Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

Our aim was to identify the possible mutations of the natriuretic peptide precursor B (NPPB) gene in a family with hereditary hypertension, and determine whether the mutations are associated with the antihypertensive effect of sodium nitroprusside. The subjects included one family with hereditary hypertension, 36 cases of sporadic hypertension and 120 healthy controls. The 5'-flanking sequence of NPPB was amplified with PCR, and the presence of mutations was analyzed by direct sequencing. Patients with hypertension were treated with sodium nitroprusside and blood pressure data and serum B-type natriuretic peptide (BNP) levels were measured. A novel complex mutation in 5'-flanking sequence of the NPPB gene was detected in three patients (II 2, III 2, and III 5) of the hypertension family, which included c.-1195_ -1176 insert 5'-CCTTCTTTCTTTCTTTCTTT-3', c.-1208 T>A, c.-1214 T>C, and c.-1216 T>A. Patients with this mutation were less sensitive to sodium nitroprusside treatment. Sporadic hypertension patients (without NPPB gene mutation) and patients with the c.-1181 T>A point mutation were sensitive to sodium nitroprusside treatment. BNP levels of patients with the complex mutation were significantly lower than that of sporadic hypertension patients and c.-1181 T>A mutation patients before and during the early stage of sodium nitroprusside treatment. The complex mutation of the NPPB gene might be an etiological factor of hereditary malignant hypertension, and it is associated with low sensitivity to the antihypertensive effect of sodium nitroprusside.

Myocardial hypertrophy is a common precursor of many diseases, and it can lead to myocardial ischemia and weaken cardiac contractility. High-sugar diets and diabetes are high risk factors for cardiac hypertrophy. O-GlcNAcylation, a dynamic and ubiquitous post-translational glycosylation of proteins on serine/threonine residues, has been usually considered as a nutrient sensor. Hyperglycemia, hyperlipidemia, and hyperinsulinemia lead to an enhancement of protein O-GlcNAcylation; however, whether excessive O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of proteins in cardiomyocytes causes cardiac hypertrophy remains unclear. In this study, we treated cultured primary cardiomyocytes or mice with streptozotocin (STZ) or PUGNAc, two inhibitors of O-GlcNAcase (OGA) to elevate cellular O-GlcNAcylation. We found that increased O-GlcNAcylation induced hypertrophy-like changes by detecting cardiomyocyte morphology or measuring the thickness of mice left ventricular wall with HE staining. The mRNA levels of cardiac hypertrophy-related genes, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), are increased in drug treatment groups. We further found that the increase of O-GlcNAcylation upregulated the activity of cAMP response element-binding protein (CREB) in cultured primary cells and in vivo by detecting the phosphorylation level of CREB by Western blot and the mRNA levels of CREB downstream targets C-fos and C-jun by RT-qPCR. These results suggest that the increased O-GlcNAcylation in cardiomyocytes is associated with cardiac hypertrophy both in cultured cells and in vivo, which provides possible intervention targets and approaches for the clinical treatment of myocardial hypertrophy triggered by high carbohydrate diets.

Keywords: CREB; Myocardial hypertrophy; O-GlcNAcylation; PUGNAc; Streptozotocin.

A complementary DNA (cDNA) encoding eel atrial natriuretic peptide (ANP) precursor was specifically amplified from eel atrial mRNAs by rapid-amplification polymerase chain reaction. The sequence analysis of the cDNA using multiple clones revealed that the preproANP consists of 140 amino acid residues carrying a signal sequence at its N-terminus and a mature ANP at its C-terminus. An additional glycine residue was attached to the C-terminus of previously isolated eel ANP. The glycine residue may be used for amidation of the C-terminus or removed after processing. The cleavage site of a signal peptide with 22 amino acid residues was confirmed by isolation of proANP protein from eel atria. The proANP sequence deduced from the cDNA was also confirmed for 71% of the isolated protein. Sequence comparison with other natriuretic peptides revealed that eel ANP is more similar to mammalian ANP than to B-type natriuretic peptide (BNP) at both amino acid and nucleotide sequence levels. The eel ANP gene was a single copy gene as shown by Southern blot analysis. Northern blot analysis showed that eel ANP mRNA is approximately 0.8 kb in size and exclusively detected in the atrium. Thus, eel ANP is a true atrial hormone judging from both the sequence and the site of production. However, reverse transcription-polymerase chain reaction detected ANP message in the brain, gill, cardiac ventricle, red body of swim bladder (rete mirabilis), intestine, head kidney (including interrenal and chromaffin tissues) and kidney. Most of these tissues are involved in ion and/or gas exchange in fishes.

The aim of this study was to investigate the correlation between the natriuretic peptide precursor B (NPPB) gene single nucleotide polymorphism (SNP) c.-1298 G/T and pulse pressure (PP) of the Chinese Han population and the association between genotype and clinical indicators of hypertension. Peripheral blood was collected from 180 unrelated patients with hypertension and 540 healthy volunteers (control group), and DNA was extracted to amplify the 5'-flanking region and 2 exons of the NPPB gene by polymerase chain reaction; the fragment was sequenced after purification. The clinical data of all subjects were recorded, the distribution of the NPPB gene c.-1298 G/T polymorphism was determined, and differences in clinical indicators between the two groups were evaluated. The mean arterial pressure PP, and creatinine levels were significantly higher in the hypertension group than in the control group (P<0.05), but no other clinical indicators differed between the groups. There were no significant differences in genotype frequency and distribution of the NPPB gene c.-1298 G/T polymorphism between the hypertension group and the control group (P>0.05); in the control group, the mean PP of individuals with the SNP c.-1298 GG genotype was greater than that of individuals with the GT+TT genotype (P<0.05). In conclusion, there was no significant correlation between the NPPB gene c.-1298 G/T polymorphism and the incidence of essential hypertension in the Han population; however, the PP of the SNP c.-1298 GG genotype was greater than that of the GT+TT genotype in the control group.

Dolphins are aquatic animals free from gravity, and this may have imposed significant changes in their cardiovascular status and its hormonal regulation compared with terrestrial animals. This study molecularly characterized two major cardiovascular hormones, atrial and B-type natriuretic peptides (ANP and BNP) and measured their changes in dolphin plasma concentrations in relation to the cardiovascular status of the animal. We initially identified ANP and BNP in three species of dolphins (Lagenorhynchus obliquidens, Phocoenoides dalli and Tursiops truncatus). ANP precursors are highly conserved in most mammals, but dolphin BNP precursors were more variable. In molecular phylogenetic analyses, dolphin ANP and BNP precursors grouped with those of artiodactyls, particularly to the camel peptides. The chromatographic characterization of tissue and plasma molecular forms using specific radioimmunoassays showed that the predominant ANP and BNP in the atrium are prohormone and mature peptide, respectively, whereas mature ANP and BNP are circulating in the dolphin blood. A mass spectrometric analysis showed that atrial BNP consists of 26 amino acids, rather than the 32-amino-acid form detected in other mammals. Finally, changes in plasma ANP and BNP concentrations were examined in captive bottlenose dolphins (Tursiops truncatus) after their pool was drained. Plasma ANP and BNP concentrations did not change after landing, unlike terrestrial mammals. Plasma angiotensin II and cortisol concentrations did not change either, showing minor stress after landing. Since landed dolphins show a different cardiovascular status on land than terrestrial mammals, plasma ANP and BNP concentrations seem to reflect the cardiovascular status characteristic of dolphins.

Diverse sensory neurons exhibit distinct neuronal morphologies with a variety of axon terminal arborizations subserving their functions. Due to its clinical significance, the molecular and cellular mechanisms of itch are being intensely studied. However, a complete analysis of itch-sensing terminal arborization is missing. Using a MrgprC11^CreERT2 transgenic mouse line, we labeled a small subset of itch-sensing neurons that express multiple itch-related molecules including MrgprA3, MrgprC11, histamine receptor H1, IL-31 receptor, 5-HT receptor 1F, natriuretic precursor peptide B, and neuromedin B. By combining sparse genetic labeling and whole-mount PLAP histochemistry, we found that itch-sensing skin arbors exhibit free endings with extensive axonal branching in the superficial epidermis and large receptive fields. These results revealed the unique morphological characteristics of itch-sensing neurons and provide intriguing insights into the basic mechanisms of itch transmission.

Background: C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models.

Methods: Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.

Results: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.

Conclusion: In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Keywords: bone diseases; endocrine; gene expression regulation; genomics; human genetics; molecular medicine.

Objective: To explore the impact of weight management and related medication intervention based on body weight changes on cardiac function among patients with chronic congestive heart failure (CHF). Methods: Using prospective, randomized, controlled study methods, consecutive CHF patients, who hospitalized in our department from June 2014 to June 2016 (n=350), were randomly divided into intervention group (n=175) and control group (n=175). Patients in the intervention group received weight management guidance and the post discharge diuretic drugs regimen was adjusted based on body weight changes. The control group received routine medical care post discharge. Left ventricular ejection fraction (LVEF), B type natriuretic peptide precursor (NT-proBNP), 6 minutes walk distance and NYHA classification at one day before discharge and after 6 months were compared between the two groups respectively. Results: Follow-up visit data were not available from 6 patients in the control and intervention group respectively. NYHA classification, LVEF, NT-proBNP and 6 minutes walk distance were similar between the two groups at one day before discharge (all P>0.05). After 6 months, the LVEF and 6 minutes walk distance were significantly higher while NT-proBNP level was significantly lower in the intervention group compared to the control group (all P<0.01). Meanwhile, the LVEF and 6 minutes walk distance were significantly increased, while NT-proBNP was significantly reduced at 6 months post discharge compared to one day before discharge in the intervention group (all P<0.01). The LVEF was also significantly improved (P=0.035), but the NT-proBNP and 6 minutes walk distance were similar (P were 0.328 and 0.807 respectively) at 6 months after discharge compared to one day before discharge in the control group. The NYHA classification was significantly lower in intervention group and in control group at 6 months after discharge compared to one day before discharge (Z=5.154, P<0.01 and Z=10.497, P<0.01), and the NYHA classification improved more in the intervention group than in control group at 6 months after discharge (Z=9.235, P<0.01). The re-hospitalization rate of CHF patients in intervention group was 11.83% (20/169), which was significantly lower than the control group (33.14% (56/169), χ(2)=21.99, P<0.01). At 6 months follow up, body weight remained unchanged in the intervention group, while body weight tended to be higher in the control group compared to one day before discharge. Conclusion: The weight management and diuretic drug regimen adjudgment intervention based on body weight changes can improve cardiac function and reduced re-hospitalization rate in CHF patients.

The study objectives were to determine the circulating levels of proBNP1-108, the precursor of B-type natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP), in patients with systolic heart failure (HF) and to assess their prognosis value for cardiovascular (CV) death over a long-term follow-up. Seventy-three patients with systolic HF and 68 healthy volunteers were included. ProBNP1-108, BNP and NT-proBNP levels were measured with automated immunoassays and their predictive value for long-term survival was assessed through an 8 years follow-up. ProBNP1-108 levels were markedly increased in patients with systolic HF in comparison to healthy volunteers. In univariate proportional hazard model, survival was related to proBNP1-108, BNP, NT-proBNP, age, EF and glomerular filtration rate (eGFR). Kaplan-Meier survival curves according to proBNP tertiles diverged significantly, and the highest proBNP levels were related to patients with the highest risk of CV death. In a multivariate analysis including age, EF, proBNP1-108, BNP, NT-proBNP, and eGFR levels, NT-proBNP was the strongest predictor of long term CV death. Our study therefore demonstrated that high levels of proBNP1-108, measured with an assay with enhanced analytical specificity, are related to the long-term risk of cardiovascular death in systolic heart failure.

B-type natriuretic peptide (BNP) is a circulating biomarker that is mainly applied in heart failure (HF) diagnosis and to monitor disease progression. Because some identical amino acid sequences occur in the precursor and metabolites of BNP, undesirable cross-reactions are common in immunoassays. This review first summarizes current analytical methods, such as immunoassay- and mass spectrometry (MS)-based approaches, including the accuracy of measurement and the inconsistency of the results. Second, the review presents some promising approaches to resolve the current barriers in clinical BNP measurement, such as how to decrease cross-reactions and increase the measurement consistency. Specific approaches include research on novel BNP assays with higher-specificity chemical antibodies, the development of International System of Units (SI)-traceable reference materials, and the development of structure characterization methods based on state-of-the-art ambient and ion mobility MS technologies. The factors that could affect MS analysis are also discussed, such as biological sample cleanup and peptide ionization efficiency. The purpose of this review is to explore and identify the main problems in BNP clinical measurement and to present three types of approaches to resolve these problems, namely, materials, methods and instruments. Although novel approaches are proposed here, in practice, it is worth noting that the BNP-related peptides including unprocessed proBNP were all measured in clinical BNP assays. Therefore, approaches that aimed to measure a specific BNP or proBNP might be an effective way for the standardization of a particular BNP form measurement, instead of the standardization of "total" immunoreactive BNP assays in clinical at present.

Background: The high molecular complexity of variably O-glycosylated and degraded pro B-type natriuretic peptide (proBNP) derived molecular forms challenges current immunoassays. Antibodies used show pronounced differences in cross-reactivities with these circulating fragments, which still need to be better characterized on a molecular level. To pave the way for advanced quantitative assays in the future, it is critical to fully understand these circulating forms.

Methods: Plasma samples were collected from 8 heart failure (HF) patients and 2 healthy controls. NT-proBNP and proBNP were purified by immunoprecipitation and analyzed by nano-flow liquid chromatography coupled to high-resolution mass spectrometry. Fragments formed during proteolysis in solution digestion were distinguished from naturally occurring peptides by using an 18O stable isotope labeling strategy.

Results: We detected 16 previously unknown circulating fragments of proBNP peptides (9 of which are located in the N-terminal and 7 in the C-terminal region), revealing a more advanced state of degradation than previously known. Two of these fragments are indicative of either unidentified processing modes or a far-reaching C-terminal degradation (or a combination thereof) of the precursor proBNP.

Conclusions: Our results further restrict ideal target epitopes for immunoassay antibodies and expand the current thinking of diversity, degradation, and processing of proBNP, as well as the distribution of circulating forms.

Keywords: NT-proBNP; heart failure; immunoaffinity-mass spectrometry; peptide fragments; pro B-type natriuretic peptide.

Ventricular cardiomyocytes secrete brain natriuretuc peptide (BNP) and an inactive moiety of its precursor (nt-proBNP). It is recommended the blood level of the latter should be monitored to ascertain the severity of myocardial lesion. This investigation was undertaken to study the diagnostic and prognostic value of a substantial increase in blood nt-proBNP levels (600 pg/ml or more) in patients operated on under extracorporeal circulation. Thirty-eight patients operated on for coronary heart disease were examined. Before surgery, the plasma concentration of nt-proBNP had been determined by electrochemiluminescence (Elescys, Roche). According to plasma nt-proBNP levels, the patients were divided into 2 groups: 1) 24 patients with nt-proBNP levels of less than 600 pg/ml; 2) 14 patients with its levels of 600 pg/ml or more. Group 1 patients showed signs of diastolic dysfunction of the right ventricle: the lower ratio of its early to atrial filling linear velocity integrals and the increased end-diastolic volume index. In the postperfusion period, nt-proBNP is a significant independent predictor of left ventricular function. The patients with the baseline nt-proBNP levels of above 600 pg/ml were found to have decreases in ejection fraction of the left ventricle and in its pump ratio along with elevated pulmonary wedge pressure.

Objective: This study was designed to explore the clinical significance of changes in troponin T (cTnT), C-reactive protein (CRP) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with heart failure (HF).

Methods: A total of 193 patients with HF admitted to our hospital from October 2013 to June 2019 were enrolled as the study subjects (group A). Another 191 healthy controls were included as group B. Both groups were compared in terms of cTnT, CRP, NT-proBNP levels and left ventricular ejection fraction (LVEF), and the correlations between LVEF and cTnT, CRP, NT-proBNP were analyzed. The differences in cTnT, CRP, NT-proBNP were compared among patients with different cardiac function, different causes of HF, and between patients with and without cardiac events.

Results: cTnT, CRP, and NT-proBNP levels in group A were higher than those in group B (P<0.05). LVEF in group A was lower than that in group B (P<0.05). Negative correlations were found between CRP, cTnT, NT-proBNP and LVEF (P<0.05). As cardiac function improved, cTnT, CRP, NT-proBNP levels also increased, with significant differences between groups (P<0.05). cTnT, CRP, and NT-proBNP levels exhibited no significant difference between the ischemic and non-ischemic HF groups (P>0.05). Patients with cardiac events showed higher levels of cTnT, CRP, and NT-proBNP than those without cardiac events (P<0.05).

Conclusion: cTnT, CRP and NT-proBNP levels were elevated in patients with HF, which were negatively correlated with LVEF, and their levels increased with the improvement of cardiac function, independent of the cause of HF. The combination of these three indices is of great significance in the diagnosis and prognosis of HF.

Keywords: C-reactive protein; Heart failure; amino-terminal brain natriuretic peptide precursor; clinical significance; troponin T.

B-type (or brain) natriuretic peptide (BNP) is synthesized in cardiac myocytes and released constitutively into the circulation. Pressure/volume overload, neurohumoral factors, cytokines, and ischemia enhance BNP gene expression, and then precursor proBNP is produced. It has been thought that proBNP is cleaved into active BNP molecule and inactive marker molecule NT-proBNP intracellularly by processing enzyme furin, and they are released into the circulation. However, recent studies have shown that considerable amount of uncleaved proBNP circulates in the blood. The commercially available BNP assay kits consist of two antibodies that sandwich the BNP molecule. Therefore, if proBNP is present, BNP assay kit cross-reacts to proBNP and measures it as BNP. Therefore, it should be noted that the current BNP value is proBNP plus BNP. BNP and NT-proBNP have been established as a biomarker for heart failure patients presenting dyspnea. But many pitfalls are present for interpreting the BNP value. For example, the presence of renal dysfunction, age, female sex, atrial fibrillation, inflammation, hyperthyroidism, use of sacubitril/valsartan, and macro-proBNPemia overestimate BNP value, whereas the presence of obesity, immediately after acute coronary syndrome onset, and pericardial effusion underestimate BNP value. In the management for heart failure patients, BNP plays an important role. Therefore, clinicians should note the pitfall of interpretation of BNP and we describe the mechanism involved.

Keywords: B-type (or brain) natriuretic peptide; Heart failure; N-terminal proBNP; Neprilysin.

Objective: To explore the changes in miR-221 and miR-222 before and after interventional therapy of coronary heart disease and their relationship with inflammatory factors and prognosis.

Methods: A total of 122 subjects with coronary heart disease who underwent interventional therapy in our hospital from January 2017 to January 2019 were chosen as the observation group, and 122 healthy people during the same period were chosen as the control group. We retrospectively analyzed the levels of serum miR-221, miR-222, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Pearson correlation analysis was used to reveal the relationship between serum levels of miR-221, miR-222 and CRP, TNF-α and IL-6, N-terminal B-type brain natriuretic peptide precursor (NT-proBNP) and left ventricular ejection fraction (LVEF%) in the observation group. The levels of serum miR-221, miR-222, TNF-α, CRP and IL-6 before and after treatment were compared in the observation group. After a follow-up of 6 months, the observation group was divided into a poor-prognosis group (26 cases) and a good-prognosis group (96 cases) according to whether there was an adverse cardiovascular event or not. The levels of serum miR-221 and miR-222 before and after intervention treatment were compared between the two groups. And the clinical values of miR-221 and miR-222 levels before and after intervention treatment in the observation group were analyzed by the ROC curve.

Results: The levels of serum miR-221, miR-222, CRP, TNF-α, and IL-6 in the observation group were markedly higher than those of the control group. And levels of serum miR-221, miR-222 were negatively correlated with LVEF% while positively correlated with CRP, TNF-α, IL-6 and NT-proBNP (P<0.05). After treatment, the levels of miR-221, miR-222, CRP, TNF-α, and IL-6 in the observation group were significantly reduced (all P<0.05). Compared with the good prognosis group, the levels of miR-221 and miR-222 before and after treatment were markedly higher in the poor prognosis group (all P<0.05). Both before and after treatment, the levels of miR-221 and miR-222 have certain clinical value in evaluating the prognosis (all AUC>0.800).

Conclusion: The levels of miR-221 and miR-222 in patients with coronary heart disease significantly increased and they were closely correlated with the inflammatory factors, NT-proBNP and LVEF%. The levels of miR-221 and miR-222 before and after treatment have certain clinical value in evaluating the prognosis of patients.

Keywords: coronary heart disease; inflammatory factors; intervention; miR-221; miR-222.

The study was aimed at evaluating the influence of selected polymorphisms of natriuretic peptide B precursor (NPPB) and natriuretic peptide receptor C (NPR3) genes on blood lead concentration (Pb-B) and blood zinc protoporphyrin concentration (ZnPP) in persons occupationally exposed to lead. Investigations were conducted on 360 persons (mean age: 44.49±9.62years), workers exposed to lead compounds. The analysis examined four polymorphisms of BNP gene, i.e.,: rs198388, rs198389, rs632793, and rs6676300; as well as one polymorphism of receptor C for natriuretic peptides, i.e., rs1421811. Heterozygosity in locus rs632793 of NPPB gene may result in higher concentrations of Pb-B, while allele A in locus rs632793 of NPPB gene seems to determine higher concentrations of ZnPP in persons occupationally exposed to lead. Workers exposed to lead and carrying allele C in locus rs198388 of NPPB gene, particularly in the heterozygotic setup, seem to be predisposed to present higher concentrations of ZnPP. Carriership of A allele in locus rs198389 of NPPB gene probably determines higher concentrations of ZnPP in study group. In summary, among persons occupationally exposed to lead, certain relationships were demonstrated between rs632793, rs198388 and rs198389 polymorphisms of NPPB gene and principal toxicological parameters characterizing exposure to lead.

Background: This study aimed to compare the echocardiographic changes and cardiac biomarkers between women with singleton and twin pregnancies.

Methods: From April 2014 to March 2016, this longitudinal cohort study invited pregnant women who were scheduled to give birth at Hokkaido University Hospital. We analyzed prospectively collected data on simultaneously determined echocardiographic parameters and blood cardiac markers of 44 women with singleton and 22 women with twin pregnancies. Furthermore, we tested the mixed-effect models for echocardiographic parameters and cardiac biomarkers.

Results: During the third trimester and immediately postpartum (within 1 week after childbirth), the mean left atrial volume index and brain natriuretic peptide (BNP) level were significantly higher in women with twin pregnancies than in those with singleton pregnancies. Women with twin pregnancies also had significantly smaller second-trimester inferior vena cava diameters and significantly higher third^-trimester creatinine levels than those with singleton pregnancies. BNP positively correlated with the left atrial volume index (β = 0.49, p < 0.01) and the ratio of early diastolic transmitral to mitral annular velocity (E/e') (β = 0.41, p < 0.01). At 1 month after childbirth in women with singleton pregnancies, BNP and N-terminal precursor protein BNP (NT-proBNP) fragments immediately postpartum negatively correlated with the later E/e' (r = - 0.33, p = 0.02 and r = - 0.36, p < 0.01, respectively).

Conclusions: The intravascular cardiac load reached maximum within 1 week after childbirth and was greater in women with twin pregnancies than in those with singleton pregnancies. BNP/NT-proBNP significantly positively correlated with LA volume index and E/e'. In women with singleton pregnancies, BNP secreted immediately after childbirth might improve the diastolic functions 1 month after childbirth.

Keywords: Brain natriuretic peptide; Diastolic function; Echocardiography; Troponin.

BACKGROUND

The natriuretic peptides play a key role in the modulation of left ventricular mass (LVM) and blood pressure (BP). We hypothesised that NPPA (natriuretic peptide precursor A gene), NPPB (natriuretic peptide precursor B gene), and NPPC (natriuretic peptide precursor C gene) are candidate genes possibly involved in the development or modulation of LVM at early life.

OBJECTIVE

To assess the relationship between NPPA, NPPB, and NPPC gene polymorphisms with LVM and BP in newborns.

METHODS

A total of 206 healthy newborns were studied by two-dimensional M-mode echocardiography. The polymorphisms NPPA rs5065, NPPB rs198389, and NPPC rs5268 were characterised.

RESULTS

Newborns carrying the C allele of the NPPB polymorphism had significantly lower LVM/body surface area (BSA) and LVM/body weight (BW) values when compared with newborns' homozygotes for the T allele (41.76 g/m2 vs. 48.31 g/m2, p adjusted = 0.044 and 2.78 g/kg vs. 3.26 g/kg, p adjusted = 0.031, respectively). An association was observed between NPPA genotype and systolic BP, diastolic BP, and mean arterial pressure ≥ 90th percentile (p = 0.029, p = 0.0048, p = 0.004, respectively). Also an association was observed for systolic BP ≥ 90th percentile for NPPB (p = 0.016).

CONCLUSIONS

The present study shows that the NPPB gene polymorphism is associated with modulation of LVM in newborns. The NPPA and NPPB gene polymorphisms are associated with BP.

Background Cardiac ischemia induces myocardial dysfunction and ventricular wall stretch, which causes the release of B-type natriuretic peptide (BNP) into the bloodstream. However, it is unclear whether inducible ischemia produces a significant change in BNP levels ("stress delta-BNP"). The objective of this study was to determine the utility of stress-delta BNP levels and its precursor NT-proBNP for detecting inducible myocardial ischemia during cardiac stress testing. Methods We conducted a systematic review and meta-analysis. We searched PubMed, EMBASE, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Ovid. Studies examining the changes in levels of BNP and its precursor, N-terminal pro-B-type natriuretic peptide (NT-proBNP), after an exercise cardiac stress test were included. Two reviewers independently analyzed titles and abstracts. Abstracts that did not provide enough information regarding eligibility criteria were kept for full-text evaluation. The same two reviewers also performed data extraction for analyses. Any disagreement was resolved by a consensus and, if it persisted, by a third reviewer adjudication. We report the median and mean values in studies in the order of sample size. Results A total of 15 studies met the inclusion criteria. Nine studies reported results in medians and six studies reported results in means. Of the nine studies, five assessed BNP alone, three assessed NT-proBNP, and one assessed both. Due to the non-normal distribution of results in these studies, they could not be meta-analyzed. Of the six studies that reported results in means, three assessed BNP and three assessed NT-proBNP. The standardized difference between normal and ischemic patients' stress-delta BNP values was -0.39 (95% confidence interval (CI): -0.61; -0.17) in a fixed-effects model and -0.73 (95% CI: -1.72; 0.28) in the random-effects model with high heterogeneity (I^2 = 94%, Q test P = 0.001). For NT-proBNP, the meta-analysis model showed no significant difference between the stress-delta test for ischemic and normal patients (standardized mean difference (SMD): -0.02, 95% CI: -0.31; 0.28). Patients without inducible ischemia appeared to have a lower baseline BNP and NT-proBNP compared to patients with inducible ischemia by stress testing. Although some studies report higher stress-delta BNP in the ischemic group, this pattern was not seen consistently across studies. There was high heterogeneity across studies which was not robust to sensitivity analysis. A random-effects model failed to find statistically significant differences in stress-delta BNP or NT-proBNP. Conclusions We failed to find a relationship between stress-delta BNP or NT-proBNP and the presence or absence of ischemia. This may be due to high heterogeneity in the underlying studies.

Brain Natriuretic Peptide (BNP) injections in adult "healthy" or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1+ cell proliferation. The Sca-1+ cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1+ cells expressing Nkx2.5, in Sca-1+ cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1+ cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1+ cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1+ cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated.

Itch stimuli are detected by specialized primary afferents, which convey the signal to the spinal cord, but how itch transmission is regulated is still incompletely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y2 receptor system on scratch behavior. The inhibitory Y2 receptor is expressed on mouse primary afferents and intrathecal administration of the Y2 agonist peptide YY (PYY)3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal pre-administration of the Y2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by α-methyl-5HT, SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to co-express itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT: The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y2 receptor. The Y2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b and interlekin 31 receptors.

Over the past 5 years, researchers have examined the utility of many experimental heart failure biomarkers that are not yet widely adopted clinically, to complement the role of B-type natriuretic peptide and its precursor. Candidate biomarkers have been identified from several different pathophysiologic categories, including markers of inflammation, myocyte necrosis, renal dysfunction, neurohumoral activation, oxidative stress and raised intracardiac pressure. Indeed, some biomarkers provide prognostic information that is independent of information obtained from conventional clinical and biomarker assessment. Moreover, some biomarkers studied help to identify dominant pathology that may predict responsiveness to specific therapies. Preliminary data also suggest a potential role for the development of comprehensive biomarker profiling models, integrating biomarkers from several categories to refine risk assessment.

<AbstractText>Analyze the parameters of the interaction between the left ventricle and the arterial system in patients with chronic forms of coronary heart disease and to identify relationships with levels of proadrenomedullin (MR‑proADM) and N‑terminal <em>precursor</em> of the brain <em>natriuretic</em> <em>peptide</em> <em>B</em> (NT‑pro<em>B</em>NP).</AbstractText><AbstractText>240 patients with chronic forms of coronary heart disease (median - 55,9 [43; 63] years) and Q‑forming myocardial infarction in the past were examined. Of these, 110 patients with myocardial infarction and preserved lef ventricular ejection fraction and 130 patients with ischemic cardiomyopathy. All patients were calculated parameters of lef ventricular‑arterial interaction and the determination in blood serum levels of MR‑proADM and NT‑pro<em>B</em>NP.</AbstractText><AbstractText>In patients with ischemic cardiomyopathy, an increase in the lef ventricular‑arterial interaction index was detected (2,51 [1,18; 5,00]), which reflects a decrease in the functional abilities and efficiency of the heart. In patients with myocardial infarction and a preserved left ventricular ejection fraction, this indicator was in the range of normal values (0,78 [0,55; 1,07]), which indicates an effective cardiac work. A study of MR‑proADM and NT‑pro<em>B</em>NP levels demonstrated an increase in both groups (1,72 [1,56; 1,98] nmol/l and 779,3 [473; 2193] pg/ml in the group of patients with ischemic cardiomyopathy; 0,89 [0,51; 1,35] nmol/l and 246 [118; 430] pg/ml in the group of patients with myocardial infarction and preserved left ventricular ejection fraction), and the correlation analysis with left ventricular‑arterial coupling interaction parameters allowed identify statistically significant connections (in the group of patients with ischemic cardiomyopathy: with the level of MR‑proADM ‑ r=0,67, p=0,006, with the level of NT‑pro<em>B</em>NP ‑ r=0,78, p&lt;0,001; in the group of patients with myocardial infarction and preserved left ventricular ejection fraction: with MR‑proADM level ‑ r=‑0,52, p=0,024, with NT‑pro<em>B</em>NP level ‑ r =‑0,38, p=0,037).</AbstractText><AbstractText>The findings suggest a pathogenetic association between the biomarkers under study and the parameters of left ventricular‑arterial coupling interaction.</AbstractText>