Divergent effects of laughter and mental stress on arterial stiffness and central hemodynamics.

OBJECTIVE: To investigate the effect of laughter and mental stress on arterial stiffness and central hemodynamics. Arterial stiffness and wave reflections are independent predictors of cardiovascular risk. Chronic psychological stress is an independent risk factor for cardiovascular events, whereas acute stress deteriorates vascular function. METHODS: Eighteen healthy individuals were studied on three occasions, according to a randomized, single-blind, crossover, sham procedure-controlled design. The effects of viewing a 30-minute segment of two films inducing laughter or stress were assessed. Carotid-femoral pulse wave velocity was used as an index of arterial stiffness; augmentation index was used as a measure of wave reflections. RESULTS: Laughter decreased pulse wave velocity (by 0.30 m/sec, p = .01), and augmentation index (by 2.72%, p = .05). Conversely, stress increased pulse wave velocity (by 0.29 m/sec, p = .05) and augmentation index (by 5.1%, p = .005). Laughter decreased cortisol levels by 1.67 microg/dl (p = .02), soluble P-selectin by 26 ng/ml (p = .02) and marginally von Willebrand factor (by 2.4%, p = .07) and increased total oxidative status (by 61 micromol/L, p < .001). Stress decreased interleukin-6 (by 0.11 pg/ml, p = .04) and increased total oxidative status (by 44 micromol/L, p = .007). Soluble CD40 ligand and fibrinogen remained unchanged. CONCLUSIONS: Positive (laughter) and negative (stress) behavioral interventions have divergent acute effects on arterial stiffness and wave reflections. These findings have important clinical implications extending the spectrum of lifestyle modifications that can ameliorate arterial function.

Inflammatory and thrombotic processes are associated with vascular dysfunction in children with familial hypercholesterolemia.

BACKGROUND: Evidence suggests that children with familial hypercholesterolemia (FH) have endothelial dysfunction. Inflammatory and haemostatic abnormalities are associated with advanced atherosclerosis and increased cardiovascular events. However, it is unknown whether these abnormalities present in FH children and contribute to their vascular dysfunction. METHODS AND RESULTS: We studied 38 children with FH (19 males, 19 females aged 14.8+/-0.9 years mean+/-S.E.) and 41 healthy children (controls; 22 males, 19 females aged 15.4+/-0.7 years). Endothelium-dependent reactive hyperemia (RH%) and endothelium-independent nitrate hyperemia dilatation (NH%) were measured by strain gauge plethysmography. Inflammatory and haemostatic parameters were assessed by ELISA. RH% and NH% were significantly reduced in FH compared to controls (91.3+/-9.3% vs. 120.4+/-10.6% and 53.6+/-3.8% vs. 74.5+/-7.4%, p<0.05 for both). Total cholesterol and lipoprotein (a) were increased in FH children compared to controls (282.3+/-8.8 mg/dl vs. 163.8+/-4.6 mg/dl and 11.0[4.6, 30.7]mg/dl vs. 5.24[2.63, 11.0]mg/dl median [IQR] respectively; p<0.001 for both). Intercellular cell adhesion molecule (ICAM-1) and interleukin 1 beta (IL-1 beta) serum levels were increased in FH compared to controls (p<0.05 and <0.001, respectively). Plasminogen activator inhibitor 1 (PAI-1) levels were also higher in FH children (p<0.001). Multivariate analysis revealed that reactive hyperemia was independently associated with nitrate-dependent reactive hyperemia (beta=0.597(0.199), p<0.01), PAI-1(beta=-6.78(2.65), p<0.05), log IL-1 beta (beta=-102.8 (30.2), p<0.01), age (beta=-5.06 (2.35), p<0.05) and FH status (beta=-25.2(10.6), p<0.05) (R(2) for the model: 0.63, p=0.001). CONCLUSIONS: Inflammatory and haemostatic abnormalities are present in FH children and contribute to the endothelial dysfunction observed in these children.

Antidepressive treatment as a modulator of inflammatory process in patients with heart failure: effects on proinflammatory cytokines and acute phase protein levels.

BACKGROUND: Depression has been associated with increased inflammatory process. Although anti-depressive medication has anti-inflammatory effect in major depression, its role in patients with heart failure (HF) is unknown. In the present study we evaluated the impact of antidepressive medication on the expression of proinflammatory cytokines and acute phase response proteins, in patients with HF and major depression. METHODS: The study population consisted of 250 patients with HF (154 suffering from major depression). Patients with major depression were under selective serotonin reuptake inhibitors (SSRIs, n=120) or tricyclic antidepressants (TCA) and/or serotonin/norepinephrine reuptake inhibitors (SNRIs) (n=34), for at least 6 months. RESULTS: Levels of TNF-alpha, IL-6, CRP and fibrinogen were not significantly different between HF patients with depression under treatment and those without depression (p=NS for all). However, TNF-alpha and CRP levels were significantly lower in patients receiving TCA/SNRI compared to patients receiving SSRIs or those without depression (p<0.05 for all). Similarly, patients under TCA/SNRI had significantly lower heart rate compared to those treated with SSRIs or those without depression. In multivariate analysis, treatment with SNRI/TCA was an independent predictor for log(TNF-alpha) (beta=0.036(SE:0.016) and log(CRP) (beta=0.099(SE:0.048), p=0.041). CONCLUSIONS: In the present study we demonstrate for the first time that treatment of patients with HF and major depression with TCAs/SNRIs, is associated with lower levels of TNF-alpha and CRP, suggesting that the type of antidepressive treatment may have a significant effect on the underlying inflammatory process.

Methionine-loading rapidly impairs endothelial function, by mechanisms independent of endothelin-1: evidence for an association of fasting total homocysteine with plasma endothelin-1 levels.

OBJECTIVE: Homocysteinemia is associated with elevated oxidative stress and impaired endothelial function. In the present study we examined the impact of oxidative stress in the development of endothelial dysfunction in both chronic and acute (methionine-induced) homocysteinemia in humans. We also examined the role of endothelin-1 (ET-1) in the development of endothelial dysfunction in these two conditions. METHODS: In this double-blind placebo controlled study, 28 subjects of both genders (14 with homocysteinemia and 14 healthy controls) underwent methionine-loading (100mg/Kg body weight) in a standard juice, containing vitamins C (2g) plus E (800IU) (n = 14) or no vitamins (placebo group, n = 14). Forearm vasodilatory response to reactive hyperemia, plasma total homocysteine (tHcy), oxidized LDL (ox-LDL), ET-1 and soluble vascular cell adhesion molecule (sVCAM-1), were evaluated at baseline and 4 hours post methionine loading (4hPML). RESULTS: Chronic homocysteinemia was associated with increased oxLDL (p < 0.01), higher ET-1 (p < 0.05) and impaired endothelial function (p < 0.01). However, oxLDL (but not ET-1) was increased 4hPML in the placebo group, an effect prevented by antioxidant vitamins. The development of severe endothelial dysfunction 4hPML was not however prevented by antioxidants. In linear regression analysis, fasting tHcy was an independent predictor of baseline oxLDL (p = 0.0001), but not of ET-1 levels. On the contrary, oxLDL was the main predictor of ET-1 (p = 0.008), suggesting that tHcy may increase ET-1 by enhancing the production of oxLDL. CONCLUSIONS: Both chronic and acute methionine-induced homocysteinemia are associated with elevated oxidative stress status. Although ET-1 is increased in chronic homocysteinemia, it does not participate in the rapid development of endothelial dysfunction after methionine loading. These findings suggest that despite its potential role in chronic homocysteinemia, ET-1 has a limited contribution to the development of endothelial dysfunction in acute, methionine-induced homocysteinemia in humans.

Association of arterial stiffness with the angiotensin-converting enzyme gene polymorphism in healthy individuals.

BACKGROUND: Arterial stiffness is an important determinant of cardiovascular morbidity and mortality. The I/D polymorphism of angiotensin-converting enzyme (ACE) gene is associated with cardiovascular disease. However, the relationship between ACE polymorphism, arterial stiffness, and wave reflections in healthy, low-risk population has not been defined yet. METHODS: The study included 282 apparently healthy, low-risk individuals (mean age 39.7 +/- 8.9 years, 178 males). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness, while wave reflections were assessed by augmentation index (AIx) of the central pressure waveform. I/D polymorphism of the ACE gene was determined in all subjects for the prevalence of the DD, ID, and II genotype (39, 44, and 17%, respectively). C-reactive protein (CRP) levels were determined as a marker of chronic, subclinical inflammation. RESULTS: After adjustment for potential confounding factors, presence of D allele was associated with lower values of PWV compared to II genotype (P < 0.05), implying lower aortic stiffness for D allele carriers. There was no association between ACE genotype and wave reflections or peripheral and central systolic pressures. CONCLUSIONS: In apparently healthy individuals, D allele is associated with lower aortic stiffness, whereas there is no association of the ACE polymorphism with wave reflections. This finding provides new insights into the possible links between ACE gene, regulation of large artery stiffness, and has implications for cardiovascular risk.

Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction.

OBJECTIVE: Erectile dysfunction is a predictor of cardiovascular risk with high prevalence in hypertensive men. We investigated whether erectile dysfunction is related to arterial structure and function in hypertensive patients. METHODS: We evaluated arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic erectile dysfunction and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment. RESULTS: Hypertensive patients with erectile dysfunction had higher common carotid intima-media thickness (0.95 +/- 0.19 vs. 0.83 +/- 0.18 mm, P = 0.003) and carotid-femoral pulse-wave velocity (8.89 +/- 1.38 vs. 8.11 +/- 1.10 m/s, P = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 +/- 1.64 vs. 4.07 +/- 1.68%, P = 0.003) and a higher level of the systemic endothelial dysfunction marker asymmetric dimethylarginine (0.67 +/- 0.13 vs. 0.57 +/- 0.16 mumol/l, P = 0.003), and the inflammatory markers high-sensitivity C-reactive protein [2.03 (1.16-2.89) vs. 1.23 (0.67-1.90) mg/l, P = 0.029] and interleukin-6 (4.13 +/- 2.38 vs. 2.77 +/- 1.92 pg/ml, P = 0.011). Multivariable analysis adjusting for age, mean pressure, other risk factors and treatment showed independent associations between erectile dysfunction and parameters of arterial structure and function. In the erectile dysfunction group, there were no significant relationships between the severity of erectile dysfunction (as expressed by the Sexual Health Inventory for Men score) and the above arterial indices and level of circulating markers (all P = NS). CONCLUSION: In hypertensive men, the presence but not the severity of vasculogenic erectile dysfunction is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation.

Selective serotonin reuptake inhibitors modify the effect of beta-blockers on long-term survival of patients with end-stage heart failure and major depression.

BACKGROUND: Major depression (MD) is a key feature in heart failure (HF), and it is unclear whether common antidepressive medications interact with cardiovascular drugs used for the treatment of patients with MD and HF, affecting their efficacy. We examined the impact of MD on long-term survival of patients with end-stage severe HF. We also evaluated the interaction between antidepressive medication and beta-blockers on the clinical outcome of these patients. METHODS AND RESULTS: The study population consisted of 250 patients with end-stage severe HF. Sixty-one percent of these patients suffered MD and were receiving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCA). All patients were followed prospectively for 18 months. The primary end point was cardiovascular death. At baseline, patients with severe MD had higher serum interleukin 6 (P < .05) and soluble vascular cell adhesion molecule (P < .01). During the follow-up, 167 cardiovascular deaths were reported, and MD was 1 of the major predictors of cardiovascular death (P = .031), whereas treatment with angiotensin receptor inhibitors and statins were also important negative predictors of mortality (P = .036 and P = .039, respectively). Although beta-blockers had a borderline nonsignificant effect on cardiovascular mortality in the overall population, they had a striking beneficial effect among those patients with major depression receiving SSRIs (P = .006), whereas they had a negative effect on mortality in those patients receiving SNRIs/TCAs (P = .025). CONCLUSIONS: MD is an independent predictor of cardiovascular death in patients with end-stage HF. beta-blockers are associated with lower cardiovascular mortality in patients with end-stage HF and depression only when they are combined with SSRIs.

The acute effect of green tea consumption on endothelial function in healthy individuals.

BACKGROUND: Tea consumption is associated with decreased cardiovascular risk. Flow-mediated dilatation (FMD) of the brachial artery is related to coronary endothelial function and it is an independent predictor of cardiovascular risk. Black tea has a beneficial effect on endothelial function; the effect, however, of green tea on brachial artery reactivity has not been defined yet. DESIGN AND METHODS: We studied 14 healthy individuals (age 30+/-3 years) with no cardiovascular risk factors except from smoking (50%) on three separate occasions on which they took: (a) 6 g of green tea, (b) 125 mg of caffeine (the amount contained in 6 g of tea), or (c) hot water. FMD of the brachial artery was measured before each intervention and 30, 90, and 120 min afterward. High-sensitivity C-reactive protein, interleukins 6 (Il-6) and 1b (Il-1b), total plasma antioxidative capacity, and total plasma oxidative status/stress were measured at baseline and at 120 min after each intervention. RESULTS: Resting and hyperemic brachial artery diameter did not change either with tea or with caffeine. FMD increased significantly with tea (by 3.69%, peak at 30 min, P<0.02), whereas it did not change significantly with caffeine (increase by 1.72%, peak at 30 min, P=NS). Neither tea nor caffeine had any effect on high-sensitivity C-reactive protein, Il-6, Il-1b, total plasma antioxidative capacity, or total plasma oxidative status/stress. CONCLUSION: Green tea consumption has an acute beneficial effect on endothelial function, assessed with FMD of the brachial artery, in healthy individuals. This may be involved in the beneficial effect of tea on cardiovascular risk.

Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system.

BACKGROUND & AIM: Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. METHODS: In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30 g), as red wine (264 ml), white wine (264 ml), beer (633 ml), whisky (79 ml) or water (250 ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4 h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4 h after alcohol consumption. RESULTS: Reactive hyperemia was significantly increased 1 h after beer and red wine consumption (p<0.05 for both), while it returned at baseline at 4 h (p=ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p<0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. CONCLUSIONS: Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults.

Effects of ramipril on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young normotensive subjects with successfully repaired coarctation of aorta: a randomized cross-over study.

OBJECTIVES: The purpose of this study was to evaluate the effect of ramipril on endothelial function and inflammatory process in a group of normotensive subjects with successfully repaired coarctation of the aorta (SCR). BACKGROUND: Subjects with SCR experience higher long-term cardiovascular risk as a result of the relapse of arterial hypertension or owing to nonreversible structural changes in the pre-coarctation arterial tree. These subjects experience endothelial dysfunction in the right forearm and appear to have elevated levels of proatherogenic inflammatory markers, even in the absence of arterial hypertension. METHODS: Twenty young individuals age 27.3 +/- 2.4 years old with SCR 13.9 +/- 2.2 years previously, received ramipril 5 mg/day for 4 weeks in a randomized, cross-over, controlled trial. Endothelial function was evaluated in the right forearm by gauge-strain plethysmography, and serum levels of interleukin (IL)-1b, IL-6, soluble CD40 ligand (sCD40L), and soluble vascular cell adhesion molecule (sVCAM)-1 were determined by enzyme-linked immunosorbent assay. RESULTS: Ramipril improved endothelial function (p < 0.001) and decreased the expression of proinflammatory cytokine IL-6 (p < 0.05) and sCD40L (p < 0.01). Furthermore, ramipril decreased serum levels of sVCAM-1 (p < 0.01) but failed to affect serum levels of C-reactive protein. These effects were independent of blood pressure lowering. CONCLUSIONS: Ramipril reversed the impaired endothelial function and decreased the expression of proinflammatory cytokine IL-6, sCD40L, and adhesion molecules in normotensive subjects with SCR. These findings imply that ramipril treatment may have antiatherogenic effects in subjects with SCR, even in the absence of arterial hypertension.

Common community infections and the risk for coronary artery disease and acute myocardial infarction: evidence for chronic over-expression of tumor necrosis factor alpha and vascular cells adhesion molecule-1.

BACKGROUND: Although several common community infections have been associated with the risk for coronary artery disease (CAD), their role in the development of acute myocardial infarction (AMI) is still unclear. We examined the prevalence of IgG and IgM (or IgA) antibodies against common infections such as HSV, Hepatitis A (HAV), Helicobacter pylori (HP), cytomegalovirus (CMV) and Chlamydia pneumoniae (CP), in CAD and AMI patients, and their relationship with pro-atherogenic inflammatory molecules. METHODS: A total number of 337 subjects were included in this study: 150 patients with angiographically documented stable CAD, 138 patients admitted with AMI and 49 healthy individuals. Serum IgG and IgM against HAV, CMV and HSV, IgG against HP and IgG/IgA against CP were determined in all participants. Serum tumor necrosis factor alpha (TNF-alpha) and soluble vascular cells adhesion molecule (sVCAM-1), were determined by ELISA. RESULTS: Patients with CAD were more likely to have anti-HAV IgG (94.4%), anti-HSV IgG (97.2%) and anti-HP IgG (55.1%) compared to healthy individuals (70.8%, 89.6% and 39.6% respectively, p<0.05 for all). In multivariate analysis, anti-HAV IgG was an independent predictor of CAD (beta(SE): 0.187(0.075), p=0.015). Among the CAD patients, the presence of anti-CP IgA was more frequent in those admitted with AMI (39%) compared to those with stable CAD (21%, p<0.05). Finally, both patients and controls had significantly higher levels of sVCAM-1 and TNF-alpha in the presence of anti-HAV IgG, compared to those without anti-HAV IgG (p<0.05 for all). CONCLUSION: Past infections with HAV, HSV and HP are associated with higher risk for coronary atherosclerosis, while the presence of anti-HAV IgG is also associated with higher levels of TNF-alpha and sVCAM-1. Furthermore, the presence of recent infection by CP is associated with higher risk for AMI among CAD patients. These findings are important since they demonstrate that past HAV, HSV and HP infections may affect cardiovascular risk, while recent CP infection may be implicated in the triggering of AMI among CAD patients.

Relationship of fibrinogen with arterial stiffness and wave reflections.

INTRODUCTION: Increased levels of fibrinogen have been related to target organ damage and cardiovascular outcomes. Arterial elastic properties are important determinants of cardiovascular performance and predictors of the corresponding risk. This study investigated whether the fibrinogen level is associated with arterial stiffness and wave reflections. METHODS: We studied 229 consecutive, non-diabetic patients with uncomplicated, never-treated essential hypertension (mean age 51 years, 149 men) and an age-matched control group of 159 normotensive individuals (mean age 50 years, 83 men). Carotid-femoral and carotid-radial pulse wave velocity (PWVc-f and PWVc-r) were measured as indices of elastic-type, aortic stiffness and muscular type, medium-sized arterial stiffness, respectively. The heart rate-corrected augmentation index (AIx75) was estimated as a composite marker of wave reflections and arterial stiffness. Plasma fibrinogen was measured using immunonephelometry. RESULTS: The fibrinogen level and arterial function indices (PWVc-f, PWVc-r, AIx75) were significantly higher in hypertensive patients than controls. In the whole population, fibrinogen level correlated with PWVc-f and AIx75 in univariable analysis, but not with PWVc-r. In multivariable analysis, an independent association was established between fibrinogen level and PWVc-f after adjusting for age, sex, mean pressure, heart rate, height, body mass index, smoking status, and total cholesterol. In contrast, no significant relationship was observed between fibrinogen and AIx75 after adjusting for confounders. CONCLUSION: The plasma fibrinogen level is independently associated with aortic stiffening. This finding underlines the important role of fibrinogen as a marker of arterial damage, and implies a possible contribution of this compound to the pathophysiology of cardiovascular disease.

Protective effect of atorvastatin on acute systemic inflammation-induced endothelial dysfunction in hypercholesterolaemic subjects.

AIMS: Recent studies suggest an association between acute inflammation and deterioration of arterial function. The effect of acute inflammation on endothelial function and the role of treatment with statins have not been investigated in subjects with dyslipidaemia. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind study, we generated a transient systemic inflammation by Salmonella typhi vaccination in 50 volunteers with mild hypercholesterolaemia after 4 days of treatment with atorvastatin 40 mg or placebo once daily. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery and circulating levels of endothelial and inflammatory markers were measured before and 8 h after the vaccine. Vaccination produced a decline on FMD at 8 h (absolute decrease of 2.55%, P = 0.001), indicating an unfavourable effect on endothelial function. In contrast, in atorvastatin-treated subjects, FMD was preserved after vaccination (decrease of 0.15%, P = 0.005 vs. placebo). The vaccination-induced decline in plasma level of nitric oxide metabolites (by 6.0 micromol/L, P = 0.007) and antioxidant capacity (by 20.6 micromol/L, P = 0.001) in the placebo group were completely abolished by atorvastatin (P = 0.038 and P = 0.005, respectively, vs. placebo). In contrast, atorvastatin had no significant effect on cytokine levels. CONCLUSION: Acute inflammation is aetiologically associated with the deterioration of vasomotor and systemic endothelial function in hypercholesterolaemic patients. Atorvastatin effectively abrogates these deleterious effects.

Relation of habitual cocoa consumption to aortic stiffness and wave reflections, and to central hemodynamics in healthy individuals.

The effect of habitual cocoa consumption on arterial stiffness and wave reflection indexes, as well as on peripheral and central blood pressure, was assessed in 198 healthy subjects. In conclusion, higher cocoa intake was an independent determinant of low arterial stiffness and wave reflection indexes and was also independently associated with significantly lower central (aortic) pulse pressure.

Negative association between serum levels of matrix metalloproteinases-2 and -9 and aortic stiffness in healthy adults.

BACKGROUND: Arterial stiffness is a marker of cardiovascular disease and independent predictor of cardiovascular risk. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade components of the extracellular matrix, which is an important determinant of the arterial elastic properties. This study sought to investigate the association between MMP-2 and MMP-9 (gelatinase A and B respectively) and arterial stiffness in healthy human subjects. METHODS: A total of 213 apparently healthy subjects (mean age 41 years, range 18 to 60, 141 males and 72 females) were studied. Carotid-femoral pulse wave velocity (PWV) and aortic augmentation index (AIx) were measured as indices of aortic stiffness and wave reflections respectively. Associations with serum levels of total MMP-2, total MMP-9 and high-sensitivity C-reactive protein (hsCRP) were evaluated with multiple regression models. RESULTS: In these models, PWV exhibited a significant negative association with both MMP-2 (standardized b=-0.177, P=0.003) and MMP-9 (b=-0.122, P=0.032), after controlling for potential confounding factors such as age, gender, blood pressure, heart rate, body-mass index, smoking habits (pack-years), blood glucose, total cholesterol, and level of subclinical inflammation expressed by hsCRP (adjusted R2 of models 0.352 and 0.338 respectively). On the other hand, no relationship between MMP-2 or MMP-9 and AIx was found. CONCLUSIONS: Circulating MMP-2 and MMP-9 are inversely associated with large artery stiffness but not with wave reflections in healthy persons. This finding implies that these gelatinases may have a possible role in the determination of arterial function and has potential implications for their involvement in the pathophysiology of cardiovascular diseases.

Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines.

BACKGROUND: Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure. OBJECTIVE: We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA. DESIGN: In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading. RESULTS: Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction. CONCLUSIONS: Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.