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Relationship Between Adrenomedullin and Left-Ventricular Systolic Function and Mortality in Acute Myocardial Infarction

Posted on: Thursday, 10 February 2005, 03:00 CST

The purpose of this study was to investigate the relationship between plasma adrenomedullin concentration levels and left- ventricular systolic function in patients with acute myocardial infarction (AMI), and to assess whether these findings can be used to predict clinical outcomes, including mortality. One hundred twenty-four consecutive first AMI attack subjects were successfully reperfused with primary percutaneous coronary intervention therapy. Plasma adrenomedullin concentrations were evaluated at 24 hours from onset. Left ventriculograms of all patients taken in the acute (soon after reperfusion therapy) and subacute (21 9 days after onset) phases were used to evaluate left-ventricular ejection fraction (LVEF), and the difference in LVEF (delta-LVEF) between the two stages calculated. There were significantly more patients with cardiogenic shock in the H-Adm group (above the median value of plasma adrenomedullin concentrations ≥3.5 Fmol/mL) than in the L-Adm (<3.5 Fmol/mL) group (p<0.0001). There was significantly higher mortality in the H-Adm group (p<0.01). Multivariate analysis identified plasma adrenomedullin concentrations alone as an independent predictor of mortality (p<0.05). There were no significant differences in acute-stage LVEF between the groups. LVEF in the subacute stage was, however, significantly lower in the H- Adm group than in the L-Adm group (52 12% vs 59 11%, p < 0.05). Also, delta-LVEF was significantly lower in the H-Adm group than in the L-Adm group (1.9 9.7% vs 6.3 10.3%, p < 0.01). Plasma adrenomedullin concentrations in the early phase of AMI correlate closely with the severity of heart failure, and may offer important prognostic information about the risk of mortality. Our data suggest that plasma adrenomedullin concentrations may be an independent predictor of the deterioration of left-ventricular systolic function.

Introduction

Adrenomedullin is a potent vasodilating peptide discovered in human pheochromocytoma tissue.1 Adrenomedullin has also been detected in human plasma, not only in the pheochromocytoma, but also in the adrenal medulla, the kidneys, lungs, vascular bed and cardiac ventricles.2 It has been found to elicit a long-lasting hypotensive effect,1 establishing that adrenomedullin is a circulating hormone that participates in the regulation of the cardiovascular system.3

Plasma levels of adrenomedullin are increased in patients with essential hypertension, chronic renal failure,4 and heart failure in proportion to the clinical severity of the condition.3,5 A recent report also suggests that plasma adrenomedullin concentrations are elevated in patients with acute myocardial infarction (AMI),6 and that the elevation is associated with long-term mortality in patients with acute myocardial infarction.7 Little is known, however, about the relationship between plasma adrenomedullin concentrations and left-ventricular (LV) systolic function in patients with AMI.

The object of the present study was to determine whether clinical prognosis after acute myocardial infarction might be predicted by acute phase plasma adrenomedullin concentrations, and to assess whether there might be any relationship between plasma adrenomedullin concentrations and LV systolic function.

Methods

Patient Population

The population comprised 124 consecutive patients (85 male, 39 female, mean 68 11 years, range 40-93) with a first AMI attack who were admitted and enrolled between July 2001 and March 2003. Diagnosis of AMI was made on basis of the following criteria: (1) complaint of chest pain and/or discomfort; (2) electrocardiographic ST-segment elevation of ≥ 0.1 mV in two or more limb leads, or ≥ 0.2 mV in two or more precordial leads, or new left bundle branch block; and (3) elevation of total serum creatine kinase more than twice the upper limit of the patient's normal range. We excluded patients with a purely posterior infarction, patients with renal failure on admission (serum creatinine level > 2.5 mg/dL), patients with an old myocardial infarction, patients who reached our hospital > 6 hours after onset, and patients who died < 24 hours after onset (i.e., when blood samples were taken). We observed anterior myocardial infarction in 65 patients, and an inferior infarction in 59 subjects. Subjects were divided into 2 groups according to their serum adrenomedullin levels by the median value of plasma adrenomedullin concentration: those with low levels of adrenomedullin <3.5 Fmol/mL (L-Adm group, n = 62) and those with high levels of adrenomedullin ≥ 3.5 Fmol/mL (H-Adm group, n = 62).

Treatment Strategy

Following oral administration of 200 mg of aspirin and 200 mg of ticlopidine, all patients successfully underwent direct percutaneous coronary intervention (PCI) therapy within 8 hours of the onset of symptoms. In 23 patients, only plain old balloon angioplasty (POBA) was required, while the remaining 101 all underwent coronary stent implantation. As a result, all patients achieved thrombolysis in myocardial Infarction (TIMI) grade III flow. For 72 hours after reperfusion therapy, patients underwent intravenous administration of lidocaine (1 mg/minute), of nicorandil (96 mg/day), and of heparin (10,000 units/day). All patients received an angiotensin- converting enzyme inhibitor (quinapril 5 mg/day) or an angiotensin II receptor blocker (losartan, 50 mg/day).

Blood Sampling

Twenty-four hours after onset, blood samples were taken from all subjects while supine. Adrenomedullin concentrations were evaluated with immuno-radiometric assay (IRMA). Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and highly sensitive C- reactive protein (CRP) were all assessed from the same blood samples. Creatine kinase (CK) was serially determined every 4 hours after admission and for 3 days. The peak value of those CK levels (peak-CK) was used to reflect the size of infarction.

Measurements of Hemodynamics and Cardiac Function

Left ventriculograms were taken for all subjects, from a single- plane with right anterior deviation of 30 degrees at the acute (soon after recanalization) and subacute (21 9 days after onset) phases to evaluate left ventricular ejection fraction (LVEF), using the area- length method. The difference in LVEF between these two stages (subacute stage vs acute stage) was expressed as delta-LVEF. Left ventricular end-diastolic pressure (LVEDP) was also evaluated in 2 stages, and we used the Killip classification to evaluate the severity of the patient's clinical course.

Statistical Analysis

Values are expressed as mean standard-deviation (SD), and compared with the use of a commercially available statistical software package (STATVIEW II, Abacus Concepts, Berkeley, CA). All statistical tests were two-tailed, and a p value < 0.05 was considered statistically significant. Univariate and multivariate logistic regression analysis were performed, with the independent variables evaluated including age, gender, coronary risk factors, culprit lesion location, the number of vessels involved, the time from onset to reperfusion (elapsed time), and CRP, BNP, ANP, peak- CK and adrenomedullin levels. Odds ratios and 95% confidence intervals were also calculated.

Table I. Comparison of patient characteristics and laboratory findings in relation to values of plasma adrenomedullin above and below the median value

Results

Clinical characteristics for the 2 groups (H-Adm group and L-Adm group) are summarized in Table I. There were no significant differences in terms of age, gender, coronary risk factors, infarct location, the existence of pre-infarction angina, multiple vessel disease, elapsed time, or the rate of use of coronary stents between the 2 groups.

In terms of the laboratory findings, plasma levels of both BNP and highly sensitive CRP, which were assessed at the same time as adrenomedullin, were significantly higher in the H-Adm group than in the L-Adm group (BNP 493 622 pg/mL vs 260 314 pg/mL, p < 0.01; CRP 5.56 5.77 mg/dL vs 2.59 2.94 mg/dL, p < 0.001). There were no significant differences in peak-CK values between groups.

Table II. Hemodynamic data at admission and severity of clinical course.

The hemodynamic data at the time of admission and the clinical severity of the patient's condition are shown in Table II. In the H- Adm group, heart rate was significantly higher (88 24 beats/ minute vs 79 18 beats/minute, p<0.05), and systolic blood pressure was significantly lower (99 38 mm Hg vs 117 26 mm Hg, p < 0.05), compared with the L-Adm group. In terms of clinical severity, there were significantly more severe heart failure (such as Killip III or IV) patients in the H-Adm group than in the L-Adm group (p < 0.0001). There were also significantly more patients with cardiogenic shock in the H-Adm group (p < 0.0001).

The follow-up period for this study was as short as 90 days. Nine patients died from cardiovascular causes during the follow up period; heart failure was the cause in 7, and cardiac rupture in 2 cases; all 9 patients were in H-Adm group. This is a significantly and remarkably higher mortality rate in the H-Adm group than in the L-Adm group (15% vs 0%, p < 0.01). Table III shows the predictors of mortality in our AMI patients for the 90 days after onset. Univariate analysis revea\ls that plasma adrenomedullin, BNP, peak- CK, CRP, and ventricular arrhythmia (ventricular tachycardia and/or ventricular fibrillation) correlated significantly with mortality. However by multivariate analysis, only plasma adrenomedullin was identified as an independent predictor of 90-day mortality (p < 0.05).

Table IV shows left-ventricular function in the acute and subacute phases. LVEDP in the acute stage was significantly higher in the H-Adm group than in the L-Adm group (17 8 mm Hg vs 13 6 mm Hg, p < 0.01). There were no significance differences in LVEF at the acute stage; however, subacute stage LVEF was significantly lower in the H-Adm group than in the L-Adm group (52 12% vs 59 11%, p < 0.05). Figure 1 shows a comparison of delta-LVEF between the two groups. Delta-LVEF was significantly lower in the H-Adm group (1.9 9.7 vs 6.3 10.3, p < 0.01). These results seem to suggest strongly that plasma adrenomedullin concentrations in the acute stage of AMI may be of prognostic value regarding the extent of the deterioration of left-ventricular systolic function.

Discussion

Adrenomedullin plays a number of physiologic roles1; in particular, it reduces blood pressure, through vasodilation, and by decreasing total peripheral resistance.9 Adrenomedullin is therefore a circulating hormone participating in the regulation of the cardiovascular system, and which is closely associated with cardiovascular conditions such as hypertension,10 pulmonary hypertension,11 left-ventricular hypertrophy,12 and congestive heart failure.13,14 With regard to AMI, it has already been documented that plasma adrenomedullin is elevated in the early stage of AMI,6 that adrenomedullin is elevated in an AMI patient in proportion to the clinical severity of the attack,7,8 that it correlates positively with capillary wedge pressure,15 and that it may correlate with the severity of the disease as well as with patient outcomes in the setting of AMI.7 Furthermore, it has been reported that intravenous administration of adrenomedullin to AMI patients may have beneficial effects in terms of the cardiac index,16 and may have myocardial-protective effects during reperfusion following an ischemic episode.17 It remains uncertain, however, whether adrenomedullin concentrations can be taken to indicate clinical outcomes and systolic function in AMI patients.

Table III. Predictors of mortality 90 days post-procedure.

Table IV. Left ventricular function in acute and subacute stage.

Figure 1. Comparison of delta-LVEF between high and low adrenomedullin group. Delta-LVEF was significantly lower in H-Adm group than in L-Adm group.

Plasma adrenomedullin concentrations are reported to peak approximately 24 hours after the onset of AMI,6,8,15 which is why we took blood samples at that time. In this study, we found that systolic blood pressure was significantly decreased and heart rate significantly increased at the time of admission in the H-Adm group. In other words, plasma adrenomedullin concentrations in patients with heart failure are elevated in proportion to the clinical severity of the AMI. In fact, there were significantly more patients with severe heart failure (Killip III or IV) and with cardiogenic shock in the H-Adm group than in the L-Adm subjects, which suggests that adrenomedullin possesses defensive properties against the further elevation of peripheral vascular resistance in the setting of heart failure,3 as opposed to any cardiotoxic effect.

It has also been reported by Yoshitomi and colleagues, that plasma levels of adrenomedullin correlate with plasma levels of ANP and BNP in AMI patients.6 Similarly, our study showed that plasma levels of BNP were significantly elevated in the H-Adm group, although there was no correlation between adrenomedullin and ANP. These findings suggest that volume expansion and overload in the left ventricle in the early phase of AMI may have an effect on the production of adrenomedullin in the left ventricle.

In recent years, more than 1 report has shown that prognosis and LV function in the setting of AMI are closely associated with inflammation and tissue injury.18-20 There was also a study that concluded that plasma adrenomedullin concentrations correlated with CRP when the condition was severe.21 CRP in our study was significantly elevated in the H-Adm group. It may be that systemic inflammation due to AMI actually causes the production of adrenomedullin.

Nagaya and colleagues reported from their study that early phase plasma adrenomedullin concentrations are associated with long-term mortality.7 Elsewhere, to give an alternative perspective, Richards and colleagues reported that plasma adrenomedullin was a less sensitive indicator than BNP,22 so if nothing else, it can be concluded that the relationship between adrenomedullin and mortality in AMI is still unclear.

Another outcome from our study was that 90-day mortality was significantly higher in the H-Adm group than in the L-Adm group. Also, multivariate analysis identified only plasma adrenomedullin as an independent predictor of short-term mortality. These results suggest that adrenomedullin may be a more sensitive indicator of mortality in AMI than BNP. Early phase plasma adrenomedullin concentrations may be able to provide important prognostic information about outcomes for AMI.

At this time, little is known about the significance of adrenomedullin in left-ventricular systolic function in human subjects in the setting of AMI. Nakamura and colleagues reported from a study using rats that continuous administration of adrenomedullin had a beneficial effect on left-ventricular remodeling in rats with MI.23 In our study, there were no differences between the 2 groups in terms of LVEF in the acute phase, but in the subacute stage, LVEF was significantly poorer in H- Adm subjects than in their L-Adm counterparts. Furthermore, delta- LVEF was significantly lower in the H-Adm group than in the L-Adm group. This would appear to signify that early phase (24 hours from onset) plasma level concentrations of adrenomedullin have a significant impact on successively occurring aggravation and deterioration of left-ventricular systolic function.

Study Limitations

This study is associated with a number of limitations. First, the small size of the study population means that our results require confirmation in a larger scale trail before any concrete significance can be extrapolated from results. Second, we excluded patients with renal failure from the study, on the basis that these patients were not able to tolerate primary coronary angioplasty; this may have introduced bias into the study protocol and into our results. Third, patients who died within the first 24 hours of the onset of symptoms of AMI were also excluded because they were unavailable for blood samples which our protocol specified were to be taken at this point; a small number of fulminant cases of AMI may therefore have been removed from the study, resulting again in the introduction of bias.

Conclusion

Plasma adrenomedullin concentrations in the early phase of AMI may be closely related to the severity of cardiac failure, and may provide important prognostic information about the risk of patient outcomes, including mortality. Our data suggest that plasma adrenomedullin concentrations can be used as an independent predictor of deteriorating left-ventricular systolic function in patients with AMI.

REFERENCES

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2. Ichiki Y, Kitamura K, Kangawa K, et al: Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma. FEBS Lett 338:6-10, 1994.

3. Nishikimi T, Saito Y, Kitamura K, et al: Increased plasma levels of adrenomedullin in patients with heart failure. J Am Coll Cardiol 26:1424-1431, 1995.

4. Ishimitsu T, Nishikimi T, Saito Y, et al: Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure. J Clin Invest 94:2158-2161, 1994.

5. Nishikimi T, Horio T, Sasaki T, et al: Cardiac production and secretion of adrenomedullin are increased in heart failure. Hypertension 30:1369-1375, 1997.

6. Yoshitomi Y, Nishikimi T, Kojima S, et al: Plasma levels of adrenomedullin in patients with acute myocardial infarction. Clinical Science 94:135-139, 1998.

7. Nagaya N, Nishikimi T, Uematsti M, et al: Plasma adrenomedullin as an indicator of prognosis after acute myocardial infarction. Heart 81:483-487, 1999.

8. Miyao Y, Nishikimi T, Goto Y, et al: Increased plasma adrenomedullin levels in patients with acute myocardial infarction. Heart 79:39-44, 1998.

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10. Kitamura K, Ichiki Y, Tanaka M, et al: Immunoreactive adrenomedullin in human plasma. FEBS Lett 341:288-290, 1994.

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12. Sumitomo T, Nishikimi T, Mukai M, et al: Plasma adrenomedullin concentrations and cardiac and arterial hypertrophy in hypertension. Hypertension 30:741-745, 1997.

13. Jougasaki M, Wei CM, McKinley LJ, et al: Elevation circulating and ventricular adrenomedullin in human congestive heart failure. Circulation 92:286-289, 1995.

14. Jougasaki M, Rodeheffer RJ, Redfield MM, et al: Cardiac secretion of adrenomedullin in human heart failure. J Clin Invest 97:2370-2376, 1996.

15. Kobayashi K, Kitamura K, Hirayama N, et al: Increased plasma adrenomedullin in acute myocardial infarction. Am Heart J 131:676- 680, 1996.

16. Nagaya N, Goto Y, Satoh T, et al: Intravenous adrenomedullin in myocardial function and energymetabolism in patients after myocardial infarction. J Cardiovasc Pharmacol 39:754-760, 2002.

17. Cao J, Zhang J, Wang X: Changes and cardiac protective effects of adrenomedullin during myocardial ischemia-reperfusion period. Zhonghua Yi Xue Za Zhi 80:261-264, 2000.

18. Morrow DA, Rifai N, Antman EM, et al: Serum amyloid A predicts early mortality in acute coronary syndromes: A TIMI 11A substudy. J Am Coll Cardiol 35:358-362, 2000.

19. Anzai T, Yoshikawa T, Shiraki H, et al: C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q- wave acute myocardial infarction. Circulation 96:778-784, 1997.

20. Liuzzo G, Biasucci LM, Gallimore JR, et al: Enhanced inflammatory responde in patients with preinfarctional unstable angina. J Am Coll Cardiol 34:1696-1703, 1999.

21. Ehlentz K, Koch B, Preuss P, et al: High levels of circulating adrenomedullin in severe illness: Correlation with C- reactive protein and evidence against the adrenal medulla as site of origin. Exp Clin Endocrinol Diabetes 105:156-162, 1997.

22. Richards AM, Nicholls MG, Yandle TG, et al: Plasma N- terminal pro-brain natriuretic peptide and adrenomedullin: New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 97:1921-1929, 1998.

23. Nakamura R, Kato J, Kitamura K, et al: Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats. Cardiovasc Res 56:373-380, 2002.

Toshiro Katayama, MD, Hiroshi Nakashima, MD, Yukiharu Honda, MD, Shin Suzuki, MD, and Katsusuke Yano, MD,* Nagasaki, Japan

Angiology 56:35-42, 2005

From the Department of Cardiology, Nagasaki Citizens Hospital, Nagasaki; * Third Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan

Correspondence: T. Katayama, MD, Department of Cardiology, Nagasaki Citizens Hospital, 6-39 Shinchi-machi, Nagasaki, 850-8555, Japan

E-mail: snowman-kt@syd.odn.ne.jp

2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, USA

Copyright Westminster Publications, Inc. Jan/Feb 2005

Source: Angiology

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