N-terminal proatrial natriuretic peptide predicts two-year remodelling in patients with acute transmural myocardial infarction

Torstein Holea,*, Christian Hallb and Terje Skjærpec

a Section of Cardiology, Medical Department, Ålesund Hospital, N-6026, Ålesund, Norway
b Research Institute for Internal Medicine, University of Oslo, Norway
c Cardiology Department, St. Olav Hospital, University Hospital Trondheim, Norway

* Corresponding author. Tel.: +47-70-10-50-00/14-91-85; fax: +47-70-15-19-45/15-39-41
E-mail address: torstein.hole{at}helse-sunnmore.no
E-mail address: torstein.hole{at}adsl.no

Received 13 May 2003; revised 1 October 2003; accepted 16 October 2003

Abstract

Aims To evaluate whether baseline N-terminal proatrial natriuretic peptide (Nt-proANP) or Doppler echocardiographic parameters could predict two-year left ventricular remodelling after acute myocardial infarction in patients without heart failure.

Methods and results Seventy-one patients were followed with Doppler echocardiographic examinations at baseline, 3 months, 1 and 2 years, and Nt-proANP was measured at baseline and 3 months. After 2 years there was a significant increase in end-diastolic volume index of 11% () and end-systolic volume index of 14% (), and no change in ejection fraction. This remodelling was confined to 12 patients (17%) with a significant increase in end-diastolic volume index above 20 ml/m2. Baseline Nt-proANP (), 3-month changes in end-diastolic volume index (), and 3-month E/A ratio () were independent positive predictors for two-year changes in end-diastolic volume index. Two-year dilatation above 20 ml/m2 was predicted by baseline Nt-proANP () and maximal velocity of systolic pulmonary venous flow ().

Conclusion Seventeen percent of patients with transmural myocardial infarction and no baseline heart failure experienced a significant left ventricular dilatation at 2 years, and this was best predicted by baseline Nt-proANP.Unstructured abstract

Seventy-one patients with acute myocardial infarction and no heart failure were followed for two years in an observational Doppler echocardiographic study. There was a significant increase in end-diastolic volume index of 11% () and end-systolic volume index of 14% (), but no change in ejection fraction after two years. Nt-proANP was the strongest independent predictor of two-year changes in end-diastolic volume index and of an increase in end-diastolic volume index above 20 ml/m2 after two years.

Key Words: Diastolic function • Systolic function • Left ventricular remodelling • Acute myocardial infarction • ProANP

Introduction

Left ventricular ejection fraction and volumes measured after acute myocardial infarction are important determinants of survival the first year after myocardial infarction.1–3 Left ventricular remodelling may start or continue after discharge and progress during months or years often with a modest impact on ejection fraction due to proportional increase in end-diastolic and end-systolic volumes.3–6 This late remodelling after myocardial infarction has been shown to be of prognostic importance.3,7 Left ventricular abnormal filling is also an important predictor of prognosis and of remodelling after acute myocardial infarction.8–11 N-terminal proatrial natriuretic peptide (Nt-proANP) has been shown to be an independent predictor of long-term prognosis after acute myocardial infarction both in patients with reduced and preserved left ventricular ejection fraction.12,13 Doppler echocardiography has provided a simple and non-invasive method of assessing left ventricular systolic and diastolic function.14 The extent to which baseline parameters may predict long-term remodelling has not been extensively studied. The aim of this study was to evaluate the extent of left ventricular dilatation in patients with acute transmural myocardial infarction and no baseline heart failure, and to evaluate whether Doppler echocardiographic parameters or Nt-proANP at baseline could predict this process.

Methods

Patient population
Clinically stable patients in sinus rhythm with acute transmural myocardial infarction without overt heart failure were included in a multicentre ( centres) echocardiographic observational study of prognostic value of left ventricular dimensions and function between June 1995 and June 1997 (the LEVEREM study).13

The definition of a transmural myocardial infarction included one of the following two criteria in addition to the development of new pathologic Q-waves in the ECG: typical chest pain or dyspnoea, or elevation of enzyme levels to above twice upper normal level. Patients with a recurrent non-Q infarction were also included, as were patients with right or left bundle branch block, provided they had chest pain and significant enzyme elevation as described.

Exclusion criteria included the following conditions during the time period from the onset of symptoms to the time point of the qualifying echocardiogram (2–7 days): unstable angina pectoris requiring coronary angiography, PCI, or coronary artery bypass grafting; heart failure necessitating ACE-inhibitor treatment (temporary short acting diuretics were allowed provided the last dose was administered at least 24 h before the initial echocardiographic examination); atrial fibrillation; current treatment with an ACE inhibitor. Patients who had been treated with PTCA or coronary artery bypass grafting within one month, or who had a myocardial infarction according to hospital records within 3 months of the index infarction, were also excluded, as were patients with co-morbid non-cardiac disease expected to shorten the patient’s life expectancy to less than the two-year follow-up period. Patients with technically limited echocardiograms to be insufficient for quantitative analysis were excluded ().

Patients from lesund Hospital were included in a single centre two-year serial Doppler echocardiographic sub study. Regional ethics committee approved the study and all patients gave written informed consent.

About 400 patients were admitted for acute myocardial infarction during the recruitment period and about 40% had transmural infarction. About 40% had some exclusion criteria, mostly clinical heart failure, and 90 patients were included in the main study.13 Three patients were excluded for administrative reasons, 15 due to technical problems with the digital recording system at the baseline examination, and one died before 3 months. One patient died after 6 months and two patients withdrew their consent at 12 months. Seventy-one patients were thus included in the sub study and 68 were followed for 2 years. None of the patients had significant valvular lesions. Four patients experienced a reinfarction, and 11 patients developed heart failure, including 2 of the patients with reinfarction. Baseline characteristics are shown in Table 1.


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Table 1 Patient characteristics ()

 
Doppler echocardiographic examination
Patients were examined between 2 and 7 days after the acute myocardial infarction, and then re-examined after 3 months, one year, and two years.

Patients were examined in left lateral position with CFM 750/800 or SystemFive (Vingmed Sound AS, Horten, Norway) with a 2.5 MHz combined Doppler-2D transducer. The recordings were done in end-expiration or quiet respiration for those who were unable to hold their breath sufficiently long. Two-dimensional recordings were done in apical 4-chamber and long axis views. Doppler recordings of mitral inflow were done with pulsed Doppler and with the sample volume between the tips of the mitral leaflets. Recordings of pulmonary venous flow were done from the right upper pulmonary vein in the apical 4-chamber view or a slight modification of it with the pulsed Doppler sample volume well inside the vein. Pulsed Doppler recordings of left ventricular outflow were done with the sample volume below the aortic valve. Digital recordings were stored on Echopac (Vingmed Sound AS, Horten, Norway) and later analysed off line blinded to patient status and previous recordings. All Doppler recordings were done with a speed of 5.0 cm/s.

Quantitative analysis of Doppler echocardiographic recordings
All measurements were done by one of the authors (TH) after the completion of the study to avoid temporal drift in the measurements. All measurements represent the average value of at least three tracings of individual waveforms or 2-D cine loops.

The outer margin of the Doppler waveforms was traced, ignoring noise artefacts. The maximal velocity of early and late mitral filling wave (), the corresponding time velocity integrals (), the ratio of the maximal velocities of the early and late filling waves , and the deceleration time of the early filling wave (EDT) and the duration of the late filling wave () were measured. The following pulmonary venous flow indices were measured: the maximal velocity of the forward systolic () and diastolic () component and the reversal with atrial contraction (), the corresponding time velocity integrals (, , ), and the ratio of the systolic to the total forward integral . In addition, the deceleration time of the diastolic component (DDT) and the duration of the atrial reversal () were measured. The difference between the duration of the late mitral filling wave () and the duration of pulmonary venous flow reversal with atrial contraction () was calculated ().

The biplane Simpson’s method15 was used to calculate left ventricular end-diastolic (EDV) and end-systolic volumes (ESV), and the corresponding ejection fraction (EF). End-diastolic and end-systolic volumes were indexed to body surface area.16

The myocardial performance index (MPI) was calculated from the Doppler tracings of mitral inflow and left ventricular outflow.17 The time period between the end and start of mitral inflow waves (MRR) was measured as well as the left ventricular ejection period (LVET). MPI was calculated from these two measurements ((MRR–LVET)/LVET).

From the Doppler recordings of mitral and pulmonary venous flow indices patients were classified as having restrictive filling pattern when EDT was below 140 ms, impaired relaxation when EDT was above 260 ms, and pseudonormal filling pattern when EDT was 140–260 ms and PVF was above 60 cm/s,18 or DDT was below 175 ms,19 or systolic fraction of forward flow was below 0.40,20 indicating elevated left ventricular filling pressure.

Reproducibility analysis
Reproducibility data for the pulmonary venous indices have previously been published from our laboratory for this patient population,21 and are from randomly selected study patients for the other indices. The coefficients of variation for repeated measurements were: EDV 2.9%, ESV 5.1%, EF 6.0%, 3.6%, 8.5%, 6.0%, 5.3%, 10.6%, EDT 8.0%, 5.5%, 8.1%, 10.6%, 6.8%, 12.6%, DDT 8.9%, 10.2%, 9.9%, LVET 2.3%, and MPI 6.9%.

Nt-proANP analysis
A blood sample was drawn for Nt-proANP measurement within 24 h of the Doppler echocardiographic recordings at baseline and 3 months. Fifty-four patients had Nt-proANP analysed at baseline and 51 at 3 months. Nt-proANP concentration was measured by radioimmunoassay technique in a core laboratory in Oslo according to Sundsfjord et al.22 The within-assay coefficient of variation was 3.2% and the between-assay coefficient of variation 5.2%, and the detection limit 200 pmol/l. Upper reference limits (97.5 percentile) in the laboratory were adjusted for age as follows (years; pmol/l) 40; 800, 40–49; 900, 50–59; 1000, 60–69; 1200, 70–79; 1500, 80; 2000.

Statistical analysis
All measurements are presented as means (±SD). To compare baseline, 3-month, one- and two-year values, and corresponding changes, analyses of variance (GLM Repeated Measures with Mauchly’s test (epsilon)) were used together with paired samples t tests.

Independent-samples t tests were used to compare sub-groups and differences in variance were tested with Levene’s test of variance. Verification of normal distribution of data was accomplished using normality plots. Categorical data were analysed with nonparametric tests as McNemar test for paired samples. Univariate and multiple (forward) linear regression analyses were performed to evaluate whether baseline values, or 3-month values and changes in Doppler echocardiographic parameters and Nt-proANP predicted changes in end-diastolic or end-systolic volume index. The mean increase linearity was tested by Curve Fit analyses (SPSS) yielding a linear fit ( 0.993). Parameters with a p value 0.20 were selected for testing in the multiple model and only parameters with an individual significant contribution were kept in the model.

A 20 ml/m2 increase in end-diastolic volume index (20% increase) was considered a significant dilatation based on the reproducibility analyses23 and represents an increase of more than 2 SD. Patients were divided into two groups according to whether they had an increase in end-diastolic volume index above 20 ml/m2 (group 1) or not (group 2). Binary logistic regression analysis was used to analyse the value of selected baseline and 3 month values as independent predictors of this dichotomous outcome with the same selection criteria as in the linear regression. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic abilities of Nt-proANP.

All tests were two-sided and a significance level of 5% was used. All analyses were performed with SPSS 11.0 (SPSS Inc, USA).

Results

Volumes and systolic function
In the whole patient group there was a statistically significant increase in end-diastolic (11%) and end-systolic (14%) volume index without any change in ejection fraction during the two years of follow-up (Table 2). Neither was there any significant change in the myocardial performance index (MPI, Tei index) during the 2-year follow-up (Table 2). The mean increase in left ventricular end-diastolic volume index was linear throughout the follow-up period.


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Table 2 Doppler echocardiographic measurements and heart rate at baseline, 3 months, and 1 and 2 years

 
Twelve patients (17%) had an increase in end-diastolic volume index above 20 ml/m2 with a mean increase of 54 (±31) ml/m2 as opposed to 1 (±11) ml/m2 in the others. In these 12 patients there was an increase in end-systolic volume index of 44 (±34) ml/m2 and a decrease in ejection fraction of 0.06 (±0.10) compared to an increase of 1 (±8) ml/m2 () in end-systolic volume index and of 0.01 (±0.057) () in ejection fraction in the other patients. The differences between groups 1 and 2 are summarised in Table 3.


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Table 3 Selected Doppler echocardiographic measurements and baseline variables in patients with (group 1, ) and without (group 2, ) significant dilatation after 2 years (see text)

 
There was no significant difference in baseline end-diastolic (91 and 97 ml/m2) or end-systolic (49 and 54 ml/m2) volume index, or ejection fraction (0.47 and 0.45) between inferior and anterior infarct location. After 2 years a significant difference in left ventricular dilatation (4 and 18 ml/m2 increase, respectively, ), change in end-systolic volume index (1 and 17 ml/m2 increase, respectively, ), and ejection fraction (increase of 0.017 and decrease of 0.037, respectively, ) were observed between inferior and anterior infarct location. There was also a significant difference in dilatation above 20 ml/m2 between anterior and inferior infarct location ().

There was a trend but no statistically significant difference between patients with and patients without preserved systolic function (ejection fraction >=0.40) in left ventricular dilatation (7±18 versus 28±46 ml/m2, ). The volume indices were, however, significantly lower both at baseline and 2 years in patients with preserved systolic function.

Diastolic filling parameters
There was a gradual increase in the time velocity integral and the deceleration time of the mitral early filling wave ( and EDT, Table 2(a)), and an increase in the duration and time velocity integral of the late mitral filling wave (), without any change in the ratio. This corresponded to a significant increase in the deceleration time of the forward diastolic component of the pulmonary venous flow (DDT, Table 2(b)), and a decrease in the difference in duration between the pulmonary and mitral A-wave (). In agreement with this there was a significant change in the classification of the Doppler filling pattern during the follow up () with less patients classified as having a restrictive filling pattern and more patients classified as having impaired relaxation.

There was no difference in baseline Doppler parameters between those with (group 1) and those without (group 2) significant dilatation. Patients with anterior myocardial infarction, however, had significantly shorter deceleration time of mitral E-wave (EDT) and pulmonary venous D-wave (DDT), and higher ratio than those with inferior location: 154 versus 189 ms (), 237 versus 275 ms (), and 1.2 versus 1.0 (), respectively. There was no significant difference in these parameters between those with and those without an ejection fraction >=0.40.

Nt-proANP
The median value of Nt-proANP at baseline and 3 months was 935 pmol/l (range 377–5250) and 989 pmol/l (range 250–3800), respectively. Nt-proANP was normally distributed after logarithmic transformation. There was no significant difference between baseline and 3-month data. Baseline Nt-proANP correlated significantly with age and creatinine.

There was a significant difference between those with (group 1) and those without (group 2) a significant dilatation both at baseline (2984 versus 1016 pmol/l, ) and 3 months (1961 versus 1018 pmol/l, ). There was also a significant difference at baseline between those with and without anterior location of their myocardial infarction (1719 versus 1011 pmol/l, ).

Predictors of left ventricular dilatation
The results of univariate and multiple regression analyses for increase in left ventricular end-diastolic volume index and the dichotomous outcome of being a dilatator or not are presented in Table 4, and the relationship between baseline Nt-proANP and two-year changes in left ventricular end-diastolic volume in Fig. 1.


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Table 4 Predictors of left ventricular dilatation after two years of follow-up

 


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Fig. 1 Relationship between baseline Nt-proANP and two-year changes in left ventricular end-diastolic volume index (left ventricular dilation) , .

 
In multiple regression analysis baseline Nt-proANP (), 3-month E/A ratio (), and 3-month changes in end-diastolic volume index () were significant positive predictors of changes in left ventricular end-diastolic volume index and entered the final model. Baseline Nt-proANP () and maximal velocity of systolic pulmonary venous flow (, ) predicted a significant dilatation (20 ml/m2) after two years in logistic regression analysis. These findings were also valid for patients with baseline ejection fraction >=0.40. The same principal findings were made in univariate regression analyses regarding predictors of changes in end-systolic volume index, and only Nt-proANP () and maximal velocity of systolic pulmonary venous flow (, ) were independent predictors in multiple analysis.

In ROC curve analysis an Nt-proANP value of 1420 pmol/l had 86% sensitivity and 85% specificity for a significant dilatation (20 ml/m2), with a significant area under the curve (AUC 0.84, ).

Discussion

Left ventricular remodelling
Gianuzzi et al.24 in their analysis of 614 patients from the GISSI-3 trial found a heterogeneous response after myocardial infarction. Nineteen percent experienced early in hospital dilatation and 16% late dilatation after 6 months. Twenty percent had non-Q-wave infarction and patients with heart failure were included. In this study the early and late dilatation was unrelated. Gadsbøll et al.7,25 in previous publications have reported a significant dilatation (20%) in the first year post-infarction in more than 50% of patients examined from 1984 to 87. Zaman et al.26 in their examination of thrombolysed anterior myocardial infarctions found a dilatation above 10 ml/m2 after 6 months in 35% of those with and 15% of those without Q-waves. Nilsson et al.27 in their MRI study of 42 patients with acute ST-elevation myocardial infarction reported a 30 % frequency of significant dilatation (11.8 ml in end-diastolic volume) at one year with unchanged ejection fraction of 0.55 (±0.12). The frequency of left ventricular dilatation in our patient population was thus less or equal to that previously reported despite a transmural extent of the myocardial infarction in our patients.

Changes in Doppler filling patterns
The diastolic filling pattern was characterised by more impaired relaxation and less restrictive filling pattern during the two-year follow up. The increase in mitral deceleration time (EDT) was paralleled both by a prolongation of the deceleration time of the pulmonary venous diastolic forward component (DDT) and a reduction in the difference in duration of mitral and pulmonary venous atrial component (). There was thus a consistency in the Doppler filling parameters indicating reduced filling pressures during follow up. Increasing prevalence of impaired relaxation in the Doppler filling pattern may be caused by a reduction in filling pressure demasking pre-existing impaired relaxation or an increasing prevalence of impaired relaxation during the follow up. Whether this was a consequence of the natural post-infarction remodelling process or may be related to medical intervention as ß-blocker treatment is not answered by this observational study. The findings are, however, consistent with those previously reported both by Cerisano et al.11 and Poulsen et al.9 who found an increase in mitral E-wave deceleration time (EDT) during follow up, and this was especially noted in patients with a restrictive filling pattern at baseline as in our study.

Predictors of left ventricular remodelling
Predicting significant dilatation may be of clinical importance to the individual patient, as it may indicate predischarge intervention with ACE-inhibitor therapy despite having ejection fraction above 0.40 and no heart failure. Changes in end-diastolic volume index were in univariate regression analyses predicted by several baseline Doppler parameters that indicate elevated filling pressure, but not by baseline volumes or systolic function. It is thus not the patients with the largest ventricles that are prone to further remodelling, but those with signs of elevated filling pressure in the Doppler filling parameters. However, both in univariate and multiple regression analyses Nt-proANP was the strongest predictor of left ventricular dilatation. Only 3-month ratio and changes in end-diastolic volume index emerged as independent predictors of two-year dilatation in addition to baseline Nt-proANP. Nt-proANP was the strongest independent predictor of a significant dilatation 20 ml/m2. This was true also for patients with preserved left ventricular function (ejection fraction >=0.40).

Nilsson et al.27 found Nt-proBNP to be the strongest predictor of significant dilatation at one year after acute myocardial infarction. In this study there were no measurements of diastolic Doppler parameters and thus further comparison of predictors of dilatation is not possible. The two studies do, however, indicate that natriuretic peptides may be clinically important predictors of left ventricular dilatation after acute myocardial infarction. The most important stimulus for secretion of cardiac natriuretic peptides is wall stress, and increasing wall stress is driving left ventricular remodelling. This may thus be the link between natriuretic peptides and remodelling. Nt-proANP is also an important prognostic marker after acute myocardial infarction12,13 and the relation to left ventricular remodelling may explain some of this prognostic value. Linking left ventricular remodelling and ventricular arrhythmias28 further underlines the possible role of natriuretic peptides in prognostic stratification after acute myocardial infarction, and possibly as a selection criterion for ACE inhibitor treatment.

The ROC curve analysis both in the article by Nilsson et al.27 and in our study indicates that elevated baseline plasma levels of natriuretic peptides could identify patients in whom significant left ventricular dilatation developed.

Infarct location did seem to have some influence on late remodelling. Patients with anterior location had significantly worse systolic function after 2 years, and the mean magnitude of dilatation and frequency of significant dilatation was higher than in inferior infarct location. The lack of significant differences between patients with and without preserved systolic function may be due to the low patient number.

Study limitations
The moderate reproducibility of Doppler echocardiographic measurements is a problem in all serial echocardiographic studies. The patient selection and relatively small patient number also limits the power of the study, and calls for caution in making conclusions regarding negative findings. Due to the explorative nature of the study and multiple testing, some of the findings may be significant only by chance.

Tissue Doppler recordings were not available at the time when the study was conducted, and might have improved classification of filling patterns and prediction of dilatation.

None of the patients had PCI acutely before the baseline echocardiogram and patients were clinically stable at the first examination. The results may thus not be applicable to a clinically unstable group of early post-infarction patients. Baseline examination was performed 2–7 days after the myocardial infarction when infarct expansion had possibly already taken place in some of the patients, and a very early remodelling may thus not have been detected.

Measurements of Nt-proANP were missing in a significant number of the patients, and the small number of patients with significant dilatation reduces the strength of the association between Nt-proANP and left ventricular dilatation. The significance level is thus dependent on few observations.

The plasma levels of natriuretic peptides may vary considerably during the first week after an acute myocardial infarction even in clinically stable patients. The time frame of 2–7 days for the measurements may thus have influenced the precise level of the relationship between Nt-proANP and remodelling.

Summary
In this observational study of post-infarction patients without heart failure we observed a significant degree of left ventricular dilatation in 17% of patients after two years. Mitral and pulmonary venous Doppler filling parameters indicated a reduction in filling pressures and increasing prevalence of impaired relaxation during the 2-year follow up. Baseline Doppler filling parameters, but not volumes or systolic function, predicted 2-year left ventricular dilatation in univariate analyses. However, baseline Nt-proANP was the strongest independent predictor both of 2-year dilatation and of a significant dilatation above 20 ml/m2.

Acknowledgments

The study was supported by a grant from the public research institution Møreforskning, Norway. We thank S Urheim, JVegsundvg, and TH Morstøl for participating in the echocardiographic examinations.

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