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Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohormonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 +/- 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 +/- 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of flosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenuated during long-term treatment, flosequinan induces sustained arterial dilatation and improves cardiac pump function without activation of circulating neurohormones.

Cardiovascular parasympathetic control reportedly is reduced in left ventricular (LV) dysfunction and in heart-failure. To evaluate whether parasympathetic intervention differentially affects coronary flow and ischemia in normal (N) vs impaired (I=ejection fraction 70% left CAD. During maximal pacing, heart rate and rate pressure product (myocardial oxygen demand) where 7% and 12% higher in N, compared to CN, but were comparable in I and CI. Moreover, 1 minute post pacing these values were 8% and 12% higher, resp., N vs CN. Vasoconstrictive circulating neurohormones (norepinephrine) increased similarly in all groups. Coronary flow increased 23% more in N than in CN and to a similar extent in I and CI. Myocardial ischemia, as indicated by changes in myocardial lactate metabolism, was less in N [lactate extraction +10% (N) vs -21% (CN), -18% (I) and -19% (CI)]. Fifteen minutes after pacing, coronary flow was still decreased by 11% and coronary vascular resistance increased by 15% in CN, as compared to N. Thus, reduction of parasympathetic tone improves coronary flow and reduces myocardial ischemia in the latter, despite similar sympathetic activation and more pronounced myocardial oxygen demand in N. This supports a greater role for cardiovascular parasympathetic control of (diseased) coronary arterial system in normal LV-function and, possibly, a new area of intervention in antiischemic therapy in the latter.

To identify the effect of L-propionylcarnitine (LPC) on ischemia, 31 fasting, untreated male patients with left coronary artery disease were studied during 2 identical pacing stress tests 45 minutes before (atrial pacing test I [APST I]) and 15 minutes after (APST II) administration of 15 mg/kg of LPC or placebo. Hemodynamic, metabolic, and nuclear angiographic variables were studied before, during, and for 10 minutes after pacing. After LPC administration, arterial total carnitine levels increased from 47 +/- 1.7 mumol/liter (control) to 730 +/- 30 mumol/liter. Hemodynamic and metabolic variables were comparable in LPC and placebo during APSI I, and reproducible in placebo during both tests. Although LPC did not affect myocardial oxygen demand and supply, it diminished myocardial ischemia, indicated by a significant 12% and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during APST II. Moreover, during APST II, left ventricular ejection fraction increased by 18% (p0.05 vs APST I). Furthermore, LPC improved recovery of myocardial function after pacing, with a reduction in the time to peak filling and a 21% increase in both peak ejection and filling rates 10 minutes after pacing (all p0.05). Thus, LPC prevents ischemia-induced ventricular dysfunction, not by affecting the myocardial oxygen supply-demand ratio but as a result of its intrinsic metabolic actions, increasing pyruvate dehydrogenase activity and flux through the citric acid cycle. Because it is well tolerated, it may be a valuable alternative or addition to available antiischemic therapy.

Antiischemic effects of beta 1-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial beta 1-agonistic activity, although useful in preserving cardiac function, may counteract such antiischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective beta 1-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p.05), whereas cardiac output fell temporarily by 9% (p.05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p.05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16 +/- 7% vs. -7 +/- 8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p.05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional beta 1-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its beta 1-antagonistic profile.

Objectives. This study was designed to compare the acute systemic and coronary hemodynamic effects of high doses of intravenous diltiazem in patients with normal versus impaired left ventricular function, investigate the safety of this drug and compare its anti-ischemic potential in these two patient groups during pacing-induced stress. Background. Because coronary hemodynamic effects and negative inotropic properties of diltiazem are dose related, high dose intravenous diltiazem may improve anti-ischemic efficacy but may not be tolerated in patients with impaired cardiac function. Methods. High dose intravenous diltiazem, 0.4 mg/kg for 5 min followed by 0.4 mg/kg for 10 min, was administered to 23 normotensive patient's with coronary artery disease, 11 (group A) with normal and 12 (group B) with impaired ventricular function (ejection fraction

Myocardial infarctions, particularly the larger ones and anterior located, may result in important macroscopic changes, i.e. expansion of the infarct region and hypertrophy of distant areas, followed by a gradual dilatation and a change from the normal ellipsoid to a more spherical form over time. These conformational changes, commonly referred to as remodelling, are accompanied by a reduction in contractility and relaxation, a decrease in cardiac pump function and an increase in wall stress. If untreated, progressive cardiac dysfunction ensues and heart failure may develop. At the cellular level, necrosis, apoptosis and collagen degradation, leading to tissue loss can be found, together with different forms of collagen formation and fibrosis and myocyte hypertrophy in non-infarcted tissue. Although cardiac hypertrophy may initially be compensatory, abnormalities in sarcolemnal receptor density, downstream signalling pathways, and in sarcoplasmatic reticulum and contractile protein function, hypertrophied cells eventually contribute inappropriately to cardiac function. There are quite a few mediators which become activated after an insult such as infarction and which trigger the remodelling processes described above. These include increased wall stress, ischemia, oxidative stress, cytokines, and in particular neurohormonal activation. The renin-angiotensin system is a well recognised neurohormonal activator of remodelling. Local tissue production of angiotensin II is observed after infarction, accompanied by increased ACE levels. ACE inhibition modulates cardiac remodelling, either or both by reducing angiotensin II formation and increased bradykinin production. Whether the latter is pivotal in this process is not entirely clear, although studies suggest that the anti-remodelling effect of the ACE inhibitor disappears when coadministered with a specific bradykinin B2 receptor antagonist [1]. Nevertheless, other studies would indicate similar effects against components of remodelling, e.g. fibrosis, by both ACE inhibitors and angiotensin II type I receptor antagonists [2]. Whatever the mechanism, in patients with left ventricular dysfunction ACE inhibition prevents cardiac dilatation over time, although it may not decrease cardiac size [3,4] As the sympathetic system and endothelins are likewise neurohormonal activators of remodelling, betablockade and endothelin antagonists are also considered to modulate cardiac remodelling. It is of interest that, at least in heart failure patients, additional betablockade with either carvedilol or metoprolol leads to a decrease in cardiac size as compared to only prevention of further dilatation as observed with ACE inhibition alone [4,5] Until recently, aldosterone was considered part of the renin-angiotensin-aldosterone system, produced in the adrenals by angiotensin II. Angiotensin II, however, is not the only stimulus, others like serum potassium, NO and ACTH stimulate aldosterone formation. Of importance, it is now realised that aldosterone and its receptor are present in target organs like the heart and the vascular wall, and may exert auto-or paracrine effects, rather than the endocrine function it was believed to have before. In the cardiovascular system aldosterone exerts a multitude of pathophysiologic actions. Sodium retention, volume expansion and diminished arterial compliance may underlie hypertension. Endothelial dysfunction, magnesium loss and increased PAI-1 levels may lead to or exacerbate ischemic events. Cardiac potassium loss, fibrosis and activation of the cardiac sympathetic system may lead to arrhythmias and sudden death. Fibrosis of the cardiovascular system is a typical feature of aldosterone and unrelated to the reninangiotensin system or to hypertensive effects of the hormone [6]. Aldosterone therefore may be viewed as a single, important player in cardiac remodelling under different conditions of pressureor volume overload. Blocking its effects with an aldosterone receptor antagonist prevents cardiac and vascular fibrosis without interfering acute scar formation. The latter would be of importance following an acute myocardial infarction.

In humans, myocardial ischemia may be induced by various different mechanisms. Besides the classic concept of a disturbed ratio between myocardial oxygen demand versus supply, whereby a fixed epicardial coronary stenosis prevents sufficient oxygen and substrate supply to the heart in relation to its instantaneous need, abnormal coronary vasomotor regulation may significantly affect myocardial perfusion and oxygen supply irrespective of demand. Such abnormalities in vasomotor control may range from severe vasospasm to merely reduced coronary vasodilatation following an appropriate stimulus. Moreover, abnormal vasomotor regulation is not restricted to severe coronary lesions, but may also occur in apparently normal epicardial arteries or microvessels when hypercholesterolemia is present.

To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance, 32 untreated, normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control, at maximal pacing rates, and at 1, 2, 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (≥0.1 mV) or myocardial lactate production, or both, patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing, chest pain was similar (20 ischemic vs 7 nonischemic patients). Also, hemodynamic measurements were comparable, except for contractility, which did not improve, and left ventricular end-diastolic pressure, which significantly increased in ischemic patients. Moreover, during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1,470 ± 60 (control) to 1,632 ± 76 dynes · s · cm−5 5 minutes after pacing (p < 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast, norepinephrine in ischemic patients increased significantly from 1.7 ± 0.2 (control) to 2.6 ± 0.3 (maximal pacing) and to 3.0 ± 0.4 nmol/liter (1 minute after pacing), whereas angiotensin II levels increased from 6.2 ± 1.4 (control) to 9.3 ± 2.1 pmol/liter (1 minute after pacing, p < 0.05). Epinephrine only increased during maximal rates (0.9 ± 0.1 vs 0.6 ± 0.1 nmol/liter at control, p < 0.05). Thus, myocardial ischemia activates circulating catecholamines and angiotensin II, accompanied by systemic vasoconstriction. Because the latter may amplify ischemia, modulation of this neuroendocrine stimulation may be of therapeutic value.

The duration and reproducibility of hemodynamic effects of flosequian, a direct-acting, balanced-type vasodilator, were studied in 19 heart failure patients (NYHA class 3.0 +/- 0.7) receiving 100 mg orally (day 1), placebo (day 2), and again 100 mg (day 3). Flosequinan immediately reduced systemic and pulmonary resistance (23% and 35%, respectively, at 60-90 minutes postdrug) and decreased pulmonary wedge, right atrial, mean pulmonary artery, and mean arterial pressure by 38%, 50%, 25%, and 7%, respectively. Concomitantly, cardiac output, and stroke volume and work increased by 26%, 20%, and 22%, respectively. Most hemodynamic effects persisted for 48 hours. In contrast, changes in pulmonary wedge and arterial pressures, stroke volume, and stroke work only lasted for 2-12 hours. Maximum absolute changes on day 3 were generally comparable with first-dose effects with, again, long-lasting effects on systemic resistance and cardiac output. However, changes in pulmonary artery, wedge, and resistance were significantly shorter than after first dose administration. These data indicate sustained and reproducible arterial dilating effects of flosequinan, but less pronounced and shorter lasting pulmonary arterial and venodilator properties.

Ischemic heart disease is the principal etiology of heart failure in the Western world. Myocardial ischemia is important in cardiac remodeling, a process that leads to a progressive change in the shape and size of the heart and significantly worsens the prognosis of patients with heart failure. Preventing ischemic events, therefore, is an important goal in the management of patients with coronary artery disease. Statins have been shown to reduce the number of ischemic events in these patients, whereas the benefit of beta‐blocker and aldosterone antagonist therapy on ischemic causes of heart failure remains unclear. Several large trials involving patients with asymptomatic left ventricular dysfunction after myocardial infarction or heart failure have shown that angiotensin‐converting enzyme (ACE) inhibitors reduce the incidence of progressive heart failure, death, and ischemic events, thus establishing ACE inhibitors as first‐line therapy for these patients. Other lines of evidence have suggested that ACE inhibitor therapy may also benefit patients with preserved left ventricular function, a hypothesis that is being evaluated in three large, controlled, randomized trials. One of these trials, the Heart Outcomes Prevention Evaluation (HOPE) study, was terminated prematurely because it demonstrated the significant positive effects of the ACE inhibitor ramipril on cardiovascular outcomes in patients with coronary artery disease and preserved left ventricular function. A growing body of data confirms the relationship between ischemia and heart failure and the benefits of ACE inhibitor treatment in a broad range of high‐risk patients.

Patients with congestive heart failure (CHF) have reduced heart rate variability (HRV). Beta-blockers (BB) therapy could improve HRV in CHF. However, HRV is influenced by heart rate. The aim of our study was to assess the effect of BB on heart rate adjusted-HRV in 52 patients from the randomized, double-blind, placebo-controlled CIBIS trial (Cardiac Insufficiency Bisoprolol Study). After progressive increase, Bisoprolol was 5 mg once a day. Holter tapes were recorded at baseline and after 2 months of therapy. To assess HRV at given heart rates, we developed a geometrical analysis of scatterplots (SCP). SCP display beat-ta-beat HRV by plotting each RR against the preceding RR interval. SCP heigth, a measure of short term HRV, was measured at the 10th, 25th, 50th, 75th and 90th percentiles of the total RR dispersion (figure). The 10th percentile represents the fastest hearts rates, whereas the 90th represents the slowest heart rates. There was no significant difference in baseline SCP measurements. Results of BB therapy on SCP heights are as follow (mean ± SD): Placebo Bisoprolol p 10th perc (ms) 58 ± 18 64 ± 30 NS 25th perc (ms) 95 ± 35 101 ± 35 NS 50th perc (ms) 133 ± 43 152 ± 37 0.02 75th perc (ms) 134 ± 53 171 ± 53 0.004 90th perc (ms) 120 ± 12 139 ± 46 0.05 In conclusion, HRV is not improved at higher heart rates. On the contrary, these results indicate that low dose Bisoprolol improves short term HRV at lower heart rates in CHF.

Whereas ACE inhibition acutely reduces myocardial ischemia (MI) through neuroendocrine modulation and, after long-term treatment (1 year), affects ischemic events in LV dysfunction. the short-term antiischemic properties in chronic, stable anginal patients and normal LV function are debated. As a pro-ischemic effect may be explained by lowering coronary artery perfusion pressure, the effects of enalapril (E) 10 mg b.i.d. on ischemia in relation to blood pressure (BP), and placebo b.i.d. were compared in 27 patients with chronic exercise-induced angina pectoris in a double-blind cross-over trial with 2 treatment periods of 2 weeks each. Exercise performance was assessed using treadmill exercise tests. No period or treatment sequence effects were observed for BP, heart rate and exercise performance. After treatment with E, resting systolic and diastolic BP were 7% and 6%, respectively, lower compared to placebo. During maximal exercise, systolic BP and ratepressure product (RPP) were similar during both treatments, whereas diastolic BP was 6% less with E. Maximal workload was comparable after both treatment periods. No differences between treatment were seen with regard to exercise duration, time to angina, maximal ST-depression (0.2 mV in both groups) and time to 0.1 mV ST-depression. When patients were divided into 2 groups according to BP response on an initial dose of 10 mg E, 11 pts ≥ 20 mmHg and 16 pts l 16 mmHg, still no differences during exercise were found. Thus, in stable chronic exercise-induced angina, short-term E does not decrease myocardial ischemia, irrespective of first-dose BP response. Also, no pro-ischemic effects as a result of lowering coronary artery perfusion pressure were observed.

Despite a well-established rationale for pharmacologically induced arterial and venous vasodilatation in congestive heart failure, the clinical usefulness of long-term vasodilator therapy without concomitant converting-enzyme inhibition generally has been disappointing. With the exception of nitrates and, possibly, the combination of nitrates and hydralazine, the use of converting-enzyme inhibitors in many aspects appears preferable in the majority of patients. This article reviews the pathophysiology of inappropriate vasoconstriction in heart failure, the cellular mode of action of the various vasodilators, hemodynamic effects with respect to the peripheral site of action, clinical usefulness and limitations of different vasodilators, and the various determinants of clinical efficacy. Finally, an attempt is made to assess when and how to introduce vasodilator treatment with and without concomitant ACE inhibition.

Pacing-induced changes in regional coronary flow were studied continuously with krypton-81m by intracoronary infusion in 25 patients: 21 with 50% or greater diameter narrowing of 1 or more left coronary arteries (group I) and 4 with less than 50% diameter reduction of a left coronary artery (group II). No changes occurred in group II. In group I, krypton-81m perfusion decreased progressively in all areas with more than 70% diameter narrowing, with a simultaneous increase in normal regions. At the end of pacing during angina, krypton-81m perfusion was reduced to 81 ± 4% of control in areas with 71 to 90% diameter reduction (n = 8) and to 69 ± 6% in areas with more than 90% diameter narrowing (n = 15). In contrast, in regions with 50 to 70% diameter reduction changes were variable (decrease in 4 regions, increase in 2 and an unchanged distribution in 1 region). Krypton-81m perfusion decreased early, before general signs of ischemia in areas with more than 90% diameter reduction, whereas this decrease occurred later in regions with 71 to 90% diameter narrowing, concurrently with ST-segment changes but before anginal pain. Although all signs of ischemia had dis-appeared between 2 and 5 minutes after pacing, changes in krypton-81m distribution persisted in most areas for 5 to 15 minutes after pacing. It is concluded that the functional significance of coronary arterial narrowing can be assessed with a continuous intracoronary infusion of krypton-81m. Changes in regional distribution persisted after cessation of pacing-induced ischemia, indicating an ongoing decrease in regional myocardial blood flow.

The acute hemodynamic and antiischemic properties of amiodarone were investigated in 16 patients with more than 70% diameter reduction of a left coronary artery. Two successive atrial pacing stress tests (APST I and II) were performed, with an interval of 40 minutes in between, and amiodarone, 5 mg/kg/5 min, was infused 30 minutes after APST I. Hemodynamic changes during amiodarone administration consisted of a 20% decrease in left ventricular (LV) systolic pressure, a 13% decrease in systemic vascular resistance and an 18% decrease in stroke work. Coronary vascular resistance was reduced 19% and coronary sinus flow increased 23%. Despite a secondary 14% increase in heart rate, contractility decreased 21%, accompanied by a 45% increase in LV end-diastolic pressure, which persisted until APST II. Although most hemodynamic changes were observed only during the infusion, contractility and LV systolic pressure were still diminished at the beginning of APST II and remained so during pacing, resulting in a reduction in myocardial oxygen demand compared to APST I. Although overall myocardial oxygen consumption and coronary flow were equal during both pacing tests, amiodarone significantly reduced pacing-induced myocardial ischemia. Lactate metabolism remained normal during APST II (lactate extraction 12 +/- 3% vs -28 +/- 8% (APST I) at maximal pacing rates [p less than 0.05]), while ST-segment depression, LV end-diastolic pressure postpacing and angina were also significantly reduced during APST II. Thus, in humans, intravenous amiodarone reduces vascular resistance and contractility and inhibits pacing-induced myocardial ischemia, presumably by reducing myocardial oxygen demand.

The temporal relation between myocardial lactate and hypoxanthine metabolism and regional changes in krypton-81m perfusion during pacing-induced ischemia was studied in 17 patients with coronary artery disease (CAD). During incremental atrial pacing, lactate production and hypoxanthine release occurred early and simultaneously, accompanied by ST-segment changes, but before angina and only few minutes after a significant (17%) reduction in krypton-81m perfusion in areas with more than 90% luminal diameter reduction. During maximal pacing heart rates, krypton-81m distribution decreased to 68 ± 7% of control in areas with more than 90% diameter reduction and to 80 ± 4% in 70 to 90% reduction (both p < 0.05 vs control). Maximal lactate production occurred 15 seconds after pacing (extraction −15 ± 7% vs 16 ± 2% during control, p < 0.05) and peak hypoxanthine release 1 minute after pacing (Δ arteriovenous −2.64 ± 0.8 μM vs 0.08 ± 0.21 μM during control, p < 0.05). Krypton-81m perfusion decreased in 20 of the 21 CAD areas. Angina, ST-segment changes, hemodynamic alterations and lactate production occurred in 15, 14, 9 and 15 patients, respectively. In contrast, hypoxanthine release was found in all cases. After pacing, lactate production and all general indexes of ischemia persisted for only 2 to 3 minutes. In contrast, krypton-81m perfusion was still significantly reduced 5 minutes after pacing and was only accompanied by hypoxanthine release (Δ arteriovenous −1.41 ± 0.6 μM, p < 0.05 vs control). Therefore, although lactate production and hypoxanthine release occur early and simultaneously during pacing-induced ischemia, closely following coronary flow changes in high-stenotic areas, hypoxanthine appears to be more sensitive and consistent as indicator of ischemia. Persistant reductions in krypton-81m perfusion and hypoxanthine release strongly suggest prolonged ischemia after cessation of pacing.

Sequential hemodynamic effects of intravenous pimobendan (UD-CG 115 BS), a novel compound with positive inotropic and vasodilating properties, were investigated during left heart catheterization in nine patients with left ventricular dysfunction (ejection fraction less than or equal to 40%) and moderate congestive heart failure (NYHA classes II and III). Studies were carried out before (C) and for 60 min after intravenous administration of 5 mg of pimobendan over 1 min. Pimobendan immediately and progressively reduced systemic resistance [16 and 28% at 10 and 60 min postdrug, respectively (p less than 0.05 vs. C)] and left ventricular end diastolic pressure [from 24 +/- 3 (C) to 12 +/- 3 mm Hg at 60 min, p less than 0.001)]. Cardiac output gradually increased by 24%, but stroke volume did not, due to an equally progressive 14% rise in heart rate, whereas stroke work increased by 21% (all p less than 0.05 vs. C). Both contractility and relaxation, measured at fixed heart rates, significantly improved by 30 and 20%, respectively, at 50 min postdrug. Thus, pimobendan has immediate and prolonged arterial vasodilating effects, together with positive inotropic and lusitropic properties, resulting in an early but sustained improvement of left ventricular pump function and filling pressures.

The acute effects of ACE inhibition on neurohormonal activation are complex. Sympathetic tone decreases as a direct result of angiotensin II reduction; however, an increase in bradykinin may stimulate sympathetic tone. Consequently, divergent coronary and systemic hemodynamic effects may ensue. As these acute ACE inhibitor effects are incompletely identified in humans, 49 pts with significant ( g 70%) CAD received enalaprilat, perindoprilat or captopril intravenously, which resulted in immediate ( ≤ 5’) 73% ACE inhibition and a 52% reduction in arterial angiotensin II. Twenty-two patients received placebo. During a 15-minute study protocol, placebo induced no changes. In the treated group, arterial norepinephrine (NE) increased at 5 and 15 minutes by 11% and 12%, respectively, and arterial epinephrine (E) by 11% and 14%, respectively. Heart rate did not change, but contractility (V MAX ) increased by 13% and 4%, respectively. Mean arterial pressure (MAP) decreased by 2% and 5% and systemic vascular resistance (SVR) decreased by 4% and 7%, respectively. Despite the reduction in coronary perfusion pressure, coronary blood flow (CBFj increased by 8% at 5 minutes, while coronary vascular resistance ICVR) decreased by 10% and 11%, respectively, at 5 and 15 minutes. Arterial 6-keto-F2α, the prostacyclin metabolite, was 52% higher compared to placebo, but increased late, at 15 minutes. Other prostaglandins and cardiac neurohormonal balances remained unaltered. Thus, in contrast to the well-known modulation of sympathetic activity by chronic converting enzyme inhibition, acute ACE inhibition results in an immediate increase in circulating catecholamines and improves myocardial contractility and coronary flow. The effect on sympathetic tone and contractility cannot be explained by changes in circulating angiotensin II and prostaglandins or cardiac renin-angiotensin, which suggests a bradykinin-related effect.

179 Comparison of the effects of metoprolol and Carvedilol on symptoms, well-being and quality-adjnsted life-years: a description of the "patient-journey" in COMET. J. Cleland I , A. DiLenarda 2, P. Hanrath 3, M. Komajda 4, J. Lubsen 5 , B. Lutiger 6, M. Metra 7, W. Remme 8 , K. Swedberg 9, R Poole-Wilson 1° on behalf of The COMET Investigators 1The Academic Cardiology Unit, Kingston upon Hull, United Kingdom; 2 0spedale di Cattinara, Department of Cardiology, Trieste, Italy; 3 Med. Klinik I der Med. Fakultgit der RW, Aachen, Germany; 4Pitie Salpetriere Hospital, Department of Cardiology, Paris, France; 5 SOCAR Research SA, Nyon 2, Switzerland; 6E Hoffmann LaRoehe, PBA, Basel, Switzerland; 7University of Brescia, Cattedra di Cardiologia, Brescia, Italy; 8Sticares Foundation, GR Rhoon, Netherlands; 9Sahlgrenska University Hospital, Department of Medicine, GOteborg, Sweden; 1°National Heart & Lung Institute, London, United Kingdom