Differential hormonal profiles of adrenomedullin and proadrenomedullin N-terminal 20 peptide in patients with heart failure and effect of treatment on their plasma levels

BACKGROUND: Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings. HYPOTHESIS: The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure. METHODS: In all, 98 patients [65 men and 33 women, aged 58.2 +/- 11.0 years, mean +/- standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 +/- 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification. RESULTS: Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration. CONCLUSIONS: Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.     

Myocardial Composition in Light-Chain Cardiac Amyloidosis More Than 1 Year After Successful Therapy

ObjectivesThe goals of this study were to characterize myocardial composition during the active and remission phases of light-chain (AL) cardiac amyloidosis.BackgroundCardiac dysfunction in AL amyloidosis is characterized by dual insults to the myocardium from infiltration and toxicity from light chains during the active phase and by infiltration alone in the remission phase.MethodsProspectively enrolled subjects with cardiac AL amyloidosis (21 remission AL amyloidosis; age: 63.4 ± 7.3 years; 47.6% male; and 48 active AL amyloidosis; age: 62.5 ± 7.4 years; 60.4% male) underwent contrast-enhanced cardiac magnetic resonance with T₁ and T₂ mapping and measurement of extracellular volume (ECV). By definition, serum free light-chain levels were normal for at least 1 year following successful AL therapy in the remission group and abnormal in the active group.ResultsMyocardial ECV was similarly expanded in the remission and active AL amyloidosis groups (0.488 ± 0.082 vs 0.519 ± 0.083, respectively; P = 0.15). However, myocardial T₂ relaxation times (47.7 ± 3.2 ms vs 45.5 ± 3.0 ms; P = 0.008) as well as native T₁ times (1,368 ms [IQR: 1,290-1,422 ms] vs 1,264 ms [IQR: 1,203-1,380 ms]; P = 0.024) were significantly higher in the remission compared to the active AL amyloidosis group.ConclusionsMyocardial ECV is substantially expanded in the active AL and remission AL cardiac amyloidosis groups, but native T₁ values were higher, suggesting a different myocardial composition. There is no evidence of myocardial edema in active AL cardiac amyloidosis. Future phenotyping studies of AL cardiac amyloidosis need to consider complementary myocardial markers that define the interstitial milieu in addition to changes in extracellular volume. (Molecular Imaging of Primary Amyloid Cardiomyopathy; NCT02641145)     

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Most, if not all, peptide- and protein-based hydrogels formed by self-assembly can be characterized as kinetically trapped 3D networks of fibrils. The propensity of disease-associated amyloid-forming peptides and proteins to assemble into polymorphic fibrils suggests that cross-β fibrils comprising hydrogels may also be polymorphic. We use solid-state NMR to determine the molecular and supramolecular structure of MAX1, a de novo designed gel-forming peptide, in its fibrillar state. We find that MAX1 adopts a β-hairpin conformation and self-assembles with high fidelity into a double-layered cross-β structure. Hairpins assemble with an in-register Syn orientation within each β-sheet layer and with an Anti orientation between layers. Surprisingly, although the MAX1 fibril network is kinetically trapped, solid-state NMR data show that fibrils within this network are monomorphic and most likely represent the thermodynamic ground state. Intermolecular interactions not available in alternative structural arrangements apparently dictate this monomorphic behavior.MAX1 is a 20-residue peptide designed de novo to fold into an amphiphilic β-hairpin that self-assembles to form a fibrillar network within a self-supporting hydrogel (1). The MAX1 gel exhibits shear thin-recovery rheological behavior (2), is cytocompatible toward mammalian cells, yet is inherently antimicrobial (3) and thus has applications in tissue engineering and drug delivery. In addition to exploring the utility of the gel, we seek to understand the mechanism of gelation, the macroscale morphology of its fibrillar network, and the underlying molecular structure of its fibrils.MAX1 contains two segments of alternating lysine and valine residues, connected by a four-residue turn-forming segment. When initially dissolved in water, electrostatic repulsions among protonated lysine sidechains lead to an ensemble of monomeric random coil conformations (1). Peptide folding and self-assembly, leading to gelation (Fig. 1), can be triggered by attenuating electrostatic repulsions, by adjusting the solution pH and/or ionic strength. Increasing the solution temperature also drives hydrophobic collapse of valine sidechains, further favoring MAX1 assembly. According to circular dichroism (1), cryo-transmission electron microscopy (TEM) (4), small-angle neutron scattering (5), and dynamic light scattering coupled with rheological measurements (4), soon after the triggering event, peptides assemble into branched clusters of β-sheet–rich, semiflexible nanofibrils throughout the solution. Individual clusters contain dangling fibril ends that grow and interpenetrate neighboring clusters as the network evolves. Multiple particle tracking microrheology shows that the time at which the fibril network percolates the entire sample volume, defining the gel point, is less than 1 min at 1% (wt/vol) peptide (6). In this mechanism of gelation, the growing fibrils become kinetically trapped in the evolving network as they percolate the sample volume. Fibrils do not precipitate, but rather form a 3D random network that defines the gel state.Open in a separate windowFig. 1.Self-assembly of MAX1 monomers leads to a hydrogel made from a kinetically trapped network of fibrils, each of which contains a putative double-layered β-sheet structure comprised of β-hairpins. Four possible supramolecular structures are shown, differing in the nature of intermolecular alignments within and between the β-sheets.Full structural models for naturally occurring amyloid (7–10) and prion (11) fibrils have been developed from solid-state NMR data, but less is known about fibril structures within designed peptide hydrogels. Disease-associated amyloid and prion fibrils are known to be polymorphic at the molecular structural level (7, 8, 12, 13), implying that structures within peptide and protein fibrils are generally not determined uniquely by amino acid sequences and do not necessarily represent thermodynamic ground states. A model for fibrils formed by the designed peptide RADA16-I has been proposed by Cormier et al. based on solid-state NMR data (14), in which RADA16-I monomers form single β-strands within a double-layered cross-β structure. Solid-state NMR spectra of this hydrogel-forming peptide also indicate coexistence of several distinct fibril structures, suggesting that polymorphism may also be a trait of designed sequences.Here, we use solid-state NMR to develop a full structural model for MAX1 fibrils, including molecular conformation, β-sheet organization, and intersheet interactions, with experimental restraints on all levels of structure. We find that MAX1 self-assembles with high fidelity to form monomorphic fibrils with well-defined and uniform structures. This structural homogeneity suggests that although the evolution of the fibril network is governed by kinetics, the molecular structure within MAX1 fibrils most likely represents the thermodynamic ground state. Additionally, results described below represent, to our knowledge, the first complete experimentally based model for a cross-β fibril structure comprised of β-hairpins.     

原发性高血压病人左室肥厚与B型利钠肽的关系

目的探讨原发性高血压（EH）病人左室肥厚（LVH）与B型利钠肽（BNP）的关系。方法EH病人83例,根据左室质量指数（LVMI）将EH病人分为LVH组与无LVH组。对两组行心脏彩色B超检查及BNP测定。结果LVH组BNP水平为（45.87±7.32）pg/mL,高于无LVH组（11.75±4.14）pg/mL（P〈0.01）,LVMI与BNP水平呈独立正相关（回归系数r=0.38,P〈0.01）。结论BNP是EH病人合并LVH的独立预测指标。     

阵发性心房颤动患者肺静脉电隔离术前后血浆N端脑钠素前体水平的变化

目的:探讨阵发性心房颤动(房颤)患者肺静脉电隔离术前后血浆心钠素(ANP)、N端脑钠素前体(NT-ProBNP)和超敏C反应蛋白(hs-CRP)变化的临床意义,以及与房颤复发的关系。方法:33例阵发性房颤患者和30例正常对照者入选,分别用放射免疫法、电化学发光免疫法、免疫比浊法测定术前、术后24h和术后3个月的ANP、NT-ProBNP和hs-CRP水平。结果:①房颤组基线血浆NT-ProBNP水平与对照组相比显著升高[(296.79±272.13):(80.81±69.13)μg/L,P=0.000],而血浆ANP和hs-CRP水平正常。术后房颤复发组的基线血浆NT-ProBNP水平较维持窦律组显著升高[(572.72±234.21):(176.82±188.73)μg/L,P=0.000]。②对13个变量如年龄、房颤史、超声参数、血浆ANP、NT-ProBNP和hs-CRP水平等进行Cox多元逐步回归,结果显示仅高的血浆NT-ProBNP水平是阵发性房颤患者肺静脉电隔离术后房颤复发的独立预测因子(χ2=20.986,P=0.000)。通过Kaplan-Meier分析,血浆NT-ProBNP水平≥423.20μg/L是房颤复发的重要危险因子(P=0.002)。结论:阵发性房颤患者血浆NT-ProBNP水平显著升高,升高的NT-ProBNP水平不仅可预测发生房颤的风险,还是早期预测房颤复发的生物标记物。     

Effects of radiofrequency catheter ablation on myocardial performance index and plasma NT-Pro-BNP levels in patients with Wolff-Parkinson-White syndrome

Background: The myocardial performance index (Tei index) is an echocardiographic index of combined systolic and diastolic functions. Brain natriuretic peptide (BNP) and its biologically inactive fragment N-terminal pro-BNP (NT-pro-BNP) are secreted by the heart in response to myocardial stretch. In this study, we investigated Tei index and NT-pro-BNP levels in patients with Wolff-Parkinson-White (WPW) syndrome before and after radiofrequency catheter ablation therapy (RFCA).
Methods: Thirty patients (19 males, 11 females, aged 35.5 ± 14.4 years) with WPW syndrome were enrolled in this study. Echocardiographic examination was performed before and 24 hours after RFCA. Tei index was calculated using Doppler echocardiography. Blood samples were taken before and 24 hours after RFCA to detect levels of NT-pro-BNP. Results: Although isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) did not change, aortic ejection time (ET) was decreased after RFCA (276 ± 22 ms vs 254 ± 30 ms, P < 0.01). So Tei index was significantly higher in postablation period (0.36 ± 0.11 vs 0.42 ± 0.21, P < 0.05). NT-pro-BNP levels did not change significantly after RFCA. Conclusions: We demonstrated that restoration of normal atrioventricular conduction by RFCA, leads to increase in Tei index but does not effect plasma NT-pro-BNP levels .     

不同剂量甲状旁腺激素相关肽对去卵巢大鼠骨骼的影响

目的 观察不同剂量甲状旁腺激素相关肽（PTHrP1-34）对去卵巢大鼠骨密度（BMD）、骨生物力学特性的影响。方法 4月龄雌性未孕大鼠60只，其中50只行双侧卵巢摘除术，10只行假手术（A组）。4周后将诱发骨质疏松模型鼠随机分为五组各10只，B组加安慰剂，C组加苯甲酸雌二醇，D、E、F组分别加PTHrP1-3420、40、80μg／kg。治疗3个月后，测定各组股骨和腰椎BMD、股骨三点弯曲及腰椎压缩等。结果 B组BMD较A组明显降低，表明大鼠骨质疏松模型建模成功。E、F组BMD、股骨最大载荷和腰椎压缩负荷比B组显著增加，与C组近似。结论PTHrP1-3440、80μg／kg皮下注射对大鼠骨质疏松有治疗作用。     

Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans

BACKGROUND & AIMS: The gut-derived peptide glucagon-like peptide 2 (GLP-2) has been suggested as a potential drug candidate for the treatment of various intestinal diseases. However, the acute effects of GLP-2 on gastric functions as well as on glucose and lipid homeostasis in humans are less well characterized. METHODS: Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 or placebo over 120 minutes in the fasting state, and pentagastrin-stimulated gastric acid output was assessed. Another 15 healthy male volunteers were studied with a 390 minutes infusion of GLP-2 or placebo during the ingestion of a solid test meal. Gastric emptying was determined using a 13C-sodium-octanote breath test. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-2, free fatty acids, free glycerol, and triglycerides were determined. RESULTS: GLP-2 administration led to a marked increase in glucagon concentrations both in the fasting state and during the meal study (P < .001). Postprandial plasma concentrations of triglycerides and free fatty acids were significantly higher during GLP-2 infusion compared with placebo (P < .01), while glycerol concentrations were similar (P = .07). GLP-2 administration caused an approximately 15% reduction in pentagastrin-stimulated gastric acid and chloride secretion (P < .01), whereas gastric emptying was not affected (P = .99). CONCLUSIONS: GLP-2 reduces gastric acid secretion but does not seem to have an influence on gastric emptying. The stimulation of glucagon secretion by GLP-2 may counteract the glucagonostatic effect of GLP-1. Changes in postprandial lipid excursions seem to reflect enhanced intestinal nutrient absorption during GLP-2 administration.     

先天性心脏病介入治疗与外科治疗临床比较

目的:对房间隔缺损(ASD)、室间隔缺损(VSD)的介入治疗(Amplatzer封堵器)和外科手术治疗的临床疗效进行比较。方法:2004年5月至12月住院患儿,符合单一左向右分流畸形ASD或VSD,根据治疗方法不同分为介入组和手术组;比较2组在疗效、费用、并发症、输血量及住院时间等方面的异同;通过放免法测定2组治疗前后的心钠素(ANP)水平。结果:2组手术成功率均为100%;介入组均未输血,手术组均输血治疗(P<0·01);术后住院时间介入组少于手术组(P<0·01);治疗费用介入组高于手术组(P<0·01);ANP水平、外科手术及介入治疗后均较治疗前降低。结论:单一ASD、VSD的介入治疗与手术治疗临床效果相同;介入组不需输血,术后住院时间短,但治疗费用较昂贵。