Åke Hjalmarson

Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy.

Adrenergic beta-blocking agents were given to 7 patients with advanced congestive cardiomyopathy who had tachycardia at rest (98 plus or minus 13 beats/min). The patients were on beta-adrenergic receptor blockade for 2 to 12 months (average 5-4 months). One patient was given alprenolol 50 mg twice daily and the other patients were given practolol 50 to 400 mg twice daily. Virus infection had occurred in 6 of the patients before the onset of symptoms of cardiac disease. All patients were in a steady state or were progressively deteriorating at the start of beta-adrenergic receptor blockade. Conventional treatment with digitalis and diuretics was unaltered or reduced during treatment with beta-blocking agents. An improvement was seen in their clinical condition shortly after administration of the drugs. Continued treatment resulted in an increase in physical working capacity and a reduction of heart size. Noninvasive investigations including phonocardiogram, carotid pulse curve, apex cardiogram, and echocardiogram showed improved ventricular function in all cases. The present study indicates that adrenergic beta-blocking agents can improve heart function in at lease some patients with congestive cardiomyopathy. Furthermore, it is suggested that increased catecholamine activity may be an important factor for the development of this disease, as has been shown in animal experiments.

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial

BACKGROUND Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. METHODS We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat. FINDINGS 310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction. INTERPRETATION Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.

Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients with Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Åke Hjalmarson, MD, PhD Sidney Goldstein, MD Björn Fagerberg, MD, PhD Hans Wedel, PhD Finn Waagstein, MD, PhD John Kjekshus, MD, PhD John Wikstrand, MD, PhD Dia El Allaf, MD Jirı́ Vı́tovec, MD, PhD Jan Aldershvile, MD, PhD Matti Halinen, MD, PhD Rainer Dietz, MD Karl-Ludwig Neuhaus, MD András Jánosi, MD, DSc Gudmundur Thorgeirsson, MD, PhD Peter H. J. M. Dunselman, MD, PhD Lars Gullestad, MD Jerzy Kuch, MD Johan Herlitz, MD, PhD Peter Rickenbacher, MD Stephen Ball, MD, PhD Stephen Gottlieb, MD Prakash Deedwania, MD for the MERIT-HF Study Group

Long-term beta-blockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol.

To evaluate the short- and long-term effects of beta-adrenergic blockade (metoprolol) as well as the reaction to withdrawal and readministration of metoprolol in severe heart failure, 33 patients (25 men and eight women; mean age, 47.6 +/- 14.0 years) with dilated cardiomyopathy were studied by right and left heart catheterization, right ventricular biopsy, two-dimensional and Doppler echocardiography, and external pulse recordings. Twenty-six of 33 patients survived more than 6 months, and 24 of the 26 patients improved their functional class (from mean 3.3 to 1.8, p less than 0.0001). These 24 patients were subjected to withdrawal of metoprolol until the number of symptoms increased and deterioration occurred as observed noninvasively (group 1, n = 16), whereas the eight patients did not deteriorate during a 12-month period (group 2). During long-term treatment with metoprolol, there was an increase in ejection fraction from 0.24 to 0.42 (p less than 0.0001), whereas there was a decrease in the left ventricular (LV) end-diastolic dimension (from 7.3 to 6.4 cm, p less than 0.0001), in the grade of mitral regurgitation (from 1.7 to 0.4, p less than 0.0001), and in the grade of tricuspid regurgitation (from 0.6 to 0.05, p less than 0.007). There was a decrease in pulmonary wedge pressure (from 23.8 to 10.7 mm Hg, p less than 0.0001), LV end-diastolic pressure (from 24.1 to 13.4 mm Hg, p less than 0.002), and systolic vascular resistance (from 1,782 to 1,499 dynes/sec/cm, p less than 0.04). There was an increase in systolic blood pressure (from 116 to 132 mm Hg, p less than 0.003), cardiac index (from 2.17 to 2.58 l/min/m2, p less than 0.005), and LV stroke work index (from 31 to 65 g.m/m2, p less than 0.0001). During withdrawal of metoprolol, the heart rate and left atrial dimension increased (p less than 0.0001), whereas ejection fraction decreased (p less than 0.0001). The 12 (of 16) patients in group 1 who survived the withdrawal period had metoprolol readministered, and subsequently, ejection fraction increased (from 0.23 to 0.33, p less than 0.002). Patients had a low number of ventricular beta-adrenergic receptors compared with healthy control subjects (30.3 +/- 2.9 vs. 97.4 +/- 8.7 fmol/mg protein, p less than 0.001), but long-term treatment with metoprolol caused a moderate up-regulation (from 30.3 +/- 2.9 to 49.0 +/- 7.1 fmol/mg protein, p less than 0.05), which may facilitate a more normal response to sympathetic stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

PROLONGATION OF SURVIVAL IN CONGESTIVE CARDIOMYOPATHY BY BETA-RECEPTOR BLOCKADE

24 patients with congestive cardiomyopathy (group I) were compared with a group of 13 controls with similar clinical findings and myocardial function who were selected retrospectively (group II) . All patients received digitalis and diuretics, but group I patients received beta-blockers as well. The survival-rate in group I patients (83%, 66%, and 52% after one, two, and three years respectively) differed significantly from that in group II subjects (46%, 19%, and 10%, respectively). This finding is supported by the demonstration that beta-blockade improved myocardial function in group I subjects. It is therefore suggested that beta-blockade prolongs survival in patients with congestive cardiomyopathy.

Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect.

BACKGROUND Autoantibodies against the beta 1-adrenoceptor have been detected in the sera of patients with idiopathic dilated cardiomyopathy (DCM). The mechanisms by which these autoantibodies can alter normal receptor function are investigated, and the results are interpreted in the light of the beneficial effects of beta 1-blockade in some of these patients. METHODS AND RESULTS Autoantibodies against the beta 1-adrenoceptor, affinity purified from sera of patients with idiopathic DCM, were analyzed in a functional test system of spontaneously beating neonatal rat heart myocytes. Antibodies from rabbits immunized with peptides derived from the amino acid sequence of this receptor were also analyzed. Autoantibodies, against the second extracellular loop increased the beating frequency of isolated myocytes in a concentration-dependent manner, to approximately 80% of maximal isoproterenol stimulation. Rabbit anti-peptide antibodies against the second extracellular loop increased the beating frequency correspondingly. Autoantibodies and rabbit anti-peptide antibodies against the second extracellular loop were able to immunoprecipitate the unliganded receptor but not the antagonist-occupied receptor. In contrast, rabbit antibodies against the extracellular N-terminal sequence 34-57 of the beta 1-adrenoceptor were able to immunoprecipitate both the unliganded and the antagonist-occupied receptor although with no effect on the beating frequency of myocytes. The positive chronotropic effect of the antibodies was completely neutralized both by the addition of increasing concentrations of the beta 1-selective antagonist bisoprolol and by preincubation with the peptide corresponding to the second extracellular loop. The antibody-induced increase in beating frequency remained unchanged for more than 6 hours. This should be compared with the isoproterenol-stimulated beating frequency, which undergoes desensitization within 60 minutes. Addition of isoproterenol to autoantibody-stimulated myocytes resulted in only a small increase in beating frequency and did not cause desensitization. Antibodies had only a marginal effect on cyclic AMP production of stimulated cardiomyocytes compared with the 10-fold increase obtained after stimulation with isoproterenol. CONCLUSIONS The second extracellular loop of the beta 1-adrenoceptor is a specific target for antibodies with stimulatory activity detected in patients with idiopathic DCM. The antibodies have a positive chronotropic effect on isolated rat heart myocytes. Autoantibody stimulation does not cause the normal agonist-induced desensitization phenomena of the effector system. These findings could contribute to our understanding of the pathophysiological mechanisms of the autoantibodies and of the beneficial effect of beta 1-blocking agents in the treatment of patients with idiopathic DCM.

Beneficial effects of long-term beta-blockade in congestive cardiomyopathy.

Twenty-eight patients with heart failure caused by congestive cardiomyopathy, which had been diagnosed according to the criteria of Goodwin and Oakley, were treated with beta-blocking agents for six to 62 months, except for four patients who died within two months. Repeated non-invasive investigations were performed before and during treatment as well as exercise tests and chest x-rays. The echocardiographic and pulse curve findings indicated an improvement in systolic and diastolic myocardial function. The ejection fraction increased from 0.32 +/- 0.02 to 0.42 +/- 0.04, and the third heart sound amplitude and rapid filling wave were significantly reduced. The functional classification improved in 15 patients while in 12 patients it remained unchanged and in one it deteriorated. During follow-up, 10 patients died, most of them suddenly. The mortality was lower than expected in this severely ill group of patients. The beneficial effect of chronic beta-blockade in patients with congestive cardiomyopathy suggests that catecholamines are involved in the pathogenesis of congestive cardiomyopathy, and that patients with congestive cardiomyopathy may have inappropriate sympathetic cardiac stimulation which can be reduced by chronic beta-blockade. It is suggested that beta-receptor blockade should be added to conventional treatment with digitalis and diuretics in all patients with severe myocardial failure caused by congestive cardiomyopathy.

Influence of Heart Rate on Mortality After Acute Myocardial Infarction

Elevated heart rate (HR) during hospitalization and after discharge has been predictive of death in patients with acute myocardial infarction (AMI), but whether this association is primarily due to associated cardiac failure is unknown. The major purpose of this study was to characterize in 1,807 patients with AMI admitted into a multicenter study the relation of HR to in-hospital, after discharge and total mortality from day 2 to 1 year in patients with and without heart failure. HR was examined on admission at maximum level in the coronary care unit, and at hospital discharge. Both in-hospital and postdischarge mortality increased with increasing admission HR, and total mortality (day 2 to 1 year) was 15% for patients with an admission HR between 50 and 60 beats/min, 41% for HR greater than 90 beats/min and 48% for HR greater than or equal to 110 beats/min. Mortality from hospital discharge to 1 year was similarly related to maximal HR in the coronary care unit and to HR at discharge. In patients with severe heart failure (grade 3 or 4 pulmonary congestion on chest x-ray, or shock), cumulative mortality was high regardless of the level of admission HR (range 61 to 68%). However, in patients with pulmonary venous congestion of grade 2, cumulative mortality for patients with admission HR greater than or equal to 90 beats/min was over twice as high as that in patients with admission HR less than 90 beats/min (39 vs 18%, respectively); the same trend was evident in patients with absent to mild heart failure (mortality 18 vs 10%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias.

During a double-blind trial in which patients with suspected myocardial infarction received metoprolol or placebo, we analyzed the occurrence of ventricular tachyarrhythmias. Metoprolol (15 mg intravenously) was given as soon as possible after admission, and thereafter 200 mg was given daily for three months. Antiarrhythmic drugs were given only for ventricular fibrillation and sustained ventricular tachycardia (greater than 60 beats per second). Definite acute myocardial infarction developed in 809 of the 1395 participants, and probable infarction in 162. Metoprolol did not influence the occurrence of premature ventricular contractions or short bursts of ventricular tachycardia. However, there were 17 cases of ventricular fibrillation in the placebo group (697 patients) and only 6 in the metoprolol group (698 patients, P less than 0.05). During the hospital stay significantly fewer patients receiving metoprolol (16) than placebo (38) (P less than 0.01) required lidocaine. In a separate analysis of 145 patients, metoprolol did not influence the occurrence of premature ventricular contractions or short bursts of ventricular tachycardia during the first 24 hours of treatment. Despite a lack of effect on less serious ventricular tachyarrhythmias, metoprolol had a prophylactic effect against ventricular fibrillation in acute myocardial infarction.

β-Blockers and Sudden Cardiac Death

Coronary artery disease remains the major cause of death in developed countries [1], despite tremendous advances in its management. One reason for this is that the changes in treatment seen in the last decade have had little effect on the incidence of sudden cardiac death, which accounts for approximately one half of cardiac mortality [2]. Indeed, in almost one fifth of men with coronary artery disease, the first and only manifestation of their illness is sudden death [3]. Defined as unexpected death from cardiac causes occurring within 1 hour of the onset of symptoms [4], sudden cardiac death is responsible for 300 000 to 400 000 deaths each year in the United States [1]. The cause in at least 80% of patients is ventricular arrhythmia occurring as a consequence of coronary heart disease [5]. A treatment that would substantially reduce the incidence of sudden cardiac death would have a major effect on overall cardiovascular mortality rates. An Approach to Cardioprotection To reduce the incidence of sudden cardiac death, it is desirable to identify those at increased risk for this event and give them effective prophylactic treatment. The most easily identified patients at risk are those with documented coronary heart disease. However, many more persons have latent heart disease, including the 50% of patients with myocardial infarction in whom the infarction is silent [6]. A relatively small proportion of those with undeclared disease can be identified, either through known risk factors for coronary heart disease or as a result of electrocardiography or electrocardiographic stress testing. Coronary angiography yields the most information in predicting risk, but this technique is not practical for investigating large numbers of patients. Some risk factors for coronary artery disease, such as hypertension, hyperlipidemia, and cigarette smoking, are both identifiable and treatable. Although reduction of blood pressure seems to be effective in preventing death from cerebrovascular accident, its effect on coronary mortality rates is less clear [7]. Experimental results in feline left ventricular hypertrophy [8] suggest that myocardial hypertrophy contributes to the adverse electrophysiologic consequences of ischemia and reperfusion. Effective long-term treatment of hypertension may thus have an indirect beneficial effect on the ventricular arrhythmias associated with coronary artery disease. Although simvastatin was recently shown to reduce mortality in patients with established coronary artery disease [9], the use of lipid-lowering drugs does not have proven efficacy in primary prevention. As a result, the commitment of individual physicians to the treatment of hyperlipidemia varies markedly. The most effective preventive measure is cessation of cigarette smoking, which significantly reduces the likelihood of coronary death [10], but the success of programs to help persons stop smoking is frequently disappointing. Other lifestyle changes, such as weight reduction and the introduction of regular physical exercise, may also help but are equally hard to achieve in practice. After high-risk persons have been identified and their risk factors modified, subsequent aims include the treatment of myocardial ischemia, if present, and the suppression of ventricular tachyarrhythmias. The cardioprotective drug chosen should ideally achieve both of these goals, and it should have been shown in clinical trials to reduce the risk for sudden cardiac death. The agents that have most successfully met these ideal criteria are the -blockers, and they have been shown to be consistently effective in large, long-term prevention trials [11]. -Blockers and Prevention of Ventricular Fibrillation: Evidence During 30 years of surveillance, the Framingham Study investigators [12] found that the overall incidence of sudden cardiac death during each 2-year period was 6.3 cases per 1000 men and 2.0 cases per 1000 women. In persons who had no previous coronary heart disease but had definite hypertension, the risk for sudden death was more than double that in persons with normal blood pressure. Incidence rates in persons with previous coronary heart disease (31.6 cases per 1000 men and 10.0 cases per 1000 women) were six to eight times greater than those of persons without coronary heart disease (4.0 cases per 1000 men and 1.6 cases per 1000 for women). Clearly, attempts to significantly reduce overall cardiovascular mortality must address in particular the hypertensive patient and the patient with established coronary heart disease. Primary Prevention of Coronary Disease Risk stratification of patients in the Framingham Heart Study [13] indicates that hypertension is a highly significant risk factor for the development of coronary disease and for sudden cardiac death. The effect of treating hypertension has been assessed in several prospective clinical trials [14]. Although diuretics appear to reduce coronary events in the elderly [15, 16], angiotensin-converting enzyme inhibitors, calcium-channel blockers, and -blockers have not been shown to reduce the frequency of myocardial infarction, nor do they reduce the risk for sudden death. In contrast, evidence shows that -blockers have a primary preventive role in men with hypertension. In the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) study [17], a mean 5-year follow-up of patients treated with metoprolol or thiazide diuretics confirmed that total mortality was significantly lower in the patients treated with metoprolol. The reduction was explained primarily by the 30% reduction in the number of sudden cardiac deaths; these deaths represented 78% of total cardiovascular mortality (Figure 1). This trial has been criticized [18, 19], but the criticisms have been answered [20]. Furthermore, data from other studies [21-23] have also shown trends favoring the use of -blockers in primary prevention. Figure 1. Sudden cardiovascular deaths in hypertensive patients. Secondary Prevention After myocardial infarction, the next most frequent cause of sudden death is arrhythmia, usually ventricular fibrillation [24]. It has been clearly shown that -blockers reduce the incidence of sudden death. Recent evidence [9] also suggests that simvastatin has a beneficial effect in patients with hypercholesterolemia. Aspirin and aspirin-like drugs have been found to reduce early and late mortality after myocardial infarction [25], but no evidence shows any effects on sudden death. An average reduction in total mortality of about 20% has been shown from pooled data from 18 000 patients during long-term treatment after myocardial infarction with -blockers [26]. This translates into an absolute reduction in risk for death from about 10% to about 8%. Even more impressive is that -blocker treatment reduces sudden death among these patients by 32% to 50% [27-30]. The results of three long-term, placebo-controlled trials of -blockers administered after infarction were published in 1981 and 1982 [27-29], providing, for the first time, evidence that medical therapy could reduce mortality after myocardial infarction. The three drugs usedthe non-selective agents timolol and propranolol and the 1-selective agent metoprololreduced total mortality by 26% to 36%. In the Norwegian Multicenter Study Group trial [27], the most pronounced effects of timolol were on the sudden cardiac death rate, which was almost halved. In the -Blocker Heart Attack Trial (BHAT) [28], propranolol reduced the incidence of sudden cardiac death from 4.6% (in participants receiving placebo) to 3.3% (P < 0.05), a reduction of almost 30%. In the Goteborg metoprolol trial [29], a 40% reduction in the number of deaths occurring within 24 hours and within 1 hour of onset of symptoms was seen. An analysis of pooled data from five different trials in which long-term metoprolol therapy was used after myocardial infarction [30] suggested that the reduction in total mortality was due primarily to a 40% reduction in the incidence of sudden cardiac death, a figure that held true for both men and women (Figure 2). Figure 2. Cumulative number of sudden deaths reported in five postinfarction trials. Two large, short-term, prospective trials of -blockers administered soon after the onset of myocardial infarction have also confirmed the efficacy of these agents in reducing mortality in the acute setting [31, 32]. The First International Study of Infarct Survival (ISIS-1) [31] included approximately 16 000 patients and found that atenolol reduced early cardiovascular mortality by 14% after 7 days. The study did not specifically analyze sudden death rates. In the Metoprolol in Acute Myocardial Infarction (MIAMI) trial [32], randomly assigning 6000 patients to metoprolol or placebo produced a 13% difference in mortality at 15 days in favor of metoprolol, but the effect was not statistically significant. On the basis of pooled data from trials of early intervention with a -blocker [33], it has been calculated that -blockers reduce mortality by about 15% in the first week. It is not possible to say from these results that all -blockers will produce similar results in the treatment of myocardial infarction. Although there appears to be a class effect in lowering blood pressure, reducing ischemia, and inhibiting the development of infarction, only a few -blockers have been shown to reduce the risk for sudden cardiac death. This is true of the lipophilic (and hence central nervous system-active) -blockers timolol [27], metoprolol [30], and propranolol [28], but a long-term prophylactic effect has not been shown for the hydrophilic -blockers atenolol [31] and sotalol [34]. The clinical evidence appears to confirm experimental observations that the reduction in sudden cardiac death is, at least in part, mediated through activity in the central nervous system. Little evidence supports the efficacy of other antihypertensive or anti-ischemic agents in the secondary prevention