fibrosis was also inhibited by both benidipine and losartan. These data suggest that, when used in an antihypertensive dose, benidipine is as effective as losartan in restoring vascular endothelial function and in suppressing of cardiovascular remodeling in an animal model of metabolic syndrome.

Physics Meets Molecules

See related article, pages 538–545 Arteries and veins are permanently exposed to hemodynamic forces because of the pulsatile nature of blood pressure and flow. Hence, the endothelium is constantly detecting different biomechanical forces, cyclic stretch and shear stress in particular,1–2 and converts the latter stimuli into intra- and extracellular signals. Endothelial cells thereby modulate multiple of physiological and pathophysiological processes: production of growth-promoting and growth-inhibiting hormones, enzymes, cytokines, etc; mediation of inflammatory responses through the expression of chemotactic and adhesion molecules on the endothelial surface; modulation of hemostasis and thrombosis via secretion of procoagulant, anticoagulant, and fibrinolytic agents; and the regulation of vascular smooth muscle cell contraction through the release of vasodilators and vasoconstrictors.3–5 This being the case, the equilibrium between physiological levels of blood flow (shear stress) and the endothelium is tightly counterbalanced. Thereby, the lumen radius of an artery is the most important denominator, which signifies that the smaller the lumen the higher the shear stress. However, once physiological shear forces are reduced, several pathological conditions may arise: proatherogenic and/or prothrombotic states and hence atherosclerosis and/or thrombosis.6–7 Inversely, high levels of shear forces play a key role in adaptive phases of arteriogenesis (collateral artery growth), the most clinically relevant mechanism of vascular development.8 In case of an arterial stenosis, these arterial/arteriolar anastomoses are the only anastomosis to the low-pressure territory and perfuse the periphery with nutrient blood flow. Elevation of shear stress and concomitant cyclic stretch are currently discussed to be the strongest inducers of arteriogenesis. In a rabbit model of femoral artery ligation, Schaper and colleagues induced an abrupt increase in shear stress by means of an arterial–venous shunt (pressure drop across collateral arteries) and accelerated the speed of arteriogenesis, surpassing the conductance values of the occluded artery when shear …

Improvement of endothelial dysfunction in hypercholesterole‐mic rabbit aortas by ex vivo gene transfer of dimethylarginine dimethylaminohydrolase −2

Improvement of endothelial dysfunction in hypercholesterole‐mic rabbit aortas by <i>ex vivo</i> gene transfer of dimethylarginine dimethylaminohydrolase −2