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European Journal of Heart Failure 2002 4(1):73-82; doi:10.1016/S1388-9842(01)00196-9
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© 2002 European Society of Cardiology

Neurohormonal activation in heart failure after acute myocardial infarction treated with beta-receptor antagonists

Hans Perssona,*, Karin Andréassonb, Thomas Kahana, Sven V. Erikssona, Bo Tidgrenc, Paul Hjemdahld, Christian Halle and Leif Erhardtf

a Section of Cardiology, Division of Internal Medicine, Karolinska Institutet Danderyd Hospital S-182 88, Stockholm, Sweden
b Division of Clinical Chemistry, Karolinska Institutet Danderyd Hospital Stockholm, Sweden
c Division of Clinical Physiology, Karolinska Institutet Danderyd Hospital Stockholm, Sweden
d Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Solna, Sweden
e Institute for Surgical Research, University of Oslo, Rikshospitalet Oslo, Norway
f Department of Cardiology, University of Lund, Malmö University Hospital Malmö, Sweden

* Corresponding author. Tel.: +46-8-655-5000; fax: +46-8-622-6810. E-mail address: hans.persson{at}med.ds.sll.se


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Few studies have described how neurohormonal activation is influenced by treatment with beta-receptor antagonists in patients with heart failure after acute myocardial infarction. The aims were to describe neurohormonal activity in relation to other variables and to investigate treatment effects of a beta1 receptor-antagonist compared to a partial beta1 receptor-agonist.

Methods: Double-blind, randomized comparison of metoprolol 50–100 mg b.i.d. (n=74), and xamoterol 100–200 mg b.i.d (n=67). Catecholamines, neuropeptide Y-like immunoreactivity (NPY-LI), renin activity, and N-terminal pro-atrial natriuretic factor (N-ANF) were measured in venous plasma before discharge and after 3 months. Clinical and echocardiographic variables were assessed.

Results: N-ANF showed the closest correlations to clinical and echocardiographic measures of heart failure severity, e.g. NYHA functional class, furosemide dose, exercise tolerance, systolic and diastolic function. Plasma norepinephrine, dopamine and renin activity decreased after 3 months on both treatments, in contrast to a small increase in NPY-LI which was greater (by 3.9 pmol/l, 95% CI 1.2–6.6) in the metoprolol group. N-ANF increased on metoprolol, and decreased on xamoterol (difference: 408 pmol/l, 95% CI 209–607). Increase above median of NPY-LI (>25.2 pmol/l, odds ratio 2.8, P=0.0050) and N-ANF (>1043 pmol/l, odds ratio 2.8, P=0.0055) were related to long term (mean follow-up 6.8 years) cardiovascular mortality.

Conclusions: Decreased neurohormonal activity, reflecting both the sympathetic nervous system and the renin–angiotensin system, was found 3 months after an acute myocardial infarction with heart failure treated with beta-receptor antagonists. The small increase in NPY-LI may suggest increased sympathetic activity or reduced clearance from plasma. The observed changes of N-ANF may be explained by changes in cardiac preload, renal function, and differences in beta-receptor mediated inhibition of atrial release of N-ANF. NPY-LI, and N-ANF at discharge were related to long term cardiovascular mortality.

Key Words: Myocardial infarction • Congestive heart failure • Neurohormonal activation • Beta-adrenergic blocking agents • Atrial natriuretic peptide • Cardiac function

Received March 21, 2001; Revised April 30, 2001; Accepted August 17, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Neurohormonal activation occurs early after acute myocardial infarction (AMI), and is related to the degree of left ventricular (LV) systolic dysfunction [1,2]. Such activation tends to subside during the first week after AMI, but venous plasma concentrations of norepinephrine and atrial natriuretic factor remain elevated in patients with LV systolic dysfunction or with clinical signs of heart failure, at least until discharge [1]. These patients also have increased plasma renin activity, which probably in part is secondary to the use of diuretics and angiotensin converting enzyme (ACE)-inhibitors [3]. Neurohormonal activation has been thought of as a compensatory mechanism to improve or maintain cardiac output and systemic blood pressure during episodes of impaired ventricular function. However, neurohormonal activation at the time of hospital discharge after AMI may further impair LV function and precipitate symptomatic heart failure, and are indeed related to poor prognosis [4]. Neurohormonal blockade is now considered a cornerstone in the treatment of LV dysfunction and heart failure. The use of ACE-inhibitors to block the effects of an activated renin–angiotensin system is well established [5]. Furthermore, beta-adrenoceptor antagonists will inhibit effects of an activated sympathetic nervous system, and such agents have been shown to reduce mortality and morbidity after AMI, especially in high risk patients with heart failure [6], as well as in chronic heart failure [7,8]. Changes in neurohormonal activity may be used to assess treatment effects [9,10]. However, few studies have described the temporal evolution of neurohormonal activation in patients after hospital discharge for AMI, complicated with heart failure, and the effects of treatment with beta-adrenoceptor antagonists.

The Metoprolol and Xamoterol Infarction Study (MEXIS) investigated long-term functional effects of the beta1-receptor antagonist metoprolol in comparison with the partial beta1-receptor agonist xamoterol, in patients with mild to moderate heart failure after AMI [11]. MEXIS is well suited to describe alterations in neurohormonal activity in relation to clinical and echocardiographic variables. Only few patients were treated with an ACE-inhibitor. Thus, the results of the study are not confounded by the influence of ACE-inhibitors on neurohormonal activation. Even though xamoterol is no longer used, the relevance of the study is high as MEXIS is a modern study using drugs with beta adrenoceptor blocking properties as first line treatment for patients with heart failure after AMI. This concept is now further tested in the CAPRICORN mortality trial.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Consecutive survivors of an AMI with clinical evidence of LV heart failure during the time while in the coronary care unit were included in MEXIS. The definition of heart failure was clinical and/or radiological heart failure signs during any time in the CCU. A mean 2.5 of five possible heart failure criteria were met (sinus tachycardia, rales, third heart sound, radiological signs of heart failure, respiratory rate >28/min at rest) [11]. Exclusion criteria were: severe heart failure (NYHA IV), unstable angina, pulmonary disease, aortic stenosis, hypertrophic obstructive cardiomyopathy, drug abuse, other disabling diseases, inability to perform a 2-min exercise test, or a poor quality echocardiographic registration. Of the available patients, 5% were excluded due to NYHA IV.

Randomized double-blind treatment with metoprolol (50–100 mg b.i.d.), and xamoterol (100–200 mg b.i.d.) was started at the time of hospital discharge, as previously reported. Concomitant therapy was kept as stable as possible throughout the study. The study was performed before the publication of the SAVE study.

2.2. Neurohormonal measurements
The neurohormonal study was prospectively planned. Blood samples were obtained before randomization, on day 6 (range 2–19) after admission, and after 3 months. An indwelling venous catheter was inserted in an antecubital vein. The patient rested quietly in the supine position for 30 min before blood was sampled into test tubes kept on ice for determinations of plasma norepinephrine, epinephrine, dopamine, neuropeptide Y-like immunoreactivity (NPY-LI), renin activity (PRA), and N-terminal pro-atrial natriuretic factor (N-ANF). Plasma was removed after centrifugation at +4 °C and stored at –80 °C until analyzed. The test tubes for PRA, N-terminal pro ANF and catecholamines contained EDTA, and for NPY-LI they contained heparin and aprotinin. Catecholamines were assayed by high performance cation exchange liquid chromatography [12]. A LKB 2150 pump (Pharmacia, Uppsala, Sweden) delivered the mobile phase to a 20 cm 4x6-mm inner diameter column with Nucleosil 5 SA (Machery & Nagel, Düren, Germany) as stationary phase. The signals from a Waters 460 detector (Waters, Milford, MA, USA) were presented on a C-R5A Chromatopac integrator (Shimadzu, Kyoto, Japan). In our hands, the inter- and intra-assay coefficients of variations were 4 and 2% for norepinephrine, 12 and 8% for epinephrine, and 15 and 18% for dopamine, respectively, within the physiological range of 2–3 nM for norepinephrine, 0.2–0.4 nM for epinephrine and 0.05–0.1 nM for dopamine. PRA was analyzed by use of a commercial radioimmunoassay kit (RIANEN Angiotensin I, I-125 kit, Dupont Scandinavia AB, Stockholm, Sweden) [13]. NPY-LI and N-ANF were assessed by radioimmunoassays [14,15]. The inter- and intra-assay coefficients of variation were <10% for all peptide assays.

2.3. Echocardiography and Doppler investigation
All patients were examined with two-dimensional and M-mode-echocardiography and Doppler investigation before randomization, on day 4 (range 1–18) after admission. M-mode echocardiographic and Doppler investigations were repeated after 3 months. An Interspec XL, equipped with a 2.5-MHz transducer, was used. Wall-motion scores according to Berning et al. were determined at baseline in all patients with an acceptable two-dimensional (n=128) registration [16].

A wall motion score of ≤1.2 (comparable to an ejection fraction of ≤36%) was considered to reflect marked systolic dysfunction. LV fractional shortening (FS), and E-point septal separation (EPSS) were measured as indices of systolic function at follow-up. Left atrial diameter (LA) was measured at end-systole. Isovolumic relaxation time (IRT) and the ratio between peak early (E-wave) and peak atrial (A-wave) flow (E/A ratio), as assessed by pulsed Doppler, were used as indices of diastolic function.

2.4. Statistical analyses
Data are presented as mean values (S.D.), unless otherwise specified. Data for all patients with assessments at follow-up are presented. Statistical evaluations include patients on treatment at the 3-month follow-up. Pearson (r) or Spearman (R) correlation coefficients were calculated to evaluate continuous or non-continuous relationships, respectively. Differences between the treatment groups at follow-up were tested with analysis of covariance. The analyses allowed for differences in group baseline data. Differences within treatment groups over time were measured with paired t-tests. PRA, epinephrine, dopamine and N-ANF were not normally distributed and were therefore log-transformed before analyses. Categorical data were compared by the Chi-square test with Yate's continuity correction. The influence of neurohormonal activity at baseline on long-term cardiovascular mortality was analyzed by performing Cox regression analyses. Survival curves were generated by the Kaplan–Meier method and differences between curves assessed by the log rank test. A P-value of <0.05 was considered statistically significant. Confidence intervals (Cl; 95%) were calculated for significant differences between the treatment groups.

2.5. Ethical consideration
The study was approved by the local Ethics Committee of the Karolinska Hospital and all patients gave informed consent to participate.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Clinical characteristics and medication
The 141 patients forming the present report are presented in Table 1. The two treatment groups were similar. Most patients received treatment with furosemide, amiloride, long-acting nitrates and aspirin at discharge. The mean furosemide dose was 71 mg (range 20–200 mg) in the metoprolol group and 69 mg (range 20–160 mg) in the xamoterol group at discharge. At 3-month follow-up, the mean doses were 73 and 68 mg, respectively. Before the 3-month follow-up, an ACE-inhibitor was introduced in one patient in the metoprolol group. The mean daily dose of trial medication at discharge was 153 (55) mg for metoprolol and 364 (83) mg for xamoterol. Four patients in each treatment group were withdrawn before the visit at 3 months. The mean dose was 133 (65) mg for metoprolol and 355 (101) mg for xamoterol at the 3-month visit. Before the 3-month visit, six patients were revascularized or had an AMI, and two patients died.


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  		Table 1 Patient characteristics at baseline

 
3.2. Mortality
During long-term follow-up (mean follow up 2500 days or 6.8 years) 35 patients (25%) died, 28 (20%) of cardiovascular causes. Cardiovascular mortality was related to traditional risk predictors such as previous AMI, heart failure and diabetes, left ventricular size, wall motion score, EPSS, and furosemide dose. NPY-LI and N-ANF were also related to cardiovascular mortality, but not the other neurohormones (Table 2 and Fig. 1). In multivariate analysis including age, sex and wall motion score, N-ANF, but not NPY-LI, was independently associated with cardiovascular mortality.


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  		Table 2 Neurohormonal activity and cardiovascular mortality

 


Figure 1
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  		Fig. 1 Kaplan–Meier curves for long-term cardiovascular survival in patients with acute myocardial infarction and heart failure. The patients are grouped according to plasma NPY-LI and N-ANF before discharge above or below median values. NPY-LI=neuropeptide Y-like immunoreactivity; N-ANF=N-terminal pro-atrial natriuretic factor. OR=odds ratio.

 
3.3. Neurohormonal measurements and effects of treatment
Venous plasma levels of neurotransmittors and hormones at baseline and at 3 months are presented in Fig. 2. Norepinephrine, dopamine and PRA decreased at 3 months, similarly in patients on metoprolol and xamoterol. Epinephrine did not change on follow-up. NPY-LI increased on both treatments, with a greater increase in the metoprolol group, the difference between the treatment groups was 3.9 pmol/l, 95% CI 1.2–6.6. N-ANF increased on metoprolol and decreased on xamoterol, the difference between the groups was 408 pmol/l, 95% CI 209–607. Even if patients treated with ACE-inhibitors were excluded from the analyses, PRA was still reduced after 3 months [metoprolol 3.6 (2.9) to 1.9 (1.6) ng ml–1 h–1, P<0.0001, xamoterol 4.9 (3.9) to 2.3 (1.8) ng ml–1 h–1, P<0.0001].


Figure 2
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  		Fig. 2 Neurohormonal measurements at baseline and after 3 months in the metoprolol group (solid bars, n=64–74) and the xamoterol group (hatched bars, n=58–66). Mean values and S.E.M. are shown. NS=not significant. See Fig. 1 for abbreviations.

 
3.4. Relations between neurohormones
A few significant correlations were found between the neurohormonal variables. Norepinephrine correlated with epinephrine at 3 months (r=0.27, P<0.01), and dopamine and NPY-LI both at baseline and at 3 months (r=0.19, P<0.05). NPY-LI correlated with PRA at baseline (r=0.28, P<0.01), and N-ANF both at baseline and at 3 months (r=0.20, P<0.05, and 0.30, P<0.01).

3.5. Neurohormonal activity in relation to clinical and echocardiographic variables
N-ANF at baseline showed the most consistent and strongest correlations with clinical and echocardiographic variables (Table 3), including diastolic indices. There was no relation between LA diameter or heart rate and N-ANF. Changes of N-ANF from baseline to 3 months correlated with changes of diastolic measures, such as E/A (r=0.48, P<0.001) and IRT (r=–0.27, P<0.01), as well as NYHA functional class (R=0.20, P<0.05), and exercise tolerance (r=–0.18, P<0.05). The relationships between the markers of neurohormonal activity and clinical and echocardiographic variables at baseline were maintained at 3 months (Table 4). Serum creatinine increased in the metoprolol group and decreased in the xamoterol group after 3 months, the difference was 10.4 µmol/l, 95% CI 3.9–16.9. Serum creatinine was related to baseline N-ANF (r=0.30, P<0.001). None of the neurohormonal changes were correlated to changes in serum creatinine.


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  		Table 3 Correlations between neurohormonal variables and echocardiographic and clinical variables at baseline

 


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  		Table 4 Correlations between neurohormonal variables at baseline and echocardiographic and clinical variables at 3 months

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
4.1. Neurohormonal activity after an acute myocardial infarction
Several neurohormonal systems, involved in cardiovascular regulation, are activated in the failing heart, both during the acute stages, such as an AMI, and in the chronic congestive state [1–4,17,18]. The present study shows clear relationships between myocardial function and the activity of the sympathetic nervous system, the renin–angiotensin system and the release of atrial natriuretic factor. Thus, we found correlations at baseline between, e.g. indices of systolic function such as wall motion score and exercise performance, and norepinephrine, NPY-LI, PRA and N-ANF. In addition, peak enzyme levels were correlated with PRA and N-ANF at baseline. Our findings support previous studies and suggest that neurohormonal activation is related to left ventricular systolic function [1,2]. We were also able to demonstrate a correlation between indices of diastolic function and the atrial natriuretic peptide, as has recently been shown in dilated cardiomyopathy, but was not found after AMI [19,20]. Furthermore, our results support previous findings that neurohormonal activity is related to the patients symptomatic status [21,22] and prognosis [4].

The second important finding in the study is that signs of activation of the sympathetic nervous system and the renin–angiotensin system were both reduced after 3 months. Sustained neurohormonal activation after AMI has previously been reported in patients with heart failure [23,10]. Our results suggest that neurohormonal activity relates to systolic and diastolic function in both the early and late phase following an AMI. The increase of NPY-LI in both treatment groups and the different changes of N-ANF in the two treatment groups are interesting findings which imply that neurohormonal responses after an AMI are not uniform, and that hormone levels can be differentially influenced by therapy [3,24,25]. However, caution is warranted in using the changes in neurohormonal activity seen with therapy to interpret effects on prognosis. Recent observations showed decreased N-ANF with flosequinan, in spite of adverse effects on prognosis [26]. The similar finding in the present study with xamoterol is in contrast to the increased mortality of xamoterol found in chronic heart failure.

4.2. Effects of therapy on indices of the sympathetic nervous system
The present study showed marked elevations of plasma norepinephrine at baseline. This is probably related to the acute stress put on the circulation by the AMI, in agreement with previous findings [2]. At 3 months we found a decrease of norepinephrine, with no differences between metoprolol or xamoterol. The reduction may in part be related to treatment effects, but probably mainly reflects the natural course after an AMI. Previous studies with beta-receptor antagonists with and without partial agonist activity show increases of norepinephrine both during an AMI and in chronic heart failure whereas beta-receptor agonists decrease catecholamine levels [27,28]. Xamoterol has been claimed to act as an agonist in this respect, but the present results do not support this idea, as there was a similar reduction with metoprolol [29].

We found correlations between norepinephrine and NPY-LI both at baseline and after 3 months. However, NPY-LI levels increased after 3 months, especially with metoprolol in spite of the reduction of norepinephrine. This temporal dissociation is in agreement with a previous report [30]. NPY is co-released with norepinephrine from the sympathetic nerve endings during nerve activity. Norepinephrine is mainly released during low frequency nerve stimulation, whereas NPY release requires nerve activation at a high frequency and of long duration [31,32]. The elevation of NPY-LI might suggest increased sympathetic nerve activity occurring in high frequency bursts, and thus releasing more NPY, in patients with heart failure. However, altered clearance of NPY from the circulation may offer an alternative explanation for the dissociated temporal changes of these neurotransmitters. NPY is mainly inactivated by degradation in the hepato-mesenteric circulation [33]. Thus, the elevated levels of NPY-LI at 3 months of follow-up may be secondary to a reduced hepato–mesenteric circulation in patients with heart failure. Increased venous plasma norepinephrine levels following beta-receptor blockade are related to reduced clearance from plasma, whereas the elevation of plasma norepinephrine in heart failure is due to increased release, rather than decreased clearance [34]. The more marked increase in NPY-LI on metoprolol than on xamoterol at 3 months is interesting. The partial beta1-receptor agonist xamoterol is likely to have a less negative influence on the hepato–mesenteric circulation than metoprolol [35]. Whether the differences in NPY-LI in the two treatment groups are secondary to such changes in the hepato–mesenteric circulation or reflect true changes in NPY release remains to be established. The finding that NPY-LI at discharge was related to long-term cardiovascular mortality after AMI has not been shown before and is interesting, and in contrast to a smaller short-term-study [30].

Plasma epinephrine levels were low at baseline and during follow-up. We used a sensitive assay for epinephrine. Thus, we failed to demonstrate adrenomedullary activation in heart failure, in contrast to previous findings [30].

4.3. Effects of therapy on N-ANF
The release of atrial natriuretic factor is related to atrial stretch and LV end-diastolic pressure [36]. N-ANF showed consistent correlations with the extent of myocardial damage, i.e. CK maximum, clinical status, and indices of both systolic and diastolic function. Thus, our results support and extend previous findings and suggest that N-ANF is a good marker of both systolic and diastolic dysfunction after AMI [22,37]. The finding of different effects of metoprolol and xamoterol on N-ANF, and the correlations to diastolic indices suggest a hemodynamic difference between the two study groups [22,36,37]. However, indirect reflectors of hemodynamic state, such as the furosemide dose and the left atrial diameter, did not differ at 3 months between the two treatment groups. Furthermore, exercise tolerance improved similarly in the two treatment groups [11]. These findings suggest that other mechanisms than hemodynamic differences contribute to the changes in N-ANF during follow-up.

It has been proposed that beta-adrenergic stimulation may inhibit atrial natriuretic factor release by a direct action on the atrial myocytes during constant atrial pressure [38]. Elevated levels of circulating atrial natriuretic factor have been reported after short- and long-term treatment with beta-receptor antagonists in hypertensive and healthy subjects [39,40]. In patients with heart failure, natriuretic peptides increased during short-term therapy with metoprolol, but not with the vasodilating beta-receptor antagonist celiprolol [41]. The high (43%) partial agonist activity of xamoterol may thus act to inhibit the release of N-ANF by this mechanism, whereas the antagonistic properties of metoprolol would lead to an increased release.

A third determinant of plasma N-ANF is renal function, as shown after AMI [42]. We found a significant correlation between N-ANF and serum creatinine. The increase of serum creatinine in the metoprolol group and the decrease in the xamoterol group after 3 months were small, in contrast to the 27% increase of N-ANF in the metoprolol group and a 3% decrease in the xamoterol group. Therefore, changes in renal function may contribute to, but not explain the difference in N-ANF levels at 3 months.

4.4. Effects of therapy on plasma renin activity
A marked activation of the renin–angiotensin system is indicated by high PRA levels at baseline in the present patients with AMI, complicated by heart failure. The two study drugs reduced PRA similarly at 3 months, suggesting that the partial beta1-receptor agonism of xamoterol did not stimulate renin release. The reductions of PRA seen in conjunction with xamoterol and metoprolol treatment are in agreement with earlier findings, whereas beta1-agonists tend to further stimulate the renin–angiotensin system [28,29,43]. Caution in interpreting the data is, however, warranted as we did not include a placebo group. Diuretics are potent activators of the renin–angiotensin system but this is not a likely confounder as the doses were stable during the course of follow-up. Also, we avoided the confounding effects of ACE-inhibitors and AT1-receptor antagonists on PRA. The reduction of PRA during follow-up is likely to be beneficial, as activation of the renin–angiotensin system may worsen the prognosis due to unfavorable effects on the heart and circulation. Indeed, the effects of beta-receptor antagonists on the renin–angiotensin system may contribute to the improved prognosis seen in heart failure patients [7,8].

In conclusion, during a 3-month follow-up of patients with heart failure after an AMI, treated with beta receptor antagonists but not with ACE-inhibitors, the degree of neurohormonal activity reflecting both the sympathetic nervous system and the renin–angiotensin system was reduced. The found increase in NPY-LI may suggest a regional increase in sympathetic activity or a reduced clearance. An increase of N-terminal pro-atrial natriuretic factor was found with metoprolol, in contrast to a decrease with xamoterol. Changes in cardiac preload and renal function, and different actions of the two drugs on beta-receptor mediated inhibition of atrial release of N-ANF may serve to explain these findings. NPY-LI and N-ANF were related to long-term cardiovascular mortality.


   Acknowledgements
 
The study was supported by grants from the Swedish Heart–Lung Foundation, the Serafimer Foundation, the Swedish Society of Medicine and Karolinska Institutet.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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