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1.
Front Cardiovasc Med ; 10: 1195082, 2023.
Article in English | MEDLINE | ID: mdl-38259307

ABSTRACT

Objectives: In dyspneic patients with atrial fibrillation (AF) or obesity, the diagnostic performance of NT-proBNP for acute heart failure is reduced. We evaluated the erythroblast derived protein erythroferrone (ERFE) as an ancillary biomarker for the diagnosis of acute decompensated heart failure (ADHF) in these comorbid subgroups in both Western and Asian populations. Methods: The diagnostic performance of ERFE (Intrinsic Lifesciences) and NT-proBNP (Roche Cobas e411) for ADHF was assessed in 479 New Zealand (NZ) and 475 Singapore (SG) patients presenting with breathlessness. Results: Plasma ERFE was higher in ADHF, compared with breathlessness from other causes, in both countries (NZ; 4.9 vs. 1.4 ng/ml, p < 0.001) and (SG; 4.2 vs. 0.4 ng/ml, p = 0.021). The receiver operating characteristic (ROC) areas under the curve (AUCs) for discrimination of ADHF were reduced in the NZ cohort compared to SG for ERFE (0.75 and 0.84, p = 0.007) and NT-proBNP (0.86 and 0.92, p = 0.004). Optimal cut-off points for ERFE yielded comparable sensitivity and positive predictive values in both cohorts, but slightly better specificity, negative predictive values and accuracy in SG compared with NZ. In patients with AF, the AUC decreased for ERFE in each cohort (NZ: 0.71, n = 105, SG: 0.61, n = 44) but increased in patients with obesity (NZ: 0.79, n = 150, SG: 0.87, n = 164). Conclusions: Circulating ERFE is higher in patients with ADHF than in other causes of new onset breathlessness with fair diagnostic utility, performing better in Asian than in Western patients. The diagnostic performance of ERFE is impaired in patients with AF but not patients with obesity.

2.
Clin Chem ; 68(10): 1292-1301, 2022 10 06.
Article in English | MEDLINE | ID: mdl-35932191

ABSTRACT

BACKGROUND: Secretion of cardioprotective B-type natriuretic peptide 1-32 (BNP1-32) is increased proportionately with cardiac dysfunction, but its measurement in plasma is difficult. Therefore, less specific BNP and amino-terminal proBNP (NT-proBNP) assays that detect the precursor molecule proBNP alongside BNP or NT-proBNP metabolites were developed to reflect BNP1-32 secretion and are now mandated in the diagnosis of heart failure (HF). We compared the diagnostic performance of 2 widely used clinical assays: the Roche proBNPII assay, and Abbott BNP assay, against our recently developed in-house assays that measure either intact BNP1-32 or NT-proBNP. METHODS: EDTA plasma samples obtained from patients presenting with breathlessness (n = 195, 60 [31%] with clinically adjudicated HF) were assayed using the Roche NT-proBNP and our specific in-house BNP1-32 and NTBNP assays. A subset (n = 75) were also assessed with the Abbott BNP assay. RESULTS: Roche NT-proBNP was highly correlated with BNP1-32 and NTBNP (Spearman rho = 0.92 and 0.90, respectively, both Ps < 0.001), and all 3 assays similarly discriminated acute HF from other causes of breathlessness (ROC analysis areas under the curve 0.85-0.89). The Abbott BNP assay performed similarly to the other assays. Roche NT-proBNP and BNP1-32 assays had similar sensitivity (83% and 80%), specificity (83% and 84%), positive (70% and 71%) and negative (91% and 90%) predictive values, and accuracy (both 83%) at their optimal cutoffs of 1536 and 12 ng/L, respectively. CONCLUSIONS: Since all assays exhibited similar performance in the diagnosis of HF, currently mandated assays provide a reliable proxy for circulating concentrations of active BNP1-32 in HF diagnosis.


Subject(s)
Heart Failure , Natriuretic Peptide, Brain , Biomarkers , Dyspnea/diagnosis , Edetic Acid , Humans , Peptide Fragments
3.
EBioMedicine ; 82: 104170, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35850010

ABSTRACT

BACKGROUND: Plasma cardiac markers may assist in prediction of incident cardiovascular disease. METHODS: The incremental value of cardiac Troponins (T and I) and NT-proBNP added to risk factors in the PREDICT score for incident cardiovascular disease (CVD) in primary care, was assessed in 4102 asymptomatic participants in a randomised controlled trial of Vitamin D (ViDA). Findings were corroborated in 2528 participants in a separate community-based observational registry of CVD-free volunteers (HVOLS). FINDINGS: Hazard ratios for first cardiovascular events adjusted for PREDICT risk factors, comparing fifth to first quintiles of marker plasma concentrations, were 2.57 (95% CI 1.47-4.49); 3.01 (1.66-5.48) and 3.38 (2.04-5.60) for hs-cTnI, hs-cTnT and NT-proBNP respectively. The C statistic for discrimination of the primary endpoint increased from 0.755 to 0.771 (+0.016, p = 0.01). Cardiac marker data correctly reclassified risk upwards in 6.7% of patients and downwards in 3.3%. These findings were corroborated by results from HVOLS. INTERPRETATION: Increments in plasma cardiac biomarkers robustly and reproducibly predicted increased hazard of incident CVD, independent of established risk factors, in two community-dwelling populations. Cardiac markers may augment risk assessment for onset of CVD in primary care. FUNDING: ViDA was funded by the Health Research Council of New Zealand (grant 10/400) and the Accident Compensation Corporation. HVOLS was funded by the Health Research Council of NZ Programme Grants (grants 02/152 and 08/070) and by grants from the Heart Foundation of NZ and the Christchurch Heart Institute Trust. Roche Diagnostics provided in-kind support for NT-proBNP and hs-cTnT assays and Abbott Laboratories for hs-cTnI assays.


Subject(s)
Cardiovascular Diseases , Troponin T , Biomarkers , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Humans , Independent Living , Laboratories , Natriuretic Peptide, Brain , Peptide Fragments , Risk Assessment/methods , Risk Factors , Troponin I , Vitamin D
4.
Sci Rep ; 11(1): 4605, 2021 02 25.
Article in English | MEDLINE | ID: mdl-33633217

ABSTRACT

To identify circulating proteins predictive of acute cardiovascular disease events in the general population, we performed a proteomic screen in plasma from asymptomatic individuals. A "Discovery cohort" of 25 individuals who subsequently incurred a cardiovascular event within 3 years (median age = 70 years, 80% male) was matched to 25 controls remaining event-free for > 5 years (median age = 72 years, 80% male). Plasma proteins were assessed by data independent acquisition mass spectrometry (DIA-MS). Associations with cardiovascular events were tested using Cox regression, adjusted for the New Zealand Cardiovascular Risk Score. Concentrations of leading protein candidates were subsequently measured with ELISAs in a larger (n = 151) independent subset. In the Discovery cohort, 76 plasma proteins were robustly quantified by DIA-MS, with 8 independently associated with cardiovascular events. These included (HR = hazard ratio [95% confidence interval] above vs below median): fibrinogen alpha chain (HR = 1.84 [1.19-2.84]); alpha-2-HS-glycoprotein (also called fetuin A) (HR = 1.86 [1.19-2.93]); clusterin isoform 2 (HR = 1.59 [1.06-2.38]); fibrinogen beta chain (HR = 1.55 [1.04-2.30]); hemoglobin subunit beta (HR = 1.49 [1.04-2.15]); complement component C9 (HR = 1.62 [1.01-2.59]), fibronectin isoform 3 (HR = 0.60 [0.37-0.99]); and lipopolysaccharide-binding protein (HR = 1.58 [1.00-2.49]). The proteins for which DIA-MS and ELISA data were correlated, fibrinogen and hemoglobin, were analyzed in an Extended cohort, with broader inclusion criteria and longer time to events, in which these two proteins were not associated with incident cardiovascular events. We have identified eight candidate proteins that may independently predict cardiovascular events occurring within three years in asymptomatic, low-to-moderate risk individuals, although these appear not to predict events beyond three years.


Subject(s)
Cardiovascular Diseases/blood , Fibrinogen/analysis , Hemoglobins/analysis , Aged , Cardiovascular Diseases/diagnosis , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Heart Disease Risk Factors , Humans , Male , Mass Spectrometry , Predictive Value of Tests , Proportional Hazards Models
5.
J Appl Lab Med ; 5(3): 506-515, 2020 05 01.
Article in English | MEDLINE | ID: mdl-32445356

ABSTRACT

BACKGROUND: B-type natriuretic peptide (BNP) is a cardiac hormone released with an N-terminal fragment (NTproBNP) under conditions of ventricular pressure or volume overload. BNP has been proposed for use as a biomarker of cardiac dysfunction in premature infants in the setting of hemodynamically significant patent ductus arteriosus (HsPDA) and bronchopulmonary dysplasia (BPD). In adult settings the presence of proBNP and glycosylated isoforms may affect assay interpretation. However, there are limited data on how immature preterm physiology may affect BNP or NTproBNP levels and no published data on post-translational BNP processing in premature infants. METHODS: Pooled serial plasma samples from preterm infants born at less than 30 weeks gestation were analyzed for BNP congeners using Luminex® assay and high performance liquid chromatography. Samples were grouped according to clinical status: Group 1, no HsPDA and no BPD, Group 2 HsPDA and no/mild BPD, Group 3 HsPDA and moderate/severe BPD. RESULTS: Plasma from 15 infants was analyzed, and across all three groups NTproBNP predominated with minimal amounts of other isoforms; no glycosylation was detected. CONCLUSIONS: NTproBNP appears to be the predominant isoform across each of our clinical groups in our pooled sample analysis with no evidence of significant glycosylation. This suggests NTproBNP is likely to be a robust marker in this clinical setting.


Subject(s)
Biomarkers , Infant, Extremely Premature/blood , Natriuretic Peptide, Brain/blood , Chromatography, High Pressure Liquid , Humans , Immunoassay , Liquid Biopsy/methods , Protein Isoforms
7.
Clin Chem ; 65(9): 1115-1124, 2019 09.
Article in English | MEDLINE | ID: mdl-31092393

ABSTRACT

BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Plasma concentrations of B-type natriuretic peptide (BNP) or its amino terminal congener (NT-proBNP) are used for HF diagnosis and risk stratification. Because BNP concentrations are inexplicably lowered in obese patients, we investigated the relationship between proBNP glycosylation, plasma NT-proBNP, and body mass index (BMI) in HF patients. METHODS: Three assays were developed to distinguish between total proBNP (glycosylated plus nonglycosylated proBNP), proBNP not glycosylated at threonine 71 (NG-T71), and proBNP not glycosylated in the central region (NG-C). Intraassay and interassay CVs were <15%; limits of detection were <21 ng/L; and samples diluted in parallel. RESULT: Applying these assays and an NT-proBNP assay to plasma samples from 106 healthy volunteers and 238 HF patients determined that concentrations [median (interquartile range)] of proBNP, NG-T71, and NT-proBNP were greater in HF patients compared with controls [300 (44-664), 114 (18-254), and 179 (880-3459) ng/L vs 36 (18-229), 36 (18-175), and 40 (17-68) ng/L, respectively; all P < 0.012]. NG-C was undetectable in most samples. ProBNP concentrations in HF patients with BMI more or less than 30 kg/m2 were not different (P = 0.85), whereas HF patients with BMI >30 kg/m2 had lower NT-proBNP and NG-T71 concentrations (P < 0.003) and higher proBNP/NT-proBNP and proBNP/NG-T71 ratios (P = 0.001 and P = 0.02, respectively) than those with BMI <30 kg/m2. CONCLUSIONS: Increased BMI is associated with decreased concentrations of proBNP not glycosylated at T71. Decreased proBNP substrate amenable to processing could partially explain the lower NT-proBNP and BNP concentrations observed in obese individuals, including those presenting with HF.


Subject(s)
Heart Failure/metabolism , Natriuretic Peptide, Brain/metabolism , Obesity/metabolism , Peptide Fragments/metabolism , Adult , Body Mass Index , Female , Glycosylation , Heart Failure/blood , Heart Failure/diagnosis , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Natriuretic Peptide, Brain/chemistry , Obesity/blood , Peptide Fragments/blood , Peptide Fragments/chemistry , Prognosis , ROC Curve , Threonine/chemistry
8.
Clin Chem ; 63(6): 1110-1117, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28428353

ABSTRACT

BACKGROUND: Plasma B-type natriuretic peptide (BNP) concentration reflects cardiac dysfunction and assists in determining the diagnosis and prognosis of heart failure (HF). Current BNP assays overestimate circulating bioactive BNP1-32 concentrations as they also detect less active BNP metabolites and proBNP. A specific BNP1-32 assay with negligible cross-reactivity to proBNP and/or BNP metabolites may be advantageous. METHODS: We developed a Luminex-based specific BNP1-32 immunoassay and compared results obtained from 3 other BNP assays (a Luminex-based total-BNP assay, our BNP RIA, and the commercially available Abbott Architect BNP assay) in plasma from 42 patients with HF and 22 healthy controls. RESULTS: The BNP1-32 assay showed 57% cross-reactivity with BNP2-32, but ≤0.1% cross-reactivity to BNP3-32, other BNP metabolites, and proBNP; its detection limit was 0.35 ng/L; and intra- and interassay CVs were <15%. BNP immunoreactivity increased with HF severity (median concentrations being 0.3, 0.8, 26.2, and 17.3 ng/L in healthy controls and 40.7, 139, 465, and 1778 ng/L in HF patients for the BNP1-32, total-BNP, BNP RIA, and Abbott BNP assays respectively). The fold increase between HF cases with the New York Heart Association (NYHA) class IV was significantly greater with the BNP1-32 assay than the Abbott BNP (P = 0.026) and the BNP RIA (P < 0.0001) but not the total-BNP assay. CONCLUSIONS: We have developed the first assay that measures BNP1-32 in plasma without interference by proBNP. Analysis of larger patient cohorts is now required to compare the performance of this assay with current less specific assays for the diagnosis or prognosis of HF.


Subject(s)
Heart Failure/blood , Immunoassay/methods , Natriuretic Peptide, Brain/blood , Aged , Cross Reactions/immunology , Female , Heart Failure/diagnosis , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/metabolism
9.
Physiol Rep ; 3(5)2015 May.
Article in English | MEDLINE | ID: mdl-26019290

ABSTRACT

This study investigated whether a prior bout of moderate-intensity exercise attenuates the glycemia-increasing effect of a maximal 30-sec sprint. A secondary aim was to determine whether the effect of antecedent exercise on the glucoregulatory response to sprinting is affected by sex. Participants (men n = 8; women n = 7) were tested on two occasions during which they either rested (CON) or cycled for 60-min at a moderate intensity of ~65% V ˙ O 2 peak (EX) before performing a 30-sec maximal cycling effort 195 min later. In response to the sprint, blood glucose increased to a similar extent between EX and CON trials, peaking at 10 min of recovery, with no difference between sexes (P > 0.05). Blood glucose then declined at a faster rate in EX, and this was associated with a glucose rate of disappearance (R d) that exceeded the glucose rate of appearance (R a) earlier in EX compared with CON, although the overall glucose R a and R d profile was higher in men compared with women (P < 0.05). The response of growth hormone was attenuated during recovery from EX compared with CON (P < 0.05), with a lower absolute response in women compared with men (P < 0.05). The response of epinephrine and norepinephrine was also lower in women compared with men (P < 0.05) but similar between trials. In summary, a prior bout of moderate-intensity exercise does not affect the magnitude of the glycemia-increasing response to a 30-sec sprint; however, the subsequent decline in blood glucose is more rapid. This blood glucose response is similar between men and women, despite less pronounced changes in glucose R a and R d, and a lower response of plasma catecholamines and growth hormone to sprinting in women.

11.
Clin Chem ; 60(3): 549-58, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24415740

ABSTRACT

BACKGROUND: The B-type natriuretic peptides (BNP and N-terminal pro-BNP) are secreted by the heart and, in the case of BNP, serve to maintain circulatory homeostasis through renal and vascular actions and oppose many effects of the renin-angiotensin system. Recent evidence suggests that in patients with severe heart failure, circulating immunoreactive BNP is made up mainly of metabolites that may have reduced bioactivity. We hypothesized that BNP may be degraded before it even leaves the heart. METHODS: Peripheral venous plasma plus atrial and ventricular tissue, obtained from explanted hearts at the time of transplantation, were collected from 3 patients with end-stage heart failure. In a separate study, plasma was collected from the coronary sinus and femoral artery of 3 separate patients undergoing cardiac catheterization. Plasma C18 reverse-phase extracts were separated on reverse-phase HPLC, and the collected fractions were subjected to RIAs with highly specific antisera directed to the amino- and carboxy-terminal ends of BNP(1-32). RESULTS: ProBNP, BNP(1-32), and 2 major BNP metabolites were present in atrial and ventricular tissue, where BNP(1-32) represented 45% and 70% of total processed BNP, respectively. Neither BNP(1-32) nor the 2 metabolites were detected in peripheral venous plasma. Nor was BNP(1-32) detected in matching coronary sinus and femoral artery plasma from the 3 patients undergoing cardiac catheterization. CONCLUSIONS: BNP(1-32) is partly degraded within the hearts of patients with end-stage heart failure, and even in patients with relatively well-preserved left ventricular systolic function, only BNP metabolites enter the systemic circulation.


Subject(s)
Coronary Sinus/metabolism , Myocardium/metabolism , Natriuretic Peptide, Brain/metabolism , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Natriuretic Peptide, Brain/blood , Protein Precursors/blood , Protein Precursors/metabolism , Regional Blood Flow , Ventricular Function, Left
12.
PLoS One ; 8(3): e57806, 2013.
Article in English | MEDLINE | ID: mdl-23516417

ABSTRACT

The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.


Subject(s)
Atrial Natriuretic Factor/metabolism , Camelus/physiology , Dehydration/metabolism , Natriuretic Peptide, Brain/metabolism , Renin-Angiotensin System/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Atrial Natriuretic Factor/blood , Dehydration/drug therapy , Losartan/pharmacology , Male , Myocardium/metabolism , Natriuretic Peptide, Brain/blood , Renin-Angiotensin System/drug effects
13.
Clin Biochem ; 46(4-5): 388-90, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23219736

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate a Milliplex NTproBNP immunoassay and to compare its performance with the Roche Elecsys assay and an in house NTproBNP radioimmunoassay (RIA). DESIGN AND METHODS: Samples were analyzed for NTproBNP in all 3 assays following the manufacturer's instructions and/or our previously published methodologies. RESULTS: Similar plasma concentrations and assay reproducibility were observed for the Roche assay and in house RIA. However, the Milliplex assay produced much lower concentrations than the other two assays (versus Roche Elecsys bias of -367.9 pg/mL, (LOA -907.6 and 171.8)), and only quantified results for 63 of the 111 samples assessed. Of these 46 samples had acceptable errors of measurement (within sample coefficients of variation <20%) equating to 41% of the total samples measured. CONCLUSIONS: The Milliplex assay, in its current form, does not produce results comparable with the Roche Elecsys 2010 assay or our in house RIA, and does not perform well as a quantitative assay. It may provide qualitative results (ie high, medium or low concentration), and serve as a rudimentary screening assay.


Subject(s)
Blood Chemical Analysis/standards , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Heart Diseases/blood , Heart Diseases/diagnosis , Humans , Limit of Detection , Radioimmunoassay/standards , Reference Standards , Reproducibility of Results
14.
PLoS One ; 7(5): e37299, 2012.
Article in English | MEDLINE | ID: mdl-22624009

ABSTRACT

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.


Subject(s)
Camelus/physiology , Dehydration/physiopathology , Dehydration/veterinary , Renin-Angiotensin System/drug effects , Aldosterone/blood , Analysis of Variance , Animals , Arginine Vasopressin/blood , Body Weights and Measures , Creatinine/blood , Losartan/pharmacology , Male , Renin-Angiotensin System/physiology , Sodium/blood , United Arab Emirates , Urea/blood
15.
Am J Physiol Endocrinol Metab ; 302(5): E576-84, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22185842

ABSTRACT

The aim of this study was to create a comprehensive mouse model of the metabolic syndrome by crossing aromatase-deficient (ArKO) mice with apolipoprotein E-deficient (ApoE(-/-)) mice. Successive crossbreeding of ArKO with ApoE(-/-)-deficient mice generated double knockout, MetS-Tg mice. The phenotypic characteristics of the MetS-Tg mice were assessed at 3, 6, and 12 mo of age and compared with age- and sex-matched wild-type (WT) controls. Blood pressure and heart rate were recorded by a noninvasive, computerized tail-cuff system. Oral glucose and intraperitoneal insulin tolerance tests were performed. Serum cholesterol levels were measured by a combined quantitative colorimetric assay. Plasma adiponectin, C-reactive protein (CRP), insulin, interleukin-6 (IL-6), leptin, resistin, and tumor necrosis factor-α (TNF-α) were measured by multiplexed ELISA. MetS-Tg mice displayed significantly increased body weight, central obesity, and elevated blood pressure at all three ages compared with WT mice. Elevated serum cholesterol was associated with higher triglycerides and LDL/VLDL cholesterol particles and was accompanied by a decrease in HDL and histological evidence of fatty liver. MetS-Tg mice of all ages showed impaired glucose tolerance. At 12 mo, MetS-Tg mice had elevated plasma levels of CRP, IL-6, leptin, and TNF-α, but resistin levels were largely unchanged. We now report that this combination of gene knockouts produces a novel strain of mice that display the diverse clinical features of the metabolic syndrome, including central obesity, progressive hypertension, an adverse serum lipid profile, fatty liver, glucose intolerance, insulin resistance, and evidence of an inflammatory state.


Subject(s)
Apolipoproteins E/physiology , Aromatase/physiology , Disease Models, Animal , Metabolic Syndrome/physiopathology , Adipose Tissue, White/immunology , Adipose Tissue, White/pathology , Animals , Aorta/immunology , Aorta/pathology , Apolipoproteins E/genetics , Aromatase/genetics , Atherosclerosis/etiology , C-Reactive Protein/analysis , Crosses, Genetic , Cytokines/blood , Fatty Liver/etiology , Female , Glucose Intolerance/etiology , Hyperlipidemias/etiology , Hypertension/etiology , Insulin Resistance , Liver/immunology , Liver/pathology , Male , Metabolic Syndrome/blood , Metabolic Syndrome/immunology , Metabolic Syndrome/pathology , Mice , Mice, Knockout , Obesity, Abdominal/etiology
16.
Clin Biochem ; 45(1-2): 168-70, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22040809

ABSTRACT

OBJECTIVES: To investigate the ratio of enzyme inhibitor volume to blood volume in angiotensin II (Ang II) blood collection tubes. DESIGN AND METHODS: Whole blood was mixed with known volumes of inhibitor prior to angiotensin II analysis. RESULTS: Imunoreactive Ang II levels increased at low blood volume to high inhibitor volume ratios, due to interference by o-phenanthroline. CONCLUSION: To prevent falsely elevated Ang II levels in low volume blood samples an appropriate volume of inhibitor solution must be used.


Subject(s)
Angiotensin II/metabolism , Enzyme Inhibitors/pharmacology , Phenanthrolines/pharmacology , Radioimmunoassay/methods , Angiotensin II/antagonists & inhibitors , Blood Pressure/drug effects , Blood Volume/drug effects , Buffers , Drug Therapy, Combination/methods , Humans , Models, Statistical , Protease Inhibitors/pharmacology
17.
Hypertension ; 57(6): 1136-44, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21536988

ABSTRACT

Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 µg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P<0.001) and output (2.6±0.1 versus 3.8±0.3 L/min; P<0.001), together with reductions in left atrial pressure (28±1 versus 12±1 mm Hg; P<0.001) and peripheral resistance (30±2 versus 20±2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74±2 versus 72±2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33±0.27 versus 0.73±0.20 nmol/L per hour; P<0.001), aldosterone (970±383 versus 396±96 pmol/L; P<0.05), vasopressin (2.4±0.8 versus 1.3±0.1 pmol/L; P<0.05), endothelin 1 (7.2±0.7 versus 4.5±0.4 pmol/L; P<0.01), and atrial (269±27 versus 150±19 pmol/L; P<0.001) and B-type (65±9 versus 29±6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure.


Subject(s)
Heart Failure/physiopathology , Hemodynamics/drug effects , Urocortins/pharmacology , Vascular Resistance/drug effects , Aldosterone/blood , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Creatinine/urine , Endocrine System/drug effects , Endocrine System/physiopathology , Endothelin-1/blood , Female , Heart/drug effects , Heart/physiopathology , Heart Failure/blood , Heart Failure/urine , Infusions, Intravenous , Kidney/drug effects , Kidney/physiopathology , Mice , Oligopeptides/blood , Renin/blood , Sheep , Sodium/urine , Time Factors , Urocortins/administration & dosage , Vasopressins/blood
18.
Ann Med ; 43(3): 188-97, 2011 May.
Article in English | MEDLINE | ID: mdl-20961274

ABSTRACT

Whereas the role of the cardiac natriuretic peptides, ANP and BNP, in some aspects of physiology and pathophysiology is clear, their potential in diagnosis, prognosis, and therapeutics in many clinical disorders remains uncertain. We predict that circulating levels of these peptides will find increasing diagnostic utility in patients presenting with dyspnoea, in guiding the complex pharmacotherapy in heart failure, and may likewise be useful in guiding the management of patients on chronic maintenance renal dialysis. We predict also that levels of these peptides will be of practical use as prognostic indicators in 'at-risk' populations (such as those with diabetes, coronary heart disease, hypertension, thalassaemia, etc.) but probably not in the general population. It appears likely that administration of these peptides will find a place in the therapeutics of acute myocardial infarction, but this is less clear for heart failure. We describe the presence of a segment of the signal peptide for BNP within the circulation and discuss its potential clinical utility.


Subject(s)
Heart Failure/drug therapy , Myocardial Infarction/drug therapy , Natriuretic Peptide, Brain/therapeutic use , Animals , Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/therapeutic use , Dyspnea/diagnosis , Dyspnea/etiology , Heart Failure/diagnosis , Heart Failure/physiopathology , Humans , Myocardial Infarction/physiopathology , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Prognosis
19.
J Hypertens ; 27(1): 3-8, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19050442

ABSTRACT

Substantial evidence points to the presence in human plasma of an inhibitor of the sodium/potassium pump which plays a central role in the pathophysiology of circulatory disorders, including essential hypertension. Studies from the 1980/90s claimed that this inhibitor was identical or very similar in structure to plant-derived ouabain and was synthesized by the adrenal cortex. However, the physical evidence in studies reporting isolation and identification of ouabain in human plasma appears insecure on closer examination. Additionally, reported circulating levels of immunoreactive ouabain in humans vary greatly, the ability of the human adrenal glands to secrete ouabain is questionable and the original commercial assay for measuring immunoreactive ouabain is no longer available. We submit that the position of ouabain as an endogenous, adrenally produced regulator of the sodium pump is of such importance that the current evidence needs either to put on a more secure footing or to lose its current status.


Subject(s)
Adrenal Glands/metabolism , Cardenolides/blood , Cardiovascular Diseases/etiology , Ouabain/blood , Saponins/blood , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Cardenolides/administration & dosage , Cardenolides/isolation & purification , Chromatography, High Pressure Liquid , Diet , Humans , Ouabain/isolation & purification , Saponins/administration & dosage , Saponins/isolation & purification
20.
Regul Pept ; 113(1-3): 149-53, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12686474

ABSTRACT

Endothelin-1 is an important factor in vasoregulation and circulating levels of the peptide are increased in a number of cardiovascular disorders. However, control of endothelin-1 secretion is only sketchily understood. The possibility that endothelin-1 influences its own release was investigated. A cell immunoblot method, which can detect local secretion of peptide from individual human vascular endothelial cells, was employed. Cells were dispersed onto a protein-binding membrane. Endothelin-1 in cells or secreted and adhering to the protein-binding membrane outside the cells was detected using immunohistochemical techniques. The numbers of cells that contained endothelin-1 and secreted endothelin-1 were counted after the cells had been incubated in control conditions, or with added endothelin-1, angiotensin-II, or endothelin receptor antagonists, bosentan and BQ788. Endothelin-1 and angiotensin-II increased the numbers of cells that secreted endothelin-1. On the other hand, bosentan and BQ788 caused a reduction in the numbers of endothelin-1-secreting cells. These results indicate that human endothelial cells contain a pathway by which endothelin-1 induces its own release. The receptor antagonists, bosentan and BQ788, inhibited basal secretion of endothelin-1.


Subject(s)
Endothelin-1/metabolism , Endothelium, Vascular/metabolism , Angiotensin II/pharmacology , Bosentan , Dose-Response Relationship, Drug , Endothelin-1/drug effects , Endothelin-1/pharmacology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Humans , Immunoblotting/methods , Oligopeptides/pharmacology , Piperidines/pharmacology , Sulfonamides/pharmacology
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