Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome

Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement of NP in the pathophysiology of metabolic disease. Based upon these findings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications.     

Autocrine and paracrine functions of cytokines in malignant lymphomas

Cytokines play important roles in the pathogenesis of lymphomas via an autocrine or a paracrine mechanism, or both. The characteristic clinical and histopathological features of malignant lymphomas may be due in part to elevated serum or tissue levels of cytokines. Determination of the effects of cytokines on the growth or differentiation of lymphoma cells is often complicated by the fact that more than one cytokine is responsible, and by the failure of anti-cytokine antibodies or antisense oligonucleotides to block the proliferation in vitro of lymphoma cells. However, it appears that IL-6 and/or IL-9 may play a prominent role in the tumor cell proliferation of Hodgkin's disease (HD), anaplastic large-cell lymphoma, or immunoblastic lymphoma. IL-6 may also be responsible for the plasmacytoid differentiation of lymphoma cells in polymorphic immunocytoma. The histopathological changes as a result of paracrine effects are most noticeable in HD. The malignant (H-RS) cells of HD have been shown to express IL-l, IL-5, IL-6, IL-9, TNF-α, M-CSF, TGF-β, and CD80, and, less frequently, IL-4 and G-CSF. These cytokines may be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression found in patients with HD. In contrast to H-RS cells, most non-HD lymphoma cells do not produce cytokines in excess amounts and reveal only a minimal cellular reaction. Exceptions include T-cell-rich B-cell lymphoma, angiocentric T-cell lymphoma, and angio-immunoblastic lymphadenopathy (AILD)-like T-cell lymphoma. IL-4 is responsible for the T-cell reaction in T-cell-rich B-cell lymphoma, whereas IL-6 accounts for the plasma cell reaction in AILD-type T-cell lymphoma. The authors extensively review the role of cytokines in lymphomas because this may lead to major advances in the understanding of the molecular processes involved in the histopathogenesis of lymphomas.     

Autocrine and paracrine effects of atrial natriuretic peptide gene transfer on vascular smooth muscle and endothelial cellular growth.

In addition to the atria, recent evidence suggests that atrial natriuretic peptide (ANP) is also synthesized in other tissues. Of particular interest is the location of ANP mRNA in the vessel wall. We and others have shown that exogenously added ANP inhibited the growth of endothelial cells and vascular smooth muscle cells (VSMC) in culture. However, it is not known if the locally synthesized ANP would act similarly. Because cultured endothelial cells and VSMC have lost the ability to express the endogenous ANP gene, we have transfected cells in culture with an expression vector expressing rat ANP and have examined the effects on growth. Cultured endothelial cells transfected with an ANP expression vector synthesized and secreted high levels of ANP. These cells also showed significantly lower rates of DNA synthesis under basal and fibroblast growth factor (FGF)-stimulated conditions. Addition of conditioned medium from endothelial cells transfected with ANP vector to nontransfected endothelial cells resulted in the significant increase in cyclic GMP. Similarly, conditioned media collected from endothelial cells transfected with ANP vector also decreased DNA synthesis in VSMC. Coculture of ANP-transfected endothelial cells with quiescent VSMC showed that released ANP from endothelial cells inhibited DNA synthesis in VSMC. Finally, we examined the autocrine effect of direct transfection of ANP vector into VSMC. Transfection of the ANP vector decreased DNA synthesis in VSMC under basal and angiotensin II-stimulated conditions. Similarly, transfection of the ANP vector resulted in a decrease in the PDGF and serum (5%)-stimulated DNA synthesis of VSMC. These results demonstrate that endogenously produced ANP can exert autocrine and paracrine inhibitory effects on endothelial cell and VSMC growth. In vivo gene transfer of ANP may provide us with the opportunity of gene therapy for vascular diseases in which the abnormalities are vasoconstriction and pathological growth.     

B型利钠肽在心脏疾病中的应用

在20世纪中叶．科学家开始把心脏作为一个具有内分泌功能的器官来研究。最初。Kisch发现心房中存在具有内分泌功能的腺体颗粒。接着Henry和Pearce报道当犬科动物的左心房发生囊性扩张后，尿量会随之明显增多。通过25年研究，DeBold在1984年证实了心房利钠肽(ANP)的结构。1988年在猪的大脑中分离出一种与ANP作用相似的多肽——脑利钠肽。但进一步研究表明BNP的主要合成位     

Diagnosis of heart failure using urinary natriuretic peptides

In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients ( P <0.001). Urine N-BNP was correlated with plasma N-BNP ( r (s)=0.53, P <0.0005). Areas under the ROC curves for urinary N-ANP, N-BNP and CNP were 0.86, 0.93 and 0.70 and for plasma N-BNP was 0.96. Correcting urinary peptide levels using urine creatinine produced ROC areas of 0.89, 0.93 and 0.76 respectively. A urine N-BNP level cut-off point of 11.6 fmol/ml had a sensitivity and specificity for heart failure detection of 97% and 78% respectively, with positive and negative predictive values of 64.7 and 98%. In conclusion, although all three natriuretic peptides were elevated in urine in heart failure, urinary N-BNP had diagnostic accuracy comparable with plasma N-BNP. Use of urinary N-BNP for heart failure diagnosis may be suitable for high-throughput screening, especially in subjects reluctant to provide blood samples.     

Biochemistry of pro-B-type natriuretic peptide-derived peptides: the endocrine heart revisited

BACKGROUND: Since the discovery of cardiac hormones almost 25 years ago, a vast amount of clinical research has identified the cardiac natriuretic peptides and their precursors as markers of heart failure. It even seems likely that the pro-B-type natriuretic peptide (proBNP)-derived peptides in plasma may become the most frequently measured peptides in the daily diagnosis and control of therapy. In contrast, the biochemistry of the peptides has received less attention. METHODS: Published data available on the National Library of Medicine (NLM) were used as the basis for the review. OUTCOME: This review shows that the present understanding of the biochemistry of peptides is far from complete. In particular, cellular synthesis, including posttranslational precursor maturation, is poorly understood. Moreover, elimination of the precursor fragments is unknown. Elucidation of the molecular heterogeneity of proBNP products will therefore contribute to the understanding of the endocrine heart and may also have important diagnostic consequences. Above all, the different proBNP-derived peptides may not always be equal markers of the same pathophysiologic processes. A different metabolism and peripheral elimination may also impose new and peptide-specific limitations for diagnostic use. CONCLUSIONS: It is necessary to focus more on the biology of the proBNP-derived peptides. In turn, new insight into the biochemistry could pave the way for more sensitive and disease-specific assays in the clinical setting.     

Cardiac natriuretic peptides: new laboratory parameters in heart failure patients

Natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide, are key regulators in the homeostasis of salt and water excretion and in the maintenance of blood pressure. During heart failure, these peptides are highly activated because of volume overload and increased myocardial wall tension. Among all natriuretic peptides and neurohormones, brain natriuretic peptide and its N-terminal prohormone fragment have been shown to be the best markers to identify patients with heart failure. They are useful prognostic markers as well. The stability of brain natriuretic peptides and N-terminal prohormones in ethylene-diamine-tetraacetic-acid whole blood is sufficient for routine use. Sensitive and specific assays without the need for plasma extraction are commercially available. The available data indicate that natriuretic peptides are powerful diagnostic and prognostic markers in heart failure patients. First data on treatment guidance are promising.     

B-type natriuretic peptides for the diagnosis of congestive heart failure in dyspneic oldest-old patients

Objectives

To evaluate the accuracy of B-type natriuretic peptide (BNP) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) for the diagnosis of congestive heart failure (CHF) in dyspneic patients aged ≥ 85 years admitted to the Emergency Department (ED), and to define threshold values in this oldest-old population.

Design and methods

This study involved 210 oldest-old patients, and 360 patients aged from 65 to 84 years (< 85 years), admitted to the ED for dyspnea.

Results

Median BNP and NT-proBNP levels were significantly higher in CHF oldest-old patients (p < 0.001). BNP and NT-proBNP threshold values were higher in oldest-old patients (290 and 2800 pg/mL, respectively) compared to that of patients < 85 years (270 and 1700 pg/mL, respectively). In a multivariate analysis, both BNP and NT-proBNP were the strongest variables associated with CHF in oldest-old patients. Neither renal function nor gender had impact on the diagnostic utility of the two tests.

Conclusion

Both BNP and NT-proBNP could potentially be reliable biomarkers for the diagnosis of CHF in oldest-old patients admitted with acute dyspnea to the ED.     

A feeling in the waters: diagnosis of heart failure using urinary natriuretic peptides

Plasma levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (N-BNP) are highly sensitive markers of ventricular dysfunction and/or hypertrophy and, in established disease, offer prognostic value and may be useful for guidance of therapy. Ng and co-workers report in this issue of Clinical Science that urinary levels of N-BNP may be as useful as plasma levels for the discrimination of patients with and without heart failure. This raises the potential for a relatively simple urine test that could be used for the diagnosis of heart failure. Roles in prognostication and the guidance of therapy may also be possible but, perhaps of most significance, measurement of urinary N-BNP may be applied to screening of patients at high risk of heart failure. The main limitations of the study were that the sample of heart failure patients comprised only 34 individuals with New York Heart Association functional Class IV and that the observed correlation between levels of urinary N-BNP and plasma creatinine seemed counter-intuitive. The latter issue needs clarification, as renal impairment is a frequent co-morbidity among patients with heart failure and will potentially confound any observed association between ventricular dysfunction and urinary N-BNP levels. Another caveat is that it is unclear if testing for urinary N-BNP can be cheaply and conveniently administered on a large scale. Nevertheless, this first demonstration of elevated N-BNP in the urine of patients with heart failure raises a number of exciting possibilities with regard to the management of patients with established or possible heart failure. Further investigation is required and eagerly awaited.     

慢性心力衰竭患者血浆肾上腺升压素和心钠素的变化

目的 观察慢性充血性心力衰竭(CHF)患者血浆肾上腺升压素(ADT)和心钠素(ANP)的变化,以探讨CHF发生发展的病理生理机制.方法 采用特异性放射免疫法检测了45例CHF患者治疗前后和20例正常人ADT和ANP的血浆浓度.结果 治疗前,ADT血浆浓度在心功能Ⅱ级为(29.98±3.56)ng/L、Ⅲ级为(33.45±3.54)ng/L,Ⅳ级为(20.71±3.37)ng/L,心功能Ⅲ级时达到高峰,心功能Ⅳ级时明显下降,并且低于正常对照组(24.89±2.19)ng/L,心力衰竭各亚组与正常对照组比较,差异均有统计学意义(均P＜0.05);经1周药物治疗后,心力衰竭各亚组患者血浆ADT含量下降.治疗前ANP血浆含量在心力衰竭各亚组较对照组明显升高(P＜0.05),心力衰竭各亚组间比较差异亦有统计学意义(均P＜0.05);治疗后,心力衰竭各亚组均下降,Ⅳ级组与治疗前相比差异有统计学意义(P＜0.05),余两组差异无统计学意义(P＞0.05).治疗前ADT和ANP在Ⅱ级组和Ⅳ级组无相关关系,Ⅲ级组有负相关关系(r=-0.46,P=0.04).结论 ADT和ANP共同参与了心力衰竭的病理进程,表明缩血管和舒血管活性肽分子间平衡被打破,反映了心力衰竭的严重程度;短期药物治疗可降低其血浆水平.     

The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertension

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are increased in conditions with cardiac ventricular volume and pressure overload. The general physiological and potential therapeutic roles of natriuretic peptides in respiratory disease, right ventricular (RV) dysfunction, and pulmonary arterial hypertension (PAH) are reviewed. BNP levels can be used to differentiate between dyspneic patients with a pure respiratory defect and those with RV dysfunction. BNP levels also correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PAH (atrial septal defect, chronic thromboembolic disease, and scleroderma). BNP is a predictor of mortality in patients with primary pulmonary hypertension (PPH). These are important clinical implications in that a noninvasive blood test may be used to identify high-risk patients for more invasive procedures such as cardiac catheterization. BNP or NT-proBNP measurements may also be used to guide therapy (e.g., pulmonary vasorelaxants) in PAH since upregulation of the natriuretic peptide pathway has been shown to reduce cardiac hypertrophy and PAH. Additionally, there may be therapeutic potential via recombinant BNP or neutral endopeptidase inhibitors in RV dysfunction and PAH.     

Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells

Langerhans cells (LCs) are bone marrow (BM)–derived epidermal dendritic cells (DCs) that develop from precursors found in the dermis. Epidermal LCs are absent in transforming growth factor (TGF) β1-deficient mice. It is not clear whether TGFβ1 acts directly on LC precursors to promote maturation or whether it acts on accessory cells, which in turn affect LC precursors. In addition, the physiologic source of TGFβ1 is uncertain because BM chimera experiments showed that neither hematopoietic nor nonhematopoietic-derived TGFβ1 is required for LC development. To address these issues, we created mice transgenic for a bacterial artificial chromosome (BAC) containing the gene for human Langerin into which Cre recombinase had been inserted by homologous recombination (Langerin-Cre). These mice express Cre selectively in LCs, and they were bred to floxed TGFβRII and TGFβ1 mice, thereby generating mice with LCs that either cannot respond to or generate TGFβ1, respectively. Langerin-Cre TGFβRII mice had substantially reduced numbers of epidermal LCs, demonstrating that TGFβ1 acts directly on LCs in vivo. Interestingly, Langerin-Cre TGFβ1 mice also had very few LCs both in the steady state and after BM transplantation. Thus, TGFβ1 derived from LCs acts directly on LCs through an autocrine/paracrine loop, and it is required for LC development and/or survival.     

The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis,prognosis and management

Heart failure (HF) is a complex disease process that is challenging to diagnose and manage. For more than 15 years, biomarkers have been used to diagnose and the guide the management of patients with this disease. The gold standard biomarkers for HF are B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP); both are used for diagnosis and prognosis. More recently, there has been an interest in use of BNP and NT-proBNP for HF management as well. Important aspects regarding production and clearance of BNP and NT-proBNP exist, which are vital for the clinician to understand. Beyond BNP or NT-proBNP, other newer biomarkers such as mid-regional pro-atrial natriuretic peptide, soluble ST2, highly sensitive troponin and renal biomarkers may add value for prognostication and possibly, patient management. In this article, the authors will discuss the established and evolving role of BNP and NT-proBNP in HF, along with consideration of select newer biomarkers in this setting.     

Combining echo and natriuretic peptides to guide heart failure care in the outpatient setting: A position paper

Background

Chronic heart failure (HF) is a relevant and growing public health problem. Although the prognosis has recently improved, it remains a lethal disease, with a mortality that equals or exceeds that of many malignancies. Furthermore, chronic HF is costly, representing a large and growing drain on healthcare resources.

Methods

This narrative review is based on the material searched for and obtained via PubMed up to May 2017. The search terms we used were as follows: “heart failure, echocardiography, natriuretic peptides” in combination with “treatment, biomarkers, guidelines.”

Results

Recent studies have supported the value of natriuretic peptides (NPs) and Doppler echocardiographic biomarkers of increased left ventricular (LV) filling pressures or pulmonary congestion as tools to scrutinize patients with impending clinically overt HF. Therefore, combination of pulsed‐wave tissue and blood flow Doppler with NPs appears valuable in guiding HF management in the outpatient setting. In as much as both the echo and the plasma levels of NPs may reflect the presence of fluid overload and elevations of LV filling pressures, integrating NP and echocardiographic biomarkers with clinical findings may help the cardiologist to identify high‐risk patients, that is to recognize whether a patient is stable or the condition is likely to evolve into decompensated HF, to optimize treatment, to improve the prognosis and to reduce rehospitalization.

Conclusion

We discussed the rationale and the clinical significance of combining follow‐up echo and NP assessment to guide management of ambulatory patients with chronic HF.     

Role of natriuretic peptides in cardiovascular surgery

Acute kidney injury is a major complication of cardiovascular surgery. Therapies to reduce or prevent acute kidney injury are highly desirable, and recent advances have helped refine the targets for such therapy, albeit with surprises and controversies. Among these therapies, natriuretic peptides have received the most scrutiny owing to the difficulty in explaining the conflicting evidence for effectiveness in some, but lack thereof, in other studies. This article examines the possible reasons for the conflicting results reported with natriuretic peptides in various clinical conditions.     

Relationship between natriuretic peptides and hemodynamics in patients with heart failure at rest and after ergometric exercise

Sixteen patients with heart failure who underwent right heart catherization were studied with regard to plasma natriuretic peptide levels and hemodynamic parameters at rest and immediately after symptom-limited ergometry. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured and correlated with left ventricular ejection fraction (LVEF), mean pulmonary arterial pressure (MPAP), pulmonary arterial wedge pressure (PAWP) and cardiac index (CI). Compared to normal controls, ANP and BNP were elevated at rest. During exercise ANP and BNP increased. BNP was highly significantly correlated with LVEF (P = 0.005) at rest, whereas ANP did not (P = 0.082). BNP significantly correlated with MPAP and PAWP after exercise and showed a significant inverse correlation with CI. Our data provide evidence that BNP might be a better indicator for LVEF at rest than ANP. In addition, BNP correlates very well with MPAP and PAWP, after exercise. This close correlation is likely to reflect a correlation of BNP with left ventricular enddistolic pressure in heart failure when patients are exposed to physical exercise.