Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated. HYPOTHESIS: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis. METHODS: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group I (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (> or = 50% stenosis of majorcoronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD. RESULTS: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66 +/- 0.17 microM vs. 0.44 +/- 0.09 microM, p < 0.001); these were accompanied by significantly lower plasma L-arginine/ADMA ratio in patients with significant CAD (Group 1 vs. 2: 194.0 +/- 55.3 vs. 136.7 +/- 50.3, p < 0.001). In a multivariate stepwise logistic regression analysis, both plasma ADMA level and plasma L-arginine/ADMA ratio were identified as independent predictors for CAD. Moreover, there were significant positive and negative correlations between coronary atherosclerotic score and plasma ADMA level as well as plasma L-arginine/ADMA ratio, respectively (plasma ADMA level: r = 0.518, p < 0.001; L-arginine/ADMA ratio: r = -0.430, p < 0.001). CONCLUSIONS: Both plasma ADMA level and plasma L-arginine/ADMA ratio were useful in predicting the presence of significant CAD and correlated significantly with the extent and severity of coronary atherosclerosis. Our findings suggest that plasma ADMA level may be a novel marker of CAD.     

Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack

Flow cytometric studies suggest that platelets are activated in ischaemic stroke or transient ischaemic attack (TIA). However, few studies have measured circulating leucocyte-platelet complexes in this patient population. Whole blood flow cytometry was used to quantify the expression of CD62P-, CD63-, and PAC1-binding, and the percentages of leucocyte-platelet complexes in acute (1-27 d, n = 79) and convalescent (79-725 d, n = 70) ischaemic cerebrovascular disease (CVD) patients compared with controls without CVD (n = 27). We performed a full blood count, and measured plasma levels of soluble P-selectin, soluble E-selectin, and von Willebrand factor antigen (VWF:Ag) as additional markers of platelet and/or endothelial cell activation. The median percentage CD62P expression and the median percentage monocyte-platelet complexes were higher in both acute and convalescent CVD patients than controls (P 相似文献   

Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack

The percentage of reticulated platelets (% RP) could be a useful marker of increased platelet production and/or turnover in patients with increased platelet activation, but few flow cytometric studies have measured the % RP in patients with ischaemic cerebrovascular disease (CVD). Whole blood flow cytometry using thiazole orange was performed to compare the % RP in patients in the early (1-27 d, n = 79) and late phases (79-725 d, n = 70) after ischaemic stroke or transient ischaemic attack (TIA) with controls without CVD (n = 27). The impact of aspirin dose escalation (75-300 mg/d) on the % RP was investigated in 10 patients in the late phase after stroke/TIA. The platelet count and mean platelet volume (MPV) were similar in CVD patients and controls. Compared with controls, the unadjusted % RP was not significantly higher in early or late phase CVD patients (P < or = 0.3). However, having adjusted for age, the % RP was higher in early (P = 0.047) and late phase CVD patients (P = 0.01). There was a positive correlation between % RP and MPV in EDTA- and citrate-anticoagulated blood in both early and late phase CVD patients (P< or = 0.01). The % RP was not significantly influenced by aspirin dose. These data do not convincingly support an excessive stimulus to platelet production in the early or late phases after ischaemic stroke/TIA, but are consistent with the hypothesis that reticulated platelets are larger than more mature 'non-reticulated' platelets in ischaemic CVD.     

Correlation of lymphocyte heat shock protein 70 levels with neurologic deficits in elderly patients with cerebral infarction

PURPOSE: To assess the association between heat shock protein 70 (HSP70) levels and the severity of ischemic stroke in elderly patients. METHODS: We conducted a case-control study to investigate the changes in lymphocyte HSP70 levels by immunoblot in 65 elderly patients with mild (n = 22), intermediate (n = 21), or severe (n = 22) stroke, and in 34 healthy controls. We analyzed correlations between HSP70 levels and neurologic deficit scores on days 1, 15, and 30 after the onset of stroke. RESULTS: Mean (+/- SD) HSP70 levels were higher in all stroke patients compared with controls (mild stroke: 709 +/- 194 units; intermediate: 585 +/- 165 units; severe: 421 +/- 124 units; controls: 86 +/- 34 units on day 1). Patients with mild stroke had higher levels at day 1 and 15 than did patients with severe stroke. HSP70 levels decreased rapidly from days 1 to 30 in all patients, except in patients with severe stroke, in whom levels decreased slowly between days 15 and 30. There were significant negative correlations between HSP70 levels and neurologic deficit scores in patients on days 1 (r = -0.53, P < 0.001) and 15 (r = -0.54, P < 0.001), but a positive correlation on day 30 (r = 0.49, P < 0.001). CONCLUSION: These data suggest that HSP70 may be a marker for neuroprotection in the early stage of ischemic stroke and a marker for a crisis in the later stages of severe cerebral infarction. Further studies on the use of lymphocyte HSP70 levels in predicting clinical outcomes and underlying mechanisms in cerebral infarction are warranted.     

Assessment of left ventricular function by Doppler tissue imaging in patients with atrial fibrillation following acute myocardial infarction

AIMS: We studied tissue Doppler parameters in patients with atrial fibrillation following acute myocardial infarction, and their relation to P wave durations and P dispersion. METHODS: Echocardiographic examination was performed in 84 consecutive patients with first anterior acute myocardial infarction. In addition to other conventional echocardiographic parameters, the peak systolic (Sm), early diastolic (Em) and late diastolic (Am) velocities were obtained at the lateral corner of the mitral annulus by pulsed wave tissue Doppler. The Em/Am ratio and the ratio of early diastolic mitral inflow velocity to Em (E/Em), which is a marker of diastolic filling pressure, were calculated. Electrocardiogram was recorded from all patients on admission; P wave measurements were also performed. RESULTS: Atrial fibrillation occurred in 20 (23.8%) of 84 patients. The patients with atrial fibrillation had significant reduction of Em (5.6+/-1.5 vs. 8.7+/-2.7 cm/s, p < 0.001), Em/Am (0.61+/-0.27 vs. 0.84+/-0.23, p = 0.001) and Sm (7.1+/-1.0 vs. 8.3+/-1.9 cm/s, p < 0.001) values compared with those without. The E/Em ratio (14.45+/-4.62 vs. 7.47+/-2.79, p < 0.001), P maximum (102+/-11 vs. 95+/-11 ms, p = 0.02) and P dispersion (35+/-7 vs. 26+/-7 ms, p < 0.001) were significantly higher in patients with atrial fibrillation than in those without. In all patients, P dispersion showed significant correlation with Em (r = -0.33, p = 0.002), Sm (r = -0.40, p < 0.001) and E/Em (r = 0.32, p = 0.003). When E/Em > or = 10 was used as cutpoint, atrial fibrillation could be predicted with a sensitivity of 90%, and a specificity of 84%. CONCLUSIONS: The patients with atrial fibrillation following acute myocardial infarction have reduced systolic and diastolic mitral annular velocities and increased E/Em ratio, P maximum and P dispersion values compared to those without. P dispersion is correlated with systolic and diastolic left ventricular function after acute myocardial infarction. The E/Em ratio appears to be a useful parameter for assessing the risk of atrial fibrillation occurrence after anterior acute myocardial infarction.     

A decrease in plasma factor which stimulates prostaglandin I2 synthesis in patients with acute myocardial infarction

PG I2 stimulating plasma factor was measured in patients with ischemic heart disease and age-matched controls. The plasma factor measured by bioassay using rat aorta was 3.2 +/- 0.6 (n = 21), 2.7 +/- 0.8 (n = 7), 1.6 +/- 1.5*** (n = 18) and 2.2 +/- 0.06** (n = 3) PG I2 ng/mg rat aorta (mean +/- SD; * p less than 0.05, ** p less than 0.01, *** p less than 0.001) in control, angina pectoris, acute myocardial infarction and old myocardial infarction with angina pectoris groups, respectively. The plasma factor measured by radioimmunoassay was 43.5 +/- 19.5 (n = 11), 35.4 +/- 13.1 (n = 4), 38.5 +/- 18.0 (n = 9), 26.0 +/- 20.1* (n = 7) and 59.5 +/- 31.2 (n = 5) ng/mg rat aortic protein/15 min in control, variant angina, stable angina, acute myocardial infarction and old myocardial infarction groups, respectively. The factor in deproteinized plasma of the acute myocardial infarction group was also smaller than that of the control group. PG I2 synthesis by rat aortic ring was inhibited by mepacrine, which inhibits phospholipase A2. The plasma factor was not inactivated by heating. The results indicate that a heat-stable plasma factor which acts on phospholipase A2 or on its surrounding reaction systems is deficient in the early stage of acute myocardial infarction. A decrease in the factor may cause PG I2 deficiency, resulting in coronary thrombosis or vasospasm and consequently in acute myocardial infarction.     

Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations

CONTEXT: Asymmetric dimethylarginine (ADMA) has recently emerged as an independent risk marker for cardiovascular disease, but studies investigating the ADMA levels in type 1 diabetes mellitus (DM) are scarce. OBJECTIVE: We aimed to evaluate plasma ADMA, L-arginine concentrations, and L-arginine to ADMA ratio in uncomplicated type 1 diabetic patients and controls. DESIGN AND SUBJECTS: Forty patients with type 1 DM who did not have clinical evidence of vascular complications and 35 healthy controls were included in the study. RESULTS: Plasma ADMA concentrations were higher (2.6 +/- 1.9 vs. 1.7 +/- 0.7 micromol/liter, P < 0.01), and L-arginine levels were lower (79.3 +/- 22.6 vs. 89.6 +/- 19.4 micromol/liter, P < 0.05) in the diabetic group, compared with controls. The L-arginine to ADMA ratio was also lower in the diabetic group (38.7 +/- 17.1 vs. 62.0 +/- 27.9, P < 0.0001). In diabetic patients, logADMA correlated positively with body mass index (BMI) (P = 0.01), fasting blood glucose (P = 0.006), and low-density lipoprotein cholesterol (LDL-c) (P = 0.01) and negatively with high-density lipoprotein cholesterol (P = 0.03). L-arginine to ADMA ratio correlated negatively with BMI (P = 0.004), fasting blood glucose (P = 0.02), and LDL-c (P = 0.01) and positively with high-density lipoprotein cholesterol (P = 0.04). In controls, logADMA and L-arginine to ADMA ratio correlated with BMI and LDL-c (P < 0.05). In regression analysis, BMI predicted 15% variance of ADMA levels (P = 0.02). CONCLUSIONS: We demonstrated that ADMA increases and L-arginine to ADMA ratio decreases, even before the development of vascular complications in type 1 DM.     

Effects of combined supplementation with B vitamins and antioxidants on plasma levels of asymmetric dimethylarginine (ADMA) in subjects with elevated risk for cardiovascular disease

Elevated plasma asymmetric dimethylarginine (ADMA) concentrations have been suggested as a potential risk factor for cardiovascular disease (CVD). Studies indicate a linkage between hyperhomocysteinemia, oxidative stress and ADMA metabolism. We tested the hypothesis that combined supplementation of B vitamins and antioxidants reduces ADMA concentrations in subjects with at least two CVD risk factors. A total of 123 men and women (58+/-8.1 years) were randomly assigned to take either a preparation including B vitamins and antioxidants (verum) or placebo for 6 months in a double-blind design. Blood concentrations of ADMA, symmetric dimethylarginine (SDMA), L-arginine, B vitamins, total homocysteine (tHcy), alpha-tocopherol, antioxidant capacity (TEAC), and oxLDL were measured pre- and post-intervention. Treatment with verum significantly decreased tHcy (-2.14 micromol/L; P<0.001) and significantly increased TEAC values (+39.3 microM; P<0.022), but no effect on ADMA was observed. OxLDL was significantly reduced in verum (-7.3 U/L; P=0.001) and placebo (-9.2U/L; P<0.001). At baseline, significant correlations were found only between ADMA and SDMA (r=0.281; P=0.002), L-arginine/ADMA and SDMA (r=-0.294; P<0.001), L-arginine/ADMA and oxLDL (r=-0.281; P=0.016), and L-arginine/ADMA and age (r=-0.231; P=0.010). Our results indicate that combined supplementation of B vitamins and antioxidants is not an adequate strategy to reduce ADMA plasma levels in subjects with elevated CVD risk.     

Right ventricular ejection fraction in patients with acute anterior and inferior myocardial infarction assessed by radionuclide angiography

We measured right and left ventricular ejection fracttion (EF) from high frequency time-activity curves obtained during the initial passage of an intravenous bolus of 99mTc (Sn) pyrophosphate. In 22 normal controls right ventricular EF averaged 0.52 +/- 0.04 (SD). In 24 acute anterior or lateral infarction patients right ventricular EF was normal (0.56 +/- 0.10), while left ventricular EF was reduced (0.45 +/- 0.10, P less than 0.001 vs controls). In 19 acute inferior infarction patients left ventricular EF also was depressed (0.51 +/- 0.09, P less than 0.001 vs controls). Among 7 of 19 inferior infarction patients with right ventricular by scintigraphy, right ventricular EF was reduced (0.39 +/- 0.05; P less than 0.001 vs normals; P less than 0.01 vs inferior infarction patients without right ventricular involvement). In the latter group right ventricular EF averaged 0.51 +/- 0.10 (NS vs normals). We conclude 1) a single injection of 99mTc (Sn) pyrophosphate can identify right and left ventricular dysfunction and infarct location in acute myocardial infarction, 2) right ventricular EF is well-preserved except when inferior infarction involves the right ventricle.     

Pathogenetic significance of reactive oxygen species in diffuse fibrosing alveolitis

Excessive release of reactive oxygen metabolites (ROM) from lung inflammatory cells has been claimed to be of major pathogenetic significance in diffuse fibrosing alveolitis. In the present study, the content of oxidized methionine residues [Met(O)] as a percentage of total methionine (Met) in BAL-derived proteins was used to assess the biologic effect of ROM. In addition, procollagen-III-peptide was measured in BAL fluid as a marker of fibroblast activation. We investigated bronchoalveolar lavage (BAL) samples from seven control patients without evidence of interstitial lung disease and from 42 patients with fibrosing alveolitis caused by idiopathic pulmonary fibrosis (IPF), n = 20, or by collagen vascular disease (CVD), n = 22. Met(O) was elevated in the patients with IPF or CVD compared with that in the control subjects (8.86 +/- 1.26 and 8.13 +/- 1.44% versus 3.36 +/- 0.49%, p less than 0.01 and p less than 0.05, respectively; mean +/- SEM). A positive correlation was found between percentage of neutrophils in BAL and Met(O) in both groups separately and combined (IPF, r = 0.84; p less than 0.001; CVD, r = 0.44; p less than 0.05; IPF and CVD, r = 0.60; p less than 0.001), whereas an inverse relationship existed between Met(O) and the percentage of alveolar macrophages in BAL (IPF, r = -0.59; p less than 0.01; CVD, r = -0.24; NS; IPF and CVD, r = -0.41; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

A case-control study on the prevalence of electrocardiographic rhythms and ischemic changes in elderly patients with acute cerebrovascular disease

Electrocardiographic (ECG) abnormalities have been observed in acute cerebrovascular events. This case-control study investigated the prevalence of ECG rhythms and ischemic changes in elderly stroke and medical patients. The ECG rhythms and ischemic changes of 97 elderly patients admitted with acute stroke or transient ischemic attack (TIA) were compared with those of 70 medical controls admitted during the same study period. Patients' median age was 80 years. Atrial fibrillation occurred in 26 stroke/TIA patients (27%) and 17 control patients (24%). Ischemic ECG changes occurred in 54 stroke/TIA patients (56%) and 32 control patients (46%) (odds ratio, 1.52; 95% confidence interval, 0.82-2.83; p=0.18). Seventeen stroke/TIA patients (18%) vs. 19 (27%) control patients had a history of ischemic heart disease. After adjustment for ischemic heart disease, the odds ratio for ischemic ECG changes was 1.80 (95% confidence interval, 0.93-3.45; p=0.079). Atrial fibrillation accounted for a quarter of ECG rhythms in elderly acute stroke/TIA patients and elderly medical patients. The high frequency of ischemic ECG changes found in the stroke/TIA patients was not significantly different from that in the control patients. After adjustment for ischemic heart disease, there emerged a trend of borderline significance to suggest that ischemic ECG changes were more strongly associated with elderly acute stroke/TIA patients than elderly control patients. Larger outcome study will be required to determine the significance of ischemic ECG changes following acute cerebrovascular events in older patients.     

Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.

OBJECTIVES: We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. BACKGROUND: Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. METHODS: Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. RESULTS: Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p < 0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. CONCLUSIONS: Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.     

Acute pulmonary edema complicating myocardial infarction: is colour M-mode Doppler of the mitral valve a valuable tool?

OBJECTIVE: To assess the value of colour M-mode Doppler of the mitral valve in patients with acute myocardial infarction complicated by pulmonary edema. DESIGN: Case-control, clinical. SETTING: Coronary care unit in a university hospital. PATIENTS/SUBJECTS: 28 patients admitted because of acute myocardial infarction, and who developed pulmonary edema (group P, cases); 39 patients with uncomplicated myocardial infarction (group C, controls). RESULTS: Patients in group P showed higher E wave (77+/-20 vs. 64+/-16 cm/s, p=0.007), E/A ratio (1.5+/-1.0 vs. 1.0+/-0.4, p=0.014), lower time of deceleration of the E wave (153+/-40 vs. 196+/-53 ms, p=0.001) and lower Ejection Fraction (35+/-10 vs. 49+/-11, p<0.001). There were no differences in the velocity of the colour M-mode Doppler of the mitral valve (Vp: 36.2+/-11 vs. 34.0+/-12 cm/s). Excluding patients with abnormal relaxation or restrictive pattern of the pulsed Doppler, Vp was identical (group P 34+/-10, group C 34+/-12). CONCLUSIONS: M-mode colour Doppler of the mitral valve was not useful to differentiate patients with acute pulmonary edema complicating myocardial infarction. Measurement of Vp is not warranted as a routine in these patients.     

Plasma homocysteine and inflammation in elderly patients with cardiovascular disease and dementia

Increased levels of plasma total homocysteine (tHcy) may play a role in both cardiovascular diseases (CVD) and old-age dementias via enhancement of vascular inflammation. However, the association between plasma tHcy and serum C-reactive protein (sCRP), taken as a marker of low-grade inflammation, is still uncertain. We investigated this association in normal aging, CVD, and dementia, and examined whether it was modified by the presence of two major comorbid diseases of older age: chronic obstructive pulmonary disease (CPOD) and peptic ulcer (PU). Six hundred-twenty-seven individuals aged > or = 65 yr (74+/-7 yr) were selected for this study: 373 healthy controls; 160 patients with CVD but no evidence of comorbid diseases (CVD+/comorbidity-); 46 patients with CVD and concurrent CPOD and/or PU (CVD+/comorbidity+); and 48 patients with dementia. A positive association between plasma tHcy and serum CRP, independent of several confounders (socio-demographic status, known tHcy and sCRP determinants, inflammation markers, traditional vascular risk factors), was found for CVD+/comorbidity+ (p=0.001; not affected by dementia type) and dementia (p=0.001; not affected by dementia type), but not for CVD+/comorbidity- and controls. The results suggest that the association between plasma tHcy and sCRP is more an aspecific reflection of poor health than a specific correlate of vascular inflammation.     

There is evidence that amniotic fluid arginine vasopressin is a marker for foetal stress in rhesus erythroblastosis

In response to different stress stimuli the foetal neurohypophysis releases arginine vasopressin (AVP). Part of the AVP is cleared from circulation by urinary excretion into the amniotic fluid (AF). Increased AF AVP levels may therefore indicate foetal stress, all the more because AF AVP solely is of foetal origin. We therefore studied AF AVP levels in 13 patients with rhesus erythroblastosis from 22 to 34 weeks of gestation. Twenty-eight patients from 14 to 34 weeks of gestation served as controls. The AVP levels were measured by RIA. Spectral absorption curves were performed and delta/E values determined at 450 nm. Mean AF AVP levels in controls were 2.39 pg/ml and were not normally distributed. There was no significant change in AF AVP levels with different gestational age. If in rhesus erythroblastosis patients the delta/E value was low (n = 7; x = 0.048 +/- 0.007 SE), the AF AVP values were not increased. If the delta/E values were within zone III (n = 6; x = 0.22 +/- 0.035 SE), indicating severe haemolysis, the AF AVP levels were significantly elevated (4.7 pg/ml +/- 0.51 SE; P = 0.001). Linear regression analysis showed a significant correlation between delta/E and AF AVP values (P = 0.05; y = 1.94 +/- 10.88 x). We conclude that there is evidence for the role of AF AVP as a marker for foetal stress in rhesus erythroblastosis.     

Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction

To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rats with infarction (n = 16) had markedly elevated plasma immunoreactive atrial natriuretic peptide concentrations (1205.8 +/- 180.9 vs. 126.7 +/- 8.9 pg/ml, p less than 0.001) and reduced immunoreactive atrial natriuretic peptide concentrations in right and left atria (31.4 +/- 4.6 vs. 61.2 +/- 3.2 ng/mg, p less than 0.001; 14.9 +/- 2.2 vs. 32.7 +/- 2.4 ng/mg, p less than 0.001, respectively). Right ventricular weight increased in proportion to infarct size, and both were correlated with plasma immunoreactive atrial natriuretic peptide levels (r = 0.825, p less than 0.001 and r = 0.816, p less than 0.001, respectively). Right atrial immunoreactive atrial natriuretic peptide content was significantly higher than left in both controls and rats with infarction. Both right and left atrial immunoreactive atrial natriuretic peptide concentrations were negatively correlated with both right ventricular weight as well as plasma immunoreactive atrial natriuretic peptide concentrations (right atrium: r = -0.816, p less than 0.001, r = -0.708, p less than 0.01; left atrium: r = -0.687, p less than 0.01, r = -0.644, p less than 0.01, respectively). These results suggest that chronic stimulation of atrial natriuretic peptide release from both atria is associated with increased turnover and depleted stores of atrial natriuretic peptide in atria in proportion to the severity of heart failure. It also suggests that plasma atrial natriuretic peptide levels may be used as a reliable index of cardiac decompensation in chronic heart failure.     

Five-year incidence of cardiovascular disease and its predictors in Greece: the ATTICA study

The 5-year incidence of cardiovascular disease (CVD) and its determinants, in a sample of men and women from Greece, was evaluated. From May 2001 to December 2002, 1514 men and 1528 women (>18 years old) without any clinical evidence of CVD, living in the Attica area, Greece, were enrolled in the ATTICA study. In 2006, a group of experts performed the 5-year follow-up (941 of the 3042 (31%) participants were lost to follow-up). Development of CVD (coronary heart disease, acute coronary syndromes, stroke, or other CVD) during the follow-up period was defined according to WHO-ICD-10 criteria. The 5-year incidence of CVD was 11.0% in men and 6.1% in women (p<0.001); the case fatality rate was 1.6%. Multi-adjusted logistic regression analysis revealed that increased age (odds ratio per year=1.09, p=0.04), waist-to-hip ratio (odds ratio=5.07, p=0.02), hypertension (odds ratio=4.53, p=0.001), diabetes (odds ratio=4.53, p=0.001) and C-reactive protein levels (odds ratio per 1 mg/dl=1.31, p=0.02) were the most significant baseline bio-clinical predictors of CVD. Furthermore, an increased education level and greater adherence to the Mediterranean diet (among 35-65-year-old individuals) were associated with a lower CVD incidence (odds ratio per 3 years of school difference=0.83, p<0.001 and odds ratio per 1/55 units in diet score=0.94, p<0.001), irrespective of various potential confounders. In conclusion, aging, central fat, hypertension and diabetes, inflammation process, low social status and abstinence from a Mediterranean diet seem to predict CVD events within a 5-year period.     

The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes mediation by superoxide production, resolution with intensive insulin administration.

OBJECTIVES: This study sought to assess the determinants of platelet nitric oxide (NO) responsiveness in diabetic patients admitted with acute coronary syndromes (ACS) and the short-term effects of aggressive glycemic control on these factors. BACKGROUND: Hyperglycemia is an independent risk factor for mortality in both diabetic patients and nondiabetic patients with ACS. The mechanism(s) underlying this observation and potential benefit from its correction remain uncertain. Although a reduction in NO bioavailability has been proposed, this remains untested in the ACS setting. METHODS: A total of 76 diabetic patients with ACS were studied. Putative correlations between admission blood sugar level (BSL), inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP), and superoxide (O2-) were assessed. Hyperglycemic patients (n = 60) were randomized to acute glycemic control with intravenous versus subcutaneous insulin, and changes in the aforementioned parameters were compared. Plasma levels of the endogenous inhibitor of NO synthase asymmetric dimethylarginine (ADMA) were also monitored. RESULTS: There was an inverse correlation between admission BSL and both platelet SNP response (p = 0.007) and ADMA levels (p = 0.045), and a positive correlation with O2- generation (p < 0.001). Intravenous insulin infusion resulted in a greater reduction (p < 0.001) in BSL, differentially improved platelet responsiveness to SNP (p = 0.049), and decreased O2- (p < 0.001) and ADMA levels (p = 0.049). CONCLUSIONS: A component of platelet dysfunction in diabetic patients with ACS is impaired responsiveness to the anti-aggregatory effects of NO, probably reflecting increased NO clearance by O2-. This phenomenon is reversed by acute aggressive glycemic control. These findings provide a further rationale for use of insulin therapy in acute myocardial infarction and suggest its extension to ACS patients.     

The A-1087IL-10 allele is associated with cardiovascular disease in SLE

The risk of cardiovascular disease (CVD) in SLE patients is very high. It is therefore surprising that IL-10 has been discussed both as pathogenic in SLE and as an atheroprotective cytokine. In contrast, TNF is believed to be atherogenic and we recently reported that raised activity in the TNF-system is implicated in SLE-related CVD. Twenty-six (aged 52 +/- 8 years) female patients with SLE and a history of CVD (myocardial infarction, angina, stroke or claudication) were compared with 26 age-matched SLE patients without CVD (SLE controls) or 26 age-matched population controls. The -1087IL-10 gene polymorphism was determined by PCR with restriction endonuclease mapping. Serum IL-10 and TNF-levels were determined by ELISA. The A allele frequency of -1087IL-10 gene in SLE/CVD was higher than in SLE controls (0.62 versus 0.42, p < 0.05). Ten (38%) of 26 SLE/CVD exhibited IL-10 AA genotype compared with five (19%) of 26 SLE controls. Serum IL-10 and TNF-levels were raised in SLE/CVD compared with SLE controls or population controls (p < 0.001). Furthermore, in SLE/CVD, a significantly reduced IL-10:TNF ratio was observed in patients with IL-10 AA genotype compared with AG or GG genotype (0.56 versus 0.77 versus 1.24, p < 0.05). In SLE controls and population controls, individuals with IL-10 GG genotype tended to have higher IL-10:TNF ratio. In conclusion, the A-1087IL-10 allele which has been reported to cause a lower capacity for IL-10 production could contribute to CVD in SLE. Furthermore, the IL-10 AA genotype is associated with reduced ratio of atheroprotective to atherogenic cytokines in SLE patients with CVD.     

Early, intracoronary growth hormone administration attenuates ventricular remodeling in a porcine model of myocardial infarction.

OBJECTIVE: Ventricular remodeling is a common corollary of myocardial infarction. We hypothesized that this process may be attenuated by growth hormone, administered as a single high-dose, selectively in the infarct zone, early postmyocardial infarction. DESIGN: In 35 pigs (29+/-4 kg), myocardial infarction was generated by inflation of an over-the-wire angioplasty balloon in the circumflex artery for 60 min and 5 further pigs were sham-operated. Ten minutes after reperfusion, the pigs were randomized (2:1) to either growth hormone (1 IU/kg) (n=23) or normal saline (n=12), delivered via the balloon catheter. All survivors were treated with captopril and were sacrificed 4 weeks after myocardial infarction. RESULTS: Compared to controls, growth hormone-treated animals displayed lower heart weight (4.1+/-0.5 g/kg body weight, versus 3.4+/-0.4 g/kg, respectively, p=0.003) and dimensions (left ventricular short axis diameter 46+/-7 mm versus 37+/-6 mm, p=0.01; right ventricular short axis diameter 38+/-7 mm versus 30+/-5 mm p=0.001). Growth hormone increased wall thickness in the infarct (6.0+/-1.8 in controls versus 9.9+/-3.7 in treated animals, p=0.004) and non-infarct zones (10.6+/-1.8 in controls versus 15.5+/-3.8 in treated animals, p=0.0006) and produced higher (p<0.05) microvascular density in both zones. CONCLUSION: Intracoronary administration of growth hormone attenuates left and right ventricular remodeling by inducing hypertrophy and by enhancing angiogenesis.