Search

Resume Le bon usage des medicaments peut etre defini simplement comme l’utilisation du bon medicament, a la bonne dose, pendant la duree necessaire, pour un patient donne qui le tolere correctement. Il est impossible, etant donne le nombre de medicaments et le nombre infini des situations cliniques individuelles de ne pas baser la prescription sur une reference. La reference peut etre unique, lorsque la situation clinique est simple et le medicament, a choisir, unique. Dans ce cas une bonne formation initiale et continue sert de reference au choix. L’usage du RCP (Resume des Caracteristiques du Produit) choisi permet d’obtenir une prescription plus precise et plus sure. Dans beaucoup de cas l’usage de telle ou telle strategie therapeutique peut conduire au resultat souhaite. Dans ces cas, des referentiels scientifiques permettent d’aider le prescripteur a choisir la meilleure strategie. Enfin les strategies therapeutiques peuvent avoir une efficacite egale et des couts tres differents. Des referentiels peuvent etre emis pour diminuer le cout d’une prescription donnee. Les difficultes issues de references ou de referentiels sont : 1. Ils ne peuvent pas couvrir l’integralite des situations cliniques. 2. Ils devraient etre evolutifs a mesure que la science progresse et cela est difficile. 3. La multiplicite des emetteurs aboutit a des messages confus parfois contradictoires. 4. Leur pertinence et leur efficacite devraient etre evaluees. 5. Ils peuvent etre inutilisables pour le prescripteur en raison de leur complexite ou de l’eloignement des situations pratiques. Nous proposons un constat et un certain nombre de solutions pour ameliorer la qualite et la pertinence des references ou referentiels : des structures de coordination choisissant les themes et definissant les methodes de redaction, la creation d’un repertoire des referentiels, un cahier des charges de tout referentiel avec exigence de qualite, une formation initiale et continue des soignants destinataires des referentiels. Il est par ailleurs necessaire de mettre en place des mesures d’impact de ces referentiels et de s’imposer une actualisation adaptee periodique. Tout cela devrait permettre une amelioration mesurable de la qualite des soins.

Resume Le Leem (Les Entreprises du Medicament) a realise un etat des lieux des besoins medicaux non ou mal couverts en 2006 en France pour 12 pathologies retenues comme priorites de sante publique dans le cadre de la loi du 9 aout 2004. Alliees aux projections epidemiologiques, les analyses ont porte, pour chaque pathologie, sur les differents stades et/ou formes de la maladie, sur les points d’impact des recommandations pour la pratique clinique, notamment en matiere de strategie therapeutique, sur les therapeutiques actuellement disponibles et sur les innovations en phase de developpement clinique avance. Avec plus de 100 produits recenses en phase III ou en phase d’enregistrement/commercialisation dans ces pathologies, l’industrie pharmaceutique apporte une contribution quasi exclusive a la mise au point de traitements medicamenteux innovants repondant a des besoins medicaux insatisfaits. Cette etude illustre la necessite imperieuse d’encourager l’innovation therapeutique menee par l’industrie pharmaceutique, acteur authentique de sante.

OBJECTIVES We sought to evaluate the influence of pretreatment systolic blood pressure (SBP) on the efficacy and safety of carvedilol in patients with chronic heart failure (CHF). BACKGROUND Although beta-blockers reduce the risk of death in CHF, there is little reported experience with these drugs in patients with a low pretreatment SBP, who may respond poorly to beta-blockade. METHODS We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. RESULTS Compared with placebo, carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason, for a cardiovascular reason, or for worsening heart failure (p 0.10). However, because patients with the lowest SBP were at highest risk of an event, they experienced the greatest absolute benefit from treatment with carvedilol. The lower the pretreatment SBP, the more likely that patients would report an adverse event, be intolerant of high doses of the study drug, or require permanent withdrawal of treatment (p < 0.001 for all). However, these risks were primarily related to the severity of the underlying illness and not to treatment with carvedilol. CONCLUSIONS The current study provides little support for concerns about using beta-blockers (particularly those with vasodilatory actions) in patients with severe CHF who have a low SBP. Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol.

Background: Neither profiles nor prognostic value of cardiac N-terminal proBNP (NT-proBNP) have been prospectively evaluated in a sufficient number of patients with severe chronic heart failure (CHF) treated with carvedilol or placebo. Methods: Baseline and follow-up plasma concentrations of NT-proBNP were measured in the European part of the COPERNICUS Trial. This study enrolled patients with an ejection fraction

Aims: This study tested the effects on cardiovascular outcomes of treatments based on nifedipine gastrointestinal therapeutic system (GITS) compared with the diuretic combination co-amilozide in a pre-specified subset of patients with isolated systolic hypertension (ISH) enrolled in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study. Major findings: Of 6321 randomized patients, 1498 (23.7%) had ISH with a baseline mean BP of 173/88 mmHg in both treatment groups. Mean BP fell by 29/10 mmHg in the nifedipine and 30/10 mmHg in the diuretic group to a mean BP of 144/78 mmHg and 143/79 mmHg, respectively, at endpoint. The percentage of primary outcomes in patients with ISH was not significantly different between the two treatment groups (nifedipine GITS 6.0%, co-amilozide 6.6%). The number of ISH patients with composite secondary outcomes was 90 (12.2%) in the nifedipine GITS group and 110 (14.5%) in the co-amilozide group (not significant). The incidence rates of primary and secondary outcomes were similar in patients without ISH. Conclusion: In patients with ISH, nifedipine GITS and co-amilozide had similar effects on clinical outcomes and BP lowering. They lend support to international guidelines for the treatment of hypertension recommending the use of long-acting dihydropyridine calcium-channel blockers as one treatment option for patients with ISH.

Background We compared the effects of a long-acting calcium-channel blocker with a thiazide-amiloride combination on cardiovascular mortality and morbidity in patients with additional cardiovascular risk factors. The primary objective was to demonstrate 25% superiority of nifedipine GITS. A secondary objective was to establish non-inferiority compared with co-amilozide. Methods A prospective, randomized, double-masked trial was carried out in Europe and Israel, involving 6321 patients of 55–80 years of age with hypertension (blood pressure \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\geq}\ {150}/{95}\) \end{document} mmHg or systolic ≥ 160 mmHg). Patients were also required to have at least one out of ten additional cardiovascular risk factors, such as diabetes or hypercholesterolaemia. Patients were assigned randomly to initial treatment with either nifedipine GITS (N), 30 mg, or co-amilozide (C) (hydrochlorothiazide, 25 mg, and amiloride, 2·5 mg), so that similar numbers of patients with each risk factor could be compared between the two drugs. Dose titration was principally by dose doubling, and addition of atenolol, 25–50 mg, or enalapril, 5–10 mg. Patients were followed for a mean period of 3 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, heart failure or stroke, Secondary outcome variables included death from any cause. Superiority analysis was of time to first event, by intention-to-treat. Non-inferiority analysis required the difference (Δ) in event-rate, and the 95% CI around Δ, to be

Summary Background The efficacy of antihypertensive drugs newer than diuretics and β-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high risk patients with hypertension. Methods We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55–80 years with hypertension (blood pressure ≥150/95 mm Hg, or ≥160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 μg plus amiloride 2·5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25–50 mg or enalapril 5–10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat. Findings Primary outcomes occurred in 200 (6·3%) patients in the nifedipine group and in 182 (5·8%) in the co-amilozide group (18·2 vs 16·5 events per 1000 patient-years; relative risk 1·10 [95% CI 0·91–1·34], p=0·35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p vs 796, p=0·02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0·81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0·33% [−0·7 to 1·4]). Interpretation Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy.

Objective: We compared the estimated costs of coronary interventions from our hospital’s cost accounting system with data from the French Diagnosis Related Group (DRG) cost database, taking the perspective of our hospital. Design: Cost data on hospital resources used by patients hospitalised for acute myocardial infarction (MI), with and without complications, including deceased patients, were collected in a tertiary care university hospital located in Paris, France. The data were collected using the hospital’s cost accounting system and then compared with the estimates provided by the DRG reimbursement schedule for similar conditions. Main outcome measures and results: The estimated costs were 849 euro (EUR) for coronary angiography, EUR4762 for coronary angioplasty with stenting, and EUR4978 to 8067 for MI. The DRG reimbursement schedule provided for acute MI was EUR3920 to 5709. Conclusions: Although the current cost of treating acute MI in a teaching hospital is reasonably close to that in the current reimbursement schedule, rapid technological changes regarding both drugs and devices renders necessary a close monitoring of costs associated with the management of these acute care patients.

Abstract —The aim of our investigation was to determine whether the presence of additional risk factors or type of hypertension (diastolic or isolated systolic) influences blood pressure (BP) response to treatment. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study is a double-blinded outcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years. Dynamic randomization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure that approximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors. Patients with isolated systolic hypertension were also separately randomized. Atenolol or enalapril was the mandatory second-line drug. In 5669 patients who completed the 18-week titration, BP fell from 172±15/99±9 mm Hg (mean±SD) while receiving placebo to 139±12/82±7 mm Hg. Twenty-six percent of patients required 2 drugs, and 4% required 3 drugs. Patients with diabetes were the most resistant to treatment, requiring second and third drugs 40% and 100% more frequently than patients without diabetes and achieving marginally the highest final BP, for any risk group, of 141±13/82±8 mm Hg. Age, smoking, gender, hypercholesterolemia, left ventricular hypertrophy, and existing atherosclerosis had little (

The alphaIIbbeta3 platelet receptor antagonist abciximab (c7E3Fab, ReoPro(R)) has proved to be effective in preventing arterial thrombosis. However, its binding capacity to the platelet precursors, megakaryocytes (MKs), which also express alphaIIbbeta3, is not known. The purpose of this study was to establish whether abciximab is able to react with alphaIIbbeta3 located on human MKs, and to follow its subsequent intracellular trafficking. MKs were grown from CD34+ progenitors from normal subjects and from a patient with type I Glanzmann's thrombasthenia, and abciximab was added at day 10 of culture (4 microgram/ml). Cells were fixed at day 12, cryosectioned, and immunolabelled for abciximab. Labelling was prominent on the MK plasma membrane; it also lined the demarcation membration system. Interestingly, alpha-granule membranes were labelled showing that the antibody was internalized and further stored into MK secretory granules. Abciximab was also strongly detected on and in newly-formed platelets. Glanzmann's disease MKs (which completely lacked alphaIIbbeta3) were consistently negative, confirming that the antibody fragment was specifically interacting with alphaIIbbeta3. In conclusion, this study demonstrated that abciximab: (i) binds MK plasma membrane and demarcation membranes, (ii) trafficks into alpha-granules, and (iii) is expressed on and in nascent platelets. These findings could be taken in account when monitoring anti-alphaIIbbeta3 receptor therapy.

OBJECTIVES We sought to evaluate Dobutamine stress echocardiography (DSE) for predicting recovery of viable myocardium after revascularization with cineangiography as a gold standard for left ventricular (LV) function. We studied the influence of late vessel reocclusion on regional LV function. BACKGROUND Dobutamine stress echocardiography is a well established evaluation method for myocardial viability assessment. In previous studies the reference method for assessing LV recovery was echocardiography; long-term vessel patency has not been systematically addressed. METHODS Sixty-eight patients with a first acute myocardial infarction (AMI) and residual stenosis of the infarct related artery (IRA) underwent DSE (mean ± standard deviation) 21 ± 12 days after AMI to evaluate myocardial viability. Revascularization of the IRA was performed in 54 patients by angioplasty (n = 43) or bypass grafting (n = 11). Coronary angiography and LV cineangiography were repeated at four months to assess LV function and IRA patency. RESULTS Sensitivity and specificity of DSE for predicting myocardial recovery after revascularization were 83% and 82%. In the case of late IRA patency, specificity increased to 95%, whereas sensitivity remained unchanged. In the 16 patients with myocardial viability and late IRA patency, echocardiographic wall motion score index decreased after revascularization from 1.83 ± 0.15 to 1.36 ± 0.17 (p = 0.0001), and left ventricular ejection fraction (LVEF) increased from 0.52 ± 0.06 to 0.57 ± 0.06 (p = 0.0004), whereas in five patients, reocclusion of the IRA prevented improvement of segmental or global LV function despite initially viable myocardium. CONCLUSIONS Dobutamine stress echocardiography is reliable to predict recovery of viable myocardium after revascularization in postinfarction patients. Late reocclusion of the IRA may prevent LV recovery and influence the accuracy of DSE.

Background and Methods Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting–enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P

Accurate echocardiographic parameters for predicting the success of cardioversion or maintenance of sinus rhythm are poorly defined. This prospective transthoracic and transesophageal echocardiographic study was conducted to test the hypothesis that the left atrial appendage flow pattern could be a predictive parameter of the success of cardioversion and maintenance of sinus rhythm in patients with nonvalvular atrial fibrillation. Eighty-two consecutive patients with nonvalvular atrial fibrillation of

Objectives. This study sought to determine whether pravastatin affects clinical or angiographic restenosis after coronary balloon angioplasty. Background. Experimental data and preliminary clinical studies suggest that lipid-lowering drugs might have a beneficial effect on restenosis after coronary angioplasty. Methods. In a multicenter, randomized, double-blind trial, 695 patients were randomized to receive pravastatin (40 mg/day) or placebo for 6 months after successful balloon angioplasty. All patients received aspirin (100 mg/day). The primary angiographic end point was minimal lumen diameter (MLD) at follow-up, assessed by quantitative coronary angiography. A sample size of 313 patients per group was required to demonstrate a difference of 0.13 mm in MLD between groups (allowing for a two-tailed alpha error of 0.05 and a beta error of 0.20). To allow for incomplete angiographic follow-up (estimated lost to follow-up rate of 10%), 690 randomized patients were required. Secondary end points were angiographic restenosis rate (restenosis assessed as a categoric variable, >50% stenosis) and clinical events (death, myocardial infarction, target vessel revascularization). Results. At baseline, clinical, demographic, angiographic and lipid variables did not differ significantly between groups. In patients treated with pravastatin, there was a significant reduction in total and low density lipoprotein cholesterol and triglyceride levels and a significant increase in high density lipoprotein cholesterol levels. At follow-up the MLD (mean ± SD) was 1.47 ± 0.62 mm in the placebo group and 1.54 ± 0.66 mm in the pravastatin group (p = 0.21). Similarly, late loss and net gain did not differ significantly between groups. The restenosis rate (recurrence >50% stenosis) was 43.8% in the placebo group and 39.2% in the pravastatin group (p = 0.26). Clinical restenosis did not differ significantly between groups. Conclusions. Although pravastatin has documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, this study shows that it has no effect on angiographic outcome at the target site 6 months after coronary angioplasty.

Objectives. The aim of this study was to assess the effects of ischemia on diastolic function by analyzing flow propagation velocity with color M-mode Doppler echocardiography.Background. Color M-mode Doppler echocardiography has been proposed as a method of assessing left ventricular filling.Methods. Color M-mode Doppler echocardiography and measurement of hemodynamic data were performed simultaneously at baseline and during angioplasty-induced ischemia. Tau was compared with flow propagation velocity. Late diastolic indexes, left ventricular pressure and flow cessation time were also investigated.Results. During ischemia, left ventricular relaxation rate (tau) increased, whereas flow propagation velocity decreased, from (mean ± SD) 46.8 ± 10 ms to 72.6 ± 18.3 ms and from 59.8 ± 15.8 cm/s to 30 ± 8 cm/s, respectively (all p < 0.0001). The maximal slowing of flow propagation velocity was observed 20 to 30 s after the beginning of the inflation, coexisting with a notch on the ascending limb of the negative rate of rise of the left ventricular pressure (dP/dt) curve. Flow propagation velocity was correlated with tau both at baseline (r = 0.53, p < 0.05) and during inflation (r = 0.53, p < 0.03). Left ventricular end-diastolic pressure increased during ischemia from 13.5 ± 8 mm Hg at baseline to 27.5 ± 7 mm Hg, while a premature cessation of the entering flow occurred −13.8 ± 23 ms before the next Q wave onset, compared with 4.5 ± 19.6 ms after the Q wave onset at baseline (all p < 0.0001).Conclusions. The analysis of flow propagation velocity showed that early filling is highly dependent on left ventricular relaxation rate, particularly through the phenomenon of asynchrony. During ischemia, the premature cessation of late filling is associated with increased diastolic pressures.(J Am Coll Cardiol 1997;29:1246–55)

Objectives. This study sought to evaluate the relation, if any, between fluid overload in congestive heart failure (CHF) and a newly discovered endogenous natriuretic factor acting like loop diuretic drugs: contransport inhibitory factor (CIF).Background. The humoral mechanisms regulating volume overload in CHF are not fully understood. Therefore, we investigated whether there is a role for CIF in this pathologic condition.Methods. Plasma and urinary CIF levels were investigated in 23 patients with chronic CHF and compared with changes in plasma atrial natriuretic peptide (ANP). Twelve patients without CHF served as control subjects.Results. CHF was associated with a highly significant threefold increase in both plasma CIF levels (mean ± SD 7.10 ± 3.01 vs. 2.28 ± 0.92 U/ml, p < 0.0001) and urinary CIF excretion (7,849 ± 3,600 vs. 2,351 ± 1,297 U/day, p < 0.0001) with respect to patients without CHF. CIF increased as a function of impairment in left ventricular ejection fraction (r = −0.703, p < 0.0001) and the severity of clinical status. Plasma ANP was also increased in patients with CHF, although to a lesser extent (68%, p = 0.0501) than plasma CIF, and was also significantly correlated with left ventricular ejection fraction (r = −0.552, p = 0.0004).Conclusions. Plasma and urinary CIF activities were strongly and very significantly increased in chronic CHF. In addition to ANP, this long-term natriuretic agent may be of potential importance in reducing fluid overload in CHF.

We undertook this study to evaluate the importance of redistribution images in thallium 201 single-photon emission computed tomography (Tl-201 SPECT) assessment of myocardial viability after acute myocardial infarction. Stress-redistribution-reinjection Tl-201 SPECT was performed in 55 consecutive patients with recent (within 1 month) acute myocardial infarction. The myocardium was divided into 16 segments and activity assessed visually with a score from 0 to 3 on stress-redistribution and stress-reinjection images. A defect was considered moderate if the stress score was 2 and severe if the stress score was 0 or 1. All moderate defects were considered viable, regardless of score on redistribution or reinjection images. Severe defects were considered viable if they were reversible (improvement of 1 score) on redistribution or reinjection images. Stress-redistribution and stress-reinjection images were visually analyzed and compared in terms of viability classification. On visual analysis, 461 segments (52%) were abnormal. One hundred eleven stress defects were moderate; of these, 28 were reversible on reinjection images only and 15 on redistribution images only. However, all of these segments were viable, regardless of the analysis chosen. Of 350 severe stress defects, 48 were reversible on reinjection and irreversible on redistribution images, and 4 were reversible on redistribution and irreversible on reinjection images. Therefore, in viability assessment, 48 segments were misclassified with stress-redistribution analysis, whereas only 4 segments were misclassified using stress-reinjection analysis. Although the usefulness of Tl-201 reinjection imaging is confirmed, redistribution images seem to be of little interest in postmyocardial infarction viability assessment.

Scintigraphic images of myocardial iodine 123-labeled metaiodobenzylguanidine (MIBG) reflect the relative distribution of adrenergic neurodensity and function in the myocardium. In patients with hypertrophic cardiomyopathy or after infarction, MIBG uptake in hypertrophied myocardium and the infarct-related myocardium was found to be decreased in comparison to blood flow distribution, delineated with thallium 201. Most intriguingly, semiquantitative measurements in patients with congestive heart failure demonstrated reduced myocardial MIBG uptake. This reduction correlated directly with indexes of left ventricular function. Decreases in neuronal density, dysfunction of adrenergic neurons, or chronically elevated circulating norepinephrine levels may account for this diminished myocardial uptake, which, as demonstrated in a pilot study of 90 patients with congestive heart failure, was found to be of predictive value for survival.

SR 33557 is a new calcium antagonist which in vitro demonstrated selectivity for smooth muscle over cardiac muscle. To assess the hemodynamic effects of SR 33557 in humans, SR 33557 was administered intravenously (i.v.) in 9 patients with normal systolic left ventricular function [LV ejection fraction (EF) = 63.7 +/- 8%] undergoing right and left catheterization. Baseline measurements were recorded before and during right atrial pacing (100 beats/min), after which 5 mg SR 33557 was infused in 10 min and hemodynamic parameters were continuously recorded until 30 min after discontinuation of the infusion. Effects of SR 33557 were evident from discontinuation of the infusion, maximal between the tenth and twentieth min after discontinuation of the infusion. Without atrial pacing, the main effect of SR 33557 infusion was to decrease heart rate (HR) from 77.7 +/- 10.7 to 61.9 +/- 9.3 beats/min (p < 0.001). Cardiac index (CI) did not change; stroke volume index (SVI) increased from 44.2 +/- 13 to 50.4 +/- 15 ml.m-2, (p < 0.05). Mean arterial pressure (MAP) decreased from 104.7 +/- 29.6 to 94.3 +/- 22.9 mm Hg (p < 0.05) with no change in filling pressures or systemic vascular resistance (SVR). Consequently, rate-pressure product (RPP) decreased from 8,211 +/- 3,092 to 5,906 +/- 2,025 mm Hg.beat-1 (p < 0.01). Peak positive LVdP/dt decreased from 1,711 +/- 257 to 1,533 +/- 194 (p < 0.01). During the pacing phase, none of the hemodynamic parameters differed from baseline; especially peak positive LVdP/dt remained unchanged. SR 33557 has negative chronotropic action but shows no direct negative inotropic effect in patients with normal systolic LV function.

If the vasodilation of the epicardial coronary arteries caused by linsidomine (SIN-1), the active metabolite of molsidomine, is well established, few data are available concerning the effects of SIN-1 on the acetylcholine (ACh)-induced vasoconstriction of epicardial coronary arteries. Fourteen patients with mild lesions of the left anterior descending artery (LAD) were studied. Intracoronary blood flow velocity was measured by a Doppler probe placed in the proximal segment of the LAD, and cross-sectional arterial area was assessed by quantitative angiography. After initial hemodynamic parameters were measured, 12 mg papaverine was injected into the left main coronary artery. When hemodynamic parameters returned to baseline values, three increasing concentrations of ACh (5 x 10(-7), 10(-6), and 5 x 10(-6) M) were selectively administered into the LAD in a 3 min period for each concentration. While the infusion of ACh 5 x 10(-6) M was continued, 1 mg SIN-1 was injected as a bolus in the ostium of the left coronary artery. After the injection of papaverine, blood flow increased by 197 +/- 8%, with a trend toward vasoconstriction of the proximal and distal segments of the LAD (p = NS). The ACh injection induced a dose-dependent vasoconstriction, reaching 51 +/- 20% on the distal segment of the LAD at the maximum concentration (p < 0.001). After an initial increase in coronary blood flow of 47 +/- 10 and 28 +/- 11% during the first two concentrations of ACh, respectively, the values decreased after the last injection to the level of baseline values. The infusion of SIN-1 antagonized the ACh-induced vasoconstriction, leading to vasodilation of 7.5 +/- 3% (p < 0.005) and 16 +/- 7% (p < 0.001) of the proximal and distal segments of the LAD, respectively; this was associated with an increase in intracoronary blood flow by 42 +/- 8%. We conclude that intracoronary administration of SIN-1 can antagonize the ACh-induced vasoconstriction of epicardial coronary arteries.

To assess the coronary hemodynamic effects of dobutamine in patients with idiopathic dilated cardiomyopathy, dobutamine was infused at the incremental infusion rates of 25, 50, 100, and 200 micrograms/min into the left main coronary artery of nine patients undergoing cardiac catheterization. In response to dobutamine infusion, systemic hemodynamic effects were dose related. At the highest infusion rate cardiac index and left ventricular peak positive rate of rise in ventricular pressure increased from 2.33 +/- 0.54 to 2.97 +/- 0.65 L/min/m (p = 0.001) and from 690 +/- 177 to 1157 +/- 275 mm Hg/sec (p = 0.001), respectively. Left ventricular end-diastolic pressure decreased from 17 +/- 8 to 8 +/- 7 mm Hg (p = 0.001) and a trend toward decrease in left ventricular wall stress was observed (from 166 +/- 75 to 148 +/- 66 gm/cm2, not significant). Heart rate and mean arterial pressure remained unchanged. The coronary hemodynamic response to dobutamine infusion was also dose related. At the highest infusion rate coronary sinus blood flow increased from 133 +/- 35 to 179 +/- 47 ml/min (p0.01) and was associated with an increase in coronary oxygen blood content from 4.5 +/- 0.6 to 7.8 +/- 1.7 ml per 100 ml (p0.01) whereas myocardial oxygen consumption remained unchanged. During dobutamine infusion norepinephrine decreased in the femoral artery and in the coronary sinus from 1.03 +/- 0.34 to 0.641 +/- 0.179 ng/ml (p0.05) and from 1.76 +/- 0.98 to 1.38 +/- 0.65 ng/ml (p0.05), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND Positron emission tomography (PET) with 11C-labeled CGP-12177 (CGP) has been shown to have the potential to noninvasively measure beta-adrenergic receptor concentration in dog heart. The present study was undertaken to evaluate the clinical value of this technique. METHODS AND RESULTS Eight normal subjects and 10 patients with heart failure related to an idiopathic cardiomyopathy were studied. Estimation of beta-receptor concentration was based on a graphic method applied on myocardial PET time-concentration curves obtained after an intravenous injection of 11C-CGP followed 30 minutes later by a coinjection of labeled and unlabeled CGP. The clinical tolerance of these injections was good. Left ventricular concentration of beta-receptors was decreased in patients compared with controls (3.12 +/- 0.51 versus 6.60 +/- 1.18 pmol/mL, respectively; p < 0.001). This 53% decrease agrees with previous in vitro data. In eight of the 10 patients, the beta-receptor concentration obtained from PET was compared with the beta-receptor density determined on left ventricular endomyocardial biopsy samples by in vitro binding technique using 3H-CGP-12177. Results obtained with both techniques were correlated (r = 0.79, p = 0.019). Moreover, decreased beta-receptor concentration correlated with the beta-contractile responsiveness to intracoronary dobutamine infusion (r = 0.83, p = 0.003), indicating a direct link between changes in the receptor number and its biological function. CONCLUSIONS PET appears to be a safe and reliable method of assessing in vivo changes in the number of left ventricular beta-adrenergic receptor sites of patients with idiopathic cardiomyopathy.

Hypercholesterolemia and atherosclerosis are conditions associated with impaired endothelium-dependent relaxation. In hypercholesterolemic animals, intravenous administration of L-arginine, the precursor of nitric oxide, normalizes endothelium-dependent vasodilator activity. In the present study, we questioned whether intracoronary administration of L-arginine in patients with coronary artery disease could improve coronary vascular reactivity to acetylcholine. Thirteen hypercholesterolemic patients with diffuse coronary atherosclerosis but nonstenotic lesions of the left anterior descending (LAD) coronary artery were investigated. Quantitative coronary angiography and subselective intracoronary Doppler flow velocity measurements were performed to determine LAD diameters and coronary blood flow. Intracoronary infusion of acetylcholine was performed during 3 consecutive 3-minute periods at incremental rates adjusted to achieve estimated final concentrations of 5 x 10(-7), 10(-6) and 5 x 10(-6) M. After evaluation of the response to acetylcholine, L-arginine was infused into the LAD at the rate of 25 mg/min (10(-3) M) and the same stepwise 3-minute infusions of acetylcholine were repeated during infusion of L-arginine. Infusion of acetylcholine induced a dose-dependent reduction of distal epicardial LAD diameter reaching -48.5 +/- 17% at 5 x 10(-6) M (p0.01 vs control values). L-arginine alone had no effect on the distal LAD diameter but attenuated acetylcholine-induced vasoconstriction to -21 +/- 9% at 5 x 10(-6) M acetylcholine (p0.01). Coronary blood flow showed a biphasic response to acetylcholine, increasing by 41 +/- 12% at 5 x 10(-7) M (p0.01) and decreasing by 21 +/- 13% at 5 x 10(-6) M (p0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship among neuropeptide Y (NPY), catecholamines and haemodynamics was assessed both at baseline and during inotropic intervention in patients with congestive heart failure. Eighteen patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction (LVEF) = 26± 10%) underwent both right and left catheterization. Haemodynamicparameters were recorded at baseline and during dobutamine infusion. To measure norepinephrine (NE), epinephrine (E) (nmol. l−1: radioenzymatic assay) and NPY (pmol. l−1: immunoradiometric assay) plasma concentrations, blood samples were drawn from the femoral artery and from the coronary sinus, both at baseline and during dobutamine infusion. At baseline, NPY concentration were 2·15±0·97pmol.l−1 in the femoral artery and 1 ·97 ±0·63 pmol. l−1 in the coronary sinus. Peripheral concentrations of NPY were, however, no different from those of patients without congestive heart failure: 2·4±2·7pmol. l−1. Peripheral NE concentration was correlated to haemodynamic parameters: L VEF (r= — 0·65; P

Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction.We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design.In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03).The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

Proper use of drugs can be defined as the use of the right product, in a correct dosage, during an adequate length of time, for a given patient and provided he has no serious side effects. It is virtually impossible, with such a number of drugs, such a number of clinical situations to prescribe adequately without using references or guidelines. References may lead to a unique choice, when the diagnosis is certain and the drug to be given is unique. With a good initial and continuous medical education, doctors can take easily this type of decision. The Summary of Products Characteristics (SPC) helps them; by sticking to this fundamental reference, prescription might be more precise and safe. In a lot of clinical situations the choice between a large numbers of therapeutic strategies necessitates use of a guideline based on scientific knowledge. Finally, a given therapeutic strategy can be as effective as and considerably less expensive than another. In such cases, payers can drive doctors to the prescription of the less expensive strategy. Some difficulties are common to all references and guidelines: 1. A lot of clinical situations are not covered by guidelines. 2. Guidelines should be updated each time there is a modification of knowledge: it is extremely difficult to do. 3. A great number of guidelines exist, issued by scientific community, health authorities or the payers. Sometime you can find a proposition in a guideline and the reverse in another guideline. It could be confusing. 4. Guidelines should be evaluated rigorously to know if they fulfil their goals. 5. Some of those guidelines simply cannot help doctors. They are too complex or do not take into account practical situations. We have made an inventory of those various guidelines and their weaknesses and we propose some solutions to increase their utility. We propose an analysis of the situation and some solutions to improve the quality and the relevance of the guidelines: to create groups of coordination to choose the aims and the elaboration methods, to initiate a register of guidelines, to list the rules for any new guideline with quality control, to propose a continue medical education for all the health workers. It is necessary to measure the impact of any new recommendation and to do periodical actualisation. The goal of these recommendations is to improve global quality of health.

Leem (French Pharmaceutical Companies) realized an inventory of unmet medical needs in 2006 in France for 12 pathologies. All of them are considered as national public health priorities by the law of August 9th, 2004. Allied to the epidemiological projections, analyses concerned various stages and/or pathology forms, impact of guidelines in clinical practice, therapeutic strategies, marketed therapeutics and pharmacological products in an advanced phase of clinical development. With more than 100 products listed in clinical phase III or pre-registration/marketed for those pathologies, French Pharmaceutical Companies contribute, quasi exclusively, to the development of innovative pharmaceutical products to answer unmet medical needs. This study illustrates the necessity of French Government to support therapeutic innovation led by Pharmaceutical Companies in France.

Immediate cardiac transplantation, or urgent implantation of devices for mechanical support of the failing heart, has been shown to be effective as life-saving procedures in patients with cardiogenic shock unresponsive to maximal sympathomimetic treatment. The intravenous administration of enoximone in these patients, in addition to previous inotropic support, should permit a ‘buying of time' strategy, leading to a reduction in the need for complex, invasive and costly techniques, such as artificial hearts. In addition, it should permit improved selection of candidates for cardiac transplantation. A prospective study was started in 1985 to obtain data on the haemodynamic and clinical efficacy of intravenous enoximone in these critically ill patients, and to determine the time gained for evaluation of the need for urgent transplantation. Cardiac index rose from 1.82 ± 0.26 litres/minute/m 2 to 2.67 ± 0.56 litres/minute/m 2 after 30 minutes, while pulmonary capillary wedge pressure decreased from 29.9 ± 7 mm Hg to 18.0 ± 7 mm Hg ( n = 30). This early beneficial effect waned progressively after 6 hours. Prior to the next intravenous infusion at 8 hours, cardiac index was 2.07 ± 0.53 litres/minute/m 2 and pulmonary capillary wedge pressure was 25 ± 8.5 mm Hg. Only four patients could not wait for a biological graft and had to be implanted with a complete artificial heart (3 patients), or a ventricular assist device (1 patient). In all, 30 patients improved and their increased survival allowed a re-evaluation for cardiac transplantation itself; 13 were rapidly (1.7 days; range 0.5–5) confirmed as good candidates. As a whole, this strategy compares favourably with the results of a strategy based on mechanical bridging alone.

As the precursor of overt heart failure, with its grim prognosis, “silent” heart failure is a concept that bears examination. The pathophysiology of congestive heart failure and the mechanisms of the impact of hypertension on the development of left ventricular hypertrophy, and silent and overt heart failure are investigated. In addition, the reasons why diuretics, especially potassium-sparing diuretics such as spironolactone, remain the most effective treatment of mild congestive heart failure, and their role in preventing the evolution of silent to overt heart failure are explained.

Thrombolytic treatment efficacy is greater when the delay between onset of pain and treatment is short. One way to shorten this delay is to give treatment at home, but one cannot recommend this technique if it has not been demonstrated first, that pre-hospital thrombolysis is feasible and safe, and second, that it is useful. We have been able to demonstrate that pre-hospital thrombolysis with APSAC is feasible and safe. Our findings are similar to those of other teams using other drugs. Whether pre-hospital thrombolysis is useful has not been adequately assessed; and we consider that first, the benefit of pre-hospital vs in-hospital thrombolysis must be determined, and second, the results of a study involving many centres, with various levels of training, practicing pre-hospital thrombolysis must be examined. Two large scale studies are currently being performed. One in Seattle, uses left ventricular ejection fraction as the major end-point, whereas the other, the European Myocardial Infarction Project, (EMIP) is using total mortality. Data currently available indicate that pre-hospital thrombolysis with APSAC is feasible, easy and safe. We hope that we will very soon be able to answer the last question: is it useful?

This paper describes the relation between lifestyle and cardiovascular risk globally and for each lifestyle risk factor. In 3 large studies (Interheart, HALE project and the Nurses' health study), four risk factors have been identified: smoking, diet, low level of exercise and low or no alcohol consumption. Prevention of atherosclerotic diseases can be obtained by smoking cessation, diet modifications aimed at lowering body weight and having a Mediterranean style diet, continuing lifelong physical activity such as walking more than two hours a week. Alcohol consumption, although related to lower risk, cannot be prescribed as a preventive action.

Background— The utility of N-terminal proBNP (NT-proBNP) to predict the occurrence of death and hospitalization was prospectively evaluated in the COPERNICUS study, which enrolled patients with an ejection fraction Methods and Results— Baseline plasma concentrations of NT-proBNP were measured in a subgroup of 814 men and 197 women with symptoms at rest or on minimal exertion who were enrolled in the COPERNICUS study and were randomized to placebo (n=506) or carvedilol (n=505). Values of NT-proBNP were markedly increased despite the requirement that patients be euvolemic before the start of treatment (mean±SD, 3235±4392 pg/mL; median, 1767 pg/mL). By univariate Cox regression analysis, NT-proBNP was found to be a powerful predictor of subsequent all-cause mortality (relative risk [RR], 2.7; 95% CI, 1.7 to 4.3; P =0.0001 for above versus below median) and all-cause mortality or hospitalization for heart failure (RR, 2.4; 95% CI, 1.8 to 3.4; P =0.0001 for above versus below median). The predictive value of NT-proBNP was similar when both placebo and carvedilol patients were analyzed separately. No significant interaction was found between NT-proBNP and treatment group ( P =0.93 for above- versus below-median NT-proBNP). Conclusions— NT-proBNP was consistently associated with increased risk for all-cause mortality and for all-cause mortality or hospitalization for heart failure in patients with severe congestive heart failure, even in those who were clinically euvolemic. This marker therefore may be a useful tool in risk stratification of patients with severe congestive heart failure.

We sought to evaluate the influence of pretreatment systolic blood pressure (SBP) on the efficacy and safety of carvedilol in patients with chronic heart failure (CHF).Although beta-blockers reduce the risk of death in CHF, there is little reported experience with these drugs in patients with a low pretreatment SBP, who may respond poorly to beta-blockade.We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.Compared with placebo, carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason, for a cardiovascular reason, or for worsening heart failure (p0.001 for all). The relative magnitude of these benefits did not vary as a function of the pretreatment SBP (all interaction: p0.10). However, because patients with the lowest SBP were at highest risk of an event, they experienced the greatest absolute benefit from treatment with carvedilol. The lower the pretreatment SBP, the more likely that patients would report an adverse event, be intolerant of high doses of the study drug, or require permanent withdrawal of treatment (p0.001 for all). However, these risks were primarily related to the severity of the underlying illness and not to treatment with carvedilol.The current study provides little support for concerns about using beta-blockers (particularly those with vasodilatory actions) in patients with severe CHF who have a low SBP. Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol.

To investigate the impact of treatment on cardiovascular mortality and morbidity, we assessed outcomes in patients with hypertension and diabetes who received co-amilozide or nifedipine in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension. Participants had to be 55 to 80 years of age, with hypertension (≥150/95 or ≥160 mm Hg) and at least one additional cardiovascular risk factor. Patients received 30 mg nifedipine once daily or co-amilozide (25 mg hydrochlorothiazide and 2.5 mg amiloride) daily. Doses were doubled if target blood pressures (P =1.00). A significant benefit for nifedipine-treated patients was seen for the composite secondary outcome (14.2% versus 18.7%; relative risk, 0.76, 95% CI, 0.59 to 0.97; P =0.03). Among patients without diabetes at baseline (n=5019), there was a significant difference in the incidence of new diabetes (nifedipine 4.3% versus co-amilozide 5.6%, P =0.023). Nifedipine GITS once daily is as effective as diuretic therapy in reducing cardiovascular complications in hypertensive diabetics. Nifedipine-treated patients were also less likely to have diabetes or have secondary events (a composite of all-cause mortality, death from a vascular cause, and death from a nonvascular cause) than co-amilozide recipients. Our results suggest that nifedipine could be considered as first-line therapy for hypertensive diabetics.

Stratification of population groups according to cardiovascular risk level is recommended for primary prevention.To assess whether the Framingham models could accurately predict the absolute risk of coronary heart disease (CHD) and stroke in a large cohort of middle-aged European patients with hypertension, and rank individual patients according to actual risk.A prospective cohort study comparing the actual risk with that predicted by either the Framingham equations or models derived from the INSIGHT study.From the INSIGHT prospective trial, conducted in eight countries of Western Europe and Israel, we selected 4407 European patients younger than 75 years without previous cardiovascular events.None.Major cardiovascular events.In this population (45% men, mean age 64.1 years), 124 (2.8%) patients had CHD and 96 (2.2%) had strokes after a median follow-up of 3.7 years. Overestimation of absolute CHD risk by the Framingham equation was observed in all countries (from 2% in the UK to 7% in France), whereas predicted risk of stroke was close to the actual risk. However, patients in the highest risk quintile within each country had a threefold greater risk of a cardiovascular event than those in the lowest quintile.The Framingham models should not be used to predict absolute CHD risk in the European population as a whole. However, these models may be used within each country, provided that cut-off points defining high-risk patients have been determined within each country.

When a medication receives an authorization for the release onto the market, it is necessary to determine the place that it will occupy in the therapeutic strategies with 2 regulatory steps: The Commission de la transparence (Commission for Transparency) gives an opinion on the target population, the placing in the therapeutic strategies, the level of medical benefit for patient, the restriction or not to hospital usage, and the inclusion in the national medical insurance reimbursement scheme for the medications that are not reserved to hospitals. The second step is the passage before the Comité économique du médicament (Medical Economics Committee) that fixes the price of re-emboursement of the product. The place that the medication will occupy depends on the expectations of the doctors, and through them the patients, and the promotional efforts of the pharmaceutic industry. The publicity is framed by a control a posteriori that relies on the advertising elements diffused in the press as much as on the documents presented or put to the doctors. The final place of a given medication in the therapeutic strategies depends on numerous factors that can lead to 2 specialised medicines having the same indications occupying very different parts of the market, without the prescribers being capable to easily justify the reasons that makes them choose one molecule over another.

The usefulness of a product can vary considerably over the course of time. Nothing is more arduous than to have to re-evaluate a medication but nothing is more necessary. The Legal Information of market authorization can become obsolete and necessitate a re-evaluation, a harmonisation with the products of the same therapeutic class, in short, a re-writing. The notion of the level of classification of drug utility can vary: arrival of new products that are more efficacious, publication of negative data concerning the efficacity or security of one or more products of the class. The decision to include in the national re-emborsement scheme, the fixation of the level of re-emborsement, and the price of the product can vary. This necessary fluidity comes up against the unwieldy nature of the procedures that must be put in place in order to carry out a re-evaluation in the proper conditions and in not distorting them at the time of active competition of the drug companies.

Background: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure. Methods: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded. Results: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P

Background: We assessed the behavior of the baroreflex (BR) gain in chronic heart failure (CHF) patients using the spectral analysis method during application of a forcing stimulus, i.e. respiration. Methods: Simultaneous RR interval and arterial pressure fluctuation recordings were obtained during two random-order periods of voluntary paced-breathing (0.15 Hz and 0.25 Hz) in seven patients with moderate CHF (NYHA class II/III; EF, 30 ± 9%; peak VO2, 18 ± 5 ml kg−1 min−1) and six age-matched controls. BR gain was assessed in the time (sequential method) and frequency (cross-spectral gain in the low and high frequency) domains. Results: Slower breathing was associated with a BR gain decrease in CHF patients whereas a BR gain increase was evidenced in controls (BR gain: 6 ± 5 ms mmHg−1 at 0.25 Hz vs. 4 ± 3 ms mmHg−1 at 0.15 Hz, P < 0.05 in CHF; BR gain: 12 ± 7 ms mmHg−1 at 0.25 Hz vs. 15 ± 7 ms mmHg−1 at 0.15 Hz, P < 0.05 in controls). Conclusions: Voluntary breathing, which involves cortical centers in the brain, had major effects on cardiovascular system controller gain in CHF patients, indicating an impairment of the central neural regulation of the autonomic outflow.

Background —Constitutive bradykinin B 1 receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg 9 -bradykinin (a B 1 receptor agonist) and the mechanisms involved. Methods and Results —Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg 9 -bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg 9 -bradykinin was less potent than bradykinin. Hoe 140 (a B 2 antagonist, 10 μg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg 9 -bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg 9 -bradykinin were maintained. Intracoronary lisinopril (0.75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg 9 -bradykinin responses. Intracoronary N ω -nitro- l -arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg 9 -bradykinin. The relaxing effect of des-Arg 9 -bradykinin on isolated coronary rings was prevented by des-Arg 9 ,[Leu 8 ]-bradykinin. Conclusions —In the conscious dog, B 1 receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B 1 receptor stimulation is not as great as that produced by B 2 receptor stimulation.

The aim of this study was to determine whether myocardial velocity gradients assessed by M-mode colour Doppler tissue imaging could be of clinical relevance and represent reliable indicators of regional left ventricular function after acute myocardial infarction.Among 64 consecutive patients with a first acute myocardial infarction, in 50 who had a marked asynergy in the parasternal short-axis view at the mid-papillary muscle level, myocardial velocities and velocity gradients were assessed in the anteroseptum and posterior wall by M-mode Doppler tissue imaging. Similar measurements were obtained in 11 matched healthy volunteers who served as a control group. In patients with anterior myocardial infarction, the peak myocardial velocity gradient in the anteroseptum was significantly lower when compared with controls (mean +/- [SD] 0.0 +/- 0.5 vs 1.1 +/- 0.7 s-1 during systole, P0.01; and 0.3 +/- 0.6 vs 2.0 +/- 0.5 s-1 during diastole, P0.01). Conversely, the peak systolic myocardial velocity gradient in the posterior wall was significantly higher than in controls (2.6 +/- 1.2 vs 1.8 +/- 1.2 s-1, P0.05). In patients with inferior myocardial infarction, the peak velocity gradient in the posterior wall was significantly lower when compared with healthy subjects (0.9 +/- 0.6 vs 1.8 +/- 1.2 s-1 during systole and 1.4 +/- 1.4 vs 4.9 +/- 1.2 s-1 during diastole, both P0.01). The peak systolic tissue velocity gradient in the anteroseptum was significantly higher than in controls (2.1 +/- 1.0 vs 1.1 +/- 0.7 s-1, P0.01).The present study indicates that myocardial velocity gradients assessed by M-mode Doppler tissue imaging are of clinical relevance for the characterization of ischaemic myocardial dysfunction after infarction and may provide quantitative assessment of segmental left ventricular function in this clinical setting.

M-mode color Doppler imaging of the myocardium affords a greater sampling rate and signal-to-noise (S/N) ratio than 2-dimensional (2D) imaging. In this study, we compared myocardial velocities assessed by 2D and M-mode Doppler tissue imaging (DTI) at the same site and evaluated the influence of the S/N ratio on velocity estimates of the currently used DTI systems. In patients with and without impaired regional left ventricular function, myocardial velocities assessed by 2D DTI were lower than those obtained with M-mode DTI. The difference between regional velocities derived from both imaging techniques was positively correlated with the extent of the "black zone," which could be considered as indirectly reflecting the S/N ratio for each frame. Thus in the clinical setting and on currently used echocardiographs, 2D DTI may provide underestimated regional myocardial velocities when compared with M-mode, mainly because of the influence of the lower sampling rate and S/N ratio on velocity estimators of the imaging system.

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains160 mmHg, or has decreased by10 mmHg since the randomization visit, or DBP is85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

Background Abnormal coronary vasomotor responses have been described in transplant patients. The aim of this study was to evaluate the graft epicardial vasomotor responses to different stimuli that increase coronary blood flow. Methods and Results Twelve heart transplant recipients with angiographically normal epicardial coronary arteries were compared 2.7±1.2 months after surgery with 6 control subjects. Coronary flow velocity was measured with a guidewire Doppler. Coronary diameter changes of the proximal and midportion of the left anterior descending coronary artery were assessed by quantitative coronary angiography during rapid atrial pacing, cold pressor test, supine exercise, and subselective infusion of papaverine and after intracoronary injection of linsidomine (SIN-1). Catecholamine plasmatic levels were determined at the different stages of the protocol. In 6 other transplant patients, a cold pressor test was performed before and after intracoronary infusion of phentolamine (10 μg·kg −1 ·min −1 ). Coronary flow velocity increased significantly in both groups during each phase of the protocol. In control subjects, dilation was observed in response to atrial pacing (8.7±7.6%; P P P P P P P P P P Conclusions These results show that flow-mediated, endothelium-dependent vasodilation is preserved early after transplantation. Sympathetic stimulation, which overrides the endothelium-dependent mechanism, can be related to hypersensitivity to catecholamines due to denervation.

Whether angioplasty of occluded vessels after myocardial infarction may have beneficial effects on left ventricular function remains unknown. Patients with a first myocardial infarction and thrombolytic therapy who had an occluded infarct-related vessel at delayed coronary angiography were referred systematically for an elective coronary angioplasty performed between 3 and 4 weeks after the myocardial infarction. All patients underwent stress-redistribution-reinjection thallium-201 single-photon emission computed tomography for myocardial viability assessment. Prior angioplasty, a quantitative evaluation of global and regional left ventricular function, was performed. The study group consisted of 38 patients (aged 57 +/- 10 years); 18 had anterior wall infarctions and 20 inferior wall infarctions, but before angioplasty 3 had a patent artery and were excluded. Angioplasty was successful in 30 patients. At follow-up 13 patients (43%) had an occluded coronary artery. In contrast with patients with an occluded coronary artery at follow-up, those with a patent coronary artery had no left ventricular enlargement and had an improvement in both left ventricular ejection fraction (from 48 +/- 9% to 52 +/- 9.8%, p = 0.002) and regional wall motion index (delta = +0.95 SD, p0.01). In patients with a patent vessel at follow-up, there was a positive correlation between the number of myocardial viable segments and improvement of the infarct zone wall motion (r = 0.52; p = 0.035), and the number of necrotic segments at baseline was positively correlated to the 4-month changes in end-diastolic volume indexes (r = 0.6; p = 0.04). Thus, elective revascularization of occluded coronary arteries with viable myocardium after myocardial infarction improves left ventricular function and lessens remodeling if the artery remains patent during follow-up.

This study was designed to assess the vasomotor response of coronary arteries to exercise and the cold pressor test, and its relationships with the endothelium-mediated dependent mechanism. Twenty-two patients were entered in the study. Group I was composed of 12 patients with a total cholesterol level200 mg/dl associated with angiographically smooth, normal coronary arteries. Group 2 consisted of 10 patients with both a cholesterol level240 mg/dl and angiographic luminal irregularities of the left anterior descending coronary artery. Coronary blood flow was assessed by a 0.018-inch tip guidewire during Doppler ultrasonography, and analysis of the coronary arterial dimension of the midportion of the left anterior descending coronary artery was performed by quantitative coronary angiography. Catecholamine concentrations were assessed at the different stages of the protocol. The rate-pressure product increased during both the cold pressure test and exercise (p0.001). Coronary blood flow velocity increased during the cold pressor and exercise tests by 24.5 +/- 10% and 72 +/- 42%, respectively (p0.001), and by 127 +/- 62% (p0.0001) after administration of papaverine. In group 1, the cold pressor test had a more pronounced vasodilating effect on epicardial coronary arteries (+11.2 +/- 16%) compared with group 2 (-2 +/- 9%, p0.05). Similarly, exercise had a vasodilating action in group 1 (11.3 +/- 15%) compared with group 2 (-1.9 +/- 8%, p0.05). Both responses were highly correlated (r = 0.92, p0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Background After angioplasty coronary reserve improves but does not normalize in most patients. The purpose of this study was to examine before and after angioplasty coronary reserve and transmural myocardial blood flow distribution using myocardial contrast echocardiography. Methods and Results Twelve patients with left anterior descending coronary artery stenosis were investigated before and immediately after angioplasty. A Doppler catheter was placed in the proximal segment. Myocardial contrast echocardiography was performed by imaging the septum in M mode in a parasternal view using a 3.0-mL bolus of sonicated amidotrizoate sodium meglumine through the guiding catheter. The gray level before injection was subtracted from the gray level after injection to maximize contrast time-intensity curves. The area under the curve was used as an indicator of myocardial blood flow, and subendocardial/subepicardial ratios were measured. After baseline measurements were obtained, Doppler and echographic data were recorded after a bolus infusion of papaverine into the left main coronary artery. The same protocol was performed in patients after angioplasty and in five control subjects with normal coronary arteries. Before angioplasty, echocardiographic and Doppler coronary reserve were 2.57±0.48 and 2.54±0.57, respectively. Both increased after angioplasty to 3.65±0.57 and 3.36±0.70, respectively ( P r =.81; P =.0001). Before angioplasty, subendocardial/subepicardial septal ratios decreased from 0.80±0.48 to 0.60±0.27 after papaverine ( P Conclusions These results show that myocardial contrast echocardiography yields flow reserve values that correlate with values obtained using intracoronary Doppler. This technique may be considered as an accurate tool to assess coronary reserve in humans.

We report a case of an almost permanent ventricular tachycardia that occurred in a 39-year-old man a few weeks before admission to the hospital. This arrhythmia was noticeable by its total irregularity and its association with a left ventricular dysfunction. The precise nosological frame for the arrhythmia was difficult to define. This case presented as an idiopathic left ventricular tachycardia, the features of which could be consistent with an atypical parasystole. The rapid abolition of the rhythm disturbance by oral verapamil without recurrence at 6 months resulted in normalization of the contractile function.