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F Zannad

Publications and source records attributed to F Zannad.

At least 37 records · Page 2Linked to original sources
PubMed2001

Environmental and genetic determinants of intima-media thickness of the carotid artery.

1. The aim of the present study was to investigate carotid intima-media thickness (CIMT) in relation to anthropometric, environmental and genetic factors, as well as cholesterol and blood pressure levels. 2. The study sample was composed of 89 families, with no documented cardiovascular disease, consisting of 369 subjects (aged from 10 to 54 years) from the Stanislas cohort. 3. Carotid intima-media thickness was measured by B-mode ultrasonography. Fifteen genetic markers, including genes involved in lipid metabolism, the regulation of blood pressure, thrombosis, platelet function and endothelial cell adhesion, were studied by multiplex assay. 4. The effects of gender, age, smoking, alcohol, body mass index, cholesterol, blood pressure and genetic factors were studied using ANOVA and bivariate and regression analyses. 5. Segregation analysis was also performed to estimate the contribution of genetic and environmental factors to CIMT variability. 6. Carotid intima-media thickness values were not affected by age or by gender up to 18 years of age. Thereafter, CIMT values increased sharply in men and remained significantly higher than in women. 7. Approximately 30% of CIMT variability was attributable to genetic factors. Associations between CIMT and polymorphisms in the apolipoprotein CIII, cholesteryl ester transfer protein, methylene tetrahydrofolate reductase and fibrinogen genes were observed and explained approximately 20% of CIMT variation in men. 8. In women, none of the studied polymorphisms was associated with CIMT variation. 9. Our study gives new perspectives for understanding CIMT variability in healthy middle-aged subjects.

Adolescent↗
PubMed2001

Hemodynamics as surrogate end points for survival in advanced heart failure: an analysis from FIRST.

BACKGROUND: Hemodynamics often are used as surrogate end points in phase II trials of acute heart failure (HF). We reviewed the Flolan International Randomized Survival Trial (FIRST) database to identify the hemodynamic variables that best predict survival in patients with advanced HF receiving epoprostenol therapy and to determine whether hemodynamics could predict the overall effect of a drug. METHODS: The trial enrolled 471 patients with class IIIb/IV HF and ejection fraction or=3 months, all of whom underwent screening pulmonary artery catheter insertion. Patients were randomly assigned to receive either epoprostenol (n = 201) or placebo (n = 235); epoprostenol therapy was guided by pulmonary artery catheter measures, and standard treatment was guided by clinical findings. Multivariable modeling was used to identify and quantify the demographic, clinical, and hemodynamic variables most associated with 1-year survival. RESULTS: In multivariable modeling, HF class, decreased pulmonary capillary wedge pressure (PCWP), and age best predicted 1-year survival. After adjustment for age and HF class, decreased PCWP still significantly predicted survival (hazard ratio, 0.96 for every 1-mm Hg decrease; 95% confidence interval, 0.94 to 0.99; P = .003). Survival was significantly higher with decreases in PCWP >or=9 versus <9 mm Hg, even after adjustment for age and HF class. Survival of patients in the PCWP >or=9 group was comparable with, and that of the PCWP <9 group was significantly higher than, survival of patients in the control group (hazard ratio, 1.44; 95% confidence interval, 1.05 to 1.99; P = .024). CONCLUSIONS: The reduction in PCWP was the hemodynamic measure most predictive of survival in patients with advanced HF. However, patients with a >or=9-mm Hg decrease had no better survival than patients in the control group, who had limited changes in hemodynamics. Thus, improvement in hemodynamics may not predict the overall effect of a drug.

Aged↗
PubMed2001

Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo.

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg. d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E(2) (PGE(2)) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LPS-mediated increase in PGE(2) was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.

Animals↗
PubMed2001

Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship.

Cardiac extracellular matrix undergoes extensive and continuous turnover involved in the lesion-reparation process, such as in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, after myocardial infarction in the transition to heart failure, and during the progression of left ventricular dysfunction. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenicity, thus potentially contributing the to progression of heart failure and sudden death. Aldosterone was shown to promote cardiac fibrosis in various experimental models. It was demonstrated that spironolactone may oppose the effect of aldosterone in promoting cardiac fibrosis. Measurement of cardiac collagen turnover by use of serological markers is a useful tool for monitoring cardiac tissue repair and fibrosis in experimental models or clinical conditions. We found that high serum levels of a marker of collagen turnover (procollagen type III N-terminal peptide ) in patients with chronic heart failure receiving conventional therapy, including ACE inhibitors, was associated with high mortality and hospitalization rates. In RALES (Randomized Aldactone Evaluation Study), in patients randomized to placebo, markers continued to increase or remained unchanged after 6-month follow-up. On the contrary, adding spironolactone 25 mg daily significantly decreased the levels of these serum markers during the same period. Most importantly, the spironolactone-related morbidity and mortality benefit was most predominant in subgroups with highest baseline levels of serum markers. These results suggest that limitation of the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.

Aldosterone↗
PubMed2001

Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function.

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Diabetes Mellitus↗
PubMed2001

Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus.

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Animals↗
PubMed2001

[APOC3, CETP, beta-fibrinogen and MTHFR are genetic determinants of carotid intim-media thickness (Stanislas cohort)].

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) interindividual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French cohort: the Stanislas cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analysis were done by ANOVA after adjustment of CIMT for age, BMI and smoking and by multiple regression analyses. No association was found with APOB Thr71 Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T and SELE Ser128Arg, polymorphism neither in men nor in women. Although, in women we found always no association for the APOC3 3206T/G, 3175C/G, 1100C/T, the CETP Ile405Val, the MTHFR 677C/T and the fibrinogen -455G/A polymorphism's, in men these polymorphism's were associated with CIMT variability (0.01 < or = p < or = 0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.

Adult↗
PubMed2001

[Association between E-selectin Leu554Phe polymorphism and blood pressure in the Stanislas cohort].

We investigated the relationship between polymorphisms of the E-selectin gene, SELE (L/F554, S/R128 and 98G/T), a cell adhesion molecule, and interindividual variability in blood pressure and changes over time. The study population was extracted from the Stanislas Cohort (1006 families), a cohort of nuclear families volunteering for a free health check-up and recruited by the Centre of Preventive Medicine in Nancy (CMP) between 1993 and 1994. For this specific study, 359 men and 337 women were selected from families that had already visited the CMP 11 years before the recruitment of the Stanislas Cohort. Measurements of blood pressure at the time -11 years (t-11) and at the time of recruitment (t0), and all other measurements necessary for the analysis (BMI, lipids, SELE genotypes) were available. Pregnant women or subjects taking antihypertensive, lipid lowering or anti-inflammatory medications were excluded from the study. During the follow-up period, systolic and diastolic blood pressure (SBP and DBP) were lower in SELE F554 allele carriers than in those with the L/L554 genotype (p < or = 0.05), whereas longitudinal changes were not related to any SELE polymorphism. Multiple regression analysis showed that at t-11 SELE L/F554 polymorphism was associated with both SBP and DBP levels (p < or = 0.01 and p < or = 0.05, respectively). However, these associations were no longer present at t0. Our results suggest an age-specific effect of the SELE L/F554 polymorphism on blood pressure levels. If confirmed in other studies, these findings would suggest that assessment of common variation in an adhesion molecule could be useful in predicting blood pressure.

Adult↗
PubMed2000

Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.

BACKGROUND: In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF. METHODS AND RESULTS: A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 microgram/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively. CONCLUSIONS: In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.

Aged↗
PubMed2000

High-performance liquid chromatographic analysis of muscular interstitial arginine and norepinephrine kinetics. A microdialysis study in rats.

Complex interactions between the L-arginine/nitric oxide synthase (NOS) pathway and the sympathetic nervous system have been reported. Methods capable of measuring L-arginine and norepinephrine (NE) have mainly been reported for plasma. We report the use of the microdialysis technique combined with high-performance liquid chromatography (HPLC) for measurement of both L-arginine and NE within the same tissue microdialysis sample. The microdialysis probe consisted of linear flexible probes (membrane length: 10 mm, outside diameter: 290 microm, molecular weight cut-off 50 kDa). The method used for L-arginine measurement was HPLC with fluorescence detection, giving a within-run and a between-day coefficient of variation of 2.9 and 12.8%, respectively. The detection limit was 0.5 pM/20 microl injected for L-/D-arginine. The method used for NE measurement was HPLC with electrochemical detection. The coefficients of variation were 4% for within-assay precision and 7.5% for between-assay precision. The detection limit for NE was 1 fmol/20 microl injected. The microdialysis technique coupled with HPLC system was validated in vivo to measure muscular interstitial concentrations of both arginine and NE under baseline conditions and after intravenous infusion of 500 mg/kg of L-arginine or D-arginine. In conclusion, the microdialysis technique coupled to HPLC allows the simultaneous measurements of both L-arginine and NE within the same tissue microenvironment and will enable the study of the complex interactions between the L-arginine/NO pathway and sympathetic nervous system within the interstitial space of different organs.

Animals↗
PubMed2000

Consequences of inspired oxygen fraction manipulation on myocardial oxygen pressure, adenosine and lactate concentrations: a combined myocardial microdialysis and sensitive oxygen electrode study in pigs.

Adenosine is a potent vasodilator whose concentration has been shown to increase in cardiac tissue in response to hypoxia. However, the time-dependent relationship between the levels of myocardial interstitial adenosine and tissue oxygenation has not yet been completely established. Therefore, the purpose of this study was to investigate the complex relationship between tissue myocardial oxygen tension (PtiO(2)) and interstitial myocardial adenosine and lactate concentrations by developing a new technique which combines a cardiac microdialysis probe and a Clark-type P O(2)electrode. The combined and the single microdialysis probes were implanted in the left ventricular myocardium of anesthetized pigs. The consequences of the combined use of microdialysis and P O(2)probes on myocardial PtiO(2)and microdialysis performances against glucose were evaluated. A moderate but significant reduction in the relative recovery against glucose of the combined probe was observed when compared to that of the single microdialysis probe (42+/-2 v 32+/-1%, mean+/-S.E. M.n=5 P<0.05), at 2microl/min microdialysis probe perfusion flow. Similarly, myocardial oxygen enrichment, measured by the P O(2)electrode, was negligible when microdialysis probe perfusion flow was 2microl/min. Systemic hypoxia (FiO(2)=0.08) resulted in a significant decrease in PtiO(2)from 30+/-4 to 11+/-2 mmHg, limited increase in coronary blood flow (CBF), and a significant increase in myocardial adenosine and lactate concentrations from 0.34+/-0.05 to 0.98+/-0.06micromol/l and from 0.45+/-0.05 to 0.97+/-0.06 mmol/l respectively (P<0.05). Increasing the FiO(2)to 0.3 restored the PtiO(2)and hemodynamic parameters to baseline values with no changes in interstitial adenosine and lactate concentrations. Nevertheless, myocardial interstitial adenosine remained significantly higher than baseline values. In conclusion, this study demonstrates the ability of a combined probe to measure simultaneously regional myocardial PtiO(2)and metabolite concentration during hypoxia. The hypoxia-induced increase in myocardial adenosine persists after correction of hypoxia. The physiological significance of this observation requires further studies.

Adenosine↗
PubMed2000

Relationship between E-selectin L/F554 polymorphism and blood pressure in the Stanislas cohort.

We investigated the relationship between polymorphisms of the E-selectin gene SELE (L/F554, S/R128 and 98G/T), a cell adhesion molecule, and interindividual variability in blood pressure and changes over time. The study population was extracted from the Stanislas cohort (1006 families), a cohort of nuclear families volunteering for a free health check-up and recruited by the Center of Preventive Medicine in Nancy (CMP) between 1993 and 1994. For this specific study 359 men and 337 women were selected from families who had already visited the CMP 11 years before recruitment of the Stanislas Cohort. Measurements of blood pressure 11 years before (t(-11)) and at the time of recruitment (t(0)), and all other measurements necessary for the analysis (body mass index, lipids, SELE genotypes) were available. Pregnant women or subjects taking antihypertensive, lipid-lowering, or anti-inflammatory medications were excluded from the study. During the follow-up period systolic and diastolic blood pressures were lower in SELE F554 allele carriers than in those with the L/L554 genotype (P<0.05), but longitudinal changes were not related to any SELE polymorphism. Multiple regression analysis showed that at t(-11) SELE L/F554 polymorphism was associated with both systolic and diastolic blood pressure levels (P<0.01 and P<0.05, respectively). However, these associations were no longer present at t(0). Our results suggest an age-specific effect of the SELE L/F554 polymorphism on blood pressure levels. If confirmed in other studies, these findings would suggest that assessment of common variation in an adhesion molecule could be useful in predicting blood pressure.

Adult↗
PubMed2000

Differential clinical prognostic classifications in dilated and ischemic advanced heart failure: the EPICAL study.

BACKGROUND: The clinical management of severe congestive heart failure (CHF) should be graded according to the prognosis of each individual patient. Our objective was to elaborate a prognostic rating system for severe CHF. METHODS: The EPICAL program (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) identified patients with severe CHF defined by hospitalization accompanied by class III/IV dyspnea, edema, or hypertension; an ejection fraction </=30% or a cardiothoracic index >/=60%. Baseline variables were tested in Cox multivariate models. RESULTS: Patients with ischemic heart disease (n = 219) had a lower 1-year survival rate (57.6%) than patients with dilated cardiomyopathy (n = 182) (69. 1%). Multivariate analysis identified 5 prognostic factors for ischemic CHF and 7 for CHF caused by dilated cardiomyopathy. These variables were used to classify patients within prognostic subgroups of good (>75%), intermediate, or poor (</=25%) 1-year survival. CONCLUSION: A score for prognostic prediction was further derived from readily available data to help physicians improve decision making and to assist in clinical trials as a stratification tool.

Adult↗
PubMed2000

Determinants of angiotensin-converting enzyme inhibitor prescription in severe heart failure with left ventricular systolic dysfunction: the EPICAL study.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to reduce morbidity and mortality rates in patients with heart failure with left ventricular systolic dysfunction. Nevertheless, these drugs are underutilized in current practice and prescribed at doses below those usually recommended. The aim of this work was to identify the social, demographic, laboratory, clinical, and therapeutic factors associated with nonprescription of ACE inhibitors and/or their prescription at doses below those recommended in the treatment of severe long-term congestive heart failure (CHF). METHODS AND RESULTS: An epidemiologic observational study, EPICAL (EPidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine), studied 417 patients with severe CHF surviving after the index hospitalization. Multivariate logistic regression determined the factors associated with ACE inhibitor nonprescription and with their prescription at lower-than-recommended doses. ACE inhibitors were taken by 75% of the patients but 38% took lower-than-recommended doses. Factors shown to be associated with nonprescription included patients >65 years of age with renal impairment (odds ratio 19.5, confidence interval [CI] 7.9-48.0), nonsinus cardiac rhythm (odds ratio 2.0, CI 1.2-3.2), and prescription of potassium-sparing diuretics (odds ratio 2.4, CI 1. 2-4.7). Renal impairment was the single most important factor associated with prescription of lower-than-recommended doses, particularly in elderly patients. CONCLUSIONS: Our results underline the need for optimal and better use of ACE inhibitor therapy. CHF treatment guidelines must be more uniformly applied by all physicians caring for patients with heart failure.

Aged↗
PubMed2000

Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study.

OBJECTIVE: To compare the efficacy of indapamide sustained release (SR) 1.5 mg and enalapril 20 mg at reducing left ventricular mass index (LVMI) in hypertensive patients with left ventricular hypertrophy (LVH). DESIGN: The LIVE study (left ventricular hypertrophy regression, indapamide versus enalapril) was a 1 year, prospective, randomized, double-blind study. For the first time, a committee validated LVH before inclusion, provided on-going quality control during the study, and performed an end-study reading of all echocardiograms blinded to sequence. SETTING: European hospitals, general practitioners and cardiologists. PATIENTS: Hypertensive patients aged > or = 20 years with LVH (LVMI in men > 120 g/m2; LVMI in women > 100 g/m2). Data were obtained from 411 of 505 randomized patients. INTERVENTIONS: Indapamide SR 1.5 mg, or enalapril 20 mg, daily for 48 weeks. MAIN OUTCOME MEASURES: LVMI variation in the perprotocol population. RESULTS: Indapamide SR 1.5 mg significantly reduced LVMI (-8.4 +/- 30.5 g/m2 from baseline; P< 0.001), but enalapril 20 mg did not (-1.9 +/- 28.3 g/m2). Indapamide SR 1.5 mg reduced LVMI significantly more than enalapril 20 mg: -6.5 g/m2, P = 0.013 (-4.3 g/m2 when adjusted for baseline values; P = 0.049). Both drugs equally and significantly reduced blood pressures (P< 0.001), without correlation with LVMI changes. Indapamide SR progressively reduced wall thicknesses throughout the 1-year treatment period. In contrast, the effect of enalapril observed at 6 months was not maintained at 12 months. CONCLUSIONS: Indapamide SR 1.5 mg was significantly more effective than enalapril 20 mg at reducing LVMI in hypertensive patients with LVH.

Adult↗
PubMed2000

The potential advantages of a modern antihypertensive therapy in the elderly.

More than 50% of hypertensive patients are aged above 65 years. Physiopathology of essential hypertension is different in the elderly as compared with the young adult. Furthermore, not only are concomitant diseases statistically more frequent in the elderly, but the aging process in itself produces several specific changes in target organs. Several trials have shown that treatment of hypertension in the elderly, including the 'old elderly', is highly beneficial in terms of reduced morbidity and mortality. The therapy used in all these major intervention trials consisted of diuretics and/or beta-blockers. Recently, the Systolic Hypertension in Europe study and the HOT study extended the list of antihypertensive agents with proven beneficial effects on cardiovascular outcomes to dihydropyridine calcium antagonists. Dihydropyridine calcium antagonists, such as lacidipine, have been advocated as first-choice agents for the treatment of hypertension in the elderly on grounds that: a) they may be more active in lowering blood pressure because of the predominantly low renin status in the elderly hypertensives; b) they may be better tolerated because the side effects related to the activation of the sympathetic system may be less frequent as a consequence of the attenuation of baroreflexes during aging; and c) they may have beneficial effects on a variety of concomitant cardiovascular diseases which are frequently present in the elderly. These assumptions are, however, not always proven in the clinical practice. Only well-designed prospective comparative trials may solve this issue. STOP-2, NICS-EH, HYVET, SCOPE and SHELL are acronyms of ongoing clinical trials specifically designed in the elderly hypertensive. The SHELL study assesses the benefits of lacidipine compared with chlortalidone on the prevention of cardiovascular events. The effects of lacidipine (vs atenolol) on the development and progression of carotid atherosclerosis are also being currently investigated in the ELSA study.

Aged↗
PubMed2000

Retinoic acid and host-pathogen interactions: effects on inducible nitric oxide synthase in vivo.

Vitamin A and its metabolite retinoic acid modulate the host response to pathogens through poorly characterized mechanisms. In vitro studies have suggested that retinoic acid decreases inducible NO synthase (NOS2, or iNOS) expression, a component of innate immunity, in several cell types stimulated with lipopolysaccharide (LPS) or cytokines. This study investigated the effect of retinoic acid on LPS-stimulated NOS2 expression in vivo. Wistar-Kyoto rats received all-trans retinoic acid (RA, 10 mg/kg) or vehicle intraperitoneally daily for 5 days followed by LPS (4 mg/kg) or saline intraperitoneally and were killed 6 h later. NOS2 activation was estimated by mRNA (RT-PCR) and protein (Western-blot) expression and plasma nitrate/nitrite accumulation. In sharp contrast to previous in vitro study reports, RA significantly enhanced NOS2 mRNA, protein expression, and plasma nitrate/nitrite concentration in LPS-injected rats but not in saline-injected rats. This was associated with increased expression of interleukin-2, interferon (IFN)-gamma and IFN regulatory factor-1 mRNAs in several organs and increased IFN-gamma plasma concentration. RA significantly increased mortality in LPS-injected rats. The NOS inhibitor aminoguanidine (50 mg/kg before LPS injection) significantly attenuated the RA-mediated increase in mortality. These results demonstrate for the first time that RA supplementation in vivo enhances activation of the LPS-triggered NOS2 pathway.

Animals↗