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Introduction Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. Methods and results BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF>40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). Conclusion Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%. [ABSTRACT FROM AUTHOR]

Aims: Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function., Methods and Results: The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft-Gault equation (GFR(c)). In the placebo group, renal function (GFR(c)) declined by 5.5 min(-1)within 1 year, vs only 0.5 ml min(-1)in the ACE inhibitor group (P<0.05). This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFR(c)(divided into tertiles: 24.0, 28.9, and 41.2%; P<0.01). The risk-ratio for GFR(c)<81 ml min(-1)vs >103 mL min(-1)was 1.86 (95% CI 1.11-3.13; P=0.019)., Conclusions: Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Aims: Residual ischaemia following acute myocardial infarction (AMI) is related to an adverse outcome, although the effect of early initiation of statin therapy is unknown., Methods: A randomized, placebo-controlled, double-blind, parallel study was performed, which compared fluvastatin 80 mg daily with placebo in patients with an AMI and total cholesterol of <6.5 mmol.l(-1). Ischaemia was measured by ambulatory electrocardiographic (AECG) monitoring over 48-h at baseline, after 6 weeks and at 12 months., Results: Five hundred and forty patients were included (83% male, age 61+/-11 years); 43% had an anterior AMI and 50% were treated with fibrinolytics in the acute phase. After 12 months, the total cholesterol (TC) level was reduced by 13% and LDL-C (low-density-lipoprotein cholesterol) by 21% (from 3.5 mmol.l(-1) to 2.7 mmol.l(-1)) in the fluvastatin treatment group. Both TC and LDL increased by 9% in the placebo group (P<0.001 between groups). At baseline, ischaemia on AECG was present in only 11% of patients, and absent in 77%; in the remaining 11%, recordings were technically inadequate. After 6 weeks, 32/48 (67%), and 12 months 35/46 (76%) of the patients with ischaemia on the baseline AECG, no longer showed signs of ischaemia. Nevertheless, ischaemia at baseline was predictive for the occurrence of any major clinical event (RR=2.35; 95% CI 1.39-3.2;P <0.001). Fluvastatin treatment did not affect ischaemia on AECG, nor the occurrence of any major clinical events as compared to placebo. Post-hoc analysis in patients with the most pronounced ischaemia at baseline showed a trend for a beneficial effect of fluvastatin on major clinical events (P=0.084)., Conclusion: Residual ischaemia after AMI is observed less frequently in the present study, than in earlier studies, although it is predictive for future cardiovascular events. As a result, the present study was underpowered, and no effect of fluvastatin on AECG ischaemia, or major clinical events in the first year after AMI, could be detected. The present data do not confirm other reports which support widespread use of statin treatment early after AMI., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd.)

Aims: To predict the long-term left ventricular volume index early after myocardial infarction and to investigate the relationship between long-term left ventricular dilatation risk and clinical outcome., Methods and Results: By applying a previously developed dilatation model, we predicted the 6-month left ventricular volume index early after myocardial infarction (median 9 days) in 13,679 GISSI-3 patients, to identify patients at high risk of long-term left ventricular dilatation. The left ventricular systolic and diastolic volume indexes at 6 months were predicted with r=0.72 and r=0.68, respectively, in the subgroup of patients in whom a pre-discharge echo was available (n=7842). Patients predicted to be at risk for long-term left ventricular dilatation had an increased risk of mortality (RR 1.87, 95% CI: 1.48 to 2.36) and heart failure at 6 months (RR 2.59, 95% CI:2.04 to 3.28), but no increased risk of reinfarction at 6 months (RR 1.12, 95% CI: 0.87 to 1.45) or of angina pectoris (RR 1.07, 95% CI: 0.95 to 1.20)., Conclusion: Our prediction of long-term left ventricular dilatation, obtained by applying our new dilatation model in over 13,000 GISSI-3 patients, correlated well with mortality and heart failure after myocardial infarction. Therefore, our new dilatation model may contribute to more efficient risk stratification early after myocardial infarction., (Copyright 2001 The European Society of Cardiology.)

Aims: Experimental evidence has suggested that semicarbazide-sensitive amine oxidase is involved in vascular endothelial damage and in the process of atherosclerosis, through the formation of reactive aldehydes, hydrogen peroxide and ammonia from endogenous substrates. Recent evidence indicates that semicarbazide-sensitive amine oxidase may be identical with the vascular adhesion protein-1. In patients with diabetes mellitus and chronic heart failure the plasma activity is raised relative to the severity of the disease. The prognostic value of plasma semicarbazide-sensitive amine oxidase is not known., Methods and Results: Plasma semicarbazide-sensitive amine oxidase activity was measured at baseline in patients with moderate to severe chronic heart failure who participated in a large European study (PRIME-II). The 372 patients who took part in a pre-defined substudy in The Netherlands were investigated and a survival follow-up (maximum 5.4 years, mean 3.4 years) was carried out. Within the follow-up period 195 patients died. Plasma semicarbazide-sensitive amine oxidase was higher at baseline in those who died than in the survivors (653+/-258 vs 540+/-242 mU. l(-1), P<0.001). Dividing the patients into two groups according to plasma values above or below the median value of 550 mU. l(-1), semicarbazide-sensitive amine oxidase was found to be a prognostic parameter for survival, both in univariate (P<0.0001) and in multivariate (P=0.0106) analysis. Semicarbazide-sensitive amine oxidase values >550 mU. l(-1)had a 1. 50 (95% CI, 1.10-2.04) times increased risk of death., Conclusion: The finding that plasma semicarbazide-sensitive amine oxidase is an independent prognostic marker for mortality in chronic heart failure supports the concept that an elevated plasma semicarbazide-sensitive amine oxidase level has deleterious effects, possibly due to vascular endothelial damage., (Copyright 2000 The European Society of Cardiology.)

Aims: To examine whether the presence, or development, of atrial fibrillation in patients with advanced chronic heart failure, is associated with a poorer prognosis, compared to patients with sinus rhythm and chronic heart failure., Methods and Results: We examined 409 patients with moderate to severe chronic heart failure, and compared patients with sinus rhythm (n=325) to those with atrial fibrillation (n=84). At baseline, the two groups were similar regarding most indices of severity of chronic heart failure, such as left ventricular ejection fraction (0.23) and New York Heart Association (NYHA) functional class, while they were different for age (70 years for atrial fibrillation vs 67 years for sinus rhythm patients), aetiology of chronic heart failure, blood pressure, concomitant treatment, and plasma neurohormones (all P<0.05). During a mean follow-up of 3.4 years (range 2.0-5.4), 203 patients (50%) died. The majority of deaths was due to progressive chronic heart failure (55%) or was sudden (28%), but there was no difference in mode of death between sinus rhythm and atrial fibrillation patients. Overall mortality was higher in atrial fibrillation patients (60%), than in those with sinus rhythm (47%; risk ratio 1.40, 95% CI 1.01-1.92, P=0. 04). After adjusting for important prognostic variables, such as age, left ventricular ejection fraction, NYHA class, renal function, and blood pressure, the presence of atrial fibrillation was no longer related to increased mortality (risk ratio 0.86, range 0.59-1.24, P=ns). Of the 325 patients who had sinus rhythm at baseline, 30 (9%) developed atrial fibrillation during the study. These patients were older (70 vs 66 years, P<0.007), and had slightly lower blood pressure and plasma norepinephrine concentrations (P<0.05), but were otherwise similar. During follow-up, mortality was similar in these two groups (47% in those with new onset atrial fibrillation, vs 47% in those who had sinus rhythm throughout the study)., Conclusions: The present data do not support the concept that the presence, or the development of atrial fibrillation in patients with advanced chronic heart failure is independently related to an adverse outcome during long-term follow-up. The generally observed higher mortality in patients with atrial fibrillation thus seems to be related to other factors, associated with atrial fibrillation., (Copyright 2000 The European Society of Cardiology.)

Aims: In patients with coronary artery disease acetylcholine (a muscarinic agonist) causes vasoconstriction. The effect of atropine (a muscarinic antagonist) on coronary vasotone in patients with normal or impaired left ventricular function is unknown., Methods and Results: Twenty-four patients who required atropine infusion (to supplement heart rate response) during atrial pacing (pacing was conducted to assess ischaemia as part of an experimental protocol) were studied; 17 patients had normal and seven impaired left ventricular function (ejection fraction < or =0.40). Two control groups were selected from a large database (from patients in whom atrial pacing was carried out but to whom atropine was not administered) to match the normal (n=20) and dysfunction (n=10) groups. In the normal left ventricular function group atropine increased rate pressure product by 12 +/- 4%, as compared to those without atropine (P < 0.05). Left ventricular end diastolic pressure increased less in the atropine group (+40 +/- 8% vs +78 +/- 6%;P < 0.05). Arterial norepinephrine increased similarly in both groups, but coronary flow (as assessed by using a thermodiluting method in the coronary sinus) increased 23 +/ -4% more in the atropine group (P < 0.05). Further, there were lower levels of myocardial lactate production and ST-segment depression in the atropine group [lactate extraction +13 +/- 6% (atropine) vs -19 +/- 4% (controls), ST-segment depression 1. 3 +/- 0.6 (atropine) vs 1.8 +/- 0.2 mm (control), both P < 0.05 between groups]. In contrast, in the dysfunction group the overall effect of atropine was less pronounced., Conclusion: In patients with normal left ventricular function atropine improves coronary flow and reduces myocardial lactate production and ST-segment depression during atrial pacing, suggesting a reduction in myocardial ischaemia., (Copyright 1999 The European Society of Cardiology.)

Aims: A large number of drugs are currently used for the treatment of chronic heart failure. Treatment for other cardiovascular disorders has been shown to differ between countries. In this study we examined whether this would also be true in heart failure., Methods and Results: We studied patients with moderate to severe heart failure, who were enrolled in an international survival study, and compared patterns of drug use between the nine countries that each included >50 patients in the study. The results were analysed to determine whether observed differences between countries could be explained by differences in the patients recruited. 1825 patients were studied (range 81-427 per country). By trial protocol, most patients were treated with angiotensin converting enzyme (ACE) inhibitors (92%) and all with diuretics, but the proportion of patients taking high doses of these drugs was markedly different between countries. Large differences were also observed in the use of digoxin (overall 64%, 39% in the U.K. to 87% in Germany) and antiarrhythmics (overall 25%, with the highest use 44% in France). The use of beta-blockers and calcium antagonists was low (overall 6% and 8%, respectively), but also different between countries. Anticoagulants (overall 43%) were used in many patients in the Netherlands and Switzerland (around 70%), while antiplatelets (overall use 30%) were most often prescribed in Denmark (51%)., Conclusions: Large differences in drug use and dosing for patients with advanced heart failure are observed between (European) countries. None of these differences could be explained by differences in patient characteristics, and whether they are related to factors such as tradition, economic circumstances and national guidelines, etc. is unknown., (Copyright 1999 The European Society of Cardiology.)

Aims: Most studies in chronic heart failure have only included patients with marked left ventricular systolic dysfunction (i.e. ejection fraction < or =0.35), and patients with mild left ventricular dysfunction are usually excluded. Further, exercise capacity strongly depends on age, but age-adjustment is usually not applied in these studies. Therefore, this study sought to establish whether (age-adjusted) peak VO2 was impaired in patients with mild left ventricular dysfunction., Methods: Peak VO2 and ventilatory anaerobic threshold were measured in 56 male patients with mild left ventricular dysfunction (ejection fraction 0.35-0.55; study population) and in 17 male patients with a normal left ventricular function (ejection fraction >0.55; control population). All patients had an old (>4 weeks) myocardial infarction. By using age-adjusted peak VO2 values, a 'decreased' exercise capacity was defined as < or = predicted peak VO2 - 1 x SD (0.81 of predicted peak VO2), and a severely decreased exercise capacity as < or = predicted peak VO2 - 2 x SD (0.62 of predicted peak VO2)., Results: Patients in the study population (age 52+/-9 years; ejection fraction 0.46+/-0.06) were mostly asymptomatic (NYHA class I: n=40, 76%), while 16 patients (24%) had mild symptoms, i.e. NYHA class II. All 17 controls (age 57+/-8 years) were asymptomatic. Mean peak VO2 was lower in patients with mild left ventricular dysfunction (23.6+/-5.7 vs 27.1+/-4.6 ml x min(-1) x kg(-1) in controls, P<0.05). In 75% of the study population patients (n=42) age-adjusted peak VO2 was decreased (NYHA I/II: n=29/13) and in 18% of them severely decreased (n=10; NYHA I/II: n=6/4). In contrast, only three patients (18%) in the control population had a decreased and none a severely decreased age-adjusted peak VO2., Conclusion: In patients with mild left ventricular dysfunction, who have either no or only mild symptoms of chronic heart failure, a substantial proportion has an impaired exercise capacity. By using age-adjustment, impairment of exercise capacity becomes more evident in younger patients. Patients with mild left ventricular dysfunction are probably under-diagnosed, and this finding has clinical and therapeutic implications.

Aims: Heart failure is a major medical problem in the elderly. Neurohormonal activation plays a role in the pathophysiology of heart failure, but is also affected by ageing. The present study was carried out to examine the influence of age on neurohormonal activation and prognosis in patients with chronic heart failure., Methods and Results: We studied 372 patients with moderate to severe chronic heart failure (New York Heart Association [NYHA] functional class III-IV), who were treated with angiotensin converting enzyme (ACE) inhibitors (95%), diuretics (99%), and digoxin (59%). Their mean age was 68 +/- 8 years (range 38-80), left ventricular ejection fraction 0.23 +/- 0.08, and 77% were males. The relationship between age and plasma neurohormones (norepineprine, epinephrine, dopamine, renin, aldosterone, atrial natriuretic peptide, N-terminal atrial natriuretic peptide, and endothelin), and age and prognosis was examined. Only atrial natriuretic peptide and N-terminal atrial natriuretic peptide showed an independent, positive correlation with age (P < 0.0001). On univariate analysis, norepinephrine also increased, while renin and aldosterone decreased (all P < 0.05). As regards mortality (25%), there was no linear increase with ageing for the group as a whole during follow-up, but patients in the highest age quartile (> 74 years) had a significantly higher mortality (risk ratio 1.9) than younger patients (P < 0.05)., Conclusions: Although several plasma neurohormones are affected by ageing on univariate analysis, only atrial natriuretic peptide and N-terminal atrial natriuretic peptide show a highly significant increase with ageing on multivariate analysis. There is no linear increase in mortality with ageing, but in the truly elderly heart failure patients (> 74 years), age alone was an independent predictor for mortality.

Unlabelled: In acute studies ibopamine, an a selective dopamine agonist, induces moderate increases of GFR and ERPF, and a fall in plasma norepinephrine levels in patients with congestive heart failure (CHF). We evaluated acute and chronic effects of ibopamine on renal haemodynamics, sodium excretion, PRA, plasma aldosterone (ALD) and norepinephrine levels in an open controlled study in 10 patients aged (51-79 years) with mild CHF, NYHA class II-III. All patients used digoxin and frusemide. After a control study day, the second study day involved the administration of 100 mg ibopamine. Subsequently the patients continued to take ibopamine 100 mg three times daily for one month, at which time the chronic effects were measured on the third study day., Results: On the second day ERPF rose from a baseline of 288 +/- 32 to a mean of 308 +/- 32 ml.min-1 x 1.73 m-2 (P < 0.05) during the 4 h after the first administration of ibopamine and GFR rose from 77 +/- 8 to a mean of 84 +/- 8 ml.min-1 x 1.73 m-2 (P < 0.05). The ratio GFR/ERPF, representing the filtration fraction (FF) remained unchanged. On the third study day GFR and ERPF at baseline were similar to those before ibopamine treatment. After the acute on chronic administration we observed an increase in GFR (from 76 +/- 6 to a mean of 85 +/- 7 ml.min-1 x 1.73 m-2 (P < 0.05)), and in ERPF (from 279 +/- 27 to a mean of 293 +/- 29 ml.min-1 x 1.73 m-2 (P < 0.05)). Plasma norepinephrine levels fell from 2.63 +/- 0.48 to 1.92 +/- 0.27 nmol.l-1 (P < 0.05) after the acute administration of ibopamine, and remained unchanged after the acute on chronic ibopamine administration (C: 1.80 +/- 0.42 nmol.l-1). No changes in sodium excretion were observed, either in blood pressure, heart rate, PRA or ALD. We conclude that renal function is preserved during chronic ibopamine treatment and the acute moderate increase of ERPF and GFR after a single dose of 100 mg of ibopamine is still present after one month of treatment with ibopamine in patients with CHF. Ibopamine lowered plasma norepinephrine levels in our patients with CHF, and these values remained unchanged after the acute on chronic administration of ibopamine.