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Association between serum corin levels and risk of acute myocardial infarction
Clinica Chimica Acta 452 (2016) 134–137
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Association between serum corin levels and risk of acute myocardial infarction San-Ming Zhang a,1, Jian-Xin Shen b,⁎,1, Hui Li c,1, Peng Zhao d, Gang Xu d, Jian-Chang Chen c,⁎⁎ a
Department of Cardiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China d Department of Cardiology, Nanjing First Hospital, Nanjing, China b c
a r t i c l e
i n f o
Article history: Received 17 September 2015 Received in revised form 5 November 2015 Accepted 10 November 2015 Available online 11 November 2015 Keywords: Acute myocardial infarction Corin Risk factor Case–control study
a b s t r a c t Background: Accumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case–control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). Methods: We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. Results: Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825 ± 263 pg/ml) compared with those in healthy controls (1246 ± 425 pg/ ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, b 0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. Conclusions: Our study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Corin is a transmembrane protease that plays a critical role in maintaining salt-water balance and blood pressure [1]. This enzyme is primarily expressed in cardiomyocytes, where it converts natriuretic peptides from inactive precursors to mature active forms. Under high blood pressure or volume overload conditions, the generation of the natriuretic peptides in the heart is increased to promote natriuresis, diuresis, and vasodilation [2]. In recent years, there is growing evidence that corin is critically involved in the regulation of normal blood pressure and cardiac function. Chan et al. reported that corin knockout mice could eventually develop spontaneous hypertension and exhibit cardiac hypertrophy and dysfunction [3]. Gladysheva et al. showed that corin expression could modulate myocardial fibrosis, cardiac function and heart failure in cardiomyopathy [4]. Dong et al. indicated that plasma corin levels were significantly lower in patients with heart failure than those in ⁎ Correspondence to: J.-X. Shen, Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, No. 12 Changqing Road, Zhangjiakou, Hebei 075000, China. ⁎⁎ Correspondence to: J.-C. Chen, Department of Cardiology, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Suzhou, Jiangsu 215004, China. E-mail addresses: [email protected] (J.-X. Shen), [email protected] (J.-C. Chen). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2015.11.012 0009-8981/© 2015 Elsevier B.V. All rights reserved.
normal individuals, and the reduction in corin levels appeared to correlate with the severity of heart failure [5]. Recently, Peng et al. carried out cross-sectional studies in Chinese adults and found that serum soluble corin was significantly associated with the incidences of obesity, hypertension and stroke [6–8]. Acute myocardial infarction (AMI), a complex syndrome with various etiologies, is a main component of cardiovascular diseases and a serious health problem worldwide. With the aging population growing, the morbidity and mortality of AMI are increasing rapidly in China. Over the past few decades, a number of risk factors have been identified associated with the development and progression AMI. However, until now the relation between serum corin and AMI has not been well established. We therefore conducted a hospital-based case–control study to evaluate the association of serum soluble corin with AMI risk using logistic regression model. 2. Methods 2.1. Study population We consecutively enrolled 856 patients with AMI, including ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) who admitted to Nanjing First Hospital between September 2012 and June 2015. AMI was diagnosed if a patient had a cardiac troponin I
S.-M. Zhang et al. / Clinica Chimica Acta 452 (2016) 134–137
level exceeding the 99th percentile of a normal reference population with at least one of the following, chest pain lasting N20 min or diagnostic serial electrocardiographic changes consisting of new pathological Q waves or ST-segment and T-wave changes [9]. Patients with heart failure or renal failure were excluded from the study. In addition, a total of 856 age- and sex-matched control subjects were randomly selected from the healthy participants who underwent a comprehensive health examination in the same hospital. This study was approved by the ethics committee of Nanjing First Hospital and written informed consent was obtained from each participant.
2.2. Clinical and biochemical assessment Demographic and clinical data were obtained from the medical records. Hypertension was defined as a systolic blood pressure ≥ 140 mm Hg or a diastolic blood pressure ≥ 90 mm Hg or receiving antihypertensive treatment. Diabetes was defined as the use of antidiabetic agents or fasting glucose level ≥7.0 mmol/l or glucose concentration ≥11.1 mmol/l at 2 h after a meal. Hyperlipidemia was defined as a total cholesterol (TC) concentration N 5.7 mmol/l or triglyceride (TG) concentration N1.7 mmol/l or low density lipoprotein (LDL) concentration N3.1 mmol/l or undergoing lipid-lowering therapy. In this study, participants were regarded as physically active if they engaged in aerobic activities for N 30 min (walking, bicycling, running, swimming, etc.) ≥3 times/ week. Venous blood was drawn from AMI patients and control subjects in a fasting state within 24 h of admission. Blood biochemistry variables, including blood glucose, TC, TG, LDL, and creatinine were determined according to the manufacturer's instructions. Serum corin levels were measured by enzyme-linked immunoabsorbent assay as previously described (R&D Systems, Minneapolis, MN, USA) [10]. Briefly, microtiter plates pre-coated with anti-human corin were incubated at 37 °C for 2 h with 100 μl/well of standard or thawed serum samples in duplicate. After removal of the liquid, 100 μl of biotinylated anti-human corin was added to each well and further incubated for 1 h. After washing, the plates were incubated with horseradish peroxidase-avidin for 1 h at 37 °C, and finally TMB substrate was added for another 30 min of incubation. The color reaction was stopped by adding 50 μl/well of stop solution and the plates were then read in a microplate reader at a wavelength of 450 nm.
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3. Results 3.1. Baseline characteristics There were 856 control subjects and 856 AMI patients (including 419 STEMI and 437 NSTEMI) in this study. The clinical and biochemical characteristics of the study population are shown in Tables 1 and 2. The serum corin levels were significantly lower in AMI patients than in the controls. Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the control subjects. In addition, patients were divided into two groups according to ST-segment changes. STEMI patients tended to be male and smokers and had higher serum corin levels, whereas NSTEMI patients were older and more likely to have histories of hypertension, diabetes, and hyperlipidemia. 3.2. Association of serum corin with AMI in men As shown in Table 3, participants were categorized into quartiles of corin levels in healthy controls to evaluate the relation between serum corin and AMI risk in men. With the lowest quartile as a reference, ORs of STEMI and NSTEMI were calculated. Our results showed that both STEMI and NSTEMI were significantly associated with the decreasing levels of serum corin (P for trend, b0.001) after adjustment for the following covariates (BMI, hypertension, diabetes, hyperlipidemia, smoking, and physical activity). Patients in the highest quartile had 0.52 × (OR = 0.52; 95% CI, 0.34–0.80) the OR of STEMI and 0.45 × (OR = 0.45; 95% CI, 0.28–0.72) the OR of NSTEMI for patients in the lowest quartile, suggesting that serum soluble corin might be more closely associated with NSTEMI than with STEMI. 3.3. Association of serum corin with AMI in women As shown in Table 4, participants were categorized into quartiles of corin levels in healthy controls to evaluate the relation between serum corin and AMI risk in women. Our results suggested that both STEMI and NSTEMI were remarkably associated with the decreasing levels of serum corin after multivariate adjustment (P for trend, b0.001). Patients in the highest quartile had 0.27× (OR = 0.27; 95% CI, 0.12–0.54) the OR of STEMI and 0.38× (OR = 0.38; 95% CI, 0.19–0.70) the OR of NSTEMI for patients in the lowest quartile.
2.3. Statistical analysis 3.4. Correlation of serum corin with Killip class Statistical analyses were performed using SPSS 20.0. Data are presented as mean ± SD or as a percentage. Continuous variables were compared using the Student's t test, and categorical variables were analyzed using the χ2 test. Odds ratio (OR) and 95% confidence interval (CI) were calculated to indicate the relation between serum corin levels and AMI risk. Multiple logistic regression analysis was used to adjust for BMI, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. A value of P b 0.05 was considered statistically significant.
The reduction in serum corin levels in patients with AMI seemed to correlate with the severity of the disease. In this study, the cardiac function of AMI patients was divided into 4 groups according to the Killip class. In patients with Killip classes I, II, III, and IV, the serum soluble corin levels were 1052 pg/ml, 794 pg/ml, 768 pg/ml, and 546 pg/ml, respectively. The serum levels of corin were progressively lower in AMI patients with more severe cardiac dysfunction (Fig. 1).
Table 1 Baseline characteristics of AMI patients and controls.
Table 2 Characteristics of patients subdivided by STEMI and NSTEMI.
Age (years) Male (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Hyperlipidemia (%) Smoking (%) Physically active (%) Creatinine (μmol/l) Corin (pg/ml)
Control (n = 856) AMI (n = 856)
P value
62.8 ± 7.6 588 (68.7) 22.7 ± 2.5 364 (42.5) 139 (16.2) 330 (38.6) 418 (48.8) 467 (54.6) 65.2 ± 12.7 1246 ± 425
NS NS b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 NS b0.001
65.3 ± 8.4 613 (71.6) 26.4 ± 3.2 521 (60.9) 238 (27.8) 534 (62.4) 571 (66.7) 375 (43.8) 68.3 ± 14.5 825 ± 263
Data are expressed as mean ± SD or numbers (percentage).
Age (y) Male (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Hyperlipidemia (%) Smoking (%) Physically active (%) Creatinine (μmol/l) Corin (pg/ml)
STEMI (n = 419)
NSTEMI (n = 437)
P value
61.1 ± 7.6 324 (77.3) 25.6 ± 2.8 227 (54.2) 98 (23.4) 233 (55.6) 312 (74.5) 178 (42.5) 71.4 ± 15.2 932 ± 290
69.3 ± 9.2 289 (66.1) 27.2 ± 3.5 294 (67.3) 140 (32.0) 301 (68.9) 259 (59.3) 197 (45.1) 65.3 ± 13.8 722 ± 245
b0.001 b0.001 NS b0.001 b0.001 b0.001 b0.001 NS NS 0.015
Data are expressed as mean ± SD or numbers (percentage).
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Table 3 Association of serum corin quartiles with STEMI and NSTEMI in men. STEMI (n = 324) Corin (quartiles) Q1 (b954 pg/ml) Q2 (954–1348 pg/ml) Q3 (1349–1792 pg/ml) Q4 (N1792 pg/ml) P for trend
Case/control 105/147 86/147 74/147 59/147
NSTEMI (n = 289) Adjusted OR⁎ (95% CI) 1.00 0.79 (0.54–1.16) 0.68 (0.45–0.98) 0.52 (0.34–0.80) b0.001
Case/control 94/147 85/147 64/147 46/147
Adjusted OR⁎ (95% CI) 1.00 0.87 (0.58–1.25) 0.63 (0.41–0.96) 0.45 (0.28–0.72) b0.001
⁎ Adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity in analysis.
Table 4 Association of serum corin quartiles with STEMI and NSTEMI in women. STEMI (n = 95) Corin (quartiles) Q1 (b682 pg/ml) Q2 (682–1076 pg/ml) Q3 (1077–1495 pg/ml) Q4 (N1495 pg/ml) P for trend
Case/control 40/67 25/67 19/67 11/67
NSTEMI (n = 148) Adjusted OR⁎ (95% CI) 1.00 0.61 (0.32–1.10) 0.45 (0.21–0.86) 0.27 (0.12–0.54) b0.001
Case/control 52/67 45/67 30/67 21/67
Adjusted OR⁎ (95% CI) 1.00 0.85 (0.49–1.43) 0.54 (0.28–0.95) 0.38 (0.19–0.70) b0.001
⁎ Adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity in analysis.
4. Discussion The present hospital-based case–control study was designed to investigate the association between serum soluble corin and AMI risk using multivariate logistic regression analysis. We found that corin levels were remarkably reduced in patients with AMI compared with those in healthy controls. ORs of STEMI and NSTEMI were significantly decreased with the increasing levels of serum corin in both men and women after multivariate adjustment, suggesting that serum soluble corin was inversely correlated with the incidences of STEMI and NSTEMI. Corin belongs to the type II transmembrane serine protease family, and it has a cytoplasmic tail and a single-span transmembrane domain near the N-terminus. In the extracellular region of corin, there are 2 frizzled-like domains, 8 low-density lipoprotein receptor repeats, 1 scavenger receptor-like domain, and a trypsin-like protease domain
Fig. 1. Serum corin levels in patients with acute myocardial infarction divided into 4 groups according to the Killip class. In patients with Killip classes I, II, III, and IV, the corin levels were 1052 pg/ml, 794 pg/ml, 768 pg/ml, and 546 pg/ml, respectively. The serum levels of corin were progressively lower in patients with more severe cardiac dysfunction. *P b 0.05 versus class I; #P b 0.05 versus class IV.
[11]. The transmembrane domain anchors corin to the cell surface but is not required for its catalytic activity [12]. Recently, accumulating evidence has indicated that corin is potentially involved in the pathogenesis of hypertension, myocardial hypertrophy and cardiac dysfunction [3,4]. In addition, a previous clinical study has demonstrated that corin deficiency might contribute to the development of heart failure and plasma corin could be used as a biomarker in the diagnosis of heart failure [5]. In the present study, we found that serum corin levels were significantly decreased in patients with AMI compared with healthy controls, which was in accordance with the results of a small sample size study that investigated the potential role of corin in patients with acute coronary syndrome [13]. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones that regulate body fluid balance and blood pressure. Upon binding to their receptor, these peptides stimulate intracellular cGMP production, thereby promoting natriuresis and diuresis in the kidney and muscle relaxation in the blood vessel. Corin has been identified as the physiological pro-ANP convertase [14]. When pro-ANP is secreted from cardiomyocytes, corin activates it on the cell surface. In addition to pro-ANP processing, corin also cleaves pro-BNP [15]. The reaction, however, is less sequence-specific and less efficient. Recent studies have shown that human pro-BNP contains abundant O-glycans that are terminally sialylated [16], and O-glycans can regulate BNP production and activity by inhibiting corin-mediated cleavage [17]. AMI is normally divided into STEMI and NSTEMI according to the STsegment changes on electrocardiogram. Patients with STEMI in most cases have a complete thrombotic occlusion of a major coronary artery that leads to transmural ischaemia, whereas NSTEMI is associated with a subtotal thrombosis at the site of plaque rupture and may cause subtotal vessel occlusion. In STEMI, coronary angiography is an emergent procedure that should be performed within 120 min from the onset of symptoms [18]. Conversely, in NSTEMI, for most patients, an early coronary revascularization strategy (b 72 h) should be employed, with only a small proportion of patients undergoing emergent coronary angiography (b120 min) [19]. In this study, we found that patients with STEMI tended to be male and smokers and had higher serum corin levels, whereas NSTEMI patients were older and more likely to have histories of hypertension, diabetes, and hyperlipidemia. Moreover, serum soluble corin was significantly and inversely associated with the incidences of STEMI and NSTEMI.
S.-M. Zhang et al. / Clinica Chimica Acta 452 (2016) 134–137
There are several limitations associated with this study. First, it is unclear whether low corin level is the cause or the result of AMI, so the conclusions drawn from this study need to be further confirmed in prospective multicenter cohort studies. Second, patients were often prescribed some medication prior to the onset of AMI, so we cannot exclude the influence of drugs on serum corin levels. Third, we did not evaluate the possible relation between serum soluble corin and infarction size in AMI patients. In summary, our study demonstrates that serum levels of corin are significantly decreased in patients with AMI compared with healthy controls. Moreover, serum corin is inversely associated with the incidences of STEMI and NSTEMI in both men and women. Prospective cohort studies are required to confirm the causal relation between serum soluble corin and AMI risk. Acknowledgment This study was supported by the Research Fund for Young Scholars of Soochow University (2014356). References [1] Q. Wu, Y.O. Xu-Cai, S. Chen, W. Wang, Corin: new insights into the natriuretic peptide system, Kidney Int. 75 (2009) 142–146. [2] L.B. Daniels, A.S. Maisel, Natriuretic peptides, J. Am. Coll. Cardiol. 50 (2007) 2357–2368. [3] J.C. Chan, O. Knudson, F. Wu, J. Morser, W.P. Dole, Q. Wu, Hypertension in mice lacking the proatrial natriuretic peptide convertase corin, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 785–790. [4] I.P. Gladysheva, D. Wang, R.A. McNamee, A.K. Houng, A.A. Mohamad, T.M. Fan, et al., Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy, Hypertension 61 (2013) 327–332.
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[5] N. Dong, S. Chen, J. Yang, L. He, P. Liu, D. Zheng, et al., Plasma soluble corin in patients with heart failure, Circ. Heart Fail. 3 (2010) 207–211. [6] H. Peng, Q. Zhang, H. Shen, Y. Liu, X. Chao, H. Tian, et al., Association between serum soluble corin and obesity in Chinese adults: a cross-sectional study, Obesity (Silver Spring) 23 (2015) 856–861. [7] H. Peng, Q. Zhang, X. Cai, Y. Liu, J. Ding, H. Tian, et al., Association between high serum soluble corin and hypertension: a cross-sectional study in a general population of China, Am. J. Hypertens. 28 (2015) 1141–1149. [8] H. Peng, F. Zhu, J. Shi, X. Han, D. Zhou, Y. Liu, et al., Serum soluble corin is decreased in stroke, Stroke 46 (2015) 1758–1763. [9] K. Thygesen, J.S. Alpert, H.D. White, Universal definition of myocardial infarction, Circulation 116 (2007) 2634–2653. [10] A. Peleg, A.S. Jaffe, Y. Hasin, Enzyme-linked immunoabsorbent assay for detection of human serine protease corin in blood, Clin. Chim. Acta 409 (2009) 85–89. [11] W. Yan, N. Sheng, M. Seto, J. Morser, Q. Wu, Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart, J. Biol. Chem. 274 (1999) 14926–14935. [12] S. Knappe, F. Wu, M.R. Madlansacay, Q. Wu, Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide, J. Biol. Chem. 279 (2004) 34464–34471. [13] A. Peleg, D. Ghanim, S. Vered, Y. Hasin, Serum corin is reduced and predicts adverse outcome in non-ST-elevation acute coronary syndrome, Eur. Heart J. Acute Cardiovasc. Care 2 (2013) 159–165. [14] Q. Wu, The serine protease corin in cardiovascular biology and disease, Front. Biosci. 12 (2007) 4179–4190. [15] A.G. Semenov, N.N. Tamm, K.R. Seferian, A.B. Postnikov, N.S. Karpova, D.V. Serebryanaya, et al., Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases, Clin. Chem. 56 (2010) 1166–1176. [16] J. Jiang, N. Pristera, W. Wang, X. Zhang, Q. Wu, Effect of sialylated O-glycans in probrain natriuretic peptide stability, Clin. Chem. 56 (2010) 959–966. [17] J. Peng, J. Jiang, W. Wang, X. Qi, X.L. Sun, Q. Wu, Glycosylation and processing of proB-type natriuretic peptide in cardiomyocytes, Biochem. Biophys. Res. Commun. 411 (2011) 593–598. [18] P.G. Steg, S.K. James, D. Atar, L.P. Badano, C. Blömstrom-Lundqvist, M.A. Borger, et al., ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur. Heart J. 33 (2012) 2569–2619. [19] J.P. Bassand, C.W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernández-Avilés, et al., Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes, Eur. Heart J. 28 (2007) 1598–1660.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Association between serum corin levels and risk of acute myocardial infarction San-Ming Zhang a,1, Jian-Xin Shen b,⁎,1, Hui Li c,1, Peng Zhao d, Gang Xu d, Jian-Chang Chen c,⁎⁎ a
Department of Cardiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China d Department of Cardiology, Nanjing First Hospital, Nanjing, China b c
a r t i c l e
i n f o
Article history: Received 17 September 2015 Received in revised form 5 November 2015 Accepted 10 November 2015 Available online 11 November 2015 Keywords: Acute myocardial infarction Corin Risk factor Case–control study
a b s t r a c t Background: Accumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case–control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). Methods: We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. Results: Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825 ± 263 pg/ml) compared with those in healthy controls (1246 ± 425 pg/ ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, b 0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. Conclusions: Our study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Corin is a transmembrane protease that plays a critical role in maintaining salt-water balance and blood pressure [1]. This enzyme is primarily expressed in cardiomyocytes, where it converts natriuretic peptides from inactive precursors to mature active forms. Under high blood pressure or volume overload conditions, the generation of the natriuretic peptides in the heart is increased to promote natriuresis, diuresis, and vasodilation [2]. In recent years, there is growing evidence that corin is critically involved in the regulation of normal blood pressure and cardiac function. Chan et al. reported that corin knockout mice could eventually develop spontaneous hypertension and exhibit cardiac hypertrophy and dysfunction [3]. Gladysheva et al. showed that corin expression could modulate myocardial fibrosis, cardiac function and heart failure in cardiomyopathy [4]. Dong et al. indicated that plasma corin levels were significantly lower in patients with heart failure than those in ⁎ Correspondence to: J.-X. Shen, Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, No. 12 Changqing Road, Zhangjiakou, Hebei 075000, China. ⁎⁎ Correspondence to: J.-C. Chen, Department of Cardiology, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Suzhou, Jiangsu 215004, China. E-mail addresses: [email protected] (J.-X. Shen), [email protected] (J.-C. Chen). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2015.11.012 0009-8981/© 2015 Elsevier B.V. All rights reserved.
normal individuals, and the reduction in corin levels appeared to correlate with the severity of heart failure [5]. Recently, Peng et al. carried out cross-sectional studies in Chinese adults and found that serum soluble corin was significantly associated with the incidences of obesity, hypertension and stroke [6–8]. Acute myocardial infarction (AMI), a complex syndrome with various etiologies, is a main component of cardiovascular diseases and a serious health problem worldwide. With the aging population growing, the morbidity and mortality of AMI are increasing rapidly in China. Over the past few decades, a number of risk factors have been identified associated with the development and progression AMI. However, until now the relation between serum corin and AMI has not been well established. We therefore conducted a hospital-based case–control study to evaluate the association of serum soluble corin with AMI risk using logistic regression model. 2. Methods 2.1. Study population We consecutively enrolled 856 patients with AMI, including ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) who admitted to Nanjing First Hospital between September 2012 and June 2015. AMI was diagnosed if a patient had a cardiac troponin I
S.-M. Zhang et al. / Clinica Chimica Acta 452 (2016) 134–137
level exceeding the 99th percentile of a normal reference population with at least one of the following, chest pain lasting N20 min or diagnostic serial electrocardiographic changes consisting of new pathological Q waves or ST-segment and T-wave changes [9]. Patients with heart failure or renal failure were excluded from the study. In addition, a total of 856 age- and sex-matched control subjects were randomly selected from the healthy participants who underwent a comprehensive health examination in the same hospital. This study was approved by the ethics committee of Nanjing First Hospital and written informed consent was obtained from each participant.
2.2. Clinical and biochemical assessment Demographic and clinical data were obtained from the medical records. Hypertension was defined as a systolic blood pressure ≥ 140 mm Hg or a diastolic blood pressure ≥ 90 mm Hg or receiving antihypertensive treatment. Diabetes was defined as the use of antidiabetic agents or fasting glucose level ≥7.0 mmol/l or glucose concentration ≥11.1 mmol/l at 2 h after a meal. Hyperlipidemia was defined as a total cholesterol (TC) concentration N 5.7 mmol/l or triglyceride (TG) concentration N1.7 mmol/l or low density lipoprotein (LDL) concentration N3.1 mmol/l or undergoing lipid-lowering therapy. In this study, participants were regarded as physically active if they engaged in aerobic activities for N 30 min (walking, bicycling, running, swimming, etc.) ≥3 times/ week. Venous blood was drawn from AMI patients and control subjects in a fasting state within 24 h of admission. Blood biochemistry variables, including blood glucose, TC, TG, LDL, and creatinine were determined according to the manufacturer's instructions. Serum corin levels were measured by enzyme-linked immunoabsorbent assay as previously described (R&D Systems, Minneapolis, MN, USA) [10]. Briefly, microtiter plates pre-coated with anti-human corin were incubated at 37 °C for 2 h with 100 μl/well of standard or thawed serum samples in duplicate. After removal of the liquid, 100 μl of biotinylated anti-human corin was added to each well and further incubated for 1 h. After washing, the plates were incubated with horseradish peroxidase-avidin for 1 h at 37 °C, and finally TMB substrate was added for another 30 min of incubation. The color reaction was stopped by adding 50 μl/well of stop solution and the plates were then read in a microplate reader at a wavelength of 450 nm.
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3. Results 3.1. Baseline characteristics There were 856 control subjects and 856 AMI patients (including 419 STEMI and 437 NSTEMI) in this study. The clinical and biochemical characteristics of the study population are shown in Tables 1 and 2. The serum corin levels were significantly lower in AMI patients than in the controls. Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the control subjects. In addition, patients were divided into two groups according to ST-segment changes. STEMI patients tended to be male and smokers and had higher serum corin levels, whereas NSTEMI patients were older and more likely to have histories of hypertension, diabetes, and hyperlipidemia. 3.2. Association of serum corin with AMI in men As shown in Table 3, participants were categorized into quartiles of corin levels in healthy controls to evaluate the relation between serum corin and AMI risk in men. With the lowest quartile as a reference, ORs of STEMI and NSTEMI were calculated. Our results showed that both STEMI and NSTEMI were significantly associated with the decreasing levels of serum corin (P for trend, b0.001) after adjustment for the following covariates (BMI, hypertension, diabetes, hyperlipidemia, smoking, and physical activity). Patients in the highest quartile had 0.52 × (OR = 0.52; 95% CI, 0.34–0.80) the OR of STEMI and 0.45 × (OR = 0.45; 95% CI, 0.28–0.72) the OR of NSTEMI for patients in the lowest quartile, suggesting that serum soluble corin might be more closely associated with NSTEMI than with STEMI. 3.3. Association of serum corin with AMI in women As shown in Table 4, participants were categorized into quartiles of corin levels in healthy controls to evaluate the relation between serum corin and AMI risk in women. Our results suggested that both STEMI and NSTEMI were remarkably associated with the decreasing levels of serum corin after multivariate adjustment (P for trend, b0.001). Patients in the highest quartile had 0.27× (OR = 0.27; 95% CI, 0.12–0.54) the OR of STEMI and 0.38× (OR = 0.38; 95% CI, 0.19–0.70) the OR of NSTEMI for patients in the lowest quartile.
2.3. Statistical analysis 3.4. Correlation of serum corin with Killip class Statistical analyses were performed using SPSS 20.0. Data are presented as mean ± SD or as a percentage. Continuous variables were compared using the Student's t test, and categorical variables were analyzed using the χ2 test. Odds ratio (OR) and 95% confidence interval (CI) were calculated to indicate the relation between serum corin levels and AMI risk. Multiple logistic regression analysis was used to adjust for BMI, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. A value of P b 0.05 was considered statistically significant.
The reduction in serum corin levels in patients with AMI seemed to correlate with the severity of the disease. In this study, the cardiac function of AMI patients was divided into 4 groups according to the Killip class. In patients with Killip classes I, II, III, and IV, the serum soluble corin levels were 1052 pg/ml, 794 pg/ml, 768 pg/ml, and 546 pg/ml, respectively. The serum levels of corin were progressively lower in AMI patients with more severe cardiac dysfunction (Fig. 1).
Table 1 Baseline characteristics of AMI patients and controls.
Table 2 Characteristics of patients subdivided by STEMI and NSTEMI.
Age (years) Male (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Hyperlipidemia (%) Smoking (%) Physically active (%) Creatinine (μmol/l) Corin (pg/ml)
Control (n = 856) AMI (n = 856)
P value
62.8 ± 7.6 588 (68.7) 22.7 ± 2.5 364 (42.5) 139 (16.2) 330 (38.6) 418 (48.8) 467 (54.6) 65.2 ± 12.7 1246 ± 425
NS NS b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 NS b0.001
65.3 ± 8.4 613 (71.6) 26.4 ± 3.2 521 (60.9) 238 (27.8) 534 (62.4) 571 (66.7) 375 (43.8) 68.3 ± 14.5 825 ± 263
Data are expressed as mean ± SD or numbers (percentage).
Age (y) Male (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Hyperlipidemia (%) Smoking (%) Physically active (%) Creatinine (μmol/l) Corin (pg/ml)
STEMI (n = 419)
NSTEMI (n = 437)
P value
61.1 ± 7.6 324 (77.3) 25.6 ± 2.8 227 (54.2) 98 (23.4) 233 (55.6) 312 (74.5) 178 (42.5) 71.4 ± 15.2 932 ± 290
69.3 ± 9.2 289 (66.1) 27.2 ± 3.5 294 (67.3) 140 (32.0) 301 (68.9) 259 (59.3) 197 (45.1) 65.3 ± 13.8 722 ± 245
b0.001 b0.001 NS b0.001 b0.001 b0.001 b0.001 NS NS 0.015
Data are expressed as mean ± SD or numbers (percentage).
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Table 3 Association of serum corin quartiles with STEMI and NSTEMI in men. STEMI (n = 324) Corin (quartiles) Q1 (b954 pg/ml) Q2 (954–1348 pg/ml) Q3 (1349–1792 pg/ml) Q4 (N1792 pg/ml) P for trend
Case/control 105/147 86/147 74/147 59/147
NSTEMI (n = 289) Adjusted OR⁎ (95% CI) 1.00 0.79 (0.54–1.16) 0.68 (0.45–0.98) 0.52 (0.34–0.80) b0.001
Case/control 94/147 85/147 64/147 46/147
Adjusted OR⁎ (95% CI) 1.00 0.87 (0.58–1.25) 0.63 (0.41–0.96) 0.45 (0.28–0.72) b0.001
⁎ Adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity in analysis.
Table 4 Association of serum corin quartiles with STEMI and NSTEMI in women. STEMI (n = 95) Corin (quartiles) Q1 (b682 pg/ml) Q2 (682–1076 pg/ml) Q3 (1077–1495 pg/ml) Q4 (N1495 pg/ml) P for trend
Case/control 40/67 25/67 19/67 11/67
NSTEMI (n = 148) Adjusted OR⁎ (95% CI) 1.00 0.61 (0.32–1.10) 0.45 (0.21–0.86) 0.27 (0.12–0.54) b0.001
Case/control 52/67 45/67 30/67 21/67
Adjusted OR⁎ (95% CI) 1.00 0.85 (0.49–1.43) 0.54 (0.28–0.95) 0.38 (0.19–0.70) b0.001
⁎ Adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity in analysis.
4. Discussion The present hospital-based case–control study was designed to investigate the association between serum soluble corin and AMI risk using multivariate logistic regression analysis. We found that corin levels were remarkably reduced in patients with AMI compared with those in healthy controls. ORs of STEMI and NSTEMI were significantly decreased with the increasing levels of serum corin in both men and women after multivariate adjustment, suggesting that serum soluble corin was inversely correlated with the incidences of STEMI and NSTEMI. Corin belongs to the type II transmembrane serine protease family, and it has a cytoplasmic tail and a single-span transmembrane domain near the N-terminus. In the extracellular region of corin, there are 2 frizzled-like domains, 8 low-density lipoprotein receptor repeats, 1 scavenger receptor-like domain, and a trypsin-like protease domain
Fig. 1. Serum corin levels in patients with acute myocardial infarction divided into 4 groups according to the Killip class. In patients with Killip classes I, II, III, and IV, the corin levels were 1052 pg/ml, 794 pg/ml, 768 pg/ml, and 546 pg/ml, respectively. The serum levels of corin were progressively lower in patients with more severe cardiac dysfunction. *P b 0.05 versus class I; #P b 0.05 versus class IV.
[11]. The transmembrane domain anchors corin to the cell surface but is not required for its catalytic activity [12]. Recently, accumulating evidence has indicated that corin is potentially involved in the pathogenesis of hypertension, myocardial hypertrophy and cardiac dysfunction [3,4]. In addition, a previous clinical study has demonstrated that corin deficiency might contribute to the development of heart failure and plasma corin could be used as a biomarker in the diagnosis of heart failure [5]. In the present study, we found that serum corin levels were significantly decreased in patients with AMI compared with healthy controls, which was in accordance with the results of a small sample size study that investigated the potential role of corin in patients with acute coronary syndrome [13]. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones that regulate body fluid balance and blood pressure. Upon binding to their receptor, these peptides stimulate intracellular cGMP production, thereby promoting natriuresis and diuresis in the kidney and muscle relaxation in the blood vessel. Corin has been identified as the physiological pro-ANP convertase [14]. When pro-ANP is secreted from cardiomyocytes, corin activates it on the cell surface. In addition to pro-ANP processing, corin also cleaves pro-BNP [15]. The reaction, however, is less sequence-specific and less efficient. Recent studies have shown that human pro-BNP contains abundant O-glycans that are terminally sialylated [16], and O-glycans can regulate BNP production and activity by inhibiting corin-mediated cleavage [17]. AMI is normally divided into STEMI and NSTEMI according to the STsegment changes on electrocardiogram. Patients with STEMI in most cases have a complete thrombotic occlusion of a major coronary artery that leads to transmural ischaemia, whereas NSTEMI is associated with a subtotal thrombosis at the site of plaque rupture and may cause subtotal vessel occlusion. In STEMI, coronary angiography is an emergent procedure that should be performed within 120 min from the onset of symptoms [18]. Conversely, in NSTEMI, for most patients, an early coronary revascularization strategy (b 72 h) should be employed, with only a small proportion of patients undergoing emergent coronary angiography (b120 min) [19]. In this study, we found that patients with STEMI tended to be male and smokers and had higher serum corin levels, whereas NSTEMI patients were older and more likely to have histories of hypertension, diabetes, and hyperlipidemia. Moreover, serum soluble corin was significantly and inversely associated with the incidences of STEMI and NSTEMI.
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There are several limitations associated with this study. First, it is unclear whether low corin level is the cause or the result of AMI, so the conclusions drawn from this study need to be further confirmed in prospective multicenter cohort studies. Second, patients were often prescribed some medication prior to the onset of AMI, so we cannot exclude the influence of drugs on serum corin levels. Third, we did not evaluate the possible relation between serum soluble corin and infarction size in AMI patients. In summary, our study demonstrates that serum levels of corin are significantly decreased in patients with AMI compared with healthy controls. Moreover, serum corin is inversely associated with the incidences of STEMI and NSTEMI in both men and women. Prospective cohort studies are required to confirm the causal relation between serum soluble corin and AMI risk. Acknowledgment This study was supported by the Research Fund for Young Scholars of Soochow University (2014356). References [1] Q. Wu, Y.O. Xu-Cai, S. Chen, W. Wang, Corin: new insights into the natriuretic peptide system, Kidney Int. 75 (2009) 142–146. [2] L.B. Daniels, A.S. Maisel, Natriuretic peptides, J. Am. Coll. Cardiol. 50 (2007) 2357–2368. [3] J.C. Chan, O. Knudson, F. Wu, J. Morser, W.P. Dole, Q. Wu, Hypertension in mice lacking the proatrial natriuretic peptide convertase corin, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 785–790. [4] I.P. Gladysheva, D. Wang, R.A. McNamee, A.K. Houng, A.A. Mohamad, T.M. Fan, et al., Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy, Hypertension 61 (2013) 327–332.
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[5] N. Dong, S. Chen, J. Yang, L. He, P. Liu, D. Zheng, et al., Plasma soluble corin in patients with heart failure, Circ. Heart Fail. 3 (2010) 207–211. [6] H. Peng, Q. Zhang, H. Shen, Y. Liu, X. Chao, H. Tian, et al., Association between serum soluble corin and obesity in Chinese adults: a cross-sectional study, Obesity (Silver Spring) 23 (2015) 856–861. [7] H. Peng, Q. Zhang, X. Cai, Y. Liu, J. Ding, H. Tian, et al., Association between high serum soluble corin and hypertension: a cross-sectional study in a general population of China, Am. J. Hypertens. 28 (2015) 1141–1149. [8] H. Peng, F. Zhu, J. Shi, X. Han, D. Zhou, Y. Liu, et al., Serum soluble corin is decreased in stroke, Stroke 46 (2015) 1758–1763. [9] K. Thygesen, J.S. Alpert, H.D. White, Universal definition of myocardial infarction, Circulation 116 (2007) 2634–2653. [10] A. Peleg, A.S. Jaffe, Y. Hasin, Enzyme-linked immunoabsorbent assay for detection of human serine protease corin in blood, Clin. Chim. Acta 409 (2009) 85–89. [11] W. Yan, N. Sheng, M. Seto, J. Morser, Q. Wu, Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart, J. Biol. Chem. 274 (1999) 14926–14935. [12] S. Knappe, F. Wu, M.R. Madlansacay, Q. Wu, Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide, J. Biol. Chem. 279 (2004) 34464–34471. [13] A. Peleg, D. Ghanim, S. Vered, Y. Hasin, Serum corin is reduced and predicts adverse outcome in non-ST-elevation acute coronary syndrome, Eur. Heart J. Acute Cardiovasc. Care 2 (2013) 159–165. [14] Q. Wu, The serine protease corin in cardiovascular biology and disease, Front. Biosci. 12 (2007) 4179–4190. [15] A.G. Semenov, N.N. Tamm, K.R. Seferian, A.B. Postnikov, N.S. Karpova, D.V. Serebryanaya, et al., Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases, Clin. Chem. 56 (2010) 1166–1176. [16] J. Jiang, N. Pristera, W. Wang, X. Zhang, Q. Wu, Effect of sialylated O-glycans in probrain natriuretic peptide stability, Clin. Chem. 56 (2010) 959–966. [17] J. Peng, J. Jiang, W. Wang, X. Qi, X.L. Sun, Q. Wu, Glycosylation and processing of proB-type natriuretic peptide in cardiomyocytes, Biochem. Biophys. Res. Commun. 411 (2011) 593–598. [18] P.G. Steg, S.K. James, D. Atar, L.P. Badano, C. Blömstrom-Lundqvist, M.A. Borger, et al., ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur. Heart J. 33 (2012) 2569–2619. [19] J.P. Bassand, C.W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernández-Avilés, et al., Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes, Eur. Heart J. 28 (2007) 1598–1660.