251 results on '"NATRIURETIC peptides"'
Search Results
2. Prognostic Impact of Cardiovascular Versus Noncardiovascular Hospitalizations in Heart Failure With Preserved Ejection Fraction: Insights From TOPCAT
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EBRAHIM Barkoudah, BRIAN L. CLAGGETT, ELDRIN F. LEWIS, EILEEN O'MEARA, NADINE CLAUSELL, RAFAEL DIAZ, JEROME L. FLEG, BERTRAM PITT, JEAN L. ROULEAU, SCOTT D. SOLOMON, MARC A. PFEFFER, and AKSHAY S. DESAI
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Heart Failure ,Hospitalization ,Aftercare ,Humans ,Stroke Volume ,Spironolactone ,Natriuretic Peptides ,Prognosis ,Cardiology and Cardiovascular Medicine ,Patient Discharge ,Ventricular Function, Left ,Mineralocorticoid Receptor Antagonists - Abstract
Patients with heart failure (HF) with preserved ejection fraction are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations owing to CV and non-CV reasons in a HF with preserved ejection fraction population.The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3445 stable outpatients with chronic HF with a left ventricular ejection fraction of 45% or greater and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n = 1767), in which 2973 hospitalizations were observed in 1062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1474 (49%) were ascribed to CV causes. Among 1056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years [PY]), but similarly elevated after first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs 12.6 per 100 PY, respectively; P = .24). Among those hospitalized for CV reasons, mortality rates were similar after hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs 12.6 per 100 PY; P = .23). Recurrent hospitalization, whether owing to CV or non-CV causes, was associated with a heightened risk for subsequent mortality, with similar death rates after hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY).Among patients with HF with preserved ejection fraction, hospitalization for any cause is associated with a heightened risk for postdischarge mortality, with an even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, the targeted management of comorbid medical illness may be critical to decreasing morbidity and mortality.
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- 2022
3. The heart, an endocrine gland: Natriuretic peptides
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Madleen, Lemaitre, Arnaud, Jannin, Benjamin, Chevalier, and Marie-Christine, Vantyghem
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Endocrinology ,Cardiovascular Diseases ,Endocrine Glands ,Endocrinology, Diabetes and Metabolism ,Natriuretic Peptide, Brain ,Animals ,Humans ,Natriuretic Peptide, C-Type ,General Medicine ,Natriuretic Peptides ,Atrial Natriuretic Factor - Abstract
The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP, secreted by the heart, act as cardiac hormones, whereas CNP is an endothelial peptide. The aim of this manuscript is to review the production, action mechanisms, effects and clinical applications of natriuretic peptides.
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- 2022
4. NPCdc, a synthetic natriuretic peptide, is a substrate to neprilysin and enhances blood pressure-lowering induced by enalapril in 5/6 nephrectomized rats
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Regina S. Aires, Ana D.O. Paixão, Marcelo Zaldini Hernandes, Linaldo Francisco da Silva Filho, Leucio D. Vieira, Marcelo F. Marcondes, Luiz Felipe Gomes Rebello Ferreira, and Adriana K. Carmona
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Male ,medicine.medical_specialty ,Mean arterial pressure ,medicine.drug_class ,medicine.medical_treatment ,Angiotensin-Converting Enzyme Inhibitors ,Blood Pressure ,Peptidyl-Dipeptidase A ,Toxicology ,Enalapril ,In vivo ,Internal medicine ,Renin–angiotensin system ,medicine ,Natriuretic peptide ,Animals ,Rats, Wistar ,Natriuretic Peptides ,Neprilysin ,Saline ,Chemistry ,Rats ,Endocrinology ,Blood pressure ,Peptides ,medicine.drug - Abstract
NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 μg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 μM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes.
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- 2021
5. Potential pitfalls when interpreting plasma BNP levels in heart failure practice
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Toshio Nishikimi and Yasuaki Nakagawa
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medicine.medical_specialty ,medicine.drug_class ,Volume overload ,030204 cardiovascular system & hematology ,Pericardial effusion ,Sacubitril ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Atrial Fibrillation ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Humans ,cardiovascular diseases ,030212 general & internal medicine ,Natriuretic Peptides ,Heart Failure ,business.industry ,Atrial fibrillation ,medicine.disease ,Peptide Fragments ,Dyspnea ,Valsartan ,Heart failure ,cardiovascular system ,Cardiology ,Biomarker (medicine) ,Female ,Cardiology and Cardiovascular Medicine ,business ,human activities ,Biomarkers ,hormones, hormone substitutes, and hormone antagonists ,circulatory and respiratory physiology ,medicine.drug - Abstract
B-type (or brain) natriuretic peptide (BNP) is synthesized in cardiac myocytes and released constitutively into the circulation. Pressure/volume overload, neurohumoral factors, cytokines, and ischemia enhance BNP gene expression, and then precursor proBNP is produced. It has been thought that proBNP is cleaved into active BNP molecule and inactive marker molecule NT-proBNP intracellularly by processing enzyme furin, and they are released into the circulation. However, recent studies have shown that considerable amount of uncleaved proBNP circulates in the blood. The commercially available BNP assay kits consist of two antibodies that sandwich the BNP molecule. Therefore, if proBNP is present, BNP assay kit cross-reacts to proBNP and measures it as BNP. Therefore, it should be noted that the current BNP value is proBNP plus BNP. BNP and NT-proBNP have been established as a biomarker for heart failure patients presenting dyspnea. But many pitfalls are present for interpreting the BNP value. For example, the presence of renal dysfunction, age, female sex, atrial fibrillation, inflammation, hyperthyroidism, use of sacubitril/valsartan, and macro-proBNPemia overestimate BNP value, whereas the presence of obesity, immediately after acute coronary syndrome onset, and pericardial effusion underestimate BNP value. In the management for heart failure patients, BNP plays an important role. Therefore, clinicians should note the pitfall of interpretation of BNP and we describe the mechanism involved.
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- 2021
6. Serum neprilysin levels are elevated in preeclampsia
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Melike Makul, Nevin Tüten, Koray Gök, Abdullah Tuten, Yahya Ozgun Oner, Kubra Hamzaoglu, Eduard Malik, Onur Guralp, Huri Bulut, İstinye Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, and Bulut, Huri
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System ,medicine.medical_specialty ,Gestational Age ,Expression ,Heart-Failure ,Gastroenterology ,Preeclampsia ,Young Adult ,chemistry.chemical_compound ,Pre-Eclampsia ,Pregnancy ,Internal medicine ,Villi ,Humans ,Medicine ,Natriuretic peptides ,Enkephalinase ,Neprilysin ,Endopeptidase ,reproductive and urinary physiology ,Inhibition ,Creatinine ,business.industry ,Hydrolysis ,fungi ,Obstetrics and Gynecology ,Gynecology and obstetrics ,Neutral endopeptidase ,medicine.disease ,Severe preeclampsia ,female genital diseases and pregnancy complications ,Blood pressure ,chemistry ,Human Placenta ,Mild preeclampsia ,Case-Control Studies ,Soluble Neprilysin ,RG1-991 ,Gestation ,Uric acid ,Female ,business ,Biomarkers - Abstract
Objective: To evaluate the possible associations between serum Neprilysin (NEP) levels and preeclampsia and mild and severe preeclampsia subgroups. Materials and methods: Fifty -five consecutive women with mild preeclampsia and fifty -five consecutive women with severe preeclampsia were compared with 110 approximately gestational age-matched (+/- 1 week) women with an uncomplicated pregnancy. Results: Mean serum NEP was significantly higher in women with preeclampsia compared to that of the gestational age-matched-controls (231.62 +/- 65.30 pg/mL vs. 187.75 +/- 84.38 pg/mL, p < 0.001). Mean serum NEP was significantly higher in the mild preeclampsia group compared to its gestational age -matched control group (228.84 +/- 67.26 pg/mL vs. 186.14 +/- 85.09 pg/mL, p = 0.008); and in the severe preeclampsia group compared to its gestational age-matched control group (234.45 +/- 63.85 pg/mL vs. 189.29 +/- 84.59 pg/mL, p = 0.004). Serum NEP was positively correlated with systolic and diastolic blood pressure, BUN, uric acid, and creatinine. Conclusion: Mean serum NEP was significantly higher in women with preeclampsia than women with an uncomplicated pregnancy. Further studies are needed to elucidate the possible therapeutic role of NEP inhibitors to treat preeclampsia. (c) 2021 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Istanbul Cerrahpasa University, Istanbul, Turkey; Carl von Ossietzky University Oldenburg, University Hospital for Obstetrics and Gynecology in Klinikum Oldenburg AoEuroR, Oldenburg, Germany This study was financed by Istanbul Cerrahpasa University, Istanbul, Turkey, and Carl von Ossietzky University Oldenburg, University Hospital for Obstetrics and Gynecology in Klinikum Oldenburg AoEuroR, Oldenburg, Germany.
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- 2021
7. Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials
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Muthiah Vaduganathan, William T. Abraham, Akshay S. Desai, Søren Lund Kristensen, Michael R. Zile, Milton Packer, Muhammad Shahzeb Khan, Lars Køber, John J.V. McMurray, Javed Butler, Kenneth Dickstein, Scott D. Solomon, and Karl Swedberg
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Male ,medicine.medical_specialty ,medicine.drug_class ,030204 cardiovascular system & hematology ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Natriuretic peptide ,medicine ,Humans ,030212 general & internal medicine ,Natriuretic Peptides ,Adverse effect ,Aged ,Heart Failure ,Ejection fraction ,business.industry ,Proportional hazards model ,Stroke Volume ,Atrial fibrillation ,Middle Aged ,Prognosis ,medicine.disease ,Clinical trial ,Heart failure ,Plasma concentration ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.
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- 2021
8. Treatment with sodium-glucose cotransporter-2 inhibitors in heart failure patients: The potential benefits of monitoring FGF-23 levels?
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Anne-Catherine Pouleur, Sylvie A. Ahn, Michel F. Rousseau, Michel P. Hermans, Damien Gruson, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Centre de pathologie sexuelle masculine, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service de cardiologie
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Fibroblast growth factor 23 ,Endocrinology, Diabetes and Metabolism ,Empagliflozin ,Sodium–glucose cotransporter 2 ,Pharmacology ,chemistry.chemical_compound ,Endocrinology ,Sodium-Glucose Transporter 2 ,Diabetes mellitus ,medicine ,Vitamin D and neurology ,Humans ,Natriuretic peptides ,Vitamin D ,Dapagliflozin ,Sodium-Glucose Transporter 2 Inhibitors ,Heart Failure ,FGF-23 ,business.industry ,Diabetes ,Biomarker ,General Medicine ,medicine.disease ,Fibroblast Growth Factors ,Glucose ,Diabetes Mellitus, Type 2 ,chemistry ,Sodium/Glucose Cotransporter 2 ,Heart failure ,Biomarker (medicine) ,business ,Biomarkers - Abstract
Les inhibiteurs du cotransporteur sodium-glucose de type 2 (iSGLT2) sont de plus en plus recommandes comme traitement de l’insuffisance cardiaque en raison d’un benefice cardio-renal et d’un effet favorable sur la mortabilite. L’utilisation de biomarqueurs pour suivre l’efficacite de ce traitement pourrait s’averer utile et notamment le Fibroblaste Growth Factor 23 (FGF-23) en raison de la relation entre ses taux circulants et le pronostic cardiovasculaire. D’autre part, la mesure de FGF-23 lors du traitement par un iSGLT2 pourrait permettre de suivre les repercussions sur le metabolisme phosphocalcique.
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- 2022
9. Sensitive detection of heart-failure biomarkers natriuretic peptides using multi-photon laser wave-mixing spectroscopy
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James, Suprapto and William G, Tong
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Heart Failure ,Spectrum Analysis ,Lasers ,Humans ,Natriuretic Peptides ,Peptides ,Analytical Chemistry - Abstract
Nonlinear laser wave-mixing spectroscopy is demonstrated as a fast and sensitive detection method for heart-failure biomarkers, pro-atrial natriuretic peptide (proANP) and brain natriuretic peptide (BNP). Wave mixing is an ultrasensitive optical absorption-based method and analytes can be detected in their native form or labeled with fluorophore and chromophore labels. In this study, we utilized Chromeo P540 dye to label the peptides for wave-mixing detection. The wave-mixing signal is created from the diffraction of incoming photons by the thermal grating at the capillary analyte cell. The signal beam is strong, collimated, and coherent (laser-like) and it is collected using a simple photodetector with an excellent signal-to-noise ratio. We demonstrated advantages of this technique over conventional assays including shorter analysis times, smaller sample requirements, and higher throughput. To enhance detection selectivity and sensitivity levels, wave mixing is effectively coupled to capillary zone electrophoresis (CZE) and field-amplified sample stacking (FASS) methods. We determined detection limits of 7.4 × 10
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- 2023
10. Gastric bypass surgery is associated with reduced subclinical myocardial injury and greater activation of the cardiac natriuretic peptide system than lifestyle intervention
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Magnus Nakrem Lyngbakken, Kirsten B. Holven, Jøran Hjelmesæth, Njord Nordstrand, Kristin M. Aakre, Torbjørn Omland, and Espen Svendsen Gjevestad
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Adult ,Male ,030213 general clinical medicine ,medicine.medical_specialty ,Diet, Reducing ,medicine.drug_class ,Clinical Biochemistry ,Gastric Bypass ,030204 cardiovascular system & hematology ,Systemic inflammation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Troponin T ,Troponin complex ,Internal medicine ,Weight Loss ,Troponin I ,Natriuretic peptide ,Humans ,Medicine ,Natriuretic Peptides ,Exercise ,Health Education ,Life Style ,Subclinical infection ,biology ,business.industry ,Gastric bypass surgery ,General Medicine ,Middle Aged ,Troponin ,Obesity, Morbid ,Myocarditis ,C-Reactive Protein ,Heart Injuries ,biology.protein ,Cardiology ,Female ,Median body ,medicine.symptom ,business - Abstract
Aims Morbid obesity is a risk factor for cardiovascular disease. The relative effects of Roux-en-Y gastric bypass surgery (GBS) and intensive lifestyle intervention (ILI) on subclinical myocardial injury, the activity of the cardiac natriuretic system, and systemic inflammation remain unclear. Methods In a 59-week non-randomized clinical trial that included 131 patients with morbid obesity, we compared the effects of GBS and ILI on concentrations of cardiac troponin T (cTnT) and I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP). Results In the GBS and ILI group, median body mass index (BMI) was reduced by 14.4 kg/m2 versus 3.9 kg/m2, respectively (p value < 0.001). Cardiac troponins decreased after GBS, p = 0.014 (cTnT) and p = 0.065 (cTnI) and increased significantly in those treated with ILI (p values ≤ 0.021) (between-group differences for deltas: p ≤ 0.003). NT-proBNP increased in both groups, but significantly more in the GBS than in the ILI group (between-group differences for deltas: p = 0.008). CRP decreased significantly within the GBS and the ILI group, with this change significantly greater in the GBS group (between-group differences for deltas p < 0.001). The dominating mediator of the biomarker changes was weight loss. Prior coronary artery disease and diabetes were predictive of the magnitude of the changes in cTnI and NT-proBNP, respectively. Conclusion Compared to ILI, GBS was associated with reduced subclinical myocardial injury and systemic inflammation, and enhancement of the cardiac natriuretic peptide system. The biomarker changes were predominantly mediated by weight loss.
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- 2020
11. Intense sport practices and cardiac biomarkers
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Patrice Dufour, C. Le Goff, Etienne Cavalier, Jean-François Kaux, and J. Farre Segura
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030213 general clinical medicine ,medicine.medical_specialty ,Cardiac fibrosis ,Galectin 3 ,Galectins ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,Running ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,medicine ,Humans ,Myocardial infarction ,Natriuretic Peptides ,biology ,Athletes ,Mechanism (biology) ,business.industry ,Myocardium ,Glycopeptides ,Blood Proteins ,General Medicine ,medicine.disease ,biology.organism_classification ,Interleukin-1 Receptor-Like 1 Protein ,Troponin ,MicroRNAs ,Heart failure ,biology.protein ,Cardiology ,Biomarker (medicine) ,business ,Biomarkers - Abstract
Biomarkers are well established for the diagnosis of myocardial infarction, heart failure and cardiac fibrosis. Different papers on cardiac biomarker evolution during exercise have been published in the literature and generally show mild to moderate elevations. However, the mechanism responsible for these elevations, reflecting physiological or even pathophysiological changes, still has to be clearly elucidated. There are also indications of higher cardiac risk in poorly trained athletes than in well-trained athletes. Whether regular repetition of intensive exercise might lead, in the longer term, to fibrosis and heart failure remains to be determined. In this review, we summarized the main research about the effects of intense exercise (in particular, running) on cardiac biomarkers (including troponins, natriuretic peptides, etc.). We found that cardiac fibrosis biomarkers seemed to be the most informative regarding the biological impact of intense physical activity.
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- 2020
12. Should We Test for Diastolic Dysfunction? How and How Often?
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Sheldon E. Litwin and Michael R. Zile
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Cardiac Catheterization ,medicine.medical_specialty ,medicine.drug_class ,Diastole ,Hemodynamics ,Inferior vena cava ,Cardiac Catheters ,Ventricular Function, Left ,Ventricular Dysfunction, Left ,Predictive Value of Tests ,Internal medicine ,Transducers, Pressure ,Ventricular Pressure ,medicine ,Natriuretic peptide ,Humans ,Radiology, Nuclear Medicine and imaging ,Diastolic function ,Natriuretic Peptides ,Heart Failure ,business.industry ,Prognosis ,medicine.disease ,medicine.vein ,Echocardiography ,Heart failure ,Ventricular Function, Right ,Cardiology ,Cardiology and Cardiovascular Medicine ,Ventricular filling ,business ,Right ventricular filling ,Biomarkers - Abstract
Symptoms of heart failure (HF) are due in large part to elevation of left and/or right ventricular filling pressures. Although abnormal diastolic function is difficult to define, it contributes to the elevation of filling pressures. Tests that characterize aspects of diastolic function or structural changes associated with diastolic dysfunction, may help in establishing a diagnosis of HF, assessing prognosis, and guiding treatments. Individual echocardiographic parameters correlate weakly with LV (LV) filling pressures measured directly. However, a combination of multiple parameters improves accuracy for detection of elevated filling pressures. Serum natriuretic peptide levels are related to ventricular filling pressures and, when elevated, are a key diagnostic criterion for HF. Currently available evidence is not adequate to recommend serial echocardiographic studies or natriuretic peptide level measurements to assess changes in filling pressures or to guide HF therapy. Measurements of inferior vena cava size and dynamics have potential for identifying inadequate decongestion during episodes of acute decompensated HF but have not yet demonstrated utility in improving HF outcomes. Direct measurement of LV filling pressures using implanted pressure sensors is the only "diastolic assessment" thus far that has proven efficacy in reducing HF hospitalization rates.
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- 2020
13. Natriuretic peptides in acute kidney injury – A sojourn on parallel tracks?
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Thomas M. Beaver, Michiko Shimada, Abhilash Koratala, A. Ahsan Ejaz, Kawther F. Alquadan, Girish Singhania, Bhagwan Dass, and Amardeep Singh
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medicine.medical_specialty ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Urology ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,law.invention ,Natriuresis ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Renal Dialysis ,law ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Cardiac Surgical Procedures ,Natriuretic Peptides ,Dialysis ,urogenital system ,business.industry ,Clinical study design ,Acute kidney injury ,Acute Kidney Injury ,medicine.disease ,female genital diseases and pregnancy complications ,Review article ,Renal blood flow ,Observational study ,business - Abstract
Objective The focus of this review was to elicit the mechanistic logic of the experimental and clinical study designs of natriuretic peptides (NP) in acute kidney injury (AKI) and to understand their respective outcomes. Methods Online search of PubMed and manual review of articles. Randomized trials, observational and physiologic studies of NPs and AKI were extracted. Rationale, design and study outcomes were analyzed. Results In experimental models of AKI, infusion of NP prevented post-ischemic fall in renal blood flow (RBF) or improvement in RBF, GFR, diuresis and natriuresis and demonstrated anti-inflammatory properties. NPs were most effective in the early stages of AKI, also in established phase of AKI but their effectiveness were limited to the time of infusion. Hypotension was a major side-effect. Based on these observations, preliminary clinical studies were performed which demonstrated improved urine output, RBF and GFR and reduced need for dialysis. However, randomized, controlled trials failed to demonstrate improvement in dialysis-free survival in different cohorts and study designs. Although NPs reduced the incidence of AKI in the postoperative period in cardiac surgery, it was not associated with improved long-term survival. In contrast to randomized trials, meta-analysis reported favorable results. Conclusions Reasons for the divergence of experimental and clinical outcomes of NPs in AKI are discussed in this review article.
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- 2020
14. A value proposition for natriuretic peptide measurement in the assessment of patients with suspected acute heart failure
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Maurice O’Kane, David Porter, Michael Oellerich, Andrew St John, Christopher P Price, Paul Jülicher, Robert H. Christenson, and Michael McCann
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0301 basic medicine ,medicine.medical_specialty ,Cost effectiveness ,medicine.drug_class ,Clinical Biochemistry ,MEDLINE ,Clinical Chemistry Tests ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Acute care ,medicine ,Natriuretic peptide ,Humans ,Business case ,Natriuretic Peptides ,Intensive care medicine ,Heart Failure ,business.industry ,Value proposition ,Biochemistry (medical) ,Stakeholder ,General Medicine ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Acute Disease ,business - Abstract
There is robust clinical trial evidence supporting the role of natriuretic peptides [NPs] in the assessment of patients presenting with suspected acute heart failure [AHF]. Despite the fact that clinical guidelines have for some time advocated NP measurement, the availability and uptake of NP testing in acute care services remains patchy and incomplete. The reasons for this are multifactorial but are underpinned by compartmentalised management and budget structures within complex healthcare delivery organisations. This paper outlines a value proposition for NP testing in the acute care setting which crosses the continuum of services and budgets. It articulates the expected benefits to each stakeholder in terms of efficiency of processes, clinical outcomes and cost effectiveness. It describes a pathway to implementation and suggests metrics that may be used to measure the effectiveness of introduction of NP testing. It is hoped that the value proposition will facilitate the uptake of NT testing fostering collaboration between laboratory, clinical, management and finance teams and by informing the development of business cases.
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- 2020
15. Evaluation of statins as a new therapy to alleviate chronotropic dysfunction in cirrhotic rats
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Qamar, Niaz, Seyed Mohammad, Tavangar, Sania, Mehreen, Mahmoud, Ghazi-Khansari, and Farahnaz, Jazaeri
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Male ,Liver Cirrhosis ,Nitric Oxide Synthase Type III ,NF-E2-Related Factor 2 ,Tumor Necrosis Factor-alpha ,Anti-Inflammatory Agents ,General Medicine ,Fibrosis ,Antioxidants ,General Biochemistry, Genetics and Molecular Biology ,Rats ,Cholesterol ,Liver ,Malondialdehyde ,Atorvastatin ,Animals ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Rats, Wistar ,General Pharmacology, Toxicology and Pharmaceutics ,Natriuretic Peptides ,rhoA GTP-Binding Protein ,Ligation - Abstract
Liver cirrhosis defines by regenerative nodules and fibrotic septa, causing a complication called cirrhotic cardiomyopathy (CCM) with chronotropic hypo-responsiveness. In addition to lowering cholesterol levels, statins yield antioxidant and anti-inflammatory effects. In liver diseases animal models, statins have been shown to decrease hepatic inflammation, fibrogenesis, and portal pressure (PP). Therefore, we evaluated the atorvastatin effect on the heart in cirrhotic rats.Bile duct ligation (BDL) or sham operation performed on male Wistar rats and grouped as cirrhotic; BDL/Saline, BDL/Ator-7d(days) (Atorvastatin 15 mg/kg/day), and BDL/Ator-14d groups, or control; Sham/Saline, Sham/Ator-7d, and Sham/Ator-14d groups. Corrected QT interval (QTc interval), chronotropic responses, serum brain natriuretic peptides (BNP), heart tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and malondialdehyde (MDA) levels were studied along with atrial Ras homolog family member A (RhoA) and endothelial nitric oxide synthase (eNOS) gene expression.The chronotropic responses decreased in BDL/Saline and increased in BDL/Ator-7d group. The QTc interval, BNP, TNF-α, and MDA levels increased in BDL/Saline and decreased in BDL/Ator-14d group. The Nrf2 level did not change in BDL/Saline and increased in BDL/Ator-14d group. The liver inflammation and fibrosis increased in BDL/Saline and did not affect BDL/Ator-7d and BDL/Ator-14d groups. The RhoA expression was down-regulated in BDL/Saline, BDL/Ator-7d, and BDL/Ator-14d groups. The eNOS expression did not change in BDL/Saline and down-regulated in BDL/Ator-14d group.Atorvastatin alleviates the chronotropic hypo-responsiveness and down-regulates the atrial RhoA and eNOS gene expression along with anti-inflammatory, antioxidant, and anti-stress effects in CCM.
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- 2022
16. Clinical Phenotypes of Heart Failure across the spectrum of Ejection Fraction: A Cluster Analysis
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Pishoy Gouda, Wendimagegn Alemayehu, Sarah Rathwell, D. Ian Paterson, Todd Anderson, Jason R.B. Dyck, Jonathan G. Howlett, Gavin Y. Oudit, Finlay A. McAlister, Richard B. Thompson, and Justin Ezekowitz
- Subjects
Heart Failure ,Phenotype ,Cluster Analysis ,Humans ,Stroke Volume ,Prospective Studies ,General Medicine ,Natriuretic Peptides ,Prognosis ,Cardiology and Cardiovascular Medicine ,Biomarkers ,Ventricular Function, Left - Abstract
Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction.Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes.Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion. Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years.Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment.
- Published
- 2022
17. Limitations of Natriuretic Peptide Levels in Establishing SGLT-2 Inhibitors for Heart Failure Care
- Author
-
Samuel W. Reinhardt and Eric J. Velazquez
- Subjects
Heart Failure ,business.industry ,medicine.drug_class ,MEDLINE ,Bioinformatics ,medicine.disease ,Peptide Fragments ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Risk Factors ,Heart failure ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Humans ,Medicine ,Canagliflozin ,Natriuretic Peptides ,Cardiology and Cardiovascular Medicine ,business ,Sodium-Glucose Transporter 2 Inhibitors - Published
- 2020
18. Hyponatremia as a risk factor for microvascular spasm following subarachnoid hemorrhage
- Author
-
Marta, Aleksandrowicz and Ewa, Kozniewska
- Subjects
Spasm ,Developmental Neuroscience ,Neurology ,Risk Factors ,Vasopressins ,Sodium ,Humans ,Vasospasm, Intracranial ,Subarachnoid Hemorrhage ,Natriuretic Peptides ,Brain Ischemia ,Hyponatremia - Abstract
Hyponatremia is a water-electrolyte balance disorder diagnosed in about 30% of patients after subarachnoid hemorrhage (SAH). The main factors responsible for hyponatremia in these patients are increased plasma concentrations of either vasopressin (leading to water retention and dilutional hyponatremia) or natriuretic peptides (leading to plasma sodium ions deficiency). Data demonstrates that the leading causes of post-SAH disability - delayed cerebrovascular spasm (CVS) and delayed cerebral ischemia (DCI) - are more often diagnosed in patients who develop hyponatremia than in normonatremic patients with SAH. Data also indicates that reducing sodium ion concentration in the blood/perfusate affects the tone and regulation of cerebral blood vessels in a manner that depends on the vessel's location in a vascular tree (intraparenchymal arterioles vs. large vessels on the brain surface) and environmental conditions. In the present article, we review possible mechanisms underlying the effects of hyponatremia on cerebral blood vessels and discuss the potential role of hyponatremia in the development of large vessels and microvascular spasm, taking into consideration the presence of vasopressin and natriuretic peptides.
- Published
- 2022
19. Natriuretic Peptide Response and Outcomes in Chronic Heart Failure With Reduced Ejection Fraction
- Author
-
Patrice Desvigne-Nickens, G. Michael Felker, Tariq Ahmad, James L. Januzzi, Kirkwood F. Adams, Nancy Houston-Miller, Mona Fiuzat, Eric S. Leifer, Gayle Passmore, David J. Whellan, Kevin J. Anstrom, Adrian Coles, Daniel B. Mark, Ileana L. Piña, Justin A. Ezekowitz, Lawton S. Cooper, Christopher M. O'Connor, and Hillary Mulder
- Subjects
Male ,medicine.medical_specialty ,Randomization ,medicine.drug_class ,030204 cardiovascular system & hematology ,Article ,Ventricular Dysfunction, Left ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Humans ,030212 general & internal medicine ,Natriuretic Peptides ,Aged ,Heart Failure ,Ejection fraction ,business.industry ,Stroke Volume ,Middle Aged ,Prognosis ,medicine.disease ,Peptide Fragments ,Treatment Outcome ,Kansas City Cardiomyopathy Questionnaire ,Heart failure ,Chronic Disease ,Practice Guidelines as Topic ,Usual care ,Cardiology ,Biomarker (medicine) ,Female ,Cardiology and Cardiovascular Medicine ,business ,Medical therapy ,Biomarkers ,hormones, hormone substitutes, and hormone antagonists - Abstract
The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to "guide" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone.The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial.A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed.A total of 198 (31.0%) subjects had an NT-proBNP ≤1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ≤1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ≤1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02).Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ≤1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).
- Published
- 2019
20. Nonischemic Causes of Cardiogenic Shock
- Author
-
Susan R. Wilcox
- Subjects
Inotrope ,Cardiac output ,medicine.medical_specialty ,Cardiotonic Agents ,Heart Diseases ,Point-of-Care Systems ,Shock, Cardiogenic ,Volume overload ,Catheterization ,Contractility ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Afterload ,Internal medicine ,medicine ,Intravascular volume status ,Humans ,Vasoconstrictor Agents ,Lactic Acid ,Medical History Taking ,Natriuretic Peptides ,Physical Examination ,Monitoring, Physiologic ,business.industry ,Cardiogenic shock ,030208 emergency & critical care medicine ,medicine.disease ,Troponin ,Preload ,Echocardiography ,Emergency Medicine ,Cardiology ,business ,Anti-Arrhythmia Agents ,Algorithms ,030217 neurology & neurosurgery - Abstract
Although cardiogenic shock is uncommon in the emergency department, it is associated with high mortality. Most cardiogenic shock is caused by ischemia, but nonischemic etiologies are essential to recognize. Clinicians should optimize preload, contractility, and afterload. Volume-responsive patients should be resuscitated in small aliquots, although some patients may require diuresis to improve cardiac output. Vasopressors are important to restore end-organ perfusion, and inotropes improve contractility. Intubation and positive pressure ventilation impact hemodynamics, which, depending on volume status, may be beneficial or deleterious. Knowing indications for mechanical circulatory support is important for timely consultation or transfer as indicated.
- Published
- 2019
21. Plecanatide for Treatment of Chronic Constipation and Irritable Bowel Syndrome
- Author
-
Bryan L. Love
- Subjects
medicine.medical_specialty ,Constipation ,Lumen (anatomy) ,030204 cardiovascular system & hematology ,Gastroenterology ,Irritable Bowel Syndrome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gastrointestinal Agents ,Internal medicine ,Humans ,Medicine ,030212 general & internal medicine ,Natriuretic Peptides ,Irritable bowel syndrome ,Chronic constipation ,Peptide analog ,business.industry ,General Medicine ,medicine.disease ,Treatment Outcome ,Receptors, Guanylate Cyclase-Coupled ,chemistry ,Defecation ,Plecanatide ,medicine.symptom ,business ,Uroguanylin - Abstract
Chronic idiopathic constipation and irritable bowel syndrome with constipation are commonly encountered in ambulatory patients, but limited options exist for patients with persistent or severe symptoms following treatment with nonprescription products. Plecanatide (Trulance, Synergy Pharmaceuticals, New York, NY) is a 16-amino acid peptide analog of uroguanylin that stimulates guanylate cyclase-C receptors to increase chloride and bicarbonate secretion into the intestine and prevents the absorption of sodium ions, thereby increasing the secretion of water into the lumen. The influx of additional fluid accelerates intestinal transit, softens the stool, and facilitates easier defecation. Plecanatide is the second guanylate cyclase-C receptor agonist to be approved by the US Food and Drug Administration for chronic idiopathic constipation and irritable bowel syndrome, but plecanatide is unique because its effects are limited to the proximal small bowel.
- Published
- 2019
22. Natriuretic peptides in heart failure: Current achievements and future perspectives
- Author
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Allegra Battistoni, Speranza Rubattu, and Massimo Volpe
- Subjects
Heart Failure ,medicine.medical_specialty ,Research groups ,medicine.drug_class ,business.industry ,Cardiovascular Agents ,Human physiology ,030204 cardiovascular system & hematology ,medicine.disease ,Renin-Angiotensin System ,Clinical biomarker ,03 medical and health sciences ,0302 clinical medicine ,Heart failure ,Natriuretic peptide ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Natriuretic Peptides ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business ,Biomarkers ,Forecasting - Abstract
The last two centuries have witnessed countless discoveries in the field of medicine that found their roots in the up growing development of technology as well as in the visionary ideas of brilliant scientists and research groups. One of the most important discoveries in the field of cardiovascular medicine allowed to break the paradigm identifying the heart with mere mechanical pump and to characterize its intriguing endocrine properties. Indeed, the discovery of hormones produced by the cardiac chambers, the natriuretic peptides, represents one of the milestones of the current conception of complexity of integrated human physiology. In the last four decades, the role of these hormones in the regulation of the cardiovascular system, in physiology and diseases, has been defined piece after piece. From diagnostic and prognostic markers, natriuretic peptides have become one of the most relevant clinical biomarker and a reliable target for establishing the efficacy of therapies. Recently and successfully, natriuretic peptide-based strategies are proposed as therapeutic weapons to improve outcome in heart failure. The future will witness potential further therapeutic application of natriuretic peptides that are currently being actively investigated.
- Published
- 2019
23. Atrial natriuretic peptide attenuates endoplasmic reticulum stress in experimental acute pancreatitis
- Author
-
Marcelo S. Vatta, Ana Paula Courreges, Ana Clara Najenson, and Liliana G. Bianciotti
- Subjects
X-Box Binding Protein 1 ,0301 basic medicine ,Eukaryotic Initiation Factor-2 ,Activating transcription factor ,Apoptosis ,Endoplasmic Reticulum ,Rats, Sprague-Dawley ,eIF-2 Kinase ,0302 clinical medicine ,Atrial natriuretic peptide ,Endoplasmic Reticulum Chaperone BiP ,Caspase 12 ,Heat-Shock Proteins ,biology ,UNFOLDED PROTEIN RESPONSE ,Chemistry ,ENDOPLASMIC RETICULUM STRESS ,purl.org/becyt/ford/3.1 [https] ,Bioquímica y Biología Molecular ,Endoplasmic Reticulum Stress ,Cell biology ,Medicina Básica ,Acute Disease ,Molecular Medicine ,Beclin-1 ,purl.org/becyt/ford/3 [https] ,030211 gastroenterology & hepatology ,Binding immunoglobulin protein ,Atrial Natriuretic Factor ,Signal Transduction ,CIENCIAS MÉDICAS Y DE LA SALUD ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,medicine ,Animals ,Pancreas ,Molecular Biology ,ATF6 ,Endoplasmic reticulum ,Autophagy ,Membrane Proteins ,ACUTE PANCREATITIS ,medicine.disease ,Activating Transcription Factor 6 ,Enzyme Activation ,NATRIURETIC PEPTIDES ,030104 developmental biology ,Pancreatitis ,Unfolded Protein Response ,Unfolded protein response ,biology.protein - Abstract
Increasing evidence shows that the endoplasmic reticulum (ER) stress is an early event that injures pancreatic acinar cells and contributes to the pathogenesis of acute pancreatitis. In the present work we sought to establish whether atrial natriuretic peptide (ANP) alleviated ER stress in rats with cerulein-induced pancreatitis. The major components of the unfolded protein response (UPR) and their downstream effectors were assessed by immunoblotting or fluorimetry and the ultrastructure of ER evaluated by electron transmission microscopy. Cross-talk with autophagy was evaluated by beclin-1 expression. ANP reduced binding immunoglobulin protein (Bip) expression (UPR major controller) which under non-stress conditions keeps inactive the stress sensor proteins: protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). Although ANP did not change PERK expression it decreased p-eIF2α and enhanced downstream effector CHOP, suggesting that ANP stimulates ER-dependent apoptosis. In accordance, ANP also decreased Bcl2 expression and enhanced proapoptotic proteins Bax and Bak. The atrial peptide enhanced ATF6 expression and although it did not affect IRE1/sXBP1 signaling, it increased caspase-2 activity, also involved in ER-dependent apoptosis. Furthermore, ANP decreased beclin-1 expression. The ultrastructure of the RE revealed decreased swelling and conserved ribosomes in the presence of ANP. Present findings support that ANP alleviates ER stress in acute pancreatitis by modulating the three branches of the UPR and stimulates ER-dependent apoptosis. Gaining insights into the modulation of ER stress may help to develop specific therapeutic strategies for acute pancreatitis and/or medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography. Fil: Courreges, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Najenson, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Vatta, Marcelo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Bianciotti, Liliana Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina
- Published
- 2019
24. Sacubitril/valsartan (LCZ696) significantly reduces aldosterone and increases cGMP circulating levels in a canine model of RAAS activation
- Author
-
Chi Hse Tang, Mathieu Peyrou, Jonathan P. Mochel, Meindert Danhof, Dean F. Rigel, and Jérôme M. Giraudel
- Subjects
Male ,Angiotensin receptor ,Tetrazoles ,Pharmaceutical Science ,Benazepril ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Plasma renin activity ,Sacubitril ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Natriuretic Peptides ,Aldosterone ,Cyclic GMP ,Heart Failure ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Aminobutyrates ,Angiotensin II ,Biphenyl Compounds ,Sodium, Dietary ,021001 nanoscience & nanotechnology ,Drug Combinations ,Valsartan ,Female ,Angiotensin I ,0210 nano-technology ,business ,Sacubitril, Valsartan ,medicine.drug - Abstract
Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675 mg/day) vs. placebo, sacubitril (360 mg/day), valsartan (900 mg/day), and benazepril (5 mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n = 18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675 mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675 mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675 mg administration was similar to that observed with valsartan 900 mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.
- Published
- 2019
25. Natriuretic peptides in human heart: Novel insight into their molecular forms, functions, and diagnostic use
- Author
-
Kenji Kangawa, Chiaki Nagai-Okatani, Ayaka Matsuo, Naoto Minamino, and Mitsuhiro Nishigori
- Subjects
medicine.medical_specialty ,Physiology ,medicine.drug_class ,030209 endocrinology & metabolism ,Peptide ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Natriuretic peptide ,Animals ,Humans ,Myocytes, Cardiac ,Natriuretic Peptides ,Heart Failure ,Body fluid ,chemistry.chemical_classification ,business.industry ,Human heart ,Heart ,medicine.disease ,Pathophysiology ,chemistry ,Pressure load ,Heart failure ,cardiovascular system ,business ,Protein Processing, Post-Translational ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Function (biology) ,circulatory and respiratory physiology - Abstract
Among the three natriuretic peptides, atrial/A-type natriuretic peptide (ANP) and brain/B-type natriuretic peptide (BNP) are primarily produced by, and secreted from, heart tissue. They maintain cardiovascular homeostasis by binding to natriuretic peptide receptor-A. Since plasma ANP and BNP concentrations, as well as expression, are elevated in response to increased body fluid volume and pressure load on the heart wall, these peptides are widely utilized as diagnostic biomarkers for evaluating heart failure. Regardless of their high utility, differences in their molecular forms between healthy and diseased subjects and how these relate to pathophysiology have not well been examined. Recent studies have shown that the circulating molecular forms of ANP and BNP are not uniform; bioactive α-ANP is the major ANP form, whereas the weakly active proBNP is the major BNP form. The relative ratios of the different molecular forms are altered under different pathophysiological conditions. These facts indicate that detailed measurements of each form may provide useful information on the pathophysiological state of heart tissue. Here, we revisit the relationship between the molecular forms of, and pathophysiological alterations in, human ANP and BNP and discuss the possible utility of the measurement of each of the molecular forms. The third peptide, C-type natriuretic peptide, activates natriuretic peptide receptor-B, but little is known about its production and function in the heart because of its extremely low levels. However, through recent studies, its role in the heart is gradually becoming clear. Here, we summarize its molecular forms, assay systems, and functions in the heart.
- Published
- 2019
26. Atrial and brain natriuretic peptides: Hormones secreted from the heart
- Author
-
Yasuaki Nakagawa, Koichiro Kuwahara, and Toshio Nishikimi
- Subjects
medicine.medical_specialty ,Physiology ,medicine.drug_class ,030209 endocrinology & metabolism ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Atrial natriuretic peptide ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Animals ,Humans ,Myocytes, Cardiac ,Secretion ,Natriuretic peptides ,cardiovascular diseases ,Cyclic guanosine monophosphate ,Heart Failure ,O-glycosylation ,business.industry ,medicine.disease ,chemistry ,Heart failure ,cardiovascular system ,Signal transduction ,business ,Protein Processing, Post-Translational ,Atrial Natriuretic Factor ,ANP ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Intracellular ,BNP ,circulatory and respiratory physiology ,Hormone - Abstract
The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Among these, ANP and BNP are secreted by the heart and act as cardiac hormones. Both ANP and BNP preferentially bind to natriuretic peptide receptor-A (NPR-A or guanylyl cyslase-A) and exert similar effects through increases in intracellular cyclic guanosine monophosphate (cGMP) within target tissues. Expression and secretion of ANP and BNP are stimulated by various factors and are regulated via multiple signaling pathways. Human ANP has three molecular forms, α-ANP, β-ANP, and proANP (or γ-ANP), with proANP predominating in healthy atrial tissue. During secretion proANP is proteolytically processed by corin, resulting in secretion of bioactive α-ANP into the peripheral circulation. ProANP and β-ANP are minor forms in the circulation but are increased in patients with heart failure. The human BNP precursor proBNP is proteolytically processed to BNP1-32 and N-terminal proBNP (NT-proBNP) within ventricular myocytes. Uncleaved proBNP as well as mature BNP1-32 and NT-proBNP is secreted from the heart, and its secretion is increased in patients with heart failure. Mature BNP, its metabolites including BNP3-32, BNP4-32, and BNP5-32, and proBNP are all detected as immunoreactive-BNP by the current BNP assay system. We recently developed an assay system that specifically detects human proBNP. Using this assay system, we observed that miR30-GALNTs-dependent O-glycosylation in the N-terminal region of proBNP contributes to regulation of the processing and secretion of proBNP from the heart.
- Published
- 2019
27. Dynamic risk stratification using serial measurements of plasma concentrations of natriuretic peptides in patients with heart failure
- Author
-
Pierpaolo Pellicori, Daniel Pan, John G.F. Cleland, Riet Dierckx, Jufen Zhang, and Andrew L. Clark
- Subjects
Male ,Cardiac & Cardiovascular Systems ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,PREDISCHARGE ,Aged, 80 and over ,OUTCOMES ,Middle Aged ,ADMISSION ,PROGNOSTIC VALUE ,Plasma concentration ,Risk stratification ,Cardiology ,TRIAL ,Female ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,NT-PROBNP ,medicine.medical_specialty ,medicine.drug_class ,1102 Cardiovascular Medicine And Haematology ,Risk Assessment ,Nyha class ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,In patient ,cardiovascular diseases ,Mortality ,Natriuretic Peptides ,Prognostic models ,Aged ,Heart Failure ,Science & Technology ,business.industry ,medicine.disease ,Peptide Fragments ,MODEL ,Cardiovascular System & Hematology ,Heart failure ,Chronic Disease ,Cardiovascular System & Cardiology ,VAL-HEFT ,business ,Biomarkers ,BNP ,Follow-Up Studies - Abstract
Background:\ud \ud Prognostic models for patients with chronic heart failure are generally based on a single assessment but treatment is often given with the intention of changing risk; re- evaluation of risk is an important aspect of care. The prognostic value of serial measurements of natriuretic peptides for the assessment of changes in risk is uncertain.\ud \ud Aims:\ud \ud To evaluate the prognostic value of serial measurements of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) during follow-up of out-patients with chronic heart failure (CHF).\ud \ud Methods:\ud \ud Patients diagnosed with CHF between 2001 and 2014 at a single out-patient clinic serving a local community were included in this analysis. NT-proBNP was measured at the initial visit and serially during follow-up. Only patients who had one or more measurements of NT-proBNP after baseline, at 4, 12 and/or 24 months were included.\ud \ud Results:\ud \ud At baseline, amongst 1998 patients enrolled, the median age was 73 (IQR: 64–79) years, 70% were men, 31% were in NYHA class III/IV, and 77% had NT-proBNP >400 pg/mL. Median follow-up was 4.8 (IQR: 2.5–8.6) years. Serial measurements of NT-proBNP improved prediction of all-cause mortality at 3 years (c- statistic = 0.71) compared with using baseline data only (c-statistic = 0.67; p
- Published
- 2018
28. Combining diastolic dysfunction and natriuretic peptides to risk stratify patients with heart failure with reduced ejection fraction
- Author
-
Valentina Kutyifa, Amil M. Shah, Dorit Knappe, Mauro Gori, Brian Claggett, Ilan Goldenberg, Scott D. Solomon, Michele Senni, Ann-Catherine Pouleur, UCL - (SLuc) Service de pathologie cardiovasculaire, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, Gori, M, Claggett, B, Senni, M, Shah, A, Goldenberg, I, Kutyifa, V, Knappe, D, Pouleur, A, and Solomon, S
- Subjects
Male ,medicine.medical_specialty ,Diastole ,030204 cardiovascular system & hematology ,Nyha class ,Ventricular Dysfunction, Left ,03 medical and health sciences ,QRS complex ,0302 clinical medicine ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Humans ,Diastolic function ,In patient ,030212 general & internal medicine ,Natriuretic Peptides ,Aged ,Heart Failure ,Ejection fraction ,business.industry ,Stroke Volume ,HFrEF ,Middle Aged ,medicine.disease ,Mild symptoms ,Heart failure ,Cardiology ,Diastolic dysfunction ,Female ,business ,Cardiology and Cardiovascular Medicine ,Natriuretic peptide - Abstract
Background: Diastolic dysfunction (DD) might help to risk stratify patients with heart failure (HF) with reduced ejection fraction (HFrEF). Nonetheless, HF guidelines/risk scores don't consider DD. We aimed to show the independent prognostic value of DD for nonfatal HF/death in patients with HFrEF on top of natriuretic peptides (NP). Methods: We analyzed 1155 baseline echocardiograms of the MADIT-CRT study (LVEF≤30%, QRS ≥ 130 ms, NYHA class I/II), classifying DD according to 2016 ASE/EACVI classification. Results: Patients were 64 ± 11 years-old, 24% females, LVEF was 24 ± 5%, 58% had abnormal BNP (≥100 pg/ml). While 45% had impaired relaxation, 33% had pseudonormal filling, 12% restrictive pattern, 6% indeterminate diastolic function, 4% were not classifiable due to missing data. During a follow-up of 2.1 ± 1.0 years, there were 233 HF/death. Compared to patients without pseudonormal/restrictive filling and with normal NP (23%), patients with pseudonormal/restrictive filling, alone (15%) or combined to elevated NP (30%), were at higher risk of events (respectively padj = 0.025 and padj < 0.001), as opposed to those with abnormal NP alone (22%; padj = 0.55). Adding DD to conventional markers of risk and NP improved prediction (C-statistic 0.733 versus 0.708, p = 0.024). DD was the first parameter to be considered to risk stratify MADIT-CRT population, according to Classification-And-Regression-Tree analysis. Conclusions: Among HFrEF patients with mild symptoms, pseudonormal/restrictive filling, either alone or combined with elevated NP, was associated with high risk of events, as opposed to isolated elevation of NP. DD provided incremental risk prediction for death/HF beyond commonly used markers. These data might suggest to integrate DD into HF guidelines/risk scores.
- Published
- 2021
29. Exercise capacity, cardiac and endothelial function in adults with repaired tetralogy of Fallot
- Author
-
Marko Novaković, Katja Prokšelj, and Borut Jug
- Subjects
Echocardiography ,Physical activity ,Exercise testing ,RC666-701 ,Diseases of the circulatory (Cardiovascular) system ,Natriuretic peptides ,Vascular function ,Tetralogy of fallot - Abstract
Background: Exercise capacity and endothelial function are impaired in adults with repaired tetralogy of Fallot (ToF). This may be related to pathophysiological determinants, such as cardiac and endothelial impairment, or to a more sedentary lifestyle. Therefore, we sought to assess if cardiac and endothelial function are associated with exercise capacity in adults with repaired ToF. Methods: In a case-control study, we compared adults with repaired ToF and controls in terms of exercise workload, peak oxygen consumption (VO2peak) and flow-mediated dilation (FMD). Additionally, we determined associations of natriuretic peptide levels, echocardiographic parameters of size, function and systolic pressure with exercise capacity. Results: A total of 26 patients (mean age 38 ± 10 years, 46% males) and 10 controls were included. Patients with repaired ToF had reduced VO2peak (25.0 vs. 36.3 ml/kg/min, p
- Published
- 2022
30. The Effect of Acid Suppression Therapy on the Safety and Efficacy of Plecanatide: Analysis of Randomized Phase III Trials
- Author
-
Baharak Moshiree, Philip Schoenfeld, Howard Franklin, and Ali Rezaie
- Subjects
Adult ,Irritable Bowel Syndrome ,Pharmacology ,Treatment Outcome ,Double-Blind Method ,Gastrointestinal Agents ,Chronic Disease ,Humans ,Pharmacology (medical) ,Defecation ,Natriuretic Peptides ,Constipation - Abstract
Plecanatide, an approved therapy for chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation, is an analogue of uroguanylin that replicates its pH-sensitive activity and binds to guanylate cyclase-C receptors expressed on intestinal epithelium, stimulating fluid secretion. This analysis explores concomitant acid suppression therapy's effect on the efficacy and safety of plecanatide in adults with CIC.Data from 2 placebo-controlled, 12-week Phase III trials of plecanatide in CIC were pooled. Patients were randomized to receive placebo, plecanatide 3 mg, or plecanatide 6 mg. The primary endpoint was the durable, overall complete spontaneous bowel movement (CSBM) response rate (defined as ≥3 CSBMs in a given week and ≥1 CSBM increase from baseline within a week for ≥9 of 12 weeks, including ≥3 of the last 4 treatment weeks). Safety was also evaluated. Results were stratified by concomitant use or nonuse of acid suppression therapy.Of the pooled intent-to-treat population, 338 of 2639 patients (12.8%) received concomitant acid suppression medication. Efficacy response rates in patients using acid suppressors were 23.6% with plecanatide 3 mg (P = 0.001 vs placebo), 22.1% with plecanatide 6 mg (P = 0.002), and 7.6% with placebo. Responses were similar in patients not using acid suppressors: 20.4% (plecanatide 3 mg, P0.001), 19.6% (plecanatide 6 mg, P0.001), and 12.1% (placebo). Serious adverse events were experienced by 3.3% of patients who used concomitant acid suppression and 1.0% of those who did not.Plecanatide treatment is safe and efficacious for patients with CIC when administered with concomitant acid suppression medication.gov identifiers: NCT02122471 and NCT01982240.
- Published
- 2022
31. Does natriuretic peptide monitoring improve outcomes in heart failure patients? A systematic review and meta-analysis
- Author
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Muhammad Shahzeb Khan, Setri Fugar, Haris Riaz, Jayakumar Sreenivasan, Tariq Jamal Siddiqi, Mohammad Hassan Murad, Vincent M. Figueredo, Farouk Mookadam, and Muhammad Usman
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Subgroup analysis ,030204 cardiovascular system & hematology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Natriuretic Peptide, Brain ,Natriuretic peptide ,medicine ,Humans ,030212 general & internal medicine ,Natriuretic Peptides ,Randomized Controlled Trials as Topic ,Heart Failure ,Ejection fraction ,business.industry ,Stroke Volume ,Guideline ,medicine.disease ,Peptide Fragments ,Treatment Outcome ,Relative risk ,Heart failure ,Meta-analysis ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background Current guidelines do not support the use of serial natriuretic peptide (NP) monitoring for heart failure with preserved (HFpEF) or reduced ejection fraction (HFrEF) treatment, despite some studies showing benefit. We conducted an updated meta-analysis to address whether medical therapy in HFpEF or HFrEF should be titrated according to NP levels. Methods MEDLINE, Scopus and Cochrane CENTRAL databases were searched for randomized controlled trials (RCTs) comparing NP versus guideline directed titration in HF patients through December 2017. The key outcomes of interest were mortality, HF hospitalizations and all-cause hospitalizations. Risk ratios and 95% confidence intervals were pooled using random effects model. Sub-group analyses were performed for type of NP used, average age and acute or chronic HF. Results Eighteen trials including 5116 patients were included. Meta-analysis showed no significant difference between the NP-guided arm versus guideline directed titration in all-cause mortality (RR = 0.91 [0.81, 1.03]; p = 0.13), HF hospitalizations (RR = 0.81 [0.65, 1.01]; p = 0.06), and all cause hospitalizations (RR = 0.93 [0.86, 1.01]; p = 0.09). The results were consistent upon subgroup analysis by biomarker type (NT-proBNP or BNP) and type of heart failure (acute or chronic and HFrEF or HFpEF). Sub-group analysis suggested that NP-guided treatment was associated with decreased all-cause hospitalizations in patients younger than 72 years of age. Conclusion The available evidence suggests that NP-guided therapy provides no additional benefit over guideline directed therapy in terms of all-cause mortality and HF-related hospitalizations in acute or chronic HF patients, regardless of their ejection fraction.
- Published
- 2018
32. Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure
- Author
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Karl Swedberg, Muthiah Vaduganathan, Milton Packer, John J.V. McMurray, Brian Claggett, Scott D. Solomon, Michael R. Zile, and Jean L. Rouleau
- Subjects
medicine.medical_specialty ,Percentile ,Cardiotonic Agents ,Randomization ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Cause of Death ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,030212 general & internal medicine ,Natriuretic Peptides ,Randomized Controlled Trials as Topic ,Heart Failure ,business.industry ,Surrogate endpoint ,Hazard ratio ,Therapeutic effect ,medicine.disease ,Hospitalization ,Clinical trial ,Treatment Outcome ,Clinical Trials, Phase III as Topic ,clinical trial methodology ,surrogate endpoints ,Heart failure ,biomarker ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Objectives This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). Background The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. Methods The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). Results Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro–B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002). Conclusions When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials.
- Published
- 2018
33. Evolution of natriuretic peptide biomarkers in heart failure: Implications for clinical care and clinical trials
- Author
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Faiez Zannad, James L. Januzzi, Nicolas Vodovar, Kirkwood F. Adams, Gillian Murtagh, Alexandre Mebazaa, and Wendy Gattis Stough
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Population ,Phases of clinical research ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Humans ,030212 general & internal medicine ,Clinical care ,Natriuretic Peptides ,Intensive care medicine ,education ,Pharmaceutical industry ,Heart Failure ,Clinical Trials as Topic ,education.field_of_study ,business.industry ,Congresses as Topic ,medicine.disease ,Clinical trial ,Clinical research ,Heart failure ,District of Columbia ,Patient Care ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Natriuretic peptides (NPs) are recommended by international guidelines to exclude non-heart failure causes of acute dyspnea and to assess prognosis. NPs are commonly used as an entry criterion for clinical trials, to minimize enrollment of misdiagnosed patients, or to ensure enrollment of a sufficiently at-risk population. NP values used to select trial populations to date have been inconsistent across studies. Future trials should consider using standardized thresholds for NP levels, with protocol-specified adaptations appropriate for the specific study and patient population to account for factors that can influence the NP level. NPs have been used as an endpoint for proof-of-concept or phase 2 clinical trials, although it is important to remember that positive results in early phase studies may be unstable due to small numbers and the play of chance, and they are not always reproducible in phase 3 trials. Likewise, failure to reduce NP in phase 2 may not necessarily indicate that a drug will be ineffective on clinical outcomes in phase 3. NP guided therapy has been intensively studied, but the clinical outcome benefits of this approach remain uncertain. Neprilysin inhibitors have stimulated further exploration of the NP system and how it influences, and is potentially influenced by, heart failure therapies. This paper discusses the utility of NPs in the current clinical research and practice environment and addresses areas in need of further research from the perspectives of academic clinical trialists, clinicians, biostatisticians, regulators, and pharmaceutical industry scientists who participated in the 13th Global Cardiovascular Clinical Trialists Forum.
- Published
- 2018
34. Biomarkers in stable coronary artery disease
- Author
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Cian P. McCarthy, John W. McEvoy, and James L. Januzzi
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Myocardial Infarction ,Disease ,030204 cardiovascular system & hematology ,Risk Assessment ,Severity of Illness Index ,law.invention ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Troponin T ,Randomized controlled trial ,Predictive Value of Tests ,law ,Internal medicine ,Severity of illness ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Natriuretic Peptides ,Intensive care medicine ,Prospective cohort study ,Peroxidase ,Randomized Controlled Trials as Topic ,business.industry ,Percutaneous coronary intervention ,Prognosis ,medicine.disease ,Survival Analysis ,C-Reactive Protein ,Cohort ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Risk assessment ,Biomarkers - Abstract
Coronary artery disease (CAD) remains a significant cause of morbidity and mortality around the world. Patients with stable CAD can have an unpredictable clinical trajectory; thus, additional tools to prognosticate risk in this cohort are warranted. In recent years, a wide range of biomarkers has been recognized for their diagnostic capabilities in patients with stable CAD, identifying those with obstructive disease who may require more intensive preventive therapies or even consideration of percutaneous coronary intervention in some circumstances. In addition, a multiple-biomarker approach may identify stable CAD patients at highest risk for future major adverse cardiac events. Thus, randomized controlled trials to assess biomarker-guided preventive therapy in this cohort appear warranted.
- Published
- 2018
35. Effects of hyperoxia on myocardial injury following cardioversion—A randomized clinical trial
- Author
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Charles D. Deakin, Simon M. Jepsen, Nete Hornung, Kasper Adelborg, Bo Løfgren, Leif F. Bach, Anders S Schmidt, Hans Rickers, and Kasper G Lauridsen
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Electric Countershock ,Myocardial Infarction ,Hyperoxia ,030204 cardiovascular system & hematology ,Cardioversion ,Risk Assessment ,Statistics, Nonparametric ,03 medical and health sciences ,0302 clinical medicine ,Copeptin ,Troponin T ,Interquartile range ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Natriuretic Peptides ,Aged ,business.industry ,Oxygen Inhalation Therapy ,Atrial fibrillation ,Middle Aged ,Prognosis ,medicine.disease ,Oxygen ,Survival Rate ,Atrial Flutter ,Elective Surgical Procedures ,Anesthesia ,Room air distribution ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Atrial flutter - Abstract
Background Oxygen has long been assumed beneficial for all ill and injured patients. However, hyperoxia may be harmful and aggravate myocardial injury such as that caused by myocardial infarction. We aimed to investigate if hyperoxia increases myocardial injury following direct current cardioversion compared with room air. Methods Patients undergoing elective biphasic cardioversion for atrial fibrillation or atrial flutter were randomized to receive room air or oxygen (10–15 L/min) during the procedure. The primary endpoint was the difference in high-sensitive Troponin I (hs-cTnI) and -T (hs-cTnT) measured 2 hours before and 4 hours after cardioversion. Secondary endpoints were differences in Copeptin and NT-pro-BNP. Results A total of 65 patients were randomized to high-flow oxygen (male: 71%, mean age 66.9 years) and 59 patients to room air (male: 80%, mean age 65.5 years). There was no difference in hs-cTnI between patients treated with oxygen compared to patients treated with room air (P = .09) and no significant difference for hs-cTnT, ratio 1.08 (95% CI: 0.99–1.18) (P = .09). Median hs-cTnI difference before and after cardioversion was 0.1 (interquartile range (IQR): −0.5 to 0.5) ng/L for the high-flow oxygen group and −0.3 (IQR: −1.1 to 0.4) ng/L for the room air group. There was no difference in Copeptin between patients treated with oxygen compared to room air (ratio 1.06 (95% CI: 0.89–1.27) (P = .51) or NT-pro-BNP (difference− 6.0 ng/L (95% CI: −78.5 to 66.6) P = .87). Conclusion Direct current cardioversion of atrial fibrillation/flutter with and without high-flow oxygen supplement was not associated with myocardial injury evaluated by high sensitive myocardial biomarkers.
- Published
- 2018
36. Interleukin-15 derived from Guanylin–GC-C-expressing macrophages inhibits fatty acid synthase in adipocytes
- Author
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Mikiya Miyazato, Kenji Kangawa, Sayaka Akieda-Asai, Yukari Date, and Takanori Ida
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Physiology ,Guanylin ,Receptors, Enterotoxin ,Adipose tissue ,Biochemistry ,Gastrointestinal Hormones ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Endocrinology ,Internal medicine ,Adipocytes ,medicine ,Animals ,adipocyte protein 2 ,Natriuretic Peptides ,Receptor ,Interleukin-15 ,Messenger RNA ,biology ,Chemistry ,Macrophages ,food and beverages ,Dietary Fats ,Rats ,Fatty Acid Synthase, Type I ,Fatty acid synthase ,030104 developmental biology ,Interleukin 15 ,biology.protein ,Phosphorylation ,Rats, Transgenic - Abstract
Recently we found that guanylin (Gn) and its receptor, guanylyl cyclase C (GC-C), are uniquely expressed in the mesenteric macrophages of some diet-resistant rats and that double-transgenic (dTg) rats overexpressing Gn and GC-C in macrophages demonstrate reduced fatty acid synthase and fat accumulation in fat tissue even when fed a high-fat diet (HFD). Lipid accumulation and fatty acid synthase mRNA levels in cocultured dTg rat adipocytes and macrophages were reduced compared with those in adipocytes cultured with WT rat macrophages. Here, we investigated whether Interleukin-15 (IL-15) derived from Gn-GC-C-expressing macrophages regulates lipid accumulation in adipocytes. IL-15 inhibited fatty acid synthase and lipid accumulation via STAT5 in cultured adipocytes. IL-15 mRNA and protein levels in the mesenteric fat of HFD-fed dTg rats were significantly higher than those of HFD-fed WT rats. Phosphorylated STAT5 levels in the mesenteric fat of HFD-fed dTg rats were increased compared with those of HFD-fed WT rats. In addition, the mRNA level of fatty acid synthase in the mesenteric fat was lower in HFD-fed dTg rats than in HFD-fed WT rats. These results support the hypothesis that IL-15 secreted from Gn-GC-C-expressing macrophages contributes to the inhibition of fatty acid synthase and lipid accumulation in adipocytes, leading to obesity resistance.
- Published
- 2018
37. Closing the Book on Androgens and Natriuretic Peptides
- Author
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James A. de Lemos and Sandeep R Das
- Subjects
medicine.medical_specialty ,business.industry ,Books ,media_common.quotation_subject ,Closing (real estate) ,Article ,Endocrinology ,Internal medicine ,Natriuretic Peptide, Brain ,Androgens ,medicine ,Testosterone ,Natriuretic Agents ,Natriuretic Peptides ,Peptides ,Cardiology and Cardiovascular Medicine ,business ,media_common - Abstract
BACKGROUND: Circulating natriuretic peptide (NP) levels are markedly lower in healthy men than women. A relative NP deficiency in men could contribute to their higher risk of hypertension and cardiovascular disease. Epidemiologic studies suggest testosterone may contribute to sex-specific NP differences. OBJECTIVES: We aimed to determine the effect of testosterone administration on NP levels using a randomized, placebo-controlled design. METHODS: 151 healthy men (aged 20–50 years) received goserelin acetate to suppress endogenous production of gonadal steroids, and anastrazole to suppress conversion of testosterone to estradiol. Subjects were randomized to placebo gel or 4 different doses of testosterone (1%) gel for 12 weeks. Serum N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and total testosterone levels were measured at baseline and follow-up. RESULTS: Men who did not receive testosterone replacement (placebo gel group) after suppression of endogenous gonadal steroid production experienced a profound decrease in serum testosterone (median 540 to 36 ng/dl, p
- Published
- 2019
38. The natriuretic peptide system in heart failure: Diagnostic and therapeutic implications
- Author
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Koichiro Kuwahara
- Subjects
Cardiotonic Agents ,medicine.drug_class ,Pharmacology ,chemistry.chemical_compound ,Atrial natriuretic peptide ,Renin–angiotensin system ,medicine ,Natriuretic peptide ,Humans ,Pharmacology (medical) ,cardiovascular diseases ,Natriuretic Peptides ,Heart Failure ,Aldosterone ,business.industry ,medicine.disease ,Brain natriuretic peptide ,Angiotensin II ,Blood pressure ,chemistry ,Heart failure ,cardiovascular system ,business ,Biomarkers ,hormones, hormone substitutes, and hormone antagonists - Abstract
Natriuretic peptides, which are activated in heart failure, play an important cardioprotective role. The most notable of the cardioprotective natriuretic peptides are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are abundantly expressed and secreted in the atrium and ventricles, respectively, and C-type natriuretic peptide (CNP), which is expressed mainly in the vasculature, central nervous system, and bone. ANP and BNP exhibit antagonistic effects against angiotensin II via diuretic/natriuretic actions, vasodilatory actions, and inhibition of aldosterone secretion, whereas CNP is involved in the regulation of vascular tone and blood pressure, among other roles. ANP and BNP are of particular interest with respect to heart failure, as their levels, most notably BNP and N-terminal proBNP-a cleavage product produced when proBNP is processed to mature BNP-are increased in patients with heart failure. Furthermore, the identification of natriuretic peptides as sensitive markers of cardiac load has driven significant research into their physiological roles in cardiovascular homeostasis and disease, as well as their potential use as both biomarkers and therapeutics. In this review, I discuss the physiological functions of the natriuretic peptide family, with a particular focus on the basic research that has led to our current understanding of its roles in maintaining cardiovascular homeostasis, and the pathophysiological implications for the onset and progression of heart failure. The clinical significance and potential of natriuretic peptides as diagnostic and/or therapeutic agents are also discussed.
- Published
- 2021
39. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy
- Author
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Nobuhide Hayashi, Tomoko Lee, Yasuhiro Takeshima, Risa Harada, Ichiro Morioka, Jun Saegusa, Tatsushi Toda, Masaaki Matsumoto, Tetsushi Yamamoto, Hiroyuki Awano, Kazumoto Iijima, Yoshitada Sakai, Mariko Taniguchi-Ikeda, and Takamitsu Imanishi
- Subjects
Male ,musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Duchenne muscular dystrophy ,Fukuyama muscular dystrophy ,Ventricular Function, Left ,Cardiac dysfunction ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Internal medicine ,Fukuyama congenital muscular dystrophy ,medicine ,Humans ,Child ,Muscle, Skeletal ,Natriuretic Peptides ,Heart Failure ,Ejection fraction ,business.industry ,Walker-Warburg Syndrome ,Skeletal muscle ,Heart ,General Medicine ,Brain natriuretic peptide ,medicine.disease ,Pathophysiology ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,medicine.anatomical_structure ,Echocardiography ,Pediatrics, Perinatology and Child Health ,Cardiology ,Female ,Neurology (clinical) ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Background One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. Aim To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). Methods We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. Results Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction ( r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD ( p = 0.046, hazard ratio = 0.348). Conclusion The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD.
- Published
- 2017
40. Biomarkers in Pulmonary Vascular Disease: Gauging Response to Therapy
- Author
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Nathan S. Bryan and Timothy J. McMahon
- Subjects
medicine.hormone ,medicine.medical_specialty ,Combination therapy ,medicine.drug_class ,Hypertension, Pulmonary ,030204 cardiovascular system & hematology ,Pharmacology ,Nitric Oxide ,Endothelins ,03 medical and health sciences ,chemistry.chemical_compound ,Soluble Guanylyl Cyclase ,0302 clinical medicine ,Atrial natriuretic peptide ,Internal medicine ,Outcome Assessment, Health Care ,Natriuretic peptide ,medicine ,Humans ,Cyclic adenosine monophosphate ,Natriuretic Peptides ,Cyclic GMP ,Cyclic guanosine monophosphate ,business.industry ,Endocrinology ,030228 respiratory system ,chemistry ,Cardiology ,Biomarker (medicine) ,Cardiology and Cardiovascular Medicine ,business ,Asymmetric dimethylarginine ,Biomarkers ,Signal Transduction - Abstract
Biomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy.
- Published
- 2017
41. Diarrheal pathogens trigger rapid evolution of the guanylate cyclase-C signaling axis in bats
- Author
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Nels C. Elde, Sarah E. Apple, Clayton M. Carey, Michael S. Kay, and Zoe A. Hilbert
- Subjects
Diarrhea ,Sodium-Hydrogen Exchangers ,Bacterial Toxins ,Cystic Fibrosis Transmembrane Conductance Regulator ,Receptors, Enterotoxin ,Cyclic GMP-Dependent Protein Kinase Type II ,Enterotoxin ,Biology ,Microbiology ,Article ,Pathogenesis ,Enterotoxins ,chemistry.chemical_compound ,Chiroptera ,Virology ,Genetic variation ,Animals ,Enterotoxigenic Escherichia coli ,Natriuretic Peptides ,Receptor ,Cyclic GMP ,Vibrio cholerae ,Genetics ,Phylogenetic tree ,Host (biology) ,biology.organism_classification ,Enterocytes ,chemistry ,Guanylate Cyclase ,Parasitology ,Bacteria ,Protein Binding ,Signal Transduction ,Uroguanylin - Abstract
The pathogenesis of infectious diarrheal diseases is largely attributed to enterotoxins that cause dehydration by disrupting intestinal water absorption. We investigated patterns of genetic variation in mammalian guanylate cyclase-C (GC-C), an intestinal receptor targeted by bacterially encoded heat-stable enterotoxins (STa), to determine how host species adapt in response to diarrheal infections. Our phylogenetic and functional analysis of GC-C supports long-standing evolutionary conflict with diarrheal bacteria in primates and bats, with highly variable susceptibility to STa across species. In bats, we further show that GC-C diversification has sparked compensatory mutations in the endogenous uroguanylin ligand, suggesting an unusual scenario of pathogen-driven evolution of an entire signaling axis. Together, these findings suggest that conflicts with diarrheal pathogens have had far-reaching impacts on the evolution of mammalian gut physiology.
- Published
- 2021
42. Postprandial variability of novel heart failure biomarkers in Fontan patients compared to healthy volunteers
- Author
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Svitlana Demyanets, Andrew M. Taylor, Ina Michel-Behnke, Vivek Muthurangu, Jakob A. Hauser, and Bejal Pandya
- Subjects
medicine.medical_specialty ,Heart disease ,medicine.drug_class ,business.industry ,Postprandial ,Hemodynamics ,Heart failure ,General Medicine ,medicine.disease ,Pathophysiology ,RC666-701 ,Internal medicine ,Natriuretic peptide ,medicine ,Cardiology ,Diseases of the circulatory (Cardiovascular) system ,Biomarker (medicine) ,Ingestion ,Natriuretic peptides ,business ,Biomarkers ,Fontan - Abstract
Background Blood-based biomarkers reflecting different components of cardiovascular pathophysiology are now used increasingly in patients with Fontan circulation due to univentricular congenital heart disease. Feeding alters haemodynamics significantly and, thus, may affect biomarker levels. As the haemodynamic responses to a meal differ between Fontan patients and normal subjects, we hypothesised that biomarker kinetics may also vary between these populations. Methods In 15 patients with Fontan physiology, and 15 matched healthy volunteers, 4 heart failure biomarkers were measured under fasting conditions, and 3 after additional timepoints over 2 h following ingestion of a standardised liquid meal. Changes in biomarker levels over time and the effect of Fontan physiology, sex and age were tested using repeated-measures mixed models. Results Under fasting conditions, high-sensitivity C-reactive protein (hsCRP), mid-regional pro-adrenomedullin (MR-proADM) and C-terminal pro-endothelin-1 (CT-proET-1) were raised significantly in Fontan patients compared to controls. Postprandially, mid-regional pro-atrial natriuretic peptide (MR-proANP) decreased significantly in patients (max. mean decrease ∼7% after 120 min). Conversely, it increased in normal subjects (max. mean increase ∼8% after 60 min). The remaining biomarkers did not change significantly. Conclusions The ingestion of food triggers contrary deflections of MR-proANP levels in patients with Fontan circulation compared to normal subjects. Therefore, this parameter should be assessed under fasting conditions in order to correct for postprandial variability.
- Published
- 2021
43. C-type natriuretic peptide-induced relaxation through cGMP-dependent protein kinase and SERCA activation is impaired in two kidney-one clip rat aorta
- Author
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Laena Pernomian, Alejandro F. Prado, Marcella D. Grando, Bruno Rodrigues Silva, Lusiane Maria Bendhack, and Tiago Dal-Cin de Paula
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,SERCA ,Endothelium ,medicine.drug_class ,Blood Pressure ,Kidney ,Nitric Oxide ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Cyclic GMP-Dependent Protein Kinases ,medicine ,Natriuretic peptide ,Animals ,Rats, Wistar ,General Pharmacology, Toxicology and Pharmaceutics ,Endothelial dysfunction ,Natriuretic Peptides ,Cyclic GMP ,biology ,Endothelial Cells ,Natriuretic Peptide, C-Type ,General Medicine ,Surgical Instruments ,medicine.disease ,Rats ,Vasodilation ,Nitric oxide synthase ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Guanylate Cyclase ,Hypertension ,cardiovascular system ,biology.protein ,Endothelium, Vascular ,Nitric Oxide Synthase ,Soluble guanylyl cyclase ,cGMP-dependent protein kinase - Abstract
Aims Hypertension underlies endothelial dysfunction, and activation of vasorelaxation signaling with low dependence on nitric oxide (NO) represents a good alternative for vascular modulation. C-type natriuretic peptide (CNP) causes relaxation by increasing cyclic guanosine 3′,5′-monophosphate (cGMP) or Gi-protein activation through its natriuretic peptide receptor-B or -C, respectively. We have hypothesized that CNP could exerts its effects and could overcome endothelial dysfunction in two kidney-one clip (2K-1C) hypertensive rat aorta. Here, we investigate the intracellular signaling involved in CNP effects in hypertension. Materials and methods The 2K-1C hypertension was induced in male Wistar rats (200 g). CNP-induced vascular relaxation and cGMP production were investigated in rat thoracic aortas. The natriuretic peptide receptor-B and -C localization was evaluated by immunofluorescence. Calcium mobilization was assessed in endothelial cells from rat aortas. Key findings CNP induced similar relaxation in normotensive and 2K-1C hypertensive rat aortas, which increased after endothelium removal. CNP-induced relaxation involved natriuretic peptide receptor-B and -C activation in 2K-1C rats. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) counter-regulated CNP-particulate GC (pGC) activation in aortas. CNP reduced endothelial calcium and increased cGMP production, which was lower in 2K-1C. CNP-induced cGMP-dependent protein kinase (PKG) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) activation was impaired in 2K-1C rat aorta. Significance Our results indicated CNP triggered relaxation through its natriuretic peptide receptor-B and -C in 2K-1C rat aortas, and that CNP-induced relaxation overcomes endothelial dysfunction in hypertension. In addition, NOS and sGC activities counter-regulate CNP-pGC activation to induce vascular relaxation.
- Published
- 2021
44. A natriuretic peptides clearance receptor’s agonist reduces pulmonary artery pressures and enhances cardiac performance in preclinical models: New hope for patients with pulmonary hypertension due to left ventricular heart failure
- Author
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Hilaire A. Ribama, Emmanuel E. Egom, Haaris A. Shiwani, Rebabonye B. Pharithi, Tiam Feridooni, Yassine El Hiani, Barkat Khan, Vincent Maher, and Kishore B.S. Pasumarthi
- Subjects
Male ,0301 basic medicine ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Heart Ventricles ,Hypertension, Pulmonary ,Pulmonary Artery ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Atrial natriuretic peptide ,Heart Rate ,medicine.artery ,Internal medicine ,Pressure ,medicine ,Animals ,Natriuretic Peptides ,Receptor ,Lung ,Heart Failure ,Pharmacology ,Medical treatment ,business.industry ,General Medicine ,medicine.disease ,Pulmonary hypertension ,Pathophysiology ,030104 developmental biology ,Heart failure ,Pulmonary artery ,Cardiology ,business ,Receptors, Atrial Natriuretic Factor ,Atrial Natriuretic Factor - Abstract
In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) is common and represents a strong predictor of death. Despite recent advances in the pathophysiological understanding there is as yet no prospect of cure of this deadly clinical entity and the majority of patients continue to progress to right ventricular failure and die. Furthermore, there is no single medical treatment currently approved for PH related to HF. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent the progressive increased or reverse the elevated pulmonary arterial pressures while enhancing cardiac performance in HF.We here reported, for the first time, using a pressure-loop (P-V) conductance catheter system, that a specific natriuretic peptides clearance receptors' agonist, the ring-deleted atrial natriuretic peptide analogue, cANF4-23 (cANF) reduces pulmonary artery pressures. Strikingly, the administration of the cANF in these mice decreased the RVSP by 50% (n=5, F 25.687, DF 14, p0.001) and heart rate (HR) by 11% (n=5, F 25.69, DF 14, p0.001) as well as enhancing cardiac performance including left ventricular contractility in mice. Most strikingly, mice lacking NPR-C were much more susceptible to develop HF, indicating that NPR-C is a critical protective receptor in the heart.Natriuretic peptides clearance receptors' agonists may, therefore represent a novel and attractive therapeutic strategy for PH related to HF, and ultimately improves the life expectancy and quality for millions of people around the planet.
- Published
- 2017
45. Effect of Pancreatic Hormones on pro-Atrial Natriuretic Peptide in Humans
- Author
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Jakob S. Hansen, Nora E. Zois, Peter Rossing, Kristine Færch, Peter Plomgaard, Jens P. Goetze, and Dijana Terzic
- Subjects
medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,lcsh:Medicine ,030209 endocrinology & metabolism ,PRESSURE ,ProANP ,030204 cardiovascular system & hematology ,Glucagon ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Hyperinsulinemia ,Humans ,Insulin ,GLUCAGON ,Natriuretic Peptides ,Pancreatic hormone ,lcsh:R5-920 ,business.industry ,lcsh:R ,RECEPTOR EXPRESSION ,IN-VITRO ,General Medicine ,medicine.disease ,Metabolism ,Endocrinology ,OBESITY ,Hyperglycemia ,SKELETAL-MUSCLE ,Blood sugar regulation ,GLUCOSE-TOLERANCE ,INDUCED INSULIN-RESISTANCE ,SENSITIVITY ,lcsh:Medicine (General) ,business ,Prediabetes ,Atrial Natriuretic Factor ,hormones, hormone substitutes, and hormone antagonists ,Research Paper ,BED-REST ,Hyperglucagonemia - Abstract
Plasma concentrations of pro-Atrial natriuretic peptide, proANP, are decreased in obesity and diabetes. Decreased proANP concentrations have also been noted after meal intake, and recently, a glucose-mediated regulation of ANP gene expression was reported. Hence, we evaluated the effects of insulin, glucagon and glucose on plasma proANP in a series of observational and experimental studies. Six healthy men underwent seven days of bed rest. Before and after the bed rest, hyperinsulinemic euglycemic clamps with serial plasma measurements of proANP were performed. Moreover, plasma proANP was quantified in 65 individuals with normal or impaired glucose regulation. Finally, the effects of infusion-induced hyperglucagonemia were examined in ten healthy men. Bed rest decreased insulin sensitivity and plasma proANP. The decrease in proANP was not associated with insulin sensitivity and the peptide concentrations remained constant during euglycemic hyperinsulinemia and hyperglycemic hyperglucagonemia. Impaired glucose regulation was not associated with decreased proANP concentrations. Bed rest per se induces a marked decrease in plasma proANP concentrations whereas insulin resistance and impaired glucose regulation was not associated with lower proANP concentrations. Neither acute hyperinsulinemia nor hyperglucagonemia seems to affect plasma proANP. Our findings thus suggest that decreased plasma proANP concentrations occur late in the development of insulin resistance., Highlights • Plasma proANP is markedly decreased in bedridden patients and should be interpreted in the light of these circumstances. • Low-grade insulin resistance was not associated with decreased proANP concentrations. • Neither acute hyperinsulinemia nor hyperglucagonemia seems to affect plasma proANP in lean individuals. Circulating concentrations of pro-ANP areis used as biomarkers of heart failure, where normal concentrations can exclude a diagnosis of cardiac pump dysfunction. In the present study, bed rest per se induced a decrease in plasma proANP. Notably, bed rest is common in patients submitted to hospitals and our findings may thus interfere with the present diagnostic cut-off values. In contrast, presence of low-grade insulin resistance and impaired glucose regulation was not associated with decreased plasma proANP. Neither acute hyperinsulinemia nor hyperglucagonemia affected plasma proANP in lean individuals. Decreased plasma proANP may thus not be evident until more progressed insulin resistance.
- Published
- 2017
46. Clinical benefits of natriuretic peptides and galectin-3 are maintained in old dyspnoeic patients
- Author
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Alain Cohen-Solal, Antônio Lúcio Teixeira, Alexandre Mebazaa, Mattia Arrigo, and Giuseppe Vergaro
- Subjects
Male ,Aging ,medicine.medical_specialty ,Health (social science) ,Galectin 3 ,Cardiovascular biomarkers ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Age groups ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Registries ,030212 general & internal medicine ,Natriuretic Peptides ,Intensive care medicine ,Prospective cohort study ,Aged ,Aged, 80 and over ,Heart Failure ,Adult patients ,business.industry ,Emergency department ,Middle Aged ,medicine.disease ,Confidence interval ,Dyspnea ,Galectin-3 ,Heart failure ,Acute Disease ,Female ,Geriatrics and Gerontology ,Emergency Service, Hospital ,business ,Gerontology ,Biomarkers - Abstract
Background Acute dyspnoea is the leading cause of unscheduled admission of elderly patients. Several biomarkers are used to diagnose acute heart failure (AHF) and assess prognosis of dyspnoeic patients, but their value in elderly patients is unclear. Objective: To compare diagnostic and prognostic performances of conventional and novel cardiovascular biomarkers in 2 age groups: young ( vs . old (≥75 years old) dyspnoeic patients. Design Prospective observational registry. Setting Emergency department (ED). Subjects Acutely dyspnoeic adult patients. Methods Blood samples were collected at ED admission. The diagnostic value of 4 natriuretic peptides (BNP, proBNP, NT-proBNP, MR-proANP) for AHF was tested. We also assessed the prognostic value of same natriuretic peptides and of 3 novel cardiovascular biomarkers (galectin-3, sST2 and proenkephalin), using 1-year all-cause mortality as end-point. Diagnostic or prognostic performances are expressed as area under the receiveroperating characteristic curve (AUC) with 95% confidence interval. Results Two hundred one acutely dyspnoeic patients were studied. AHF was the cause of dyspnoea in 57% of old and 44% of young patients, respectively. All 4 natriuretic peptides performed well in diagnosing AHF in both age groups (all AUC > 0.7). BNP showed the best diagnostic performance in both old (AUC: 0.98 [0.97–1.00]) and young (AUC 0.98 [0.95–1.00]) patients. Galectin-3 showed the best prognostic performance in both old (AUC 0.74 [0.62–0.87]) and young patients (AUC 0.75 [0.56–0.94]). Conclusions BNP and galectin-3 show good clinical benefits in both oldand young acutely dyspnoeic patients.
- Published
- 2017
47. Changes in natriuretic peptides after acute hospital presentation for heart failure with preserved ejection fraction: A feasible surrogate trial endpoint? A report from the prospective Karen study
- Author
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Camilla Hage, Erwan Donal, Gianluigi Savarese, Cecilia Linde, Jean-Claude Daubert, Hans Persson, Emmanuel Oger, Lars H. Lund, Department of Cardiology, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,Research Report ,heart failure with preserved ejection fraction ,medicine.medical_specialty ,Acute decompensated heart failure ,Acute decompensated heart failure with preserved ejection fraction ,Heart failure ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Humans ,Prospective Studies ,Natriuretic peptides ,030212 general & internal medicine ,Aged ,Aged, 80 and over ,Ejection fraction ,Surrogate endpoint ,business.industry ,Proportional hazards model ,Hazard ratio ,Acute heart failure ,Stroke Volume ,Odds ratio ,medicine.disease ,Peptide Fragments ,3. Good health ,Hospitalization ,Acute Disease ,Cardiology ,Feasibility Studies ,Female ,[SDV.IB]Life Sciences [q-bio]/Bioengineering ,Cardiology and Cardiovascular Medicine ,Heart failure with preserved ejection fraction ,business ,Biomarkers ,Follow-Up Studies - Abstract
International audience; BACKGROUND: In acute decompensated heart failure (ADHF) with preserved ejection fraction (HFpEF) there are no surrogate endpoints for early phase trials. The aim of the current study was to evaluate whether a reduction in natriuretic peptides (NP) between acute hospital presentation to stable follow-up is associated with improved mortality and morbidity. METHODS: Patients presenting acutely to the hospital for ADHF with HFpEF enrolled in the Karolinska Rennes (KaRen) study and reporting N-terminal pro-B-type NP or B-type NP assessment at baseline hospital presentation and at 4-8weeks follow-up were prospectively studied. Logistic regression analyses were performed to detect the predictors of baseline and changes in NPs. Cox regression models were performed to assess the impact of NP reductions on mortality and the composite of mortality and HF hospitalization. RESULTS: Of 361 patients (median follow-up 585days), 267 (74%) reported an improvement in NPs, while 94 (26%) reported worsening. At baseline, the independent predictors of lower NPs were higher glomerular filtration rate (Odds Ratio [OR] per unit: 1.013; 95% Confidence Interval [CI]: 1.005-1.021) and younger age (OR per year: 0.972; CI: 0.947-0.998). Improvement in NPs at follow-up was predicted by higher heart rate at baseline (OR per bpm: 1.014; CI: 1.003-1.025). After adjustments, the hazard ratio for all-cause death was 0.730 (CI: 0.456-1.169) and for the composite outcome 0.814 (CI: 0.582-1.139) for patients who improved vs. worsened in NP levels. CONCLUSIONS: In patients presenting acutely to the hospital with HFPEF, an improvement in NP levels did not independently and significantly predict improved mortality and/or morbidity. NPs as surrogate endpoints in acute HFpEF require further study.
- Published
- 2017
48. Modulation of RAAS-natriuretic peptides in the treatment of HF: Old guys and newcomers
- Author
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Annalisa Capuano, Francesco Rossi, Micaela Gliozzi, Vincenzo Mollace, Mollace, Vincenzo, Gliozzi, Micaela, Capuano, Annalisa, and Rossi, Francesco
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.drug_class ,Angiotensin-Converting Enzyme Inhibitors ,Disease ,030204 cardiovascular system & hematology ,Pharmacology ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,Natriuretic peptide ,Humans ,Medicine ,Natriuretic Peptides ,Neprilysin ,Heart Failure ,Angiotensin II receptor type 1 ,business.industry ,AT2-receptor modulator ,medicine.disease ,AT1-receptor modulator ,Treatment Outcome ,030104 developmental biology ,Endocrinology ,Renin-angiotensin-aldosterone system ,Heart failure ,Pharmacodynamics ,Drug Therapy, Combination ,RAAS inhibitor ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers - Abstract
The use of renin–angiotensin–aldosterone system (RAAS) inhibitors in the treatment of chronic heart failure (HF) and arterial hypertension is recommended by the European Society of Cardiology Guidelines on the basis of consolidated evidence supporting their efficacy in the development of such a disease. However, the high incidence of re-hospitalization and mortality in patients undergoing chronic HF, leads to the need for the development of novel RAAS inhibitors possessing a better pharmacokinetic/pharmacodynamics profile in approaching hemodynamic imbalance and myocardial dysfunction associated with the development of chronic HF. Here we summarize some of the recent advances in the area of RAAS-modulators, including novel renin inhibitors, mineralcorticoid receptor antagonists and novel AT1 and AT2-receptor modulators. In addition, the pharmacology of a new class of compounds which display both AT1-receptor blocking properties combined with inhibition of neprilysin, the vasopeptidase enzyme degradating natriuretic peptide (ARNi), will be reviewed, alongside with their impact in the pathophysiology of chronic HF.
- Published
- 2017
49. Natriuretic Peptide Measurement Is Key to a Solution in the Clinical Trial and Clinical Practice
- Author
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Yasuyuki Shiraishi, Tsutomu Yoshikawa, Keiichi Fukuda, Shun Kohsaka, and Mizuki Momoi
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Vasodilator Agents ,030204 cardiovascular system & hematology ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Natriuretic Peptides ,Stroke ,Heart Failure ,Rivaroxaban ,business.industry ,medicine.disease ,Clinical Practice ,Clinical trial ,Heart failure ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
In this issue of JACC: Heart Failure , Jonathan et al. ([1][1]) analyzed the data from the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease
- Published
- 2020
50. Is natriuretic peptide lowering strategy superior to symptomatically based management of chronic heart failure with reduced ejection fraction?
- Author
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Samarthkumar Thakkar, Igor Vaz, Monil Majmundar, Rajkumar Doshi, Ashish Kumar, Devina Adalja, and Mariam Shariff
- Subjects
Heart Failure ,medicine.medical_specialty ,Ejection fraction ,business.industry ,medicine.drug_class ,Stroke Volume ,Stroke volume ,medicine.disease ,Peptide Fragments ,Ventricular Dysfunction, Left ,Text mining ,Heart failure ,Internal medicine ,Natriuretic Peptide, Brain ,Internal Medicine ,medicine ,Natriuretic peptide ,Cardiology ,Humans ,Natriuretic Peptides ,business ,Biomarkers - Published
- 2020
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