The value of repeated echocardiographic evaluation in patients with idiopathic dilated cardiomyopathy during treatment with metoprolol or captopril.

Serial echocardiographic investigations were carried out on patients with idiopathic dilated cardiomyopathy, to evaluate treatment effects on left ventricular (LV) performance during therapy with either metoprolol or captopril. Thirty-two patients (23 males and 9 females) with mild to moderate symptoms of heart failure (NYHA II-III) and a mean age of 49 years were included in the investigation. The patients were investigated with Doppler echocardiography before treatment, after 3 and 6 months of treatment (either metoprolol or captopril) and 1 month after withdrawal of treatment. Intra- and inter-investigator reproducibility was acceptable, with a coefficient of variation of less than 5% for LV dimensions. A reduction in LV dimensions was seen in both treatment groups. In the metoprolol group there was also an increase in LV stroke volume and fractional shortening. The non-invasive data were in accordance with invasive measurements of stroke volume and LV filling pressure. In patients with idiopathic dilated cardiomyopathy and mild to moderate symptoms of heart failure, echocardiography seemed to be sufficiently reproducible to be used for determination of treatment effects in a longitudinal heart failure study. Both metoprolol and captopril were well tolerated and had favourable effects on LV performance.

The effects of metoprolol and captopril on heart rate variability in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: The effects of treatment with captopril or metoprolol on heart rate variability (HRV) were investigated in 38 patients (29 men and 9 women) with mild to moderate symptoms of heart failure due to idiopathic dilated cardiomyopathy (DCM). HYPOTHESIS: The aim of the study was to investigate and compare the effects of the angiotensin-converting enzyme inhibitor captopril with those of the selective beta-adrenergic receptor blocker metoprolol on HRV in patients with idiopathic DCM. METHODS: Heart rate variability was analyzed in the time and frequency domains from 18th of Holter monitoring before randomized treatment was started, after 6 months of therapy, and 1 month after therapy was stopped. RESULTS: Captopril treatment increased HRV expressed as total power and low-frequency power in the frequency domain. There was no change in the time domain. In the metoprolol group, there was a pronounced increase in both time- and frequency-domain indices of HRV. The increase in total power was partly maintained 1 month after therapy was stopped in both treatment groups. CONCLUSION: Treatment with captopril and metoprolol increases HRV in patients with DCM. This effect seems to be maintained for at least 1 month after therapy is stopped. The increase in HRV seems to be more pronounced with metoprolol, and the two different pharmacologic approaches may have additive effects that are of prognostic importance in patients with heart failure.

The circulating renin-angiotensin system during treatment with metoprolol or captopril in patients with heart failure due to non-ischaemic dilated cardiomyopathy.

OBJECTIVE: To investigate the effects of beta-blocker (metoprolol) or angiotensin-converting enzyme inhibitor (captopril) treatment on neurohormonal function in a randomized prospective study on patients with heart failure due to dilated cardiomyopathy. PATIENTS: Fifty-four patients (42 men and 12 women, mean age 50 years) were studied. There were three patients in NYHA (New York Heart Association) functional class I, 32 patients in class II and 19 patients in class III. METHODS: Measurements of plasma renin activity (PRA). plasma angiotensin II (A II) concentration and plasma atrial natriuretic peptide (ANP) concentration were made at rest and also in a subgroup (n = 32) during exercise. The urinary excretion of aldosterone was also determined. Investigations were performed at baseline, and after 3 and 6 months. Therapy was then stopped and the patients were re-investigated 1 month thereafter. RESULTS: The mean level of PRA was normal at baseline, reduced during therapy with metoprolol, and increased during therapy with captopril. The mean plasma concentration of A II was reduced during exercise and there was a trend towards a reduction even at rest in the metoprolol group, but not in the captopril group. The urinary excretion of aldosterone decreased in both groups. The mean plasma concentration of ANP was elevated at baseline and declined during exercise in the metoprolol group. CONCLUSION: In patients with dilated cardiomyopathy and only a partly activated renin-angiotensin system, both metoprolol and captopril reduced urinary excretion of aldosterone. Furthermore, metoprolol suppressed the exercise-induced increase in ANP, suggesting a favourable effect on ventricular performance.

Intravenous nitroglycerin reduces ischaemia in unstable angina pectoris: a double-blind placebo-controlled study.

OBJECTIVE: To study whether intravenous nitroglycerin (NTG) reduces the incidence of ischaemic events and leucocyte activation, as well as inhibiting platelet aggregation in patients with unstable angina pectoris. DESIGN: Randomized double-blind placebo-controlled study. SUBJECTS: One hundred and sixty-two patients with a history and electrocardiographic changes suggesting unstable angina pectoris. INTERVENTIONS: A 48-hour titrated intravenous infusion of NTG or placebo. RESULTS: Of the 162 randomized patients, 19 were excluded because of an acute myocardial infarction on randomization (11 patients) or proven presence of a non-ischaemic cause of the pain (6 patients). Other causes (2 patients). No differences in the clinical findings were detected between the groups on randomization. In the comparison of NTG and placebo, fewer patients in the former group had more than two new attacks of chest pain lasting for < 20 min or one new attack of chest pain lasting > 20 min, despite sublingual NTG (13/25, P < 0.03). In addition, the attacks of pain lasting > 20 min in the NTG group were delayed compared to those in the placebo group (P < 0.05), suggesting a beneficial effect on these more severe episodes. Fewer patients in the NTG group required more than two sublingual NTG tablets (P < 0.005). NTG also reduced the rate-pressure product (P < 0.05), compared to placebo after 2 h but not after 24 h. Compared to baseline, platelet aggregation was inhibited in the patients who had received an NTG infusion for 2 h (P < 0.05). In both groups, leucocytes were activated at baseline, but remained unchanged thereafter. CONCLUSIONS: Intravenous NTG seems to reduce myocardial ischaemia in patients with unstable angina pectoris more than the placebo.

The glycoprotein IIb/IIIa platelet receptor blocker tirofiban, but not heparin, counteracts platelet aggregation in unstable angina pectoris.

In this study, despite concomitant aspirin treatment, tirofiban, but not heparin, reduced platelet aggregation in patients with acute myocardial ischemia. Platelet aggregation was determined with 2 independent methods, filtragometry and whole blood aggregometry.

More favourable haemodynamic effects from metoprolol than from captopril in patients with dilated cardiomyopathy.

AIM: The object of this study was to investigate and compare the haemodynamic effects of treatment with a beta receptor blocker (metoprolol) or an angiotensin-converting-enzyme inhibitor (captopril) in 54 patients with idiopathic dilated cardiomyopathy. METHOD: All patients had cardiac catheterization performed at rest and during exercise, before and after 3 months of treatment. RESULTS: The mean dose of metoprolol was 135 mg.day-1 and of captopril 98 mg.day-1. After treatment there was a significant reduction in left ventricular filling pressure both at rest (from 16 to 12 mmHg) and during exercise (from 27 to 20 mmHg) in the metoprolol group. In the captopril group a significant reduction was seen only during exercise (25 to 20 mmHg), compared to baseline. The stroke volume increased significantly after 3 months of therapy in the metoprolol group, both at rest (53 to 70 ml) and during exercise (56 to 79 ml). In the captopril group the increase reached significance only during exercise (72 to 79 ml). Cardiac output was maintained in both groups. CONCLUSION: There were positive effects on left ventricular function in the metoprolol group as well as in the captopril group. Metoprolol reduced left ventricular filling pressure at rest and increased stroke volume both at rest and during exercise significantly more than captopril.

Effects of adenosine on ex vivo filtragometry platelet aggregation in relation to plasma levels.

The aim of the present study was to investigate the concentration effect of adenosine on unstimulated platelet aggregation in humans. Adenosine infusion was given intravenously to 12 volunteers in the antecubital vein with infusion rates increasing from 20 to 100 micrograms kg-1 min-1. Filtragometry measurements were obtained from the contralateral antecubital vein before and during 100 micrograms kg-1 min-1 or during maximal tolerable infusion rate. In another set of experiments with 10 volunteers, basal filtragometry measurements were obtained before and after infusion of various concentrations of adenosine into the filtragometer test unit. With intravenous infusion aggregation time tended to increase from 333 +/- 42 to 418 +/- 8 s (mean +/- SEM) and increased the venous plasma adenosine concentration from 0.42 +/- 0.09 microM to 1.52 +/- 0.38 microM. Adenosine infusion into the filtragometer tubing system dose-dependently inhibited aggregation (P < 0.05). Adenosine was rapidly eliminated with a half-life of adenosine in the filtragometry tubing system calculated to be about 6 s. These data extend our knowledge from an in vitro to an ex vivo situation that adenosine dose-dependently has a platelet antiaggregatory effect.

Peak skeletal muscle perfusion is maintained in patients with chronic heart failure when only a small muscle mass is exercised.

OBJECTIVES: The issue to be resolved was whether peripheral leg blood flow in patients with chronic heart failure (CHF) is reduced by low local flow capacity or as a function of the amount of muscle mass activated during exercise. METHODS AND RESULTS: In ten CHF patients (ejection fraction 26 (9)%), and 12 healthy controls central and peripheral circulatory responses were assessed during dynamic one- and two-legged knee extensor work. The patients reached a peak perfusion of 234 (16) ml 100 g-1 min-1 in the one-legged mode, which was similar to the controls (244 (11) ml 100 g-1 min-1). At peak two-legged work muscle perfusion was reduced in the patients by 24% (P < 0.05). In contrast the controls maintained their peak muscle perfusion. The mass of the quadriceps femoris muscle and peak leg blood flow correlated closely for both groups at peak one-legged work (r = 0.85, P < 0.001). Peak oxygen uptake in the active limb during one-legged exercise was similar for patients and controls (0.52 (0.06) vs. 0.63 (0.06) l min-1), but it was 38% lower (P < 0.05) in patients than controls during exhaustive two-legged exercise. Arterial systemic oxygen delivery (cardiac output x arterial oxygen content), at peak exercise was highly correlated with peak one- and two-legged workload for both groups, explaining 70% of the difference in peak workload attained (P < 0.001). At peak two-legged exercise non-exercising tissues of the body in the male CHF patients with the largest limb muscle mass, received a blood flow of only 1.2 (0.7) 1 min-1. Mean arterial blood pressure at peak work in both test conditions was significantly lower for the patients than the controls. A higher sympathetic nerve activity in the patients, as evaluated by arterial noradrenaline concentration (NA) and leg NA spillover, contributed to maintain the perfusion pressure. CONCLUSIONS: Patients with moderate CHF can reach a peak skeletal muscle perfusion and a leg oxygen uptake comparable to that of healthy individuals when a sufficiently small muscle mass is activated. Exercise involving a larger muscle mass, for the patients in this study about 4 kg, markedly reduces peak leg blood flow, perfusion and oxygen uptake as well as blood flow to non-exercising organs and tissues.

Effect of nicotine infusion in humans on platelet aggregation and urinary excretion of a major thromboxane metabolite.

The objective of this study was to evaluate further a possible role of nicotine as a stimulator of platelet aggregability and platelet arachidonic acid metabolism in vivo. In six healthy, non-smoking males, platelet aggregability was assessed by filtragometry and impedance aggregometry before, during and after an intravenous infusion of nicotine at two different doses (0.25 and 0.5 microgram kg-1 min-1) for 30 min. The aggregatory response was also measured after the addition of nicotine at final concentrations ranging from 10(-11) mol L-1 directly to the aggregating blood. The synthesis of thromboxane A2 (TxA2) in platelets was estimated by quantitating the urinary excretion of 2.3-dinor-thromboxane B2 (Tx-M). Despite the plasma concentrations of nicotine, cotinine and catecholamines in the range of those occurring during acute cigarette exposure, the excretion of Tx-M (204 +/- 36 pg mg-1 creatinine) remained unaltered during nicotine infusion. Similarly, platelet aggregatory response to collagen was not influenced by nicotine when infused or added in vitro. However, an enhanced aggregability was detected by filtragometry during the infusion of nicotine at the higher dose employed. The results indicate that nicotine, infused at moderate doses, produces a weak platelet stimulation that is not accompanied by significant release of thromboxane A2, as monitored by urinary excretion of Tx-M. Although a direct action of nicotine on platelets cannot be excluded, it appears more likely that the enhancement of platelet function is mediated by other, secondary mechanisms.

Platelet and leukocyte activation after myocardial infarction. Influence of enalapril.

In this double-blind placebo-controlled study with enalapril, 74 patients with acute myocardial infarction were followed at 0, 7, 30, 60 and 180 days after the event. Platelets and leukocytes were activated during the first 7 days. During the 6-month period fibrinogen, leukocytes, elastase, and B beta 30-43 remained elevated in 50, 15, 30 and 80% of the patients, respectively, but there was no detectable angiotensin converting enzyme activity in platelets. Enalapril did not modulate fibrinogen, leukocyte count or elastase, while B beta 30-43 peptide showed decreased levels, although the proportion of patients with values above the reference limit did not differ from placebo. In conclusion, in the 6-month post acute myocardial infarction period, while platelet function is activated only during the first week after acute myocardial infarction, fibrinogen and leukocyte function continue to be activated throughout the 6 months in a considerable proportion of patients. These signs may indicate an ongoing atherosclerotic process. Enalapril has no major influence on these reactivities.

SIN-1 partially and RGDS totally counteracts platelet aggregation as assessed in vitro by two independent whole blood methods.

The cyclic GMP stimulant SIN-1 and the GP IIB/IIIA receptor antagonist RGDS were compared with regard to platelet antiaggregatory effects as measured in vitro by filtragometry and by whole blood aggregometry. In filtragometry platelet aggregation is measured as the time to partial occlusion of a filter in the test unit. Beta-thromboglobulin concentrations increased over the filter (p < 0.002) indicating that in filtragometry part of the mechanism of aggregation could be platelet activation across the filter. In whole blood aggregometry platelet aggregation is induced by a chemical stimulant. As tested in blood from healthy volunteers, linear dose-effect relations were found with both methods, for SIN-1 in the 10(-7)-10(-6) M range (p < 0.02, filtragometry and p < 0.05, whole blood aggregometry) and for RGDS in the 10(-5)-10(-4) M range (p < 0.0001, filtragometry and p < 0.02, whole blood aggregometry). At the highest dose RGDS totally counteracted platelet aggregation in both test systems. Maximal SIN-1 platelet antiaggregatory effects were less (p < 0.04, filtragometry and p < 0.01, whole blood aggregometry) than for RGDS. SIN-1 concentrations in the 10(-4) M range had no further antiaggregatory effects. In conclusion, with two principally different methods for the assessment of whole blood platelet aggregation, SIN-1 was found to be a partial antagonist while RGDS a total antagonist.

Comparison of three independent methods as estimates of platelet inhibition after a single dose of acetylsalicylic acid.

In order to assess the ability of three different (one in vivo, one ex vivo and one in vitro) methods to estimate platelet function, 10 healthy volunteers were given a single oral dose of 160 mg ASA. Platelet function was assessed before, 4, 24, 48 and 72 h after dosing by urinary excretion of thromboxane B2, filtragometry and collagen-based whole blood aggregometry. Further, in order to study mechanisms for platelet aggregation in filtragometry, platelet activation was assessed by measurements of beta-thromboglobulin at three different places within the filtragometer test unit in another nine healthy subjects. Four hours after ASA, the aggregation time during filtragometry increased by 213 +/- 133% (p < 0.001) and was parallelled by a decrease in impedance 85 +/- 7% (p < 0.001) indicating an inhibition of platelet aggregability in both tests. A subsequent gradual recovery was observed with both methods. The excretion of thromboxane B2 followed the aggregability pattern being maximally reduced by 72 +/- 6% (p < 0.01) 24 h after ASA and then gradually recovering. All three methods indicated that platelet function was still decreased 72 h after dosing. The urinary excretion of prostacyclin did not change significantly. The results of filtragometry and impedance aggregometry correlated to the logarithm of thromboxane B2 excretion (r = 0.60; p < 0.01 and r = 0.49; p < 0.01, respectively) and to each other (r = 0.70; p < 0.001). In filtragometry beta-thromboglobulin increased significantly (p < 0.05) over the filter.(ABSTRACT TRUNCATED AT 250 WORDS)

Streptokinase, but not tissue plasminogen activator, attenuates platelet aggregation in patients with acute myocardial infarction.

OBJECTIVES: To investigate if tissue plasminogen activator (tPA) and streptokinase given during acute myocardial infarction (AMI) have different effects on platelet aggregation which could contribute to the higher reocclusion rate observed after tPA. DESIGN: Open labelled on consecutive patients. SETTING: Coronary care unit. SUBJECTS: Twenty patients with chest pain and ST elevations on an electrocardiogram suggestive of AMI. INTERVENTIONS: Ten patients were treated with tPA (100 mg 3 h-1), 10 patients with streptokinase (1.5 x 10(6) IU 1 h-1). MAIN OUTCOME MEASURES: Before, immediately after and 24 h after fibrinolytic therapy, platelet aggregation was estimated with filtragometry and whole blood aggregometry. Fibrinogen, beta-thromboglobulin, elastase and the fibrinogen-derived peptide B beta 30-43 were also measured. RESULTS: The groups were comparable at baseline. Directly after treatment, streptokinase prolonged aggregation time in filtragometry with 112 +/- 140 s (P < 0.03) and reduced conductance in whole blood aggregometry by 6.2 +/- 6.1 omega (P < 0.03), both tests indicating inhibited platelet function. Fibrinogen decreased 2.5 +/- 1.0 g l-1 (P < 0.02). In the tPA-treated group corresponding changes were 68 +/- 225 s (NS) and 2.5 +/- 7 omega (NS) with no significant reduction in fibrinogen. After 24 h, at which time every patient was on acetylsalicylic acid, aggregation was inhibited in both groups as measured by aggregometry. Directly after fibrinolytic treatment, neutrophils were similarly activated in both groups with increments of elastase and B beta 30-43 by 26 +/- 46 micrograms l-1 (P < 0.03) and 280 +/- 381 pmol l-1 (P < 0.03) respectively (streptokinase) and by 12 +/- 6 micrograms l-1 (P < 0.02) and 919 +/- 856 pmol l-1 (P < 0.02) respectively (tPA). CONCLUSIONS: Despite similar degrees of platelet and leucocyte activation, streptokinase but not tPA treatment appears to inhibit platelet aggregation. One possible reason could be a streptokinase-induced pronounced decrease of fibrinogen and increase of fibrinogen split products. Therefore, further development of adjuvant antiplatelet therapy could be of clinical importance.

Heparin enhances platelet aggregation irrespective of anticoagulation with citrate or with hirudin.

The effects of anticoagulation with citrate or hirudin on heparin effects on platelet aggregation was studied with whole blood aggregometry on blood from healthy volunteers. Platelet aggregation was initiated by collagen. The heparin effect was also studied with filtragometry where hirudin was used as the anticoagulant. In citrated blood, a mean collagen dose of 0.42 +/- 0.04 micrograms/ml resulted in an impedance change of 1.1 +/- 0.3 Ohm. Preincubation with heparin doses of 0.5, 2.5 and 5 IU/ml enhanced the impedance induced by the same dose of collagen by 2.9 +/- 1.4, 11.4 +/- 1.6 and 9.9 +/- 2.3 times, respectively (p less than 0.0001, ANOVA). In hirudinized blood a similar degree of change in impedance (1.5 +/- 0.2 Ohm) was achieved at significantly lower concentration of collagen (0.08 +/- 0.006 micrograms/ml, p less than 0.0001). Preincubation with heparin in doses of 0.5, 2.5 and 5 IU/ml increased impedance by 1.5 +/- 0.5, 3.9 +/- 1.6 and 1.3 +/- 0.5 times, respectively (p less than 0.0001, ANOVA). The dose-related increments were smaller in hirudinized blood as compared to citrated blood (p less than 0.04). With filtragometry, heparin dose-dependently shortened the aggregation time (p less than 0.0007). Compared to hirudin alone as anticoagulant, heparin in an equipotent dose in these experiments shortened aggregation time (p less than 0.05). In conclusion, heparin enhanced platelet aggregation both in calcium-chelated blood and in blood anticoagulated with hirudin. Heparin also dose-dependently increased platelet aggregation in filtragometry. Thus the heparin potentiating effect on platelet aggregation seems to be independent of extracellular ionized calcium and be operative at physiological calcium concentrations.

Enhanced platelet function in acute myocardial infarction is attenuated by streptokinase treatment.

The aim of this study was to determine whether platelets are activated and aggregation is increased in myocardial infarction treated with streptokinase. Twelve consecutive patients were studied. Before streptokinase infusion (1.5 x 10(6) IU i.v. over a period of 1 h), 7 +/- 4 h after the onset of symptoms, fibrinogen, leucocyte and platelet functions were enhanced compared to reference values. Plasma fibrinogen was 3.1 +/- 0.6 g 1-1 (P less than 0.03), leucocyte count was 14.3 +/- 3.3 x 10(3) l-1 (P less than 0.0005), elastase was 39 +/- 8 micrograms l-1 (P less than 0.0002), beta-thromboglobulin was 68 +/- 71 micrograms 1-1 (P less than 0.0001) and filtragometer platelet aggregation time was 137 +/- 40 s (P less than 0.0001). After streptokinase the leucocyte count, elastase and beta-thromboglobulin levels increased further, by about 40% (P less than 0.02), 130% (P less than 0.02) and 140% (P less than 0.005), respectively. Fibrinogen was almost eliminated. Despite signs of increased activation, platelet aggregation was decreased as indicated by both filtragometer aggregation time, which increased by about 480% (P less than 0.003), and whole-blood aggregometry, in which electrical impedance decreased by about 65% (P less than 0.01).

Dose-dependent effect of intravenous nitroglycerin on platelet aggregation, and correlation with plasma glyceryl dinitrate concentration in healthy men.

Nitroglycerin has been reported to reduce mortality in patients with acute myocardial infarction. This beneficial effect has been attributed to vasodilation, but it was speculated that part of this effect may be due to altered platelet function. The influence of intravenous nitroglycerin on platelet aggregation was assessed. Eight healthy subjects (aged 22 to 48 years) were studied using filtragometry at baseline, and 3 different nitroglycerin doses. Compared with baseline, aggregation time (which indexes platelet aggregation) increased dose-dependently by 91 +/- 68% (p less than 0.001) at the maximal dose of nitroglycerin (1.1 +/- 0.3 micrograms/kg/min). Plasma concentration-effect relations were observed between nitroglycerin as well as the glyceryl dinitrate metabolites and platelet aggregation (r = 0.6 [p less than 0.002] and r = 0.8 [p less than 0.0001], respectively). It is concluded that increasing doses of intravenous nitroglycerin profoundly and dose-dependently inhibit platelet aggregation. This inhibitory effect correlates with glyceryl dinitrate formation.

Heparin and low molecular weight heparin but not hirudin stimulate platelet aggregation in whole blood from acetylsalicylic acid treated healthy volunteers.

The platelet aggregatory effect of heparin was investigated with whole blood aggregometry in blood from healthy volunteers with collagen as activator. Tests were performed before and 3 hours after 0.5 g acetylsalicylic acid given perorally. Three protocols were tested. In the first experiment and before acetylsalicylic acid low doses (2.5 and 5 IU/ml) of heparin and low molecular weight heparin (LMW-heparin) did not affect aggregation while higher doses (25 and 250 IU/ml) had an antiaggregatory effect (p less than 0.0001). After acetylsalicylic acid, and with the same amount of collagen as before acetylsalicylic acid, aggregation decreased by 82 +/- 4%. Both heparin and LMW-heparin increased the aggregation (p less than 0.05). In the second experiment the collagen dose was titrated to give a similar light to moderate degree of aggregation before as compared to after acetylsalicylic acid. Low doses of heparin (p less than 0.01) but not hirudin increased the aggregation to the same degree before and after acetylsalicylic acid. In the third experiment the RGDS peptide (ARG-GLY-ASP-SER), a blocker of GPIIb/IIIa platelet receptor dose dependently inhibited platelet aggregation by 93 +/- 17%. With added RGDS peptide heparin still increased aggregation (p less than 0.001). In conclusion, with whole blood aggregometry both heparin and LMW-heparin but not the specific thrombin inhibitor hirudin stimulated platelet aggregation before and after acetylsalicylic acid ingestion. The heparin aggregatory effect was not inhibited by the RGDS peptide implying platelet activation via non specific mechanisms. These heparin effects could be of clinical importance for the treatment of arterial thromboembolic disease.