Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy.

BACKGROUND: the effects of long-term administration of beta-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial. PATIENTS AND METHODS: patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) < or =0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo. RESULTS: metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01). CONCLUSION: metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.

First dose hypotension with enalapril and prazosin in congestive heart failure.

Since the introduction of angiotensin converting enzyme inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the angiotensin converting enzyme inhibitor enalapril a multicenter, open, randomized, prazosin-controlled trial was designed comparing the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 mg prazosin. Subjects were 1210 inpatients with New York Heart Association functional class (I)/II and III who were not adequately compensated with digitalis and/or diuretics. In the group receiving enalapril, 3 patients (0.5%) experienced severe hypotension on day 1 and 28 patients (4.7%) moderate hypotension. In those given prazosin, 15 patients (2.6%) experienced severe hypotension and 60 patients (10.3%) moderate hypotension. The difference is statistically significant (P less than or equal to 0.000012). All patients recovered. It was concluded that treatment of patients suffering from congestive heart failure New York Heart Association functional class (I)/II or III with enalapril is comparably well tolerated.

Changes in plasma catecholamine concentrations in patients with coronary heart disease during pacing and physical exercise.

To study the difference in sympathetic activity during pacing the right atrium or during physical exercise in patients with coronary heart disease, we investigated circulating plasma catecholamine concentrations in the coronary sinus and brachial artery radioenzymatically in 11 male patients with well documented coronary artery disease. Heart rate was increased stepwise 20 beats/min from 90 beats/min up to 150 beats/min by pacing the right atrium and physical exercise was performed by increasing work load stepwise by 25 from 25 up to 100 W on an ergometric bicycle. Plasma noradrenaline and adrenaline concentrations were increased significantly only during physical exercise. In addition, there was an increase in arterial-coronary sinus noradrenaline difference during graded physical exercise, whereas no further release of noradrenaline from the myocardium occurred during pacing. An enhanced cardiac sympathetic tone in patients with coronary heart disease is discussed. It is suggested that atrial pacing is not an adequate stimulus evoking an overall increase of cardiac and peripheral sympathetic tone.

Beneficial clinical effect of very early enalapril treatment in patients with acute left ventricular failure complicating myocardial infarction.

Acute myocardial infarction (AMI) leads to left ventricular dysfunction, the extent of which predicts mortality. We studied the effect of very early enalapril treatment in patients with left ventricular failure (Killip classification II-III) resulting from AMI. In a double-blind randomized trial, patients on conventional treatment were started on placebo (PL, n = 15) or 2.5 mg enalapril (EN, n = 15) twice daily as early as 24 to 30 h after AMI and were followed up over a period of 21 days. One patient died in each treatment group. There were three dropouts in the placebo group (progressive heart failure requiring antiotensin-converting enzyme inhibition) and one dropout in the enalapril group (malignant ventricular arrhythmias). Plasma atrial natriuretic peptide (ANP) and norepinephrine decreased similarly in both groups from elevated baseline concentrations. The patients with the highest baseline ANP levels died in both groups: EN: 579 fmol/ml (mean 65.3 +/- 34.4 fmol/ml), PL: 403 fmol/ml (mean 63.5 +/- 37.6 fmol/ml). Killip classification improved in 9 of 13 patients on enalapril but only in 5 of 11 patients on placebo. On echocardiography an increase in fractional shortening (FS) (3.2 +/- 7.5%, p < 0.05) was found with enalapril only. Patients on placebo required more diuretics, and plasma aldosterone increased threefold. Thus, very early enalapril treatment may help prevent left ventricular failure after AMI. Extremely high initial plasma ANP concentrations may predict an unfavorable outcome.

[Adams-Stokes syndrome in a case of Mobitz type II AV-block triggered by premature atrial contractions]. / Adams-Stokes-Anfälle durch Vorhofextrasystolen bei AV-Block II. Grades

The case of a patient with Mobitz type II AV-block is presented who suffered from recurrent dizzy spells and syncopal attacks. These episodes were due to intermittent asystoles lasting for 3-17 seconds, and it could be shown that they were triggered by two or more successive premature atrial contractions. The observation that there were no subsidiary escape beats or rhythms during the asystolic intervals and the ECG pattern for the conducted beats (RBBB and LAH) suggest an intraventricular (trifascicular) level of AV-block. The exact analysis of the asystolic pauses makes it likely that these were initiated by the penetration of the premature atrial impulses into the left posterior subdivision of the left bundle (concealed conduction). The present case demonstrates the fact that premature atrial contractions may produce prolonged asystolic attacks in patients with advanced intraventricular conduction disturbances.

[Natural history in patients with mitral- and aorticvalve-disease (author's transl)]. / Natürlicher Verlauf bei Patienten mit Mitral- und Aortenklappenfehlern

Knowledge and due consideration of the natural history of valvular heart disease are prerequisites for their operative therapy. Presumptive mortality and morbidity of the surgical intervention must be weighted against the expected prognosis under medical treatment alone. The timing of the operation depends on these considerations. Mitral stenosis and the chronic forms of mitral and aortic incompetence have similar natural histories and for both signs and symptoms are good indicators for an eventual progression of the condition. The length of the period during which the patient is free of complaints may be quite variable but a critical change in the natural history comes about once the disease causes signs and symptoms. Surgical repair is indicated when the patient reaches stage III according to the NYHA-classification. The prognosis is worst for aortic stenosis, in particular due to the danger of sudden death. Patients with high pressure gradients are at particularly high risk; this holds even true for those patients which are not yet suffering from any complaints. The prognosis becomes even more serious, when signs such as dyspnea, anginal pain, or syncopal attacks occur. Prognosis and indication for surgical intervention cannot be evaluated reliably by considering only the clinical signs without knowledge of hemodynamic parameters. Acute mitral and aortic incompetence, in paricular when they occur during baterial endocarditis, must be observed very closely because of their most serious prognosis; if necessary, emergency surgery must be carried out in these cases.

[Haemodynamic effect of dobutamine in cardiac failure (author's transl)]. / Hämodynamische Wirkung von Dobutamin bei Patienten mit Herzinsuffizienz

Dobutamine, a new catecholamine with a positive inotropic action, was given by infusion to 9 patients with cardiac failure in a dosage of 5 and 7.5 mug/kg-min over a period of 15 minutes. An improvement of left ventricular function was proven by an increase of cardiac output by 33%, a reduction of end-diastolic pressure from 21 to 14 mm Hg, an improvement of left ventricular ejection fraction from 29 to 39% and of the mean circumferential fibre contraction velocity from 0.4 to 0.8 circ/s. The systolic aortic pressure increased by a mean of 14% (5 mug/kg-min) and 23% (7.5 mug/kg-min). However, the resistance of the systemic circulation decreased from 1858 to 1439 and 1444 dyn-s-cm-5. Cardiac frequency remained unchanged with a dosage of 5 mug/kg-min and increased by a mere 7 beats/min with a dosage of 7.5 mug/kg-min. There was no increased tendency for arrhythmia. Dobutamine thus appears to act relatively selectively on myocardial beta-1 receptors. Results so far indicate therapeutic success in patients with severe cardiac failure, particularly in the low-output syndrome.

[Sinus-node recovery time in the sick-sinus syndrome (author's transl)]. / Bedeutung der Sinusknotenerholungszeit beim Sinusknotensyndrom

Sinus-node recovery times were measured, before and after atropine administration, in 21 patients with the clinical diagnosis of sick-sinus syndrome. The results were compared with those reported by other workers. It is concluded that sinus-node recovery times of more than 1 400 ms are most likely due to sinus-node damage (sick-sinus syndrome); normal recovery times are rare in such patients. The diagnosis of the syndrome is strengthened if the recovery time remains abnormally long even after atropine. Further useful diagnostic information can be obtained from the total stimulation phase (duration until restoration of the basic rhythm), this being overall longer in patients with the syndrome than in normal subjects. The increased incidence of A-V nodal rhythms before restoration of the basic rhythm is another indication of organic damage to the sinus node, especially if it also occurs after atropine. The significance of a recovery time which is prolonged before but normal after atropine is less clear: a raised sensitivity to vagotonic influences may be the determining factor here.

The effect of carotid sinus nerve stimulation on muscle and skin nerve sympathetic activity in man.

Microelectrode recordings of multi-unit sympathetic activity were made in the right peroneal nerve of 4 awake human subjects during carotid sinus nerve stimulation. 36 periods of CSN-stimulation gave in all cases an inhibition of the muscle nerve sympathetic activity and there was good temporal agreement between this effect and the reduction of heart rate and blood pressure. The neural inhibition was marked during the first part of the stimulation but with continued stimulation the sympathetic activity reappeared, in most cases with reduced strength. In contrast, 20 periods of CSN-stimulation had no reproducible effect on skin nerve sympathetic activity. In most cases, the neural activity remained unchanged but both increases and decreases could occur. The results demonstrate that stimulation of carotid sinus baroreceptors in man has different effects on sympathetic outflow to different regions: a clear inhibition of the outflow to the muscles but no discernable effect on impulses destined to the skin.

[Sinus node syndrome]. / Das Sinusknoten-Syndrom

Recently disorders of sinus node function have found increasing interest in clinical medicine thanks to new diagnostic and therapeutic developments. This paper represents a comprehensive review of these conditions, combined under the name "Sick Sinus Syndrome" (SSS). Besides a detailed analysis of 63 cases seen at our institution, the results of other groups are compared and extensively discussed. The clinical picture of the SSS is characterized by a wide variety of bradycardiac and tachycardic atrial arrhythmias, occurring separately or in combination. These can be classified in three subgroups: Patients with exclusive sinus bradycardia; patients with sinoatrial exit block or transient episodes of sinus arrest with or without AV escape rhythms; and finally patients with the bradycardia/tachycardia-syndrome, which are complicated by additional atrial tachyarrhythmias. The symptomatology of the SSS is multiform and extends from symptomless cases and those with only general signs of reduced cardiac function to patients with recurrent severe syncopal attacks which may lead to cerebral damage and even death. Besides the typical history, the diagnosis of the SSS primarily rests upon the ECG, especially the long term ECG recorded continuously on a 24 hrs. tape (Holter technique). Also the exercise ECG is of some value, characteristically showing an inadequate increase in the sinus rate, sometimes with AV escape systoles and -rhythms. In addition various provocative tests have been devised which are of help to differentiate between a pathologic and a normal sinus node function. Among these the determination of the sinus node recovery time following overdrive atrial pacing has gained wide acceptance. In most cases the exact etiology of the SSS is not known. In addition to coronary and inflammatory heart diseases a primarily degenerative lesion of the sinus node, comparable to cases with "primary heart block" are discussed. There is also a remarkably frequent past history diththeria. Rarer causes of the condition represent cases with cardiomyopathy, thyreotoxic heart disease, collagen and other disorders and also a familial manifestation of the SSS has been described. Therapeutically, pharmacologic treatment with vagolytic, beta-adrenergic or the common antiarrhythmic drugs is often unsuccessful, especially in the treatment of the Brady-Tachy-Syndrome. Digitalis glycosides, however, are frequently of some value, as they represent an effective prophylactic agent against atrial tachyarrhythmias without prolonging the sinus node recovery time or reducing significantly the sinus rate. While a few patients do not require any treatment, an artificial cardiac pacemaker has to be inserted in most cases. Atrial stimulation may be superior to ventricular on-demand pacing in some patients, and also a special system for the treatment of the SSS combined with significant AV block (binodal disease) has been designed, the bifocal sequential pacemaker.

[Positive inotropic effects of doxaminol in congestive heart failure]. / Positiv-inotrope Akuteffekte von Doxaminol bei Herzinsuffizienz.

The hemodynamic effects of doxaminol, a new, orally applicable beta-agonist, chemically dissimilar to catecholamines, were studied in comparison to those of dobutamine by means of thermodilution. After single-dose application of doxaminol in cases of congestive heart failure, cardiac output and stroke volume increased, heart rate increased slightly, pulmonary and systemic arterial pressure remained constant, and peripheral vascular resistance decreased. No arrhythmias appeared, but one patient suffered an attack of angina.

[Initial systolic ejection rate as a parameter of ventricular function in valvular heart disease (author's transl)]. / Initiale systolische Austreibungsgeschwindigkeit als Mass der Ventrikelfunktion bei Herzklappenerkrankungen.

In patients with valvular heart disease the initial systolic ejection rate was determined in an attempt to characterize ventricular function in pressure and volume overload. By means of left ventricular cineangiography, the volume change during the initial third of the ejection phase was determined and the mean ejection rate of this period was calculated. A total of 40 patients were examined, 7 patients without heart disease, 15 patients with pure aortic regurgitation, 9 patient with pure aortic stenosis and 9 patients with pure mitral regurgitation. In patients with pure aortic regurgitation and high-normal values for ejection fraction and mean velocity of circumferential fiber shortening (mVcf) a significant increase in initial systolic ejection rate when compared to the group of normals was observed. The distribution of the stroke volume for each third of the ejection phase corresponded to the normal pattern. In contrast, in patients with low-normal values for ejection fraction and mVcf, a decrease in the initial systolic ejection rate below the normal value was observed, along with a pathological distribution of the stroke volume during the ejection phase. This finding was also noted in all patients with pure mitral regurgitation and pure aortic stenosis. In aortic stenosis, the decline in initial systolic ejection rate was regarded as a consequence of the outflow tract obstruction, whereas in volume overload, this was regarded as a sign of a decline in ventricular function which is not recognized with global parameters such as ejection fraction and mVcf.