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BackgroundLevels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels.MethodsWe included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP.ResultsOf the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (β = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (β = –0.37; 95%CI = –0.39, –0.35), hepcidin (β = –0.22, 95%CI = –0.24, –0.20), and TSAT (β = –0.07, 95% CI = –0.08, –0.06). Lower ferritin (β = –0.05, 95%CI = –0.08, –0.02), lower hepcidin (β = –0.04, 95%CI = –0.07, –0.006), and higher TSAT (β = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association.ConclusionOur findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF.

Human patients with mutations within NPPC or NPR2 genes (encoding C-type natriuretic peptide (CNP) and guanylyl cyclase-B (GC-B), respectively) display clinical signs associated with skeletal abnormalities, such as overgrowth or short stature. Mice with induced models of Nppc or Npr2 deletion display profound achondroplasia, dwarfism and early death. Recent pharmacological therapies to treat short stature are utilizing long-acting CNP analogues, but the effects of manipulating CNP expression during development remain unknown. Here, we use Danio rerio (zebrafish) as a model for vertebrate development, employing both pharmacological and reverse genetics approaches to alter expression of genes encoding CNP in zebrafish. Four orthologues of CNP were identified in zebrafish, and spatiotemporal expression profiling confirmed their presence during development. Bioinformatic analyses suggested that nppcl is the most likely the orthologue of mammalian CNP. Exogenous CNP treatment of developing zebrafish embryos resulted in impaired growth characteristics, such as body length, head width and eye diameter. This reduced growth was potentially caused by increased apoptosis following CNP treatment. Expression of endogenous nppcl was downregulated in these CNP-treated embryos, suggesting that negative feedback of the CNP system might influence growth during development. CRISPR knock-down of endogenous nppcl in developing zebrafish embryos also resulted in impaired growth characteristics. Collectively, these data suggest that CNP in zebrafish is crucial for normal embryonic development, specifically with regard to growth.

Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5′-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.

Objective. Systematic evaluation of the efficacy of natriuretic recombination in human brain on disease myocardial infarction, left ventricular heart failure, and the efficacy and safety of long-term left ventricular remodeling. Methods. Computerized search of CNKI, Wanfang database, Wipro Chinese Technology Publications (VIP) numerical database, Chinese Biomedical Literature Database (CBM), Medline Cochrane Library, clinical Trail.Gov clinical collection, and other documents. Randomized controlled trials (RCT) of recombinant human brain natriuretic peptide in the treatment of acute myocardial infarction from inception to December 2021 were searched. Based on the Jadad scale, inclusion-exclusion data for diseases were collected and elaborated by meta by RevMan 5.3 simulation software. In a total of 23 randomized controlled trials, 2 024 cases were used as the basic data, the control group was routinely treated for 1 012 cases, and 1 012 cases in the experimental group were also treated with natriuretic peptide in the recombinant human brain on the previous basis. Results. In terms of overall efficacy, the experimental group was better than the control group, statistically significant (OR = 4.30 , 95% CI (3.26, 5.67), P < 0.000 01), left ventricular ejection fraction in the experimental group than the control group (OR = 1.58 , 95% CI (1.27, 1.90), P < 0.000 01). In terms of a myocardial strain in the left ventricle, the experimental group was superior to the control group. The difference was significant (OR = − 0.91 , 95% CI (-1.50, -0.33), P = 0.002). In terms of the cardiac output volume, the experimental group was superior to the control group (OR = 1.24 , 95% CI (0.55, 1.94), P = 0.0005). Regarding brain natriuretic peptide precursors, the experimental group was superior to the control group (OR = − 4.37 , 95% CI (-6.21, -3.25), P < 0.00001). In terms of the heart rate, the experimental group was superior to the control group. Measurement of differential significance is as follows: OR = − 13.70 , 95% CI (-14.95, -12.46), P < 0.00001. In terms of contraction, the experimental group was superior to the comparison group (OR = − 12.38 , 95% CI (-17.98, -6.79), P < 0.00001). The experimental group outperformed the control group (OR = − 7.42 , 95% CI (-8.53, -6.30), P < 0.00001). In terms of bad influence, the measurement is as follows: OR = 0.95 , 95% CI (0.29, 3.16), P = 0.94. Conclusion. In patients with acute myocardial infarction and left ventricular remodeling, if treated with a heavy treatment of the group of cerebral natriuretic peptide mode, it can increase clinical treatment, improve the cardiac effect, inhibit ventricular remodeling, improve blood pressure and heart rhythm, and have greater clinical treatment and safety. [ABSTRACT FROM AUTHOR]

Elevated N-terminal pro-B-type natriuretic peptides (NT-proBNP) and cardiac troponin T (cTnT) are associated with poor outcome in patients with chronic coronary syndrome (CCS). The performance of these biomarkers in diagnosing ischemia, and their association with myocardial hypoperfusion and hypokinesis is unclear. Patients with suspected CCS (history of angina, estimated cardiovascular risk >15% or a positive stress test) were included in the prospective, multi-center DOPPLER-CIP study. Patients underwent Single Positron Emission Computed Tomography for assessment of ischemia and NT-proBNP and cTnT were measured in venous blood samples. We included 430 patients (25% female) aged 64 ± 8 years. Reversible hypoperfusion and hypokinesis were present in 139 (32%) and 89 (21%), respectively. Concentrations of NT-proBNP and cTnT correlated moderately (rho = 0.50, p < 0.001). NT-proBNP and cTnT concentrations (median [IQR]) were higher in patients with versus without reversible ischemia: 150 (73–294) versus 87 (44–192) ng/L and 10 (6–13) versus 7 (4–11) ng/L, respectively (p < 0.001 for both), and the associations persisted after adjusting for possible confounders. The C-statistics to discriminate ischemia ranged from 63%–73%, were comparable for cTnT and NT-proBNP, and higher for hypokinesis than hypoperfusion, and both were superior to exercise electrocardiography and stress echocardiography. Very low concentrations (≤5 ng/L cTnT and ≤ 60 ng/L NT-proBNP) ruled out reversible hypokinesis with negative predictive value >90%. cTnT and NT-proBNP are associated with irreversible and reversible ischemia in patients with suspected CCS, particularly hypokinesis. The diagnostic performance was comparable between the biomarkers, and very low concentrations may reliably rule out ischemia. • Cardiac troponin and NT-proBNP are associated with reversible and irreversible ischemia, even after adjusting for cardiac structure and function. • Very low concentrations of both biomarkers may have a value in ruling out ischemia. • The association was stronger for hypokinesis than hypoperfusion for both biomarkers, suggesting that the functional effects of ischemia may be a stronger stimulus than ischemia per se. • cTnT and NT-proBNP performed better than exercise ECG and stress echocardiography in discriminating for ischemia. [ABSTRACT FROM AUTHOR]

Descurainia sophia seeds (DS), Astragalus mongholicus (AM), and their formulas are widely used to treat heart failure caused by various cardiac diseases in traditional Chinese medicine practice. However, the molecular mechanism of action of DS and AM has not been completely understood. Herein, we first used mass spectrometry coupled to UPLC to characterize the chemical components of DS and AM decoctions, then applied MS-based quantitative proteomic analysis to profile protein expression in the heart of rats with isoproterenolinduced cardiomyopathy (ISO-iCM) before and after treated with DS alone or combined with AM, astragaloside IV (AS4), calycosin-7-glucoside (C7G), and Astragalus polysaccharides (APS) from AM. We demonstrated for the first time that DS decoction alone could reverse the most of differentially expressed proteins in the heart of the rats with ISO-iCM, including the commonly recognized biomarkers natriuretic peptides (NPPA) of cardiomyopathy and sarcomeric myosin light chain 4 (MYL4), relieving ISO-iCM in rats, but AM did not pronouncedly improve the pharmacological efficiency of DS. Significantly, we revealed that AS4 remarkably promoted the pharmacological potency of DS by complementarily reversing myosin motor MYH6/7, and further downregulating NPPA and MYL4. In contrast, APS reduced the efficiency of DS due to upregulating NPPA and MYL4. These findings not only provide novel insights to better understanding in the combination principle of traditional Chinese medicine but also highlight the power of mass spectrometric proteomics strategy combined with conventional pathological approaches for the traditional medicine research. [ABSTRACT FROM AUTHOR]

Simple Summary: Reactivation of the fetal cardiac gene program, such as those encoding atrial and brain natriuretic peptides (ANP and BNP, respectively), is a characteristic feature of failing hearts. We previously revealed that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also called repressor element-1-silencing transcription factor (REST), plays a crucial role in the transcriptional control of ANP, BNP and other fetal cardiac genes through collaboration with various other transcription factors to maintain physiological cardiac function and electrical stability. Increased production of ANP and BNP prevents the progression of heart failure, but reactivation of Gαo and fetal-type cardiac ion channels (T-type Ca2+ and HCN channels) leads to deteriorated cardiac function and lethal arrhythmias observed in mice with disturbed NRSF function. Epigenetic regulators with which NRSF forms a complex modify histone acetylation and methylation, thereby participating in NRSF-mediated transcriptional regulation. Further comprehensive studies will lead to clarification of the molecular mechanisms underlying the development of cardiac dysfunction and heart failure. Reactivation of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a key feature of pathological cardiac remodeling and heart failure. Intensive studies on the regulation of ANP and BNP have revealed the involvement of numerous transcriptional factors in the regulation of the fetal cardiac gene program. Among these, we identified that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also named repressor element-1-silencing transcription factor (REST), which was initially detected as a transcriptional repressor of neuron-specific genes in non-neuronal cells, plays a pivotal role in the transcriptional regulation of ANP, BNP and other fetal cardiac genes. Here we review the transcriptional regulation of ANP and BNP gene expression and the role of the NRSF repressor complex in the regulation of cardiac gene expression and the maintenance of cardiac homeostasis. [ABSTRACT FROM AUTHOR]

• RAAS inhibition is a mainstay of the pharmacological treatment of HFrEF • In HFrEF, whenever possible, the use of ARNI should be preferred over ACE inhibitor • ARNI should be considered as first line therapy in de novo HFrEF patients • ARNI should be considered in HFmrEF, no definitive evidence support them in HFpEF Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community. [ABSTRACT FROM AUTHOR]

Aim: Heart failure (HF), a progressive disease, is accompanied by chronic inflammation and changes in osmolality. The neutrophil-to-lymphocyte ratio (NLR) demonstrates a systemic inflammatory response in most diseases; however, the relationship between plasma osmolality and the systemic inflammatory response in HF patients is not yet clear. Therefore, we aimed to investigate the possible associations of NLR with plasma osmolality levels in patients with HF. Materials and Methods: The present study included 189 consecutive patients with chronic HF with an ejection fraction (EF) of <40%. They were classified into four groups based on admission plasma osmolality quartiles: hypo-osmolar (first quartile), normohypo-osmolar (second quartile), normo-hyperosmolar (third quartile), and hyperosmolar (fourth quartile). We evaluated the relationship between NLR, plasma osmolality, type-B natriuretic peptide (BNP), and the New York Heart Association (NYHA) functional class. Results: The hyperosmolar group had an increased NLR (p = 0.007). The presence of NYHA class 3-4 functional capacity, high-sensitivity C-reactive protein, and high osmolality were independent predictors of increased NLR. In correlation analysis, osmolality was significantly positively correlated with NLR (r = 0.201, p = 0.011). Conclusion: Higher NLR values may be associated with increased plasma osmolality, which may indicate an increased inflammatory status in the HF phenomenon. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia–reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia–reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired. [ABSTRACT FROM AUTHOR]

Background and objectives: To identify clinical, echocardiographic, and laboratory parameters that affect the early recurrence of atrial fibrillation (AF) after restoring sinus rhythm (SR) by electrical cardioversion (ECV), and to determine whether left atrial (LA) strain, as a noninvasive indicator reflecting fibrosis, is associated with laboratory indicators affecting the development of fibrosis, interleukin 6 (IL-6) or tumor necrosis factor α (TNF-α). Materials and Methods: The study included 92 persistent AF patients who underwent elective ECV. The effective maintenance of SR was evaluated after 40 ± 10 days of ECV. Echocardiography, inflammatory markers (high-sensitivity c-reactive protein (hs-CRP), IL-6, and TNF-α), and natriuretic peptides (N-terminal pro b-type natriuretic peptide (NT-proBNP) and N-terminal pro a-type natriuretic peptide (NT-proANP)) were assessed. Results: After a 40 ± 10 days observation period, 51 patients (55.4%) were in SR. Patients with AF recurrence had a significantly longer duration of AF (p = 0.008) and of arterial hypertension (p = 0.035), lower LA ejection fraction (p = 0.009), lower LA strain (p < 0.0001), higher left ventricular global longitudinal strain (p = 0.001), and a higher E/e' ratio (p < 0.0001). LA strain was an independent predictor of early AF recurrence (OR: 0.65; 95% Cl 0.5–0.9, p = 0.004). LA strain < 11.85% predicted AF recurrence with 70% sensitivity and 88% specificity (AUC 0.855, 95% CI 0.77–0.94, p < 0.0001). LA strain demonstrated the association with NT-proBNP (r = −0.489, p < 0.0001) and NT-proANP (r = −0.378, p = 0.002), as well as with hs-CRP (r = −0.243, p = 0.04). Conclusions: LA strain appeared to be the most accurate predictor of early AF recurrence after ECV in patients with persistent AF. LA strain inversely correlated with NT-proBNP and NT-proANP, but no significant association with any of the inflammatory markers was identified. [ABSTRACT FROM AUTHOR]

Background: Clinical cardiovascular disease (CVD) and cognition impairment are common and often coexist in aging populations, and CVD is associated with greater cognition impairment risk; however, the association between cognition impairment and CVD risk is inconsistent. It is unknown if pathways that contribute to CVD are caused by impaired cognition. We hypothesized that cognition impairment would be associated with greater subclinical CVD including subclinical myocardial damage [assessed by high-sensitivity cardiac troponin T (hs-cTnT)] and cardiac strain or dysfunction [assessed by N-terminal pro-B-type natriuretic peptide (NT-proBNP)]. Methods: This analysis included Atherosclerosis Risk in Communities Study (ARIC) participants who underwent global cognition z-score tests between 1991 and 1993. Cardiac biomarkers were measured from stored plasma samples collected between 1996 and 1999. Logistic regression models were used to determine the association of cognitive function with subclinical CVD risk. Results: There were 558/9216 (6.1%) and 447/9097 (5.0%) participants with incident elevated hs-CTnT (≥14 ng/L) and NT-proBNP (≥300 pg/mL) levels, respectively. Comparing the lowest and highest quartiles of global cognition z-scores, a higher incidence of elevated hs-CTnT [odds ratio (OR) = 1.511, 95% confidence interval (CI): 1.093-2.088, P = 0.013] and NT-proBNP (OR = 1.929, 95% CI: 1.350-2.755, P < 0.001) were observed, respectively. In structural equation modeling, the indirect effect of global cognition z-score on major adverse cardiac events was 42.1% (P < 0.05). Conclusion: Impairments in baseline cognitive function were associated with subclinical myocardial damage or wall strain. Although future studies are warranted to investigate the pathophysiological mechanisms behind these associations, our study suggests common pathways between cognitive and cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Particulate Guanylyl Cyclase Receptor A (pGC-A) is a natriuretic peptide membrane receptor, playing a vital role in controlling cardiovascular, renal, and endocrine functions. The extracellular domain interacts with natriuretic peptides and triggers the intracellular guanylyl cyclase domain to convert GTP to cGMP. To effectively develop methods to regulate pGC-A, structural information on the full-length form is needed. However, structural data on the transmembrane and intracellular domains are lacking. This work presents expression and optimization using baculovirus, along with the first purification of functional full-length human pGC-A. In vitro assays revealed the pGC-A tetramer was functional in detergent micelle solution. Based on our purification results and previous findings that dimer formation is required for functionality, we propose a tetramer complex model with two functional subunits. Previous research suggested pGC-A signal transduction is an ATP-dependent, two-step mechanism. Our results show the binding ligand also moderately activates pGC-A, and ATP is not crucial for activation of guanylyl cyclase. Furthermore, crystallization of full-length pGC-A was achieved, toward determination of its structure. Needle-shaped crystals with 3 Å diffraction were observed by serial crystallography. This work paves the road for determination of the full-length pGC-A structure and provides new information on the signal transduction mechanism. [ABSTRACT FROM AUTHOR]

Simple Summary: The endocrine effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the vasculature, and the autocrine effects of ANP and BNP in cardiomyocytes are mediated by the common guanylyl cyclase A receptor (GC-A) expressed in various tissues and cell types. C-type natriuretic peptide (CNP) has paracrine actions that regulate vascular resistance and moderate myocardial stiffness via guanylyl cyclase B receptor (GC-B). Genetically modified mice have revealed the physiological roles of ANP and BNP in blood pressure, cardiac remodeling, and acute myocardial infarction. Molecular pathways in GC-A signaling specifically in cardiomyocytes were also investigated. ANP and BNP via the GC-A signaling phosphorylate regulator of G-protein signaling subtype 4 (RGS4) result in the inhibition of Gαq signaling coupled with angiotensin II type 1A receptor, inhibit the activation of transient receptor potential C6 (TRPC6), and attenuate genomic actions of the cardiac mineralocorticoid receptor (MR). Moreover, recent studies showed the physiological roles of CNP via GC-B in blood pressure and cardiac stiffness. Since natriuretic peptides are degraded by neprilysin (NEP), inhibiting NEP activity is expected to enhance the actions of natriuretic peptides. Experimental studies and clinical trials have shown the effect of NEP inhibition on cardiac remodeling, acute myocardial infarction, and hypertension. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The body of an average person weighing 70 kg contains approximately 39 trillion bacterial cells, which densely inhabit the gastrointestinal tract, skin, mucous membranes, etc. Bacteria respond to the signaling molecules in the human body, regulate the expression of the necessary genes, and thus adapt to the physiology of the host. Signaling molecules include hormones, neurotransmitters, immune system molecules, as well as natriuretic peptides, which are involved in the regulation of the circulatory system, water and electrolyte metabolism, and adipose tissue metabolism. Brain natriuretic peptide (BNP) is secreted by the ventricles during congestion and signals heart failure. This study showed that the presence of BNP in the growth medium of human symbiont bacteria affects their growth characteristics, survival, and stress resistance, including antibiotic resistance. It was concluded that bacterial populations that develop in a healthy person at a BNP level of up to 250 pg/mL will be more stress resistant than in a person suffering from heart failure. Our findings are promising to be used both in clinical medical practice and in the production of bacterial preparations for cosmetology, agriculture, and waste management. Brain natriuretic peptide (BNP) is secreted by the ventricles of the heart during overload to signal heart failure. Slight bilateral skin itching induced by BNP has been associated with response activity of the skin microbiota. In this work, we studied the effect of 25–250,000 pg BNP/mL on the growth, long-term survival, and stress (H2O2, antibiotics, salinity, heat and pH shock) resistance of human symbiont bacteria: Gram-positive Micrococcus luteus C01 and Gram-negative Alcaligenes faecalis DOS7. The effect of BNP turned out to be dose-dependent. Up to 250 pg BNP/mL made bacteria more stress resistant. At 2500 pg BNP/mL (heart failure) the thermosensitivity of the bacteria increased. Almost all considered BNP concentrations increased the resistance of bacteria to the action of tetracycline and ciprofloxacin. Both bacteria survived 1.3–1.7 times better during long-term (up to 4 months) storage. Our findings are important both for clinical medical practice and for practical application in other areas. For example, BNP can be used to obtain stress-resistant bacteria, which is important in the collection of microorganisms, as well as for the production of bacterial preparations and probiotics for cosmetology, agriculture, and waste management. [ABSTRACT FROM AUTHOR]

Simple Summary: CNP is the third natriuretic peptide to be isolated and is widely expressed in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by the other two natriuretic peptides, ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. Research into the actions of CNP has shown that CNP attenuates cardiac remodeling in animal models of cardiac hypertrophy, myocardial infarction, and myocarditis. Studies examining CNP/GC-B signaling showed that it contributes to the prevention of cardiac stiffness. Endogenous CNP, perhaps acting in part through CNP/NPR-C signaling, contributes to the regulation of vascular function and blood pressure. CNP regulates vascular remodeling and angiogenesis via CNP/GC-B/CGK signaling. CNP attenuates interstitial fibrosis and fibrosis-related gene expression in pressure overload and myocardial infarction models. The clinical application of CNP as a therapeutic agent for cardiovascular diseases is anticipated. The natriuretic peptide family consists of three biologically active peptides: ANP, BNP, and CNP. CNP is more widely expressed than the other two peptides, with significant levels in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. CNP knockout leads to severe dwarfism, and there has been important research into the role of CNP in the osteochondral system. As a result, a CNP analog is now available for clinical use in patients with achondroplasia. In the cardiovascular system, CNP and its downstream signaling are involved in the regulatory mechanisms underlying myocardial remodeling, cardiac function, vascular tone, angiogenesis, and fibrosis, among others. This review focuses on the roles of CNP in the cardiovascular system and considers its potential for clinical application in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Besides being a muscle and an electrochemically active organ, the heart is a true endocrine organ. As endocrine cells, cardiac myocytes possess all the needed chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In addition, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we highlight the biochemical phenotype of the endocrine heart, recapitulating that the cardiac myocytes are truly and fully capable endocrine cells. Production and release of natriuretic peptides and other vasoactive peptides are tightly regulated in mammalian physiology and involved in cardiovascular homeostasis. As endocrine cells, the cardiac myocytes seem to possess almost all known chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In several ways, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we will highlight the biochemical phenotype of the endocrine heart recapitulating that the cardiac myocytes are capable endocrine cells. Understanding the basal biochemistry of the endocrine heart in producing and secreting peptides to circulation could lead to new discoveries concerning known peptide products as well as hitherto unidentified cardiac peptide products. In perspective, studies on natriuretic peptides in the heart have shown that the post-translational phase of gene expression is not only relevant for human physiology but may prove implicated also in the development and, perhaps one day, cure of human cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: We used data from people initially free of clinical cardiovascular disease to evaluate the association between metabolic syndrome (MS) and incident preclinical heart failure (pHF). Methods and Results: STANISLAS was a familial, single-center, longitudinal prospective cohort study composed of 1,006 families from Nancy, France (median follow-up, 17 years [1993–2016]). Age- and sex-adjusted logistic regression and inverse probability weighting models were used to evaluate the association between MS and pHF, which was defined by diastolic dysfunction, atrial enlargement, ventricular hypertrophy, or elevated natriuretic peptides. Among 944 people who were adults at the first and final visit, those with baseline MS were more likely to be older (63 vs. 61 vs. 59 years of age) and male (73% vs. 55% vs. 45%) compared to people who developed incident MS and people who had no baseline MS, respectively. Furthermore, compared to people without baseline MS, the risk of pHF was numerically larger among people with baseline MS (adjusted odds ratio [aOR] 2.27, 95% CI: 1.07–4.81) and people who developed incident MS (aOR 1.56, 95% CI: 1.00–2.43). Concerning the metabolic determinants of MS, the risk of pHF was most elevated in people with baseline hypertension (aOR 3.19, 95% CI: 1.80–5.63) and elevated waist circumference (aOR 2.59, 95% CI: 1.47–4.57). Conclusion: Overall, HF is an important public health concern given the high risk of mortality when patients with MS or elevated fasting glucose become established with the disease. Early aggressive lifestyle modification and medical intervention among patients free of cardiovascular disease with an obese-hypertensive phenotype may be warranted to prevent HF development. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a complex syndrome with high mortality and hospitalization rates. Conventional care in patients with HF is usually based on clinical history and physical examination. Natriuretic peptides (NPs), B-type NP (BNP) and N-terminal proBNP, are the gold-standard biomarkers in HF. They are recommended for diagnosing HF, when the physician is uncertain of the diagnosis, and for estimating the prognosis. NPs also guide therapy in HF, as serial NP measurements inform medication adjustments to achieve targets independently of symptoms. In this regard, the data are conflicting. In patients with HF and reduced left ventricular ejection fraction (HFrEF) there is a suggestion that NP-guided therapy is helpful. The studies STARS-BNP and PROTECT demonstrated a reduction in cardiac events with NP-guided therapy. Additionally, mortality in patients aged <75 years reduced in the BATTLESCARRED and TIME-CHF studies, and in a meta-analysis. On the contrary, no differences were observed in the studies PRIMA and GUIDE-IT. In HF with preserved ejection fraction (HFpEF) and in the acute setting, no differences were detected with NP-guided therapy compared with conventional care. In patients at risk of developing HF, NP can be useful to guide therapy and prevent HF. In summary, NP-guided therapy seems to be useful in patients with HFrEF, especially in those aged <75 years, but has no use in HFpEF or in acute HF. [ABSTRACT FROM AUTHOR]

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin and that its levels seem to be a target of management. A total of 153 type 2 diabetes mellitus (T2DM) patients with II/III HF NYHA class and average left ventricular (LV) ejection fraction (EF) of 46% have been enrolled and treated with dapagliflosin. The serum levels of apelin and N-terminal brain natriuretic pro-peptide (NT-proBNP) were measured at baseline and over a 6-month period of dapagliflosin administration. We noticed that administration of dapagliflozin was associated with a significant increase in apelin levels of up to 18.3% and a decrease in NT-proBNP of up to 41.0%. Multivariate logistic regression showed that relative changes of LVEF, LA volume index, and early diastolic blood filling to longitudinal strain ratio were strongly associated with the levels of apelin, whereas NT-proBNP exhibited a borderline significance in this matter. In conclusion, dapagiflosin exerted a positive impact on echocardiographic parameters in close association with an increase in serum apelin levels, which could be a surrogate target for HF management. [ABSTRACT FROM AUTHOR]

Objectives: Identifying right ventricle (RV) abnormalities is important to stratifying pulmonary embolism (PE) severity. Disposition decisions are influenced by concerns about early deterioration. Triaging strategies, like the Simplified Pulmonary Embolism Severity Index (sPESI), do not include RV assessments as predictors or early deterioration as outcome(s). We aimed to (1) determine if RV assessment variables add prognostic accuracy for 5‐day clinical deterioration in patients classified low risk by sPESI, and (2) determine the prognostic importance of RV assessments compared to other variables and to each other. Methods: We identified low risk sPESI patients (sPESI = 0) from a prospective PE registry. From a large field of candidate variables, we developed, and compared prognostic accuracy of, full and reduced random forest models (with and without RV assessment variables, respectively) on a validation database. We reported variable importance plots from full random forest and provided odds ratios for statistical inference of importance from multivariable logistic regression. Outcomes were death, cardiac arrest, hypotension, dysrhythmia, or respiratory failure within 5 days of PE. Results: Of 1736 patients, 610 (35.1%) were low risk by sPESI and 72 (11.8%) experienced early deterioration. Of the 610, RV abnormality was present in 157 (25.7%) by CT, 121 (19.8%) by echocardiography, 132 (21.6%) by natriuretic peptide, and 107 (17.5%) by troponin. For deterioration, the receiver operating characteristics for full and reduced random forest prognostic models were 0.80 (0.77–0.82) and 0.71 (0.68–0.73), respectively. RV assessments were the top four in the variable importance plot for the random forest model. Echocardiography and CT significantly increased predicted probability of 5‐day clinical deterioration by the multivariable logistic regression. Conclusions: A PE triaging strategy with RV imaging assessments had superior prognostic performance at classifying low risk for 5‐day clinical deterioration versus one without. [ABSTRACT FROM AUTHOR]

Objective. It was to investigate the mechanism of atrial fibrillation after mitral valve replacement under extracorporeal circulation in patients with rheumatic heart disease under sevoflurane anesthesia maintenance and to provide scientific and effective basis for clinical treatment. Methods. Forty patients with rheumatic heart disease who underwent mitral valve replacement were randomly rolled into group I (sinus rhythm of propofol anesthesia, n = 10), group II (atrial fibrillation rhythm of propofol anesthesia, n = 10), group III (sinus rhythm of sevoflurane anesthesia, n = 10), and group IV (atrial fibrillation rhythm of sevoflurane anesthesia, n = 10). Inflammatory factors, free tissue of right atrium, and incidence of postoperative atrial fibrillation were compared among all groups. Results. (i) The serum levels of NT-proBNP, CRP, sST-2, IL-6, TNF-α, and TGF-β1 in group II were higher than those in group I, group III, and group IV, and the indexes in group III were higher than those in group IV (P < 0.05). (ii) The relative expression levels of PLB, CaMK II, Bax, and TP53 in the free tissue of right atrium in group II were higher than those in group I, III, and IV, and the index levels in group IV were higher than those in group III (P < 0.05). (iii) The incidence of postoperative atrial fibrillation in group III (0.00%) was significantly lower than that in group I (30%), group II (50%), and group IV (40.0%), and group II (50%) was the highest (P < 0.05). Conclusion. The maintenance of sevoflurane anesthesia can improve the inflammatory response and myocardial tissue autophagy in patients with sinus rhythm and atrial fibrillation rhythm and can reduce the incidence of postoperative atrial fibrillation in patients. [ABSTRACT FROM AUTHOR]

Objective. To investigate the clinical efficacy of cedilanid and isosorbide dinitrate plus pericardial dissection for chronic constrictive pericarditis in the elderly. Methods. Ninety elderly patients with chronic constrictive pericarditis admitted to our hospital from March 2018 to October 2020 were recruited and assigned to receive either cedilanid and isosorbide dinitrate (control group A), pericardial dissection (control group B), or cedilanid and isosorbide dinitrate plus pericardial dissection (combination group) via random number table method, with 30 patients in each group. Outcome measures included plasma endothelin, atrial natriuretic peptide, system immune-inflammation indices, treatment effect, quality of life, mental state, and treatment satisfaction. Results. The combination group had significantly higher treatment satisfaction and treatment efficacy than control groups A and B (P > 0.05). The combination group showed the lowest levels of atrial natriuretic peptide and endothelin, followed by control group A, and group B (P < 0.001). The combined therapy resulted in significantly lower levels of system immunity index, lower Hospital Anxiety and Depression Scale (HAD) scores, and better General Quality of Life Inventory-74 (GQOLI-74) scores than those of the control group B, followed by group A (P < 0.001). Conclusion. Cedilanid and isosorbide dinitrate plus pericardial dissection for elderly patients with chronic constrictive pericarditis enhances the level of plasma endothelin, atrial natriuretic peptide, and systemic immune-inflammation indexes of patients and improves their quality of life, which shows great potential for clinical promotion. [ABSTRACT FROM AUTHOR]

Aim: To validate the predictive value of the European coLlaboration on Acute decompeNsated Heart Failure (ELAN-HF) score, and to assess the effect of self-care behaviour on readmission and mortality in patients after admission with acute decompensated heart failure (ADHF). Design: Quantitative, prospective, single centre, cohort study. Methods: N-Terminal pro–B-type natriuretic peptide (NT-proBNP) levels were measured on admission and discharge, and were used together with clinical and laboratory parameters to calculate the ELAN-HF score. Patients were stratified into four risk groups (low, intermediate, high, very high) according to their ELAN-HF score. The performance of the ELAN-HF score was evaluated and compared to the original study. Self-care behaviour was assessed by the European Heart Failure Self-care Behaviour Scale (EHFScBS-9). Survival analysis was used to estimate the association between both scores and re-admission for HF and/or all-cause mortality within 180 days. Results: 88 patients were included. The median age of the study population was 75 years (IQR 69–83), 43% was female. NYHA III/IV functional class was present at discharge in 68 patients (85%) and 27 patients (34%) had a left ventricular ejection fraction < 40%. Complete data and 180 day follow up was available for 80 patients. 55% reached the endpoint of readmission and/or all-cause mortality. There was a significant association between the ELAN-HF score and re-admission and/or mortality < 180 days (HR = 1.25, 95% CI 1.08—1.45, p = 0.003). The median EHFScBS-9 score was 68.1 (IQR 58.3 – 77.8). There was no significant association between the EHFScBS-9 score and readmission and/or mortality < 180 days (HR = 1.01, 95% CI 0.99—1.03, p = 0.174). Conclusion: This study confirms the validity and therefore the potential of the ELAN-HF score to triage patients with ADHF before discharge. Using this score may optimize the follow-up treatment on the nurse-led heart failure clinic in order to decrease readmission and mortality. Self-care behaviour was non-significantly associated with readmission and/or mortality in our study population. Trial Registration: This study has been registered with the ethics committee MEC-U (Nieuwegein, The Netherlands), registration nr: V.160999/W18.208/HG/mk. [ABSTRACT FROM AUTHOR]

We aimed to determine, whether epicardial adipose tissue (EAT) as local source of inflammation, as well as its change over time, associates with the development of heart failure with preserved ejection fraction (HFpEF) in patients with coronary artery disease. We retrospectively included 379patients (aged 65.2 ± 11.7 years, 70.2%male) with coronary artery disease but without heart failure at baseline, undergoing clinical and echocardiographic assessment in 2010–2013 and receiving a second assessment in 2014–2018. EAT thickness was defined as space between the myocardium and the pericardium and indexed (EATi) by body surface area. Change in EATi was calculated as the difference of follow-up and baseline EATi. HFpEF was defined according to presence of dyspnea, elevated natriuretic peptides, and structural and/or functional alterations on echocardiography in accordance with current European Society of Cardiology guidelines. During a median follow-up of 4.3 years, 142patients (37.5%) developed HFpEF. Patients with onset of HFpEF had higher EATi at baseline (2.4 ± 1.3 vs. 1.9 ± 0.9 mm/m2, p = 0.001). In multivariable regression analysis, EATi associated with onset of HFpEF (1.25 [1.01–1.54], p = 0.04). Likewise, an increase in EATi over time was linked HFpEF development, independent of other risk factors and baseline EATi (1.39 [1.04–1.87], p = 0.03). EATi was significantly associated with follow-up b-type natriuretic peptide (BNP) levels (4.31[0.58–8.05], p = 0.024), but not with baseline BNP (2.24[−0.27–4.76], p = 0.08). EATi is associated with the development of HFpEF. The finding of changes in EATi altering the risk of HFpEF manifestation support the rationale for further research on epicardial fat modulation as a treatment target for HFpEF. • Epicardial adipose tissue is associated with the development of HFpEF. • Changes in epicardial adipose tissue modulate the risk of HFpEF development. • Epicardial adipose tissue may qualify as potential treatment target in HFpEF. [ABSTRACT FROM AUTHOR]

Aims In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil. Methods and results GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II–IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n  = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P  = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P  = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P  = 0.47) or in digoxin users not in AFF. Conclusion Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin. Clinical Trial Registration: NCT02929329 [ABSTRACT FROM AUTHOR]

Oryeongsan (Wulingsan in China and Goreisan in Japan), a formula composed of five herbal medicines, has long been used for the treatment of imbalance of the body fluid homeostasis in Asian countries. However, the mechanism by which Oryeongsan (ORS) improves the impaired body fluid and salt metabolism is not clearly defined. The present study was performed to define the role of the cardiorenal humoral system in the ORS-induced changes in blood pressure and renal function in hypertension. Experiments were performed in normotensive and two-kidney, one-clip hypertensive rats. Changes in the fluid and salt balance were measured in rats individually housed in metabolic cages. Changes in the systemic and local renin-angiotensin system (RAS) and cardiac natriuretic peptide hormone system (NPS) were evaluated. ORS water extract was administered by oral gavage (100 mg/kg daily) for 3 weeks. ORS induced diuresis and natriuresis along with an increase in glomerular filtration rate and downregulation of the Na+/H+ exchanger 3 (NHE3) and aquaporin 2 expression in the renal cortex and medulla, respectively. Furthermore, treatment with ORS significantly decreased systolic blood pressure with contraction of body sodium and water accumulation in hypertensive rats. ORS-induced changes were accompanied by modulation of the RAS and NPS, downregulation of the systemic RAS and cardiorenal expression of angiotensin-converting enzyme (ACE) and angiotensin II subtype 1 (AT1) receptor, and upregulation of the plasma ANP concentration and cardiorenal expression of ANP, ACE2, Mas receptor, and AT2 receptor. These findings indicate that ORS induces beneficial effects on the high blood pressure through modulation of the RAS and NPS of the cardiorenal system, suppression of the prohypertensive ACE-AT1 receptor pathway and NHE3, accentuation of the antihypertensive ACE2-Mas axis/AT2 receptor pathway in the kidney, suppression of the systemic RAS, and elevation of the plasma ANP levels and its synthesis in the heart. The present study provides a biological basis for the use of ORS in the treatment of impaired volume and pressure homeostasis. [ABSTRACT FROM AUTHOR]

Purpose: The pathophysiology of nocturia and nocturnal polyuria (NP), conditions that become more prevalent with aging, may in part be explained by changes in hormones involved in water homeostasis. The purpose of this study was to analyze the impact of aging on urinary natriuretic peptides in nocturia and NP. Methods: Patients aged =18 years completed 24-hour bladder diaries for assessment of nocturia and NP. They were divided into subgroups of =65 years old and <65 years old. Urine samples were collected and analyzed for natriuretic peptide (NTproANP, NT-proBNP, and NT-proCNP) levels. Peptide levels were compared between patients with and without nocturia/NP and within age subgroups; correlation to the NP index (NPi) was determined. Results: Compared to patients without nocturia (N=15), patients with nocturia (N=36) had higher median levels of urinary NT-proANP (15.8 pmol/mmol Cr vs. 10.9 pmol/mmol Cr, P=0.016) and NT-proBNP (6.3 pmol/mmol Cr vs. 4.5 pmol/mmol Cr, P=0.021), but showed no differences in NT-proCNP (2.4 pmol/mmol Cr vs. 2.5 pmol/mmol Cr, P=0.967). Patients =65 years old with nocturia had higher NT-proANP (29.8 pmol/mmol Cr vs. 11.0 pmol/mmol Cr, P<0.001) and NT-proBNP (9.6 pmol/mmol Cr vs. 5.0 pmol/mmol Cr, P<0.001) than patients <65 years old. Additionally, patients with NP (N=30) showed higher urinary NT-proANP (19.6 pmol/mmol Cr vs. 10.5 pmol/mmol Cr, P<0.001) and NT-proBNP (6.7 pmol/mmol Cr vs. 4.7 pmol/mmol Cr, P=0.020) compared to patients without NP (N=21). NP patients =65 years had higher NT-proANP (29.8 pmol/mmol Cr vs. 12.5 pmol/mmol Cr, P<0.001) and NT-proBNP (9.6 pmol/mmol Cr vs. 4.4 pmol/mmol Cr, P=0.004) than patients <65 years old. NPi positively correlated with urinary NT-proANP (RS=0.417, P=0.002) and NT-proBNP (RS=0.303, P=0.031), but not with NT-proCNP (RS=-0.094, P=0.510). Conclusions: Since urinary NT-proANP and NT-proBNP were greater in aged patients with nocturia and NP, natriuretic peptides may contribute to the pathophysiology of these conditions and further research should aim to explore them as targets for management. [ABSTRACT FROM AUTHOR]

Simple Summary: C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), CNP was not previously regarded as an important cardiac modulator. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with its cognate natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. In this review, I introduce the history of research on CNP in the cardiac field. C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike other members, i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are cardiac hormones secreted from the atrium and ventricle of the heart, respectively, CNP is regarded as an autocrine/paracrine regulator with broad expression in the body. Because of its low expression levels compared to ANP and BNP, early studies failed to show its existence and role in the heart. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with the distribution of its specific natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. NPR-B generates intracellular cyclic guanosine 3′,5′-monophosphate (cGMP) upon CNP binding, followed by various molecular effects including the activation of cGMP-dependent protein kinases, which generates diverse cytoprotective actions in cardiomyocytes, as well as in cardiac fibroblasts. CNP exerts negative inotropic and positive lusitropic responses in both normal and failing heart models. Furthermore, osteocrin, the intrinsic and specific ligand for the clearance receptor for natriuretic peptides, can augment the effects of CNP and may supply a novel therapeutic strategy for cardiac protection. [ABSTRACT FROM AUTHOR]

Simple Summary: Natriuretic peptides are endogenous hormones produced in the heart and vascular endothelium, and they enable cardiorenal protective actions or bone growth via cGMP stimulation through their receptor guanylyl cyclase receptor A or B. To optimize the drug for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). This review summarizes attempts to develop novel natriuretic peptide-based therapeutics, including novel designer natriuretic peptides and oral drugs to enhance endogenous natriuretic peptides. We introduce some therapeutics that have been successful in clinical practice, as well as the prospective drug developments in the natriuretic peptide system for disease states. The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A (NPR-A)), and C-type natriuretic peptide (CNP), which binds to the GC-B receptor (also called the NPR-B) and then synthesizes intracellular cGMP. GC-A receptor stimulation has natriuretic, vasodilatory, cardiorenal protective and anti-renin–angiotensin–aldosterone system actions, and GC-B receptor stimulation can suppress myocardial fibrosis and can activate bone growth before epiphyseal plate closure. These physiological effects are useful as therapeutics for some disease states, such as heart failure, hypertension, and dwarfism. To optimize the therapeutics for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). We review the cardiac NP system; new designer NPs, such as modified/combined NPs and modified peptides that can bind to not only NP receptors but receptors for other systems; and oral drugs that enhance endogenous NP activity. Finally, we discuss prospective drug discoveries and the development of novel NP therapeutics. [ABSTRACT FROM AUTHOR]

Aneurysmal Subarachnoid haemorrhage (aSAH) is one of the most common causes of neurocritical care admission. Consistent evidence has been suggestive of endocrine dysregulation in aSAH. This review aims to provide an up-to-date presentation of the available evidence regarding endocrine dysregulation in aneurysmal subarachnoid haemorrhage. A comprehensive literature search was performed using PubMed database. All available evidence related to endocrine dysregulation in hypothalamic-pituitary hormones, adrenal hormones and natriuretic peptides after aSAH, published since 2010, were reviewed. There have been reports of varying prevalence of dysregulation in hypothalamic-pituitary and adrenal hormones in aSAH. The cause of this dysregulation and its pattern remain unclear. Hypothalamic-pituitary and adrenal dysregulation have been associated with higher incidence of poor neurological outcome and increased mortality. Whilst there is evidence that long-term dysregulation of these axes may also develop, it appears to be less frequent than the acute-phase dysregulation and transient in pattern. Increased levels of catecholamines have been reported in the hyper-acute phase of aSAH with reported inconsistent correlation with the outcomes and the complications of the disease. There is growing evidence that of a causal link between the endocrine dysregulation and the development of hyponatraemia and delayed cerebral ischaemia, in the acute phase of aSAH. However, the pathophysiological mechanism and pattern of endocrine dysregulation which could be causally associated with these complications still remain debatable. The evidence, mainly from small observational and heterogeneous in methodology studies, is suggestive of adverse effects of the endocrine dysregulation on the outcome and the incidence of complications of the disease. However, the cause of this dysregulation and a pathophysiological mechanism that could link its presence with the development of acute complications and the outcome of the aSAH remain unclear. Further research is warranted to elucidate the clinical significance of endocrine dysregulation in subarachnoid haemorrhage. [ABSTRACT FROM AUTHOR]

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy. [ABSTRACT FROM AUTHOR]

Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3′-5′-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether. [ABSTRACT FROM AUTHOR]

Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies. [ABSTRACT FROM AUTHOR]

Brain natriuretic peptide (BNP) and its inactive N-terminal fragment, NT-proBNP, are serum biomarkers with key roles in the management of heart failure (HF). An increase in the serum levels of these peptides is closely associated with the pathophysiological mechanisms underlying HF such as the presence of structural and functional cardiac abnormalities, myocardial stretch associated with a high filling pressure and neuro-hormonal activation. As BNP and NT-proBNP measurements are possible, several studies have investigated their clinical utility in the diagnosis, prognostic stratification, monitoring and guiding therapy of patients with HF. BNP and NT-proBNP have also been used as criteria for enrollment in randomized trials evaluating the efficacy of new therapeutic strategies for HF. Nevertheless, the use of natriuretic peptides is still limited in clinical practice due to the controversial aspect of their use in different clinical settings. The purpose of this review is to discuss the main issues associated with using BNP and NT-proBNP serum levels in the management of patients with HF under current clinical and therapeutic scenarios. [ABSTRACT FROM AUTHOR]