Cardiovascular risk in subjects with left ventricular concentric remodeling at baseline examination: a meta-analysis.

It is debated whether subjects with concentric remodeling (CR, normal left ventricular mass index (LVMI) and increased relative wall thickness (RWT)) are at higher cardiovascular risk than those with normal geometry (NG, normal LVMI and RWT). The aim of this study was to perform a meta-analysis of studies evaluating cardiovascular events in subjects with CR and NG according to baseline classification. We searched for articles evaluating cardiovascular outcome in subjects with CR compared with those with NG, and reporting adjusted hazard ratio (HR) and 95% confidence interval (CI). Six studies were included in the meta-analysis. The pooled population consisted of 7465 subjects with CR and NG. During the follow-up, they experienced 852 events. When compared with NG, the overall adjusted HR was 1.36 (95% CI 1.03-1.78) for CR, P<0.03. There was some heterogeneity between studies. Subgroup meta-analysis showed that increased cardiovascular risk in subjects with CR was more relevant in studies evaluating hypertensive and Caucasian subjects and reporting both fatal and non-fatal events. Cardiovascular risk is significantly higher in subjects with CR than in those with NG. This aspect is more evident in studies including hypertensive patients and Caucasian populations and reporting global cardiovascular risk.

Short- and long-term risk of cardiovascular events in white-coat hypertension.

The prognostic impact of white-coat hypertension is not yet completely clear. In this study, we investigated cardiovascular outcome in sustained hypertension, white-coat hypertension and normotension in the short and long term. The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1732 subjects with clinical hypertension (1333 with sustained and 399 with white-coat hypertension) and 305 with normotension. White-coat hypertension was defined as clinical hypertension and daytime blood pressure <135/85 mm Hg. During the period of observation (mean 6.4 years, range 0.7-13.1), 152 cardiovascular events occurred. The event rate per 100 patient-years in subjects with normotension, white-coat and sustained hypertension was 0.38, 0.44 and 1.58, respectively. Event-free survival was significantly different among the groups (P<0.0001). After adjustment for several covariates, Cox regression analysis showed that cardiovascular risk was significantly higher in patients with sustained than in those with white-coat hypertension (relative risk (RR) 3.32, 95% confidence interval (CI) 1.81-6.12, P=0.0001), whereas there was no significant difference between normotension and white-coat hypertension. When events were analysed separately, cardiac and cerebrovascular risk were significantly higher in sustained than in white-coat hypertension (RR 4.16, 95% CI 1.48-11.6, P=0.007, and RR 4.12, 95% CI 1.62-10.5, P=0.003, respectively) and not significantly different between white-coat hypertension and normotension. Event-free survival had the same trend for the whole period of observation both when cardiovascular events were examined together and when cardiac and cerebrovascular events were analysed separately. In this study, cardiovascular risk in white-coat hypertension was significantly lower than that in sustained hypertension and not significantly different from normotension both in the short and long term.

Eosinophilic esophagitis is a component of the anticonvulsant hypersensitivity syndrome: description of two cases.

Anticonvulsant hypersensitivity syndrome is a rare syndrome caused by a specific, severe unusual reaction to antiepileptic agents; anticonvulsant hypersensitivity syndrome develops 1 week to 3 months after the introduction of the drug and most frequently consists of a multisystemic and multiorgan involvement. Drug withdrawal usually leads to rapid improvement of symptoms. Up to now no oesophageal damage has been described. We present two cases of carbamazepine hypersensitivity syndrome with concomitant development of eosinophilic oesophagitis that resolved after drug withdrawal.

Circulating homocysteine levels in sustained and white coat hypertension.

Although white coat hypertension has been widely studied in the last years, its risk profile is not yet completely clear. The aim of this study was to evaluate circulating homocysteine levels, an emerging cardiovascular risk factor, in subjects with white coat and sustained hypertension. We selected 31 sustained hypertensive subjects, 31 white coat hypertensive subjects and 31 normotensive subjects matched for age, gender, body mass index and occupation. Women were also matched for menopausal status. Subjects with smoking habit, dyslipidaemia and diabetes mellitus were excluded from the study. White coat hypertension was defined as clinical hypertension and daytime ambulatory blood pressure <135/85 mmHg. Blood samples were drawn after a fasting period of 12 h for routine laboratory tests and homocysteine determination. Homocysteine levels were evaluated by fluorescence polarization immunoassay. Creatinine, glucose, cholesterol and triglycerides were not different among the groups. White coat hypertensive subjects had significantly lower homocysteine levels than sustained hypertensive patients (8.2+/-2.0 vs 12.6+/-3.9 micromol/l, P=0.0003). No significant difference was observed between white coat hypertensive and normotensive subjects regarding this parameter (8.2+/-2.0 vs 7.6+/-1.9 micromol/l, P=0.9). In conclusion, our data show that middle-aged white coat hypertensive subjects without other cardiovascular risk factors have lower circulating homocysteine levels than sustained hypertensive patients suggesting that they are at lower cardiovascular risk.

Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma.

The thiobarbituric acid (TBA) reactivity of human plasma was studied to evaluate its adequacy in quantifying lipid peroxidation as an index of systemic oxidative stress. Two spectrophotometric TBA tests based on the use of either phosphoric acid (pH 2.0, method A) or trichloroacetic plus hydrochloric acid (pH 0.9, method B) were employed with and without sodium sulfate (SS) to inhibit sialic acid (SA) reactivity with TBA. To correct for background absorption, the absorbance values at 572 nm were subtracted from those at 532 nm, which represent the absorption maximum of the TBA:MDA adduct. Method B gave values of TBA-reactive substances (TBARS) 2-fold higher than those detected with method A. SS lowered TBARS by about 50% with both methods, indicating a significant involvement of SA in plasma TBA reactivity. Standard SA, at a physiologically relevant concentration of 1.5 mM, reacted with TBA, creating interference problems, which were substantially eliminated by SS plus correction for background absorbance. When method B was carried out in the lipid and protein fraction of plasma, SS inhibited by 65% TBARS formation only in the latter. Protein TBARS may be largely ascribed to SA-containing glycoproteins and, to a minor extent, protein-bound MDA. Indeed, EDTA did not affect protein TBARS assessed in the presence of SS. TBA reactivity of whole plasma and of its lipid fraction was instead inhibited by EDTA, suggesting that lipoperoxides (and possibly monofunctional lipoperoxidation aldehydes) are involved as MDA precursors in the TBA test. Pretreatment of plasma with KI, a specific reductant of hydroperoxides, decreased TBARS by about 27%. Moreover, aspirin administration to humans to inhibit prostaglandin endoperoxide generation reduced plasma TBARS by 40%. In conclusion, reaction conditions affect the relationship between TBA reactivity and lipid peroxidation in human plasma. After correction for the interfering effects of SA in the TBA test, 40% of plasma TBARS appears related to in vivo generated prostaglandin endoperoxides and only about 60% to lipoperoxidation products. Thus, the TBA test is not totally specific to oxidant-driven lipid peroxidation in human plasma.

Antioxidant activity of amiodarone on human lipoprotein oxidation.

Lipoprotein oxidation is crucial in atherogenic processes. Amiodarone is a lipophilic antiarrhythmic/antianginal drug which is able to influence the physicochemical status of biological lipid components. Since oxidation of lipids is affected by their physicochemical state and amiodarone binds to lipoproteins, we hypothesized that the drug may exert an antioxidant activity on human lipoprotein oxidation. Dose-dependent effects of therapeutically achievable amiodarone concentrations (1.5, 3, 5, 7 and 10 microM) were studied on copper-catalysed oxidation of the non-HDL fraction in vitro. Amiodarone inhibited oxidation as judged by generation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and fluorescent products of lipoperoxidation (FPL) as well as from the kinetics of conjugated diene formation. This antioxidant activity was significant at 1.5 microM with total inhibition at 10 microM and an IC(50) of 4 microM. The primary in vivo metabolite of amiodarone, namely desethylamiodarone, also exhibited specific antioxidant properties although it was less effective than amiodarone with an IC(50) of 7 microM. In further in vivo experiments, susceptibility to copper-mediated oxidation of the non-HDL fraction was investigated before and 4 weeks after oral amiodarone administration to humans. Following treatment, significant inhibition of TBARS, LOOH and FPL generation was observed in comparison with baseline levels and a placebo-treated control group, highlighting an effective antioxidant capacity of amiodarone in vivo. Amiodarone did not change lipoprotein vitamin E and phospholipid content in vivo and did not show scavenging effects on oxidizing species involved in lipoprotein oxidation, such as peroxyl radicals, nor metal-binding/inactivating properties, suggesting that physicochemical modifications of lipoprotein lipids induced by the lipophilic drug may be involved in its antioxidant activity. In conclusion, amiodarone, and its primary metabolite desethylamiodarone, show previously unrecognized antioxidant activity on human lipoprotein oxidation. This effect is also evident in vivo and at therapeutically achievable drug concentrations. Thus, amiodarone may act as an antioxidant/antiatherosclerotic agent in humans, although this issue warrants further clinical study.

Vitamin E and lipid peroxide plasma levels predict the risk of cardiovascular events in a group of healthy very old people.

OBJECTIVES: To assess whether systemic oxidative stress can predict the risk of first myocardial infarction, ischemic stroke, and congestive heart failure. DESIGN: A longitudinal study started in 1992 and completed in 1997. SETTING: Community-based, outpatient. PARTICIPANTS: 102 apparently healthy, community-dwelling subjects age 80 and older from the Vibrata valley, Teramo, Italy. MEASUREMENTS: Plasma vitamin E, beta-carotene, vitamin C, fluorescent products of lipid peroxidation (FPLPs), and serum lipids were determined at enrollment. RESULTS: Thirty-two cardiovascular events were recorded in 47.4 months of follow-up. The subjects with vitamin E levels in the highest quartile had a risk of cardiovascular events one-sixth those with vitamin E levels in the lowest quartile (relative risk (RR) = 0.16; 95% confidence interval (CI) = 0.04-0.55). The subjects with FPLPs in the highest quartile had a risk seven times greater than those with FPLPs in the lowest quartile (RR = 7.61; 95% CI = 2.23-25.96). No association was observed for vitamin C, beta-carotene, or total cholesterol. Multivariate adjustment for known risk factors did not significantly change the results. CONCLUSIONS: Our results suggest that in apparently healthy, community-dwelling very old subjects, base-line plasma concentration of vitamin E and FPLPs predicts the risk of future cardiovascular events. We confirm previous data showing that total cholesterol is not a predictor of cardiovascular disease in people age 80 and older.

High vitamin E plasma levels and low low-density lipoprotein oxidation are associated with the absence of atherosclerosis in octogenarians.

OBJECTIVES: To identify the biological characteristics of older subjects with vascular successful aging (VASA), defined as the absence of instrumental signs and clinical symptoms of atherosclerosis in the extracoronary and coronary vessels. DESIGN: A cross-sectional study. SETTING: A university-affiliated outpatient clinic. PARTICIPANTS: Sixty older subjects (30 with VASA and 30 controls with moderate carotid atherosclerosis (AG group)) from a sample of 705 subjects age 75 and older consecutively screened. MEASUREMENTS: Clinical examination; ultrasonographic examination of carotid, vertebral, abdominal aortic, iliac, and femoral arteries; electrocardiogram; and laboratory evaluation (lipid profile, lipophilic antioxidants, and markers of low-density lipoprotein (LDL) oxidation). RESULTS: Compared with controls, there were more females in the VASA group (82% vs 50%, P <.01), and fewer previous smokers (20.5% vs 52.5%, P <.01). Vitamin E/total cholesterol levels both in plasma (4.81 vs 3.51 micromol/mmol, P <.001) and in isolated LDLs (2.71 vs 1.86 microg/mg LDL cholesterol (LDL-C), P <.01), were higher in the VASA group, as was the resistance of LDLs to in vitro oxidation (as indicated by a longer duration of the lag phase: 80.2 vs 65.6 minutes, P <.001). The level of fluorescent products of lipid peroxidation (FPLPs) in native LDLs was lower in the VASA group (13.5 vs 18.8 URF/mg LDL-C, P <.001). Multivariate logistic regression analysis showed that only plasma vitamin E level (odds ratio (OR) = 6.04, 95% confidence interval (CI) = 1.48-24.63) and FPLPs in LDLs (OR = 0.53, 95% CI = 0.31-0.91) were independently associated with VASA. CONCLUSIONS: These results suggest that an appropriate level of vitamin E and a low level of LDL oxidation might be important for reaching advanced age without developing atherosclerosis.

Endogenous ouabain and hemodynamic and left ventricular geometric patterns in essential hypertension.

We sought to evaluate the relationships among circulating levels of an endogenous ouabain-like factor (EO) and systemic hemodynamics and left ventricular (LV) geometry in patients with recently diagnosed essential hypertension. We selected 92 never-treated patients with essential hypertension. Blood samples were drawn for estimation of plasma EO (radioimmunoassay) and subjects underwent echocardiographic examination to evaluate LV end-systolic and end-diastolic wall thickness and internal dimensions. LV volumes, stroke volume, cardiac output, total peripheral resistance, LV mass, and relative wall thickness were calculated, and all except the last parameter were indexed by body surface area. LV mass also was indexed by height. On the basis of the values of LV mass index (body surface area or height) and relative wall thickness, subjects were divided into groups with either normal geometry, concentric remodeling, concentric hypertrophy, or eccentric nondilated hypertrophy. In the study population as a whole, circulating EO levels were significantly and directly correlated with mean blood pressure (r = 0.21, P = .048), relative wall thickness (r = 0.34, P = .001), and total peripheral resistance index (r = 0.37, P = .0003). Plasma EO also was significantly and inversely correlated with LV end-diastolic volume index (r = -0.32, P = .002), stroke index (r = -0.34, P = .0009), and cardiac index (r = -0.35, P = .0007). In multiple regression analysis, plasma EO was an independent correlate of total peripheral resistance index, cardiac index, and relative wall thickness. Regardless of the indexation method used for LV mass, plasma EO was higher in patients with concentric remodeling than in those with either normal geometry or concentric hypertrophy. Plasma EO tended to be higher (indexation by body surface area) or was significantly higher (indexation by height) in subjects with concentric remodeling than in those with eccentric nondilated hypertrophy. Patients with concentric remodeling showed the highest total peripheral resistance index and the lowest cardiac index. Our data suggest that EO plays a role in regulating systemic hemodynamics and LV geometry in patients with essential hypertension.

Clinic and ambulatory heart rate in sustained and white-coat hypertension.

BACKGROUND: Sustained and white-coat hypertensives show hypertension in the office setting but different blood pressure values outside the clinical environment. So far, only a few incomplete data on heart rate are available inside and outside the clinical setting in these groups of patient. The aim of this study was to evaluate clinic and ambulatory heart in sustained hypertensives, white-coat hypertensives and normotensives. METHODS: We selected 236 sustained hypertensives, 236 white-coat hypertensives and 236 normotensives matched for age, gender and body mass index, and with a similar occupation. The subjects had been submitted to clinic evaluation and the non-invasive monitoring of blood pressure and heart rate. White-coat hypertension was defined as clinic hypertension and a daytime blood pressure of less than 135/85 mmHg. RESULTS: The clinic heart rate was significantly higher in sustained hypertensives and white-coat hypertensives than in normotensives (76 +/- 11 versus 75.5 +/- 10 versus 70 +/- 9 beats/min [bpm], respectively, P < 0.05). The daytime heart rate was significantly higher in sustained hypertensives than in white-coat hypertensives and normotensives (79.4 +/- 10 versus 74.6 +/- 8.5 versus 74.5 +/- 8.5 bpm, respectively, P < 0.05), as were the night-time heart rate (67 +/- 8.5 versus 63 +/- 8 versus 63 +/- 8 bpm, respectively, P < 0.05) and 24 h heart rate (76.3 +/- 9 versus 72 +/- 7.8 versus 72 +/- 8 bpm, respectively, P < 0.05). When men and women were analyzed separately, the same trend was observed. CONCLUSIONS: The clinic heart rate is similar in sustained and white-coat hypertensives, but the ambulatory heart rate is lower in white-coat hypertensives. As ambulatory heart rate is more representative of 24 h heart rate load and may be a better indicator of the detrimental effect of heart rate, our findings suggest that white-coat hypertensives are at lower cardiovascular risk than sustained hypertensives.

Twenty-four-hour autonomic nervous function in sustained and "white coat" hypertension.

BACKGROUND: It is unknown whether "white coat" hypertension, also known as isolated clinic hypertension, shares similarities in pathophysiologic background with sustained hypertension. Therefore we evaluated 24-hour autonomic nervous function in sustained and white coat hypertension. METHODS: We selected 12 patients with sustained hypertension (clinic blood pressure >/=140/90 mm Hg and daytime blood pressure >135/85 mm Hg) and 12 patients with white coat hypertension (clinic blood pressure >/=140/90 mm Hg and daytime blood pressure <135/85 mm Hg) from patients undergoing ambulatory blood pressure monitoring and 12 normotensives for study inclusion. Groups were matched for age, sex, and body mass index and had similar dietary pattern and occupational status (civil servants with sedentary jobs). Subjects underwent noninvasive 24-hour monitoring of blood pressure, R-R interval of the electrocardiogram, body position, activity rate, and ambient temperature. Power spectral analysis of R-R intervals was performed with an autoregressive model to obtain the low-frequency component, the high-frequency component, and their ratio. Subjects also collected 24-hour urine samples for examination of norepinephrine and epinephrine excretion by high-performance liquid chromatography. RESULTS: Work and sleep time, body position, ambient temperature, and activity were not different among the groups. Daytime, nighttime, and 24-hour low-frequency/high-frequency ratios were significantly higher in patients with sustained hypertension than in patients with white coat hypertension (3.4 +/- 0.45 vs 2.65 +/- 0.45, 2.35 +/- 0.60 vs 1. 82 +/- 0.45, and 3.04 +/- 0.45 vs 2.4 +/- 0.35, respectively, P <. 05). Urinary norepinephrine excretion (53 +/- 12 microg vs 29.5 +/- 6 microg; P <.05) and vanillylmandelic acid excretion (4.45 +/- 0.6 mg vs 3.1 +/- 0.55 mg; P <.05) during the 24 hours were significantly higher in patients with sustained hypertension than in those with white coat hypertension. There was no difference between those with white coat hypertension and normotensives concerning the aforementioned parameters. CONCLUSIONS: Our findings indicate whole-day sympathetic overactivity in sustained hypertension but not in white coat hypertension, suggesting that these conditions show some differences in pathophysiologic background.

Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration.

Hyperglycemia has been causally linked to vascular and glomerular dysfunction by a variety of biochemical mechanisms, including a glucose-dependent abnormality in nitric oxide (NO) production and action. NO is a candidate for mediating hyperfiltration and the increased vascular permeability induced by diabetes. Serum nitrite and nitrate (NO2-+ NO3-) concentrations were assessed as an index of NO production in 30 adolescents and young adults with type 1 diabetes, 15 with and 15 without microalbuminuria (albumin excretion rate [AER] between 20 and 200 microg/min), compared with a well-balanced group of healthy control subjects. In all subjects, glomerular filtration rate (GFR) was determined by radionuclide imaging. Our study showed that NO2- + NO3- serum content and GFR values were significantly higher in microalbuminuric diabetic patients than in the other 2 groups. GFR was significantly and positively related to AER levels (r2 = 0.75, P < 0.0001), whereas NO2- + NO3- serum content was independently associated with both AER and GFR values (beta = 2.086, P = 0.05, beta = 1.273, P = 0.0085, respectively), suggesting a strong link between circulating NO, glomerular hyperfiltration, and microalbuminuria in young type 1 diabetic patients with early nephropathy. Interestingly, mean HbA1c, serum concentration was significantly higher in microalbuminuric than in normoalbuminuric diabetic subjects (P < 0.05) and was independently associated with AER values, suggesting a role for chronic hyperglycemia in the genesis of diabetic nephropathy. Moreover, HbA1c serum concentration was significantly and positively related to NO2 + NO3 serum content (r2 = 0.45, P = 0.0063) and GFR values (r2 = 0.57, P = 0.0011), suggesting that chronic hyperglycemia may act through a mechanism that involves increased NO generation and/or action. In conclusion, we suggest that in young type 1 diabetic patients with early nephropathy, chronic hyperglycemia is associated with an increased NO biosynthesis and action that contributes to generating glomerular hyperfiltration and persistent microalbuminuria.

Increased systemic oxidative stress after elective endarterectomy: relation to vascular healing and remodeling.

It has been reported that systemic and local redox state may have an important role in the functional and organic changes characterizing the process of vascular response to injury. Carotid endarterectomy to remove atherosclerotic plaque is followed by a long lasting healing and remodeling process that can be carefully followed over time with noninvasive ultrasonography. Plasma vitamin C concentration and native LDL (n-LDL) content in lipid peroxides, vitamin E, beta-carotene, and lycopene as well as LDL susceptibility to peroxidation were assessed in 45 patients undergoing elective endarterectomy for internal carotid stenosis, at baseline, 24 hours, 3 and 15 days, and 1 month after surgery. Serial duplex scans were performed in all patients postoperatively and 3, 6, and 12 months. The changes in far wall thickness (FW) and % renarrowing from postoperatively to 12 months were used as remodeling indices. Plasma antioxidant vitamins and lag-phase showed a sharp and significant decrease during the first 24-hours after surgery remaining unchanged until the third day, whereas, an opposite trend was evidenced for n-LDL content in lipid peroxides and serum ceruloplasmin. After the third day all the parameters returned progressively to baseline within one month from endarterectomy. Interestingly, the n-LDL lipid peroxide content, the serum ceruloplasmin and the plasma vitamin C concentration, measured at 24 and 3 days from surgery, were significantly associated to the change in % renarrowing from postoperatively to 12 months. The higher the LDL content in lipid peroxides, the higher the serum level of ceruloplasmin, the lower the plasma content in vitamin C and the higher the % of vessel renarrowing. In conclusion, carotid endarterectomy with atherosclerotic plaque removal is associated with an acute and prolonged increase in systemic oxidative stress that influences vascular healing and late luminal loss.

Blunted nocturnal fall in blood pressure and oxidative stress in men and women with essential hypertension.

Low-density lipoprotein oxidation and antioxidant vitamins E and C were investigated in dipper (nocturnal blood pressure fall > 10%) and nondipper (nocturnal blood pressure fall < 10%) hypertensives. We studied 40 dippers and 28 nondippers balanced for gender, age, and body mass index. Blood samples were drawn for lipid profile determination, assessment of thiobarbituric acid-reactive substances, and fluorescent products of lipid peroxidation in native low-density lipoprotein, evaluation of susceptibility to low-density lipoprotein oxidation in vitro (lag phase and propagation rate), and determination of low-density lipoprotein vitamin E and plasma vitamins E and C contents. Compared with dippers, nondippers had significantly higher thiobarbituric acid-reactive substances and fluorescent products of lipid peroxidation (0.63 +/- 0.1 v 0.77 +/- 0.08 nmol malondialdehyde/mg low-density lipoprotein protein, and 14.5 +/- 6 v 17.9 +/- 4 units of relative fluorescence/mg low-density lipoprotein protein, respectively, both P < .05), shorter lag phase (56 +/- 13 v 49 +/- 9 min, P < .05), and lower plasma vitamin C content (42 +/- 9 v 35 +/- 10 micromol/L, P < .05). When gender was taken into account, differences were not significant between dipper and nondipper men, whereas, compared with dipper women, nondipper women showed significantly higher thiobarbituric acid-reactive substances and fluorescent products of lipid peroxidation (0.56 +/- 0.1 v 0.77 +/- 0.07 nmol malondialdehyde/mg low-density lipoprotein protein, and 12.5 +/- 4 v 17.5 +/- 4.6 units of relative fluorescence/mg low-density lipoprotein protein, respectively, both P < .05), shorter lag phase (62.5 +/- 11 v 49 +/- 9.5 min, P < .05), and lower plasma vitamin C content (44.9 +/- 10 v 34.7 +/- 10.8 micromol/L, P < .05). Given the role of low-density lipoprotein oxidation in the pathogenesis of atherosclerosis and that of vitamin C in protecting against it, our data suggest that nondippers, especially among women, show higher atherogenic risk than dippers.

Haemostatic abnormalities, cardiac involvement and serum tumor necrosis factor levels in X-linked dystrophic patients.

Left ventricular thrombosis and systemic emboli have been demonstrated to complicate cardiomyopathy in Duchenne and Becker muscular dystrophy (DMD, BMD). We investigated plasma levels of prothrombin fragment 1+2 (F1+2). thrombin-antithrombin III complex (TAT) and circulating levels of tumor necrosis factor-alpha (TNF-alpha), a procoagulant cytokine that has been shown to be elevated in patients with depressed cardiac function, in 20 patients with DMD and 12 patients with BMD as compared with 30 age-matched control subjects. Significantly elevated levels of F1+2 (DMD: 1.4+/-0.8 nmol/l; BMD: 1.8+/-0.8 nmol/l vs. controls: 0.7+/-0.2 nmol/l, p <0.01 and p <0.001, respectively), TAT complexes (DMD: 4.7+/-2.7 microg/l, BMD: 5+/-2.3 microg/l vs. controls: 1.6+/-0.5 microg/l, p <0.001) and TNF-alpha (54+/-9 vs. 25+/-7 pg/ml, p <0.001) were observed in patients with the dystrophic disease compared to control subjects. A significantly negative correlation was also found between F1+2 and TAT complexes and left ventricular ejection fraction (r = -0.65, p <0.0001; r = -0.80, p < 0.0001, respectively) and a positive correlation between F1+2 and TAT complexes and serum TNF-alpha levels (r = 0.67, p <0.0001; r = 0.70, p <0.0001, respectively). Our results indicate a hypercoagulable state in X-linked dystrophic patients. A possible relationship between haemostatic activation, left ventricular dysfunction and TNF-alpha system upregulation may be suggested.

Vascular non-protein thiols: prooxidants or antioxidants in atherogenesis?

Abstract-cell-mediated lipoprotein oxidation may be due to generation of non-protein thiols (NP-SH) from cystine with formation of oxidizing species. However, NP-SH, especially GSH, may also exert antioxidant effects in vitro and in vivo. To further investigate whether vascular NP-SH could be prooxidants or antioxidants in atherosclerosis, we have correlated the aortic content of NP-SH with that of lipoperoxides in 10 rabbits fed on a fat-enriched atherogenic diet for 9 weeks. As compared to 7 control rabbits, aortic NP-SH and lipoperoxides were significantly increased in the fat-fed animals. The levels of NP-SH were strongly and inversely correlated with those of lipid peroxidation in the atherosclerotic aorta (r(s) -0.92, P < 0.0001 for thiobarbituric acid reactive substances, and r(s) -0.80, P < 0.01 for fluorescent damage products of lipid peroxidation). A similar trend was evident also in the control rabbits (r(s) -0.60 for both indices of lipid peroxidation). Thus, the present data suggest that vascular NP-SH exert significant antioxidant-antilipoperoxidative effects in vivo especially in fat diet-related atherogenic conditions.

Copper/zinc ratio and systemic oxidant load: effect of aging and aging-related degenerative diseases.

There is evidence that copper and zinc have pro-oxidant and antioxidant properties, respectively, so that their imbalance may be expected to condition oxidative stress status. Oxidative stress is relevant in aging and in age-related degenerative diseases. In this study, blood content of copper, zinc, and ceruloplasmin as well as of lipid peroxides were investigated in 81 healthy and 62 disabled octo-nonagenarians affected by chronic degenerative diseases, and in 81 healthy adults. Serum copper/zinc ratio and ceruloplasmin were significantly higher in the elderly than in the healthy adults. Moreover, all these parameters were significantly higher in the disabled than in the healthy elderly. Notably, the increased copper/zinc ratio found in healthy elderly was due to high copper values, whereas in the disabled, both high copper and low serum zinc concentrations were present. The copper/zinc ratio was significantly and positively related to systemic oxidative stress status in all groups. The higher the serum copper/zinc ratio the higher the lipid peroxides plasma content. We conclude that there is a strict relationship between copper/zinc ratio and systemic oxidant burden. Moreover, advanced age and, particularly, advanced age-related chronic degenerative diseases are associated with a significant increase in the copper/zinc ratio and systemic oxidative stress.

Antioxidant properties of ticlopidine on human low density lipoprotein oxidation.

We found that ticlopidine, at therapeutically relevant concentrations (2.5-10 microM), but not aspirin nor salicylate, significantly counteracted copper-driven human LDL oxidation. Ticlopidine, at 5 and 10 microM, was also antioxidant on peroxyl radical-induced LDL oxidation; yet it was ineffectual on thiol and ascorbate oxidation mediated by peroxyl radicals themselves, suggesting that drug antioxidant capacity is somehow related to the lipoprotein nature of the oxidizable substrate, but not to radical scavenging. The drug could not indeed react with the stable free radical 1,1-diphenyl-2-pycrylhydrazyl, nor had apparent metal complexing-inactivating activity. Thus, ticlopidine has antioxidant effects on LDL oxidation, which, together with its anti-platelet activity, could confer peculiar antiatherogenic properties to the drug in vivo.

Circadian blood pressure changes and myocardial ischemia in hypertensive patients with coronary artery disease.

OBJECTIVES: We sought to evaluate whether different circadian blood pressure (BP) changes could influence the occurrence of ischemic episodes in untreated and treated hypertensive patients with stable coronary artery disease (CAD). BACKGROUND: In hypertensive patients with CAD the occurrence of myocardial ischemia could be influenced by either high or low BP values. Ambulatory monitoring has shown that circadian BP profile is not uniform in hypertensive patients. METHODS: Twenty-one patients with a nighttime BP fall < 10% ("nondippers"), 35 with a nighttime BP fall between > 10% and < 20% ("dippers") and 14 with a nighttime BP fall > 20% ("overdippers") with CAD underwent simultaneous ambulatory BP and electrocardiographic monitoring before and during drug therapy with nitrates and atenolol or verapamil in a prospective, randomized, open, blinded end point design. RESULTS: Daytime BP was not significantly different among the groups both before and during therapy. Nighttime BP was different by definition. Treatment significantly reduced BP values in each group (p < 0.05). Daytime ischemic episodes did not differ among the groups either before or during therapy. Drug therapy significantly reduced daytime ischemia (p < 0.05). In untreated patients, nighttime ischemia was more frequent in nondippers than in dippers and overdippers (p < 0.05). Drug therapy significantly reduced nocturnal ischemia in nondippers (p < 0.05), had no significant effect in dippers and significantly increased nighttime ischemia in overdippers (p < 0.05). During treatment, nighttime ischemia was more frequent in overdippers than in dippers and nondippers (p < 0.05). The same results were achieved when ischemic episodes were defined with more restrictive criteria (ST segment depression > or = 2 mm). CONCLUSIONS: Circadian BP changes can influence the occurrence of myocardial ischemia in untreated and treated hypertensive patients with CAD. Nocturnal ischemia was found to be more frequent in nondippers among untreated patients and in overdippers among treated patients, potentially suggesting different therapeutic approaches based on circadian BP profile.