Early recanalization and plasma brain natriuretic peptide as an indicator of left ventricular function after acute myocardial infarction

Early recanalization and plasma brain natriuretic peptide as an indicator of left ventricular function after acute myocardial infarction Teruo Inoue, MD, Masashi Sakuma, MD, Isao Yaguchi, MD, Keiichi Mizoguchi, MD, Toshihiko Uchida, MD, Kan Takayanagi, MD, Terumi Hayashi, MD, and Shigenori Morooka, MD Saitama, Japan

Background Although plasma brain natriuretic peptide (BNP) levels have been widely measured in patients with acute myocardial infarction (AMI), it is still uncertain whether the early recanalization modulates the levels and whether the levels can predict chronic stage left ventricular function. This study was designed to elucidate these issues. Methods In 80 consecutive patients with AMI, plasma BNP levels were measured at admission and at 4 hours, 24 hours, 48 hours, and 1 month after admission.

Results In 35 of the 80 patients, the infarct-related artery was patent within 6 hours from the onset of MI (6-hour patency group), and in 27 patients, the artery was still occluded after 6 hours (6-hour occlusion group). The remaining 18 patients in whom it was unclear whether recanalization of the infarct-related artery had occurred within 6 hours or not were excluded from the analyses. In the 6-hour patency group, the BNP level gradually increased and reached a maximum value at 24 hours after admission. In the 6-hour occlusion group, the level increased more, with the values at 4 hours, 24 hours, and 48 hours significantly higher than those in the 6-hour patency group (86 ⫾ 18 pmol/L versus 35 ⫾ 8 pmol/L; P ⬍ .01; 112 ⫾ 13 pmol/L versus 74 ⫾ 9 pmol/L; P ⬍ .05; 102 ⫾ 15 pmol/L versus 53 ⫾ 11 pmol/L; P ⬍ .01). Chronic stage left ventricular function was correlated with not only the BNP level at same stage but also that at 24 hours and that at 48 hours after admission. Multiple regression analysis indicated that the BNP level at 24 hours was the most powerful predictor of chronic stage left ventricular function. Conclusion Plasma BNP levels can predict subsequent cardiac function. In addition, the importance of early recanalization may also be supported with BNP kinetics. (Am Heart J 2002;143:790-6.)

The cardiac natriuretic peptide system is activated after acute myocardial infarction (AMI).1-6 Elevated circulating levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone in the subacute phase have been shown to predict adverse outcome in patients with AMI.7-11 Recent data suggest that circulating concentrations of the predominantly ventricular-derived brain natriuretic peptide (BNP) may increase proportionally more than circulating ANP concentrations after AMI.3,4 The BNP levels in the acute stage12 and those in the chronic stage13 increase in proportion to the extent of the left ventricular dysfunction in the same stages. In addition, BNP levels in the acute stage are considered to have more powerful predictive value for long-term prognosis than

From the Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine. Submitted April 1, 2001; accepted December 3, 2001. Reprint requests: Teruo Inoue, MD, Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, 2–1-50 Minamikoshigaya, Koshigaya-City, Saitama 343– 8555, Japan. © 2002 Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 ⫹ 0 4/1/122170 doi:10.1067/mhj.2002.122170

ANP levels.12 On the other hand, in patients with AMI, early recanalization of the infarct-related artery, which is achieved with thrombolysis or coronary angioplasty or occurs spontaneously, maintains left ventricular function and beneficially influences short-term and long-term outcome.14,15 However, it is still uncertain whether the early recanalization modulates the BNP levels. Furthermore, the relationship between BNP levels in the acute stage and left ventricular function in the chronic stage has not been determined. In this study, we compared the plasma BNP kinetics of patients with and without early recanalization after AMI and evaluated a prognostic value of acute stage BNP levels in the chronic stage left ventricular function. This study was performed as a substudy of the COmbining Monteplase with Angioplasty (COMA) trial.

Methods Study protocol The COMA trial is a prospective randomized single-center trial for the evaluation of the effectiveness of pretreatment of the mutant tissue-type plasminogen activator, monteplase (Eisai, Co, Tokyo, Japan), before emergency coronary angio-

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plasty in AMI, in comparison with direct coronary angioplasty. From April 1999, we recruited into the COMA study 146 consecutive patients, with first episodes of AMI, who were admitted to the Emergency Room of Koshigaya Hospital, Dokkyo University School of Medicine. The diagnosis of AMI was made on the basis of typical chest pain lasting longer than 30 minutes, ST-segment elevation of ⬎0.2 mV in 2 continuous leads on standard 12-lead electrocardiogram results, and an elevation of serum creatine kinase level (CK)MB fraction to more than twice the upper limit of the normal range. The entry criteria included hospitalization within 12 hours after the onset of chest pain, emergent coronary angiography within 60 minutes after the hospitalization, age of less than 80 years, no cardiogenic shock or cardiac arrest, and indications for thrombolytic therapy with no history of gastroduodenal ulcer or intracranial hemorrhage. Patients who had had a previous MI or patients who underwent previous coronary angioplasty or coronary artery bypass surgery were excluded. The study design was approved by the Dokkyo University Institutional Review Board, and informed consent was obtained from all patients. Before emergent coronary angiography, incidence of heart failure was clinically assessed with the Killip classification, and Killip II or III was defined as heart failure. Patients were randomly assigned to undergo direct coronary angioplasty or coronary angioplasty followed by a single bolus injection of intravenous monteplase (27,500 IU/kg weight). The primary study endpoint was patency of the infarct-related artery angiographically evaluated before angioplasty. The patency was assessed according to thrombolysis-in-myocardial-infarction (TIMI) perfusion criteria by 2 independent observers who were unaware of the grouping. Coronary patency was defined as TIMI grade 3 or 2, and coronary occlusion as grade 1 or 0. Subsequent coronary angioplasty was performed for total occlusion lesions or for lesions of ⱖ75% diameter stenosis even with TIMI grade 3 flow. If the lesions of the infarctrelated artery showed ⬍75% stenosis, the angioplasty was not performed. Stents were implanted in bail-out situations or because of unsatisfactory post– balloon angioplasty results. After coronary angioplasty, hemodynamics were assessed with right cardiac catheterization, and pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were measured. Serum creatine kinase MB (CK-MB) values were measured every 3 hours on the first hospital day, every 6 hours on the next day, and every 12 hours on the third hospital day to assess peak levels. The secondary study endpoint was clinical outcome 1 month after admission, including death or any cardiac event, and patency of the infarct-related coronary artery or left ventricular function evaluated with 1 month follow-up angiography. Left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were calculated with the area-length method with left ventriculography. Both volumes were corrected according to the body surface area (LVEDV index [LVEDVI] and LVESV index [LVESVI]). Ejection fraction (EF) was calculated as (LVEDV ⫺ LVESV)/LVEDV. In this study, the first 80 consecutive patients were selected for measurement of plasma BNP levels. All of these patients could be followed 1 month after admission and underwent follow-up angiography. In these patients, peripheral blood samples were taken at admission and at 4 hours, 24 hours, 48 hours, and 1 month after admission. The blood was

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collected into a tube containing sodium citrate. The samples were immediately centrifuged at 3000 rpm or for 15 minutes at 4°C, and aliquots of samples were immediately stored at ⫺80°C until used.

Determination of plasma BNP levels Plasma BNP levels were determined with a specific immunoradiometric assay (Shionoria BNP kit) manufactured by Shionogi & Co, Ltd (Osaka, Japan). The assay uses 2 monoclonal antibodies, which recognize the carboxyterminal sequence and the ring structure of human BNP. The minimal detectable quantity of BNP is 2 pg/mL. The intraassay and interassay coefficients of variation were 5.3% and 5.9%, respectively.

Statistical analysis Data were expressed as the mean ⫾ the standard error of the mean. The differences of the values over time in the 2 patient groups were analyzed with the repeated measures analysis of variance method. Comparisons between the 2 groups were performed with unpaired t tests for continuous variables and ␹2 tests for categoric variables. Correlation between the acute stage BNP levels and chronic stage left ventricular function parameters was assessed with simple linear regression. A multiple regression analysis was performed for prediction of chronic stage left ventricular function with age, gender, and various acute stage parameters, including BNP levels. In categoric variables (gender, anterior MI, 6-hour patency of the infarct-related artery, or Killip classification), male gender, the presence of anterior MI, 6-hour occlusion, or Killip III were coded as “1” and female gender, the absence of anterior MI, 6-hour patency, or Killip I/II were coded as “0.” The other parameters were assessed as continuous variables. A P value ⬍ .05 was considered to be significant.

Results Substudy of the COMA trial In 80 patients who were selected for measurement of plasma BNP levels, emergent coronary angiography was performed within 13 hours (6.28 ⫾ 0.38 hours) after the onset of MI. In 35 of these 80 patients, coronary angiography was performed within 6 hours after the onset of MI and the patency of the infarct-related artery was confirmed through either monteplase-induced recanalization, angioplasty-induced recanalization, or spontaneous recanalization (6-hour patency group). In 27 patients, coronary angiography was performed after 6 hours from the onset of MI and neither monteplase-induced recanalization nor spontaneous recanalization were obtained, so the infarct-related artery was occluded at 6 hours after the onset of MI (6hour occlusion group). In the latter group, patency of the infarct-related artery was finally achieved with angioplasty after 6 hours from the onset of MI. In the remaining 18 patients, coronary angiography was performed after 6 hours from the onset of MI and either monteplase-induced recanalization or spontaneous recanalization was obtained, so patency of the infarct-

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Table I. Patient characteristics of the 6h-patent group versus 6h-occluded group 6h-patent group (n ⴝ 35)

6h-occluded group (n ⴝ 27)

P

58.2 ⫾ 1.7 25/10 18 (51) 12/16/7 14 (40) 6 (17) 8 (23) 32 (91) 29/6 336 ⫾ 42 11.2 ⫾ 0.2

59.4 ⫾ 1.4 20/7 14 (52) 8/13/16 12 (44) 5 (19) 8 (30) 24 (89) 20/7 313 ⫾ 42 18.6 ⫾ 0.5

.56 .92 .97 .10 .75 .89 .55 .74 .26 .39 .02

14.3 ⫾ 0.8 3.42 ⫾ 0.42

14.6 ⫾ 0.7 3.24 ⫾ 0.26

.66 .59

78 ⫾ 4 34 ⫾ 3 0.59 ⫾ 0.15

82 ⫾ 5 38 ⫾ 4 0.55 ⫾ 0.24

.58 .31 .15

Age (y) Sex (M/F) Anterior MI (%) Affected vessel (single/double/triple) Hypertension (%) Diabetes (%) Hyperlipidemia (%) Smoking (%) Killip I/II or III Peak CK-MB (U/L) Time to peak CK-MB (h) Acute phase hemodynamics PCWP (mm Hg) CI (L/min/m2) Left ventricle function at 1 month follow-up LVEDVI (mL/m2) LVESVI (mL/m2) EF

Time to patency is time to patency of the infarct-related artery from the onset of MI.

related artery was angiographically confirmed after 6 hours from the onset of MI, but it was unclear whether the recanalization had occurred within 6 hours or not. These 18 patients were excluded from the final analyses of this study.

Comparison between 6-hour patency and 6-hour occlusion groups There were no significant differences in the baseline patient characteristics and coronary risk factors between both groups. The incidence rate of heart failure assessed with the Killip classification was also similar in both groups. In the acute phase hemodynamic study, PCWP (14.2 ⫾ 0.8 mm Hg versus 14.6 ⫾ 0.7 mm Hg) and CI (3.42 ⫾ 0.42 L/min/m2 versus 3.24 ⫾ 0.26 L/min/m2) were similar in both the 6-hour patency group and the 6-hour occlusion group, respectively. Although peak CK-MB levels were similar in both groups (336 ⫾ 42 U/L versus 313 ⫾ 42 U/L), time to peak CK-MB from the onset of MI was shorter (11.2 ⫾ 0.2 hours versus 18.6 ⫾ 0.5 hours; P ⬍ .05) in the 6-hour patency group than in the 6-hour occlusion group. At 1 month after admission, no patients had died or had any cardiac events. In the assessment of cardiac function at follow-up angiography 1 month after admission, LVEDVI (78 ⫾ 4 mL/m2 versus 82 ⫾ 5 mL/m2 in the 6-hour patency and 6-hour occlusion groups, respectively), LVESVI (34 ⫾ 3 mL/m2 versus 38 ⫾ 4 mL/m2) and EF (0.59 ⫾ 0.15 versus 0.55 ⫾ 0.24) were similar in both groups (Table I).

Serial changes in plasma BNP levels in 6-hour patency and 6-hour occlusion groups Baseline plasma BNP level at admission was 22 ⫾ 6 pmol/L in the 6-hour patency group, identical to the value of 26 ⫾ 11 pmol/L in the 6-hour occlusion group. In the 6-hour patency group, the BNP level increased to 35 ⫾ 8 pmol/L at 4 hours after admission (P ⬍ .05 versus baseline), to 74 ⫾ 9 pmol/L at 24 hours (P ⬍ .001 versus baseline), and to 53 ⫾ 11 pmol/L at 48 hours (P ⬍ .01 versus baseline). In the 6-hour occlusion group, however, the level increased more to 86 ⫾ 11 pmol/L at 4 hours after admission (P ⬍ .001 versus baseline), to 112 ⫾ 13 pmol/L at 24 hours (P ⬍ .001 versus baseline), and to 102 ⫾ 15 pmol/L at 48 hours (P ⬍ .001 versus baseline). These values of the 6-hour occlusion group were significantly higher than the values at 4 hours, 24 hours, and 48 hours after admission in the 6-hour patency group (P ⬍ .01; P ⬍ .05; P ⬍ .01, respectively). At 1 month after admission, the BNP levels decreased in both the 6-hour patency group and the 6-hour occlusion group (37 ⫾ 6 pmol/L and 50 ⫾ 16 pmol/L, respectively) and the values of both groups were similar (Figure 1).

Relationship between BNP levels and incidence of heart failure at admission In all of the selected 62 patients, 13 patients had an incidence of heart failure (Killip II or III) and the remaining 49 had no incidence of heart failure (Killip I). In patients with heart failure, the plasma BNP level at admission was 36 ⫾ 12 pmol/L, which was slightly

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Figure 1

Serial changes in plasma BNP levels in 6-hour patency and 6-hour occlusion groups. Baseline plasma BNP level at admission was identical in both groups. Then, BNP level increased in both groups. In 6-hour occlusion group, however, increase in BNP level at each point at 4 hours, 24 hours, and 48 hours after admission was greater than in 6-hour patency group. Levels of 6-hour occlusion group at 4 hours, 24 hours, and 48 hours were significantly higher than those in 6-hour patency group. At 1 month after admission, BNP level decreased in both groups, returning to identical values.

higher (P ⬍ .05) than the value of 12 ⫾ 6 pmol/L in patients without heart failure. The BNP levels at 4 hours (64 ⫾ 16 pmol/L versus 56 ⫾ 12 pmol/L), 24 hours (96 ⫾ 12 pmol/L versus 92 ⫾ 10 pmol/L), 48 hours (75 ⫾ 12 pmol/L versus 72 ⫾ 14 pmol/L), and 1 month (36 ⫾ 14 pmol/L versus 40 ⫾ 12 pmol/L) after admission were similar in both patients with and without heart failure.

Relationship between acute stage BNP levels and chronic stage left ventricular function Results of the simple linear regression analysis in overall patients are shown in Table II. LVEDVI, LVESVI, and EF at 1 month after the onset of MI did not correlate with the BNP level at admission and that at 4 hours after admission. However, LVEDVI and LVESVI were positively correlated with the BNP level at 1 month after admission (r ⫽ 0.329, P ⬍ .05; r ⫽ 0.277, P ⬍ .05, respectively). Both were more strongly correlated with BNP levels at 24 hours (r ⫽ 0.434, P ⬍ .001; r ⫽ 0.497, P ⬍ .001, respectively) and 48 hours after admission (r ⫽ 0.396, P ⬍ .001; r ⫽ 0.378, P ⬍ .01, respectively; Figure 2). EF was negatively correlated with the BNP level at 1 month after admission (r ⫽ ⫺0.286, P ⬍ .05) and was more strongly correlated with BNP levels at 24 hours (r ⫽ ⫺0.495, P ⬍ .001) and 48 hours after admission (r ⫽ ⫺0.353,

Table II. Relationship between BNP levels at each point after admission and left ventricular function LVEDVI

Admission 4h 24 h 48 h 1m

LVESVI

EF

r

P

r

P

r

P

0.026 0.210 0.434 0.396 0.329

.846 .107 ⬍.001 .002 .012

0.022 0.237 0.497 0.378 0.277

.866 .069 ⬍.001 .003 .037

–0.027 –0.231 –0.495 –0.353 –0.286

.838 .077 ⬍.001 .006 .031

P ⬍ .01; Figure 2). On the other hand, the BNP levels at 24 hours and 48 hours after admission were both independent of peak CK-MB level (Figure 3). Multiple regression analyses for prediction of chronic stage left ventricular function were performed with acute stage parameters. Age, gender, anterior MI, affected vessel disease number, 6-hour patency (patent or occluded) of the infarct-related artery, peak CK-MB, time to peak CK-MB, and acute stage PCWP and CI values, and plasma BNP levels at 24 hours and 48 hours after admission, were analyzed. The results showed that plasma BNP level at 24 hours after admission was the most powerful predictor for each of LVEDVI (r ⫽ 0.388, P ⬍ .01), LVESVI (r ⫽ 0.362, P ⬍ .01), and EF (r ⫽ ⫺0.421, P ⬍ .01; Table III).

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Figure 2

Relationship between acute stage BNP levels and chronic stage left ventricular function. LVEDVI, LVESVI, and EF 1 month after admission were strongly correlated with each BNP level at 24 hours and 48 hours after admission.

Figure 3

Relationship between BNP levels and peak CK-MB level. BNP levels at 24 hours and 48 hours after admission were both independent of peak CK-MB level.

Discussion The COMA trial recruited patients with AMI who underwent emergency coronary angioplasty with or without thrombolysis pretreatment with intravenous monteplase. This study was performed as a substudy of the COMA trial. In this study, we serially measured

plasma BNP levels in patients with AMI in the acute stage and compared the serial change in the BNP levels between the group of patients in which the infarctrelated coronary artery was patent within 6 hours after the onset of AMI (6-hour patency group) and the group of patients with occlusion at 6 hours (6-hour

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Table III. Multiple regression analysis for predicting chronic stage left ventricular function LVEDVI

Age Sex Anterior MI Affected vessel 6-h patency Peak CK Time to peak CK Killip I/II or III PCWP CI BNP (24 h) BNP (48 h)

LVEDSI

EF

r

P

r

P

r

P

0.152 –0.058 0.251 0.225 0.265 0.103 0.235 0.098 0.042 0.184 0.388 0.322

.269 .661 .038 .048 .026 .385 .041 .485 .724 .116 .002 .009

0.128 0.205 0.215 0.207 0.124 –0.102 0.098 0.196 –0.158 0.132 0.362 0.268

.316 .098 .062 .086 .208 .318 .467 .102 .274 .301 .004 .032

–0.114 –0.052 –0.285 –0.285 0.298 0.106 –0.237 0.129 0.085 0.095 –0.421 –0.320

.285 .692 .012 .039 .021 .452 .052 .236 .524 .601 .001 .009

occlusion group). Results showed that plasma BNP levels increased during the first 24 hours and had decreased by 1 month after admission in both the 6-hour patency group and the 6-hour occlusion group. The BNP levels at 4 hours, 24 hours, and 48 hours after admission were higher in the 6-hour occlusion group than in the 6-hour patency group, although the level at admission and that at 1 month were identical in both groups. These results indicated that early recanalization of the infarctrelated artery could suppress the increase in the BNP level. The BNP levels in the acute stage can provide information on early patency of the infarct-related artery. In relationship with the incidence of heart failure, the BNP level at admission was slightly higher in patients with heart failure than in patients without heart failure. However, subsequent BNP levels were identical in both patient groups with and without heart failure. On the other hand, values for LVEDVI, LVESVI, and EF at 1 month after the onset of MI did correlate with the BNP level at 1 month. Furthermore, these values were more strongly correlated with the BNP levels at 24 hours and 48 hours after admission, although the BNP levels at 24 hours and 48 hours after admission were independent of peak CK-MB level. These results suggest not only that plasma BNP level in the chronic stage might be an indicator of left ventricular function in the same stage but also that the BNP level in the acute stage could predict the chronic stage left ventricular function in patients with AMI.

Clinical significance of plasma BNP level in acute myocardial infarction BNP appears to be the most powerful neurohormonal predictor of left ventricular function and prognosis in heart failure.16,17 The BNP is secreted from the left ventricle in response to changes in left ventricular wall stretch.18 Concentrations of BNP are related to left ventricular filling pressure19 and wall stress.20

During the acute phase of AMI, plasma BNP levels primarily increase within 24 hours and then gradually decrease (monophasic pattern) or secondarily increase again at 5 to 7 days (biphasic pattern).4,21 Unlike CK, BNP is considered not to be released from necrotizing myocardium but to be from viable myocardium around the infarct area, possibly in response to increased left ventricular wall stress.22 Therefore, plasma BNP levels are considered to reflect left ventricular function. Sumida et al13 showed that plasma BNP levels at an average of 65 days after the onset of MI were correlated with EF at the same stage. However, to the best of our knowledge, our study is the first to indicate that early stage plasma BNP levels could predict the chronic stage EF. The second increase in plasma BNP levels at 5 to 7 days in patients with the biphasic pattern is considered to be caused by left ventricular remodeling after AMI.4,21 Our results that show LVEDVI at 1 month being correlated with not only the BNP level at 1 month but also the level at 24 hours or 48 hours may suggest the predictability of early stage BNP levels for chronic stage left ventricular remodeling. Although EF and LVEDVI were identical between the 6-hour patency and 6-hour occlusion groups in our study, difference in the early stage BNP kinetics by patency status of the infarct-related artery may support a concept that early recanalization is essential to maintain left ventricular systolic function and to prevent left ventricular remodeling. On the other hand, it has been suggested that early stage BNP levels can also predict long-term prognosis.12,23 The relationship between BNP and long-term survival is believed to be mainly on the basis of their reflection of left ventricular dysfunction.24 Therefore, our results that show the relationship between the acute stage BNP levels and chronic stage left ventricular function suggest that the acute stage BNP levels may also predict long-term prognosis. In addition, our results that show that the BNP levels in the acute stage were lower in the 6-hour patency group than in the 6-hour occlusion group may support the importance of early recanalization of the infarctrelated artery in prevention of left ventricular remodeling, maintenance of left ventricular function, and improvement of long-term prognosis in patients with AMI.

Study limitation Because we did not measure the plasma BNP at 5 to 7 days after the onset of MI in this study, the secondary peak of the BNP values could not be detected. For a detailed discussion of the relationship between the BNP levels and ventricular remodeling, the levels on days 5 to 7 should be also considered because the remodeling is initiated at about that time. In our study population, we could not evaluate the long-term prognosis because patient entry for the COMA trial started 1 year ago. The final study endpoint of the COMA trial

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is long-term prognosis, so a relationship between the acute stage BNP levels and the prognosis should be confirmed also in our study population.

Clinical implication Current landmark trials have established that some types of cardioactive drugs, including angiotensinconverting enzyme inhibitors25 or ␤-blockers,26 as cornerstone therapies reduce mortality and morbidity rates in patients with MI. However, it has been questionable as to in what cases we should use these therapies, how these therapies should be implemented, and what doses are best. Recently, it has been reported that treatment of heart failure guided with plasma BNP levels reduced total cardiovascular events and delayed time to first event, compared with that guided with conventional clinical assessments only.27 Because the BNP levels can predict subsequent cardiac function or long-term prognosis, cornerstone therapies guided with serial measurement of BNP may be a powerful strategy for reduction of mortality or morbidity rates in patients with MI. In addition, the importance of early recanalization may also be supported by the difference in plasma BNP kinetics between the 6-hour patency and the 6-hour occlusion groups in our results. We thank Mr Kan Hasegawa (Diagnostic Science Department, Shionogi & Co, Ltd, Osaka, Japan) for assay of BNP. We thank Mr Ryoichi Nishiki (Eisai Co, Tokyo, Japan) and Mr Toshiaki Hashimoto (Shionogi & Co, Ltd) for their secretarial assistances in preparation of the manuscript.

References 1. Tan AC, van Loenhout T, Lamfers EJ, et al. Atrial natriuretic peptide after myocardial infarction. Am Heart J 1989;118:490-4. 2. Jougasaki M, Yasue H, Mukoyama M, et al. Appearance of atrial natriuretic peptide in the ventricles in patients with myocardial infarction. Am Heart J 1990;119:92-6. 3. Mukoyama M, Nakao K, Obata K, et al. Augmented secretion of brain natriuretic peptide in acute myocardial infarction. Biochem Biophys Res Commun 1991;180:431-6. 4. Morita E, Yasue H, Yoshimura M, et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1993;88:82-91. 5. Arakawa N, Nakamura M, Aoki H, et al. Relationship between plasma level of brain natriuretic peptide and myocardial infarct size. Cardiology 1994;127:334-40. 6. Kettunen RV, Leppa ¨ luoto J, Jounela A, et al. Plasma N-terminal atrial natriuretic peptide in acute myocardial infarction. Am Heart J 1994;127:1449-55. 7. Omland T, Aasland T, Aakvaag A, et al. Prognostic value of plasma atrial natriuretic factor, norepinephrine and epinephrine in acute myocardial infarction. Am J Cardiol 1993;72:255-9. 8. Omland T, Bonarjee VV, Nilson DW, et al. Prognostic significance of N-terminal pro-atrial natriuretic factor (1-99) in acute myocardial infarction: comparison with atrial natriuretic factor (99-126) and clinical evaluation. Br Heart J 1993;70:409-14.

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9. Hall C, Rouleau JL, Moye´ LA, et al. N-terminal proatrial natriuretic factor: an independent predictor of long-term prognosis after myocardial infarction. Circulation 1994;89:1934-42. 10. Rouleau JL, Packer M, Moye´ LA, et al. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol 1994;24:583-91. 11. Omland T, Bonarjee VV, Lie RT, et al. Neurohumoral measurements as indicators of long-term prognosis after myocardial infarction. Am J Cardiol 1995;76:230-5. 12. Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963-9. 13. Sumida H, Yasue H, Yoshimura M, et al. Comparison of secretion pattern A-type and B-type natriuretic peptides in patients with old myocardial infarction. J Am Coll Cardiol 1995;25:1105-10. 14. ISIS-2 collaborative group. Randomized trial of intravenous streptokinase, oral aspirin or both or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349-60. 15. White HD, Norris RM, Brown MA, et al. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987;317:850-5. 16. Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90:195-203. 17. Richard AM, Nicholls MG, Yandle TG, et al. Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group. Heart 1999;81:114-20. 18. Kinnunen P, Vuolteenaho O, Ruskoaho H. Mechanism of atrial and brain natriuretic peptide release from rat ventricular myocardium: effect of stretching. Endocrinology 1993;132:1961-70. 19. Richard AM, Crizier IG, Yandle TG, et al. Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease. Br Heart J 1993;69:414-7. 20. Magga J, Vuolteenaho O, Takola H, et al. B-type natriuretic peptide: a myocyte-specific marker for characterizing load-induced alterations in cardiac gene expression. Ann Med 1998;30(suppl 1):39-45. 21. Horio T, Shimada K, Kohno M, et al. Serial changes in atrial and brain natriuretic peptides in patients with acute myocardial infarction treated with early coronary angioplasty. Am Heart J 1993; 126:293-9. 22. Hama N, Itoh H, Shirakami G, et al. Rapid ventricular induction of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1995;92:1558-64. 23. Arakawa N, Nakamura M, Aoki H, et al. Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction. J Am Coll Cardiol 1996;27:1656-61. 24. Remes J. Neuroendocrine activation after myocardial infarction. Br Heart J 1994;72(suppl 3):65-9. 25. Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. N Engl J Med 1992;327:678-84. 26. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55. 27. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided plasma aminoterminal brain natriuretic peptide (N-BNP) concentration. Lancet 2000;355:1126-30.