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Chen S. Two-sample bi-directional causality between two traits with some invalid IVs in both directions using GWAS summary statistics. HGG ADVANCES 2025; 6:100449. [PMID: 40336198 DOI: 10.1016/j.xhgg.2025.100449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 05/01/2025] [Accepted: 05/01/2025] [Indexed: 05/09/2025] Open
Abstract
Mendelian randomization (MR) is a widely used method for assessing causal relationships between risk factors and outcomes using genetic variants as instrumental variables (IVs). While traditional MR assumes uni-directional causality, bi-directional MR aims to identify the true causal direction. In uni-directional MR, invalid IVs due to pleiotropy can violate assumptions and introduce biases. In bi-directional MR, traditional MR can be performed separately for each direction, but the presence of invalid IVs poses even greater challenges. We introduce a new bi-directional MR method incorporating stepwise selection (Bidir-SW) designed to address these challenges. Our approach leverages public genome-wide association study (GWAS) datasets for two traits and uses model selection criteria to identify invalid IVs iteratively by stepwise selection. This method accounts for potential bi-directional causality in the presence of common invalid IVs for both directions, even if only GWAS summary statistics are provided. Through simulation studies, we demonstrate that our method outperforms traditional MR techniques, such as MR-Egger and inverse-variance weighted (IVW), with uncorrelated SNPs. We also provide simulations to compare our approach with existing transcriptome-wide association study (TWAS) to show its effectiveness. Finally, we apply the proposed method to genetic traits such as CRP levels and BMI to explore possible bi-directional relationships among these traits. We also used the proposed method to discover causal protein biomarkers. Our findings suggest that the Bidir-SW approach is a powerful tool for bi-directional MR or TWAS, which can provide a valuable framework for future genetic epidemiology studies.
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Affiliation(s)
- Siyi Chen
- School of Public Health, LSU Health Sciences Center New Orleans, New Orleans, LA 70112, USA.
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2
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Meulendijks ER, Krul SPJ, Baalman SW, de Vries TAC, Wesselink R, Ernault AC, Kawasaki M, Al-Shama R, Neefs J, Limpens J, de Groot JR. Circulating adipose tissue proteins involved in atrial fibrillation: An explorative scoping review. Trends Cardiovasc Med 2024; 34:148-158. [PMID: 36538994 DOI: 10.1016/j.tcm.2022.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Obesity increases the risk of atrial fibrillation (AF), potentially through proteins secreted by adipose tissue (AT) that affect atrial electrical and structural remodeling. We aim to give a comprehensive overview of circulating AT proteins involved in inflammation and fibrosis, that are associated with prevalent AF (paroxysmal or persistent) and the risk on developing new-onset AF. These include adipokines, defined as proteins enriched in AT as adiponectin, but also proteins less specific to AT. We systematically performed an explorative search for studies reporting associations between proteins secreted from cells residing in the AT and AF, and additionally assessed the effect of obesity on these proteins by a secondary search. The AT proteins involved in inflammation were mostly increased in patients with prevalent and new-onset AF, and with obesity, while the AT enriched adipokines were mostly not associated with AF. This review provides insight into circulating adipose tissue proteins involved in AF substrate formation.
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Affiliation(s)
- Eva R Meulendijks
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands.
| | - Sébastien P J Krul
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands
| | - Sarah W Baalman
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands
| | - Tim A C de Vries
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Robin Wesselink
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Auriane C Ernault
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Makiri Kawasaki
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands
| | - Rushd Al-Shama
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Jolien Neefs
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands
| | - Jacqueline Limpens
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands
| | - Joris R de Groot
- Amsterdam UMC, University of Amsterdam, Heart Center, department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
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van Oers JAH, Pouwels S, Ramnarain D, Kluiters Y, Bons JAP, de Lange DW, de Grooth HJ, Girbes ARJ. Mid-regional proadrenomedullin, C-terminal proendothelin-1 values, and disease course are not different in critically ill SARS-CoV-2 pneumonia patients with obesity. Int J Obes (Lond) 2022; 46:1801-1807. [PMID: 35840771 PMCID: PMC9283850 DOI: 10.1038/s41366-022-01184-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 07/01/2022] [Accepted: 07/01/2022] [Indexed: 01/08/2023]
Abstract
Background/objectives Patients affected by obesity and Coronavirus disease 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have a higher risk for intensive care (ICU) admission. A state of low-grade chronic inflammation in obesity has been suggested as one of the underlying mechanisms. We investigated whether obesity is associated with differences in new inflammatory biomarkers mid-regional proadrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and clinical outcomes in critically ill patients with SARS-CoV-2 pneumonia. Subjects/methods A total of 105 critically ill patients with SARS-CoV-2 pneumonia were divided in patients with obesity (body mass index (BMI) ≥ 30 kg/m2, n = 42) and patients without obesity (BMI < 30 kg/m2, n = 63) and studied in a retrospective observational cohort study. MR-proADM, CT-proET-1 concentrations, and conventional markers of white blood count (WBC), C-reactive protein (CRP), and procalcitonin (PCT) were collected during the first 7 days. Results BMI was 33.5 (32–36.1) and 26.2 (24.7–27.8) kg/m2 in the group with and without obesity. There were no significant differences in concentrations MR-proADM, CT-proET-1, WBC, CRP, and PCT at baseline and the next 6 days between patients with and without obesity. Only MR-proADM changed significantly over time (p = 0.039). Also, BMI did not correlate with inflammatory biomarkers (MR-proADM rho = 0.150, p = 0.125, CT-proET-1 rho = 0.179, p = 0.067, WBC rho = −0.044, p = 0.654, CRP rho = 0.057, p = 0.564, PCT rho = 0.022, p = 0.842). Finally, no significant differences in time on a ventilator, ICU length of stay, and 28-day mortality between patients with or without obesity were observed. Conclusions In critically ill patients with confirmed SARS-CoV-2 pneumonia, obesity was not associated with differences in MR-proADM, and CT-proET-1, or impaired outcome. Trial registration Netherlands Trial Register, NL8460.
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Affiliation(s)
- Jos A H van Oers
- Department of Intensive Care Medicine, Elisabeth Tweesteden Ziekenhuis, Tilburg, The Netherlands.
| | - Sjaak Pouwels
- Department of Intensive Care Medicine, Elisabeth Tweesteden Ziekenhuis, Tilburg, The Netherlands
| | - Dharmanand Ramnarain
- Department of Intensive Care Medicine, Elisabeth Tweesteden Ziekenhuis, Tilburg, The Netherlands
| | - Yvette Kluiters
- Department of Clinical Chemistry, Elisabeth Tweesteden Ziekenhuis, Tilburg, The Netherlands
| | - Judith A P Bons
- Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Dylan W de Lange
- Department of Intensive Care Medicine, University Medical Centre Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Harm-Jan de Grooth
- Department of Intensive Care Medicine, Amsterdam UMC, Medical Centres, VU University Medical Centre, Amsterdam, The Netherlands
| | - Armand R J Girbes
- Department of Intensive Care Medicine, Amsterdam UMC, Medical Centres, VU University Medical Centre, Amsterdam, The Netherlands
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Lammert J, Basrai M, Struck J, Hartmann O, Engel C, Bischoff SC, Berling-Ernst A, Halle M, Kiechle M, Grill S. Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers. Geburtshilfe Frauenheilkd 2022; 82:601-609. [PMID: 35903716 PMCID: PMC9315398 DOI: 10.1055/a-1811-2164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/28/2022] [Indexed: 11/18/2022] Open
Abstract
Background
Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking
in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to
lifestyle changes that lead to improved cardiovascular health. As
BRCA1/2
mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma
ADM levels in a cohort of
BRCA
mutation carriers and to assess their association with cardiovascular risk factors.
Methods
Plasma ADM concentrations were measured in 292 female
BRCA1/2
mutation carriers with and without a history of breast cancer. Subjects were classified into high versus
low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several
cardiovascular risk factors.
Results
Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years).
Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness
(OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a
previous diagnosis of breast cancer (p = 0.28).
Conclusions
This is the first study in
BRCA
mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical
implications of these findings are yet to be determined.
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Affiliation(s)
- Jacqueline Lammert
- Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich,
Germany
| | - Maryam Basrai
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | | | | | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Stephan C. Bischoff
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Anika Berling-Ernst
- Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Martin Halle
- Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Marion Kiechle
- Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich,
Germany
| | - Sabine Grill
- Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich,
Germany
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Stanisz-Kempa J, Gąsior Z, Kułach A. Proadrenomedullin in Patients with Preserved Left Ventricular Systolic Function Undergoing Coronary Artery Bypass Grafting. Braz J Cardiovasc Surg 2022; 37:219-226. [PMID: 35522058 PMCID: PMC9054142 DOI: 10.21470/1678-9741-2020-0616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Introduction A potentially new marker of cardiovascular diseases — proadrenomedullin is the precursor of adrenomedullin, which is a multifunctional peptide hormone, produced in most of the tissues in response to cellular stress, ischemia, and hypoxia. Methods Ninety-three people, aged 51-79 years, were included in the study. Exclusion criteria were severe or corrected valvular disease, acute coronary syndrome, age ≥ 80 years, glomerular filtration rate < 45 ml/min, active infectious diseases, and cancer. The subjects were observed for adverse events, including reduced left ventricular ejection fraction (LVEF) by ≥ 10%, first incidence of atrial fibrillation (AF), and the necessity of using dopamine during hospitalization. Results Use of pressure amines, occurrence of the first AF episode, and left ventricular dysfunction defined by a decrease in LVEF by at least 10% compared to the value before surgery were reported in the perioperative period. No death, sudden cardiac arrest with effective resuscitation, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, or heart failure were observed. Significantly higher proadrenomedullin concentration was observed in the group with reduced postoperative LVEF (1.68 vs. 0.77 nmol/l, P=0.005). The relative risk of a decrease in ejection fraction in the group of patients with proadrenomedullin concentration ≥ 0.77 nmol/l was more than twelve-fold higher (95% confidence interval 1.69-888.33; P=0.013) than in the group of patients with a concentration of proadrenomedullin < 0.77 nmol/l. Conclusion The higher baseline concentration of proadrenomedullin has a predominantly predictive value of postoperative left ventricular systolic dysfunction.
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Affiliation(s)
| | - Zbigniew Gąsior
- 2nd Department of Cardiology, Upper Silesian Medical Center, Katowice, Poland
| | - Andrzej Kułach
- 2nd Department of Cardiology, Upper Silesian Medical Center, Katowice, Poland
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Comba C, Ozdemir IA, Demirayak G, Erdogan SV, Demir O, Özlem Yıldız G, Bulut H, Karakas S, Gulseren V, Afsar S, Gungorduk K. The effect of omentectomy on the blood levels of adipokines in obese patients with endometrial cancer. Obes Res Clin Pract 2022; 16:242-248. [PMID: 35701296 DOI: 10.1016/j.orcp.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 04/18/2022] [Accepted: 06/01/2022] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To investigate the blood levels of adipokines in obese patients with endometrial cancer who have and have not undergone omentectomy. METHODS Between September 2017 and September 2019, the study recruited 54 patients with endometrial cancer. Measurements were taken of blood levels of human leptin, perilipin-1, adiponectin, adipolin, resistin, visfatin, and estrone preoperatively and postoperatively before adjuvant therapy or at the end of one month. The serum samples were separated by centrifugation for 10 mins at 3,000 revolutions/min, then stored at -80 °C until assay. RESULTS In this prospective study, a total of 54 endometrial cancer patients were analyzed in two separate groups according to the omentectomy status. Comprehensive staging surgery with omentectomy and without omentectomy was performed in 26 patients and 28 patients, respectively. The age, body mass index, body fat index, waist circumference, and skin thickness values of the patients with and without omentectomy were found to be similar. No statistically significant difference was determined between the patients with and without omentectomy in respect of the blood level of the adipokines measured preoperatively. A strong statistically significant correlation was determined between the pre and postoperative levels of Human Leptin (p = 0.002), perilipin-1(p = 0.001), adipolin (p < 0.001), adiponectin (p < 0.001), resistin (p = 0.001), visfatin (p < 0.001), and estrone (p = 0.004) (r = -0.43, -0.47, 0.75, 0.84, -0.47, - 0.58, -0.41, respectively) CONCLUSIONS: Omentectomy affected the postoperative blood levels of adipokines in obese patients with endometrial cancer. As omentectomy may have some positive effects on metabolism in these patients, it may be considered during endometrial cancer surgery due to the possible positive metabolic effects.
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Affiliation(s)
- Cihan Comba
- Department of Gynecologic Oncology, Istanbul Aydin University VM Medical Park Hospital, Istanbul, Turkey.
| | - Isa Aykut Ozdemir
- Department of Gynecologic Oncology, Medipol University Hospital, Istanbul, Turkey.
| | - Gokhan Demirayak
- Department of Gynecologic Oncology, Memorial Sisli Hospital, İstanbul, Turkey.
| | - Sakir Volkan Erdogan
- Department of Obstetrics and Gynecology, Memorial Sisli Hospital, İstanbul, Turkey.
| | - Omer Demir
- Department of Obstetrics and Gynecology, Karadeniz Technical University Hospital, Trabzon, Turkey.
| | - Güneş Özlem Yıldız
- Department of Anesthesiology, Bakırköy Dr Sadi Konuk Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.
| | - Huri Bulut
- Department of Medical Biology, Istinye University Hospital, Istanbul, Turkey.
| | - Sema Karakas
- Department of Gynecologic Oncology, Bakırköy Dr Sadi Konuk Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.
| | - Varol Gulseren
- Department of Gynecologic Oncology, Erciyes University, Kayseri, Turkey.
| | - Selim Afsar
- Department of Gynecologic Oncology, Balikesir University Hospital, Balikesir, Turkey.
| | - Kemal Gungorduk
- Department of Gynecologic Oncology, Muğla Sıtkı Koçman University, Education and Research Hospital, Muğla, Turkey.
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Gar C, Thorand B, Herder C, Sujana C, Heier M, Meisinger C, Peters A, Koenig W, Rathmann W, Roden M, Stumvoll M, Maalmi H, Meitinger T, Then H, Seissler J, Then C. Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: Results from the KORA F4 cohort study. PLoS One 2022; 17:e0262330. [PMID: 34990470 PMCID: PMC8735665 DOI: 10.1371/journal.pone.0262330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 12/22/2021] [Indexed: 11/23/2022] Open
Abstract
Background and aim Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. Methods Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8–9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603–1551). Results MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72–3.26) and 2.31 (1.67–3.20)) and cardiovascular mortality (4.28 (2.19–8.39) and 4.44 (2.25–8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. Conclusions We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.
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Affiliation(s)
- Christina Gar
- Department of Medicine IV, University Hospital, LMU Munich, Germany
- Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universität München and Helmholtz Zentrum München, Munich, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- * E-mail:
| | - Barbara Thorand
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Christian Herder
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Chaterina Sujana
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig-Maximilians-Universität, Munich, Germany
| | - Margit Heier
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- KORA Study Centre, University Hospital Augsburg, Augsburg, Germany
| | - Christa Meisinger
- Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Chair of Epidemiology at University Hospital Augsburg, Augsburg, Germany
| | - Annette Peters
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Wolfgang Koenig
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
| | - Wolfgang Rathmann
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- German Diabetes Center, Leibniz Institute at Heinrich Heine University Düsseldorf, Institute of Biometrics and Epidemiology, Düsseldorf, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | - Haifa Maalmi
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Thomas Meitinger
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Holger Then
- Freie Waldorfschule Augsburg, Augsburg, Germany
| | - Jochen Seissler
- Department of Medicine IV, University Hospital, LMU Munich, Germany
- Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universität München and Helmholtz Zentrum München, Munich, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Cornelia Then
- Department of Medicine IV, University Hospital, LMU Munich, Germany
- Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universität München and Helmholtz Zentrum München, Munich, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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8
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Ouyang M, Tu D, Tong L, Sarwar M, Bhimaraj A, Li C, Coté GL, Di Carlo D. A review of biosensor technologies for blood biomarkers toward monitoring cardiovascular diseases at the point-of-care. Biosens Bioelectron 2021; 171:112621. [PMID: 33120234 DOI: 10.1016/j.bios.2020.112621] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 09/06/2020] [Accepted: 09/14/2020] [Indexed: 01/03/2023]
Abstract
Cardiovascular diseases (CVDs) cause significant mortality globally. Notably, CVDs disproportionately negatively impact underserved populations, such as those that are economically disadvantaged and often located in remote regions. Devices to measure cardiac biomarkers have traditionally been focused on large instruments in a central laboratory but the development of affordable, portable devices that measure multiple cardiac biomarkers at the point-of-care (POC) are needed to improve clinical outcomes for patients, especially in underserved populations. Considering the enormity of the global CVD problem, complexity of CVDs, and the large candidate pool of biomarkers, it is of great interest to evaluate and compare biomarker performance and identify potential multiplexed panels that can be used in combination with affordable and robust biosensors at the POC toward improved patient care. This review focuses on describing the known and emerging CVD biosensing technologies for analysis of cardiac biomarkers from blood. Initially, the global burden of CVDs and the standard of care for the primary CVD categories, namely heart failure (HF) and acute coronary syndrome (ACS) including myocardial infarction (MI) are discussed. The latest United States, Canadian and European society guidelines recommended standalone, emerging, and add-on cardiac biomarkers, as well as their combinations are then described for the prognosis, diagnosis, and risk stratification of CVDs. Finally, both commercial in vitro biosensing devices and recent state-of-art techniques for detection of cardiac biomarkers are reviewed that leverage single and multiplexed panels of cardiac biomarkers with a view toward affordable, compact devices with excellent performance for POC diagnosis and monitoring.
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Affiliation(s)
- Mengxing Ouyang
- Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, Los Angeles, CA, 90095, USA
| | - Dandan Tu
- Department of Biomedical Engineering, Texas A&M University, 400 Bizzell St, College Station, TX, 77843, USA
| | - Lin Tong
- Nanobioengineering/Bioelectronics Lab, Department of Biomedical Engineering, Florida International University, 10555 West Flagler Street, Miami, FL, 33174, USA
| | - Mehenur Sarwar
- Nanobioengineering/Bioelectronics Lab, Department of Biomedical Engineering, Florida International University, 10555 West Flagler Street, Miami, FL, 33174, USA
| | - Arvind Bhimaraj
- Department of Cardiology, Houston Methodist J.C. Walter Transplant Center, Houston Methodist Hospital, 6550 Fannin St., Houston, TX, 77030, USA
| | - Chenzhong Li
- Nanobioengineering/Bioelectronics Lab, Department of Biomedical Engineering, Florida International University, 10555 West Flagler Street, Miami, FL, 33174, USA.
| | - Gerard L Coté
- Department of Biomedical Engineering, Texas A&M University, 400 Bizzell St, College Station, TX, 77843, USA; Center for Remote Health Technologies & Systems, Texas A&M Engineering Experiment Station, 101 Bizzell St, College Station, TX, 77840, USA.
| | - Dino Di Carlo
- Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, Los Angeles, CA, 90095, USA.
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Koyama T, Kuriyama N, Uehara R. Midregional Proadrenomedullin Can Reflect the Accumulation of Visceral Adipose Tissue-A Key to Explaining the Obesity Paradox. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17113968. [PMID: 32503285 PMCID: PMC7312365 DOI: 10.3390/ijerph17113968] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 12/25/2022]
Abstract
Background: The aim of this study was to investigate whether plasma midregional proadrenomedullin (MR-proADM) reflected body composition, such as body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), VAT/SAT ratio, body fat mass (BFM), and skeletal muscle mass (SMM). Methods: A total of 2244 individuals (727 men and 1517 women) were included in the study. Multiple regression analysis was performed to assess the combined influence of variables: age, daily alcohol consumption, Brinkman index, sleeping time, metabolic equivalents, anamnesis for hypertension, dyslipidemia, diabetes, and body composition of MR-proADM, by using a stepwise forward selection method. Results: MR-proADM was significantly related to all anthropometric indices (BMI, VAT, SAT, VAT/SAT ratio, BFM, and SMM) in men and women. On the basis of a stepwise forward selection method, VAT (men: beta = 0.184, p < 0.001, women: beta = 0.203, p < 0.001) and BFM (beta = 0.181, p < 0.001) in women, were found to be significantly associated with MR-proADM. Conclusion: This study suggests that plasma MR-proADM concentration is a more reliable indicator of VAT for fat distribution, and thus, MR-proADM may help better understand the obesity paradox. Changes in circulating levels of MR-proADM could possibly reflect changes in body composition, endocrine, and metabolic milieu.
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Gaborit FS, Kistorp C, Kümler T, Hassager C, Tønder N, Iversen K, Kamstrup PR, Faber J, Køber L, Schou M. Early Stages of Obesity-related Heart Failure Are Associated with Natriuretic Peptide Deficiency and an Overall Lack of Neurohormonal Activation: The Copenhagen Heart Failure Risk Study. Glob Heart 2020; 15:25. [PMID: 32489798 PMCID: PMC7218759 DOI: 10.5334/gh.776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 02/18/2020] [Indexed: 12/27/2022] Open
Abstract
Objective This study evaluated the associations between the natriuretic peptide activity and the neurohormonal response in non-obese and obese outpatients with and without heart failure (HF). Background Obesity-related HF may be a distinct subtype of HF. Obesity is associated with lower plasma concentrations of natriuretic peptides. The associations between obesity and neurohormonal activation estimated by mid-regional pro-adrenomedullin (MR-proADM) and copeptin in patients with HF is not elucidated. Methods This prospective cohort-study included 392 outpatients ≥60years, plus ≥1 risk-factor(-s) for HF (hypertension, ischemic heart disease, atrial fibrillation, diabetes, chronic kidney disease), and without known HF. Patients were categorized 'non-obese' BMI = 18.5-29.9 kg/m2 (n = 273) and 'obese' BMI ≥ 30 kg/m2 (n = 119). The diagnosis of HF required signs, symptoms, and abnormal echocardiography. NT-proBNP, MR-proANP, MR-proADM, and copeptin were analyzed. Results Obese patients were younger, had a higher prevalence of diabetes and chronic kidney disease, but a lower prevalence of atrial fibrillation. A total of 39 (14.3%) non-obese and 26 (21.8%) obese patients were diagnosed with HF. In obese patients, HF was not associated with higher plasma concentrations of NT-proBNP (Estimate: 0.063; 95%CI: -0.037-1.300; P = 0.064), MR-proANP (Estimate: 0.207; 95%CI: -0.101-0.515; P = 0.187), MR-proADM (Estimate: 0.112; 95%CI: -0.047-0.271; P = 0.168), or copeptin (Estimate: 0.093; 95%CI: -0.333-0.518; P = 0.669). Additionally, obese patients with HF had lower plasma concentrations of NT-proBNP (Estimate: -0.998; 95%CI: -1.778-0.218; P = 0.012), and MR-proANP (Estimate: -0.488; 95%CI: -0.845-0.132; P = 0.007) compared to non-obese patients with HF, whereas plasma concentrations of MR-proADM (Estimate: 0.066; 95%CI: -0.119-0.250; P = 0.484) and copeptin (Estimate: 0.140; 95%CI: -0.354-0.633; P = 0.578) were comparable. Conclusions Patients with obesity-related HF have natriuretic peptide deficiency and lack of increased plasma concentrations of MR-proADM and copeptin suggesting that patients with obesity-related HF have a blunted overall neurohormonal activity.
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Affiliation(s)
- Freja Stoltze Gaborit
- Department of Cardiology, Herlev Gentofte University Hospital, DK
- Faculty of Health and Medical Science, University of Copenhagen, DK
| | - Caroline Kistorp
- Department Endocrinology, Rigshospitalet, Copenhagen, DK
- Department of Clinical Medicine, University of Copenhagen, DK
| | - Thomas Kümler
- Department of Cardiology, Herlev Gentofte University Hospital, DK
| | - Christian Hassager
- Department of Cardiology, Rigshospitalet, Copenhagen, DK
- Department of Clinical Medicine, University of Copenhagen, DK
| | - Niels Tønder
- Department of Cardiology, North Zealand University Hospital, DK
| | - Kasper Iversen
- Department of Cardiology, Herlev Gentofte University Hospital, DK
- Department of Clinical Medicine, University of Copenhagen, DK
| | - Pia R. Kamstrup
- Department of Clinical Biochemistry, Herlev Gentofte University Hospital, DK
| | - Jens Faber
- Department Endocrinology, Rigshospitalet, Copenhagen, DK
- Department Endocrinology, Herlev Gentofte University Hospital, DK
| | - Lars Køber
- Department of Cardiology, Rigshospitalet, Copenhagen, DK
- Department of Clinical Medicine, University of Copenhagen, DK
| | - Morten Schou
- Department of Cardiology, Herlev Gentofte University Hospital, DK
- Department of Clinical Medicine, University of Copenhagen, DK
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Bech EM, Voldum-Clausen K, Pedersen SL, Fabricius K, Rudkjær LC, Hansen HH, Jelsing J. Adrenomedullin and glucagon-like peptide-1 have additive effects on food intake in mice. Biomed Pharmacother 2019; 109:167-173. [DOI: 10.1016/j.biopha.2018.10.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 01/20/2023] Open
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Frøssing S, Nylander M, Kistorp C, Skouby SO, Faber J. Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS. Endocr Connect 2018; 7:115-123. [PMID: 29295870 PMCID: PMC5754509 DOI: 10.1530/ec-17-0327] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 11/28/2017] [Indexed: 12/12/2022]
Abstract
CONTEXT Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease (CVD), and biomarkers can be used to detect early subclinical CVD. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial natriuretic peptide (MR-proANP) and copeptin are all associated with CVD and part of the delicate system controlling fluid and hemodynamic homeostasis through vascular tonus and diuresis. The GLP-1 receptor agonist liraglutide, developed for treatment of type 2 diabetes (T2D), improves cardiovascular outcomes in patients with T2D including a decrease in particular MR-proANP. OBJECTIVE To investigate if treatment with liraglutide in women with PCOS reduces levels of the cardiovascular biomarkers MR-proADM, MR-proANP and copeptin. METHODS Seventy-two overweight women with PCOS were treated with 1.8 mg/day liraglutide or placebo for 26 weeks in a placebo-controlled RCT. Biomarkers, anthropometrics, insulin resistance, body composition (DXA) and visceral fat (MRI) were examined. RESULTS Baseline median (IQR) levels were as follows: MR-proADM 0.52 (0.45-0.56) nmol/L, MR-proANP 44.8 (34.6-56.7) pmol/L and copeptin 4.95 (3.50-6.50) pmol/L. Mean percentage differences (95% CI) between liraglutide and placebo group after treatment were as follows: MR-proADM -6% (-11 to 2, P = 0.058), MR-proANP -25% (-37 to -11, P = 0.001) and copeptin +4% (-13 to 25, P = 0.64). Reduction in MR-proANP concentration correlated with both increased heart rate and diastolic blood pressure in the liraglutide group. Multiple regression analyses with adjustment for BMI, free testosterone, insulin resistance, visceral fat, heart rate and eGFR showed reductions in MR-proANP to be independently correlated with an increase in the heart rate. CONCLUSION In an RCT, liraglutide treatment in women with PCOS reduced levels of the cardiovascular risk biomarkers MR-proANP with 25% and MR-proADM with 6% (borderline significance) compared with placebo. The decrease in MR-proANP was independently associated with an increase in the heart rate.
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Affiliation(s)
- Signe Frøssing
- Department of Internal MedicineCenter of Endocrinology and Metabolism, Herlev Gentofte Hospital, Copenhagen, Denmark
- Faculty of Health and Medical SciencesCopenhagen University, Copenhagen, Denmark
| | - Malin Nylander
- Faculty of Health and Medical SciencesCopenhagen University, Copenhagen, Denmark
- Department of Obstetrics & GynecologyHerlev Gentofte Hospital, Copenhagen, Denmark
| | - Caroline Kistorp
- Department of Internal MedicineCenter of Endocrinology and Metabolism, Herlev Gentofte Hospital, Copenhagen, Denmark
- Faculty of Health and Medical SciencesCopenhagen University, Copenhagen, Denmark
| | - Sven O Skouby
- Faculty of Health and Medical SciencesCopenhagen University, Copenhagen, Denmark
- Department of Obstetrics & GynecologyHerlev Gentofte Hospital, Copenhagen, Denmark
| | - Jens Faber
- Department of Internal MedicineCenter of Endocrinology and Metabolism, Herlev Gentofte Hospital, Copenhagen, Denmark
- Faculty of Health and Medical SciencesCopenhagen University, Copenhagen, Denmark
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Frøssing S, Nylander M, Aziz M, Skouby SO, Kistorp C, Faber J. Atrial natriuretic peptide, copeptin and adrenomedullin levels in polycystic ovary syndrome: a case-control study. Gynecol Endocrinol 2017; 33:30-33. [PMID: 27424881 DOI: 10.1080/09513590.2016.1202915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) defined by the Rotterdam criteria does not take into account the unhealthy metabolic profile of the syndrome with increased insulin resistance (IR) and overweight favoring development of type 2 diabetes, hypertension and cardiovascular disease (CVD). We assess three vasoactive peptides associated with CVD in women with PCOS. METHOD Plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin and mid-regional pro-adrenomedullin (MR-proADM) were measured in 98 PCOS patients and 46 age- and BMI-matched healthy women. RESULTS We found no difference in levels of MR-proANP, copeptin and MR-proADM between the PCOS and control group. Multiple regression analyses on a combined group of PCOS and control subjects demonstrated an inverse correlation between MR-proANP and IR (measured by fasting C-peptide) and a positive correlations between copeptin and IR as well as MR-proADM and BMI. We found no association between peptide levels and different Rotterdam phenotypes. CONCLUSION Plasma concentrations of MR-proANP, copeptin and MR-proADM were not increased in PCOS compared to age- and BMI-matched controls. Thus, these peptides cannot be used to detect increased risk of CVD in a young PCOS cohort.
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Affiliation(s)
- Signe Frøssing
- a Department of Internal Medicine , Division of Endocrinology , and
| | - Malin Nylander
- b Department of Gynecology and Obstetrics , Herlev University Hospital , Copenhagen , Denmark , and
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Mubeena Aziz
- b Department of Gynecology and Obstetrics , Herlev University Hospital , Copenhagen , Denmark , and
| | - Sven O Skouby
- b Department of Gynecology and Obstetrics , Herlev University Hospital , Copenhagen , Denmark , and
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Caroline Kistorp
- a Department of Internal Medicine , Division of Endocrinology , and
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Jens Faber
- a Department of Internal Medicine , Division of Endocrinology , and
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
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Braun N, Hoess C, Kutz A, Christ-Crain M, Thomann R, Henzen C, Zimmerli W, Mueller B, Schuetz P. Obesity paradox in patients with community-acquired pneumonia: Is inflammation the missing link? Nutrition 2016; 33:304-310. [PMID: 27742103 DOI: 10.1016/j.nut.2016.07.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 07/18/2016] [Accepted: 07/24/2016] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Positive associations between body mass index (BMI) and clinical outcomes have been found and are called "the obesity survival paradox." However, whether obesity has protective effects or if this paradox is because of confounding remains unclear. Herein, we analyzed the effects of weight on long-term mortality in a large cohort of patients with community-acquired pneumonia (CAP) and investigated whether the differential effects of obesity on inflammation pathways accounted for mortality differences. METHODS For this secondary analysis, we followed prospectively for 6 y 763 CAP patients who were previously included in a multicenter trial (the ProHOSP Trial). To assess associations of BMI with mortality and with several inflammatory biomarker levels, we calculated three regression models adjusted for severity: the pneumonia severity index (PSI); fully adjusted for PSI, age, sex, metabolic factors, cardiovascular diseases, and other comorbidities; and fully adjusted including biomarker levels. RESULTS Within the 763 patients studied, all-cause 6-y mortality was significantly lower in obese patients (BMI >30 kg/m2) compared with normal-weight patients (BMI 18.5-25 kg/m2), with a severity-adjusted hazard ratio of 0.641 (95% confidence interval 0.462-0.889) and robust results in fully adjusted and fully adjusted plus biomarker models. No associations of increased BMI and C-reactive protein, procalcitonin, or white blood cell count were found, but BMI > 30 kg/m2 was associated with higher proadrenomedullin levels. CONCLUSIONS Over a 6-y long-term follow-up, we found obesity to be associated with lower all-cause mortality in CAP patients, confirming the obesity paradox in this population. However, differences in inflammatory pathways did not explain these findings.
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Affiliation(s)
- Nina Braun
- Internal Medicine, Kantonsspital Münsterlingen, Switzerland; University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland
| | - Claus Hoess
- Internal Medicine, Kantonsspital Münsterlingen, Switzerland
| | - Alexander Kutz
- University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland
| | - Mirjam Christ-Crain
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Universitätsspital Basel, Basel, Switzerland
| | - Robert Thomann
- Department of Internal Medicine, Bürgerspital Solothurn, Solothurn, Switzerland
| | - Christoph Henzen
- Department of Internal Medicine, Luzerner Kantonsspital, Lucerne, Switzerland
| | | | - Beat Mueller
- University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Basel, Switzerland
| | - Philipp Schuetz
- University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Basel, Switzerland.
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Novel Vasoregulatory Aspects of Hereditary Angioedema: the Role of Arginine Vasopressin, Adrenomedullin and Endothelin-1. J Clin Immunol 2016; 36:160-70. [DOI: 10.1007/s10875-016-0239-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/28/2016] [Indexed: 01/14/2023]
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Mid-regional-pro-adrenomedullin plasma levels are increased in obese adolescents. Eur J Nutr 2015; 55:1255-60. [PMID: 26018656 DOI: 10.1007/s00394-015-0938-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 05/20/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE Recently, adrenomedullin (ADM) was defined as a new member of the adipokine family. ADM secreted by adipocytes, through its vasodilator and antioxidant actions, might be protective against metabolic syndrome-associated cardiovascular complications. The aim of the study was to assess plasma mid-regional (MR)-proADM levels in obese adolescents compared to normal-weight subjects and its relation with BMI, body composition and metabolic indices. METHODS Plasma MR-proADM was measured in 32 healthy adolescents [BMI z-score (mean ± SEM) = 0.6 ± 0.09 and 0.8 ± 0.07 in females and males, respectively] and in 51 age-matched obese adolescents [BMI z-score (mean ± SEM) = 2.8 ± 0.12 and 2.9 ± 0.08 in female and males, respectively] by a time-resolved amplified cryptate emission technology assay. RESULTS Plasma MR-proADM levels resulted significantly higher in obese than in normal-weight adolescents (MR-proADM: 0.33 ± 0.1 vs 0.40 ± 0.1 nmol/L, p < 0.0001). Using univariate analysis, we observed that MR-proADM correlated significantly with BMI z-score (p < 0.0001), fat mass (p < 0.0001), circulating insulin (p < 0.004), HOMA-IR (p < 0.005), total cholesterol (p < 0.03) and LDL-cholesterol (p < 0.05). Including MR-proADM as response variable and its significant correlates into a multiple regression analysis, we observed that fat mass (p = 0.014) and BMI z-score (p = 0.036) were independent determinants of circulating MR-proADM. CONCLUSIONS Our study shows for the first time that obese adolescents have higher circulating levels of MR-proADM compared with normal-weight, appropriate controls suggesting its important involvement in obese patients.
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Ivorra C, Fraga MF, Bayón GF, Fernández AF, Garcia-Vicent C, Chaves FJ, Redon J, Lurbe E. DNA methylation patterns in newborns exposed to tobacco in utero. J Transl Med 2015; 13:25. [PMID: 25623364 PMCID: PMC4312439 DOI: 10.1186/s12967-015-0384-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 01/08/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Maternal smoking during pregnancy is a major risk factor for adverse health outcomes. The main objective of the study was to assess the impact of in utero tobacco exposure on DNA methylation in children born at term with appropriate weight at birth. METHODS Twenty mother-newborn dyads, after uncomplicated pregnancies, in the absence of perinatal illness were included. All mothers were healthy with no cardiovascular risk factors, except for the associated risks among those mothers who smoked. Umbilical cord blood and maternal peripheral venous blood were collected and an epigenome-wide association study was performed using a 450 K epigenome-wide scan (Illumina Infinium HumanMethylation 450BeadChip) with adjustment to normalize the DNA methylation for data cell variability in whole blood. RESULTS The maternal plasmatic cotinine levels ranged from 10.70-115.40 ng/ml in the exposed group to 0-0.59 ng/ml in the non-exposed group. After adjusting for multiple comparisons in 427102 probes, statistically significant differences for 31 CpG sites, associated to 25 genes were observed. There was a greater than expected proportion of statistically-significant loci located in CpG islands (Fisher's exact test, p = 0.029) and of those CpG islands, 90.3% exhibit higher methylation levels in the exposed group. The most striking and significant CpG site, cg05727225, is located in the chromosome 11p15.4, within the adrenomedullin gene. CONCLUSIONS In utero tobacco exposure, even in the absence of fetal growth restriction, may alter the epigenome, contributing to global DNA hypomethylation. Therefore, DNA status can be used as a biomarker of prenatal insults. Considering the possibility to reverse epigenetic modifications, a window of opportunity exists to change the programmed chronic disease.
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Affiliation(s)
- Carmen Ivorra
- Pediatrics Department, Consorcio Hospital General, University of Valencia, Valencia, Spain.
- CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain.
| | - Mario F Fraga
- IUOPA Cancer Epigenetics Laboratory, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain.
| | - Gustavo F Bayón
- IUOPA Cancer Epigenetics Laboratory, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain.
| | - Agustín F Fernández
- IUOPA Cancer Epigenetics Laboratory, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain.
| | - Consuelo Garcia-Vicent
- Pediatrics Department, Consorcio Hospital General, University of Valencia, Valencia, Spain.
| | - F Javier Chaves
- Hospital Clínico de Valencia-INCLIVA Valencia, University of Valencia, Valencia, Spain.
- CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
| | - Josep Redon
- CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain.
- Hospital Clínico de Valencia-INCLIVA Valencia, University of Valencia, Valencia, Spain.
| | - Empar Lurbe
- Pediatrics Department, Consorcio Hospital General, University of Valencia, Valencia, Spain.
- CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain.
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Kistorp C, Bliddal H, Goetze JP, Christensen R, Faber J. Cardiac natriuretic peptides in plasma increase after dietary induced weight loss in obesity. BMC OBESITY 2014. [PMID: 26217511 PMCID: PMC4511261 DOI: 10.1186/s40608-014-0024-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Background Cardiac natriuretic peptides are established biomarkers in heart disease, but are also affected by body mass index (BMI). The purpose of the present study was to examine the impact of weight loss and changes in body composition following dietary intervention on plasma concentrations of the prohormones to A- and B-type natriuretic peptides (proANP and proBNP) and adrenomedullin (proADM). Results A total of 52 healthy obese subjects, 47 women and 5 men (BMI 36.5 ± 5.6 kg/m2) were randomised to either an intensive weight reduction programme using a combination of very low calorie diet (810 kcal/day) and conventional hypo-energetic diet (1200 kcal/day) for 52 weeks, or to a control group that was offered diet-related counselling. N-terminal proBNP (NT-proBNP), mid-regional proANP (MR-proANP) and proADM (MR-proADM) and body composition using dual-energy x-ray absorptiometry (DEXA) scanning were determined at baseline and after 52 weeks. Comparisons between groups were analysed using t-tests. Changes from the baseline within the groups were analysed with paired tests. Changes in the variables, delta (∆), were calculated as 52 weeks minus the baseline. In the intervention group, BMI decreased by almost 20% (31.6 ± 6.2 vs. 37.1 ± 6.1 kg/m2; P <0.001) with a loss of body fat of 23.5 ± 15.5% (P < 0.001). Plasma concentrations of NT-proBNP and MR-proANP increased (from 55 ± 31 to 97 ± 55 pg/ml; P < 0.001, and from 59 ± 21 to 74 ± 26 pmol/L; P < 0.001), whereas MR-proADM decreased (from 573 ± 153 to 534 ± 173 pmol/L; P <0.001). Changes (Δ) in MR-proANP correlated with Δfat mass (r = −0.359; P = 0.011) and Δglucose (r = −0.495; P <0.001), while increases in NT-proBNP were primarily associated with reduced plasma glucose (r = −0.462; P <0.001). A modest but significant weight loss of 6% (P < 0.001) was found in the control group with no changes in plasma concentrations of NT-proBNP or MR-proANP, and a minor change in MR-proADM. Conclusions Plasma NT-proBNP and MR-proANP concentrations increase and MR-proADM concentration decreases during weight loss, underlining the dynamic impact of BMI, body composition and glucose metabolism on these cardiovascular biomarkers.
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Affiliation(s)
- Caroline Kistorp
- Department of Endocrinology, Medicine O, Endocrine Unit, Herlev University Hospital, Herlev Ringvej 75, Herlev, DK-2730 Denmark ; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henning Bliddal
- The Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Copenhagen, Denmark ; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens P Goetze
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Robin Christensen
- The Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens Faber
- Department of Endocrinology, Medicine O, Endocrine Unit, Herlev University Hospital, Herlev Ringvej 75, Herlev, DK-2730 Denmark ; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Finelli C, Padula MC, Martelli G, Tarantino G. Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion? World J Gastroenterol 2014; 20:16649-16664. [PMID: 25469034 PMCID: PMC4248209 DOI: 10.3748/wjg.v20.i44.16649] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 05/27/2014] [Accepted: 06/25/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical.
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Christensen HM, Kistorp C, Schou M, Keller N, Zerahn B, Frystyk J, Flyvbjerg A, Faber J. Cross-talk between the heart and adipose tissue in cachectic heart failure patients with respect to alterations in body composition: a prospective study. Metabolism 2014; 63:141-9. [PMID: 24140097 DOI: 10.1016/j.metabol.2013.09.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 09/17/2013] [Accepted: 09/18/2013] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cardiac cachexia (CC) is associated with changes in body composition. Lipolysis and increased energy expenditure caused by A- and B natriuretic peptides (NPs) have been suggested to play a role in CC. We tested the hypothesis that neurohormones and adipokines are associated with body composition in CC and that a progressive loss of fat free mass (FFM) and fat mass (FM) takes place. METHODS Body composition with regard to FFM, FM, and body fat distribution was assessed by dual energy X-ray absorptiometry (DXA) in 19 non-diabetic patients with chronic heart failure (CHF) and CC and 38 controls (non-cachectic CHF and individuals with prior myocardial infarction-both n = 19) who were followed for 12 months. Biomarkers of neurohormonal stimulation, inflammation, and endothelial dysfunction were measured. RESULTS N-terminal proBNP (NT-proBNP), midregional proANP (MR-proANP), and total adiponectin were elevated in CHF (p<0.001) and correlated inversely to BMI and FM. An inverse correlation was observed between pro-adrenomedullin (MR-proADM) and FFM. During follow up body weight was unaltered in all groups even though FM increased by 1.35 kg (p<0.05) and FFM decreased by 0.5 kg (p<0.05) in CC patients. The latter correlated inversely to baseline NT-proBNP, MR-proANP, and MR-proADM (p<0.05). No correlation to changes in FM was found. CONCLUSIONS FM was associated with plasma NPs and total adiponectin at baseline; whereas changes in FM and FFM did not correlate to changes in NPs or adiponectin during follow up. Prospectively, FFM decreased but FM increased, despite stable body weight in CC.
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Affiliation(s)
- Heidi Marie Christensen
- Department of Endocrinology, Herlev University Hospital, Denmark; Department of Cardiology, Herlev University Hospital, Denmark.
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Christensen HM, Schou M, Goetze JP, Faber J, Frystyk J, Flyvbjerg A, Kistorp C. Body mass index in chronic heart failure: association with biomarkers of neurohormonal activation, inflammation and endothelial dysfunction. BMC Cardiovasc Disord 2013; 13:80. [PMID: 24083942 PMCID: PMC3850723 DOI: 10.1186/1471-2261-13-80] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 09/26/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Low body mass index (BMI) is associated with a poor outcome in chronic heart failure (CHF). An inverse association between BMI and adiponectin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been reported. The aim of the present study was to investigate whether novel markers of neurohormonal activation, inflammation, and endothelial dysfunction are associated with BMI in CHF. METHODS In a cross-sectional study including 171 patients with CHF and a left ventricular ejection fraction (LVEF) ≤45% the impact of BMI on circulating plasma concentrations of adiponectin, α-defensins, high sensitivity C-reactive protein (hsCRP), copeptin, mid-regional pro-adrenomedullin (MR-proADM), NT-proBNP, and mid-regional pro-A-type natriuretic peptide (MR-proANP) were evaluated. RESULTS In multivariable linear regression analysis including age, sex, LVEF, New York Heart Association functional classification (NYHA), estimated glomerular filtration rate (eGFR), and diabetes, only NT-proBNP (β = -0.32) and adiponectin (β = -0.39) remained independently associated with BMI. MR-proANP was associated with BMI but adjusting for age attenuated the relation being no longer significant. CONCLUSIONS Among biomarkers typically increased in patients with CHF only adiponectin and NT-proBNP demonstrated independent inverse associations with BMI. This indicates a direct effect of these two biomarkers enhancing the wasting process seen in CHF.
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Affiliation(s)
- Heidi M Christensen
- Departments of Cardiology and Endocrinology, Herlev University Hospital, Ringvej 75, Herlev 2730, Denmark.
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Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia. Curr Opin Infect Dis 2013; 26:159-67. [DOI: 10.1097/qco.0b013e32835d0bec] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Sahin I, Celik O, Celik N, Keskin L, Dogru A, Dogru I, Yürekli M, Yologlu S. Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome. J Endocrinol Invest 2012; 35:553-6. [PMID: 21791966 DOI: 10.3275/7872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.
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Affiliation(s)
- I Sahin
- Endocrinology and Metabolism, Inönü University, Malatya, Turkey.
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Belting M, Almgren P, Manjer J, Hedblad B, Struck J, Wang TJ, Bergmann A, Melander O. Vasoactive Peptides with Angiogenesis-Regulating Activity Predict Cancer Risk in Males. Cancer Epidemiol Biomarkers Prev 2012; 21:513-22. [DOI: 10.1158/1055-9965.epi-11-0840] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Serum leptin levels are inversely correlated with omental gene expression of adiponectin and markedly decreased after gastric bypass surgery. Surg Endosc 2011; 26:1476-80. [PMID: 22179449 DOI: 10.1007/s00464-011-2059-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 11/07/2011] [Indexed: 01/04/2023]
Abstract
BACKGROUND Adipose tissue is the most abundant endocrine tissue in the body, producing leptin, a hormone important in regulating hunger, and adiponectin, a hormone involved in insulin sensitivity and inflammation. This study aimed to assess the impact of gastric bypass surgery (GBS) on leptin levels and its relation to the adipose tissue expression of adiponectin. METHODS Omental and subcutaneous adipose tissue and serum were obtained from 40 obese patients undergoing GBS, from 13 patients 1 year or more after GBS, and from 16 non-obese individuals with a body mass index of 20 to 29 kg/m(2). Adiponectin gene expression was measured by quantitative real-time polymerase chain reaction, and the gene expression was normalized for the GAPDH gene. Serum leptin and adiponectin were measured by a high-sensitivity enzymatic assay. RESULTS Leptin levels were significantly lower in the post-GBS patients (19.8 ± 6.7) than in the pre-GBS patients (59.0 ± 5.1; P = 0.0001), and similar to those in the non-obese control subjects (18.2 ± 4; P = 0.8). Univariate analysis showed an inverse correlation between serum leptin levels and omental adiponectin gene expression (r = -0.32; P = 0.01). CONCLUSIONS Gastric bypass surgery results in resolution of the leptin resistance status that characterizes obese subjects. The study also demonstrated a significant correlation between leptin and adiponectin. This correlation provides preliminary evidence for studying a potential adiponectin-leptin cross-talking that may represent one of the physiologic pathways responsible for the regulation of food intake in humans.
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Vila G, Riedl M, Anderwald C, Resl M, Handisurya A, Clodi M, Prager G, Ludvik B, Krebs M, Luger A. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin Chem 2010; 57:309-16. [PMID: 21164037 DOI: 10.1373/clinchem.2010.153726] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A(1c), and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.
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Affiliation(s)
- Greisa Vila
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Harvey EJ, Arroyo K, Korner J, Inabnet WB. Hormone Changes Affecting Energy Homeostasis after Metabolic Surgery. ACTA ACUST UNITED AC 2010; 77:446-65. [DOI: 10.1002/msj.20203] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Maier C, Clodi M, Neuhold S, Resl M, Elhenicky M, Prager R, Moertl D, Strunk G, Luger A, Struck J, Pacher R, Hülsmann M. Endothelial markers may link kidney function to cardiovascular events in type 2 diabetes. Diabetes Care 2009; 32:1890-5. [PMID: 19564455 PMCID: PMC2752942 DOI: 10.2337/dc08-2168] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes. RESEARCH DESIGN AND METHODS This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively. RESULTS MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 +/- 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l). CONCLUSIONS The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.
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Affiliation(s)
- Christina Maier
- Department of Endocrinology, Medical University Hospital Vienna, Vienna, Austria
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Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity. ACTA ACUST UNITED AC 2009; 158:127-31. [PMID: 19706311 DOI: 10.1016/j.regpep.2009.08.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Revised: 06/20/2009] [Accepted: 08/16/2009] [Indexed: 11/21/2022]
Abstract
Adrenomedullin (AM) is a cardiovascular protective peptide produced in various organs and tissues including adipose tissue. In the present study, we measured the plasma AM levels of subjects with or without obesity by two assay methods to separately evaluate the biologically active AM-NH(2) and the intermediate form of AM-glycine (AM-Gly). We measured the total AM and AM-NH(2) levels of plasma in 52 obese and 172 non-obese residents of a Japanese community, who received regular health check-ups and had no overt cardiovascular disease. AM-Gly values were obtained by subtracting AM-NH(2) levels from those of total AM. Both the AM-NH(2) and AM-Gly levels of the subjects with obesity were higher than those without obesity, and significant relationships were noted between body mass index (BMI) and the plasma levels of the two molecular forms of AM in a simple regression analysis. Moreover, the significant factors identified by multivariate analyses were BMI and serum triglyceride for AM-NH(2) and diastolic blood pressure, insulin, high-density lipoprotein-cholesterol, and plasma renin activity for AM-Gly. These results suggest active roles for the two molecular forms of AM in metabolic disorders associated with obesity in subjects without overt cardiovascular disease.
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