Relationship between transcardiac gradient of endothelin-1 and left ventricular remodelling in patients with first anterior myocardial infarction
T. Tsutamoto*,
A. Wada,
M. Hayashi,
T. Tsutsui,
K. Maeda,
M. Ohnishi,
M. Fujii,
T. Matsumoto,
T. Yamamoto,
T. Takayama,
C. Ishii and
M. Kinoshita
First Department of Internal Medicine, Shiga University of Medical Science, Seta-Tsukinowa,Otsu 520-2192, Japan
Received May 23, 2002;
accepted June 12, 2002
* Corresponding author. Tel.: +81-775-48-2213; fax: +81-775-43-5839
tutamoto{at}belle.shiga-med.ac.jp
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Abstract
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Aims To evaluate whether plasma endothelin-1 (ET-1) is extracted or produced through the heart in patients with acute myocardial infarction (AMI), and the relationship between transcardiac extraction of plasma ET-1 and left ventricular (LV) remodelling.
Methods and results We measured the plasma level of ET-1 in the aortic root (Ao) and coronary sinus (CS) in 48 consecutive patients, who received successful revascularization and enalapril, for a first anterior AMI. In the acute phase the plasma ET-1 level was significantly higher both in the Ao and the CS compared to the control subjects. However, the plasma ET-1 level was significantly lower in the CS than in the Ao in the acute phase and after 1 month. There were significant correlations between transcardiac extraction of ET-1 in the acute phase and LV ejection fraction and LV end-diastolic volume index (LVEDVI) after 1 month. Stepwise multivariate analysis showed that maximal creatine phosphokinase and transcardiac extraction of plasma ET-1 during the acute phase were independently and positively correlated with the absolute change in LVEDVI after 1 month.
Conclusions These results indicate that elevated circulating ET-1 is extracted through the heart in patients with a first anterior AMI and that the extracted ET-1 plays a significant role in modulating post-infarct LV remodelling.
Key Words: Acute myocardial infarction Endothelin-1 Brain natriuretic peptide Ventricular remodelling
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1. Introduction
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Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide,1 and its long-term effects include stimulation of myocardial hypertrophy,2 fibroblast proliferation,3 interstitial fibrosis,4 and myocardial cell injury,5 suggesting an important role in ventricular remodelling after acute myocardial infarction (AMI). In an experimental model of AMI, ET-1 systems including prepro ET-1 mRNA and ET receptor mRNA are activated in the heart,68 and ET-1 receptor antagonists had beneficial effects on mortality and left ventricularremodelling.6,9,10 In addition, a high plasma ET-1 is an important prognostic predictor in patients with AMI,11 suggesting that endogenous ET-1 has animportant role in the pathogenesis of AMI. Moreover, we recently demonstrated that suppressionof plasma ET-1 during the acute phase of AMIprevented postinfarct left ventricular remodelling.12 ET-1 is produced not only by the endothelial cells but also by ventricular myocytes,13,14 especially in pathological states such as hypertrophy and myocardial infarction,6,15,16 suggesting that the elevated circulating ET-1 is partly derived from the heart in patients with AMI.
Recent reports, including ours, showed thatelevated circulating ET-1 is extracted across the failing heart in patients with severe congestive heart failure (CHF).17,18 Moreover, there was asignificant correlation between the transcardiac gradient of plasma ET-1 and the left ventricular end-diastolic volume index (LVEDVI)17 in patients with CHF. However, the cause and effect of the relation between the transcardiac gradient of plasma ET-1 and LVEDVI remains unknown because we could not repeatedly measure these parameters in the previous study.17 Previous reports, including ours, showed that the main source of increased ET-1 is the pulmonary circulation in patients with CHF.17,19 However, whether circulating ET-1 is spilled over or extracted across the heart, therole of endogenous ET-1 on left ventricular (LV) remodelling in patients with AMI remains unknown.
In the present study, we evaluated (1) whether plasma ET-1 is extracted or produced through the heart during the acute-phase, and (2) if plasma ET-1 is extracted, whether the transcardiac extraction of plasma ET-1 during the acute phase is related to LV remodelling after 1 month in patients with a first anterior AMI, who received successful revascularization and enalapril.
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2. Method
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2.1. Study population
We prospectively studied 54 patients, the study population, who were admitted to the coronary care unit of our institution with a first anterior AMI, and presented Thrombolysis in Myocardial Infarction (TIMI) grade 0 or 1 flow at initial coronary angiography. Admission criteria included prolonged chest pain (>30min), an electrocardiographic ST segment elevation >2mV in two or more adjacent precordial leads, successful reperfusion therapy within 24h of the onset of chest pain documented by coronary angiography, and a more than threefold increase in serum creatine phosphokinase(CK) levels. Admission criteria was the same as previously reported.12 The patients who had prior myocardial infarction; significant stenosis of a coronary artery not related to the infarcted area and residual stenosis (>70%) of the infarct-related coronary artery were excluded from this study. We also selected 14 age-matched normal subjects (age, 44 to 72, mean=58 years) who were admitted complaining of chest pain, whose hearts proved to be normal by coronary angiography. All patients gave informed consent, and the study was approved by the Committee on Human Investigation at our institution.
Patients were classified into two groups; Remodelling () group and Remodelling (+) group, based on the absolute change of LVEDVI. The cutoff level was the median value for the absolute change of LVEDVI after 1 month.
2.2. Study design and protocol
All patients underwent cardiac catheterization by the femoral approach. Patients with persistentocclusion of the infarct-related vessel underwent percutaneous transluminal coronary angioplasty following standard techniques. Patients who could not obtain more than 70% patency and/or TIMI 3 flow were excluded from this study. After obtaining revascularization (patency
70% and TIMI 3 flow) and assuring hemodynamic stability, right-sided cardiac catheterization using a 7F Swan-Ganzcatheter and measurement of LV end-diastolic pressure (LVEDP) using a 5F pig tail catheter were performed.
Blood samples for measuring plasma ET-1 were collected simultaneously from the Ao and CS as previously reported.17 We also measured plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and aldosterone in theAo and CS. After angioplasty and blood sampling was done, contrast left ventriculography wasperformed.
After admission to the coronary care unit, all patients received oral aspirin and/or ticlopidine. ACE inhibitors (enalapril) were administrated toall patients. Repeat cardiac catheterization andcontrast left ventriculography were performed1 month after the initial catheterization to determine culprit artery patency and LV function. Left ventriculography performed by contrast medium was analysed for LV ejection fraction (LVEF) and LV volume by cardiologists who were unaware ofthe patients' data at the acute-phase and after1 month. Hemodynamic measurement using a SwanGanz catheter, and blood sampling from the Ao and CS were also performed. Patients with significant restenosis (>70%) of the culprit lesion wereexcluded from the study.
2.3. Measurement of neurohumoral factors
The plasma ET-1 level was determined using an antibody directed against synthetic ET-1 (Peninsula Laboratories, Inc., Belmont, CA, USA) and 125I ET-1 (Amersham Japan, Tokyo, Japan) as previouslyreported.20 Plasma concentrations of ANP and BNP were measured with a specific immunoradiometric assay using a commercial kit (Shionogi, Osaka,Japan) as previously reported.21 Plasma aldosterone levels were measured using a commercial kit as previously reported.12
2.4. Statistical analysis
All results are expressed as the mean±SEM. Categoric data were compared against chi-squared distribution. Student's t test was used for continuous variables between groups, and paired t test was used for within group comparison. Linear regression analysis was used to determine the relation between continuous variables. To evaluate the contribution of ET-1 extraction at the acute-phase to LVEDVI 1 month after onset, univariate and stepwise multivariate analysis were used among the14 variables. A values of
was considered significant.
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3. Results
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3.1. Clinical characteristics (Table 1)
Fifty-four consecutive patients who met the entry criteria were enrolled. One patient died of lethal arrhythmia, two died of CHF. Three patientswere excluded from this study due to restenosis of the culprit coronary artery. Therefore, 48 of 54 patients enrolled in the trial completed the entire protocol. There were no differences in baseline characteristics including the dose of ACE inhibitor (enalapril). However, maximal CK was significantly higher in the Remodelling (+) group than in the Remodelling () group.
3.2. Difference between plasma concentration of ET-1 in the Ao and the CS
In 14 age-matched control subjects, the plasma ET-1 level was significantly higher in CS than in Ao (1.7±0.1 vs 1.5±0.07pgml1,
) (Fig. 1). In 48 patients with AMI in the acute phase, plasma ET-1 level was significantly higher both in the Ao and the CS compared to that in the control subjects, and plasma ET-1 level was significantly lower in CS than Ao in the acute phase (Fig. 1) and 1 month after onset of AMI. The transcardiac extraction of ET-1 in the acute phase was significantly higher in the Remodelling (+) group than in the Remodelling () group (Fig. 2).

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Fig. 2 Comparison of the transcardiac gradient of endothelin-1 (ET-1) between the Remodelling () group and the Remodelling (+) group in patients with a first anterior acute myocardial infarction (AMI). Closed bars show the transcardiac gradient of ET-1 during the acute phase and open bars showed the transcardiac gradient of ET-1 after 1 month in patients with AMI. Ao=aortic root; CS=coronary sinus. vs the value of the remodelling () group.
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3.3. Hemodynamic parameters, and LV function and volume (Table 2)
In the acute phase, there were no significant differences in hemodynamic parameters such as mean blood pressure and mean pulmonary arterial pressure between the Remodelling (+) group and the Remodelling () group. Pulmonary capillary wedge pressure and LV end-diastolic pressure in the Remodelling (+) group were higher than those in the Remodelling () group.
Regarding LV function and volumes in the acute phase, there was no difference in LVEDVI and the LV end-systolic volume index between the two groups. LVEF in the Remodelling (+) group was significantly lower than that in the Remodelling () group. One month after onset, absolute change in LVEF was significantly higher in the Remodelling () group than in the Remodelling (+) group.
3.4. Neurohumoral factors (Table 3)
In the acute phase, there were no significant differences in plasma levels of ANP, BNP, or ET-1 in the Ao and the CS between between the Remodelling (+) group and the Remodelling () group. However, the transcardiac extraction of ET-1 was significantly higher in the Remodelling (+) group than in the Remodelling () group.
One month after onset, plasma BNP in the Ao and the transcardiac gradient of BNP in the Remodelling (+) were significantly higher group than those in the Remodelling () group. There was no difference of the transcardiac extraction of ET-1 between the two groups.
3.5. Relationship of plasma ET-1 extraction across the heart and LV remodelling
Although there was no correlation between the transcardiac extraction of ET-1 in the acute phase and LV function in the acute phase, such as LVEF and LVEDVI, there were significant correlations between the transcardiac extraction of ET-1 in the acute phase, and LVEF (
,
) and LVEDVI (
,
) after 1 month (Fig. 3). Moreover, there were significant positive correlations between the plasma ET-1 in the Ao and the transcardiac gradient of ET-1 (Fig. 4A), and between the transcardiac gradient of ET-1 in the acute phase and the absolute change in LVEDVI after 1 month (Fig. 4B). Table 4 shows the results of univariate and multivariate analysis among 14 variables related to the acute phase to assess factors regulating the absolute change in LVEDVI 1 month after onset. According to stepwise multivariate analysis, high levels of transcardiac extraction of ET-1
and aldosterone in the acute phase
and maximal CK
were significant independent predictors of theabsolute change in LVEDVI after 1 month.

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Fig. 3 Correlation between the transcardiac gradient of endothelin-1 (ET-1) during the acute phase and left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume index (LVEDVI) after 1 month in patients with a first anterior acute myocardial infarction. Ao=aortic root; CS=coronary sinus.
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Fig. 4 (A): Correlation between the plasma endothelin-1 (ET-1) in the aortic root (Ao) and transcardiac gradient of ET-1 during the acute phase in patients with a first anterior acute myocardial infarction. (B): Correlation between the transcardiac gradient of endothelin-1 (ET-1) during the acute phase and absolute change in left ventricular end-diastolic volume index (LVEDVI) after 1 month in patients with a first anterior acute myocardial infarction. Ao=aortic root; CS=coronary sinus.
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Table 4 Univariate and multivariate linear model of the absolute change of LVEDVI 1 month after onset in 48 patients with first anterior AMI
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4. Discussion
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The results of this study demonstrated that (1) plasma ET-1 is extracted through the heart in the acute phase and 1 month after onset of the first anterior AMI, and (2) the transcardiac gradient of plasma ET-1 in the acute phase correlates with the absolute change in LVEDVI 1 month after onset, independent of maximal CK. These results indicated that elevated circulating ET-1 is extracted through the heart and that the transcardiac extraction of ET-1 is a significant predictor of postinfarct remodelling independent of infarct size and plasma aldosterone levels in patients with a first anterior AMI, who received successful revascularization and enalapril.
4.1. Plasma ET-1 difference between the Ao and CS in patients with AMI
ET-1 systems, including ET receptors, are activated and ET-1 antagonists had beneficial effects on mortality in the experimental model of AMI.610 In addition, a high plasma ET-1 is an important prognostic predictor in patients with AMI,11 suggesting that endogenous ET-1 plays an important role in the pathogenesis of AMI. ET-1 is produced not only by endothelial cells but also by ventricular myocytes, especially in pathological states such as hypertrophy and myocardial infarction,1315 suggesting that the elevated circulating ET-1 is partly derived from the heart in patients with AMI. Previous reports, including ours, showed that the main source of the increased ET-1 is pulmonary circulation in patients with CHF.19,20 To our knowledge, there were no reports on whether plasma ET-1 is a spillover or extracted across the human heart after an AMI. In the present study, the plasma ET-1 level was significantly higher both in the Ao and the CS compared to the control subjects, and was significantly lower in CS than Ao in patients with AMI in the acute phase. Therefore, we demonstrated for the first time, that elevated circulating plasma ET-1 is extracted through the heart in the acute phase of AMI. These findings were similar to those of our previous report17 and the recent study by Azevedo et al.18 in patients with CHF, suggesting that plasma ET-1 is also extracted through the heart in patients with AMI and that the increase in ET-1 concentration in the heart with AMI is partly due to the extraction of circulating ET-1 through the heart.
4.2. Possibility of upregulation of ET-1 receptors in the heart of patients with AMI
The present findings suggest that ET receptors are upregulated after ischemia and reperfusion inpatients with AMI, which is supported by the experimental study.6,8,22 As described for beta adrenoreceptors, where ischemia causes an increase in cardiac beta adrenoreceptor density despite raised plasma levels of catecholamines,23 we speculate that the possible increase in ET-1 binding sites is caused by an acute phase reactant response to severe cellular stress induced by ischemia and reperfusion. Liu et al., reported that 125I-ET-1 binding sites in rat cardiomyocytes were increased after ischemia and reperfusion,22 suggesting the upregulation of ET-1 receptors in the rat heart with AMI in the acute phase. There was no data on whether ET-1 receptors are upregulated in the human heart with AMI just after revascularization. However, our findings suggest that ET-1 receptors are upregulated in the heart of AMI patients in the acute phase, which is consistent with the experimental data.22 Indeed, Liu et al.22 commented that the ischemia and reperfusion induced increase in ET-1 binding sites is caused by externalization of latent receptors.
4.3. Transcardiac extraction of ET-1 and LV remodelling in patients with AMI
The transcardiac extraction of ET-1 in the acute phase and after 1 month were significantly higher in the Remodelling (+) group than in the Remodelling () group. In addition, we demonstrated a significant positive correlation of the transcardiac ET-1 gradient at the acute-phase with LVEDVI after1 month and a significant positive correlation between the transcardiac extraction of ET-1 in the acute phase and the absolute change in LVEDVI, indicating that circulating ET-1 is extracted through the heart and promotes LV remodelling via ET-1 receptors in these patients. Recently, we reported that elevated circulating ET-1 is extracted across the failing heart with a significant correlationbetween the transcardiac gradient of plasma ET-1 and LVEDVI,17 suggesting that ET receptors are upregulated in the failing ventricle and that the elevated circulating ET-1 might stimulate theprocess of left ventricular remodelling in patients with severe CHF. However, the cause and effect of the relation between the transcardiac gradient of plasma ET-1 and LVEDVI remains unknownbecause we could not repeatedly measure these parameters in the previous study.17 In the present study, we repeatedly evaluated the relationship between the transcardiac gradient of plasma ET-1 and LVEDVI in patients with AMI. Taken together with the findings of the present study, sustained ET-1 extraction may cause post infarct LV remodelling.
LV remodelling was shown to be regulated by multiple factors, including mechanical, neurohumoral and therapeutic factors. Recently, we reported that plasma aldosterone is extracted through the heart and that the extracted aldosterone plays an important role in modulating post-infarct LV remodeling.24 According to stepwise multivariate analysis, high transcardiac gradient levels of plasma ET-1 and aldosterone in the acute phase and a high level of maximal CK among the 14 acute-phase variables were significant independent predictors of a large LVEDVI at 1 month, suggesting that the extraction of ET-1 during the acute phase, along with infarct size and the extraction of aldosterone plays a significant role in modulating LV remodelling after AMI.
4.4. Clinical implications
MI is one of the major etiological factors leading to CHF. The evidence of increased cardiac ET systems after AMI and the fact that ET-1 receptor antagonists had beneficial effects on mortality and left ventricular remodelling of rat AMI have important pathophysiological implications. Increased plasma ET-1 in patients with AMI has been shown to be a strong and independent predictor of 1-year mortality. In the present study, there was a significant positive correlation between plasma ET-1 in the Ao and the transcardiac extraction of ET-1 in patients with AMI. Moreover, ET receptor antagonists can reduce the degree of myocardial fibrosis inexperimental MI.
In the present study, we demonstrated thattranscardiac extraction of plasma ET-1 in the acute phase correlates with the absolute change in LVEDVI after 1 month of onset in AMI patients who received ACE inhibitors. Our data suggest that therapy to decrease the plasma levels of ET-1 and aldosterone12 and ET-1 receptor antagonists could prevent LV remodelling in patients with a first anterior AMI. However, further studies are needed to clarify the role of endogenous ET-1 on postinfarct LV remodelling.
4.5. Study limitation
In this clinical study, we could not clearly demonstrate that ET-1 extracted through the heart plays a causal role in modulating postinfarct LV remodelling and we cannot deny the possibility that the transcardiac extraction of ET-1 is one of themarkers of the extent of LV remodelling. However, treatment to decrease plasma ET-1, which correlated with the transcardiac extraction of ET-1, in combination with ACE inhibitors12 prevented LV remodelling in patients with a first anterior AMI. Furthermore, in an experimental model of AMI, ET-1 receptor antagonists had beneficial effects on mortality and left ventricular remodeling.6,9,10 Therefore, these findings seem to support our hypothesis. In this study, patients with multivessel and prior myocardial infarction were excluded from this study. This study also excluded patients with restenosis of the culprit lesion because significantstenosis (>70%) might reduce coronary flow and perfusion. To verify the effect of ET-1 extraction under such complex conditions, further studies are needed. Being unable to measure the total amount of ET-1 extraction, because CS flow was notmeasured, is also a limitation of this study. However, in the present study, patients with a significant coronary stenosis were excluded when the blood samplings indicated that the transcardiac gradient of ET-1 reflected the amount of ET-1extraction through the heart.
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5. Conclusions
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In patients with AMI, plasma ET-1 during the acute phase was significantly lower in the CS than in the Ao, suggesting ET-1 extraction across the heart. The transcardiac gradient of plasma ET-1 in the acute phase was correlated with the absolute change in LVEDVI 1 month after onset. Moreover, transcardiac ET-1 extraction in the acute phase affected LVEDVI after 1 month independent ofinfarct size. These findings suggest that elevated transcardiac ET-1 extraction through the heart plays a significant role in regulating post-infarct LV remodelling in patients with AMI.
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Acknowledgments
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This study was partly supported by a Japanese Grant-in-Aid for Scientific Research. We wish to thank Ms Ikuko Sakaguchi for excellent technical assistance. We also express thanks to Mr Daniel Mrozek for assistance in preparing the manuscript.
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