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Aims Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40–49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21–33%), including 575 patients with LVEF 40–49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40–49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34–1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24–0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when Conclusion Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF

Aims The adrenergic nervous system is of major importance in congestive heart failure. No genetic polymorphism has previously been identified in the beta1-adrenergic receptor gene. The aim of this study was to find possible mutations in this gene and to relate such findings to morbidity and prognosis in heart failure. Methods and Results Genomic DNA was extracted from blood leukocytes from patients with congestive heart failure (n=184) and from age-matched controls (n=77). The part of the beta1-adrenergic receptor gene corresponding to nucleotide 1–255 was amplified by polymerase chain reaction and analysed by automated sequencing. The patients were investigated by echocardiography and followed regarding symptoms and survival for 5 years. A missense mutation was identified at nucleotide position 145 in the beta1-adrenergic receptor gene, which predicted an amino acid substitution at position 49 ( Ser49Gly ). The allele frequency of the Gly49 variant was 0·13 in controls and 0·18 in patients ( P =0·19). At the time of the 5-years follow-up, 62% of the patients with the wild type gene and 39% of the patients with the Ser49Gly variant had died or had experienced hospitalization ( P =0·005). Patients without the mutation had significantly poorer survival compared to those with the mutation, risk ratio 2·34 (95% CI 1·30–4·20), P =0·003. In a mulivariate analysis, the risk ratio was 2·03 (95% CI 0·99–4·16) P =0·05. Conclusion A novel missense mution in the beta1-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure. These data suggest that the beta1-receptor Ser49Gly variant might be associated with altered receptor function, resulting in myocardial protection in patients with heart failure.

Aim Experimental data in heart failure models and an open trial of seven patients with idiopathic dilated cardiomyo-pathy have suggested beneficial effects of growth hormone on cardiac function. The aim of the present study was to evaluate growth hormone effects on cardiac function in a placebo-controlled study. Methods Twenty two patients with congestive heart failure of different aetiologies in NYHA II and III and an echocardiographic ejection fraction

To describe the occurrence of death, development of acute myocardial infarction and need for hospitalization among patients on the waiting list for coronary artery bypass grafting and percutaneous transluminal coronary angioplasty.All the patients on the waiting list for possible coronary revascularization in September 1990 in western Sweden.Of 718 patients waiting for either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, 15 (2.1%) died between the actual week in September 1990 and prior to revascularization and 12 (1.7%) developed a non-fatal acute myocardial infarction during the same period. All 15 patients who died before undergoing revascularization died a cardiac death. Death and/or the development of an acute myocardial infarction was significantly more frequent among the elderly, among patients with a low ejection fraction and among patients with a history of diabetes mellitus. In all, 29% required hospitalization prior to the procedure. The most common reason was symptoms of angina pectoris requiring hospitalization in 23% of the patients.Among patients on the waiting list before either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, 15 (2.1%) died prior to the procedure and 1.7% developed a non-fatal acute myocardial infarction. The risk of either death or developing an acute myocardial infarction was highest among patients in the older age groups, among patients with a history of diabetes mellitus and among patients with a lower ejection fraction.

Objective To describe mortality and morbidity during a period of 2 years after coronary artery bypass grafting in relation to gender. Design Prospective follow-up study. Setting Two regional cardiothoracic centres which performed all the coronary artery bypass operations in western Sweden at the time. Sub|ects A total of 2129 (1727 (81%) men and 402 (19%) women) consecutive patients undergoing coronary artery bypass surgery between June 1988 and June 1991 without concomitant procedures. Results Females were older and more frequently had a history of hypertension, diabetes mellitus, congestive heart failure, renal dysfunction and obesity. In a multivariate analysis, taking account of age, history of cardiovascula r diseases and renal dysfunction, female sex appeared as a significant independent predictor of mortality during the 30 days after coronary artery bypass grafting (/>

This study aims at describing the in-hospital prognosis of patients admitted with suspected acute myocardial infarction, focusing on the possibility of emergency room prediction of the risk for death and severe complications. From 7157 consecutive patients with chest pain or other symptoms suggestive of acute myocardial infarction in the emergency room, 4690 were hospitalized. Of these, 246 (5%) died in hospital, with a mortality rate among the 921 patients who developed myocardial infarction of 14%, and among those without infarction of 3%. From the clinical history, examination and electrocardiogram in the emergency room, independent predictors of death and death or any severe complication were determined by logistic regression analysis. These included age, initial degree of suspicion of infarction, electrocardiographic pattern, history of diabetes mellitus, history of congestive heart failure and on admission arrhythmias, loss of consciousness, acute congestive heart failure, or unspecific symptoms. From these analyses the probability of death or death or any severe complication can be calculated. Thus, 18% of patients hospitalized due to suspected acute myocardial infarction suffered a severe complication or died in hospital. From a statistical model it is possible to predict the in-hospital prognosis of every such patient.

In 917 patients with acute myocardial infarction (AMI) we evaluated the impact of previous angina pectoris on the prognosis. Thirty-four percent of the patients had chronic angina prior to AMI, and 22% had angina pectoris of short duration. Patients with chronic angina pectoris differed from the remaining patients having a more frequent previous history of AMI, diabetes mellitus, hypertension, and congestive heart failure. They less frequently developed a Q-wave AMI, and had smaller infarcts according to maximum serum-enzyme activity as compared with the remaining patients. They had a higher one-year mortality rate (36%) as compared with those having angina pectoris of short duration (22%), and those with no angina pectoris (26%). Their reinfarction rate was also higher (26%) as compared with that in the other two groups (15% and 9% respectively). In a multivariate analysis considering age, sex, clinical history, initial symptoms, initial electrocardiogram and estimated infarct size, previous chronic angina pectoris was not an independent risk factor for death, but was independently associated with the risk of reinfarction (P < 0.001). Among patients with a history of angina pectoris the outcome was related to medication prior to onset of AMI and at discharge from hospital. Patients in whom beta-blockers were prescribed at discharge had a one-year mortality of 13% as compared with 30% in the remaining patients (P < 0.001).

It is claimed that long-term treatment with beta-blockers improves cardiac function and exercise capacity in patients with various forms of congestive heart failure. This was first reported by Waagstein and coworkers in patients with idiopathic dilated cardiomyopathy in 1975 and was later confirmed in 8 further studies in this type of patient. A total of 211 patients with idiopathic dilated cardiomyopathy were treated for 12–19 months. About two thirds of the patients have improved to some extent. Seven other studies reported favourable long-term effects of beta-blockers in 120 patients with other forms of dilated cardiomyopathy, e.g. caused by coronary artery disease, adriamycin, diabetes, or valvular heart disease. Pooled data from 10 studies on 153 patients with various forms of cardiomyopathy, showed that ejection fraction was improved by 40% from 27 to 38%. Only two studies were inconclusive, both with only one month's treatment. In all studies with favourable effects of long-term beta-blockade, treatment was given for more than 2 months and in most cases for about 6 months. A number of beta-blockers have been used in the studies, including acebutulol, alprenolol, bucindolol, labetalol, metoprolol, practolol and propranolol. In most cases, a rather low dose was given initially and there was a stepwise increase in the dosages. After 6–8 weeks most patients were given beta-blockers in daily doses comparable to those given in patients with angina pectoris and hypertension. There is at present no indication that one beta-blocker is superior to others. It therefore seems reasonable to believe that the effects are due to beta1-blockade. Two studies have included a phase of withdrawal of beta-blocker therapy. This has resulted in marked patient deterioration. Reinstitution of therapy resulted in improvement. This strongly supports the idea that improvement is related to the beta-blocker treatment and is not a spontaneous improvement over time. A number of possible mechanisms might be involved in the beneficial effects of the beta-lockers. It has not been possible to demonstrate any factor that might predict why some patients respond favourably to treatment while others are nonresponders.

Restenosis after coronary angioplasty (PTCA) is a major problem, limiting the long-term efficacy of the procedure. Lipoprotein levels are associated with the development of atherosclerosis and may also be associated with restenosis. In this study the serum levels of cholesterol (CH), triglycerides (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL) were analysed in 157 patients undergoing 161 PTCA procedures. Follow-up coronary angiograms were performed after 6.0 +/- 4.3 months. The restenosis rate was 33%. Treatment with aspirin and a residual stenosis of 25-49% immediately after successful PTCA were the only variables associated with restenosis (P less than 0.05), otherwise the clinical and angiographic characteristics were similar with and without restenosis. There was no relationship between restenosis and the levels of CH, TG, HDL or LDL (P greater than 0.05). In univariate and multivariate analysis of males (n = 121) and females (n = 40) separately, restenosis was associated with low HDL in men and high HDL in women (P less than 0.05), but not with CH, TG or LDL (P greater than 0.05). We conclude that the serum levels of CH, TG and LDL do not seem to be related to restenosis after PTCA. It is suggested that low HDL in males and high HDL in females is related to restenosis.

Several postinfarction trials have evaluated the effect of secondary prophylaxis with different beta-blockers. Although so called meta-analysis of the results from all the trials have shown a beneficial effect of postinfarction beta-blockade, many of the individual studies have shown inconclusive results, mainly due to low statistical power. In order to obtain an evaluation of the merits of postinfarction therapy with metoprolol, data from the five available studies with metoprolol have been pooled into one database. In the total material 5474 patients (4353 men, 1121 women) have been studied during double-blind therapy with metoprolol 100 mg twice daily or matching placebo. The follow-up ranges from 3 months to 3 years. In total 4732 patient years of observation have been obtained. In total there were 223 deaths in the placebo-treated patients as compared to 188 deaths in the metoprolol-treated patients (P = 0.036), which corresponds to mortality rates of 97.0 and 78.3 per 1000 patient years, respectively. The mortality reduction was found both in men and women. As has been reported from individual postinfarction beta-blocker trials, the pooled results showed a marked reduction in sudden deaths (104 in the placebo group, 62 in the metoprolol group, P = 0.002). In a Cox regression model the influence of sex, age and smoking habits on the effect of metoprolol was evaluated. None of these factors influenced the metoprolol effect significantly. It is concluded that metoprolol therapy after acute myocardial infarction reduces the total number of deaths, and especially sudden cardiac deaths. The mortality reduction was independent of gender, age and smoking habits. Available data support a continuous beneficial effect.

This review article deals with the role of beta blockade in the limitation of infarct development. A large number of studies have reported that early administration of beta blockers limits infarct size in animals. In a few, however, these results were not reconfirmed. In man, several large randomized trials have shown that early administration of beta blockade limits infarct development judged from serum enzyme activity and ECG recordings. Delay time between the onset of symptoms and start of treatment is of major importance. It appears as though patients with a higher initial rate pressure product respond most favourably. Although these results are encouraging, the role of infarct limitation in relation to effects on early mortality, chest pain and arrhythmias have not been clearly defined.

The relation of central haemodynamic changes to subsequent mortality and peak enzyme activity was investigated in 190 patients with acute myocardial infarction. The mean delay time from onset of symptoms to the haemodynamic study was 7.2 hours. Major exclusion criteria were heart rate less than 65 beats min-1, systolic blood pressure less than 105 mmHg and lung rales to a distance of greater than 10 cm above the lung bases. Nine patients (4.7%) died within 15 days and 16 patients (8.4%) within 90 days after the infarction. Compared to survivors, non-survivors were characterized by baseline depression of cardiac index, stroke volume index and left ventricular stroke work index, while pulmonary capillary wedge pressure and peripheral resistance were increased. However, a wide overlap between survivors and non-survivors makes the predictive value low in the individual patient. Peak serum aspartate aminotransferase (S-ASAT) activity was weakly related to baseline pulmonary capillary wedge pressure (r = 0.28; P less than 0.001) and stroke volume index (r = -0.22; P less than 0.01). The correlation to pulmonary capillary wedge pressure was only found in anterior (r = 0.34) infarcts. Peak serum lactate dehydrogenase (LD1) was not correlated with baseline haemodynamics.

The central haemodynamic effects of metoprolol in patients with acute myocardial infarction and with heart rate less than or equal to 65 beats min-1 have been investigated in a randomized double-blind trial. The aim was to study the tolerance in this selected patient group and to assess possible differences in haemodynamic response amongst patients with initially higher heart rates. Exclusion criteria were: treatment with beta blockers; heart rate greater than 65 beats min-1; systolic blood pressure less than 110 mmHg; and physical signs of serious heart failure. Following pulmonary artery catheterization, 22 patients were randomized to metoprolol 15 mg i.v. + 50 mg q.i.d. orally (N = 12) or placebo (N = 10). Central pressures and cardiac output were recorded before and during the 24 hours after drug administration. There was a significant fall in heart rate, cardiac index, rate pressure product and stroke work index of 10-20% in the metoprolol, compared with the placebo group. The differences were most pronounced immediately after the metoprolol injection. The pulmonary artery capillary wedge pressure was not significantly changed. The overall haemodynamic response to metoprolol was similar to that reported in patients with acute myocardial infarction and heart rate above 65 beats min-1. Tolerance was good.

In 539 patients 5 years after myocardial infarction (MI), quality of life and factors influencing life quality were studied. All patients originally participated in an early intervention trial with metoprolol. A cardiac follow-up questionnaire and the Nottingham Health Profile were answered by 82%. In the former, information about subjective symptoms, smoking, work and current medication was obtained; the latter described health-related quality of life in terms of energy, sleep, emotions, mobility, pain and social isolation. The rate of and the reasons for rehospitalization were registered in the patients' records. The MI patients reported a comparatively high quality of life. Compared with 'normal' population, a decrease was noted in energy, sleep and mobility, and in sex life, hobby-activity and holiday activity. A nonparametric multivariate analysis disclosed that dyspnoea, angina pectoris and anxiety were closely associated with decreased quality of life. In conclusion, 5 years after MI most patients seemed well-adjusted. Impaired quality of life was reported by patients suffering from angina pectoris, dyspnoea and emotional distress. No relationship was found between health-related quality of life and the beta blocker, metoprolol, which was the most frequently used drug.

Prognosis in congestive cardiomyopathy (COCM) with marked dilatation and heart failure is poor. A low rate of spontaneous recovery was observed. A high level of circulating catecholamines is often found, which may explain the common finding of resting tachycardia. An early series of COCM patients with tachycardia responded surprisingly well when chronic beta-blockade was added to the conventional treatment of failure. Later, even patients without tachycardia were included with a period of placebo preceding beta-blocker treatment in order to exclude patients with spontaneous recovery. Acute beta-blockade was surprisingly well tolerated, possibly because the reduction in contractility was compensated for by an increase in myocardial compliance. After long-term beta-blockade, improvement was observed after 6 months and further improvement was seen after 24 months. In patients improving functionally, there was reduction in heart size and left ventricular end diastolic diameter and increase in working performance. For the whole group, there was a decrease in rapid filling wave in apex cardiogram, reduction in third heart sound and increase in ejection fraction. Changes in the reverse way were seen in these three variables after beta-blocker withdrawal and relapse into heart failure occurred in 6/15 patients. Changes in diastolic function may be an early important effect of beta-blockade in COCM. Increase in survival was seen when beta-blocker-treated patients with COCM were compared to well matched COCM controls. It is suggested that increased sensitivity to sympathetic stimulation contributes to the pathogenesis in some patients with COCM and that improvement in myocardial function explains prolonged survival.

Transmembrane potentials and local extracellular electrograms were recorded from isolated Langendorff perfused canine and porcine hearts. Experiments were also performed on hearts in open-chested anaesthetized animals. Following occlusion of a major coronary artery, resting membrane potential decreased, resulting in depression of the TQ segment. Action potential amplitude and upstroke velocity decreased, leading to ST elevation and delayed activation. At resting membrane potentials around -60 mV, ischaemic cells became inexcitable. Arguments are presented that action potentials during the first 10 min of ischaemia, when malignant ventricular arrhythmias frequently occur, are not 'slow responses' but are instead 'depressed fast responses' where inward current is carried by Na+ ions through partially inactivated fast channels. Mapping experiments, in which 60 to 98 electrograms were simultaneously recorded during spontaneous ventricular arrhythmias demonstrated that ventricular tachycardia is due to macro-re-entry with the re-entrant pathway having a wavelength of the order of 6 cm. No evidence was found for macro-re-entry being the cause of ventricular premature depolarizations. A hypothesis is put forward, whereby the experimental findings of a 'focal' origin are explained on the basis of electrotonic transmission through a small inexcitable zone close to the ischaemic border.