Author + information
- Received December 30, 2015
- Revision received February 14, 2016
- Accepted February 16, 2016
- Published online May 3, 2016.
- Xiang Zhou, MD, PhDa,∗ (, )
- Jianchang Chen, MD, PhDa,
- Qing Zhang, MDb,
- Jing Shao, MDb,
- Kang Du, MDc,
- Xiaohua Xu, MDd and
- Yuan Kong, PhDd
- aDepartment of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- bDepartment of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- cDepartment of Cardiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- dDepartment of Epidemiology and Biostatistics, Nanjing Medical University, Nanjing, China
- ↵∗Reprint requests and correspondence:
Dr. Xiang Zhou, Department of Cardiology, The Second Affiliated Hospital of Soochow University, No.1055 Sanxiang Road, Suzhou, Jiangsu 215004, P.R. China.
Background Recent studies in animal models and humans have shown that corin is critically involved in the regulation of salt–water balance, blood pressure, and cardiac function.
Objectives The goal of this study was to investigate the prognostic value of plasma soluble corin in patients with acute myocardial infarction (AMI).
Methods We enrolled 1,382 consecutive AMI patients in a prospective cohort study and explored the association of plasma corin with AMI outcomes using multivariable Cox proportional hazards analysis.
Results Patients with low corin levels were more likely to be female and to have histories of hypertension and heart failure (HF). Kaplan-Meier survival curves indicated that patients with corin levels above the median had a lower incidence of major adverse cardiac events (MACE) and all-cause mortality compared with those whose corin levels were below the median. Multivariate Cox regression analysis suggested that log corin was an independent predictor of MACE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.42 to 0.96; p = 0.029), together with age, previous histories of AMI, HF, and diabetes, Killip class, percutaneous coronary intervention, coronary artery bypass graft, beta-blocker use, and log N-terminal pro-B-type natriuretic peptide. The C-statistic and integrated discrimination improvement for MACE were improved significantly by the addition of corin to the reference model. Moreover, log corin was also found to be a significant predictor of death (HR: 0.65; 95% CI: 0.41 to 0.97; p = 0.036) and HF hospitalization (HR: 0.48; 95% CI: 0.23 to 0.90; p = 0.009) after adjustment for clinical variables and established biomarkers of adverse prognosis.
Conclusions Our study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors.
Corin, a key transmembrane serine protease in the synthesis of mature atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), plays critical roles in maintaining salt–water balance, blood pressure, and cardiac function (1). The human corin gene, located on the short arm of chromosome 4 at p12-13, has 22 exons and spans >200 kb in length. Corin is highly expressed in the heart, especially in the ANP-expressing atrial cardiomyocytes and, to a lesser extent, in the BNP-expressing ventricles. It has been well-documented that transcriptional control, intracellular protein trafficking, cell surface targeting, zymogen activation, and ectodomain shedding are important mechanisms regulating corin expression and activity in the heart (2).
In the past decade, accumulating evidence has demonstrated that corin might serve as a potential prognostic factor in cardiovascular diseases (3–5). Peleg et al. (5) indicated that patients with non–ST-segment elevation acute coronary syndrome had lower serum corin levels and corin could be a useful biomarker for cardiovascular risk stratification and outcome prediction in patients with acute coronary syndrome. However, in this study, the sample size was relatively small and patients were enrolled nonconsecutively. Therefore, we carried out a large-scale prospective cohort study to evaluate the prognostic utility of plasma soluble corin in hospitalized patients with acute myocardial infarction (AMI).
A total of 1,382 consecutive patients with diagnosed AMI, including ST-segment elevation (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI), admitted to the affiliated hospitals of Nanjing Medical University were recruited between March 2010 and June 2013. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Nanjing Medical University. AMI was diagnosed if a patient had a cardiac troponin I level exceeding the 99th percentile of a normal reference population with ≥1 of the following: chest pain lasting >20 min, diagnostic serial electrocardiographic changes consisting of new pathologic Q waves, or ST-segment and T-wave changes (6). Patients with known malignancy or end-stage renal disease were excluded from this study. Demographic, clinical, and biochemical data were obtained from the medical records. All patients received standard medical treatment and written informed consent was obtained from each participant.
Measurement of plasma corin
Blood samples were collected from AMI patients on admission. Plasma was obtained by centrifugation for 10 min at 3,000 rpm and then stored at -80°C until analysis. Soluble corin levels in plasma were measured using an enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minnesota). Briefly, microtiter plates were coated with an anti-corin antibody. Plasma samples were added and incubated for 2 h at room temperature. The plates were washed with phosphate-buffered saline, and then a biotin-labeled anti-corin antibody was added and incubated for 2 h. After washing, peroxidase-conjugated streptavidin was added and incubated for 20 min at room temperature. The reaction was visualized by adding a horseradish peroxidase substrate, and the optical density was detected at 450 nm in the spectrometer.
The primary composite endpoint was major adverse cardiac events (MACE), including all-cause mortality, hospitalization for heart failure (HF), or recurrent AMI. The secondary endpoints consisted of death, hospitalization for HF, and recurrent AMI. Hospitalization for HF was defined as a hospital readmission for which HF was the primary reason. Recurrent AMI was diagnosed in accordance with established criteria as described (6). Endpoints were obtained by reviewing the hospital database and by contacting each patient individually.
Statistical analyses were performed using SPSS version 18.0 (SPSS, Chicago, Illinois). Continuous variables were compared using the Mann-Whitney U test. Categorical variables were compared using the chi-square test. Normality of continuous variables was assessed by the Kolmogorov-Smirnov test. Multiple linear regression analysis was applied to determine factors influencing corin levels. The association between baseline variables and MACE was evaluated using univariable and multivariable Cox proportional hazards analysis. The factors entered into the Cox regression models for the primary and secondary endpoints were age; sex; previous histories of AMI; HF; hypertension; diabetes; smoking; AMI type; Killip class; percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); treatment with aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor, and angiotensin receptor blocker; estimated glomerular filtration rate; troponin I; N-terminal pro-BNP (NT-proBNP); and corin. Levels of troponin I, NT-proBNP, and corin were normalized by log10 transformation. Kaplan-Meier survival analysis was conducted to compare the difference in survival rate between patients with high and low levels of corin using the log-rank test. The increased discriminative value of corin in the prediction of MACE was assessed using the C-statistic and integrated discrimination improvement (IDI). The IDI is the difference between the mean of the estimated prediction probabilities for subjects with events and the corresponding mean for subjects without events. A subgroup analysis was undertaken to determine whether corin was a significant predictor for MACE in both STEMI and NSTEMI patients (interaction term was found to be significant). A 2-tailed p value of <0.05 was considered statistically significant in this study.
Patient characteristics and influencing factors of corin
Characteristics of the study population are shown in Table 1. AMI patients were divided into 2 groups according to their median levels of corin. Patients with low corin levels were more likely to be female and have histories of hypertension and HF. Corin seemed to be positively associated with male sex, smoking, beta-blocker use, and eGFR, whereas it was inversely correlated with HF, hypertension, Killip class, and NT-proBNP.
There were a total of 762 STEMI patients and 620 NSTEMI patients enrolled in this study. Our results showed no difference in corin levels between STEMI and NSTEMI patients. The median length of follow-up was 634 days (range, 1 to 1,845). During the follow-up period, 138 patients died, 156 were readmitted with HF, and 130 experienced recurrent AMI. No patient was lost to follow-up.
Multiple linear regression analysis was performed to identify variables that may independently influence plasma corin levels. The results indicated that female sex (p < 0.001), hypertension (p = 0.003), and HF (p = 0.012) were strong independent predictors of low corin in patients with AMI. The R2 value of this model was 0.56.
Kaplan-Meier survival analysis was carried out to compare the difference in survival rate between patients with high and low levels of corin. The findings showed that low corin was a useful predictor of MACE and all-cause mortality in patients with AMI (Figure 1). Patients above the median levels of corin had a significantly lower incidence of MACE (log-rank test, p < 0.001) and all-cause mortality (log-rank test, p < 0.001) compared with those below the median.
Primary endpoint: MACE
Survival analysis using the Cox regression model showed that age, sex, previous history of AMI, HF, hypertension, diabetes, and smoking, Killip class, revascularization therapy, treatment with beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and aspirin, eGFR, log NT-proBNP, and log corin were univariate predictors of the primary endpoint of MACE, which was a composite of all-cause mortality, HF hospitalization, and recurrent AMI. Moreover, the multivariate Cox regression analysis revealed that log corin remained a significant predictor of MACE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.42 to 0.96; p = 0.029), together with age, previous histories of AMI, HF and diabetes, Killip class, PCI, CABG, beta-blocker use, and log NT-proBNP (Table 2). The C-statistic for MACE increased from 0.75 to 0.80 (p < 0.001) after the addition of corin to the reference model and the IDI also significantly improved (IDI: 0.032; 95% CI: 0.013 to 0.057; p = 0.006).
In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between corin and AMI type (HR: 1.27; 95% CI: 1.03 to 1.58; p = 0.043 for interaction). A subgroup analysis was then conducted to determine whether corin was a significant prognostic marker in both STEMI and NSTEMI patients (Table 3). In STEMI, log corin was an independent predictor of MACE (HR: 0.54; 95% CI: 0.26 to 0.92; p = 0.012), together with previous histories of: AMI, HF, diabetes, Killip class, PCI, CABG, treatment with beta-blocker and aspirin, log troponin I, and log NT-proBNP. However, in NSTEMI, log corin was not associated with MACE (HR: 0.71; 95% CI: 0.49 to 1.08; p = 0.175).
Secondary endpoints: Death, HF hospitalization, or recurrent AMI
Cox regression models were constructed for the secondary endpoints of death, HF hospitalization, or recurrent AMI (Table 4). Our findings indicated that log corin was an independent predictor of all-cause mortality (HR: 0.65; 95% CI: 0.41 to 0.97; p = 0.036) and HF hospitalization (HR: 0.48; 95% CI: 0.23 to 0.90, p = 0.009) after adjustment for age; sex; previous histories of AMI, HF, hypertension, diabetes, and smoking; AMI type; Killip class; PCI; CABG; treatment with aspirin, statin, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; eGFR; log troponin I; and log NT-proBNP. In addition, log corin was not found to be a predictor of recurrent AMI (HR: 0.91; 95% CI: 0.60 to 1.57; p = 0.596).
Current tools available to clinicians enabling risk stratification for AMI involve various scoring systems, such as Thrombolysis In Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) scores. Biochemical markers, including troponin I and NT-proBNP, can also provide prognostic value for MACE in patients with AMI (7,8). Risk stratification at an early stage after AMI may be useful in helping to select treatment regimens for patients. Recently, a small prospective study reported that serum corin was significantly reduced in patients with NSTEMI acute coronary syndrome and could be a potential predictor for MACE (5). To further confirm the prognostic value of corin in AMI, we enrolled 1,382 consecutive patients in a prospective cohort study and investigated the association of plasma corin with AMI outcomes using Cox regression analysis. Our findings suggested that corin could provide important prognostic information for AMI risk stratification and might be a useful biomarker of MACE in AMI patients.
Corin is a transmembrane serine protease identified in the heart, where it converts natriuretic peptides from inactive precursors to mature active forms (9). ANP and BNP are cardiac hormones involved in the regulation of salt–water balance and blood pressure. Upon binding to their receptors, these peptides stimulate intracellular production of cyclic guanosine monophosphate, thereby promoting natriuresis and diuresis and inducing blood vessel relaxation. Corin plays a central role in the processing of pro-ANP. Knockout of the corin gene in mice abolished ANP generation (10), indicating that no other enzymes act redundantly for this function. In addition, corin, together with an intracellular endoprotease, furin, can also cleave pro-BNP (11). However, this reaction is less sequence specific and less efficient.
The molecular weight of corin ranges from 150 to 200 kDa, depending on the degree of N-glycosylation, which is essential for cell surface expression of corin and modulates its biological activity on the surface of cardiomyocytes (12). In addition to its dominant membrane form, several isoforms of soluble corin (∼180, ∼160, and ∼100 kDa) have been identified in cultured transfected HEK293 cells and HL-1 cardiomyocytes (13). These fragments are most likely generated from proteolytic cleavage. ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive proteolytic activities in the heart (13).
Chan et al. (10) generated corin-deficient mice and found that mice eventually developed spontaneous hypertension and exhibited cardiac hypertrophy and dysfunction, suggesting that corin is critically involved in the regulation of blood pressure and cardiac function. Gladysheva et al. (14) established a mouse model of dilated cardiomyopathy and found that the mice displayed increased myocardial fibrosis and impaired contractile function in the setting of low corin expression, whereas corin overexpression resulted in the improvement in cardiac structure and function. Pang et al. (15) demonstrated that corin exerted cardioprotection by activating the ANP pathway in diabetic cardiomyopathy, and that down-regulation of corin led to endothelial dysfunction and vascular remodeling. In addition to experimental studies in animal models, clinical studies have investigated the roles of corin in cardiovascular diseases. Dong et al. (3) revealed that corin deficiency might contribute to the pathogenesis of HF and that plasma corin could be used as a biomarker in the diagnosis of HF. Rame et al. (4) indicated that the dysfunctional corin i555(p568) allele was associated with adverse outcomes and impaired BNP processing in blacks with systolic HF.
In the present study, we found that female sex, hypertension, and HF were significantly associated with reduced corin levels in patients with AMI. Low corin was confirmed to be an independent predictor for the composite primary endpoint of MACE and the secondary endpoints of death and HF hospitalization after adjusting for clinical variables and established biomarkers of adverse prognosis (Central Illustration). In addition, the C-statistic and IDI for MACE were significantly improved after adding corin to the reference model. Furthermore, in the subgroup analysis, low corin was found to be a significant predictor of MACE in STEMI, but not in NSTEMI.
First, this cohort study was performed in a Chinese population, and the findings should be extrapolated cautiously to other populations with different genetic backgrounds. Second, we collected data on all-cause mortality, not cardiovascular mortality, in the composite primary endpoint. Third, we did not conduct serial measurements of plasma corin levels after the occurrence of AMI. Finally, we did not compare the prognostic value of corin with other serum biomarkers, such as troponin I and NT-proBNP, in AMI patients.
Our study demonstrates that corin is a prognostic marker of MACE in AMI patients, independent of established conventional risk factors, which will provide valuable information for the early risk stratification of AMI.
COMPETENCY IN MEDICAL KNOWLEDGE: Corin is a serine protease that regulates the synthesis of natriuretic peptides and plays critical roles in maintaining salt and water balance, blood pressure, and cardiac function. In patients with AMI, low corin levels were associated with adverse cardiac events including death and hospitalization for decompensated heart failure.
TRANSLATIONAL OUTLOOK: Further research should address the implications of serial measurements of plasma corin levels in patients with AMI and compare the prognostic value of this assay with other serum biomarkers, such as troponin I and NT-proBNP.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute myocardial infarction
- atrial natriuretic peptide
- B-type natriuretic peptide
- coronary artery bypass grafting
- estimated glomerular filtration rate
- heart failure
- integrated discrimination improvement
- major adverse cardiac event(s)
- N-terminal pro-B-type natriuretic peptide
- non–ST-segment elevation myocardial infarction
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received December 30, 2015.
- Revision received February 14, 2016.
- Accepted February 16, 2016.
- American College of Cardiology Foundation
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