Author + information
- Received February 3, 2016
- Revision received March 8, 2016
- Accepted March 10, 2016
- Published online August 1, 2016.
- Xiang Zhou, MD, PhDa,∗ (, )
- Jian-Chang Chen, MD, PhDa,
- Ying Liu, MDb,
- Hui Yang, MDb,
- Kang Du, MDc,
- Yuan Kong, PhDd and
- Xiao-Hua Xu, MDd
- 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.
Objectives The aim of this study was to determine the prognostic value of plasma corin in patients with chronic heart failure (CHF).
Background In recent years, accumulating evidence has indicated that corin plays a critical role in regulating blood pressure and cardiac function.
Methods We enrolled 1,148 consecutive CHF patients in a prospective cohort study and explored the association between plasma corin levels and clinical prognosis using multivariate Cox regression analysis.
Results Patients with low corin levels (<458 pg/ml) were more likely to be women and to be hypertensive. Low corin was found to be associated with an increase in New York Heart Association (NYHA) functional class and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and a decrease in left ventricular ejection fraction (LVEF) and the estimated glomerular filtration rate (eGFR). Multivariate Cox regression analysis suggested that log corin was an independent predictor of major adverse cardiac event(s) (MACE) (hazard ratio: 0.62; 95% confidence interval: 0.39 to 0.95), together with age, diabetes, NYHA functional class, LVEF, eGFR, and log NT-proBNP. In addition, log corin was also a significant predictor for cardiovascular death (p = 0.041) and heart failure rehospitalization (p = 0.015) after adjustment for clinical variables and established biomarkers of adverse prognosis. The Kaplan-Meier survival curves showed that low corin was a significant predictor of MACE in patients with NT-proBNP levels above and below the median.
Conclusions Our study demonstrates that plasma corin is a valuable prognostic marker of MACE in patients with CHF, independent of established conventional risk factors.
Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts natriuretic peptides from inactive precursors to mature active forms (1). Human corin protein contains an N-terminal cytoplasmic tail of 45 amino acids, followed by a single-span transmembrane domain of 21 amino acids. The extracellular region consists of 2 frizzled-like, cysteine-rich domains, 8 low-density lipoprotein receptor repeats, a macrophage scavenger receptor–like domain, and a trypsin-like protease domain (2).
In recent years, there has been growing evidence that corin plays critical roles in the regulation of salt–water balance, blood pressure, and cardiac function. Chan et al. (3) reported that corin knockout mice eventually developed spontaneous hypertension and exhibited cardiac hypertrophy and dysfunction. Gladysheva et al. (4) showed that corin overexpression could attenuate myocardial fibrosis and improve cardiac function in transgenic mice with dilated cardiomyopathy. Pang et al. (5) indicated that corin was down-regulated and exerted cardioprotective action via activating the atrial natriuretic peptide (ANP) pathway in diabetic cardiomyopathy. In African Americans, the corin variant with impaired natriuretic peptide processing activity was correlated with hypertension, cardiac hypertrophy, and adverse outcomes of heart failure (HF) (6–8).
A clinical study conducted by Dong et al. (9) 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. Moreover, Ibebuogu et al. (10) showed that decompensated HF was associated with reduced corin levels and decreased cleavage of pro-ANP. However, until now, it has remained unclear whether low corin is correlated with a poor prognosis in patients with chronic heart failure (CHF). Therefore, we carried out a prospective cohort study to evaluate the prognostic usefulness of plasma corin in CHF patients.
A total of 1,148 consecutive patients with CHF admitted to the affiliated hospitals of Nanjing Medical University were recruited between January 1, 2010 and August 31, 2013. This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Nanjing Medical University. The diagnosis of CHF was on the basis of typical symptoms and signs and evidence of left ventricular enlargement and systolic functional impairment by echocardiography, according to the American College of Cardiology/American Heart Association guidelines (11). All patients had a history of CHF for at least 6 months and were in stable condition on medication for at least 2 weeks before blood sampling. Patients with known malignancy or end-stage renal disease were excluded from the 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 CHF patients and transferred into tubes containing ethylenediaminetetraacetic acid as an anticoagulant agent. Plasma was obtained by centrifugation for 10 min at 3,000 rpm and stored at −80°C. An enzyme-linked immunoabsorbent assay kit (R&D Systems, Minneapolis, Minnesota) was used to measure plasma soluble corin as previously described (9).
The primary composite endpoint was major adverse cardiac event(s) (MACE), which was defined as cardiovascular death and rehospitalization due to worsening HF. The secondary endpoints were the individual components of the primary outcome, including cardiovascular mortality and HF rehospitalization. Endpoints were obtained by reviewing the hospital database and by contacting each patient individually.
Statistical analyses were performed using SPSS version 18.0 (IBM, Armonk, New York). 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. The association between baseline variables and MACE was evaluated using univariable and multivariable Cox proportional hazards analysis. The factors entered into the Cox regression model were age, sex, ischemic etiology, hypertension, diabetes, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), N-terminal pro–B-type natriuretic peptide (NT-proBNP), and corin. Levels of NT-proBNP and corin were normalized by log10 transformation. Kaplan-Meier analysis was conducted to compare the differences in survival rates between patients with high and low levels of corin using the log-rank test. The effect of adding corin to the reference model for the prediction of MACE was evaluated using integrated discrimination improvement (IDI). In this study, a 2-tailed p value <0.05 was considered to be statistically significant.
The baseline characteristics of the study population are shown in Table 1. CHF patients were divided into 2 groups according to the median levels of plasma corin. Patients with low corin levels (<458 pg/ml) were more likely to be women and to be hypertensive, and less likely to be treated with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers. Low corin was found to be associated with an increase in NYHA functional class and NT-proBNP levels and a decrease in LVEF and eGFR. In this study, the median length of follow-up was 569 days (range 64 to 1,932 days). No patient was lost to follow-up.
Primary endpoint: MACE
Survival analysis using the Cox regression model indicated that age, hypertension, diabetes, NYHA functional class, LVEF, eGFR, log NT-proBNP, and log corin were univariate predictors of the primary endpoint of MACE, which was a composite of cardiovascular mortality and HF rehospitalization (Table 2). In addition, multivariate Cox regression analysis revealed that log corin remained a significant predictor of MACE (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.39 to 0.95), together with age (HR: 1.24; 95% CI: 1.08 to 1.52), diabetes (HR: 1.49; 95% CI: 1.06 to 2.18), NYHA functional class (HR: 1.53; 95% CI: 1.22 to 2.05), LVEF (HR: 1.74; 95% CI: 1.38 to 2.47), eGFR (HR: 0.72; 95% CI: 0.51 to 0.96), and log NT-proBNP (HR: 1.81; 95% CI: 1.45 to 2.50) (Table 2). The IDI for MACE was significantly improved by the addition of corin to the reference model (IDI: 0.023; 95% CI: 0.015 to 0.036; p = 0.014). Furthermore, the results of subgroup analysis showed that age, NYHA functional class, LVEF, log NT-proBNP, and log corin were significant predictors of MACE in both male and female CHF patients (Table 3).
Secondary endpoints: Cardiovascular death and HF rehospitalization
Cox regression models were constructed for the secondary endpoints of cardiovascular death and HF rehospitalization (Table 4). Our results revealed that log corin was an independent predictor for cardiovascular mortality (HR: 0.65; 95% CI: 0.45 to 0.96; p = 0.041) and HF rehospitalization (HR: 0.59; 95% CI: 0.38 to 0.91; p = 0.015) after adjustment for age, sex, ischemic etiology, hypertension, diabetes, NYHA functional class, LVEF, eGFR, and log NT-proBNP. Moreover, there was a significant improvement in IDI for cardiovascular death (IDI: 0.019; 95% CI: 0.012 to 0.028; p = 0.036) and HF rehospitalization (IDI: 0.030; 95% CI: 0.021 to 0.045; p < 0.001) after the addition of corin to the reference model.
Kaplan-meier survival analysis
CHF patients were stratified into 4 groups according to the median levels of NT-proBNP (4,360 pg/ml) and corin (458 pg/ml). The Kaplan-Meier survival curves showed that low corin was a useful predictor of MACE in patients with NT-proBNP levels above and below the median (Figure 1). Patients above the median levels of corin had a significantly lower incidence of MACE compared with those below the median.
The present prospective cohort study was designed to assess the prognostic value of plasma corin in patients with CHF using multivariate Cox regression models. Our findings demonstrated that corin could provide independent prognostic information for CHF risk stratification and that it might be a useful biomarker of MACE in CHF patients.
CHF, which is a complex clinical syndrome characterized by decreased myocardial contractility, hemodynamic abnormality, and neuroendocrine activation, carries an approximately 50% 5-year mortality rate in the United States (12). The past decade has witnessed remarkable progress in the treatment of CHF. The clinical applications of ACEI/ARB, beta-blockers, and aldosterone antagonists have significantly reduced cardiovascular events and improved prognosis in CHF patients (13). However, CHF remains a leading cause of morbidity and mortality throughout the world. In recent years, several biological markers have been identified and associated with the progression and prognosis of CHF (14,15), which could facilitate early risk stratification for patients.
Corin, a serine protease involved in the synthesis of mature ANP and BNP, plays critical roles in maintaining salt–water balance, blood pressure, and cardiac function (1). Recently, Peng et al. (16–18) carried out cross-sectional studies in a Chinese population and found that serum soluble corin was possibly associated with obesity, hypertension, and stroke. Dong et al. (9) revealed that plasma corin levels were significantly reduced in HF patients and that corin deficiency might contribute to the pathogenesis of HF. In this cohort study, multivariate Cox regression analysis showed that low corin was an independent predictor for the composite primary endpoint of MACE and the secondary endpoints of cardiovascular death and HF rehospitalization after adjustment for clinical variables and established biomarkers of adverse prognosis. Our findings also indicated that plasma corin levels were markedly reduced in female patients compared with male patients. This may be an important mechanism with regard to the sex difference in the various stages of HF. Specifically, the worsening outcomes observed in female CHF patients may be partly explained by the relative corin deficiency that impairs natriuretic peptide processing. However, the potential mechanisms for this sex dimorphism with respect to plasma corin levels in CHF have yet to be identified. Moreover, in the subgroup analysis, we found that age, NYHA functional class, LVEF, log NT-proBNP, and log corin were significant predictors of MACE in both male and female patients with CHF.
A reduced corin level has been suggested to contribute to a lower rate of active BNP production. However, in this study, our findings revealed the inverse relationship between corin and NT-proBNP. A recent study by Lee et al. (19) identified endoplasmic reticulum stress in the failing myocardium as a possible mechanism of corin deficiency in humans with advanced systolic HF. In addition, the reduced corin levels in CHF may result from the negative feedback of the activated natriuretic peptide system. Therefore, both of these potential mechanisms, increased endoplasmic reticulum stress and the feedback loop of natriuretic peptide system, could reconcile the observation that decreased corin levels are associated with increased NT-proBNP.
In the present study, our findings indicate that low corin levels portend a poor prognosis in patients with CHF. It has been documented that neprilysin is a neutral endopeptidase responsible for degrading natriuretic peptides and vasoactive substances. The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) study suggested that an angiotensin receptor–neprilysin inhibitor was superior to enalapril in reducing the risks of death and HF hospitalization (20), which provides important evidence for adding neprilysin inhibition to standard CHF therapy. Thus, our study supports a potential mechanism to explain the findings of the landmark clinical trial. Corin deficiency is an important intermediate phenotype to define in CHF because these patients may stand to benefit the most from a strategy of inhibiting the neprilysin-dependent breakdown pathway of natriuretic peptide. Moreover, our study calls for the development of pharmacological agents that could restore the capacity of natriuretic peptide conversion in the treatment of CHF.
First, this study was performed in a Chinese population, and the findings should be extrapolated cautiously to other populations with different genetic backgrounds. Second, the observational nature of this study and the presence of unmeasured confounders that may have contributed to the strength of the association should be considered. Third, we did not conduct serial measurements of plasma corin levels after patients were discharged. Last, we did not compare the prognostic value of corin with another useful biomarker, ST-2, in CHF.
Our study demonstrates that plasma corin is an independent prognostic marker of MACE in patients with CHF. The addition of corin to conventional risk factors will substantially improve the risk stratification of MACE in CHF patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Previous studies have indicated that corin plays critical roles in maintaining salt–water balance, blood pressure, and cardiac function. We carried out a prospective cohort study to evaluate the prognostic usefulness of corin in patients with chronic heart failure. Multivariate Cox regression analysis showed that low corin was an independent predictor of major adverse cardiac events, cardiovascular death, and heart failure rehospitalization after adjustment for established conventional risk factors.
TRANSLATIONAL OUTLOOK: The addition of corin to conventional risk factors will substantially improve the risk stratification for major adverse cardiac events in patients with chronic heart failure.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiotensin-converting enzyme inhibitor
- atrial natriuretic peptide
- angiotensin receptor blocker
- brain natriuretic peptide
- chronic heart failure
- confidence interval
- estimated glomerular filtration rate
- heart failure
- hazard ratio
- integrated discrimination improvement
- left ventricular ejection fraction
- major adverse cardiac event(s)
- N-terminal pro–B-type natriuretic peptide
- New York Heart Association
- Received February 3, 2016.
- Revision received March 8, 2016.
- Accepted March 10, 2016.
- American College of Cardiology Foundation
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