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European Journal of Heart Failure 2001 3(1):69-78; doi:10.1016/S1388-9842(00)00137-9
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© 2001 European Society of Cardiology

Early neurohormonal effects of trandolapril in patients with left ventricular dysfunction and a recent acute myocardial infarction: a double-blind, randomized, placebo-controlled multicentre study

A. Sigurdssona,*, S.V. Erikssonb, C. Hallc, T. Kahanb and K. Swedbergd

a Department of Medicine, Division of Cardiology, Landspitalinn v. Hringbraut 101 Reykjavik, Iceland
b Division of Internal Medicine, Karolinska Institutet Danderyd Hospital Danderyd, Sweden
c Institute for Surgical Research, University of Oslo Rikshospitalet, Oslo, Norway
d Department of Medicine Sahlgrenska University Hospital/Östra Göteborg, Sweden

* Corresponding author. Tel.: +354-5601000; fax: +354-5601287. E-mail address: axelfsig{at}rsp.is (A. Sigurdsson).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Angiotensin-converting enzyme inhibitors improve long-term survival in patients with left ventricular dysfunction after a myocardial infarction, but their mechanism of action is not entirely clear. The neurohormonal effects may be important in this respect, as well as an early hemodynamic unloading induced by these drugs. The primary objective was to assess the effect of trandolapril on plasma levels of atrial natriuretic peptide. A secondary objective was to assess the effects of trandolapril on selected neurohormones, vasoactive peptides and enzymes, which may be important in the development of left ventricular remodeling and heart failure following an acute myocardial infarction. A total of 119 patients with an acute myocardial infarction and a wall motion index ≤1.2 (16-segment echocardiographic model) were randomized to double blind treatment with trandolapril or placebo within 3–7 days after the onset of infarction. Blind treatment was discontinued 21 days after the index infarction. Venous blood samples were collected at rest, before randomization and on the day after treatment was discontinued. At the end of the study, there were no differences in plasma levels of atrial natriuretic peptide between the two treatment groups. Angiotensin-converting enzyme activity was suppressed and plasma renin activity was higher in the trandolapril group. No differences in plasma levels of N-terminal pro-atrial natriuretic peptide, brain natriuretic peptide, aldosterone, noradrenaline, adrenaline, vasopressin, big endothelin-1 and neuropeptide Y were found between the two treatment groups. There were positive correlations between several markers of neurohormonal activation at baseline and variables expressing left ventricular dysfunction and clinical heart failure. Neurohormonal activation is related to left ventricular dysfunction. The effects of 2–3 weeks of angiotensin-converting enzyme inhibition on neurohormonal activation does not predict the already established beneficial long-term effects after myocardial infarction. Thus, early modulation of circulatory neurohormone levels may not be a major mechanism for the efficacy of angiotensin-converting enzyme inhibitors in these patients. Selected plasma hormone markers may still be used to identify patients who might get the greatest benefit from treatment.

Key Words: Neurohormonal activation • Acute myocardial infarction • Left ventricular dysfunction • Angiotensin converting enzyme inhibitors

Received April 10, 2000; Revised August 29, 2000; Accepted October 12, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The use of angiotensin-converting enzyme (ACE) inhibitors in patients with an acute myocardial infarction and concomitant subjective or objective criteria of left ventricular dysfunction has been shown to reduce cardiovascular morbidity and mortality [1–3]. Attenuation of left ventricular dilatation may be an important mechanism by which these drugs exert their effects. It has been implicated that left ventricular remodeling after an acute myocardial infarction may partly be initiated and maintained by the systemic activation of neurohormonal mechanisms [4]. Neurohormonal activation occurs early after an acute myocardial infarction and appears to be associated with the extent of myocardial damage, as well as the degree of left ventricular dysfunction [5,6]. Furthermore, angiotensin II, catecholamines, and other trophic factors released during the acute myocardial injury could initiate reactive hypertrophy, which may be fundamental for the remodeling process [7]. Moreover, some of the natriuretic peptides released from the heart may be used as markers of left ventricular dysfunction [8,9].

It is not exactly known by which mechanisms ACE inhibitors exert their beneficial effects in patients after an acute myocardial infarction. Apart from the direct hemodynamic effects, with a reduction in peripheral vascular resistance and left ventricular wall stress, the modulation of endocrine, paracrine and autocrine mechanisms might be operative. The present trial was designed specifically to study the early effects of the ACE inhibitor trandolapril on neurohormones and different enzyme activities, which may be involved in the pathogenesis of left ventricular remodeling and heart failure, in patients with left ventricular dysfunction following a recent acute myocardial infarction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study population
This was a double-blind placebo-controlled trial with parallel groups, performed at 10 hospitals in Sweden. Patients were eligible for the study within 3–7 days after an acute myocardial infarction, if left ventricular wall motion index, as measured by echocardiography, was ≤1.2. Eligible patients were randomized to either trandolapril or placebo. Informed consent was obtained from all patients.

An acute myocardial infarction was considered present if cardiac-specific enzymes were significantly elevated, together with typical chest pain and/or ECG with at least one of the following: ST elevations >1 mm followed by T-wave inversion; new Q waves; or bundle branch block.

Exclusion criteria included: ongoing treatment with an angiotensin-converting enzyme inhibitor; hypotension with systolic blood pressure persistently below 90 mmHg; uncontrolled hypertension; unstable angina pectoris; unstable hemodynamic situation; a cerebrovascular accident within the last 6 months; uncontrolled diabetes mellitus; severe hyponatremia; serum creatinine >200 µmol/l; and serum potassium <3.4 or >5.2 mmol/l.

2.2. Echocardiographic evaluation
Patients with an acute myocardial infarction were screened by two-dimensional echocardiography between days 1 and 6 after the onset of symptoms. Parasternal short-axis views were obtained at three levels of the left ventricle: mitral valve level (mitral valve leaflets visible), high papillary muscle level (chordal attachments visible) and low papillary muscle level (papillary muscle body visible without chordal attachments). All videotape recordings were analyzed at each participating center according to a 16-segment model, as recommended by the American Society of Echocardiography [10]. If more than two segments could not be evaluated, the patient was excluded from further analysis. Segmental wall motion was interpreted in multiple views and according to a modified standard nomenclature [11]. The endocardial motion of each segment was scored as follows: –1=dyskinesia (systolic wall thinning and outward motion); 0=akinesia or severe hypokinesia (absence of or severely depressed systolic wall thickening and motion); 1=hypokinesia (slightly reduced systolic wall thickening and motion); 2=normal; and 3=hyperkinesia (increased systolic wall thickening and motion). The data reported represent the average of the measurements of individual segments. For each patient, an echocardiographic wall motion index was calculated as the quotient of the aggregate segmental score from the segments, divided by the number of segments scored.

2.3. Study drugs
Study drugs (trandolapril or placebo) were initiated by dose titration. There were four dose levels: 0.5; 1; 2; and 4 mg/day. Treatment was initiated with 0.5 mg once daily, and thereafter the dose was increased over the next 5 days to 4 mg/day. If side effects occurred, such as hypotension, a lower dose level could be maintained. Treatment was continued until day 19–22 after the infarction. Other drug therapies were used at the discretion of the responsible physician.

2.4. Neuroendocrine analyses
Blood samples were obtained before randomization (on day 3–7) and on the day after the last dose of study drug was taken (i.e. day 20–23). Patients were fasting for at least 4 h. Samples were obtained from an indwelling catheter in an antecubital vein after 30 min of rest in the supine position. Venous occlusion was avoided. Blood was transferred to tubes prechilled on ice for subsequent separation of plasma and serum after centrifugation at 1500xg for 20 min at +4°C. Samples for aldosterone and ACE activity were centrifuged within 60–120 min; all other samples were centrifuged within 30 min from sampling. All samples were stored at –70°C until analysis.

C-Terminal atrial natriuretic peptide (ANP) was measured by radioimmunoassay in EDTA plasma after extraction by chromatography on Sep-Pac C18 columns [12] [limit of detection, 9.8 pmol/l; between-assay CV, 16.8% (n=10, sample mean 46.9 pmol/l); recovery, 113% (results not corrected for recovery)].

N-Terminal atrial natriuretic peptide (N-terminal proANP) was measured by radioimmunoassay directly in EDTA plasma without prior extraction [13] [limit of detection, 185 pmol/l; between-assay CV, 4.1% (n=10, sample mean 1063 pmol/l)].

Brain natriuretic peptide (BNP) was measured by radioimmunoassay in EDTA plasma after extraction by chromatography on Sep-Pac C18 columns [limit of detection, 2.1 pmol/l; within-assay CV, 7% (n=10, sample mean 7.9 pmol/l); recovery, 60% (results not corrected for recovery)]. Polyclonal antibodies supplied by Peninsula Laboratories [9] were used.

ACE activity was determined in serum by a radioenzymatic method [14,15]. The low molecular-weight substrate used probably means that angiotensin II generation by the tonin–macroglobulin complex [16] will be measured as angiotensin-converting enzyme activity.

Analysis of plasma renin activity (PRA) was based on determinations of generated angiotensin I in EDTA plasma by radioimmunoassay. Cross-reactions with angiotensin II, III, fragment 1–13 or angiotensin II pentapeptide are always <0.04% [17,18].

Aldosterone was determined in serum by radioimmunoassay according to Walsh and co-workers [19].

Nordrenaline and adrenaline were determined in EDTA plasma by high performance liquid chromatography with electrochemical detection [20].

Vasopressin was determined by radioimmunoassay. The tracer used was vasopressin-8-arginine monoiodinated (New England Nuclear, Boston, MA, USA), with a non-specific binding <3%, using antiserum AS-2849 [21].

Heparin plasma with aprotinin was used for determination of neuropeptide Y (NPY) [22] and big endothelin 1 (big ET-1) [23] by radioimmunoassay.

2.5. Statistical methods
The primary objective was to compare the effect of trandolapril and placebo on plasma concentrations of ANP. A secondary objective was to investigate the effects on the following neurohormonal markers: N-terminal proANP; BNP; ACE activity; PRA; aldosterone; noradrenaline; adrenaline; vasopressin; big ET-1; and NPY.

The final calculation of sample size was based on the hypothesis of a 30% change in ANP, tested with a two-sample two-sided Student's t-test. Assuming a mean level of 77.8 pmol/l, a sample size of 96 was required in order to detect a 30% change, with an alpha level of 5% and a power of 80%. In order to account for an approximate frequency of dropouts of 20%, the total number of patients required was estimated to be 116.

A stratification was made based on whether the wall motion index at baseline was <0.8 or ≥0.8. The homogenicity of the two randomized groups regarding qualitative data was checked using a Cochran Mantel Haenzel test for proportions and a two-tailed Fisher exact test for discrete characteristics. For continuous variables, the comparison between groups was carried out using two-way ANOVA. For all neurohormonal markers, due to a possible deviation from normal distribution, the analyses were carried out on log-transformed values. To evaluate the effect of trandolapril on neurohormonal markers, the changes between baseline values and post-treatment values were compared using analysis of covariance. Prior to the closure of the database, all cases with missing values were excluded from analyses, as well as cases where blood sampling took place more than 48 h after the last study drug intake. The relationship between neurohormonal concentrations and clinical variables or measurements was tested with a factorial ANOVA and simple regression for continuous variables. A P value of <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. General
There were 119 patients randomized to either placebo (n=58) or trandolapril (n=61). Descriptive statistics on the baseline characteristics and measurements are shown in Table 1. The patient demographics were comparable in the two groups. Overall, 69% were men, mean age was 69.8 years, 25% were smokers, 15% had a history of diabetes mellitus and 29% had hypertension. Mean left ventricular wall motion index was 0.97 and 14% had a wall motion index <0.8. In the placebo group, 52 patients completed the trial; four patients were excluded because of adverse events and two patients for other reasons. In the group randomized to trandolapril, 50 patients completed the study; nine patients were excluded because of adverse events and two patients for other reasons. All patients who completed the study were on randomized therapy by the end of the trial.


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  		Table 1 Pre-randomization characteristicsa

 
3.2. Effects of trandolapril on neurohormones and enzyme activities
The mean values of plasma neurohormones and enzyme activities and the mean change in each treatment group during the study period are shown in Table 2. ANP was significantly lower in both groups at the end of the study, as compared to the pre-randomization levels. There was no evidence of a treatment effect. N-Terminal proANP increased significantly in the trandolapril group, but not in placebo. However, the changes were not significantly different between the groups. BNP levels were unchanged during the study in both groups, and there was no treatment effect. ACE activity decreased significantly on trandolapril, but remained unchanged on placebo, with a significant difference between the study groups. Accordingly, PRA increased significantly by trandolapril and decreased by placebo, with a significant treatment effect. Aldosterone and noradrenaline tended to decrease similarly in both groups, whereas adrenaline remained low during the trial. Vasopressin and big ET-1 were similar in both groups at baseline and did not change significantly in either group. NPY increased significantly from baseline in both groups, but there was no significant treatment effect. Overall, mean levels of all neurohormonal markers were either within, or slightly above, normal levels.


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  		Table 2 Mean (S.D.) values of neurohormones, mean change, within-group comparison and test of treatment effect (between-group comparison)

 
3.3. Relationship between neurohormonal activation, and clinical and laboratory variables
The relationship between markers of neurohormonal activation and the following variables was studied: previous myocardial infarction; history of congestive heart failure; wall motion index; ST elevation on the admission electrocardiogram, Killip classification; and peak serum CKMB concentration.

PRA was significantly higher among patients with a previous myocardial infarction than among those with no history of a myocardial infarction (3.5 vs. 2.2 ng/ml/h; P<0.05). Otherwise, there was no relationship between neurohormonal activation and a previous myocardial infarction. The following neurohormones were significantly higher among patients with a history of congestive heart failure than among those without heart failure: ANP; N-terminal proANP; aldosterone; and big ET-1 (Fig. 1). Wall motion index correlated inversely with plasma concentration of N-terminal proANP (r=–0.24, P<0.01), PRA (r=–0.27, P<0.01), aldosterone (r=–0.27, P<0.01) and NPY (r=–0.28, P<0.01). There was no relationship between the presence of ST elevation on the admission electrocardiogram and the degree of neurohormonal activation. There were positive correlations between Killip class and N-terminal proANP, BNP, PRA, aldosterone, vasopressin or NPY (Fig. 2). Peak serum CKMB correlated significantly with plasma vasopressin (r=0.22, P<0.05).


Figure 1
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  		Fig. 1 Median plasma concentration of ANP, N-terminal proANP, aldosterone and endothelin at baseline in patients with and without a history of congestive heart failure (CHF).

 


Figure 2
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  		Fig. 2 Median levels of N-terminal proANP, BNP, PRA, aldosterone, vasopressin and NPY at baseline in patients in Killip classes 1, 2 and 3, respectively.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
An early activation of the sympathetic nervous system and the renin–angiotensin aldosterone system in conjunction with an acute myocardial infarction is fairly well established [5,6]. Some studies have also shown increased concentrations of ANP, N-terminal proANP and BNP [6,9]. Increased plasma concentrations of these natriuretic peptides have been associated with complications in the acute phase of an myocardial infarction, and with an unfavorable long-term prognosis [24–26]. Furthermore, drugs which modulate the effects of neurohormonal activation, such as beta-adrenoceptor blocking agents and ACE inhibitors, have been shown to improve prognosis [27,28]. However, it is still unclear how neurohormonal mechanisms are influenced by pharmacological treatment, and whether treatment efficacy may be predicted by drug-induced effects on plasma neurohormone concentrations.

In patients with left ventricular dysfunction after an acute myocardial infarction, randomized to trandolapril or to placebo in the TRACE study [3], survival was improved by trandolapril. The present study investigated the early effects of trandolapril on neurohormonal activation, and used the same inclusion criteria as the TRACE study. Our hypothesis was that ANP might be used as an early indicator of treatment efficacy. ANP was selected because of the relatively strong inverse correlation with left ventricular function [29], as well as its association with prognosis [25,26]. The lack of treatment effect by trandolapril on ANP in the present study suggests that early changes in ANP may not be used to predict the efficacy of ACE inhibitor treatment following an acute myocardial infarction. The results may seem to be in contrast to some earlier studies on patients with congestive heart failure, where ANP was reduced by ACE inhibitor treatment [30–32]. However, an important difference is that we studied short-term effects of pharmacological blockade with an ACE inhibitor in the early phase following an acute myocardial infarction, whereas the other studies have evaluated long-term effects in patients with congestive heart failure. Furthermore, our findings with ANP are supported by the lack of effect of trandolapril on N-terminal-proANP. Although it would have been interesting to compare the possible differences in the effects of short- and long-term treatment, it was not considered possible to give prolonged placebo treatment to this group of patients, due to ethical reasons.

In the trandolapril group, ANP and N-terminal proANP changed in opposite directions over time. The mechanism behind this finding remains unclear. However, since the two peptides are co-secreted from the heart, the discrepancy is most likely due to a differential effect of the drug on the peptide-clearing mechanisms.

BNP was unaffected by trandolapril treatment. Although BNP has been shown to be associated with the degree of left ventricular dysfunction [9], our findings suggest that ACE inhibition with trandolapril for 2–3 weeks does not have a significant effect on this peptide.

Plasma ACE activity was suppressed by trandolapril, in agreement with earlier studies [29,33], and PRA increased in the trandolapril group, as anticipated. These effects of trandolapril on ACE activity and PRA indicate that effective drug concentrations were achieved in our study. However, the reductions in aldosterone were small, and similar in both groups. This would be compatible with an aldosterone escape phenomenon, as described previously, and may be related to stimulation of aldosterone release by alternative mechanisms, including conversion of angiotensin I to angiotensin II via enzyme systems that are independent of ACE [34–36].

Treatment with trandolapril did not affect the plasma levels of noradrenaline and adrenaline. This is in agreement with previous findings with enalapril on plasma catecholamine levels after an acute myocardial infarction [29]. Angiotensin II can facilitate the release of noradrenaline from sympathetic nerve endings, but in an experimental model, it was not possible to show that ACE inhibition could reduce sympathetic neurotransmission in vivo [37]. Taken together, it seems unlikely that the beneficial effects of ACE inhibitor therapy in patients with a recent acute myocardial infarction are mediated by an early decrease in circulating plasma catecholamine levels, due to an interaction with peripheral sympathetic neurotransmission.

Previous studies have indicated that elevated plasma levels of endothelin [38–40], vasopressin [41] and NPY [42] may be associated with an unfavorable long-term prognosis after an acute myocardial infarction. Plasma levels of NPY, vasopressin and big ET-1 were not affected by ACE inhibition in the present trial, suggesting that alterations in circulating levels of NPY, vasopressin and endothelin are not directly modulated by short-term ACE inhibition. The present study shows a significant correlation between plasma levels of NPY and echocardiographically determined left ventricular systolic function, extending previous observations [43,44]. NPY is considered to be co-released with noradrenaline from peripheral sympathetic nerves. An interesting finding is that noradrenaline tended to decrease, while NPY increased, during the study period. This temporal dissociation, in agreement with previous reports [42,44], may suggest a preferential release of NPY from sympathetic nerves in heart failure. It is, however, more likely, that the increase in NPY levels reflects an impaired elimination of the peptide, due to a reduced hepato-mesenteric circulation, secondary to the development of heart failure [45].

We studied the relationship between the degree of neuroendocrine activation at baseline on one hand, and clinical and laboratory variables expressing extensive myocardial damage, left ventricular dysfunction and heart failure on the other. N-Terminal proANP, PRA and aldosterone were significantly related to three of these variables. Vasopressin and NPY correlated with two variables. ANP, BNP and big ET-1 correlated with one variable only, whereas ACE activity, noradrenaline and adrenaline showed no relationship. Killip classification correlated significantly with six of the neurohormone markers, and left ventricular wall motion index correlated with five. The overall finding is a relationship between neurohormonal activation and left ventricular dysfunction and clinical heart failure in the early phase following an acute myocardial infarction.

There was an inverse correlation between N-terminal proANP and left ventricular wall motion index. This is supported by previous observations, where multivariate analysis showed that N-terminal-proANP correlated significantly with prognosis in patients with left ventricular dysfunction after a myocardial infarction [26]. Earlier studies have indicated a relationship between left ventricular dysfunction and plasma levels of ANP and BNP [9,29], but we were unable to show this in the present study. ANP and BNP may not be as strongly related to left ventricular dysfunction as N-terminal pro-ANP. Indeed, a majority (86%) of our patients had a wall motion index in the relatively narrow range of 0.8–1.2, which may make it difficult to find such correlations. Our results suggest that N-terminal proANP may be useful to identify patients at risk after a myocardial infarction.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
We studied the early effects of ACE inhibition on neurohormonal activation, assessed by plasma neurohormone levels, in patients with a recent myocardial infarction and concomitant left ventricular dysfunction. Trandolapril, which has been demonstrated to have marked beneficial effects on prognosis, inhibited ACE activity and raised PRA, indicating effective doses. However, natriuretic peptides, indices of peripheral sympathetic neurotransmission, vasopressin or endothelin were largely unchanged by trandolapril. The results suggest that the beneficial effects of ACE inhibitors in patients with left ventricular dysfunction after a myocardial infarction are probably not related to early modulation of neurohormonal activation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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