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F Zannad

Publications and source records attributed to F Zannad.

At least 19 recordsLinked to original sources
PubMed2006

Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006.

Intima-media thickness (IMT) is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases). The necessity to promote further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is expressed through this updated consensus. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is based on physics, technical and disease-related principles as well as agreements on how to perform, interpret and document study results. Harmonization of carotid image acquisition and analysis is needed for the comparison of the IMT results obtained from epidemiological and interventional studies around the world. The consensus concludes that there is no need to 'treat IMT values' nor to monitor IMT values in individual patients apart from exceptions named, which emphasize that inside randomized clinical trials should be performed. Although IMT has been suggested to represent an important risk marker, according to the current evidence it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of randomized clinical trials incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Adult↗
PubMed2006

Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Aged↗
PubMed2005

Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance.

OBJECTIVES: The present study was undertaken to assess the differential impact of insulin resistance, leptin and body composition on myocardial mass and serum markers of cardiac fibrosis in obese subjects, within a small range of elevated BMI (30-40 kg/m(2)), without pulmonary disease, cardiovascular disease, hypertension, cardiac hypertrophy or other cardiovascular disease. BACKGROUND: Obesity is an independent predictor of left ventricular mass (LVM) and is associated with disturbances in cardiac structure. The extent of the interstitial fibrosis in obese patients is not known, especially in the absence of cardiac hypertrophy. METHODS AND RESULTS: We included 160 obese subjects. The LVM was obtained using the Devereux formula. Body composition was estimated from a total body scan. Insulin sensitivity was assessed by homeostasis model assessment (HOMA), and cardiac collagen turnover by measurement of procollagen type III aminopeptide (PIIINP). PIIINP was correlated to the E/A ratio (r=0.24; P=0.012), a marker of ventricular function. PIIINP was independently correlated with glucose concentration (r=0.27; P=0.004), indexes of insulin resistance (HOMA (r=0.27; P=0.003), insulin (r=0.24; P=0.008)), and parameters associated with the insulin-resistance syndrome (HDL-cholesterol r=-0.27; P=0.004) and fat trunk/fat leg ratio (r=0.24; P=0.053)). The variable most correlated with PIIINP was HDL-cholesterol, followed by HOMA (r (2)=0.13). When HOMA was substituted for blood glucose concentration and insulinemia (Model 2), HDL-cholesterol was strongly related to lower PIIINP levels, followed by higher glucose concentration (r (2)=0.21). Regression analyses showed that LVM had the strongest independent positive correlation with fat-free mass (FFM) (r=0.39; P=0.0002), followed by systolic blood pressure (r=0.19; P=0.034). Neither adipose mass nor height independently added information to multivariate models. The ratio leptin/fat mass was correlated with LVM (r=-0.27; P=0.004), but not independently of the FFM. Markers for fibrosis were not significantly correlated with LVM. As a result, FFM was the most predictive factor of LVM in obese subjects. CONCLUSION: We found that serum levels of markers of cardiac collagen synthesis were significantly associated with insulin resistance in normotensive, nondiabetic obese subjects, and not related to the LVM. As a result, PIIINP could be a very early marker of ventricular dysfunction in these patients. Furthermore, we suggest that, for better detection of left ventricle hypertrophy in obese subjects, LVM should be indexed to FFM rather than to body surface area, or height.

Adult↗
PubMed2005

Managing hypertension: a question of STRATHE.

Current international guidelines recommend the use of therapeutic strategies with proven efficacy in the management of hypertension to achieve a target blood pressure of < 140/90 mmHg. After lifestyle intervention, they endorse three different management strategies: (i) first-line use of a low-dose combination of two agents from different antihypertensive classes, with the option of doubling the dose of the combination; (ii) use of a sequential monotherapy strategy, initiating with one antihypertensive to be replaced by another one from a different class, if necessary; and (iii) a stepped care strategy, initiating with one antihypertensive, and increasing the dose or adding another agent from a different class, if necessary. The objective of the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study was to compare the efficacy and tolerability of these three treatment strategies in patients with uncomplicated essential hypertension (n = 533). In all, 62% of the patients in the low-dose combination group were normalised (< 140/90 mmHg), compared with 49% of the sequential monotherapy group (P = 0.01) and 47% of the stepped-care group (P = 0.005). The percentage of patients achieving normalisation without experiencing drug-related adverse events was also significantly higher in the low-dose combination group (56%) than in the sequential monotherapy (42%, P = 0.001) and stepped-care groups (42%, P = 0.004), consistent with the observation that the reduced dosage of the antihypertensive agents in such preparations translates into improved acceptability. The results of STRATHE provide further support for an antihypertensive management strategy involving the low-dose combination of perindopril (2 mg) and indapamide (0.625 mg).

Antihypertensive Agents↗
PubMed2005

Educational governance for the regulation of industry sponsored continuing medical education in interventional and device based therapies.

The relationship between industry and clinicians in educational programmes needs to be regulated. Industry may be best placed to deliver educational programmes in "craft" related specialties and particularly in areas where device implantation/technology based therapy has a major clinical role. The authors supervise industry sponsored clinical teaching at a purpose built independent teaching facility, and have developed the concept of educational governance to regulate their relationship with their industry sponsor and that concept is presented.

Biomedical Research↗
PubMed2004

Mannheim intima-media thickness consensus.

Intima-media thickness (IMT) is increasingly used in clinical trials as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. The necessity for unified criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is addressed in this consensus statement. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of > or =1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is recommended in all epidemiological and interventional trials dealing with vascular diseases to improve characterization of the population investigated. The consensus concludes that there is no need to 'treat IMT values' nor to monitor IMT values in individual patients apart from few exceptions. Although IMT has been suggested to represent an important risk marker, it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of studies incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Arteriosclerosis↗
PubMed2004

Pharmacogenomics in cardiovascular clinical trials.

Genomics - having quickly emerged as the central discipline in basic science and biomedical research - is poised to take the center stage in clinical medicine as well over the next few decades. Although there is no specific regulatory guideline on the application of pharmacogenetics to drug development, some recommendations are already included in several published guidelines on drug development. The patients more likely to provide the most valuable information on the specific contribution of a given gene or its variant are those who fail to respond to a drug ('therapeutic failures') and those who develop toxicity to the drug. However, before drawing definite conclusions on subgroups following pharmacogenomic analyses, one must be aware of disease classification, data collection, and how much is known about the disease process. It seems reasonable to collect genomic DNA from all patients enrolled in clinical drug trials (along with appropriate consent to permit pharmacogenetic studies) for the purpose of post hoc analyses. One exception to post hoc genomic analysis is when patients with a specific genotype are excluded from randomization into a clinical trial. Physicians will need to understand the concept of genetic variability, its interactions with the environment (e.g. drug-drug or drug-disease interactions), and its implication for patient care.

Biomedical Research↗
PubMed2002

Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study).

BACKGROUND: In patients with congestive heart failure (CHF), clinical trials have demonstrated the benefit of a number of drugs on morbidity and mortality. Nevertheless so far, there is no published controlled study of long-term antithrombotic therapy in patients with CHF. The aim of this work was to identify the relationship between cardiovascular drug use, especially antithrombotic therapy, and survival of CHF patients in current clinical practice, using an observational, population-based database. METHODS: The EPICAL study (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) has identified prospectively all patients with severe CHF in the community of Lorraine. Inclusion criteria were age 20-80 years in 1994, at least one hospitalisation for cardiac decompensation, NYHA III/IV HF, ventricular ejection fraction < or =30% or cardiothoracic index > or =60% and arterial hypotension or peripheral and/or pulmonary oedema. A total of 417 consecutive patients surviving at hospital discharge were included in the database. The average follow-up period was 5 years. Univariate Cox models were used to test the relationship of baseline biological and clinical factors to survival. Cardiovascular drug prescriptions were tested in a multivariate Cox model adjusted by other known predictive factors. RESULTS: Duration of disease >1 year, renal failure, serum sodium > or =138 mmol/l, old age, serious comorbidity, previous decompensation, high doses of furosemide and vasodilators use were independently associated with poor prognosis at 1 and 5 years. Oral anticoagulants, aspirin, lipid lowering drugs and beta-blockers use were associated with better survival. There was no interaction between aspirin and angiotensin converting enzyme inhibitor use on survival. CONCLUSION: Antithrombotic therapy was associated with a better long-term survival in our study population of severe CHF. These results together with other previously published circumstantial evidence urge for a prospective, controlled and randomised trial specifically designed to evaluate optimal oral anticoagulants and aspirin in patients with congestive heart failure.

Adrenergic beta-Antagonists↗
PubMed2002

[Treatment with lepirudin in heparin-induced thrombocytopenia. A case report].

We report the case of a 71 old woman presenting a bilateral massive pulmonary embolism with intraventricular right thrombus complicating heparin induced thrombocytopenia (HIT) persistent after one month of conventional anticoagulant processing. We underline the effectiveness of lepirudin (Refludan) in the curative processing of pulmonary embolism allowing here to avoid a complex surgical thromboembolectomy. We evoke the place of this molecule in the curative therapeutic strategy of HIT with thrombotic phenomena.

Aged↗
PubMed2001

Lipopolysaccharide-induced increase of prostaglandin E(2) is mediated by inducible nitric oxide synthase activation of the constitutive cyclooxygenase and induction of membrane-associated prostaglandin E synthase.

NO produced by the inducible NO synthase (NOS2) and prostanoids generated by the cyclooxygenase (COX) isoforms and terminal prostanoid synthases are major components of the host innate immune and inflammatory response. Evidence exists that pharmacological manipulation of one pathway could result in cross-modulation of the other, but the sense, amplitude, and relevance of these interactions are controversial, especially in vivo. Administration of 6 mg/kg LPS to rats i.p. resulted 6 h later in induction of NOS2 and the membrane-associated PGE synthase (mPGES) expression, and decreased constitutive COX (COX-1) expression. Low level inducible COX (COX-2) mRNA with absent COX-2 protein expression was observed. The NOS2 inhibitor aminoguanidine (50 and 100 mg/kg i.p.) dose dependently decreased both NO and prostanoid production. The LPS-induced increase in PGE(2) concentration was mediated by NOS2-derived NO-dependent activation of COX-1 pathway and by induction of mPGES. Despite absent COX-2 protein, SC-236, a putative COX-2-specific inhibitor, decreased mPGES RNA expression and PGE(2) concentration. Ketoprofen, a nonspecific COX inhibitor, and SC-236 had no effect on the NOS2 pathway. Our results suggest that in a model of systemic inflammation characterized by the absence of COX-2 protein expression, NOS2-derived NO activates COX-1 pathway, and inhibitors of COX isoforms have no effect on NOS2 or NOS3 (endothelial NOS) pathways. These results could explain, at least in part, the deleterious effects of NOS2 inhibitors in some experimental and clinical settings, and could imply that there is a major conceptual limitation to the use of NOS2 inhibitors during systemic inflammation.

Animals↗
PubMed2001

Evidence of functional myocardial ischemia associated with myocardial dysfunction in brain-dead pigs.

BACKGROUND: Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs. METHODS AND RESULTS: Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10+/-3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt(max), rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt(max), RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt(max), RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism. CONCLUSIONS: Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.

Adenosine↗
PubMed2001

Retinoic acid attenuates inducible nitric oxide synthase (NOS2) activation in cultured rat cardiac myocytes and microvascular endothelial cells.

S. Grosjean, Y. Devaux, C. Seguin, C. Meistelman, F. Zannad, P.-M. Mertes, R. A. Kelly and D. Ungureanu-Longrois. Retinoic Acid Attenuates Inducible Nitric Oxide Synthase (NOS2) Activation in Cultured Rat Cardiac Myocytes and Microvascular Endothelial Cells. Journal of Molecular and Cellular Cardiology (2001) 33, 933-945. The inducible NO synthase (NOS2) in cardiac tissue contributes to myocardial and coronary inflammation and dysfunction. Several natural (endogenous) hormones such as retinoic acid, the active metabolite of vitamin A, have the ability to attenuate NOS2 activation in inflammatory cells. The aim of this study was to investigate the effect of RA on NOS2 activation in cultured cardiac microvascular endothelial cells (CMEC) and adult rat ventricular myocytes (ARVM). CMEC were stimulated either with a combination of 10 microg/ml lipopolysaccharide (LPS) and 50 IU/ml interferon- gamma (IFN- gamma) or with a combination of 1 ng/ml interleukin-1 beta (IL-1 beta)+IFN- gamma whereas ARVM were stimulated with 1 ng/ml IL-1 beta and 50 IU/ml IFN- gamma in the absence or presence of all-trans retinoic acid (atRA). Activation of the NOS2 pathway was estimated by measurement of mRNA (Northern blot) and protein (Western blot) expression, enzyme activity by conversion of [(3)H]L -arginine to [(3)H]L -citrulline, and nitrite accumulation. NOS2 mRNA half-life was studied in CMEC and ARVM in the presence of actinomycin D. In CMEC and ARVM stimulated with a combination of LPS and/or cytokines, atRA (10(-6), 10(-5)M) significantly (P<0.05) attenuated NOS2 mRNA and protein expression, enzymatic activity and reduced supernatant nitrite concentration. Upon stimulation with LPS/IFN- gamma, atRA significantly decreased NOS2 mRNA half-life. This was not seen after stimulation with IL-1 beta/IFN- gamma. These results document for the first time an effect of RA on NOS2 activation in cardiac cells. They may contribute to the characterization of the immunomodulatory effects of retinoids in myocardial and coronary inflammatory disorders.

Animals↗
PubMed2001

Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance.

The objectives of this study were to investigate cardiac and peripheral autonomic nervous system changes in normotensive overweight or obese subjects and the possible relation between these changes and insulin resistance independent of age. The authors used spectral analysis to measure simultaneously the short-term variability of heart rate (HR) and blood pressure (BP) using a Finapres device, in 67 normotensive overweight or obese patients (age 37 +/- 12 y, body mass index [BMI] = 37 +/- 9 kg/m2) and 45 never-obese subjects (controls; age 41 +/- 13 y, BMI 22 +/- 2 kg/m2). The spectral density was determined in three situations: subjects in the supine position, spontaneously breathing; subjects in the supine with controlled breathing; and subjects standing. The insulin sensitivity of overweight and obese subjects was determined from homeostatic model assessment (HOMA). The variability of normalized low-frequency (LF) spectral analysis of both HR and BP was lower in overweight or obese subjects than in controls, in the supine and standing positions (p <0.01). Normalized LF spectral analysis was negatively correlated to BMI independent of age, whatever the position. Homeostatic model assessment values were negatively correlated to the normalized LF spectral of HR, systolic BP and diastolic BP, in the standing position independent of BMI and age (p <0.05). Normalized high frequency (HF) of HR during controlled breathing decreased with age but not with BMI. In normotensive overweight or obese subjects, changes in sympathetic nervous system modulation are strongly correlated to insulin resistance. Decreased HR and BP variability could partly account for the higher cardiovascular risk and incidence of sudden death in obese persons.

Adolescent↗
PubMed2001

The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: the VAMPHYRE study.

The aim of the present study was to compare the effects of a long-acting dihydropyridine (amlodipine) and a nondihydropyridine (verapamil) on autonomic function in patients with mild to moderate hypertension. A total of 145 patients with a diastolic blood pressure (BP) between 95 and 110 mm Hg received 8 weeks of verapamil sustained release (240 mg) and amlodipine (5 mg) in a prospective randomized, double blind, cross-over study, both after 4 weeks of placebo. The 24-h autonomic balance was measured by analysis of 24-h heart rate variability and short-term autonomic control of BP by baroreflex sensitivity measurements. Plasma norepinephrine was sampled at rest. Blood pressure was equally reduced from 153/100 mm Hg to 139/91 mm Hg with verapamil and 138/91 mm Hg with amlodipine, P = .50/.59. The low- to high-frequency ratio (LF/HF), reflecting sympathovagal balance, was higher with amlodipine than with verapamil (4.66 v 4.10; P = .001). Baroreflex function was improved by both treatments; however, baroreflex sensitivity (BRS) was significantly higher with verapamil than with amlodipine (8.47 v 8.06 msec/mm Hg; P = .01). Plasma norepinephrine (NE) level was higher with amlodipine than with verapamil (1.59 v 1.32 nmol/L; P < .0001). Amlodipine induces a shift in sympathovagal balance, as measured by heart rate variability indices and plasma NE, toward sympathetic predominance compared with vagal predominance with verapamil. Short-term autonomic control of BP, as assessed by BRS, is more effectively improved by verapamil than by amlodipine. These contrasting effects on autonomic function suggest that the nondihydropyridine calcium antagonist verapamil may have additional beneficial effects beyond lowering BP compared with the dihydropyridine amlodipine.

Adult↗
PubMed2001

APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort).

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) inter-individual 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 analyses were carried out by ANOVA, after adjustment of CIMT for age, body mass index, and smoking, and by multiple regression analyses. No association was found with APOB Thr71Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T, and SELE Ser128Arg, polymorphisms neither in men nor in women. Although, in women we did not find any association for APOC3 3206T/G, 3175C/G, 1100C/T, CETP Ile405Val, MTHFR 677C/T and fibrinogen -455G/A polymorphisms; in men these polymorphisms were associated with CIMT variability (p< or =0.01; 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

Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension.

AIMS: To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. METHODS: One-hundred and forty-five patients with mild to moderate hypertension and a mean (+/- s.e.mean) age of 51 +/- 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. RESULTS: Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 +/- 2 vs 30 +/- 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P < 0.01) and rate-pressure product (3.1 +/- 0.2 vs 3.6 +/- 0.3 x 10(3) mmHg x beats min(-1), difference 0.5, 95% CI (0.1, 0.9), P < 0.01) during handgrip compared with amlodipine. Similar results were observed during cold pressor. Plasma noradrenaline levels were lower with verapamil compared with amlodipine at rest and after both tests, but the increases in plasma noradrenaline were not significantly different. CONCLUSIONS: Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.

Adult↗