Decreased level of serum NT-proCNP associates with disease severity in COVID-19.

BACKGROUND: C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. METHODS: In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). RESULTS: The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. CONCLUSIONS: Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021.

Circulating Concentrations of C-Type Natriuretic Peptides Increase with Sacubitril/Valsartan Treatment in Healthy Young Men.

BACKGROUND: C-type natriuretic peptide (CNP) is a cardioprotective peptide with high affinity for the ectoenzyme neutral endopeptidase (neprilysin). We aimed to determine whether angiotensin receptor-neprilysin inhibitor treatment acutely affects circulating concentrations of bioactive CNP and its molecular amino-terminal precursor (NT-proCNP). METHODS: We included 9 and 10 healthy young men in 2 randomized crossover trials with sacubitril/valsartan vs control (Trial 1) and sacubitril/valsartan and sitagliptin vs sitagliptin (Trial 2). The participants were randomized to a single dose of sacubitril/valsartan (194/206 mg) or control at the first visit 30 min prior to a standardized meal intake. We obtained blood samples at 12 time points over 5 h and measured plasma concentrations of NT-proCNP in both trials and CNP in Trial 2. RESULTS: NT-proCNP concentrations increased 3.5 h after sacubitril/valsartan treatment, and at 4.5 h concentrations were 42% and 65% higher compared with control in Trial 1 and Trial 2, respectively. The total area under the curve (tAUC)15-270 min was 22% higher (P = 0.007) in Trial 1 and 17% higher with treatment (P = 0.017) in Trial 2. Concentrations of bioactive CNP followed a similar temporal pattern with an increase of 93% at 4.5 h and a 31% higher tAUC15-270 min compared with control (P = 0.001) in Trial 2. CONCLUSIONS: Sacubitril/valsartan augments circulating concentrations of both bioactive CNP and NT-proCNP in healthy young men. The increase in bioactive CNP is most likely caused by de novo synthesis and secretion rather than diminished breakdown through neprilysin inhibition.ClinicalTrials.gov registration number NCT03717688.

Elevated N-terminal pro C-type natriuretic peptide is associated with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Unlike N-terminal pro-B-type natriuretic peptide (NT-proBNP), which have been extensively studied, little is known about the role of N-terminal pro-C-type natriuretic peptide (NT-proCNP) for predicting survival post transcatheter aortic valve replacement (TAVR). METHODS: A total of 309 patients were included in the analysis. Patients were grouped into quartiles (Q1-4) according to the baseline NT-proCNP value. Blood for NT-proCNP analysis was obtained prior to TAVR procedure. The primary endpoint was mortality after a median follow-up of 32 months. Multivariable Cox proportional hazards regression models analyzed prognostic factors. The predictive capability was compared between NT-proBNP and NT-proCNP using receiver operator curve (ROC) analysis. RESULTS: A total of 309 subjects with the mean age of 76.8 ± 6.3 years, among whom 58.6% were male, were included in the analysis. A total of 58 (18.8%) patients died during follow-up. Cox multivariable analyses indicated society of thoracic surgeons (STS)-score was a strong independent predictor for mortality (hazard ratio (HR) 1.08, 95% confidential interval (CI) 1.05-1.12, P < 0.001). Elevated NT-proCNP was associated with a higher risk of cardiovascular mortality (HR 1.02, 95% CI 1.00-1.03, P = 0.025) and All-cause mortality (HR 1.01, 95% CI 1.00-1.03, P = 0.027), whereas NT-proBNP showed a small effect size on mortality. ROC analysis indicated that NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with left ventricular ejection fraction (LVEF) < 50% [(Area under the curve (AUC)-values of 0.79 (0.69; 0.87) vs. 0.59 (0.48; 0.69), P = 0.0453]. CONCLUSIONS: NT-proCNP and STS-Score were the independent prognostic factors of mortality among TAVR patients. Furthermore, NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with LVEF < 50%. Trial registration NCT02803294, 16/06/2016.

N-Terminal Pro-C-Type Natriuretic Peptide: The Novel Marker in Selected Disease Units.

Amino-terminal pro-C-type natriuretic peptide (NT-proCNP) is the N-terminal fragment of the CNP precursor. NT-proCNP occurs in an equimolar concentration with CNP in human plasma and is considered to be a marker of the extent of CNP biosynthesis. A recent study has shown associations between plasma NT-proCNP and blood pressure; it is also an independent predictor of death and cardiac readmission in people with unstable angina. Beyond that, recent studies have focused on the applicability of assessing NT-proCNP peptide levels in the diagnosis of diseases with different etiologies but the same denominator, i.e., inflammation. This study reviewed recent results on the usability of NT-proCNP peptide levels in the diagnosis of diseases accompanied by statistical analysis of previously reported results. The data obtained confirmed the applicability of the assessment of NT-proCNP levels in biological fluids in diseases, such as Parkinson's disease, sepsis, meningitis, and asthenozoospermia. The reported results demonstrated that NT-proCNP is helpful in a variety of diseases. Furthermore, changes in serum or CSF levels of NT-proCNP reflect only inflammatory states related to general inflammation. Local inflammation does not trigger an increase in NT-proCNP level.

Higher level of NT-proCNP in cerebrospinal fluid of patients with meningitis.

Aminoterminal pro-C type natriuretic peptide (NT-proCNP) as an active form of CNP, has been recently proven to be a potential marker of sepsis and to be linked to inflammatory diseases. So far, there are no studies describing the level of NT-proCNP in meningitis. The purpose of this study was to evaluate the diagnostic value of NT-proCNP in cerebrospinal fluid (CSF) in patients with meningitis and to compare it with the serum level of CRP and procalcitonin (PCT) in this group of patients. The results were compared to serum levels of CRP, PCT and CSF levels of cytosis, protein and lactate. NT-proCNP levels were statistically significant between the control group and the meningitis groups (p=0.02; R=0.3). We also noted a correlation between the level of NT-proCNP in the CSF of all of the study groups (controls and meningitis patients) and the CSF levels of cytosis (p<0.5; R=0.43), protein (p<0.05; R=0.39) and lactate (p<0.05; R=0.34), and also the serum level of CRP (p<0.05; R=0.30), but not serum PCT (p>0.05; R=0.11). These results suggest that NT-proCNP could be a potential marker of meningitis, but it cannot be used to distinguish between the types of meningitis.

The evaluation of NT-proCNP, C-reactive protein and serum amyloid A protein concentration in patients with multiple myeloma undergoing stem cell transplantation.

The importance of proinflamatory cytokines and acute phase proteins in pathogenesis and progression of MM is well known. However, there are any studies evaluating the role of NT-proCN in management and treatment of MM. The aim of our study was to evaluate the concentration of NT-proCNP and acute phase proteins in patients with MM before and after stem cell transplantation. We involved 40 newly diagnosed MM patients in stage III according to the Durie-Salmon classification and treated with high dose of melphalan (200mg/m2) prior to ASCT. Concentration of NT-proCNP, hs-CRP and SAA were measured before conditioning treatment and every 4days until the 24th day after stem cell infusion. We observed low NT-proCNP levels before conditioning treatment (0.121±0.04pmol/l), the higher in day on ASCT (0.28±0.14pmol/l). Further we showed significant gradual increase concentration of NT-proCNP up to 12days after stem cells infusion (1.07±0.72pmol/l). The kinetics of hs-CRP and SAA levels were similar to NT-proCNP. We showed positive correlation between NT-proCNP levels and absolute neutrophil and platelets count in patients after ASCT. NT-proCNP can be useful parameter to assess effectiveness of treatment and monitoring of hematopoetic recovery time in patients with MM after stem cell transplantations.

Cardiac C-type natriuretic peptide gene expression and plasma concentrations in neonatal piglets.

BACKGROUND: C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family. Cardiac ANP and BNP expressions are firmly established, whereas CNP expression in the mammalian heart remains controversial. In the present report, we used a porcine model of the neonatal period with high expressions of cardiac ANP and BNP in order to elucidate the cardiac CNP expression profile. METHODS: Plasma and cardiac tissue were obtained from newborn piglets during the first 72 h of life. The chamber-specific CNP mRNA contents were quantified by real-time PCR analysis. The proCNP concentrations in plasma and cardiac tissue extracts were quantified by a porcine-specific radioimmunoassay. RESULTS: Cardiac CNP mRNA contents (n=24) were low compared to sites of known expression, where porcine seminal vesicle CNP mRNA contents were 200-fold higher. In addition, plasma proCNP concentrations in the newborn piglets (n=44) were exceedingly low compared to proANP concentrations (5.3 pmol/L (3.2-8.6) vs. 3438 pmol/L (2790-5418), p<0.0001). The proCNP concentrations in atrial tissue extracts were barely detectable (≤0.06 pmol/g) (n=2) compared to ventricular proANP (130 pmol/g (101-159)) and atrial proANP (12,303 pmol/g (10,623-15,412)). CONCLUSION: Our data show that the heart is not a major source of circulating proCNP in neonatal piglets.

Prognostic value of N-terminal pro C-type natriuretic peptide in heart failure patients with preserved and reduced ejection fraction.

AIMS: A-type and B-type natriuretic peptides are established markers in chronic heart failure (HF). C-type natriuretic peptide (CNP) belongs to the same peptide family, but is predominantly localized in the endothelium. The prognostic role of CNP in heart failure has not been established. The aim of the study was to determine the prognostic power and clinical correlates of the N-terminal part of pro CNP (NT-proCNP) in patients with chronic HF. METHODS AND RESULTS: In 567 hospitalized heart failure patients, NT-proCNP levels were measured at hospital discharge. The primary endpoint was a combined endpoint of all-cause mortality and HF hospitalization after 18 months. Heart failure with a preserved ejection fraction (HFpEF) was pre-defined as an LVEF >40%. Mean (±SD) age was 71 ± 11 years, 62% were male, mean LVEF was 32 ± 14%, and 23% had HFpEF. In multivariate linear regression, NT-proCNP levels showed a positive correlation with NT-proBNP levels and parameters of renal function, whereas a negative correlation with female sex and vascular endothelial growth factor was observed. After 18 months follow-up, 240 patients reached the combined endpoint. We observed interaction between NT-proCNP and LVEF for outcome (P = 0.046). Multivariate analyses revealed NT-proCNP to be strongly predictive for the primary endpoint [hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.18-2.67, P = 0.006) in patients with HFpEF, but not in patients with a reduced ejection fraction (HFrEF) (HR 1.07, 95% CI 0.81-1.43, P = 0.616). Finally, reclassification showed significant additive value in patients with HFpEF (P < 0.001), but not in those with HFrEF (P = 0.453). CONCLUSION: NT-proCNP is a strong independent marker for outcome in patients with HFpEF, but not in those with HFrEF.

Alterations of natriuretic peptides amino-terminal pro B-type natriuretic peptide and amino-terminal pro C-type natriuretic peptide during the pregnancy.

OBJECTIVE: The aim of this study was to determine the plasma levels of natriuretic peptides amino-terminal pro B-type natriuretic peptide (NT proBNP) and amino-terminal pro C-type natriuretic peptide (NT proCNP) during pregnancy and any possible changes occurring in each trimester. METHODS: This was a prospective longitudinal case-control study conducted in a University Hospital antenatal outpatient clinic. Subjects were all healthy pregnant women without a history of previous cardiac disease, hypertension or preeclampsia, and each patient was assessed during every trimester, and blood samples were collected for the measurement of NT proBNP and NT proCNP levels. RESULTS: Twenty pregnant women were followed-up during pregnancy without any complications. We obtained longitudinal levels of natriuretic peptides in each trimester. The mean NT proBNP levels were 14.95 ± 16.8, 9.37 ± 10.76, 52.48 ± 126.65 pmol/ml and the mean NT proCNP levels were 44.64 ± 41.64, 45.70 ± 47.03, 47.22 ± 55.09 pmol/l, respectively. No statistically significant alteration of plasma levels of natriuretic peptides was detected between trimesters. CONCLUSION: This is the first study evaluating the longitudinal levels of NT proCNP during the pregnancy, and demonstrates that NT proCNP remained constant, but NT proBNP levels do not significantly alter during pregnancy.