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.

Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin.

BACKGROUND: Lipid-lowering therapy can improve endothelial function in patients with coronary artery disease (CAD) and hypercholesterolemia. Little is known about induced changes in myocardial microcirculation. This study prospectively investigated the temporal effects of lipid-lowering therapy with fluvastatin on coronary flow and flow reserve (CFR) in patients with CAD assessed by PET. METHODS AND RESULTS: In an open clinical trial, CFR was studied in 15 patients with angiographically documented multivessel CAD and hypercholesterolemia (LDL >160 mg/dL). Dynamic 13N-labeled ammonia PET imaging in conjunction with adenosine was used to assess regional and global CFR at baseline as well as at 2 and 6 months during treatment with fluvastatin (60 to 80 mg/d). Despite a rapid decrease in total cholesterol (29+/-6%) and LDL (37+/-9%), myocardial blood flow at rest and during stress was unchanged after 2 months of treatment (2.7+/-0.9 versus 2.5+/-0.6 mL x g-1 x min-1). At 6 months, stress blood flow as well as CFR increased significantly (3.4+/-1.0 mL x g-1 x min-1). No change in hemodynamic parameters was noted during the entire study. Nine of 15 patients increased CFR by >20%. All responders demonstrated improvement in anginal symptoms, whereas nonresponders stated no change (n=4) or worsening of symptoms (n=2). The improvement in CFR was not related to the amount of lipid lowering and was independent of the severity of stenoses. CONCLUSIONS: Improvement in stress blood flow and CFR is delayed compared with the lipid-lowering effect of fluvastatin, suggesting a slow recovery of the vasodilatory response to adenosine.

Comparison of temocapril and atenolol in the long-term treatment of mild to moderate essential hypertension.

This 1-year, dose-titration, General Practitioner (GP) study compared efficacy, tolerability and safety of oral temocapril (10-40 mg once daily) with atenolol (25-100 mg once daily) in mild to moderate adult hypertensives (diastolic blood pressure (DBP) 95-114 mmHg). A 12-week dose-titration period, randomized 3:1 temocapril: atenolol, preceded 40 weeks long-term treatment. An intent-to-treat population of 472 patients was analysed for efficacy after 12 weeks dose-titration. Sitting DBP fell significantly (p < 0.001) in both groups, by mean +/- standard deviation (SD) 15.9 +/- 5.7 mmHg on temocapril and by 16.6 +/- 5.9 mmHg on atenolol. Therapeutic equivalence was demonstrated using the two one-sided t-tests procedure according to Schuirmann (equivalence interval [theta 1 - theta 2] < or = 5 mmHg). Responders (DBP < or = 90 mmHg) represented 89.9% of temocapril and 94.0% of atenolol patients. The lower doses were effective in 70.9% of temocapril patients (10 or 20 mg) and in 63.7% of atenolol patients (25 or 50 mg), these doses being continued after the dose titration period. No clinically relevant changes in haematological, biochemical and urinalysis variables occurred. Adverse events were few, largely unrelated to treatment and comparable between groups. In conclusion, temocapril and atenolol proved to be therapeutically equivalent antihypertensives.

[Combined lytic and heart surgical therapy of in open foramen ovale incarcerated giant thrombus with pulmonary and cerebral embolization]. / Kombinierte lytische und herzchirurgische Therapie eines im offenen Foramen ovale inkarzerierten Riesenthrombus mit pulmonaler und zerebraler Embolisation.

A case of phlebothrombosis with recurrent pulmonary and cerebral embolism is presented which occurred in a 42 year old patient two weeks after treatment of a traumatic crural fracture despite of prophylaxis with low molecular heparin. By means of transthoracic echocardiography a large intracardiac thrombus was detected, entrapped in an patent foramen ovale (PFO) and prolapsing through both atrioventricular valves into both ventricles. This was found after systemic thrombolysis with rtPA had been performed because of fulminant pulmonary embolism. Subsequently the intracardiac thrombus was surgically removed and the PFO closed. The importance of an PFO for paradoxical embolism is discussed as well as the various therapeutical paths to treat an "embolus-in-transit" (cardiac surgery, thrombolytic therapy or anti-coagulation).

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.

Dose-related effects of ACE inhibition in man: quinapril in patients with moderate congestive heart failure. The Study Group on Neurohormonal Regulation in Congestive Heart Failure: Lausanne, Switzerland; Berlin, Düsseldorf, Munich, Germany.

Early treatment with ACE inhibitors of even moderate heart failure is clinically beneficial, even though haemodynamic measurements cannot adequately quantitate such improvement. Neurohumoral assessment is, however, supposed to be more accurate. In 55 patients with moderate heart failure (ejection fraction < or = 35%), we investigated the dose-dependent effects of ACE inhibition with quinapril taken orally (2.5, 5 or 10 mg b.i.d.) following a placebo-controlled, parallel design protocol over 12 weeks. Plasma components of the renin angiotensin system, catecholamines and ANF were measured together with haemodynamics both at rest and during exercise. Before ACE inhibitor treatment, median PRA, Ang I and II and catecholamines were normal, while ANF was increased. All these parameters, including ACE activity, rose during exercise. Chronic inhibition of ACE activity was dose-dependent and the maximal fall in Ang II occurred with quinapril 20 mg.day-1. Humoral changes appeared more assessible than haemodynamic alterations even though many of these changes were reasonably correlated. The effects of chronic ACE inhibition on circulating neurohumoral components in patients with moderate heart failure are small and dose-dependent. Since humoral changes are related to haemodynamics they should account for the clinical benefit. Appropriately high doses of ACE inhibitors should be chosen for treatment of heart failure.

[Severe pancytopenia in old age after 12-month ACE inhibitor therapy]. / Schwere Panzytopenie im hohen Lebensalter nach zwölfmonatiger ACE-Hemmer-Therapie.

A sprightly 79-year-old woman was treated for high blood pressure with indapamide (2.5 mg/day) and the angiotensin converting enzyme (ACE) inhibitor lisinopril (5 mg/day). About 12 months after starting treatment a blood count carried out because of a syncopal attack revealed pancytopenia (haemoglobin 3.3 g/dl, erythrocytes 1.0 x 10(6)/microliters, leucocytes 1100/microliters, platelets 8000/microliters). Until then the blood count had been unremarkable. The bone marrow showed severe hypoplasia of all three cell lines with reactive plasmocytosis. Malignant cells were not present. The patient received a total of nine units of erythrocytes and seven units of platelets. Her care included reverse barrier nursing and antibiotic treatment. She was also given high dose steroid therapy (methylprednisone up to 150 mg/day) and granulocyte colony stimulating factor (filgrastim 300 micrograms/day subcutaneously for 25 days), and after a latent period of several weeks juvenile myeloid precursors reappeared in the blood. Before discharge from hospital the results rose to subnormal levels without further transfusions (haemoglobin 8.5/dl, erythrocytes 3.1 x 10(6)/microliters, leucocytes 3900/microliters, platelets 21.000/microliters). In the bone marrow, all three cell lines were beginning to recover. The final diagnosis was incompletely reversible pancytopenia resulting from secondary aplastic anaemia during ACE inhibitor therapy.

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.

Design and analysis of the HYPREN-trial: safety of enalapril and prazosin in the initial treatment phase of patients with congestive heart failure.

Since the introduction of angiotensin converting enzyme (ACE) 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 ACE inhibitor enalapril a multicenter, randomized, prazosin-controlled trial was designed that compared the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 prazosin. Subjects were 1210 inpatients with New York Heart Association (NYHA) functional class II and III. Patients who received enalapril experienced clinically and statistically significantly less symptomatic hypotension (5.2%) than the patients who received prazosin (12.9%). All patients recovered. It was concluded that treatment with enalapril was well tolerated and it is, therefore, unreasonable to restrict the initiation of treatment with enalapril to inpatients.

[The effect of intravenous nifedipine administration on coronary occlusion during coronary angioplasty on ischemia tolerance and collateral function]. / Die Wirkung der intravenösen Nifedipingabe bei koronarer Okklusion während Koronarangioplastie auf Ischämietoleranz und Kollateralfunktion.

In 29 consecutive patients (pts) coronary wedge pressure (CWP) was determined as an indicator of coronary collateral function during coronary angioplasty. Collaterals to the target vessel were angiographically detectable in 21 pts. CPW, aortic pressure (AOP), pulmonary wedge pressure (PCP), intervals to appearance of angina pectoris, surface and intracoronary ECG-changes were registered during two (n = 10) or three (n = 19) consecutive balloon dilatations. A total of 21 pts received 0.8-1.0 mg nifedipine intravenously before a second or third dilatation was performed; a control group (n = 8) received placebo. Hemodynamic parameters were reproducible for all dilatations without nifedipine. After administration of nifedipine significant changes occurred: decreases of CPW (from 34 to 29 mm Hg), AOP (from 121 to 110 mmHg), and PCP (from 12.4 to 9.4 mm Hg), and increase of ischemic tolerance time (angina pectoris) (from 35 to 56 s) (p less than 0.01). Changes in CWP and AOP showed a statistical tendency to correlate (p = 10). Thus, intravenous administration of nifedipine can improve ischemic tolerance during coronary angioplasty. Simultaneous measurement of coronary wedge pressure could not prove enhancement of collateral function as being responsible for these antiischemic effects.

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.

Effect of ketanserin on hemodynamics, plasma-catecholamine concentrations, and serotonin uptake by platelets in volunteers and patients with congestive heart failure.

Ketanserin, which preferentially blocks 5-HT2-serotonergic receptors, was injected intravenously (i.v.) to patients with congestive heart failure in a bolus dose of 10 mg, followed by an i.v. infusion of 3 mg/h over a period of 4 h. The drug caused a decrease in total peripheral resistance and, conversely, an increase in stroke volume. Right atrial and pulmonary artery pressures were decreased. Plasma noradrenaline rose twofold over the basal levels shortly after injection, but showed a distinct fall 2 h after beginning of the treatment. The concentrations of ketanserin in plasma after bolus injection approximated 100-150 ng/ml. The sympathoneuronal and sympathoadrenal reaction during tilting were increased after i.v. injection of 10 mg ketanserin in volunteers. The noradrenaline and adrenaline levels in plasma rose significantly more when compared with values before the injection of the drug. In vitro as well as in vivo ketanserin exerts a concentration-dependent inhibitory effect on the active transport of serotonin and catecholamines (dopamine, noradrenaline, adrenaline) into human platelets. Considering platelets as a model of the sympathetic neurons, the inhibition of reuptake of catecholamines by ketanserin could contribute to the observed increase in circulating catecholamines after injection of the drug.

[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.

[Effects of acute beta-adrenoceptor blockage (metoprolol i.v.) on plasma norepinephrine concentration and hemodynamics in postmyocardial infarction patients]. / Wirkungen einer akuten Blockade adrenerger beta-Rezeptoren aug Noradrenalinkonzentration und Hämodynamik bei Patienten nach Myokardinfarkt.

The effect of acute beta-adrenoceptor blockage (Metoprolol) (M), 0.1 mg/kg i.v.) on left ventricular performance has been investigated at rest and during exercise in 15 patients with 2--3 months old transmural myocardial infarctions. Coronary venous and arterial norepinephrine (NE) concentrations were determined. There was no significant change in arterial and coronary venous NE concentrations (0.27 and 0.22 ng/ml, respectively) after blockage of beta-adrenoceptors (0.36 vs 0.26 ng/ml), which caused a fall of stroke volume from 79 to 68 ml, a reduction of ejection fraction from 62 to 55% and of circumferential fibre shortening form 1.2 to 0.9 circ/sec. During physical exercise the plasma NE concentration in the arterial (0.51 ng/ml) and coronary venous (0.6 ng/ml) blood increased significantly and increased even further to 0.65 and 0.76 ng/ml, respectively, following administration of Metoprolol. The arterio-coronary sinus difference in NE concentrations demonstrate a release of NE from the myocardium. As compared to control values, heart rate following Metoprolol was lower (116 vs 106/min), mean PCV pressure was slightly increased (from 21 to 23 mm Hg) and there was a fall of cardiac index from 6.3 to 5.2 l/min X m2. It is likely that the increased sympathetic activity after Metoprolol and during exercise is a compensatory reaction due to the hemodynamic effects of blockade of beta-adrenoceptors. Further studies are in preparation in order to find out if this is only a transient phenomenon during the early adaptation phase after blockade of beta-adrenoceptors.