http://informahealthcare.com/bmk ISSN: 1354-750X (print), 1366-5804 (electronic) Biomarkers, 2014; 19(7): 620–624 ! 2014 Informa UK Ltd. DOI: 10.3109/1354750X.2014.960452

RESEARCH ARTICLE

Dynamic changes and clinical significance of serum tryptase levels in STEMI patients treated with primary PCI Shaomin Chen, Di Mu, Ming Cui, Chuan Ren, Shu Zhang, Lijun Guo, and Wei Gao

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Department of Cardiology, Key Laboratory of Cardiovascular Molecular Biology and Regulatory peptides, Ministry of Health, Peking University Third Hospital, Beijing, China Abstract

Keywords

Objective: To investigate the dynamic changes in serum tryptase levels and their association with clinical data in patients with acute ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Methods: Serum tryptase levels were measured in 99 STEMI patients and 25 control subjects. Results: Tryptase levels were significantly increased at admission, and descended after primary PCI. Tryptase levels at 0.5, 2 and 6 h after PCI were negatively correlated with the percentage of ST-segment resolution (STR) as well as left ventricular ejection fraction (LVEF). Conclusions: High tryptase levels after PCI were associated with poor myocardial reperfusion and poor cardiac function.

Acute myocardial infarction, mast cell, ST-segment resolution, tryptase

Introduction Mast cells are well known for their role in hypersensitivity reactions. However, there is increasing evidence that they might be involved in atherogenesis and coronary heart disease (CHD) (Kaartinen et al., 1994; Kovanen et al., 1995; Laine et al., 1999; Ramalho et al., 2013). Studies have shown that increased number of mast cells was found in the shoulder region of atherosclerotic plaques, particularly in coronary atheroma (Kaartinen et al., 1994; Kovanen et al., 1995). At the immediate site of plaque erosion or rupture, the number of mast cells was found to be up to 6-fold higher than in the unaffected areas of the same infarct-related coronary artery (Laine et al., 1999). Tryptase is a trypsin-like serine proteinase which is stored fully active in the cytoplasmic granules of all human mast cells, and is estimated to constitute approximately 20% of the total cellular protein (Schwartz et al., 1990). Once released, tryptase is capable of activating matrix metalloproteinases and degrading various components of the pericellular/extracellular matrix, and so predisposes a plaque to rupture (He et al., 2013). Thus, mast cell activation occurs as an inflammatory event in atherogenesis and may be involved in plaque instability. Since tryptase is specific to human mast cells, the serum tryptase level is a useful marker for mast cell degranulation.

Address for correspondence: Ming Cui, Department of Cardiology, Key Laboratory of Cardiovascular Molecular Biology and Regulatory peptides, Ministry of Health, Peking University Third Hospital, 49 Huayuan-Bei Road, Beijing 100191, China. E-mail: [email protected] bjmu.edu.cn

History Received 28 July 2014 Revised 27 August 2014 Accepted 28 August 2014 Published online 16 October 2014

Clinical studies showed that serum tryptase levels were significantly elevated in patients with CHD, especially in patients with acute coronary syndrome (Deliargyris et al., 2005; Xiang et al., 2011). However, the dynamic changes and clinical significance of serum tryptase levels in patients with ST-elevation myocardial infarction (STEMI) are unknown. This study will investigate the changes of tryptase levels in STEMI patients before and after primary percutaneous coronary intervention (PCI) and their relationship with clinical data.

Materials and methods Patient selection A total of 99 consecutive patients with first STEMI admitted to the Department of Cardiology, Peking University Third Hospital, from May 2012 to April 2013 were included. STEMI was diagnosed according to the 2004 American College of Cardiology/American Heart Association guideline (Pollack et al., 2005). All patients received primary PCI within 12 h from symptom onset. Exclusion criteria were: (1) age 480 years, (2) cardiogenic shock, (3) previous history of myocardial infarction, (4) congenital heart disease or significant valvular heart disease, (5) cerebral infarction in the past 6 months, (6) chronic heart failure, (7) chronic inflammatory diseases or allergic diseases, (8) significant kidney or hepatic diseases, (9) tumor. During the same study period, 25 subjects who were admitted to the same hospital because of atypical chest pain but with normal coronary arteries confirmed by coronary angiography were included as controls. This study was approved by the ethics review boards of Peking University Third hospital. All patients gave their consent to use part of their blood for scientific purposes.

Serum tryptase levels in STEMI patients

DOI: 10.3109/1354750X.2014.960452

Statistical analysis Clinical parameters and tryptase levels of STEMI patients and the controls were compared using Student’s unpaired t-tests, Mann–Whitney U-test or chi-squared tests. Changes of tryptase levels of STEMI patients were analyzed by repeated measures. Spearman or Pearson correlation was used to identify the bivariate correlations. Statistical significance was defined as p50.05. All analyses were performed with SPSS for Windows version 15.0 (SPSS, Chicago, IL).

Results Clinical characteristics and serum tryptase levels The clinical characteristics and serum tryptase levels of STEMI patients and control subjects are summarized

STEMI patients (n ¼ 99)

Controls (n ¼ 25)

p Value

82 (82.8) 58.5 ± 12.2 25.3 ± 4.8 79 (80.6) 47 (48.0) 27 (27.6) 23 (23.7) 10.9 ± 3.7 6.6 (3.0–15.5) 9.6 ± 4.8 75.3 ± 12.6

12 (48.0) 60.8 ± 9.1 27.1 ± 3.5 11 (44.0) 16 (64.0) 6 (24.0) 8 (32.0) 6.7 ± 1.1 1.6 (1.2–2.2) 5.5 ± 0.7 75.5 ± 9.0

50.001 0.379 0.141 50.001 0.152 0.721 0.396 50.001 50.001 0.001 0.824

30.9 ± 2.6

50.001 50.001 50.001 50.001 50.001 50.001 0.022

207.7 ± 13.3 154.0 ± 10.9 132.7 ± 9.4 92.6 ± 7.6 63.6 ± 6.5 51.4 ± 6.7 32.9 ± 5.0

Values represent mean ± SD, median (inter-quartile range), or the percentage of STEMI patients and control subjects. BMI, body mass index; Hs-CRP, high sensitivity-C reactive protein; STEMI, ST-elevation myocardial infarction; WBC, white blood cell.

0 -20 -40 -60 -80

7d

48 h

24 h

6h

-100

2h

Venous blood samples of STEMI patients were collected at admission (baseline), 0.5 h, 2 h, 6 h, 24 h, 48 h and 7 d after PCI, while the serum samples of control patients were collected before coronary angiography. All samples were collected into vacuum blood collection tubes with clot activator and were immediately placed in 4  C refrigerators. Within 30 min after collection, samples were centrifuged at 3000 rpm for 10 min at 4  C, divided into aliquots, and stored at 80 C until analysis. Repeated freeze-thaw cycles were avoided. Serum tryptase levels were measured by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction (ELISA kit, R&D Systems, Shanghai, China). These assays were performed by an investigator blinded to the sources of the samples. The minimal detection limit was 15.6 pg/mL. A standard 12-lead ECG was recorded at baseline and 2 h after PCI. ECG measurements were conducted by a trained cardiologist blinded to other clinical and laboratory data. ST segments were measured 20 ms after the end of the QRS complex and the TP segment was used as the isoelectric reference baseline. The percentage of ST-segment resolution (STR) in the leads with maximal initial ST-segment elevation was calculated. STEMI patients underwent echocardiography within 24 h after admission, using a GE-VingMedV echocardiographic machine (Vivid 7) with a 3.3-MHz multiphase array probe. Left ventricular ejection fraction (LVEF) was obtained using a modified biplane version of Simpson’s method with apical two- and four-chamber views. These examinations were performed by experienced cardiologists.

0. 5h

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Laboratory assays

Male, n(%) Age, years BMI, kg/m2 Current smoker, n(%) Hypertension, n(%) Hyperlipidemia, n(%) Diabetes mellitus, n(%) WBC count, 109/L Hs-CRP, mg/L Glucose, mmol/L Creatinine, lmol/L Tryptase, pg/mL Baseline 0.5 h 2h 6h 24 h 48 h 7d

% changes from baseline

STEMI patients were treated with a loading dose of aspirin 300 mg and clopidogrel 300–600 mg at admission, and a bolus of 5000 IU of heparin before PCI. The PCI procedure was then completed according to standard technique (Kolh et al., 2010). Coronary TIMI flow grading was assessed before and after PCI. All STEMI patients received standard therapy including aspirin, clopidogrel, statins, b blockers and angiotensinconverting enzyme (ACE) inhibitors if there were no contraindications after PCI. The control subjects received aspirin 100 mg and clopidogrel 75 mg per day before angiography.

Table 1. Clinical characteristics and serum tryptase levels in STEMI patients and controls.

Ba se lin e

Treatment and procedures

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Figure 1. Changes of serum tryptase levels in STEMI patients.

in Table 1. The percentage of male patients and current smokers was higher in STEMI patients as compared with control subjects (p50.05). STEMI patients had higher white blood cell (WBC) count, high-sensitivity C-reactive protein (hs-CRP) and glucose levels than control subjects. There were no significant differences in age, body mass index (BMI), concomitant illnesses between the two groups. STEMI patients exhibited significant higher tryptase levels from baseline to 7 d after PCI (p50.01). Tryptase levels in STEMI patients decreased during the first week after PCI (analysis of repeated measures, p50.001, Figure 1). Presentation characteristics of STEMI patients are shown in Table 2. Median (inter-quartile range) time from symptom onset to admission and to balloon were 150 (90–240) min and 240 (192–370) min separately. Serum cardiac troponin T (cTnT) levels were lower than 0.014ng/mL at admission in 71.7% of the patients.

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Table 2. Presentation characteristics of STEMI patients. Characteristic

Value 150 (90–240) 240 (192–370) 25 (25.3) 38 (38.4) 36 (36.4) 49 (49.5) 19 (19.2) 31 (31.3) 81 (81.8) 90 (90.9) 17 (17.2) 71 (71.7) 4.2 (3.0–6.2) 60.0 ± 26.7 55.0 ± 9.6

Values represent mean ± SD, median (inter-quartile range) or the percentage of STEMI patients. cTnT, cardiac troponin T; LAD, left anterior descending artery; LCX, left circumflex artery; LVEF, Left ventricular ejection fraction; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction; STR, ST-segment resolution; TIMI, thrombolysis in myocardial infarction.

Discussion The present study demonstrates that serum tryptase levels were elevated in STEMI patients, and quickly decreased after primary PCI; tryptase levels at 0.5, 2 and 6 h after PCI were negatively correlated with the percentage of STR and LVEF. Kounis firstly reported that the inflammatory mediators (e.g. tryptase) released from mast cells are present in allergic angina and allergic myocardial infarction (Kounis et al., 2006). However, Patients with allergic diseases were excluded from this study. Therefore, a common pathway between

r =-0.360 P< 0.001

100 80 60 40

r =-0.384 P< 0.001

70 LVEF, %

ST-segment resolution, %

Serum tryptase levels 0.5, 2 and 6 h after PCI in STEMI patients were negatively correlated with the percentage of STR and LVEF (Figure 2). Tryptase levels at all time points showed no significant association with sex, age, BMI, smoking status, past history of hypertension, hyperlipidemia, diabetes mellitus, time from symptom onset to admission or to balloon, number of diseased vessels, culprit vessel, initial or final TIMI flow, peak cTnT, WBC count, hs-CRP, glucose or creatinine levels (data not shown).

(B)

(A)

20 0

60 50 40 30

110

130

150

170

190

110

Tryptase level at 0.5h after PCI, pg/mL

r =-0.438 P< 0.001

100 80 60 40

130

150

170

190

Tryptase level at 0.5h after PCI, pg/mL (D)

LVEF, %

ST-segment resolution,%

(C)

20 0

r =-0.342 P= 0.001

70 60 50 40 30

100

120

140

160

100

Tryptase level at 2h after PCI, pg/mL (E)

r =-0.385 P< 0.001

100 80 60 40 20 0

120

140

160

Tryptase level at 2h after PCI, pg/mL

(F)

LVEF, %

ST-segment resolution, %

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Symptom onset to admission, min Symptom onset to balloon, min Number of diseased vessels, n(%) 1 2 3 Culprit vessel, n(%) LAD LCX RCA Initial TIMI flow 0, n(%) Final TIMI flow 3, n(%) Heart failure during hospitalization, n(%) cTnT50.014ng/mL at admission, n(%) Peak cTnT, ng/mL STR, % LVEF, %

Association between serum tryptase levels and clinical parameters

r =-0.217 P= 0.032

70 60 50 40 30

60

80

100

120

Tryptase level at 6h after PCI, pg/mL

60

80

100

120

Tryptase level at 6h after PCI, pg/mL

Figure 2. Correlation between tryptase level at 0.5 h after PCI and (A)STR; (B) LVEF; (C) STR; (D) LVEF; (E) STR; (F) LVEF. LVEF, Left ventricular ejection fraction; PCI, percutaneous coronary intervention.

Serum tryptase levels in STEMI patients

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DOI: 10.3109/1354750X.2014.960452

allergic and non-allergic coronary events seem to exist. In an animal model of myocardial infarction, the number of mast cells peaked at 1 d and 21 d in the infarct region (Kwon et al., 2011). Mast cell degranulation is an early event in ischemia/ reperfusion (I/R) injury. Tryptase and histamine were rapidly released from heart during ischemia within 10 min (Matsui et al., 2005). In the study by Filipiak et al., persistent tryptase elevation has been detected in patients with nonallergic acute coronary syndromes, both in the acute phase and at follow-up. A former study from China (Xiang et al., 2011) showed that serum tryptase levels were nearly doubled in patients with acute myocardial infarction (including both STEMI and non-ST-elevation myocardial infarction (NSTEMI) patients) as compared with unsubstantial CHD patients. In the present study, tryptase levels in STEMI patient at admission were nearly 7-fold higher than in control subjects. Tryptase, like other inflammatory mediators, is short lived and has a half-life of about 90 min (Schwartz et al., 1989). Therefore, it has been suggested that the best time to obtain samples for tryptase determinations is 1–2 h after the precipitating event (Kounis, 2007). The median symptom onset to admission time was 150 (90–240) min in this study, but we still found significant increase in tryptase levels in STEMI patients, suggesting a persistent release of tryptase from mast cells. Over 70% of them had cTnT 50.014 ng/mL at admission, indicating circulating tryptase levels may increase earlier than cTnT in STEMI patients. After primary PCI, tryptase levels quickly decreased. This is concordant with a previous study in the isolated perfused guinea pig heart, which showed that tryptase was released into the coronary effluent during ischemia, but not during reperfusion (Matsui et al., 2005). In a variable proportion of STEMI patients, ranging from 5% to 50%, primary PCI achieves epicardial coronary artery reperfusion but not myocardial reperfusion. This phenomenon has a multifactorial pathogenesis including distal embolization, I/R injury, and individual predisposition of coronary microcirculation to injury. STR550% or 570% is considered as a marker of poor myocardial perfusion, and increases the risk of heart failure (Niccoli et al., 2009). In this study, serum tryptase levels 0.5, 2 and 6 h after PCI were negatively correlated with the percentage of STR as well as LVEF. First, good myocardial perfusion after PCI relieves myocardial ischemia, leading to rapid decrease of tryptase release from the heart. Second, mast cell degranulation may promote poor myocardial perfusion. A previous study (Zhang et al., 2010) showed that coronary microembolisation was associated with increases in the number of degranulating mast cells and cardiomyocyte apoptosis; mast cell stabilizer suppressed cardiomyocyte apoptosis and improved regional and global cardiac function. There is also evidence that mast cell degranulation promotes I/R injury in many organs (Rork et al., 2008; Yang et al., 2014). Tryptase could stimulate neutrophil adhesion by up-regulating endothelial expression of P-selectin (Meyer et al., 2005), and induce endothelial barrier dysfunction through proteinase-activated receptor-2 (Itoh et al., 2005 ). Mast cell stabilizers as well as tryptase inhibitors have been shown to be able to attenuate I/R injury (Jaggi et al., 2007; Liu et al., 2012).

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Although tryptase levels were correlated with the percentage of STR, the present study failed to show association of tryptase levels with final TIMI flow. First, few patients had TIMI flow 53 after PCI. Second, TIMI flow may reflect epicardial coronary artery reperfusion but not myocardial reperfusion. This present study found no association of tryptase levels with markers of inflammation such as Hs-CRP, or markers of myocardial necrosis such as cTnT. The sample size of this study is small and, therefore, our data need confirmation in future studies. In conclusion, serum tryptase levels in STEMI patients were significantly increased at admission, and decreased after primary PCI. High tryptase levels after PCI are associated with poor myocardial reperfusion and poor cardiac function. Blocking of trypase release might be beneficial for preventing myocardial infarction and improving myocardial reperfusion after PCI.

Declaration of interest The authors declare no conflicts of interest in this work.

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Dynamic changes and clinical significance of serum tryptase levels in STEMI patients treated with primary PCI.

To investigate the dynamic changes in serum tryptase levels and their association with clinical data in patients with acute ST-elevation myocardial in...
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