Plasma C-type Natriuretic Peptide Levels Research Articles

CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation.

The renin-angiotensin-aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.

Is Plasma C-Type Natriuretic Peptide Level Suitable for Diagnosing and Typing Skeletal Dysplasia?

Objective: Skeletal dysplasia is a heterogeneous group of diseases that lead to abnormal enchondral ossification and typing of the disease is quite complex. C-type natriuretic peptide (CNP), one of the members of the natriuretic peptide family, has been implicated in bone development, and CNP levels are high in some types of skeletal dysplasia. The aim of this study was to evaluate the use of CNP as a marker for skeletal dysplasia types and to investigate its role in typing. Methods: Thirty-seven patients aged six months to 18 years [26 (70.3%) girls] were included in this cross-sectional study from among 75 skeletal dysplasia patients. All subjects were physically examined; anthropometric measurements were obtained, and bone surveys were evaluated. ELISA was used to assess CNP plasma levels. Forty-nine healthy children aged six months to 18 years [24 girls (49%)] comprised the control group. Results: The CNP concentration of the patient group (n=37) was 1.31±1.40 ng/mL which was similar to the control group (n=49) at 1.04±1.40 ng/mL (p=0.207). However, the CNP concentration of patients with achondroplasia (n=17) was significantly higher (1.79±1.64 ng/mL) than the control group (p=0.032). Conclusion: Our study contributes evidence concerning CNP values of both healthy children and children with skeletal dysplasia. Compared with healthy children, those with achondroplasia have elevated plasma levels of CNP. Further larger studies are necessary to assess the use CNP as a marker for the diagnosis and typing of skeletal dysplasia.

C-type natriuretic peptide in childhood obesity

According to the World Health Organization obesity is the result of an energy imbalance between calories assumed and expended and over the past 30 years its incidence has dramatically increased. Recently, the problem of obesity has drastically increased also in childhood, assuming a social relevance. Childhood obesity, in fact, increases the possibility to be obese in adulthood, representing a risk for cardiovascular morbidity and mortality. Aim of this review was to carry out a revision of the literature on childhood obesity focusing on natriuretic peptides (NPs) and in particular on the role of C-type natriuretic peptide (CNP). In obesity NPs play a fundamental role in the regulation of body weight and energy metabolism. Data on plasma CNP levels in children are scarce. The review of the literature relating to the role of CNP in adolescents showed a progressive reduction in the CNP plasma levels in overweight/obese adolescents compared to normal-weight subjects, as previously observed in obese adults, as well as a different modulation in CNP mRNA expression. An independent association between CNP levels and obesity as well as a significant association with the endothelial dysfunction index was reported, indicating that the peptide could play a very important role as a marker of risk of developing obesity. The results of these studies indicate the importance of adopting healthy lifestyles to improve glucometabolic control as well as to provide the rationale for designing and developing new drugs to modulate the NPs system.

Prognostic Value of Urinary and Plasma C-Type Natriuretic Peptide in Acute Decompensated Heart Failure

ObjectivesThis study sought to characterize urinary and plasma C-type natriuretic peptide (CNP) in acute decompensated heart failure (ADHF) to define their relationship with clinical variables and to determine whether urinary and plasma CNP together add prognostic value. BackgroundCNP is a protective hormone that is synthesized in the kidney and endothelium and possesses antiremodeling properties. Urinary and plasma CNP levels are elevated in pathophysiological conditions; however, their regulation and prognostic value in heart failure (HF) is unclear. MethodsUrinary and plasma CNP were measured in 109 healthy subjects and 208 patients with ADHF; the 95th percentile of CNP values from healthy subjects established the normal contemporary cutoffs. Patients with ADHF were stratified based on urinary and plasma CNP levels for clinical characterization and the assessment of risk for adverse outcomes. ResultsThere was no significant correlation between urinary and plasma CNP in both cohorts. Urinary and plasma CNP were significantly elevated in patients with ADHF, and both increased with disease severity and were positively correlated with plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP). Of the patients with ADHF, 23% had elevations in both urinary and plasma CNP, whereas 24% had normal CNP levels. During a median follow-up of 3 years, patients with elevated urinary and plasma CNP had a significantly higher risk of rehospitalization and/or death (HR: 1.79; P = 0.03) and rehospitalization (HR: 2.16; P = 0.01) after adjusting for age, sex, left ventricular ejection fraction, renal function, and plasma NT-proBNP. The C-statistic and integrated discrimination analyses further supported that the addition of urinary and plasma CNP to established risk models improved the prediction of adverse outcomes in patients with ADHF. ConclusionsUrinary and plasma CNP are differentially regulated in ADHF, and elevations in both provided independent prognostic value for predicting adverse outcomes.

Prognostic Implications of Urinary and Plasma C-type Natriuretic Peptide in Human Acute Decompensated Heart Failure

Introduction C-type natriuretic peptide (CNP) is a cardiorenal-derived hormone that possesses potent anti-fibrotic, anti-hypertrophic, anti-apoptotic and cardiac unloading properties. While plasma and urinary CNP have been shown to be elevated in heart failure (HF) patients, limited studies have simultaneously characterized and evaluated the clinical utility of plasma and urinary CNP in acute decompensated HF (ADHF). Hypothesis We hypothesize that plasma and urinary CNP are elevated and distinctly regulated in ADHF and elevation of both are a marker of disease severity and will have additional prognostic value for adverse outcomes. Methods ADHF patients (n=208) and healthy subjects (n=109) were prospectively recruited and urinary and plasma CNP, plasma NT-proBNP, eGFR and urinary protein/creatinine were determined. The 95th percentile (%) of CNP values from healthy subjects were used to establish normal cutoffs. ADHF patients were stratified based on whether their CNP levels were considered as elevated (> 95th % of normal) or normal (≤ 95th % of normal). The adverse outcomes were all-cause rehospitalization and/or death over 3.0 (1.0, 4.9) years of follow-up. Results ADHF patients had elevated plasma and urinary CNP levels compared to healthy subjects [plasma CNP: 18.2 (10.7-30.3) vs 11.8 (9.5-15.0) pg/mL; urinary CNP: 43.1 (27.9-74.7) vs 15.8 (12.1-20.2) ng/g Cr; P Conclusions This study is the largest to date to provide novel pathophysiological insights into plasma and urinary CNP. We report for the first time that elevations of both CNP indices are associated with disease severity and have prognostic utility beyond robust clinical risk models in ADHF.

Is C-type natriuretic peptid level can be an early indicator for acute kidney injury?

Acute kidney injury (AKI) is defined as a reduction of renal function in hours, including both structural damage and loss of function. There are limited number of biomarkers for early detection and staging of severity. C-type natriuretic peptide (CNP) has been detected in at several tissues. We aimed to evaluate plasma CNP and creatinine levels correlated with duration of ischemia in an experimentally induced AKI rat model. Forty male Sprague-Dawley type rats (aged 8 to 12 weeks, weighing 250-350 g) were used. The animals were randomly seperated into 4 groups: Group 1(n:10): Only laparotomy was performed. The left renal artery was clamped for 3, 6 and 9 hours in groups 2 ( n:10), 3 (n:10) and 4 (n:10) respectively. CNP and creatinine levels were measured in serum samples from rats. A significant increase in creatinine levels was determined in group 2 according to group 1 (p=0.006). The mean plasma creatinine values in group 3 and 4 were decreased compared to group 2 but this difference was not statistically significant (p=0.0862). The mean CNP level in Group 2 (39.5 ± 7.93 mg/dl) was found numerically higher than group 1 (37.90 ± 5.38mg/dl). There was a statistically insignificant decrease in mean CNP levels in group 3 and 4 compared with group 2. Renal ischemia increases the level of CNP. Although the increase in CNP levels is not significant, it can be said that clinical and experimental studies evaluating the timing of ischemia involving different durations should be performed.

C-type natriuretic peptide plasma levels and whole blood mRNA expression show different trends in adolescents with different degree of endothelial dysfunction

C-type natriuretic peptide (CNP) is an endogenous adipogenesis regulator whose plasma levels in childhood are known, while no data are available on its expression. Our aim was to evaluate both CNP plasma levels and CNP system expression in whole blood obtained from normal-weight (N, n = 24) and obese (O, n = 16) adolescents (age:13.5 ± 0.4 years). Endothelial function was assessed measuring reactive hyperemia index (RHI). CNP plasma levels, evaluated with specific RIA, resulted significantly lower in O than in N (6.1 ± 0.8 vs.15.2 ± 1.3 pg/mL; p < 0.0001), while CNP/NPR-B/NPR-C mRNA, measured by Real-Time PCR, resulted similar in N (4.1 ± 1.7; 5.0 ± 1.6; 2.2 ± 0.9) and in O (4.3 ± 1.6; 3.5 ± 1.1; 2.3 ± 0.8). RHI was significantly lower in O than in N (1.4 ± 0.08 vs.2.1 ± 0.04, p < 0.0001). Dividing all subjects according to the RHI median value, irrespective of the presence or absence of obesity (Group 1 > 1.9, n = 23, Group 2 < 1.9, n = 17), CNP plasma concentrations resulted significantly (p = 0.014) higher in Group 1 (14.6 ± 1.6) than in Group 2 (7.5 ± 1.0), showing a significant correlation with RHI (p = 0.0026), while CNP mRNA expression was, surprisingly, higher in Group 2 (7.0 ± 2.3) than in Group 1 (1.8 ± 0.4; p = 0.02). NPR-B mRNA resulted similar in both Groups (4.3 ± 1.6; 4.7 ± 1.3) and NPR-C significantly higher in Group 2 (p = 0.02). Our data suggest different trends between CNP plasma levels and expression, assessed for the first time in whole blood, that could reflect changes occurring both at CNP transcriptional level in activated leukocytes due to inflammation, and at circulating levels, due to CNP paracrine/autocrine activities. This could represent an interesting area for new therapies able to modulate endothelial dysfunction.

C-type natriuretic peptide plasma levels and mRNA expression in adolescents with of endothelial dysfunction

C-type natriuretic peptide plasma levels and mRNA expression in adolescents with of endothelial dysfunction

C53: A Novel CNP-Based Therapeutic Strategy Targeting Cardiac Fibrosis and Heart Failure

Background: Cardiac fibrosis is a characteristic feature of the failing heart for which there is an unmet need of fibro-inhibiting therapies targeting heart failure (HF). C-type natriuretic peptide (CNP), a human endothelial derived 22 amino acid (AA) peptide, is a guanylyl cyclase B (GC-B) activator that mediates potent anti-fibrotic actions via its second messenger, cGMP. However, the endogenous anti-fibrotic actions of CNP are limited, in part, due to its rapid metabolic clearance by the clearance receptor (NPRC), which has been reported to be up regulated in HF patients. Considering the fibro-suppressing properties of GC-B activation, we engineered a novel 53 AA peptide (C53) based upon the CNP and proCNP sequence with the goal of advancing C53‘s therapeutic potential including reduced NPRC binding. Hypothesis: We hypothesized C53 would have enhanced cGMP generating actions in vivo due to reduced NPRC binding compared to CNP and C53 would activate cGMP in human cardiac fibroblasts (hCFs). Methods: Therapeutic dose of CNP, equimolar dose of C53 and vehicle were IV infused into normal anesthetized rats (n = 12) and in vivo CNP and cGMP levels were assessed. NPRC binding with C53 and CNP were assessed using a modified AlphaScreen luminescent proximity assay (ALPA). In vitro cGMP activating property of C53 (10−8M and 10−6M) compared to no treatment in hCFs was assessed. Data are mean ± SE and significance was achieved with P < .05. Results: In vivo, C53 significantly increased plasma and urinary cGMP compared to equimolar CNP and vehicle (P < .05), which correlated with higher plasma CNP levels with C53 IV infusion (P < .05). Binding studies using the ALPA demonstrated that C53 had reduced binding to NPRC compared to CNP. In hCFs, C53 generated cGMP at 10−8M and markedly activated cGMP at 10−6M compared to no treatment (no treatment: 0.00 ± 0.00; 10−8M: 0.17 ± 0.03; 10−6M: 1.79 ± 0.02, pmol/well, P < .05). Conclusion: We report a newly engineered CNP-based peptide, C53, has cGMP activating actions in hCFs and has superior in vivo cGMP generation than CNP which may, in part, be related to reduced binding to the metabolic clearance receptor NPRC. These studies suggest that C53 may be a novel therapeutic strategy for the prevention and treatment of cardiac fibrosis in HF and further investigations are warranted.

Dynamic response of C-type natriuretic peptide and its aminoterminal propeptide (NTproCNP) to growth hormone treatment in children with short stature.

C-type natriuretic peptide (CNP) and its aminoterminal propeptide (NTproCNP) are potential biomarkers of recombinant human growth hormone (rhGH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTproCNP levels in response to rhGH treatment and to identify the optimal time of sampling after starting rhGH. This was a prospective, observational study. Subjects were treated with rhGH for 1 year, with blood sampled at regular intervals. Eighteen prepubertal children, eight with low levels of GH on biochemical testing and ten with idiopathic short stature, completed the study. Blood levels of CNP, NTproCNP, GH, insulin-like growth factor-I, leptin and bone-specific alkaline phosphatase were measured. Anthropometrics were obtained. Plasma levels of both CNP and NTproCNP reached peak levels 7-28 days after starting rhGH treatment and then declined to intermediate levels through the first year. Plasma NTproCNP levels after 14 days trended towards a correlation with height velocity after 6 and 12 months of treatment. Unexpectedly, serum GH levels measured 2 and 28 days after starting rhGH correlated strongly with height velocity after 6 and 12 months of treatment. This study identified 14 days after starting rhGH treatment as the optimal time for assessing CNP and NTproCNP levels as biomarkers of rhGH efficacy. Additionally, we identified GH levels as a potential biomarker. Larger, prospective studies are now needed to test the clinical utility of these biomarkers.

Total Peripheral Vascular Resistance, Cardiac Output, and Plasma C-Type Natriuretic Peptide Level in Children with Postural Tachycardia Syndrome

To investigate the total peripheral vascular resistance (TPVR), cardiac output (CO), and plasma C-type natriuretic peptide (CNP) levels in children with postural tachycardia syndrome (POTS) during supine, upright, and return to supine. Twenty-nine children with POTS, aged 12 ± 3 years, were recruited, and 32 healthy children, aged 11 ± 2 years, served as controls. Heart rate (HR), blood pressure, TPVR, and CO were continuously monitored with Finapres Medical System, and plasma CNP levels were detected with Sandwich immunoluminescence assay. In children with POTS, upright TPVR and CO were significantly lower than those in supine position, and they rose again when they returned to supine position. However, in healthy control patients, both TPVR and CO did not change during supine, upright, and supine again positions. Also, in the supine position, there was no significant difference in TPVR and CO between POTS children and control subjects (P > .05). When upright, however, TPVR and CO in children with POTS were significantly lower than those of controls. Plasma CNP levels were significantly greater in children with POTS than that of controls (32.8 ± 9.7 vs 24.2 ± 8.4 [pg/mL], P < .01), and symptom scores and ΔHR positively correlated with plasma CNP levels in children with POTS (symptom scores: r = 0.490, P < .01; ΔHR: r = 0.508, P < .001), but CO negatively correlated with plasma CNP levels (r = -0.446, P < .01). Reduced TPVR and CO associated with the elevated plasma CNP might be involved in the pathogenesis of POTS.

Exogenous C-type natriuretic peptide infusion ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis in rats

Although many experimental therapeutic roles for C-type natriuretic peptide (CNP) have been documented in the field of cardiovascular and pulmonary-vascular disease, the therapeutic uses of CNP to nephropathies are not as well documented. In this study, we established a rat model of unilateral ureteral obstruction (UUO) to observe the beneficial effects of CNP on tubulointerstitial fibrosis (TIF). In UUO rats, CNP administration induced a significant increase in plasma CNP levels, and caused a significant decrease in blood urea nitrogen and creatinine levels. In addition, CNP infusion also alleviated the pathological lesions and collagen IV accumulation in the obstructed kidneys through downregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression. In conclusion, exogenous CNP infusion can ameliorate UUO-induced TIF in rats. However, the use of CNP as a therapeutic agent requires further evaluation before being considered for human TIF.

C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia.

C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In a previous report of a child with acromesomelic dysplasia, Maroteaux type (AMDM), caused by loss-of-function of the CNP receptor (natriuretic peptide receptor-B [NPR-B]), plasma levels of CNP were elevated. In vitro studies have shown that activation of the MAPK kinase (MEK)/ERK MAPK pathway causes functional inhibition of NPR-B. Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in overactivation of the MEK/ERK MAPK pathway. The purpose of this study was to determine whether these syndromes exhibit evidence of CNP resistance as reflected by increases in plasma CNP and its amino-terminal propeptide (NTproCNP). This was a prospective, observational study. Participants were 63 children and 20 adults with achondroplasia, 6 children with hypochondroplasia, 2 children with thanatophoric dysplasia, and 4 children and 1 adult with AMDM. Plasma levels of CNP and NTproCNP were higher in children with achondroplasia with CNP SD scores (SDSs) of 1.0 (0.3-1.4) (median [interquartile range]) and NTproCNP SDSs of 1.4 (0.4-1.8; P < .0005). NTproCNP levels correlated with height velocity. Levels were also elevated in adults with achondroplasia (CNP SDSs of 1.5 [0.7-2.1] and NTproCNP SDSs of 0.5 [0.1-1.0], P < .005). In children with hypochondroplasia, CNP SDSs were 1.3 (0.7-1.5) (P = .08) and NTproCNP SDSs were 1.9 (1.8-2.3) (P < .05). In children with AMDM, CNP SDSs were 1.6 (1.4-3.3) and NTproCNP SDSs were 4.2 (2.7-6.2) (P < .01). In these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP.

Dipyridamole-induced C-type natriuretic peptide mRNA overexpression in a minipig model of pacing-induced left ventricular dysfunction

Dipyridamole (DP) restores ischemic tissue blood flow stimulating angiogenesis in eNOS-dependent pathways. C-type natriuretic peptide (CNP) is expected to mimic the migration-stimulatory effect of NO via a cGMP-dependent mechanism. Aim of this study was to assess the role of concomitant treatment with DP on CNP levels in blood and myocardial tissue of minipigs with left ventricular dysfunction (LVD) induced by pacing at 200bpm in the right ventricular apex. Minipigs with DP therapy (DP+, n=4) or placebo (DP−, n=4) and controls (C-SHAM, n=4) underwent 2D-EchoDoppler examination and blood collection before and after 4 weeks of pacing, when cardiac tissue was collected. Histological/immunohistochemical analyses were performed. CNP levels were determined by radioimmunoassay; cardiac CNP, BNP, natriuretic receptors expression by Real-Time PCR. After pacing, cardiac parameters resulted less impaired in DP+ compared to DP−. Histological sections presented normal morphology while the arteriolar density resulted: C-SHAM: 9.0±1.2; DP−: 4.9±0.3; DP+: 6.5±0.6number/mm2; C-SHAM vs DP− and DP+ p=0.004, p=0.04, respectively. CNP mRNA resulted lower in DP− compared to C-SHAM and DP+ as well as NPR-B (p=0.011, DP− vs DP+). Both NPR-A/NPR-C mRNA expressions were significantly (p<0.001) lower both in DP− and DP+ compared to C-SHAM. BNP mRNA was higher in LVD. CNP plasma levels showed a similar trend with respect to gene expression (C-SHAM: 30.5±15; DP−: 18.6±5.5; DP+: 21.2±4.7pg/ml). These data suggest that DP may serve as a preconditioning agent to increase the protective CNP-mediated endocrine response in LVD. This response, mediated by its specific receptor NPR-B, may offer new insights into molecular targets for treatment of LVD.

Diagnostic value of plasma C-type natriuretic peptide levels in determination of the duration of mesenteric ischaemia.

SummaryObjectiveMesenteric arteries release C-type natriuretic peptide (CNP), which hyperpolarises vascular smooth muscle. We measured the levels of this peptide after inducing mesenteric ischaemia over a series of time intervals, so as to determine its predictive value in demonstrating the severity of ischaemia in a rat model.MethodsA total of 32 rats were allocated to four groups containing eight rats each. Basal CNP reference levels were measured in the control group, which was not exposed to any intervention. In groups I, II and III, mesenteric ischaemia was induced over three, six and nine hours, respectively, and plasma CNP levels were measured afterwards. Mesenteric ischaemia was induced by clamping the superior mesenteric artery.ResultsIn comparison with the controls (2.38 ± 0.18 pg/ml), CNP levels were relatively lower in group I (2.54 ± 0.42 pg/ml). However, significant increases in plasma CNP levels were observed over longer periods of ischaemia in group II, at 5.23 ± 0.22 pg/ml, and in group III, at 6.19 ± 0.67 pg/ml (p < 0.05). A significant direct relationship was determined between plasma CNP levels and prolonged intervals of mesenteric ischaemia (R = 0.56, p < 0.001).ConclusionMeasuring plasma CNP levels in patients with acute mesenteric ischaemia may be beneficial in estimating the time period over which the ischaemic injury has occurred.

C-type natriuretic peptide plasma levels are reduced in obese adolescents

The high prevalence of obesity in children may increase the magnitude of lifetime risk of cardiovascular disease (CD). At present, explicit data for recommending biomarkers as routine pre-clinical markers of CD in children are lacking. C-type natriuretic peptide (CNP) is assuming increasing importance in CD; in adults with heart failure, its plasma levels are related to clinical and functional disease severity. We have previously reported five different reference intervals for blood CNP as a function of age in healthy children; however, data on plasma CNP levels in obese children are still lacking. Aim of this study was to assess CNP levels in obese adolescents and verify whether they differ from healthy subjects. Plasma CNP was measured in 29 obese adolescents (age: 11.8±0.4 years; BMI: 29.8±0.82) by radioimmunoassay and compared with the reference values of healthy subjects. BNP was also measured. Both plasma CNP and BNP levels were significantly lower in the obese adolescents compared to the appropriate reference values (CNP: 3.4±0.2 vs 13.6±2.3pg/ml, p<0.0001; BNP: 18.8±2.6 vs 36.9±5.5pg/ml, p=0.003). There was no significant difference between CNP values in males and females. As reported in adults, we observed lower plasma CNP and BNP levels in obese children, suggesting a defective natriuretic peptide system in these patients. An altered regulation of production, clearance and function of natriuretic peptides, already operating in obese adolescents, may possibly contribute to the future development of CD. Thus, the availability of drugs promoting the action of natriuretic peptides may represent an attractive therapeutic option to prevent CD.

Plasma C-type natriuretic peptide levels in healthy children

C-type natriuretic peptide (CNP) is assuming increasing importance in cardiovascular disease, and in adults its plasma levels are related to clinical and functional disease severity. Data are scarce regarding the reference values for CNP in infancy. Aim of this study was to assess the reference intervals for CNP in human healthy newborns and infants. Plasma CNP was measured in 121 healthy children divided into: 41 newborns (age 0–3 days), 24 newborns (4–30 days), 22 infants (1–12 months) and 32 children (1–12 years). A group of 32 healthy adult subjects (age 64±1 years) was also studied. CNP was measured by a specific radioimmunoassay. Between- and within-assay variability resulted ≤30 and 20%, respectively and analytical sensitivity 0.77±0.05pg/tube. Plasma CNP resulted significantly higher in children than in adult subjects (13.6±1.2pg/ml vs. 7.4±1.0pg/ml, p=0.030). When the results were analyzed as a function of the age the reference intervals for plasma CNP resulted: 11.6±2.1pg/ml for newborns (0–3 days), 16.4±3.7pg/ml for newborns (4–30 days), 15.4±2.7pg/ml for infants (1–12 months), 13.6±2.3pg/ml for children (1–12 years) [p=0.01 newborns (4–30 days) vs. adults; p=0.03 infants (1–12 months) vs. adults]. CNP showed the highest concentrations after 12h of life with a peak between 4 and 5 days of life and with a progressive decline afterwards. According to these data at least five different reference intervals for CNP determinations should be used. These observations may be helpful for future clinical application of CNP in human children.

Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging

Renal aging is characterized by structural changes in the kidney including fibrosis, which contributes to the increased risk of kidney and cardiac failure in the elderly. Studies involving healthy kidney donors demonstrated subclinical age-related nephropathy on renal biopsy that was not detected by standard diagnostic tests. Thus there is a high-priority need for novel noninvasive biomarkers to detect the presence of preclinical age-associated renal structural and functional changes. C-type natriuretic peptide (CNP) possesses renoprotective properties and is present in the kidney; however, its modulation during aging remains undefined. We assessed circulating and urinary CNP in a Fischer rat model of experimental aging and also determined renal structural and functional adaptations to the aging process. Histological and electron microscopic analysis demonstrated significant renal fibrosis, glomerular basement membrane thickening, and mesangial matrix expansion with aging. While plasma CNP levels progressively declined with aging, urinary CNP excretion increased, along with the ratio of urinary to plasma CNP, which preceded significant elevations in proteinuria and blood pressure. Also, CNP immunoreactivity was increased in the distal and proximal tubules in both the aging rat and aging human kidneys. Our findings provide evidence that urinary CNP and its ratio to plasma CNP may represent a novel biomarker for early age-mediated renal structural alterations, particularly fibrosis. Thus urinary CNP could potentially aid in identifying subjects with preclinical structural changes before the onset of symptoms and disease, allowing for the initiation of strategies designed to prevent the progression of chronic kidney disease particularly in the aging population.

Bio-Molecular Markers for Cardiovascular Disease: Significance of Natriuretic Peptides and Adrenomedullin

There are many established and proposed bio-molecular markers for cardiovascular disease, including vasoactive substances, substances related to inflammation and oxidative stress, and substances involved in tissue structure and remodeling. Among these substances, we focused on natriuretic peptides and adrenomedullin (AM) as clinically useful bio-molecular markers in this review. Three natriuretic peptides-atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP)-play various important roles in the cardiovascular system. ANP and BNP are released from the heart and exist primarily as circulating hormones. They participate in the regulation of blood pressure and fluid levels. Plasma levels of ANP and BNP are increased in various pathological conditions such as heart failure, myocardial infarction, and hypertension with cardiac hypertrophy. BNP is now essential as a biochemical marker in managing patients with cardiovascular disease. CNP is mainly produced in vascular endothelium. It contributes to smooth muscle relaxation and growth inhibition as a local hormone, but it is also synthesized in cardiac fibroblasts and inhibits fibroblast proliferation and myocyte growth. However, the significance of plasma CNP levels remains to be elucidated. AM is widely distributed in various organs and tissues, including the cardiovascular system. Not only it is a potent vasodilator peptide, but it also has protective effects against vascular and cardiac cell injury and excessive growth. Plasma AM levels are increased in several cardiovascular diseases, including hypertension, heart failure, myocardial infarction, and atherosclerotic disease, and AM appears to be a predictive and prognostic marker in the setting of cardiovascular disease. (Korean Circ J 2008;38:507-513)