Transcardiac gradients of N-terminal B-type natriuretic peptide in aortic valve stenosis

BACKGROUND: Plasma B-type natriuretic peptide (BNP), as well as the N-terminal part of the prohormone (Nt-BNP), are frequently elevated in aortic valve stenosis (AS). Yet, their release from the heart into the circulation has never been directly studied in AS. AIM: To assess the release of Nt-BNP in AS with focus on the identification of its main determinants. METHODS: We studied 49 adult patients undergoing preoperative cardiac catheterization for isolated AS. Blood was sampled from the aortic root and the coronary sinus for Nt-BNP determination by immunoassay. RESULTS: The mean (+/-S.E.) transcardiac Nt-BNP step-up averaged 79+/-53 pmol/l in 11 control patients free of structural heart disease, 75+/-32 pmol/l in 31 AS patients free of heart failure (HF), 236+/-62 pmol/l in 8 AS patients with diastolic HF (ejection fraction > or = 50%, pulmonary wedge pressure > 14 mm Hg) and 469+/-66 pmol/l in 7 AS patients with systolic HF (ejection fraction < 50%, wedge pressure > 14 mm Hg) (p<0.001). The transcardiac Nt-BNP gradient was independently associated with left ventricular (LV) end-diastolic pressure (beta=0.47, p<0.001) and ejection fraction (beta=-0.29, p<0.019) and with co-existent coronary artery disease (beta=0.23, p=0.050). CONCLUSION: LV diastolic and systolic dysfunction along with coronary artery disease are likely to be the key determinants of cardiac Nt-BNP release in AS. The transcardiac Nt-BNP gradient increases on average three-fold with the development of diastolic HF and six-fold in systolic HF.     

利尿钠肽在主动脉瓣狭窄中的作用

主动脉瓣狭窄是临床最常见的瓣膜疾病之一,可导致心力衰竭和死亡风险增加,其发病率在未来20年内可能会随着人口老龄化而翻倍。目前有症状的严重主动脉瓣狭窄患者的首选治疗方法是手术或经导管主动脉瓣置换术,然而无症状严重主动脉瓣狭窄患者的最佳手术时机仍存在争议,警惕的等待策略既安全又可行,但猝死的风险每年几乎达到5%。研究发现,血浆利尿钠肽水平与主动脉瓣狭窄的严重程度、症状的发展以及预后相关,有助于监测疾病进展,并确定哪些患者将从早期治疗干预中获益最大,从而降低长期不良事件的风险。文章概述了利尿钠肽在主动脉瓣狭窄的诊断、临床管理、风险分层和潜在治疗意义中的作用。     

Plasma levels of B-type natriuretic peptide in children and adolescents with aortic valve stenosis: reply

We thank Drs Koch and Singer for reporting their interestingfindings on B-type natriuretic peptide     

Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide.

To elucidate the ligand-receptor relationship of the natriuretic peptide system, which comprises at least three endogenous ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and three receptors, the ANP-A receptor or guanylate cyclase-A (GC-A), the ANP-B receptor or guanylate cyclase-B (GC-B), and the clearance receptor (C-receptor), we characterized the receptor preparations from human, bovine, and rat tissues and cultured cells with the aid of the binding assay, Northern blot technique, and the cGMP production method. Using these receptor preparations, we examined the binding affinities of ANP, BNP, and CNP for the C-receptor and their potencies for cGMP production via the ANP-A receptor (GC-A) and the ANP-B receptor (GC-B). These analyses revealed the presence of a marked species difference in the receptor selectivity of the natriuretic peptide family, especially among BNPs. Therefore, we investigated the receptor selectivity of the natriuretic peptide family using the homologous assay system with endogenous ligands and receptors of the same species. The rank order of binding affinity for the C-receptor was ANP greater than CNP greater than BNP in both humans and rats. The rank order of potency for cGMP production via the ANP-A receptor (GC-A) was ANP greater than or equal to BNP much greater than CNP, but that via the ANP-B receptor (GC-B) was CNP greater than ANP greater than or equal to BNP. These findings on the receptor selectivity of the natriuretic peptide family provide a new insight into the understanding of the physiological and clinical implications of the natriuretic peptide system.     

The effect of aortic valve replacement on N-terminal natriuretic propeptides in patients with aortic stenosis

BACKGROUND: Increased plasma concentrations of natriuretic peptides have been demonstrated to be associated with increased intracardiac pressure and left ventricular (LV) hypertrophy. After aortic valve replacement (AVR) in aortic stenosis patients, there is a relief of the left outflow obstruction with a substantial hemodynamic improvement. This is followed by a gradual regression of the LV hypertrophy. HYPOTHESIS: After AVR, reduction in LV filling pressure is expected to occur rapidly, while regression of LV hypertrophy will take place over a longer time period. On this basis we hypothesized that the plasma levels of N-terminal proatrial natriuretic peptide (NT-proANP) would be reduced early in the postoperative period, while N-terminal probrain natriuretic peptide (NT-proBNP), through its closer reflection of LV hypertrophy, would be sustained for a longer period. METHODS: Two groups of patients with aortic stenosis undergoing AVR were followed for 4 and 12 months, respectively. Plasma concentrations of NT-proANP and NT-proBNP were measured before and after AVR and related to preoperative findings and changes in the aortic valve area index. RESULTS: Before AVR, the patients had significantly increased plasma levels of NT-proANP and NT-proBNP. After AVR, NT- proANP was decreased at 4 and 12 months but remained elevated compared with controls. N-terminal-proBNP tended to decrease, but did not change significantly. When the patients were followed for 12 months, only those with elevated preoperative pulmonary capillary wedge pressure had decreased peptide levels (NT-proANP: p = 0.017, NT-proBNP: p = 0.058). There was no regression of LV hypertrophy. The patients with the largest postoperative valve area index [1.27 (1.10-1.55) cm2/m2] had the largest reduction of NT-proBNP (47%). Those with the smallest valve area index [0.67 (0.54-0.73) cm2/m2] had no decrease in NT-proBNP. CONCLUSIONS: Our study suggests that a reduction in left atrial pressure is the main factor causing the change of NT-proANP level after AVR. A small prosthetic valve orifice area with a high aortic valve gradient might prevent regression of LV hypertrophy, thus representing a stimulus for increased cardiac secretion of NT-proBNP.     

Novel snake venom ligand dendroaspis natriuretic peptide is selective for natriuretic peptide receptor-A in human heart: downregulation of natriuretic peptide receptor-A in heart failure

The natriuretic peptides are considered to be cardioprotective; however, their receptors have not been identified in human myocardium using radiolabeled analogs. Dendroaspis natriuretic peptide (DNP) has been recently identified as a new member of this peptide family and is thought to be less susceptible to enzymatic degradation. Therefore, we have developed the novel radiolabeled analog [125I]-DNP and used this to localize high-affinity (K(D)=0.2 nmol/L), saturable, specific binding sites in adult human heart (n=6) and coronary artery (n=8). In competition binding experiments, atrial natriuretic peptide and brain type natriuretic peptide had greater affinity for [125I]-DNP binding sites than C-type natriuretic peptide and the natriuretic peptide receptor (NPR)-C ligand, cANF. This rank order of potency suggested binding of [125I]-DNP was specific to NPR-A. Messenger RNA encoding NPR-A was identified in left ventricle and coronary artery smooth muscle, and expression was confirmed by immunocytochemical studies at the protein level. In addition, fluorescence dual labeling immunocytochemistry localized NPR-A protein to cardiomyocytes, endocardial endothelial cells, and smooth muscle of intramyocardial vessels. Importantly, we demonstrated a significant downregulation in the density of NPR-A in heart and coronary artery of patients with ischemic heart disease that may explain, in part, the attenuated natriuretic peptide response reported in this patient group.     

Transcatheter aortic valve replacement in unicuspid aortic valve stenosis

Unicuspid aortic valve (UAV) offers unique challenges to transcatheter aortic valve replacement (TAVR), due to asymmetric expansion and apposition of the prosthesis during implantation. Although TAVR in bicuspid is now a well described experience, TAVR in unicuspid valve has not yet been described. A challenging case is described with TAVR in UAV using a Edwards Sapiens prosthesis via transapical approach. © 2016 Wiley Periodicals, Inc.     

Relation of N-terminal pro-B-type natriuretic peptide to severity of valvular aortic stenosis

N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been shown to be a reliable biochemical marker for left ventricular wall stress and is increased in patients with aortic stenosis (AS). We evaluated the role of NT pro-BNP as a biochemical marker in the diagnosis of AS and whether it contributes to the optimal timing for aortic valve replacement (AVR). Included in this study were 146 patients who had AS, 31 who underwent AVR, and 32 who had "normal valve function" (controls). Increased NT pro-BNP was closely linked to severity of AS (mild AS 612 +/- 151 pg/ml, moderate AS 1,441 +/- 32 pg/ml, severe AS 2,579 +/- 13 pg/ml, AVR 593 +/- 148 pg/ml, controls 140 +/- 27 pg/ml; p <0,01) and to New York Heart Association functional class (class I 601 +/- 116 pg/ml, class II 1,119 +/- 216 pg/ml, class III 1,998 +/- 459 pg/ml, class IV 5,107 +/- 1,512 pg/ml; p <0.01). Area under the receiver-operating characteristic curve for NT pro-BNP as a predictor for AVR was 0.73. Using an optimized cutoff of 550 pg/ml for NT-proBNP, the positive predictive value was 85%. Thus, NT pro-BNP is linked to severity of AS and New York Heart Association class and is an indication for AVR. Therefore, it is a useful biochemical marker to evaluate severity of AS, monitor disease progression at an early stage, and decide on the optimal time for AVR.     

Four functionally distinct C-type natriuretic peptides found in fish reveal evolutionary history of the natriuretic peptide system

Natriuretic peptides (NPs) are major cardiovascular and osmoregulatory hormones in vertebrates. Although tetrapods generally have three subtypes, atrial NP (ANP), B-type NP (BNP), and C-type NP (CNP), some teleosts lack BNP, and sharks and hagfish have only one NP. Thus, NPs have diverged during fish evolution, possibly reflecting changes in osmoregulatory systems. In this study, we found, by cDNA cloning, four distinct CNPs (1 through 4) in the medaka (Oryzias latipes) and puffer fish (Takifugu rubripes), although to our knowledge no more than two CNPs have been isolated from a vertebrate species. Predicted mature CNP-1 was most similar, and CNP-4 was most dissimilar, to mammalian CNPs. However, synthetic CNP-4 most potently activated OlGC1, a medaka CNP-specific receptor (NPR-B) expressed in cultured cells, whereas CNP-1 and CNP-3 most activated OlGC7 and OlGC2, two medaka homologues of the ANP/BNP receptor (NPR-A), respectively. Linkage mapping in medaka followed by comparative genomic analyses among fishes and humans located four CNP genes in separate medaka chromosomes corresponding to human chromosomes 1, 2, 12, and 17. From conserved synteny, the following evolutionary history of NPs was evoked: (i) four CNP genes were generated by chromosomal duplications before the divergence of elasmobranchs; (ii) the CNP-3 gene generated ANP and BNP genes through tandem duplication before the divergence of tetrapods and teleosts; (iii) CNP-1 and -2 genes were retained in the teleost lineage but not in the tetrapod lineage; (iv) the CNP-3 gene disappeared from the tetrapod lineage after divergence of amphibians; and (v) the CNP-4 gene is retained in humans as CNP.     

C-type natriuretic peptide in growth: A new paradigm

C-type natriuretic peptide (CNP), acting through its receptor, natriuretic peptide receptor-B (NPR-B), plays a critical role in linear growth. Knockout mice for CNP and NPR-B are dwarfed, and transgenic mice overexpressing CNP are overgrown. CNP has a direct regulatory effect on growth plate chondrocytes, acting primarily to promote terminal differentiation and hypertrophy. In humans, homozygous NPR-B mutations are the cause of acromesomelic dysplasia, Maroteaux type (AMDM), a severe form of disproportionate dwarfism. A patient with AMDM and the NPR-B knockout mouse both have low insulin-like growth factor I (IGF-I) levels, suggesting an interaction between these regulatory systems. Heterozygous carriers of NPR-B mutations also have reduced stature, but no other abnormalities. Hence, heterozygous NPR-B mutations are another cause of “idiopathic” short stature. The CNP–NPR-B system has only recently been found to be an important regulator of human growth, and abnormalities in this system have clinical implications. Considerable work is needed to further understand this new paradigm of human growth regulation.     

C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.