Plasma Corin Research Articles

Plasma Corin: A New Biochemical Marker for Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder. Atrial natriuretic peptide (ANP) is a risk factor for PCOS. Corin protein has an essential role in ANP synthesis. This study aimed to evaluate corin as a sensitive biomarker for PCOS. A case-control study was conducted with 70 PCOS patients and 70 healthy females. Plasma Corin levels were quantified using enzyme-linked immunosorbent assay. The median plasma corin levels in PCOS patients and controls were 1785 and 822.5 pg/mL, respectively. Plasma corin levels were significantly elevated in PCOS patients than in the controls (p < 0.001). The optimal cut-off value was set at 1186 pg/mL. The sensitivity and specificity of Corin were 100% and 97.1%, respectively. Plasma corin levels were surrogate predictors for infertility in women with PCOS. It had an odds ratio of 5.9 (95% confidence interval: 1.1-32.7) (p = 0.04). Plasma corin levels were more highly detected in patients with PCOS than in the controls. Plasma corin level has reasonable diagnostic interpretation for PCOS. Corin appears as a worthy distinct predictor of infertility in PCOS women. Therefore, Corin may be a substantial biomarker for PCOS.

Impact of high intensity interval and moderate continuous training on plasma ratios of ProBNP1-108/BNP1-32 and NT-pro-BNP1-76/BNP1-32 after coronary artery bypass grafting surgery.

Background: ProBNP1-108/BNP1-32, and NT-pro-BNP1-76/BNP1-32 ratios are significant indices for predicting complications after coronary artery bypass grafting (CABG) surgery. However, the effect of aerobic training types on these biomarkers has not been fully understood. So, the current study aimed to determine the impact of aerobic interval and continuous training programs on plasma ratios of ProBNP1-108/BNP1-32 and NT-pro-BNP1-76/BNP1-32 after coronary artery bypass grafting surgery. Method: 36 patients were selected purposive (27 men and 9 women with mean of age 60.32 ± 5.81years, height 164.64 ± 9.25cm, weight 73.86 ± 14.23kg, fat 32.30 ± 4.28, SBP 142.67 ± 6.49, DBP 84.5 ± 5.16mmHg in seated position at rest situation and functional capacity of 7.08 ± 2.49 METs) and then divided randomly into three groups: control (C) group (without training program) moderate continuous training (MCT) and high intensity interval training (HIIT) (exercise training program was performed 3days/week for 8weeks) with intensities 65%-80% and 80%-95% of reserve heart rate in order. Blood samples were taken 48h before the first session and 48h after the last training session to measure the plasma levels of ProBNP1-108, corin enzyme, BNP1-32, and NT-pro-BNP1-76 using the enzyme-linked immunosorbent assay (ELISA) technique. Wilcoxin and kruskal wallis tests were used for analyzing data. Results: The plasma corin enzyme was increased, and the ratios of proBNP1-108/BNP1-32 and NT-pro-BNP1-76/BNP1-32 were reduced in both training groups in compared with control group (p = 0.004, p = 0000, p = 0.016, p = 0.003, p = 0.009, and p = 0.016) when there was no significant difference was found between training groups (p = 0.074, p = 450, and p = 0.295). Conclusion: Both high intensity interval training and moderate continuous training in compared with inactivity have positive effects on ratios of ProBNP1-108/BNP1-32, NT-pro-BNP1-76/BNP1-32 and could be effective to promote the health of coronary arteries and prevention of HF in post-CABG patients.

Increases in plasma corin levels following experimental myocardial infarction reflect the severity of ischemic injury.

Following acute myocardial infarction, clinical studies show alterations in the blood levels of corin, a cardiac-selective activator of the natriuretic peptides pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). However, the temporal changes in circulating and cardiac corin levels and their relationships to the severity of myocardial infarction have not been studied. The main objective of this study was to examine the relationship between cardiac and circulating corin levels and their association with cardiac systolic function and infarct size during the early phase of acute myocardial infarction (<72 h) in a translationally relevant induced coronary ligation mouse model. This acute phase timeline was chosen to correlate with the clinical practice within which blood samples are collected from myocardial infarction patients. Heart and plasma samples were examined at 3, 24, and 72 hours post acute myocardial infarction. Plasma corin levels were examined by enzyme-linked immunosorbent assay, transcripts of cardiac corin, pro-ANP and pro-BNP by quantitative real-time polymerase chain reaction, cardiac corin expression by immunohistology, infarct size by histology and heart function by echocardiography. Plasma corin levels were significantly increased at 3 (P<0.05), 24 (P<0.001), and 72 hours (P<0.01) post-acute myocardial infarction. In contrast, cardiac corin transcript levels dropped by 5% (P>0.05), 69% (P<0.001) and 65% (P<0.001) and immunoreactive cardiac corin protein levels dropped by 30% (P<0.05), 76% (P<0.001) and 75% (P<0.001), while cardiac pro-ANP and pro-BNP transcript levels showed an opposite pattern. Plasma corin levels were negatively correlated with immunoreactive cardiac corin (P<0.01), ejection fraction (P<0.05) and fractional shortening (P<0.05), but positively correlated with infarct size (P<0.01). In conclusion, acute myocardial infarction induces rapid increases in plasma corin and decreases in cardiac corin levels. In the early phase of acute myocardial infarction, plasma corin levels are inversely correlated with heart function and may reflect the severity of myocardial damage.

Aberrant pro-atrial natriuretic peptide/corin/natriuretic peptide receptor signaling is present in maternal vascular endothelium in preeclampsia.

Corin is a serine protease that converts pro-atrial natriuretic peptide (pro-ANP) to atrial natriuretic peptide (ANP), a cardiac hormone that regulates salt-water balance and blood pressure. ANP is degraded by natriuretic peptide receptor (NPR). This study was to determine if aberrant pro-ANP/corin/NPR signaling is present in maternal vascular system in preeclampsia. Maternal venous blood was obtained from 197 pregnant women (84 normotensive, 16 complicated with chronic hypertension (CHT), 11 mild and 86 severe preeclampsia). Plasma corin and pro-ANP concentrations were measured by enzyme-linked immunosorbent assay. Maternal subcutaneous fat tissue was obtained from 12 pregnant women with cesarean section delivery (6 normotensive and 6 preeclampsia). Vascular ANP and its receptors NPR-A, NPR-B, and NPR-C expression were examined by immunostaining of paraffin embedded subcutaneous fat tissue sections. Corin concentrations were significantly higher in mild (2.78 ± 0.67 ng/ml, p < .05) and severe (2.53 ± 0.18 ng/ml, p < .01) preeclampsia than in normotensive (1.58 ± 0.08 ng/ml) and CHT (1.55 ± 0.20 ng/ml) groups. Pro-ANP concentrations were significantly higher in CHT (1.59 ± 0.53 ng/ml, p < .05) and severe preeclampsia (1.42 ± 0.24 ng/ml, p < .01) than in normotensive (0.48 ± 0.06 ng/ml) and mild preeclampsia (0.52 ± 0.09 ng/ml) groups. ANP and NPR-B expression was undetectable in maternal vessels from normotensive and preeclamptic pregnancies, but reduced NPR-A expression and increased NPR-C expression was found in maternal vessel endothelium in preeclampsia. ANP is a vasodilator and NPR-C is a clearance receptor for ANP. The finding of upregulation of NPR-C expression suggests that circulating ANP clearance or degradation is increased in preeclampsia. These results also suggest that pro-ANP/corin/NPR signaling is dominant in the vascular system in preeclampsia.

Abstract P349: Plasma Corin Levels Reflect Dynamic Changes in Cardiac Expression Induced by Experimental Acute Myocardial Infarction

Introduction: Corin is a cardiac membrane protease that activates pro-ANP and pro-BNP. Changes in circulating corin levels have been linked to poor clinical outcomes following acute myocardial infarction (AMI) in some, but not all studies and the pathophysiologic mechanisms responsible for these changes are not understood. Hypothesis: We examined the hypothesis that plasma corin levels are closely correlated with alterations in cardiac corin expression related to acute ischemic injury. Methods: AMI was induced by left anterior descending coronary artery ligation. Hearts and plasma were assessed at 3 hrs, 24 hrs and 3 days post AMI. We measured plasma corin, troponin T levels, cardiac corin, infarct size, ANP and BNP expression by ELISA, qRT-PCR and histology staining. Cardiac function was assessed by echocardiography. Data represent means ± SE of n = 7-9 mice per group. Results: Plasma corin levels were significantly increased at 3 hrs (1090±237.50 pg/ml, P&lt;0.05), 24 hrs (1666±214.50 pg/ml, P&lt;0.001), and 3 days (1221±185.90 pg/ml, P&lt;0.01P&lt;0.01) post-AMI with a “rise-and-fall” pattern similar as troponin T when compared to non-MI group (553.9±96.13 pg/ml). In contrast, at the same time-points, cardiac corin expression dropped by 5% (P&gt;0.05), 69% (P&lt;0.001) and 65% (P&lt;0.001) as measured by real time PCR and 30% (P&lt;0.05), 76% (P&lt;0.001) and 75% (P&lt;0.001) by immunohistology. Transcript levels of pro-ANP increased at 24 hrs (20%) and 3 days (3.8-fold, P&lt;0.001) vs. non-MI mice. Transcript levels of pro-BNP also increased 3.2-fold at 24 hrs (P&lt;0.001) and 1.8-fold at 3 days (P&lt;0.01) post MI. EF% and FS% consistently dropped by 36% (P&lt;0.01), 60% (P&lt;0.001) and 68% (P&lt;0.001) and 42% (P&lt;0.01), 63% (P&lt;0.001) and 72% (P&lt;0.001) respectively. Plasma corin levels were negatively correlated with cardiac corin (P&lt;0.01), EF% and FS% (P&lt;0.05) and positively correlated with infarct sizes (P&lt;0.01). Conclusions: Plasma corin levels markedly increase and then decline following AMI, reflecting dynamic changes of cardiac corin expression related to acute cardiomyocyte injury. As such, plasma corin levels may serve as a valuable marker to indicate the severity of acute myocardial injury and, over a longer term, expression by the remaining viable cardiomyocyte mass.

Plasma Corin as a Predictor of Cardiovascular Events in Patients With Chronic Heart Failure

ObjectivesThe aim of this study was to determine the prognostic value of plasma corin in patients with chronic heart failure (CHF). BackgroundIn recent years, accumulating evidence has indicated that corin plays a critical role in regulating blood pressure and cardiac function. MethodsWe 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. ResultsPatients 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. ConclusionsOur study demonstrates that plasma corin is a valuable prognostic marker of MACE in patients with CHF, independent of established conventional risk factors.

Prognostic Value of Plasma Soluble Corin in Patients With Acute Myocardial Infarction

BackgroundRecent 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. ObjectivesThe goal of this study was to investigate the prognostic value of plasma soluble corin in patients with acute myocardial infarction (AMI). MethodsWe 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. ResultsPatients 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. ConclusionsOur study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors.

Increased plasma corin levels in patients with atrial fibrillation

BackgroundNPPA mutations/polymorphisms were associated with atrial fibrillation (AF), and plasma proatrial natriuretic peptide (proANP) concentrations were increased in AF patients. Corin, as a transmembrane protease that processes proANP in the heart, may play a potential role in AF. MethodsTo test whether corin concentrations are altered in AF patients, we used ELISA to measure corin and N-terminal proANP (NT-proANP) concentrations in plasma samples from control (n=127) and AF patients (n=141), including paroxysmal AF (PAF, n=83) and persistent AF (PeAF, n=58). ResultsIn patients with AF, plasma corin concentrations were 1209±510pg/ml, which were significantly higher than in the controls (973±528pg/ml, P<0.001). The increased plasma corin concentrations were found in both male and female patients. Plasma NT-proANP concentrations in AF patients were 3.1±2.42nmol/l, which were higher than in the controls (1.77±1.04nmol/l, P<0.001). Gender (P=0.003), weight (P=0.016) and PR interval (P=0.028) were independent predictors of plasma corin concentrations in AF patients. A positive correlation was found between corin concentrations and left atrial diameter/PR interval in AF patients. ConclusionHigh plasma corin concentrations in AF patients suggest that corin may play an important role in the pathology of AF.

Circulating corin concentrations are related to infarct size in patients after ST-segment elevation myocardial infarction

Corin, a type II transmembrane serine protease, is expressed almost exclusively by cardiomyocytes [ 1 Yan W. Sheng N. Seto M. Morser J. Wu Q. Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. J. Biol. Chem. 1999; 274: 14926-14935 Crossref PubMed Scopus (220) Google Scholar , 2 Hooper J.D. Scarman A.L. Clarke B.E. Normyle J.F. Antalis T.M. Localization of the mosaic transmembrane serine protease corin to heart myocytes. Eur. J. Biochem. 2000; 267: 6931-6937 Crossref PubMed Scopus (88) Google Scholar ]. It converts the precursor molecules of A- and B-type natriuretic peptides into active proteins [ [3] Knappe S. Wu F. Madlansacay M.R. Wu Q. Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide. J. Biol. Chem. 2004; 279: 34464-34471 Crossref PubMed Scopus (69) Google Scholar ]. Thus, corin plays a key role in the regulation of blood volume, blood pressure and cardiac function. Corin is shed from the myocyte cell surface and enters circulation, a process that might reflect homeostasis within the heart [ [4] Dong N. Chen S. Yang J. et al. Plasma soluble corin in patients with heart failure. Circ. Heart Fail. 2010; 3: 207-211 Crossref PubMed Scopus (123) Google Scholar ]. Recently, plasma corin concentrations were shown to be lower in patients with heart failure compared to healthy controls [ [5] Ibebuogu U.N. Gladysheva I.P. Houng A.K. Reed G.L. Decompensated heart failure is associated with reduced corin levels and decreased cleavage of pro-atrial natriuretic peptide. Circ Heart Fail. 2011; 4: 114-120 Crossref PubMed Scopus (99) Google Scholar ]. Chronic loss of cardiomyocytes as well as reduced corin synthesis and shedding might be responsible for this finding.

95-OR

Objectives Corin, an atrial natriuretic peptide-converting enzyme, has been found to promote trophoblast invasion and spiral artery remodeling. Reduced maternal plasma atrial natriuretic peptide (ANP) levels and elevated corin levels have been reported in pregnancies complicated by PE. The aim of this study was to investigate longitudinal changes in maternal plasma levels of corin and midregional proatrial natriuretic peptide (MR-PANP) in pregnancies that develop preeclampsia (PE) and gestational hypertension (GH). Methods Nested case control study drawn from a larger prospective longitudinal study in singleton pregnancies identified by screening at 11 + 0 − 13 + 6 weeks’ gestation as being at high risk for PE. Blood samples were taken every four weeks until delivery. Values were compared in pregnancies that developed preterm-PE (requiring delivery before 37 weeks), term-PE, GH, and those that remained normotensive. The distribution of maternal plasma corin and PANP were made Gaussian after log 10 transformation. Analysis of repeated measures with multilevel mixed-effects linear model (fixed effects and random effects) was performed. The multilevel model was compared to one-level model by the likelihood radio (LR) test. Results A total of 471 samples were analyzed from 122 women, including 85 that remained normotensive, 12 that developed GH, 13 term-PE and 12 preterm-PE. In the normotensive group, log10corin levels were associated with gestational age ( p p = 0.001). In the GH and term-PE groups, corin did not differ significantly from the normotensive group ( p = 0.64 and p = 0.16, respectively). Compared to the normotensive group, MR-PANP levels were significantly higher in the pregnancies that developed preterm-PE and GH ( p = 0.046 and p = 0.019, respectively), but not term-PE ( p = 0.47). Conclusions Maternal plasma corin and MR-PANP could potentially be useful biomarkers for the prediction of preterm-PE. Disclosures A. Khalil: Research Support Recipient; Commercial Interests: USCOM, Roche, Alere, NICOM, Q-fFN; Speaker: Roche.

A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity.

Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. CORIN variants have been associated with hypertension and heart disease in African Americans. In this study, we conducted targeted exome sequencing and identified an insertion variant, c.102_103insA, in exon 1 of the CORIN gene. Analysis of two independent cohorts showed that the variant was preferentially present in hypertensive patients (38/795 or 4.78% vs. 4/632 or 0.63% in normal individuals, p = 4.14E-6). The insertion shifted the reading frame, resulting in a corin variant with a truncated cytoplasmic tail. In cell-based studies, the corin variant exhibited poor trafficking in the Golgi, reduced cell surface expression and zymogen activation, and low natriuretic peptide processing activity. Compared with normal individuals with the wild-type allele, individuals with the variant allele had lower levels of plasma corin [0.59 ± 0.07 ng/mL (n = 25) vs. 0.91 ± 0.02 ng/mL (n = 215), p<0.001] and higher levels of plasma N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) [2.39 ± 3.6 nmol/L (n = 21) vs. 0.87 ± 0.6 nmol/L (n = 48), p = 0.005]. These results indicate that the variant altered corin structure and impaired the natriuretic peptide processing activity in vivo. The results highlight corin defects as an important underlying mechanism in hypertension.

Plasma corin decreases after coronary artery bypass graft surgery and is associated with postoperative heart failure: a pilot study.

Corin is a natriuretic peptide-converting enzyme that cleaves precursor pro-B-type natriuretic peptide to active B-type natriuretic peptide (BNP) (diuretic, natriuretic, and vasodilatory properties). Increased plasma BNP is a known diagnostic and prognostic heart failure (HF) biomarker in ambulatory and surgical patients. Recent studies indicate that plasma corin is decreased significantly in chronic HF patients, yet perioperative plasma corin concentrations have not been assessed in cardiac surgical patients. The objectives of this study were to determine the effect of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) on plasma corin concentrations and to assess the association between change in perioperative plasma corin concentration and long-term postoperative HF hospitalization or death. It was hypothesized that plasma corin concentrations decrease significantly from preoperative baseline during postoperative days 1 to 4 and that hospitalization or death from HF during the 5 years after surgery is associated with higher relative difference (preoperative baseline to postoperative nadir) in plasma corin concentrations. Prospective observational pilot study. Two institutions: Brigham and Women's Hospital, Boston, Massachusetts and the Texas Heart Institute, St. Luke's Hospital, Houston, Texas. 99 patients of European ancestry who underwent isolated primary CABG surgery with CPB. Nonemergency isolated primary CABG surgery with CPB. Plasma corin concentration was assessed preoperatively and at 4 postoperative time points (postoperative days 1-4). HF hospitalization or HF death events during the 5 years after surgery were identified by review of hospital and death records. Postoperative plasma corin concentrations were significantly lower than preoperative baseline concentrations (p<0.0001). Perioperative corin concentrations were significantly higher in males than in females (p<0.0001). Fifteen patients experienced long-term postoperative HF events. Patients who experienced HF hospitalization or HF death during study follow-up had significantly higher relative difference in plasma corin concentration (preoperative baseline to postoperative nadir) than patients who did not experience HF events during study follow-up (p=0.03). Plasma corin concentrations decrease significantly from preoperative concentrations after CABG surgery. HF hospitalization or HF death during the 5 years after CABG surgery with CPB is associated with larger relative decrease in plasma corin concentration from preoperative baseline. Further investigation is warranted to determine the role of corin in postoperative HF biology.

Heart Failure

See related article, pp 327–332 Atrial and brain natriuretic peptides (ANP and BNP) possess important regulatory cardiorenal functions, such as promoting natriuresis, diuresis, vasodilatation, and activation of antihypertrophic responses on pathophysiological stress. Release of ANP and BNP is significantly increased in response to atrial and ventricular stretch, respectively. Both ANP and BNP are produced and stored as prohormones and are present in the circulation as a mixture of propeptide and active 28- and 32-amino acid, carboxyl-terminal peptide hormones, respectively.1 Both ANP and BNP bind to the natriuretic peptide receptor-A, which is coupled to particulate guanylate cyclase to generate cGMP, the primary second messenger mediating downstream signaling cascades in target tissues. Despite stimulation of the same receptor, the physiological effects of ANP and BNP are somewhat different: ANP predominantly regulates sodium-water homeostasis and blood pressure, whereas BNP has more antihypertrophic effects, although there is substantial overlap.1 In theory, increases in generation of ANP and BNP in response to myocardial stretch should occur as part of compensatory mechanism(s) to restore homeostatic balance. However, the lusitropic, antihypertrophic, and natriuretic effects of ANP and BNP are significantly attenuated in congestive heart failure despite a considerable apparent increase in plasma concentrations. It is now increasingly accepted that the key reason for this discrepancy is because of variable activation/processing of natriuretic peptides, resulting in much greater proportion …

Decompensated Heart Failure Is Associated With Reduced Corin Levels and Decreased Cleavage of Pro–Atrial Natriuretic Peptide

By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides suggests that this compensatory system is limited. Levels of circulating corin (the pro-ANP-converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n=14) had severe heart failure (New York Heart Association class III-IV) with a median ejection fraction of 18% and median brain natriuretic peptide levels of 1940 pg/mL. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal control subjects (180 versus 1368 pg/mL, P<0.01). In contrast, in patients with heart failure, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 versus 7.5 ng/mL, P<0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in patients with heart failure (P<0.01), suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cyclic guanosine monophosphate were elevated in patients with heart failure (150.0 versus 7.6 pmol/mL, P<0.01), and plasma cyclic guanosine monophosphate levels positively correlated with the fractional amount of cleaved pro-ANP (r(s)=0.59, P<0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact. Taken together, these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.

Corin Is Present in the Normal Human Heart, Kidney, and Blood, with Pro–B-Type Natriuretic Peptide Processing in the Circulation

B-type natriuretic peptide (BNP), which is activated in heart failure (HF), is processed to an active form by corin. The corin gene is expressed in the human heart and kidney, but corin protein expression in the heart, kidney, and circulation, along with whether proBNP is processed by circulating corin, remains unknown. We examined corin protein expression by immunostaining and Western blot in human heart and kidney, and we assessed the circulating corin concentration by ELISA. We examined histidine-tagged (His-tag) proBNP(1-108) processing in serum and plasma by immunoprecipitation and Western blot and sequenced the processed form. Normal human heart and kidney displayed the presence of corin, especially in cells around the vasculature. Both corin and proBNP(1-108) were present in the plasma of healthy human subjects, with circulating corin significantly higher in men than women (P < 0.0001) and a positive correlation of corin to age (P = 0.0497, r = 0.27). In fresh normal plasma and serum, His-tag proBNP(1-108) was processed to a lower molecular weight form confirmed to be BNP. Processed BNP was higher in men than women (P = 0.041) and was positively correlated to plasma corin concentrations (P = 0.041, r = 0.65). Our results support the concept that proBNP(1-108) may be processed outside of the heart in the circulation where the proprotein convertase is present. Moreover, sex may impact this process, since corin concentrations are higher in men. These findings may have important physiologic and pathophysiologic implications for the proBNP/corin system in the human.

Effects of anticoagulants on human plasma soluble corin levels measured by ELISA

Background Recently, soluble corin was detected in human plasma. In patients with heart failure, plasma corin levels were lower than that of normal controls. In this study, we analyzed experimental conditions for measuring plasma or serum corin by an immunoassay. Methods Serum and plasma corin levels were measured by ELISA. Effects of different anticoagulants (EDTA, heparin and sodium citrate) on plasma corin levels were examined. Results Corin levels in serum were similar to that in plasma with heparin (950 ± 305 vs. 929 ± 301 pg/ml, n = 40, p = 0.73), but were significantly higher than those in plasma with sodium citrate (735 ± 237 pg/ml, p < 0.01) or EDTA (716 ± 261 pg/ml, p < 0.001). Native and recombinant human corin proteins were stable in human plasma with EDTA at 4 °C or underwent freezing-and-thawing. In 348 healthy Chinese individuals, plasma corin levels ranged from 216 to 1663 pg/ml. The levels were higher in males than that in females (842 ± 283 vs. 569 ± 192 pg/ml, p < 0.001). Conclusion Soluble corin was stable in plasma samples. Plasma soluble corin levels vary depending on anticoagulants used. Samples containing heparin had significantly higher levels of corin than that in samples with EDTA or sodium citrate.

Plasma Corin Levels Provide Minimal Prognostic Utility Incremental to Natriuretic Peptides in Chronic Systolic Heart Failure

Background Corin is a serine protease that cleaves pro-atrial and pro-B-type natriuretic peptides into biologically active hormones. The relationship between soluble plasma corin levels, plasma natriuretic peptide levels, myocardial structure and performance, and long-term clinical outcomes in the setting of chronic systolic heart failure has not been described. Methods and Results In 126 patients with chronic systolic heart failure (left ventricular ejection fraction ≤35%, New York Heart Association functional Class I-IV), we measured plasma corin and natriuretic peptide levels and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse clinical events (all-cause mortality, cardiac transplantation, or heart failure hospitalization) were prospectively tracked for a median of 38 months. Plasma corin levels modestly correlated with echocardiographic indices of cardiac structure, including left ventricular mass index ( r = 0.30, P = .003) and interventricular septum width ( r = 0.22, P = .013). However, plasma corin levels did not correlate with age, arterial pressures, estimated glomerular filtration rate, echocardiographic indices of systolic or diastolic function, or plasma natriuretic peptide levels. In Cox proportional hazards analysis, higher plasma corin levels did not predict reduced risk of adverse clinical events (hazard ratio 0.91; 95% confidence interval 0.67-1.24, P = .52), and did not provide incremental prognostic value to natriuretic peptide levels. Conclusion In our cohort of ambulatory patients with chronic systolic heart failure, soluble plasma corin levels did not provide prognostic utility incremental to that of natriuretic peptides.

Plasma Soluble Corin in Patients With Heart Failure

Corin is a transmembrane protease that processes natriuretic peptides in the heart. Like many membrane proteins, corin is shed from the cell surface. In this study, we obtained plasma samples from healthy controls and patients with heart failure (HF) and acute myocardial infarction. Soluble corin levels in plasma were measured by an ELISA method. In healthy adults (n=198), plasma corin levels were 690 pg/mL (SD, 260 pg/mL). The corin levels did not differ significantly among different age groups. In patients with HF (n=291), plasma corin levels were significantly lower compared with that of healthy controls (365 pg/mL [SD, 259]; P<0.001). The reduction in plasma corin levels seemed to correlate with the severity of HF. In patients of New York Heart Association classes II, III, and IV, plasma corin levels were 450 pg/mL (SD, 281 pg/mL; n=69), 377 pg/mL (SD, 270 pg/mL; n=132), and 282 pg/mL (SD, 194 pg/mL; n=90), respectively (P<0.001 class II vs class IV; P<0.05 class III vs class IV). In contrast, plasma corin levels in patients with acute myocardial infarction (n=73) were similar to that of healthy controls (678 pg/mL [SD, 285 pg/mL]; P>0.05). Soluble corin was detected in human plasma. Plasma corin levels were reduced significantly in patients with HF but not in those with acute myocardial infarction. Our results indicate that corin deficiency may contribute to the pathogenesis of HF and that plasma corin may be used as a biomarker in the diagnosis of HF.

Loss of systemic endothelial function post-PCI

Loss of endothelial function (LEF) post-PCI may contribute to both acute and long-term complications. A protective effect of BNP on endothelium was suggested previously. Flow-mediated vasodilation (FMD) of the brachial artery, as well as plasma levels of endothelin, BNP, Pro BNP and corin were measured before and following routine PCI. 49 patients with normal baseline endothelial function were recruited. 30 patients developed LEF and were randomized to i.v. nesiritide (the commercially available recombinant form of human BNP) or saline infusion for 3 h. Patients who developed LEF post-PCI had reduced baseline plasma corin levels and their BNP/ProBNP ratio was reduced after the procedure. Nesiritide infusion significantly improved FMD both immediately (Nesiritide versus saline: 2.87+/-0.78% versus 0.51+/-0.25%, P=0.007) and 24 h after the treatment (2.52+/-0.69% versus 0.72+/-0.32%, P=0.025). The elevated plasma ET-1 was reduced by Nesiritide (0.38+/-0.11 fmol/ml 24 h post-PCI versus 0.16+/-0.02 fmol/ml 24 h post BNP, P=0.047), but remained unchanged in saline group (0.39+/-0.21 fmol/ml versus 0.42+/-0.23 fmol/ml, P=0.749). Systemic LEF post-PCI is a frequent event. It may be related to impaired cleavage of ProBNP to BNP. Short-term i.v. nesiritide improves systemic LEF post-PCI.