Endothelium and angiogenesis in white coat hypertension

Hypertensive patients are at particular risk of cardiovascular complications, possibly related to endothelial damage or dysfunction, or to abnormal angiogenesis. The aim of this study was to compare the risk conferred by white coat hypertension (WCH) vs sustained hypertension in the development of the endothelial dysfunction and abnormal angiogenesis by evaluating nitric oxide (NO=NO2+NO3), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and E-selectin levels in plasma. The study group included 102 subjects, 34 with WCH (17 male and 17 female patients) aged 49+/-11 years, 34 sustained hypertensives (HT) (15 male and 19 female patients) aged 47+/-11 years and 34 normotensive control subjects (NT) (16 male and 18 female patients) aged 48+/-10 years. WCH was defined as clinical hypertension and daytime ambulatory blood pressure less than 135/85 mmHg. The subjects were matched for age, gender, body mass index and the patients with smoking habit, dyslipidaemia, and diabetes mellitus were excluded from the study. The NO, ET-1, VEGF and E-selectin levels were analysed by ELISA technique. The WCH subjects had significantly higher levels of NO than the HT (41.68+/-2.23 vs 32.18+/-2.68 micromol/l; P<0.001) and significantly lower values than the NT (48.24+/-4.29 micromol/l; P<0.001). ET-1 levels of the WCH group were significantly higher than the NT (8.10+/-0.92 vs 5.95+/-0.26 ng/ml; P<0.001) and significantly lower than the HT (11.46+/-0.59 ng/ml; P<0.001). Considering with VEGF, the WCH group had significantly higher levels than the NT (195.88+/-11.84 vs 146.26+/-18.67 pg/ml; P<0.001), but the difference from the HT group was not significant (203.35+/-7.48 pg/ml; P=0.062). E-selectin in the WCH group was significantly lower than the HT (4.77+/-0.52 vs 8.49+/-2.85; P<0.001), but the difference from the NT group was not significant (3.86+/-0.67; P=0.077). Our data demonstrate that WCH is associated with endothelial dysfunction and abnormal angiogenesis. The degree of these changes is not as severe as observed in hypertensive population.     

Target organ damage and changes in arterial compliance in white coat hypertension. Is white coat innocent?

The aim of this study was to perform an extensive evaluation of target organ status, metabolic abnormalities and hemodynamic alterations in white coat hypertension (WCH). Fifty normotensive (NT), 90 WCH (ambulatory daytime blood pressure < 135/85 mmHg) and 101 hypertensive (HT) subjects underwent extensive biochemical, echocardiographic, fundoscopic examination. In a subgroup study, arterial compliance and intima-media thickness (IMT) were measured by Doppler ultrasound in left common carotid artery. WCH subjects were found to have higher body mass index (BMI) than the NTs (p = 0.042). Left ventricle mass index (LVMI) was greater in the WCHs than the NTs (p < 0.001), but significantly less than the HTs (p < 0.001). Hypertensive retinopathy was observed in the WCHs, but was less severe and rare compared to the HTs (13% vs 27%). Both WCHs and HTs had high levels of urinary albumin excretion (UAE) (p = not significant). Total cholesterol was higher in WCHs than in the NTs (p = 0.04) The distensibility coefficient (DC) of the WCHs was significantly greater than the HTs (p < 0.01), while significantly smaller than the NTs (p < 0.01). The compliance coefficient (CC) of the WCHs was significantly higher than the HTs (p < 0.01), and significantly less than the NTs (p < 0.01). The IMT in the HTs was significantly higher than the WCHs (0.81 +/- 0.05 vs 0.70 +/- 0.04 mm; p < 0.001) and the NTs (p < 0.001). The difference between the NTs and the WCHs was not significant. Our data indicate that patients with WCH represent an intermediate group between NTs and sustained HTs where target organ damage and cardiovascular risk is concerned.     

Metabolic syndrome in subjects with white-coat hypertension: impact on left ventricular structure and function

Some reports have suggested that white-coat hypertension (WCH) is associated with some features of the metabolic syndrome (MetS). These metabolic disturbances, instead of WCH per se, may potentially explain the greater extent of end-organ damage sometimes observed in WCH subjects (WCHs) when compared to normotensive individuals (NTs). The aim of the present cross-sectional study was to compare left ventricular (LV) structure and function in three groups of subjects: WCHs with MetS, WCHs without MetS and NTs. A total of 145 WCHs, 35% of whom had MetS, were enrolled. As controls, 35 NTs were also studied. In all subjects, routine blood chemistry, echocardiographic examination and 24-h ambulatory blood pressure monitoring were performed. When compared with WCHs without MetS, those with MetS showed higher LV mass indexed by height elevated by a power of 2.7 (LVMH(2.7)) (49.6+/-14.8 vs 38.9+/-9.8 g/m(2.7); P<0.0001). The same parameter was greater in WCHs without MetS than in NTs (32+/-8 g/m(2.7); P=0.004). Moreover, the E-wave deceleration time was longer in WCHs with MetS than in those without it (236.2+/-66.4 vs 200.5+/-30.8 ms; P<0.0001). The relationship of MetS with LVMH(2.7) was confirmed in multivariate regression models. Our results seem to suggest that MetS may have a deleterious influence on LV structure and function in WCH. However, WCH, being associated with an increased LV mass, also in subjects without MetS, may not be considered as an innocuous phenomenon.     

Hyperhomocysteinemia: an additional risk factor in white coat hypertension

The association between homocysteine and sustained hypertension (HT) has been studied. The aim of this study was to assess homocysteine levels in white coat hypertension (WCH) as an indicator of increased risk in the development of cardiovascular diseases. WCH was defined as clinical hypertension and a daytime ambulatory blood pressure of < 135/85 mmHg. Plasma levels of homocysteine were determined in patients with WCH, hypertension, and normotension (NT). The study group included 100 subjects, 33 with WCH (16 males, 17 females) aged 49.1 +/- 1.9; 35 sustained hypertensives (17 males,18 females) aged 48.5 +/- 1.7 and 32 normotensive control subjects (15 males, 17 females) aged 48.8 +/- 2.2. The subjects were matched for age, gender, and body mass index. Patients with a smoking habit, dyslipidemia, or diabetes mellitus were not included in the study. Homocysteine levels were analyzed by ELISA. Plasma homocysteine levels were significantly higher in the WCH group compared to the controls (12.32 +/- 1.07 versus 5.35 +/- 1.38 micromol/L; P < 0.001) and the WCH group had significantly lower homocysteine values than the hypertensives (19.03 +/- 0.76 micromol/L P < 0.001). Total cholesterol and tri-glycerides were not different among the groups. There were no statistically significant differences in urinary albumin excretion (UAE) or creatinine clearance between the three groups. Hypertensive retinopathy was observed in the WCH group, but was less severe and less frequent compared to HTs. LVMI was greater in the WCH group compared to the NTs, but significantly less than HTs. The data demonstrate that WCH is associated with high levels of homocysteine. The increase in homocysteine level in WCH is not as high as in SHT. Since an elevated plasma homocysteine level is a strong risk factor for coronary artery disease and there was target organ damage in our WCH group, we conclude that WCH should not be considered to be an innocent trait.     

Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

BACKGROUND/AIMS: The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. This study was designed to determine whether plasma levels of ADMA and NO production are altered in patients with compensated and decompensated alcoholic cirrhosis. METHODS: Plasma levels of l-arginine, ADMA, symmetric dimethylarginine (SDMA) and NO (nitrite plus nitrate, NOx) were measured in nine patients with compensated alcoholic cirrhosis (Child-Pugh A) and 11 patients with advanced cirrhosis (Child-Pugh B-C). Seven healthy volunteers served as controls. RESULTS: ADMA and NOx concentrations in decompensated cirrhosis were higher than in the compensated group and control group (ADMA: 1.12+/-0.08 vs. 0.58+/-0.05 and 0.58+/-0.07micromol/l, respectively; P<0.05; NOx 97.90+/-10.27 vs. 37.42+/-3.91 and 40.43+/-5.30micromol/l, respectively; P<0.05). There was a positive correlation between the clinical score of the patients and concentrations of ADMA (r(2)=0.547, P<0.01) and NOx (r(2)=0.689, P<0.01). SDMA and l-arginine levels were not significantly different between the three groups. CONCLUSIONS: The results suggest that hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis.     

Asymmetric dimethylarginine and coronary collateral vessel development

INTRODUCTION: Nitric oxide (NO) plays a major role in collateral vessel development. Asymmetric dimethylarginine (ADMA) that is an endogenous inhibitor of NO synthesis may impair the effective coronary collateral vessel development. The aim of this study was to evaluate the relationship between plasma ADMA level and coronary collateral vessel development. METHODS: The patients with a greater than or equal to 95% obstruction in at least one epicardial coronary artery were included in the study. Degree of coronary collateral development was determined according to Rentrop method. Patients with grade 2-3 collateral development were regarded as good collateral group and formed group I. The patients with grade 0-1 collateral development were regarded as poor collateral group and were included in group II. Group III that had been formed as a control group included the patients with a normal coronary angiogram. We compared the plasma ADMA, symmetric dimethylarginine, L-arginine/ADMA ratio among three groups. RESULTS: Seventy-four patients have been included in the study. Patients with good collateral development had lower plasma ADMA level in comparison with patients with poor collateral development (0.41+/-0.25 micromol/l vs. 0.70+/-0.23 micromol/l, P=0.001) and had similar plasma ADMA levels with the patients who have normal coronary arteries. When we compared L-arginine/ADMA ratio between good and poor collateral groups, we found that the patients with higher L-arginine/ADMA ratio have significantly better collateral development (270.8+/-168.0 vs. 120.9+/-92.1, P<0.001). In the analyses comparing Rentrop score with ADMA level and L-arginine/ADMA ratio, there were significant correlations (r=-0.444, P=0.008 and r=0.553, P=0.001, respectively). In multivariate analysis, ADMA level (odds ratio, 0.009; 95% confidence interval, 0.000-0.466, P=0.020) and L-arginine/ADMA ratio (odds ratio, 1.010; 95% confidence interval, 1.001-1.020, P=0.032) were independent predictors of collateral development. CONCLUSION: Increased plasma ADMA levels are related with poor coronary collateral development. ADMA may be responsible for the difference in coronary collateral vessel development among different patients with coronary artery disease. NO inhibitors that have a determinative relation with endothelial cell functions may be integral prerequisite in all steps of collateral development.     

White coat hypertension is a cardiovascular risk factor: a 10-year follow-up study

The objective of this paper was to evaluate the cardiovascular risk in white coat hypertension (WCH). WCH is a well-known clinical entity defined by persistently elevated blood pressure (BP) in the doctor's office, whereas BP in other conditions is normal. The prognosis of WCH is unsettled, although two prospective studies that include normal control groups imply that the condition is benign. This study is a 10-year follow-up study on 420 patients with grade I-II hypertension newly diagnosed by their general practitioner and 146 normal controls (NTs). Ambulatory blood pressure (ABP) monitoring was performed at baseline. With our protocollated cutoff value of daytime-ABP <135/90 mmHg, 76 (18.1%) of the 420 hypertensives were white coat hypertensives (WCHs) and 344 were established hypertensives (EHs). With a lower cutoff of 135/85 mmHg, 40 (9.5%) were WCHs. Complete follow-up data were obtained for all 566 subjects. The mean duration of follow-up was 10.2 years (range 9.0-12.5). In the WCH group, 14 first events were recorded (18.4%) consisting of two cardiovascular deaths and 12 nonfatal cardiovascular events. In the EH group, the corresponding number of events were 56 first events (16.3%), 12 cardiovascular deaths and 44 nonfatal cardiovascular events, and in the NT group 10 first events (6.8%), two cardiovascular deaths and eight nonfatal cardiovascular events. The event rate was similar in the WCH group and the EH group and significantly lower in the NT group (P<0.05). When corrected for daytime-ABP, age and other confounders, the difference remained statistically significant. When using the lower cutoff of 135/85 mmHg, WCH was still associated with a significantly higher cardiovascular event rate. In conclusion, the main finding of this 10-year follow-up study is an increased cardiovascular risk in WCH compared to normotensive controls.     

Oxidative stress in white coat hypertension; role of paraoxonase

Oxidative stress in sustained hypertension was shown with several biochemical parameters. Oxidized low-density lipoprotein (oxLDL) plays an important role during the atherosclerosis process and paraoxonase (PON1) can significantly inhibit lipid peroxidation. Serum PON1 activity, oxLDL and malondialdehyde (MDA) concentrations and their relationship with serum lipid parameters and systolic and diastolic blood pressures (SBP and DBP) were determined in subjects with white coat hypertension (WCH), sustained hypertension (HT) and normotension (NT). The study group consisted of a total of 86 subjects, 30 with WCH (14 male, 16 female subjects), 30 with HT (13 male, 17 female subjects) and 26 with NT (12 male, 14 female subjects). Both white coat hypertensive and hypertensive subjects had significantly higher levels of MDA than normotensives (P<0.026 and P<0.001, respectively). The oxLDL level of the HT group was significantly higher than the NT group (P<0.023). The WCH group had an oxLDL level similar to both hypertensive and normotensive groups. HT and WCH groups had significantly lower PON1 levels than the normotensive group (P<0.001). oxLDL correlated with MDA positively (P=0.008), and PON1 negatively (P=0.008). A negative correlation between MDA and PON1 (P=0.014) was detected. MDA correlated positively with both SBP and DBP (P=0.001), while PON1 correlated with both of them negatively (P=0.01 and P=0.008, respectively). OxLDL correlated with diastolic blood pressure positively (P=0.008). Our data demonstrate that oxidative stress increase in WCH is associated with a decrease in PON1 activity. The reduction in PON1 activity may be one of the factors leading to an increase in oxidative status in WCH.     

Asymmetric dimethylarginine (ADMA) in the aqueous humor of diabetic patients

Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase (NOS) inhibitor whose production is enhanced by oxidative stress. Recent studies have shown that ADMA may also directly stimulate the production of reactive oxygen species (ROS) by up-regulation of the renin-angiotensin system independently of NOS inhibition. In this study, to investigate the clinical association of ADMA with diabetic retinopathy, we evaluated the levels of ADMA and NO oxides (NO2- and NO3-) in serum and aqueous humor obtained during cataract surgery from non-diabetic subjects (n = 21) and diabetic patients (n = 17). We found that the ADMA existed in aqueous humor and its level was similar to that in serum. The ADMA levels in both serum and aqueous humor were higher in diabetic patients, especially those with severe retinopathy, than in the non-diabetic group (serum ADMA: 0.67 +/- 0.26 vs. 0.53 +/- 0.08 micromol/l, p<0.05; aqueous humor ADMA: 0.55 +/- 0.20 vs. 0.32 +/- 0.16 micromol/l, p<0.05). Also, the aqueous humor level of ADMA, but not the serum level, was correlated with HbA1c on analysis of all the patients (R = 0.33, p<0.05 by simple regression analysis). However, a correlation between the ADMA levels in serum and aqueous humor was not observed in either the non-diabetic group or the diabetic group. Furthermore, serum and aqueous humor levels of NOx did not differ between the two groups, and no correlation with ADMA levels was observed in either group. These results suggest that ROS production may be enhanced in the eyes of diabetics. Since ADMA may act to potentiate ROS production independently of its inhibition of NOS, further investigation is required to clarify the possible contribution of ADMA to the development or progression of retinopathy.     

Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension

OBJECTIVE: We explored the potential role of the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) in patients with idiopathic pulmonary arterial hypertension (IPAH). Method and Results- We correlated plasma ADMA levels and cardiovascular indices from right heart catheterization in 57 patients with IPAH. Predictors of survival in patients with IPAH were studied. Furthermore, the effect of systemic ADMA infusion on pulmonary ventricular resistance and stroke volume was investigated in healthy volunteers using right heart catheterization. Mean plasma ADMA concentrations were significantly higher in patients with IPAH than in control subjects (0.53+/-0.15 versus 0.36+/-0.05 micromol/L; P<0.001). ADMA plasma concentrations correlated significantly with indices of right ventricular function, such as mixed-venous oxygen saturation (r=-0.49; P<0.0001), right atrial pressure (r=0.39; P<0.003), cardiac index (r=-0.35; P<0.008), as well as survival (r=-0.47; P<0.0001). Multiple regression analysis revealed that right atrial pressure (r=0.31; P<0.026) and ADMA (r=0.29; P<0.039) were independent predictors of mortality. Moreover, patients with supra-median plasma ADMA levels had significantly (P<0.021) worse survival than patients with infra-median ADMA values. ADMA infusion in healthy volunteers increased pulmonary vascular resistance (68.9+/-7.6 versus 95.6+/-6.3 dyne x s x cm(-5); P<0.05) and decreased stroke volume (101.1+/-6.7 mL versus 95.6+/-6.3 mL; P<0.05). CONCLUSIONS: Increased ADMA plasma levels are associated with unfavorable pulmonary hemodynamics and worse outcome in patients with IPAH.     

Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events.

AIMS: We investigated the role of asymmetric dimethylarginine (ADMA) for clinical outcome of patients with unstable angina. METHODS AND RESULTS: Forty-five patients with stable angina, 36 patients with unstable angina, and 40 healthy controls were included in this study. Coronary artery disease (CAD) patients were prospectively followed for 1 year. ADMA levels were measured at baseline and after 6 weeks using a validated ELISA. Baseline ADMA concentration in controls was significantly lower than in patients with CAD (0.59+/-0.23 vs. 0.76+/-0.17 micromol/L; P<0.001). Patients with unstable angina had significantly higher baseline ADMA levels than patients with stable angina (0.82+/-0.18 vs. 0.73+/-0.15 micromol/L; P=0.01). There was a significant reduction of ADMA levels at 6 weeks after percutaneous coronary intervention (PCI) in patients with unstable angina who experienced no recurrent cardiovascular event (from 0.81+/-0.14 to 0.73+/-0.19 micromol/L; P<0.05). In contrast, patients with unstable angina who had an event showed no significant decrease in ADMA at 6 weeks. Actuarial survival analysis showed a significantly higher event rate in patients with persistently elevated ADMA plasma concentrations. CONCLUSION: ADMA is significantly elevated in patients with unstable angina. A reduced ADMA level at 6 weeks after PCI may indicate a decreased risk of recurrent cardiovascular events.     

Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA

Hyperhomocysteinemia is associated with an enhanced risk for cardiovascular disease. Patients with peripheral arterial disease (PAD) show an increased prevalence of hyperhomocysteinemia. A decreased biological activity of nitric oxide (NO) may contribute to homocysteine-associated endothelial dysfunction. This study was designed to investigate whether elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are involved in endothelial dysfunction in patients with chronic hyperhomocysteinemia and PAD. A total of 76 patients (58 males and 18 females; mean age 65.2 +/- 2.0 years) with PAD were included in the analysis and characterized according to demographic variables and cardiovascular risk factors. Flow-dependent vasodilation (FDD) was determined by high-resolution ultrasound in the radial artery. Total plasma homocysteine (plasma tHcy) and ADMA levels were measured by HPLC. Urinary nitrate was quantified using gas chromatography-mass spectrometry. Patients with plasma tHcy in the highest tertile (n = 27; i.e. > 10.6 micromol/l) had a mean plasma level of 14.4 +/- 1.21 mol/l compared with 9.9 +/- 0.1 micromol/l in those patients in the middle tertile (n = 22; p < 0.05) and 9.4 +/- 0.1 micromol/l in those in the lowest tertile (n = 27; i.e. <9.6 micromol/l; p < 0.05). The hyperhomocysteinemic individuals (highest tertile) had a significantly decreased FDD compared with healthy age-matched controls (n = 15) (7.6 +/- 1.0 vs 13.0 +/- 0.4%; p < 0.05), higher plasma ADMA concentrations (4.0 +/- 0.3 vs 2.6 +/- 0.3 micromol/l; p < 0.05), and a lower urinary nitrate excretion rate (89.5 +/- 13.4 vs 131.3 +/- 17.9 micromol/mmol creatinine; p < 0.05) compared with patients with plasma tHcy in the lowest tertile. Multivariate regression analysis including plasma tHcy, ADMA, total cholesterol, diabetes mellitus, smoking, and systolic blood pressure revealed ADMA as the only significant factor determining FDD (p < 0.05). In conclusion, we demonstrated a stronger relationship between impaired endothelial function and elevated ADMA levels in comparison with plasma tHcy concentrations in patients with PAD and chronic hyperhomocysteinemia. This may raise the question of whether different therapeutical options that interact indirectly with plasma tHcy, i.e. treatment with ACE inhibitors and AT1-receptor blockers to reduce ADMA plasma concentrations or L-arginine, could be a beneficial tool for treating patients with hyperhomocysteinemia.     

Salt loading on plasma asymmetrical dimethylarginine and the protective role of potassium supplement in normotensive salt-sensitive asians

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. Because endothelial NO pathway is compromised in patients with salt-sensitive hypertension, we investigated whether the plasma ADMA can be modulated by chronic salt loading in normotensive salt-sensitive persons and its relationship with NO, and we further determined whether or not dietary potassium supplementation can reverse them. Sixty normotensive subjects (aged 20 to 60 years) were selected from a rural community of Northern China. All of the people were sequentially maintained on a low-salt diet for 7 days (3 g/day, NaCl), then a high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). After salt loading, the plasma ADMA concentrations increased significantly in salt-sensitive subjects (0.89+/-0.02 micromol/L versus 0.51+/-0.02 micromol/L; P<0.05), whereas the plasma NOx levels reduced considerably (41.8+/-2.1 micromol/L versus 63.5+/-2.1 micromol/L; P<0.01). All of the abnormalities normalized when dietary potassium were supplemented (0.52+/-0.03 micromol/L versus 0.89+/-0.02 micromol/L for ADMA and 58.1+/-0.9 micromol/L versus 41.8+/-2.1 micromol/L for NOx). Statistically significant correlations were found among plasma ADMA level, the mean blood pressure, and the level of NO after salt loading in normotensive salt sensitive individuals. Our study indicates that high dietary potassium intake reduces blood pressure and ADMA levels while increasing NO bioactivity in normotensive salt-sensitive but not salt-resistant Asian subjects after salt loading.     

Differential Expression of Hypertension-Associated MicroRNAs in the Plasma of Patients With White Coat Hypertension

White coat hypertension (WCH) is a high cardiovascular risk condition, and a fundamental understanding of the cause and pathophysiology of the disorder is still lacking. Recent studies demonstrated that microRNAs (miRNAs) are involved in hypertension; however, the roles of miRNAs in WCH are not known.The expressions of selected 10 miRNAs were investigated independently in plasma samples from 30 hypertension (HT) patients, 30 WCH patients, and 30 normotensive (NT) subjects.MiR-21, miR-122, miR-637, and let-7e expression levels were significantly upregulated in the HT group compared with the NT groups (P = 0.017, P = 0.022, P = 0.048, and P = 0.013, respectively). MiR-122 and miR-637 expressions were also significantly upregulated in the WCH group compared with the NT group (P = 0.048 and P = 0.039, respectively). MiR-296-5p expression level was significantly downregulated in HT patients and upregulated in the WCH patients compared with the NT group (P = 0.049 and P = 0.039, respectively).Additionally, the ambulatory 24-hour and daytime systolic and diastolic blood pressures were negatively correlated with miR-296-5p. MiR-296 and miR-637 had area under the curve (AUC) values of 0.778 and 0.774, respectively, which demonstrates their sufficiency to distinguish WCH from NT individuals. MiR-296 and miR-637 had AUC values of 0.868 and 0.680, respectively, which shows their potential to distinguish WCH from HT individuals.We report for the first time a plasma miRNA profile for WCH patients and demonstrate a novel link between miRNA and WCH. These findings may reveal crucial insights into the development of WCH.     

Plasma asymmetric dimethylarginine and L-arginine levels in patients with cardiac syndrome X

BACKGROUND: Endothelial dysfunction and subsequently impaired microvascular circulation are the leading mechanisms in the development of cardiac syndrome X (CSX). The study evaluated the plasma asymmetric dimethylarginine (ADMA) and L-arginine levels of the patients with CSX and the control group and aimed to determine any relationship between these parameters and epicardial coronary blood flow and myocardial tissue perfusion. METHODS: The study group consisted of 32 patients (mean age: 52.6+/-9.4 years, 14 men) with typical exertional angina, positive exercise test, and normal coronary arteries diagnosed as CSX. Plasma ADMA, L-arginine levels, and L-arginine/ADMA ratio were compared with the values of the control group, which consisted of 17 age-matched and sex-matched individuals. Concentrations of L-arginine and ADMA were measured by high-performance liquid chromatography. In all the coronary territories, epicardial coronary flow was assessed by thrombolysis in myocardial infarction (TIMI) frame count (TFC) method, and tissue level perfusion, by myocardial blush grade (MBG) method. A MBG score less than 3 was considered an impaired myocardial perfusion, and a MBG score of '3' in all the coronary territories, a normal myocardial perfusion. RESULTS: The plasma ADMA levels of the study group were higher than those of the control group (0.83+/-0.38 vs. 0.55+/-0.44 micromol/l, P=0.03), whereas plasma L-arginine levels were similar in both groups (70.25+/-21.89 vs. 76.09+/-18.22 micromol/l, P=0.36), resulting in a diminished L-arginine/ADMA ratio in the patients with CSX [82.3 (60.2-128.8) vs. 242.2 (76.7-386.4), P=0.003]. In CSX group, the patients with abnormal myocardial tissue perfusion had increased plasma ADMA levels compared with those with normal tissue perfusion (0.99+/-0.37 vs. 0.69+/-0.34 micromol/l, P=0.02), whereas plasma L-arginine levels were similar in both groups. No correlations were observed between TFC values and plasma ADMA, L-arginine levels, and L-arginine/ADMA ratio. Plasma ADMA levels, however, were negatively correlated with MBG scores (r=-0.349, P=0.014). CONCLUSION: We have shown for the first time that in the patients with CSX, increased plasma ADMA levels might be associated with impaired myocardial tissue perfusion when assessed by MBG.     

Symmetric dimethylarginine is an independent predictor of intradialytic hypotension

BACKGROUND: Hemodialysis (HD) is associated with significant reductions in the plasma concentrations of the nitric oxide (NO) inhibitors N(G)-monomethyl L-arginine (L-NMMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We sought to determine whether elevated concentrations of these NO inhibitors pre-HD and/or their acute decrease during HD might mediate intradialytic hypotension (IDH). METHODS: Systolic blood pressure (SBP), L-arginine, L-NMMA, ADMA, and SDMA were measured at the beginning (pre-HD) and at the end (end-HD) in 52 consecutive HD patients (age 64.4 +/- 13.4 years). IDH was defined as a SBP reduction of >20 mm Hg end-HD vs. pre-HD. RESULTS: Fourteen patients demonstrated IDH. The mean SBP reduction during HD in this group was -35 +/- 13 mm Hg compared to an increase of +2 +/- 12 mm Hg among the 38 patients without IDH (no-IDH). Baseline demographic, clinical, and biochemical parameters did not differ between the IDH and no-IDH groups. However, the IDH group had higher pre-HD SBP (155 +/- 17 vs. 132 +/- 14 mm Hg, P < 0.001), pre-HD plasma SDMA concentrations (1.98 +/- 0.61 vs. 1.64 +/- 0.46 micromol/l, P = 0.04), and greater SDMA reductions during HD (-0.78 +/- 0.43 vs. -0.56 +/- 0.32 micromol/l, P = 0.06) than the no-IHD group. After adjusting for pre-HD SBP, the odds of IDH occurring were higher with increased pre-HD SDMA plasma concentrations (OR = 1.31 per 0.1 micromol/l SDMA increase; 95% CI = 1.04-1.65, P = 0.02) and with decreases in SDMA during HD (OR = 1.39 per 0.1 micromol/l SDMA decrease; 95% CI = 1.02-1.91, P = 0.04). CONCLUSION: Increased pre-HD SDMA plasma concentrations and greater SDMA reductions during HD independently predict IDH after adjusting for demographic and clinical variables, pre-HD SBP, and other methylated forms of L-arginine.     

Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure

BACKGROUND: In chronic heart failure, oxidative stress is thought to lead to endothelial dysfunction. In this study, we assessed the effect of home-based exercise training on variables of the NO and purine pathways. METHODS AND RESULTS: Eighteen patients and nine controls were randomly assigned in cross-over design to 8 weeks of exercise training (5 days/week, submaximal bicycle ergometer training, 30 min/day; calisthenics 9 min/day) and 8 weeks of sedentary lifestyle. Hypoxanthine, xanthine, l-arginine, asymmetric dimethylarginine (ADMA), symmetric DMA (SDMA) and nitrite were measured. In patients, exercise training led to an increase in peak VO(2) (p<0.003). At baseline hypoxanthine-a pro-oxidant substrate and marker of hypoxia-was higher in patients than in controls (24.6+/-4.3 vs. 11.9+/-4.2 micromol/l; p<0.05). After training there was a reduction in hypoxanthine (p<0.01). Nitrite levels were lower in patients (416+/-31 micromol/l) than in healthy controls (583+/-35 micromol/l, p<0.001). Although nitrite levels were highest after exercise, the changes did not reach statistical significance (p=n.s.). l-Arginine, ADMA, and SDMA levels were not different between groups and were not altered by exercise training. CONCLUSIONS: Chronic heart failure is associated with increased levels of hypoxanthine and decreased levels of nitrite. This imbalance can be beneficially modulated by chronic home-based exercise training.     

Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis

Hypertension (HT) is highly prevalent in rheumatoid arthritis (RA). Serum uric acid (SUA) has been associated with HT in the general population. The mutual exclusion of gout and RA, and the systemic inflammatory component of RA may alter this association in this patient population. We explored a potential association between SUA levels and HT in RA and evaluated whether this association is independent of HT risk factors, RA characteristics and relevant drugs. A total of 400 consecutive RA patients were assessed. SUA and complete biochemical profile were measured. Demographic, HT-related factors, RA characteristics and drugs were assessed as potential covariates. Results were analysed using binary logistic models to test the independence of the association between SUA and HT. SUA levels were higher in hypertensive compared to normotensive RA patients (5.44+/-1.6 mg dl(-1) (323.57+/-95.17 micromol l(-1)) vs 4.56+/-1.1 mg dl(-1) (271.23+/-65.43 micromol l(-1)), P<0.001). When adjusted for HT risk factors, renal function, RA characteristics, non-steroidal anti-inflammatory drugs, oral prednisolone, cyclosporine, leflunomide and low-dose aspirin, the odds of being a hypertensive RA patient per 1 mg dl(-1)(59.48 micromol l(-1)) SUA increase were significantly increased: OR=1.59 (95% CI: 1.21-2.1, P=0.001). This was also significant for the subgroup of patients who were not on diuretics (OR=1.5, 95% CI: 1.1-2.05; P=0.011). This cross-sectional study suggests that SUA levels are independently associated with HT in RA patients. Prospective longitudinal studies are needed to confirm and further explore the causes and implications of this association.     

Plasma nitrites/nitrates in HCV infection and hepatocellular carcinoma

OBJECTIVE: Nitric oxide (NO) is produced in response to inflammatory and mitogenic stimuli and may have a role in carcinogenesis. However, the role of NO in hepatitis C-associated hepatocellular carcinoma (HCC) is unclear. In this study, we investigated the potential role of NO in HCC complicating hepatitis C virus (HCV) infection. METHOD: We measured plasma nitrites/nitrates as being representative for NO release in blood of patients with chronic hepatitis C without cirrhosis (n = 20), cirrhosis of different aetiologies (n = 30) including HCV, HCC (n = 22) and in healthy controls (n = 8), by an enzyme-linked immunosorbent assay. RESULTS: Plasma NO levels in patients with chronic hepatitis C without cirrhosis (32.3+/-8.94 micromol/l) were not significantly different from those in healthy control subjects (35.5+/-15.12 micromol/l). Also, there were no statistical differences between plasma NO levels in patients on alpha-interferon (alpha-IFN) therapy (n = 10) (31.60+/-10.55 micromol/l) and in non-treated patients (n = 10) (33.00+/-7.51 micromol/l) within the group of chronic hepatitis C. Plasma NO levels in patients with cirrhosis (42.36+/-26.86 micromol/l) were significantly higher than those with chronic hepatitis C (P < 0.001). The cause of cirrhosis had no effect on plasma NO levels. Plasma NO levels in patients with HCC (49.40+/-49.11 micromol/l) were significantly higher than those with liver cirrhosis (P < 0.03). No significant correlation was found between plasma NO and serum ALT (alanine aminotransferase) levels. There were positive correlations between plasma NO levels and alkaline phosphatase (r = 0.528) (P = 0.0001), bilirubin (r = 0.244) (P = 0.039) and GGT (gamma glutamyltransferase) (r = 0.255) (P = 0.030). CONCLUSION: The results of this study demonstrate that patients with chronic hepatitis C without cirrhosis have the same plasma NO levels as controls, and that alpha-IFN therapy had no effect on NO production in these patients. However, patients with HCC have elevated plasma NO levels compared with patients with cirrhosis. These data support the concept that NO is elevated in cirrhosis and HCC, but HCV infection does not appear to be responsible for the increase of NO in these patients. The severity of liver disease may be an important factor.     

Leptin and membrane fluidity of erythrocytes in essential hypertension. An electron paramagnetic resonance investigation

There has been an indication that leptin, the product of the human obesity gene, actively participates not only in metabolic regulation but also in the control of blood pressure. Recently, it has been proposed that abnormalities in the physical property of cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. We have shown previously that leptin significantly increased the membrane fluidity and improved the microviscosity of erythrocytes in humans through the nitric oxide-dependent mechanism. In the present study, we examined the effects of leptin on membrane fluidity of erythrocytes in subjects with essential hypertension by means of an electron paramagnetic resonance (EPR) and spin-labeling method. The values of the order parameter (S) and the peak height ratio (ho/h-1) obtained from the EPR spectra of erythrocytes were significantly greater in patients with essential hypertension (HT) than in age-matched normotensive subjects (NT) (S: HT 0.719 +/- 0.002, n = 16, NT 0.713 +/- 0.001, n = 29, P < .05; ho/h-1: HT 5.17 +/- 0.02, n = 16, NT 5.05 +/- 0.02, n = 29, P < .05). The finding indicated that the erythrocyte membrane fluidity was lower in patients with HT than in NT. Leptin decreased S and ho/h-1 in a dose-dependent manner in both NTs and HTs. The effect of leptin on the membrane fluidity was significantly more pronounced in HTs than in NTs (percent change in S: leptin 10(-8) g/mL, HT -3.4% +/- 0.2%, n = 16, NT -2.3% +/- 0.1%, n = 29, P < .05; leptin 10(-7) g/mL, HT -4.3% +/- 0.3%, n = 16, NT -3.3% +/- 0.1%, n = 29, P < .05). The results of the present study showed that leptin might have a crucial role in the regulation of the rheologic behavior of erythrocytes and the microcirculation in hypertension.