S. Wei1, 2 · L. Mao3 · B. Liu1 · L. Zhong1

1  Department of Cardiology, The Fourth Clinical Hospital of Harbin 

Medical University, Nangang District, Harbin2  Department of Cell Developmental and Integrative Biology, 

University of Alabama at Birmingham, Birmingham3 Department of Neurology, University of Alabama at Birmingham, Birmingham

Serum biomarkers  and the prognosis of  AMI patients

e-Herz: Original article

Acute myocardial infarction (AMI) is life-threatening and only emergent per-cutaneous coronary intervention (PCI) and thrombolytic therapy are thought to be effective [1]. However, limited by the narrowing time window for these ther-apies, many patients, especially those transferred from general hospitals, can-not benefit from them [2]. Thus, the most frequent therapy for AMI patients is elec-tive PCI. Elective PCI is still valuable, al-though it is not as effective as emergent PCI in terms of saving more cardiomy-ocytes and thereby cardiac function. It is considered safe based on the fact that these patients are most likely with sta-ble vital signs compare to those under-going emergent PCI [3]. However, the long-term outcomes are not very prom-ising and a considerable number of pa-tients suffer from major adverse cardi-ac events (MACE), i.e., all-cause death, Q-wave and non-Q-wave MI, and target vessel revascularization (TVR) [4]. Be-sides the well-known factors—such as age, sex, lesion length and complexity—certain serum biomarkers have recently been shown to predict MACE. High-sen-sitivity C-reactive protein (hs-CRP), ho-mocysteine, uric acid, and creatinine are biomarkers that were shown to be inde-pendent factors for MACE in the long-term follow-up of patients after PCI [5, 6, 7, 8].

Bilirubin is another useful serum biomarker for the evaluation of adverse events in certain inflammatory diseas-es [9]. As a major metabolite of heme, it shows antioxidant properties and is thought to be representative of the in-flammatory status of the body. Notably, its level also served as a useful tool for evaluating the heme oxygenase-1 (HO-1) during AMI [10]. In our previous work, we found that bilirubin was related to coronary artery lesion types [11]. Fur-thermore, although it was not found to be an independent factor in predicting the prognosis of systolic heart failure patients, it merited further exploration [12]. Another commonly used biomark-er for AMI in clinics is lactate dehydro-genase (LDH), the level of which deter-mines the size of the infarct area in the heart. Higher LDH levels are often asso-ciated with worse outcomes in AMI pa-tients, but how LDH is related to MACE in AMI patients undergoing PCI is still unknown. In this study, we monitored the bilirubin and LDH levels and calcu-lated their ratio to investigate how this ratio, together with other biomarkers, is related to MACE in AMI patients under-going elective PCI.

Methods

Study population

This was a retrospective case-control clinical study conducted at the Fourth Affiliated Hospital of Harbin Medical University. The cases of 477 AMI patients who were admitted to our hospital and underwent coronary angiography be-tween 2007 and 2008 were reviewed. We enrolled 239 patients (men, 193; mean age, 59.9±11.2 years) in the study. The in-clusion criteria were: (1) de novo acute myocardial infarction patients admit-ted to the hospital between 24 and 48 h; (2) patients had elective PCI 1 week after onset of symptoms; (3) patients who did not have previous coronary artery bypass surgery, dilated cardiomyopathy, valvu-lar heart disease, and/or heart transplan-tation. The exclusion criteria were: (1) missed time window for blood sampling (24–48 h, 184 patients); (2) unwilling to participate in the study (22 patients); (3) lost to follow-up (32 patients). All the pa-tients were followed up for an average of 3.2±0.4 years. All the procedures were in accordance with the ethical standards of Harbin Medical University. The study protocol was approved by the ethics com-mittee of Harbin Medical University and all patients signed a consent form before the follow-ups.

e-Herz: Original article

e-Herz

Herz 2013 DOI 10.1007/s00059-013-3828-9Received: 5 March 2013Revised: 1 April 2013Accepted: 3 April 2013© Urban & Vogel 2013

1Herz 2013  | 

Physical examination

Blood pressure including systolic and di-astolic pressure and heart rate were re-corded on admission. The histories of other diseases, such as hypertension and diabetes were recorded as reported by the patients.

Coronary angiography

Coronary angiography was performed with the standard Judkins approach in all patients who gave written consent as described previously [11]. It was conduct-ed with a GE INNOVA 2000 system (GE Healthcare, Milwaukee, WI, USA). More

than 50% of stenosis in one of three ma-jor coronary arteries including the left anterior descending artery (LAD), left circumflex artery (LCX), and right cor-onary artery (RCA) or in their first-or-der branches was considered as severe CAD, while 10–50% was considered as mild CAD; patients who had less than 10% of stenosis were assigned to the con-trol group (free of CAD). Patients with more than 70% of stenosis in one of three major coronary arteries including the left anterior descending artery (LAD), left circumflex artery (LCX), and right coro-nary artery (RCA) or in their first-order branches were eligible for PCI.

Left ventricular ejection fraction

A Vivid 7 color Doppler ultrasonic de-vice (GE Healthcare, Shanghai, China) was used for the evaluation of cardiac function. Simpson’s method was applied for evaluation of left ventricular ejection fraction as described previously [13]. The ejection fraction of patients was con-firmed by echocardiographic assessment.

Laboratory tests

Blood samples were collected when the patients were admitted to hospital 24–48 h after the onset of symptoms. Brief-ly, blood samples were collected, centri-fuged, and serum was extracted. All kits were purchased from Roche (Mannheim, Germany). Biochemical tests were per-formed using the Roche Automatic Mod-ular Analytics P system (Mannheim, Germany) under a set program. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), LDH, total bilirubin (TB), hs-CRP, cystatin C, uric acid, and creatinine were measured and recorded for analysis.

Study end points

The study end points were major ad-verse cardiac events (MACE) during fol-low-up, defined as the composite of all-cause death, non-Q-wave myocardial infarction (MI), Q-wave MI, and TVR (CABG and repeated percutaneous cor-onary intervention). MI was defined as

Tab. 1  Patient characteristics

  All patients(n=239)

Patients without MACE(n=169)

Patients with MACE(n=70)

p value

Age (years) 59.9±11.2 59.2±10.9 61.8±11.8 NS

Men 193(81) 143 (85) 50 (71) NS

LVEF (%) 57.9±7.9 57.5±7.9 59.1±8.1 NS

History of hyper-tension

113 (47) 82 (49) 31 (44) NS

Diabetes mel-litus

58 (24) 42 (25) 16 (23) NS

Laboratory results

Creatinine (μmol/l)

88.5±42.8 87.1±40.1 91.9±45.6 NS

Uric acid (μmol/l)

365.6±113.7 343.2±108.2 419.6±109.2 <0.01

Total cholesterol (mmol/l)

4.8±1.1 4.7±1.1 4.8±1.1 NS

Triglycerides (mmol/l)

1.7±1.1 1.7±1.1 1.8±1.1 NS

HDL (mmol/l) 1.1±0.3 1.2±0.3 1.1±0.2 NS

LDL (mmol/l) 2.9±0.8 2.8±0.8 3.0±0.8 NS

TB (μmol/l) 17.3±6.8 18.3±6.7 14.8±6.5 <0.01

ALT (U/l) 54.4±43.1 54.6±45.4 53.9±37.1 NS

AST(U/l) 239.2±127.6 232.0±118.7 256.6±146.3 NS

LDH (U/l) 1211.5±504.6 1151.7±415.4 1355.8±654.3 <0.01

LDH/TB 84.6±49.5 61.2±26.5 141.1±46.3 <0.01

Cystatin C (mg/l) 1.20±0.24 1.00±0.46 1.69±0.76 <0.01

Hs-CRP (μmol/l) 3.98±3.72 2.13±1.32 8.47±3.84 <0.01

Pharmacotherapy

ACE inhibitor or ARB

189 (55) 133 (79) 56 (80) NS

β-Blocker 166 (58) 115 (68) 51 (73) NS

Digitalis 24 (10) 18 (11) 6 (10) NS

Diuretic 34 (14) 22 (13) 12 (17) NS

Statin 232 (97) 163 (96) 69 (99) NSData are number (%) or mean ± standard deviationACE angiotensin-converting enzyme, ARB angiotensin receptor blocker, HDL high-density lipoprotein, hs-CRP high-sensitivity C-reactive protein, LDL low-density li-poprotein, LVEF left ventricular ejection fraction, TB total bilirubin, ALT alanine aminotransferase, AST aspartate aminotransferase LDH lactate dehydrogenase

Tab. 2  Cox multivariable analysis

  HR (95% CI) P value

LDH (U/l) 2.72 (2.69–2.72) 0.042

LDH/TB 2.76 (2.74–2.78) <0.001

Cysteine C (mg/l) 6.74 (4.28–12.24) <0.001CI confidence interval, TB total bilirubin, HR hazard ratio, LDH Lactate dehydrogenase

2 |  Herz 2013

e-Herz: Original article

the occurrence of an elevated creatine ki-nase (CK)–MB fraction over three times the upper limit of normal. Patients with enzymatic elevation were further strati-fied into those with and without appear-ance of pathological Q waves on serial electrocardiograms (ECGs). Cardiac en-zymes (total CK and CK-MB) were mea-sured before treatment and at 4–8 h after the procedure.

Long-term follow-up

All patients underwent long-term fol-low-up. Periodical physical examinations were performed every 3 months either at home or in the hospital for 3 years for all patients enrolled as of 2007–2008. Blood tests were performed at the same time. For patients experiencing more than one adverse outcome, only the first one was considered. All information regarding potential adverse outcomes was acquired by reviewing the source data, including hospital record forms, death certificates, and other original documents.

Statistical analysis

SPSS 17.0 software was used to analyze the data. Results are reported as group means ± standard error of the mean (SE). Differences between group means were determined by t test. Differences of p<0.05 were considered significant. Cox proportional hazards regression analy-sis was performed on the follow-up da-ta; among 16 variables tested (. Tab. 1), only those variables with statistical sig-nificance (p<0.05) at univariate analy-sis were included in a multivariate cox regression model to determine the in-dependent predictors of adverse events (. Tab. 2).

Results

General patient characteristics

Of 477 patients reviewed, 239 met the study criteria and were enrolled. Gen-eral information on the patients is pre-sented in . Tab. 1. Significant differ-ences were seen in the levels of hs-CRP, TB, LDH, cystatin C, uric acid and in the ratio of LDH and TB: 2.13±1.32 vs.

Abstract · Zusammenfassung

Herz 2013 · [jvn]:[afp]–[alp]   DOI 10.1007/s00059-013-3828-9© Urban & Vogel 2013

S. Wei · L. Mao · B. Liu · L. ZhongSerum biomarkers and the prognosis of AMI patients

AbstractBackground.  It has been proven that serum lactate dehydrogenase (LDH) and total biliru-bin (TB) increase during acute myocardial in-farction (AMI). However, how they influence the prognosis of AMI patients is still not com-pletely known.Methods.  A total of 239 patients diagnosed with AMI and admitted to the Fourth Clini-cal Hospital of Harbin Medical University, be-tween 2007 and 2008, were enrolled in this study. All the patients had not undergone pri-mary percutaneous coronary intervention (PCI) because the time window (24 h) was missed. They all underwent PCI 1 week after the onset of symptoms. Serum high-sensitiv-ity C-reactive protein (hs-CRP), TB, LDH, and other biomarkers were determined between 24 and 48 h of symptom onset. All of the pa-tients were followed up for an average of 3.2±0.4 years for occurrence of major adverse cardiac events (MACE).Results.  Patients with MACE had significant-ly higher levels of hs-CRP, LDH, cystatin C, 

uric acid, a higher ratio of LDH and TB (LDH/TB), and a lower level of TB: 8.48±3.84 vs. 2.13±1.32 μmol/l, p<0.01; 1,355.8±654.3 vs. 1,151.7±415.4 U/l, p<0.01; 1.69±0.76 vs. 1.00±0.46 mg/l, p<0.01; 419.6±109.2 vs. 343.2±108.2 μmol/l, p<0.01 and 141.1±46.2 vs. 61.2±26.5, p<0.01; 18.3±6.7 vs. 14.8±6.6 mg/l, p<0.01, respectively. In the multivariate COX analysis, LDH, cystatin C, and LDH/TB were significantly associated with the prognosis of these patients.Conclusions.  Patients under higher oxida-tive stress tend to have more MACE. LDH, cys-tatin C, and LDH/TB are strongly related to the prognosis of AMI patients undergoing elective PCI.

KeywordsBilirubin · Cystatin C · High-sensitivity C-reactive protein · Major adverse cardiac events · Percutaneous coronary intervention

Serum-Biomarker und die Prognose von AMI-Patienten

ZusammenfassungHintergrund.  Zwar ist nachgewiesen, dass die Serumkonzentrationen von Laktatdehy-drogenase (LDH) und Gesamtbilirubin (TB) während eines akuten Myokardinfarkts (AMI) ansteigen, doch wie sie die Prognose bee-influssen, ist nach wie vor nicht vollständig geklärt.Methoden.  Insgesamt 239 zwischen 2007 und 2008 in der vierten medizinischen Klinik der Harbin Medical University behandelte Patienten wurden in die Studie aufgenom-men. Alle hatten zeitfensterbedingt (24 h) ke-ine primäre perkutane Koronarintervention (PCI) erhalten und unterzogen sich innerhalb von einer Woche nach Symptombeginn ein-er PCI. Zwischen 24 und 48 h wurden die Se-rumkonzentrationen von hoch sensitivem C-reaktiven Protein (Hs-CRP), TB, LDH und an-deren Biomarkern bestimmt, und alle Patient-en wurden über eine Follow-up-Periode von durchschnittlich 3,2 (±0,4) Jahren hinsichtlich schwerwiegender unerwünschter kardialer Ereignisse (MACE) nachbeobachtet.Ergebnisse.  Signifikant höhere hs-CRP-, LDH-, Cystatin-C- und Harnsäurekonzentra-

tionen sowie ein erhöhtes LDH/TB-Verhältnis und ein geringeres TB fanden sich bei Patient-en mit MACE: 8,48±3,84 vs. 2,13±1,32 μmol/l, p<0,01; 1355,8±654,3 vs. 1151,7±415,4 U/l, p<0,01; 1,69±0,76 vs. 1,00±0,46 mg/l, p<0,01; 419,6±109,2 vs. 343,2±108,2 μmol/l, p<0,01 und 141,1±46,2 vs. 61,2±26,5, p<0,01; 18,3±6,7 vs. 14,8±6,6 mg/l, p<0,01. In der multivariaten COX-Regressionsanalyse zeigte sich ein signifikanter Zusammenhang zwischen der Prognose und LDH, Cystatin C sowie LDH/TB.Fazit.  Bei hohem oxidativen Stress kommt es eher zu MACE. Zwischen LDH, Cystatin C sowie LDH/TB und der Prognose von AMI-Pa-tienten mit elektiver PCI besteht eine enge Beziehung.

SchlüsselwörterBilirubin · Cystatin C · Hoch sensitives C-reaktives Protein · Schwerwiegende unerwünschte kardiale Ereignisse  · Perkutane Koronarintervention

3Herz 2013  | 

8.48±3.84 μmol/l, p<0.01; 14.8±6.6 vs. 18.3±6.7 mg/l, p<0.01; 1151.7±415.4 vs. 1355.8±654.3 U/l, p<0.01; 1.00±0.46 vs. 1.69±0.76 mg/l, p<0.01; 343.2±108.2 vs. 419.6±109.2 μmol/l, p<0.01; and 61.2±26.5 vs. 141.1±46.2, p<0.01, respec-tively. The average follow-up duration was 3.2±0.4 years during which 70 pa-tients had MACE (see . Tab. 3). Of these 70 patients, 2 died; 1 in hospital 2 days after PCI and the other died af-ter a hemorrhage stroke 1 year after PCI. Non-Q-wave MI was diagnosed in 24 pa-tients and 19 of them underwent revas-cularization; 19 patients had Q-wave MI and 17 of them underwent revascu-larization. Twenty-five patients had re-current unstable angina associated with previous lesions and eight of them were treated with coronary artery bypass graft (CABG) and others with repeated PCI. No differences were present in terms of lesion types and length, stent length, and number of stents between the two groups (see . Tab. 4).

Independent risk factors for MACE

Further Cox regression analysis was per-formed to identify independent risk fac-tors for MACE among AMI patients un-dergoing elective PCI. Our data indi-cate that LDH together with cystatin C and LDH/TB were independent risk fac-tors for MACE. In particular, LDH/TB and cystatin C had the strongest rela-tionship with MACE (p<0.001), which was much more significant than LDH alone (p=0.042), as shown in . Tab. 2. Kaplan–Meier analysis (. Fig. 1c) indi-cated that patients with a lower ratio of LDH and TB tended to have better out-comes, whereas those with a higher ra-tio exhibited worse results. Cystatin C and LDH had the same trend as LDH/TB (. Fig. 1a, b).

Discussion

Serum biomarkers have long raised the interest of clinical researchers for their

roles in predicting the prognosis of pa-tients with certain inflammatory diseas-es, e.g., hs-CRP, homocysteine, cystatin C etc. [14, 15, 16]. We were prompted to study the prognostic correlates of these biomarkers because their levels are al-ways affected by the status of oxidative stress, which is very important in the ini-tiation and progression of inflammatory disorders such as CAD, AMI, and oth-er diseases. In our study, besides cystatin C, a recently recognized marker for oxi-dative stress, we showed that the ratio of traditionally measured biomarkers, LDH and TB, had a very strong relationship with MACE among AMI patients under-going elective PCI. Patients with a low-er LDH/TB ratio tended to have fewer MACE and vice versa.

As a serum biomarker for AMI, high LDH levels have been used for years to indicate MI dating back up to 10 days. Without a doubt, the level of LDH rep-resents the infarct size in the heart and is associated with the prognosis of AMI patients. TB is another serum biomark-er that gained attention recently. It was reported that TB was related to severi-ty and/or prognosis of many diseases in-cluding cardiovascular disease, such as heart failure, hypertension, and AMI [10, 17, 18]. TB is also considered an antioxi-dant and the protective effect of TB can be traced to its catalytic enzyme, heme oxygenase (HO), which is the rate-limit-ing enzyme in the degradation of heme. Researchers have reported clinical results showing that patients with higher biliru-bin levels before statin treatment had a lower cardiovascular disease risk [19]. Moreover, it was shown that patients with Gilbert syndrome (these patients have hyperbilirubinemia) had augmen-tation of endothelial function and de-creased oxidative stress [20]. Our data also showed that AMI patients without MACE had higher serum TB levels than those with MACE, although TB was not qualified as an independent risk factor in our study. This trend motivated us to test the ratio of LDH and TB as a predic-tor for the prognosis of AMI. We hypoth-esized that patients with MACE should have a higher LDH and lower TB level, and in this case the ratio would be a bet-ter predictor of the prognosis of these

Tab. 3  Distribution of MACE

MACE cat-egories

First year(n)

Second year (n)

Third year (n) Number of patients (n)

% of MACE

All-cause death

1 1 0 2 2.9

Non-Q-wave MI

6 8 10 24 34.2

Q-wave MI 5 5 9 19 27.1

Target lesion revascularization

CABG 2 0 6 8 11.4

Repeated PCI 5 7 5 17 24.3

Total 19 21 30 70 100MI myocardial infarction, CABG coronary artery bypass graft, PCI percutaneous coronary intervention

Tab. 4  Percutaneous coronary interventions

  All patients(n=239)

Patients without MACE(n=169)

Patients with MACE(n=70)

p value

Coronary lesion types

A 40 (17) 29 (17) 11 (16) NS

B1 42 (18) 27 (16) 15 (21) NS

B2 83 (35) 61 (37) 22 (32) NS

C 74 (30) 52 (30) 22 (31) NS

Average lesion length (mm)

16.2±6.6 15.8±5.7 17.2±6.9 NS

Stent type (BMS/DES)

(3/236) (2/167) (1/70) NS

Number of stents 1.51±0.67 1.50±0.48 1.53±0.55 NS

Average stent length (mm)

21.6±8.7 21.4±6.8  22.1±9.4 NS

4 |  Herz 2013

e-Herz: Original article

patients; i.e., it would be more sensitive than other markers in this study. Our study clearly showed that patients with lower LDH/TB ratios had better out-comes and vice versa.

As reported by others, TB started to increase several hours after AMI and peaked at 48 h, similar to LDH [10]. Thus, patients admitted to our hospi-tal between 24 and 48 h were selected for the study, because they had the right time point for measuring the LDH/TB ratio. On the other hand, these patients missed the time window for emergent PCI, which is a factor that may interfere with the peak time of the biomarkers. We also compared other factors, such as le-sion length, stent length, etc. (shown in . Tab. 4) to rule out other factors that may affect the evaluation of these bio-markers.

Cystatin C is another biomarker that has gained attention in the last few years. It was originally applied as a serum bio-marker for renal function because it had a higher sensitivity than creatinine [21]. It was realized later that cystatin C is a very sensitive serum marker for inflammato-ry diseases. Our group has shown that cystatin C is associated with the progno-sis of systolic heart failure patients [12]. Other researchers also pointed out that the plasma cystatin C level was useful in predicting the severity of coronary ar-tery disease [22, 23]. One of our ongo-

ing research projects also demonstrated that cystatin C is associated with in-stent restenosis among CAD patients treat-ed with stent implantation at 12 months’ follow-up [24]. In the present study, we found that cystatin C had a very strong relationship with MACE in our study population. Patients with MACE had a much higher cystatin C level than those without, while there was no significant difference in the creatinine levels be-tween groups. The most likely explana-tion for this is that in the acute phase of inflammatory diseases, such as heart fail-ure [25], cystatin C may not only be an index of renal function, but rather an in-dex of the overall status of the body. Al-though cystatin C levels varied with car-diac function, the serum creatinine lev-el stayed unchanged, which most likely also occurred in our study. Cystatin C is more sensitive than traditional markers like hs-CRP, uric acid, and LDL. Certain traditional risk factors were not related to MACE among these patients. This is most likely due to the small sample size, and thus larger surveys including more patients should be carried out to identi-fy additional factors that could be use-ful in predicting the prognosis of these patients.

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Fig. 1 8 a Cumulative proportion of patients without adverse events during follow-up (Kaplan–Meier). Survival is shown sep-arately for patients with different levels of cystatin C, <1.0 mg/l (▲; censored cases) and >1.0 mg/l (Δ; censored cases). Log-rank test, p<0.001. b Cumulative proportion of patients without adverse events during follow-up (Kaplan–Meier). Survival is shown separately for patients with different levels of LDH, <1,223.8 U/l (▲; censored cases) and >1,223.8 μmol/l (Δ; censored cases). Log-rank test, p<0.05. c Cumulative proportion of patients without adverse events during follow-up (Kaplan–Meier). Survival is shown separately for patients with different levels of LDH/TB, <71.3 (▲; censored cases) and >71.3 (Δ; censored cas-es). Log-rank test, p<0.001

Conclusion

LDH, cystatin C, and the LDH/TB ratio were strong independent risk factors in evaluating the prognosis of AMI pa-tients undergoing elective PCI, especial-ly the LDH/TB ratio, which may be ap-plied for clinical use in the future.

Corresponding address

Dr. S. WeiDepartment of Cardiology,  The Fourth Clinical Hospital  of Harbin Medical University,  Nangang District37 Yiyuan Str., 150001 HarbinChinashipengwei@yahoo.com

Acknowledgments.  This research was supported by an educational grant for technology of the Heilongji-ang Province to L.Z. (grant number 11541125) and S.W. (grant number 12511309).

Conflict of interest.  On behalf of all authors, the corresponding author states that there are no con-flicts of interest.

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6 |  Herz 2013

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