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Jheng JR, DesJardin JT, Chen YY, Huot JR, Bai Y, Cook T, Hibbard LM, Rupp JM, Fisher A, Zhang Y, Duarte JD, Desai AA, Machado RF, Simon MA, Lai YC. Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction. Arterioscler Thromb Vasc Biol 2024; 44:1570-1583. [PMID: 38813697 PMCID: PMC11208054 DOI: 10.1161/atvbaha.123.320270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 05/13/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
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MESH Headings
- Adult
- Aged
- Animals
- Humans
- Male
- Mice
- Middle Aged
- beta 2-Microglobulin/genetics
- beta 2-Microglobulin/blood
- beta 2-Microglobulin/metabolism
- Biomarkers/blood
- Case-Control Studies
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Disease Models, Animal
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Heart Failure/physiopathology
- Heart Failure/metabolism
- Heart Failure/blood
- Heart Failure/genetics
- Hypertension, Pulmonary/physiopathology
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/blood
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/genetics
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle, Skeletal/metabolism
- Proteomics/methods
- Pulmonary Artery/physiopathology
- Pulmonary Artery/metabolism
- Sirtuin 3/genetics
- Sirtuin 3/metabolism
- Stroke Volume
- Vascular Remodeling
- Ventricular Function, Left
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Affiliation(s)
- Jia-Rong Jheng
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
| | | | - Yi-Yun Chen
- Academia Sinica Common Mass Spectrometry Facilities for Proteomics and Protein Modification Analysis, Nankang, Taipei, Taiwan (Y.-Y.C.)
- Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan (Y.-Y.C.)
| | - Joshua R. Huot
- Department of Anatomy, Cell Biology and Physiology (J.R.H., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
| | - Yang Bai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang (Y.B.)
| | - Todd Cook
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
| | - Lainey M. Hibbard
- Department of Medical and Molecular Genetics (L.M.H., J.M.R.), Indiana University School of Medicine, Indianapolis
| | - Jennifer M. Rupp
- Department of Medical and Molecular Genetics (L.M.H., J.M.R.), Indiana University School of Medicine, Indianapolis
| | - Amanda Fisher
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
| | - Yingze Zhang
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, PA (Y.Z.)
| | - Julio D. Duarte
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville (J.D.D.)
| | - Ankit A. Desai
- Krannert Cardiovascular Research Center (A.A.D.), Indiana University School of Medicine, Indianapolis
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
- Department of Anatomy, Cell Biology and Physiology (J.R.H., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
| | - Marc A. Simon
- Division of Cardiology, University of California, San Francisco (J.T.D.J., M.A.S.)
| | - Yen-Chun Lai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.B., T.C., A.F., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
- Department of Anatomy, Cell Biology and Physiology (J.R.H., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis
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Franchina M, Cavalcoli F, Falco O, La Milia M, Elvevi A, Massironi S. Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development-A Comprehensive Review. Diagnostics (Basel) 2024; 14:1289. [PMID: 38928704 PMCID: PMC11203125 DOI: 10.3390/diagnostics14121289] [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: 05/08/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.
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Affiliation(s)
- Marianna Franchina
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Federica Cavalcoli
- Gastroenterology and Digestive Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Olga Falco
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Marta La Milia
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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3
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Wetz C, Ruhwedel T, Schatka I, Grabowski J, Jann H, Metzger G, Galler M, Amthauer H, Rogasch JMM. Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy. Cancers (Basel) 2023; 15:5717. [PMID: 38136263 PMCID: PMC10741556 DOI: 10.3390/cancers15245717] [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: 10/19/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. METHODS A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. RESULTS Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). CONCLUSIONS Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.
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Affiliation(s)
- Christoph Wetz
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Tristan Ruhwedel
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Imke Schatka
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Jane Grabowski
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
| | - Giulia Metzger
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Markus Galler
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Julian M. M. Rogasch
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
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Chakraborty P, Po SS, Yabluchanskiy A, Dasari TW. Protein kinase A: A potential marker of sympathovagal imbalance in heart failure. Life Sci 2023; 331:122069. [PMID: 37666387 DOI: 10.1016/j.lfs.2023.122069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/23/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification of a biomarker for the quantification of sympathovagal balance, the potential target of 'neuromodulation' strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF.
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Affiliation(s)
- Praloy Chakraborty
- Cardiovascular Section, Department of Internal Medicine, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sunny S Po
- Cardiovascular Section, Department of Internal Medicine, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Tarun W Dasari
- Cardiovascular Section, Department of Internal Medicine, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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5
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Eisenhofer G, Pamporaki C, Lenders JWM. Biochemical Assessment of Pheochromocytoma and Paraganglioma. Endocr Rev 2023; 44:862-909. [PMID: 36996131 DOI: 10.1210/endrev/bnad011] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/24/2023] [Accepted: 03/29/2023] [Indexed: 03/31/2023]
Abstract
Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances.
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Affiliation(s)
- Graeme Eisenhofer
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Christina Pamporaki
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Jacques W M Lenders
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Department of Internal Medicine, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
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6
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Ioannidis M, Mahata SK, van den Bogaart G. The immunomodulatory functions of chromogranin A-derived peptide pancreastatin. Peptides 2022; 158:170893. [PMID: 36244579 PMCID: PMC10760928 DOI: 10.1016/j.peptides.2022.170893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/08/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
Chromogranin A (CgA) is a 439 amino acid protein secreted by neuroendocrine cells. Proteolytic processing of CgA results in the production of different bioactive peptides. These peptides have been associated with inflammatory bowel disease, diabetes, and cancer. One of the chromogranin A-derived peptides is ∼52 amino acid long Pancreastatin (PST: human (h)CgA250-301, murine (m)CgA263-314). PST is a glycogenolytic peptide that inhibits glucose-induced insulin secretion from pancreatic islet β-cells. In addition to this metabolic role, evidence is emerging that PST also has inflammatory properties. This review will discuss the immunomodulatory properties of PST and its possible mechanisms of action and regulation. Moreover, this review will discuss the potential translation to humans and how PST may be an interesting therapeutic target for treating inflammatory diseases.
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Affiliation(s)
- Melina Ioannidis
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands
| | - Sushil K Mahata
- VA San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
| | - Geert van den Bogaart
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands; Department of Medical Biology and Pathology, University Medical Center Groningen, Groningen, the Netherlands.
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Mohan IK, Baba KSSS, Iyyapu R, Thirumalasetty S, Satish OS. Advances in congestive heart failure biomarkers. Adv Clin Chem 2022; 112:205-248. [PMID: 36642484 DOI: 10.1016/bs.acc.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Congestive heart failure (CHF) is the leading cause of morbidity and mortality in the elderly worldwide. Although many biomarkers associated with in heart failure, these are generally prognostic and identify patients with moderate and severe disease. Unfortunately, the role of biomarkers in decision making for early and advanced heart failure remains largely unexplored. Previous studies suggest the natriuretic peptides have the potential to improve the diagnosis of heart failure, but they still have significant limitations related to cut-off values. Although some promising cardiac biomarkers have emerged, comprehensive data from large cohort studies is lacking. The utility of multiple biomarkers that reflect various pathophysiologic pathways are increasingly being explored in heart failure risk stratification and to diagnose disease conditions promptly and accurately. MicroRNAs serve as mediators and/or regulators of renin-angiotensin-induced cardiac remodeling by directly targeting enzymes, receptors and signaling molecules. The role of miRNA in HF diagnosis is a promising area of research and further exploration may offer both diagnostic and prognostic applications and phenotype-specific targets. In this review, we provide insight into the classification of different biochemical and molecular markers associated with CHF, examine clinical usefulness in CHF and highlight the most clinically relevant.
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Affiliation(s)
| | - K S S Sai Baba
- Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Telangana, India
| | - Rohit Iyyapu
- Katuri Medical College & Hospital, Guntur, Andhra Pradesh, India
| | | | - O Sai Satish
- Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Telangana, India
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Zdanowicz A, Urban S, Ponikowska B, Iwanek G, Zymliński R, Ponikowski P, Biegus J. Novel Biomarkers of Renal Dysfunction and Congestion in Heart Failure. J Pers Med 2022; 12:jpm12060898. [PMID: 35743683 PMCID: PMC9224642 DOI: 10.3390/jpm12060898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/15/2022] [Accepted: 05/26/2022] [Indexed: 02/04/2023] Open
Abstract
Heart failure is a major public health problem and, despite the constantly emerging, new, effective treatments, it remains a leading cause of morbidity and mortality. Reliable tools for early diagnosis and risk stratification are crucial in the management of HF. This explains a growing interest in the development of new biomarkers related to various pathophysiological mechanisms of HF. In the course of this review, we focused on the markers of congestion and renal dysfunction in terms of their interference with cardiovascular homeostasis. Congestion is a hallmark feature of heart failure, contributing to symptoms, morbidity, and hospitalizations of patients with HF and has, therefore, become a therapeutic target in AHF. On the other hand, impaired renal function by altering the volume status contributes to the development and progression of HF and serves as a marker of an adverse clinical outcome. Early detection of congestion and an adequate assessment of renal status are essential for the prompt administration of patient-tailored therapy. This review provides an insight into recent advances in the field of HF biomarkers that could be potentially implemented in diagnosis and risk stratification of patients with HF.
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Affiliation(s)
- Agata Zdanowicz
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Szymon Urban
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
- Correspondence: ; Tel.: +48-71-733-11-12
| | - Barbara Ponikowska
- Student Scientific Organization, Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland;
| | - Gracjan Iwanek
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Robert Zymliński
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Piotr Ponikowski
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Jan Biegus
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
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9
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Tüten N, Tuten A, Gök K, Hamzaoglu K, Bulut H, Malik E, Guralp O. Serum Vasostatin-1 Level is Increased in Women with Preeclampsia. Z Geburtshilfe Neonatol 2022; 226:178-185. [PMID: 35181881 DOI: 10.1055/a-1747-3738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVE To evaluate the serum vasostatin-1 levels in preeclamptic and non-preeclamptic pregnant women. MATERIALS AND METHODS Thirty consecutive women with mild preeclampsia and sixty consecutive women with severe preeclampsia were compared with ninety gestational age-matched (±1 week) non-preeclamptic pregnant women with an appropriate-for-gestational-age (AGA) fetus. RESULTS Mean serum vasostatin-1 was significantly higher in women with preeclampsia than gestational age-matched controls. Mean serum vasostatin-1 was significantly higher in the mild preeclampsia group compared to its gestational age-matched control group, and in the severe preeclampsia group compared to its gestational age-matched control group. There was no significant difference in mean serum vasostatin-1 levels between the mild and severe preeclampsia groups, and in severe early- and severe late-onset preeclampsia groups. Serum vasostatin-1 had positive correlations with systolic and diastolic blood pressure. CONCLUSION Serum vasostatin-1 was significantly higher in women with preeclampsia compared to those of the gestational age-matched controls. There was no significant difference in mean serum vasostatin-1 levels between the mild and severe preeclampsia groups and severe early- and severe late-onset preeclampsia groups.
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Affiliation(s)
- Nevin Tüten
- Obstetrics and Gynecology, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Abdullah Tuten
- Obstetrics and Gynecology, Istanbul University Cerrahpasa Faculty of Medicine, Fatih, Turkey
| | - Koray Gök
- Perinatology, Sakarya Training and Research Hospital, Sakarya, Turkey
| | - Kubra Hamzaoglu
- Obstetric and Gynecology, Istanbul Universitesi-Cerrahpasa, Istanbul, Turkey
| | - Huri Bulut
- Biochemistry, Istinye University, Istanbul, Turkey
| | - Eduard Malik
- University Hospital for Obstetrics and Gynecology, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Onur Guralp
- University Hospital for Obstetrics and Gynecology, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
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10
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Wei J, Wang Y, Yang S, Hao Z, Pan X, Ma A. Plasma chromogranin A levels are associated with acute ischemic stroke with anterior circulation large vessel occlusion. Nutr Metab Cardiovasc Dis 2022; 32:195-202. [PMID: 34893409 DOI: 10.1016/j.numecd.2021.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 08/17/2021] [Accepted: 09/21/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIMS To investigate the relationship between chromogranin A (CgA) levels and acute ischemic stroke (AIS), especially anterior circulation large vessel occlusion (LVO). METHODS AND RESULTS 587 subjects were included in this study, including 205 AIS patients with anterior circulation LVO and 205 nonocclusive patients, as well as 177 healthy controls. On admission, plasma CgA levels were measured and neurological deficits were assessed by the NIH Stroke Scale. Outcomes were assessed by the modified Rankin Scale at 3 months. The predictive properties of CgA were evaluated by receiver operating characteristic (ROC) curve analysis. Binary logistic analysis assessed the association of CgA levels and AIS or anterior circulation LVO. AIS patients had lower CgA levels than health controls (p < 0.001). Anterior circulation LVO patients had lower CgA levels than nonocclusive patients (p < 0.001). The area under the ROC curve of plasma CgA levels in predicting anterior circulation LVO from AIS was 0.744 and the optimal cutoff value was 15.49 ng/mL with a Youden value of 0.332. Logistic analysis showed that CgA ≤15.49 ng/mL remained an independent risk factor for anterior circulation LVO after adjusting for related factors (OR = 6.519, 95% CI: 3.790-11.214, p < 0.001). CgA was an independent protective factor for mild stroke and good prognosis (p = 0.009, p = 0.005); however, the association disappeared after adjusting for occlusion (p = 0.768, p = 0.335). CONCLUSION CgA levels were lower in AIS patients, especially in anterior circulation LVO patients. Lower CgA levels are potential biomarker for anterior circulation LVO, and they may indicate good prognosis at 3 months in AIS.
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Affiliation(s)
- Jin Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Yuan Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Shaonan Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Zhongnan Hao
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China.
| | - Aijun Ma
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China.
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11
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Vasostatin-1 as a potential novel circulating biomarker in patients with chronic systolic heart failure: A pilot study. Clin Chim Acta 2021; 526:49-54. [PMID: 34973182 DOI: 10.1016/j.cca.2021.12.024] [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: 11/17/2021] [Revised: 12/20/2021] [Accepted: 12/26/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Previous studies have shown that circulating chromogranin A (CgA) increases in patients with chronic systolic heart failure (HF). Aim of the present study is to evaluate the potential role of circulating vasostatin-1 (VS-1), a cardioregulatory fragment of CgA, as prognostic marker in patients with chronic HF. MATERIALS AND METHODS The plasma levels of CgA and VS-1 were determined in 80 patients with chronic systolic HF. Patients were followed-up to evaluate the occurrence of cardiovascular (CV) events. RESULTS CgA and VS-1 plasma levels were significantly higher in patients with CV events at follow-up. VS-1, but not CgA, was associated to NT-proBNP. No significant association of CgA and VS-1 with left ventricular ejection fraction (LVEF) was observed. CgA, NT-proBNP and age, but not VS-1, were independent predictors of CV events. CONCLUSION In patients with chronic systolic HF those who experienced CV events had higher levels of VS-1 and CgA. Given its established effect on cardiac cells, the association of VS-1 levels with NT-proBNP levels but not with LVEF, suggests that this fragment might provide complementary information to NT-proBNP and CgA in HF patients.
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12
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Shen Y, Aihemaiti M, Shu XY, Yang CD, Chen JW, Dai Y, Ding FH, Yang ZK, Hu J, Zhang RY, Lu L, Wang XQ, Shen WF. Circulating Chromogranin B Is Associated With Left Ventricular Functional Recovery After Successful Recanalization of Chronic Total Occlusion. Front Cardiovasc Med 2021; 8:756594. [PMID: 35004878 PMCID: PMC8740892 DOI: 10.3389/fcvm.2021.756594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/01/2021] [Indexed: 11/24/2022] Open
Abstract
Background: Chromogranin B (CgB) is increased in heart failure and proportionate to disease severity. We investigated whether circulating CgB level is associated with left ventricular (LV) functional recovery potential after successful recanalization of chronic total occlusion (CTO). Methods: Serum levels of CgB were assayed in 53 patients with stable angina with LV functional recovery [an absolute increase in LV ejection fraction (EF) of ≥5%] and 53 age- and sex-matched non-recovery controls after successful recanalization of CTO during 12-month follow-up. Results: We found that CgB level was significantly lower in the recovery group than in the non-recovery group (593 [IQR 454-934] vs. 1,108 [IQR 696-2020] pg/ml, P < 0.001), and that it was inversely correlated with changes in LVEF (Spearman's r = -0.31, P = 0.001). Receiver operating characteristic (ROC) analysis showed that the area under the curve of CgB for predicting LVEF improvement was 0.76 (95% CI 0.664-0.856), and that the optimal cutoff value was 972.5 pg/ml. In multivariate analyses, after adjusting for confounding factors, high CgB level remained an independent determinant of impaired LV functional recovery after CTO recanalization. LV functional improvement appeared to be more responsive to CgB in patients with poor than with good coronary collaterals. Conclusions: Elevated circulating CgB level confers an increased risk of impaired LV functional recovery after successful recanalization of CTO in patients with stable coronary artery disease.
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Affiliation(s)
- Ying Shen
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Muladili Aihemaiti
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xin Yi Shu
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Chen Die Yang
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jia Wei Chen
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yang Dai
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Feng Hua Ding
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhen Kun Yang
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jian Hu
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Rui Yan Zhang
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Lin Lu
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xiao Qun Wang
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wei Feng Shen
- Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Institute of Cardiovascular Diseases, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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13
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Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective. Biomedicines 2021; 9:biomedicines9121757. [PMID: 34944578 PMCID: PMC8698910 DOI: 10.3390/biomedicines9121757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.
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14
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Kim HN, Yang DH, Park BE, Park YJ, Kim HJ, Jang SY, Bae MH, Lee JH, Park HS, Cho Y, Chae SC. Prognostic impact of chromogranin A in patients with acute heart failure. Yeungnam Univ J Med 2021; 38:337-343. [PMID: 34233402 PMCID: PMC8688787 DOI: 10.12701/yujm.2020.00843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 06/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background Chromogranin A (CgA) levels have been reported to predict mortality in patients with heart failure. However, information on the prognostic value and clinical availability of CgA is limited. We compared the prognostic value of CgA to that of previously proven natriuretic peptide biomarkers in patients with acute heart failure. Methods We retrospectively evaluated 272 patients (mean age, 68.5±15.6 years; 62.9% male) who underwent CgA test in the acute stage of heart failure hospitalization between June 2017 and June 2018. The median follow-up period was 348 days. Prognosis was assessed using the composite events of 1-year death and heart failure hospitalization. Results In-hospital mortality rate during index admission was 7.0% (n=19). During the 1-year follow-up, a composite event rate was observed in 12.1% (n=33) of the patients. The areas under the receiver-operating characteristic curves for predicting 1-year adverse events were 0.737 and 0.697 for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and CgA, respectively. During follow-up, patients with high CgA levels (>158 pmol/L) had worse outcomes than those with low CgA levels (≤158 pmol/L) (85.2% vs. 58.6%, p<0.001). When stratifying the patients into four subgroups based on CgA and NT-proBNP levels, patients with high NT-proBNP and high CgA had the worst outcome. CgA had an incremental prognostic value when added to the combination of NT-proBNP and clinically relevant risk factors. Conclusion The prognostic power of CgA was comparable to that of NT-proBNP in patients with acute heart failure. The combination of CgA and NT-proBNP can improve prognosis prediction in these patients.
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Affiliation(s)
- Hong Nyun Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Dong Heon Yang
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bo Eun Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Yoon Jung Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Hyeon Jeong Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Se Yong Jang
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Myung Hwan Bae
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jang Hoon Lee
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Hun Sik Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yongkeun Cho
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Shung Chull Chae
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
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15
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The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease. Int J Mol Sci 2021; 22:ijms22116118. [PMID: 34204153 PMCID: PMC8201018 DOI: 10.3390/ijms22116118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.
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16
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Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies. Cancers (Basel) 2021; 13:cancers13102286. [PMID: 34064565 PMCID: PMC8150833 DOI: 10.3390/cancers13102286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary This study describes the expression of synaptophysin on platelet surfaces of neuroendocrine neoplasms (NENs). Compared to healthy donors, platelet-expressed synaptophysin was shown to be significantly upregulated in NENs patients. Platelet-expressed synaptophysin was significantly correlated with tumor proliferation and metastasis, demonstrating the involvement of platelets in tumor biology. Expression of synaptophysin on platelet surfaces was finally shown to predict progression-free survival in NEN. This study conceptually explored platelet-expressed synaptophysin as a novel biomarker in NEN. Abstract Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.
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17
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Castiglione V, Aimo A, Vergaro G, Saccaro L, Passino C, Emdin M. Biomarkers for the diagnosis and management of heart failure. Heart Fail Rev 2021; 27:625-643. [PMID: 33852110 PMCID: PMC8898236 DOI: 10.1007/s10741-021-10105-w] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/06/2021] [Indexed: 12/16/2022]
Abstract
Heart failure (HF) is a significant cause of morbidity and mortality worldwide. Circulating biomarkers reflecting pathophysiological pathways involved in HF development and progression may assist clinicians in early diagnosis and management of HF patients. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. The roles of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification in HF have been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the role of NPs as a guide to HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, with independent value to NPs. Other biomarkers evaluated as predictors of adverse outcome are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin, and makers of renal dysfunction. Multi-marker scores and genomic, transcriptomic, proteomic, and metabolomic analyses could further refine HF management.
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Affiliation(s)
| | - Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy. .,Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
| | - Giuseppe Vergaro
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Luigi Saccaro
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Fondazione Toscana Gabriele Monasterio, Pisa, Italy
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18
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Rocca C, Grande F, Granieri MC, Colombo B, De Bartolo A, Giordano F, Rago V, Amodio N, Tota B, Cerra MC, Rizzuti B, Corti A, Angelone T, Pasqua T. The chromogranin A 1-373 fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1. Acta Physiol (Oxf) 2021; 231:e13570. [PMID: 33073482 DOI: 10.1111/apha.13570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/16/2022]
Abstract
AIM Chromogranin A (CgA), a 439-residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA1-373 proangiogenic fragment. The present work investigated the possibility that human CgA1-373 influences the mammalian cardiac performance, evaluating the role of its C-terminal sequence. METHODS Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. RESULTS On the ex vivo heart, CgA1-373 elicited direct dose-dependent negative inotropism and vasodilation, while CgA1-372 , a fragment lacking the C-terminal R373 residue, was ineffective. Antibodies against the PGPQLR373 C-terminal sequence abrogated the CgA1-373 -dependent cardiac and coronary modulation. Ex vivo studies showed that CgA1-373 -dependent effects were mediated by endothelium, neuropilin-1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S-nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA1-373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol-induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all-atom molecular dynamics simulations strongly supported the hypothesis that the C-terminal R373 residue of CgA1-373 directly interacts with NRP1. CONCLUSION These results suggest that CgA1-373 is a new cardioregulatory hormone and that the removal of R373 represents a critical switch for turning "off" its cardioregulatory activity.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Fedora Grande
- Laboratory of Medicinal and Analytical Chemistry Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Maria Concetta Granieri
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Barbara Colombo
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Anna De Bartolo
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Vittoria Rago
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Rende Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine Magna Graecia University of Catanzaro Catanzaro Italy
| | - Bruno Tota
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Maria Carmela Cerra
- Laboratory of Organ and System Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
| | - Bruno Rizzuti
- CNR‐NANOTEC Licryl‐UOS Cosenza and CEMIF.Cal Department of Physics University of Calabria Rende Italy
| | - Angelo Corti
- Division of Experimental Oncology Vita‐Salute San Raffaele University–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute Milan Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- National Institute of Cardiovascular Research (INRC) Bologna Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiovascular Patho‐Physiology Department of Biology, E. and E.S. University of Calabria Rende Italy
- "Fondazione Umberto Veronesi" Milan Italy
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Eeckhout K, Van Cotthem K, Guerti K. Evaluation of three commercially available ELISA kits for the determination of chromogranin A. J Immunoassay Immunochem 2021; 42:95-105. [PMID: 33043835 DOI: 10.1080/15321819.2020.1830105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Chromogranin A (CgA) is currently the most valuable tumor biomarker for diagnostic work-up, management and follow-up of neuro-endocrine tumors (NET). The aim of our study was to compare three different commercially available CgA ELISA kits and to evaluate their analytical and clinical performance. CgA was measured with three different commercial ELISA kits on leftover sera from 40 patients: Chromoa R assay (Cis), Hu chromogranin A ELISA (Dia), and Neolisa chromogranin A (Euro). Analytical and clinical performance was evaluated by measuring precision, area under the ROC curve, sensitivity, specificity, positive and negative predictive value, correlation coefficients and Passing and Bablok regression analyses. Precision (CV%) was acceptable for all evaluated ELISA's (Cis 10.3%; Dia 9.8%; Euro 14.5%). The area under the curve (AUC) was comparable between the three assays (Cis 0.693; Dia 0.627; Euro 0.721). Sensitivity varied between 41.2% and 64.7%. Specificity ranged between 69.6% and 82.6%. Pairwise comparison revealed significant systematic and proportional differences when comparing Cis versus Dia (Cis = 25.30 + 1.94 Dia) and Euro versus Dia (Euro = 26.54 + 1.92 Dia). Analytical and clinical performance was comparable for the three ELISA's. CgA results obtained with different ELISA's are not interchangeable.AbbreviationsCgA: Chromogranin A; ELISA: Enzyme-linked immunosorbent assay; IRMA: Immunoradiometric assay; NET: Neuroendocrine tumors; PPI: Proton-pump inhibitors; RIA: Radioimmunoassay.
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Affiliation(s)
- Katrien Eeckhout
- Department of Clinical Chemistry, University Hospital Antwerp, Edegem, Belgium
| | - Karin Van Cotthem
- Department of Clinical Chemistry, University Hospital Antwerp, Edegem, Belgium
| | - Khadija Guerti
- Department of Clinical Chemistry, University Hospital Antwerp, Edegem, Belgium
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Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker? Cells 2021; 10:cells10020457. [PMID: 33669936 PMCID: PMC7924864 DOI: 10.3390/cells10020457] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.
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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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Höglund K, Häggström J, Höglund OV, Stridsberg M, Tidholm A, Ljungvall I. The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease. Acta Vet Scand 2020; 62:43. [PMID: 32758260 PMCID: PMC7405357 DOI: 10.1186/s13028-020-00541-3] [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] [Received: 02/06/2020] [Accepted: 07/30/2020] [Indexed: 11/10/2022] Open
Abstract
Background The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay. Results Catestatin concentration decreased with increasing left atrial and ventricular size (R2 ≤ 0.09, P ≤ 0.019), and increased with increasing systolic and diastolic blood pressures (R2 ≤ 0.08, P ≤ 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study. Conclusions In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.
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Tarantino N, Santoro F, Di Biase L, Di Terlizzi V, Vitale E, Barone R, Della Rocca DG, De Leon De La Cruz NS, Di Biase M, Brunetti ND. Chromogranin-A serum levels in patients with takotsubo syndrome and ST elevation acute myocardial infarction. Int J Cardiol 2020; 320:12-17. [PMID: 32739447 DOI: 10.1016/j.ijcard.2020.07.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/20/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sympathergic hyperactivity is considered one of the main trigger precipitating takotsubo syndrome (TTS). Chromogranin-A (CgA), a prognostic biomarker of sympatho-adrenal activation, is markedly high in acute coronary syndrome (ACS) and heart failure (HF), but its role in TTS is unknown. METHODS CgA serum levels from patients with TTS and symptoms onset <24 hours were consecutively evaluated and compared with anterior ST-elevation myocardial infarction (STEMI) patients from November 2016 to December 2019. Short and long-term follow-up data were recorded. RESULTS Eleven women with TTS and 10 subjects with anterior STEMI were analyzed and compared; differences were not significant in terms of age, gender and cardiovascular risk factors. NT-pro-BNP levels were similar (9,887 ± 12,170 vs 8,969 ± 15,053 pg/ml, p = .88), while troponin-I levels were higher in patients with STEMI (4 ± 3.2 vs 13.3 ± 10 ng/dl, p = .03). CgA admission levels were significantly lower in TTS patients (2.2 ± 1.5 vs 7.3 ± 6.2 nMol/l, p = .017), even after multivariable correction for principal bias. CgA levels correlated with NTproBNP levels (p = .02) and were higher in subjects with in-hospital events (3.7 ± 1.1 vs 1.6 ± 1.2 nMol/l, p = .03), even after multivariable forward stepwise analysis (p < .01). CgA levels <3.25 nMol/l (AUC 0.754, 95% C.I. 0.54-0.968) were able to discriminate TTS from anterior STEMI (negative predictive power of 99%). CONCLUSIONS Systemic CgA levels in the acute phase of TTS are lower than in anterior STEMI, possibly indicating a greater myocardial catecholamine release rather than adrenal.
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Affiliation(s)
- Nicola Tarantino
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy; Arrhythmia Service, Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Francesco Santoro
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Luigi Di Biase
- Arrhythmia Service, Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA; Texas Cardiac Arrhyhtmia Institute (TCAI) at St. David's Hospital, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, University of Texas, Austin, TX, USA; Department of Internal Medicine, Dell Medical School, University of Texas, Austin, TX, USA
| | - Vito Di Terlizzi
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Enrica Vitale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Roberta Barone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | | | - Matteo Di Biase
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Chen H, Wu M, Jiang W, Liu X, Zhang J, Yu C. iTRAQ‑based quantitative proteomics analysis of the potential application of secretoneurin gene therapy for cardiac hypertrophy induced by DL‑isoproterenol hydrochloride in mice. Int J Mol Med 2020; 45:793-804. [PMID: 31985029 PMCID: PMC7015125 DOI: 10.3892/ijmm.2020.4472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 12/17/2019] [Indexed: 02/05/2023] Open
Abstract
A previous study by our group demonstrated a protective role of the neuropeptide secretoneurin (SN) in DL‑isoproterenol hydrochloride (ISO)‑induced cardiac hypertrophy in mice. To further characterize the molecular mechanism of SN treatment, an isobaric tags for relative and absolute quantification (iTRAQ)‑based quantitative proteomic analysis was applied to identify putative target proteins and molecular pathways. An SN expression vector was injected into the myocardial tissues of mice, and the animals were then subcutaneously injected with ISO (5 mg/kg/day) for 7 days to induce cardiac hypertrophy. The results of echocardiography and hemodynamic measurements indicated that the function of the heart impaired by ISO treatment was significantly ameliorated via SN gene injection. The investigation of heart proteomics was performed by iTRAQ‑based liquid chromatography‑tandem mass spectrometry analysis. A total of 2,044 quantified proteins and 15 differentially expressed proteins were associated with SN overexpression in mice with cardiac hypertrophy. Functional enrichment analysis demonstrated that these effects were possibly associated with metabolic processes. A protein‑protein interaction network analysis was constructed and the data indicated that apolipoprotein C‑III (Apoc3) was associated with the positive effect of SN on the induction of cardiac hypertrophy in mice. The present study proposed a potential mechanism of SN action on Apoc3 upregulation that may contribute to the amelioration of cardiac hypertrophy. These findings can aid the clinical application of SN in patients with cardiac hypertrophy.
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Affiliation(s)
| | - Mingjun Wu
- Institute of Life Science, Chongqing Medical University, Chongqing 400016
| | - Wei Jiang
- State Key Laboratory of Biotherapy, Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiang Liu
- Institute of Life Science, Chongqing Medical University, Chongqing 400016
| | - Jun Zhang
- Institute of Life Science, Chongqing Medical University, Chongqing 400016
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Dang H, Li J, Liu C, Xu F. Chromogranin A provides additional prognostic information in children with severe hand, foot, and mouth disease: A prospective observational study. Int J Infect Dis 2020; 93:367-374. [PMID: 32109626 DOI: 10.1016/j.ijid.2020.02.035] [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: 11/19/2019] [Revised: 02/15/2020] [Accepted: 02/19/2020] [Indexed: 10/24/2022] Open
Abstract
OBJECTIVE Severe hand, foot, and mouth disease (HFMD) is associated with high mortality in children, and persistent sympathetic activation is a common presentation. The aim of this study was to prospectively investigate serum chromogranin A (CHGA) levels and their prognostic role in this condition. METHODS Serum CHGA, creatine kinase myocardial band (CK-MB), serum D-dimer, norepinephrine, blood glucose, lactate, and C-reactive protein levels, white blood cell (WBC) counts, usage of vasopressors, pediatric risk of mortality Ⅲ (PRISM-Ⅲ) scores, and viral etiology were measured upon pediatric intensive care unit (PICU) admission. The correlation between clinical outcomes and the indicators listed above were analyzed, and the ability of CHGA as a biomarker to predict mortality was evaluated. RESULTS Serum CHGA levels were higher in the non-survivors group than in the survivors group (median (interquartile range): 434.8 (374.3-502.4) vs 183.3 (131.9-246.9) μg/l; p < 0.001) and were correlated with norepinephrine (r = 0.37. p < 0.001), blood glucose (r = 0.32, p = 0.001), lactate (r = 0.25, p = 0.009), WBC (r = 0.20, p = 0.039), and PRISM-Ⅲ scores (r = 0.748, p < 0.0001). Patients suffering neurogenic pulmonary edema, those infected with enterovirus A71, and those requiring more vasopressors had higher serum CHGA levels (median (interquartile range): 385 (239.9-488.8) vs 161 (115.6-222.9), 340.6 (190.6-436.0) vs 150.5 (112.1-210.0), 395.6 (209.1-487.0) vs 167.7 (110.5-240.5) μg/l, respectively; p < 0.0001). The CHGA level upon PICU admission in severe HFMD could be an independent risk factor for mortality (adjusted odds ratio 2.459, 95% confidence interval 1.054-5.906, p = 0.038) with high specificity (87.5%) and sensitivity (82.6%) (cut-off value at 339.6 μg/l). CONCLUSIONS The CHGA level in severe HFMD was found to be associated with cardiopulmonary failure. If measured upon PICU admission, CHGA may provide additional prognostic information in this disease.
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Affiliation(s)
- Hongxing Dang
- Department of PICU, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China
| | - Jing Li
- Department of PICU, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China
| | - Chengjun Liu
- Department of PICU, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China
| | - Feng Xu
- Department of PICU, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China; Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing 400014, China.
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Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann N Y Acad Sci 2019; 1455:34-58. [PMID: 31588572 PMCID: PMC6899468 DOI: 10.1111/nyas.14249] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/09/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
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Affiliation(s)
- Sushil K Mahata
- VA San Diego Healthcare System, San Diego, California.,Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Angelo Corti
- IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
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Editorial commentary: Pathophysiological effects of proton pump inhibitors in cardiac patients: Time for a critical reappraisal. Trends Cardiovasc Med 2019; 29:361-362. [DOI: 10.1016/j.tcm.2018.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/07/2023]
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Modulation of the coronary tone in the expanding scenario of Chromogranin-A and its derived peptides. Future Med Chem 2019; 11:1501-1511. [DOI: 10.4155/fmc-2018-0585] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The cardiac function critically depends on an adequate myocardial oxygenation and on a correct coronary blood flow. Endothelial, hormonal and extravascular factors work together generating a fine balance between oxygen supply and oxygen utilization through the coronary circulation. Among the regulatory factors that contribute to the coronary tone, increasing attention is paid to the cardiac endocrines, such as chromogranin A, a prohormone for many biologically active peptides, including vasostatin and catestatin. In this review, we will summarize the available evidences about the coronary effects of these molecules, and their putative mechanism of action. Laboratory and clinical data on chromogranin A and its derived fragments will be analyzed in relation to the scenario of the endocrine heart, and of its putative clinical perspectives.
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Re: Neuroendocrine differentiation markers guide treatment sequence selection in metastatic castration-resistant prostate cancer. The Prostate. 2019;1-7. Prostate 2019; 79:813-814. [PMID: 30995357 DOI: 10.1002/pros.23775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/22/2019] [Indexed: 11/07/2022]
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Rocca C, Scavello F, Colombo B, Gasparri AM, Dallatomasina A, Granieri MC, Amelio D, Pasqua T, Cerra MC, Tota B, Corti A, Angelone T. Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity. FASEB J 2019; 33:7734-7747. [PMID: 30973759 DOI: 10.1096/fj.201802707r] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose-dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full-length recombinant CgA on Doxo-induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo-induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury. On the other hand, CgA did not impair the anticancer activity of Doxo in all the murine models investigated. Furthermore, we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low-dose CgA to patients with low levels of endogenous CgA might represent a novel approach to prevent Doxo-induced adverse events without impairing antitumor effects.-Rocca, C., Scavello, F., Colombo, B., Gasparri, A. M., Dallatomasina, A., Granieri, M. C., Amelio, D., Pasqua, T., Cerra, M. C., Tota, B., Corti, A., Angelone, T. Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Francesco Scavello
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Barbara Colombo
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Anna Maria Gasparri
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Alice Dallatomasina
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Maria Concetta Granieri
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Daniela Amelio
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy
| | - Maria Carmela Cerra
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Bruno Tota
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Angelo Corti
- Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiac Pathophysiology, Department of Biology, Ecology, and Earth Science, University of Calabria, Rende (Cosenza), Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
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Dallatomasina A, Gasparri AM, Colombo B, Sacchi A, Bianco M, Daniele T, Esposito A, Pastorino F, Ponzoni M, Marcucci F, Curnis F, Corti A. Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement. Cancer Res 2019; 79:1925-1937. [PMID: 30796053 DOI: 10.1158/0008-5472.can-18-0289] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 08/08/2018] [Accepted: 02/15/2019] [Indexed: 11/16/2022]
Abstract
The unbalanced production of pro- and antiangiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vasoregulatory neurosecretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368-373 of human CgA1-373, a fragment that has proangiogenic activity. Antibodies against this site, unable to bind full-length CgA, inhibited angiogenesis and reduced tumor perfusion and growth. The PGPQLR sequence of the fragment, but not of the precursor, bound the VEGF-binding site of neuropilin-1; the C-terminal arginine (R373) of the sequence was crucial for binding. The proangiogenic activity of the CgA1-373 was blocked by anti-neuropilin-1 antibodies as well as by nicotinic acetylcholine receptor antagonists, suggesting that these receptors, in addition to neuropilin-1, play a role in the proangiogenic activity of CgA1-373. The R373 residue was enzymatically removed in plasma, causing loss of neuropilin-1 binding and gain of antiangiogenic activity. These results suggest that cleavage of the R373R374 site of circulating human CgA in tumors and the subsequent removal of R373 in the blood represent an important "on/off" switch for the spatiotemporal regulation of tumor angiogenesis and may serve as a novel therapeutic target. SIGNIFICANCE: This work reveals that the interaction between fragmented chromogranin A and neuropilin-1 is required for tumor growth and represents a novel potential therapeutic target.
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Affiliation(s)
| | - Anna Maria Gasparri
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelina Sacchi
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mimma Bianco
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tiziana Daniele
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Esposito
- San Raffaele Vita-Salute University, Milan, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabio Pastorino
- Laboratory of Experimental Therapy in Oncology, Istituto Giannina Gaslini, Genoa, Italy
| | - Mirco Ponzoni
- Laboratory of Experimental Therapy in Oncology, Istituto Giannina Gaslini, Genoa, Italy
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Flavio Curnis
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- San Raffaele Vita-Salute University, Milan, Italy. .,Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Andreasi V, Partelli S, Manzoni M, Muffatti F, Colombo B, Corti A, Falconi M. Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET). Pancreatology 2019; 19:57-63. [PMID: 30470614 DOI: 10.1016/j.pan.2018.11.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 11/01/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET. METHODS Patients submitted to surgery for sporadic localized NF-PanNET at San Raffaele Hospital were included. Preoperative plasma samples were prospectively collected. Circulating levels of total-CgA and VS-1 were retrospectively investigated by sandwich Enzyme-Linked ImmunoSorbent Assays. RESULTS Overall, 50 patients were included. VS-1 value (P=0.0001) was the only preoperatively retrievable factor independently associated with NF-PanNET size. No significant correlation between CgA and tumor diameter was found (P = 0.057). A VS-1 value of 0.39 nM was identified as the optimal VS-1 cut-off accurately associated with NF-PanNET larger than 4 cm. Patients with VS-1 > 0.39 nM had a significantly higher frequency of microvascular invasion (P = 0.005) and nodal metastasis (P = 0.027). Median VS-1 plasma level was significantly higher in the presence of microvascular invasion (P = 0.001) and nodal metastasis (P = 0.012). PPI assumption significantly increased total-CgA levels, but not those of VS-1 (P = 0.111). CONCLUSIONS In localized, non-metastatic NF-PanNET, VS-1 is strongly associated to tumor dimension and its plasma levels are significantly higher in the presence of microvascular invasion and nodal metastases; moreover, VS-1 value is not affected by the PPI use.
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Affiliation(s)
- Valentina Andreasi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; "Vita e Salute" University, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; "Vita e Salute" University, Milan, Italy
| | - Marco Manzoni
- Endocrinology Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Muffatti
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; "Vita e Salute" University, Milan, Italy
| | - Barbara Colombo
- Experimental Oncology Division, San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- Experimental Oncology Division, San Raffaele Scientific Institute, Milan, Italy; "Vita e Salute" University, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; "Vita e Salute" University, Milan, Italy.
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Muntjewerff EM, Dunkel G, Nicolasen MJT, Mahata SK, van den Bogaart G. Catestatin as a Target for Treatment of Inflammatory Diseases. Front Immunol 2018; 9:2199. [PMID: 30337922 PMCID: PMC6180191 DOI: 10.3389/fimmu.2018.02199] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/05/2018] [Indexed: 12/12/2022] Open
Abstract
It is increasingly clear that inflammatory diseases and cancers are influenced by cleavage products of the pro-hormone chromogranin A (CgA), such as the 21-amino acids long catestatin (CST). The goal of this review is to provide an overview of the anti-inflammatory effects of CST and its mechanism of action. We discuss evidence proving that CST and its precursor CgA are crucial for maintaining metabolic and immune homeostasis. CST could reduce inflammation in various mouse models for diabetes, colitis and atherosclerosis. In these mouse models, CST treatment resulted in less infiltration of immune cells in affected tissues, although in vitro monocyte migration was increased by CST. Both in vivo and in vitro, CST can shift macrophage differentiation from a pro- to an anti-inflammatory phenotype. Thus, the concept is emerging that CST plays a role in tissue homeostasis by regulating immune cell infiltration and macrophage differentiation. These findings warrant studying the effects of CST in humans and make it an interesting therapeutic target for treatment and/or diagnosis of various metabolic and immune diseases.
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Affiliation(s)
- Elke M Muntjewerff
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Gina Dunkel
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mara J T Nicolasen
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Sushil K Mahata
- VA San Diego Healthcare System, San Diego, CA, United States.,Department of Medicine, University of California at San Diego, La Jolla, CA, United States
| | - Geert van den Bogaart
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands
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Di Giacinto P, Rota F, Rizza L, Campana D, Isidori A, Lania A, Lenzi A, Zuppi P, Baldelli R. Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors. Int J Endocrinol 2018; 2018:8126087. [PMID: 30057604 PMCID: PMC6051263 DOI: 10.1155/2018/8126087] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 02/12/2018] [Indexed: 12/13/2022] Open
Abstract
Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy.
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Affiliation(s)
- Paola Di Giacinto
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, Rome, Italy
| | - Francesca Rota
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, Rome, Italy
| | - Laura Rizza
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, Rome, Italy
| | - Davide Campana
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Andrea Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Lania
- Department of Endocrinology, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paolo Zuppi
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, Rome, Italy
| | - Roberto Baldelli
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, Rome, Italy
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Magnusson MK, Lasson A, Stridsberg M, Isaksson S, Strid H, Öhman L. Faecal secretogranin and chromogranin levels persist over time and are unrelated to disease history and outcome in patients with ulcerative colitis. COGENT MEDICINE 2018. [DOI: 10.1080/2331205x.2018.1484602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Affiliation(s)
- Maria K. Magnusson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Lasson
- Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Mats Stridsberg
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Stefan Isaksson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Kruljac I, Vurnek I, Maasberg S, Kust D, Blaslov K, Ladika Davidović B, Štefanović M, Demirović A, Bišćanin A, Filipović-Čugura J, Marić Brozić J, Pape UF, Vrkljan M. A score derived from routine biochemical parameters increases the diagnostic accuracy of chromogranin A in detecting patients with neuroendocrine neoplasms. Endocrine 2018; 60:395-406. [PMID: 29633144 DOI: 10.1007/s12020-018-1592-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/02/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroendocrine neoplasms (NENs). However, various comorbidities may influence serum CgA, which decreases its diagnostic accuracy. We aimed to investigate which laboratory parameters are independently associated with increased CgA in real-life setting and to develop a scoring system, which could improve the diagnostic accuracy of CgA in detecting patients with NENs. METHODS This retrospective study included 55 treatment naïve patients with NENs and160 patients with various comorbidities but without NEN (nonNENs). Scoring system (CgA-score) was developed based on z-scores obtained from receiver operating curve analysis for each parameter that was associated with elevated serum CgA in nonNENs. RESULTS CgA correlated positively with serum BUN, creatinine, α2-globulin, red-cell distribution width, erythrocyte sedimentation rate, plasma glucose and correlated inversely with hemoglobin, thrombocytes and serum albumin. Serum CgA was also associated with the presence of chronic renal failure, arterial hypertension and diabetes and the use of PPI. In the entire study population, CgA showed an area under the curve of 0.656. Aforementioned parameters were used to develop a CgA-score. In a cohort of patients with CgA-score <12.0 (N = 87), serum CgA >156.5 ng/ml had 77.8% sensitivity and 91.5% specificity for detecting NENs (AUC 0.841, 95% CI 0.713-0.969, P < 0.001). Serum CgA had no diagnostic value in detecting NENs in patients with CgA-score >12.0 (AUC 0.554, 95% CI 0.405-0.702, P = 0.430). CONCLUSIONS CgA-score encompasses a wide range of comorbidities and represents a promising tool that could improve diagnostic performance of CgA in everyday clinical practice.
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Affiliation(s)
- Ivan Kruljac
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia.
| | - Ivan Vurnek
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sebastian Maasberg
- Department of Hepatology and Gastroenterology, ENETS Center of Excellence for Neuroendocrine Tumors, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Davor Kust
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Kristina Blaslov
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
| | - Blaženka Ladika Davidović
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Mario Štefanović
- Clinical Institute of Chemistry, University Hospital Center "Sestre Milosrdnice", University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
| | - Alma Demirović
- Department of Pathology, University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alen Bišćanin
- Department of Gastroenterology and Hepatology, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | | | - Jasmina Marić Brozić
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Ulrich-Frank Pape
- Department of Hepatology and Gastroenterology, ENETS Center of Excellence for Neuroendocrine Tumors, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Milan Vrkljan
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
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Corsello A, Di Filippo L, Massironi S, Sileo F, Dolcetta Capuzzo A, Gemma M, Carlucci C, Cusini C, Colombo B, Dallatomasina A, Franchi GM, Corti A, Manzoni MF. Vasostatin-1: A novel circulating biomarker for ileal and pancreatic neuroendocrine neoplasms. PLoS One 2018; 13:e0196858. [PMID: 29723285 PMCID: PMC5933774 DOI: 10.1371/journal.pone.0196858] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. METHODS In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA1-439) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. RESULTS Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25th-75th-percentiles); total-CgA: 1.85 nM (1.01-4.28) vs 0.75 nM (0.52-0.89), p = 0.004; VS-1: 2.76 nM (1.09-7.10) vs 0.29 nM (0.26-0.32), p<0.001, respectively], but not of CgA1-439 or CgA1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p<0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1. CONCLUSION These findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA.
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Affiliation(s)
- Andrea Corsello
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Di Filippo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Sara Massironi
- Department of Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Sileo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Dolcetta Capuzzo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Marco Gemma
- Department of Neurointensive Care, San Raffaele Scientific Institute, Milan, Italy
| | - Claudia Carlucci
- Clinical study & Data Management Unit, Haematology Project Foundation, Vicenza, Italy
| | - Claudio Cusini
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Alice Dallatomasina
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Maria Franchi
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
- San Raffaele Vita-Salute University, Milan, Italy
| | - Marco Federico Manzoni
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
- San Raffaele Vita-Salute University, Milan, Italy
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Chiba A, Watanabe-Takano H, Miyazaki T, Mochizuki N. Cardiomyokines from the heart. Cell Mol Life Sci 2018; 75:1349-1362. [PMID: 29238844 PMCID: PMC11105766 DOI: 10.1007/s00018-017-2723-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/21/2017] [Accepted: 11/27/2017] [Indexed: 12/12/2022]
Abstract
The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions.
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Affiliation(s)
- Ayano Chiba
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan
| | - Haruko Watanabe-Takano
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan
| | - Takahiro Miyazaki
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan
| | - Naoki Mochizuki
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan.
- AMED-CREST, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan.
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Curnis F, Dallatomasina A, Bianco M, Gasparri A, Sacchi A, Colombo B, Fiocchi M, Perani L, Venturini M, Tacchetti C, Sen S, Borges R, Dondossola E, Esposito A, Mahata SK, Corti A. Regulation of tumor growth by circulating full-length chromogranin A. Oncotarget 2018; 7:72716-72732. [PMID: 27683038 PMCID: PMC5341939 DOI: 10.18632/oncotarget.12237] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/17/2016] [Indexed: 12/04/2022] Open
Abstract
Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves. Tumor growth inhibition was associated with reduction of microvessel density and blood flow in neoplastic tissues. Neutralization of endogenous CgA with antibodies against its C-terminal region (residues 410-439) promoted tumor growth. Structure-function studies showed that the C-terminal region of CgA contains a bioactive site and that cleavage of this region causes a marked loss of anti-angiogenic and anti-tumor potency. Mechanistic studies showed that full-length CgA could induce, with a U-shaped dose-response curve, the production of protease nexin-1 in endothelial cells, a serine protease inhibitor endowed of anti-angiogenic activity. Gene silencing or neutralization of protease nexin-1 with specific antibodies abolished both anti-angiogenic and anti-tumor effects of CgA. These results suggest that circulating full-length CgA is an important inhibitor of angiogenesis and tumor growth, and that cleavage of its C-terminal region markedly reduces its activity. Pathophysiological changes in CgA blood levels and/or its fragmentation might regulate disease progression in cancer patients.
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Affiliation(s)
- Flavio Curnis
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alice Dallatomasina
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mimma Bianco
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Anna Gasparri
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelina Sacchi
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Fiocchi
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Laura Perani
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Venturini
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carlo Tacchetti
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Suvajit Sen
- University of California, Los Angeles, CA, USA
| | | | - Eleonora Dondossola
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Esposito
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Sushil K Mahata
- VA San Diego Healthcare System and University of California, San Diego, La Jolla, CA, USA
| | - Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
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Abstract
Pulmonary and digestive neuroendocrine tumors (NETs) are a group of neoplasms whose incidence and prevalence has been constantly increasing over the last years thanks to the significant improvements in instrumental diagnostic techniques. Because NETs are extremely heterogeneous a correct histopathological diagnosis is essential for appropriate treatment. More specifically, the histopathological diagnosis of NETs can be regarded as a multistep: identification of the neuroendocrine nature of the neoplasm, determination of tumor grading; identification of unknown primary. Laboratory biomarkers for the study of gastroenteropancreatic neuroendocrine tumors include both specific markers and non-specific or general markers. At the moment, chromogranin A is the best available and most frequently used biomarker for the diagnosis of NETs, offering the highest overall sensitivity. CgA has also demonstrated some utility in the assessment of response to treatment and as indicator of tumor recurrence. Free full text available at www.tumorionline.it
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Affiliation(s)
- Massimo Milione
- Dipartimento di Patologia e Diagnostica di Laboratorio, Milan, Italy
| | - Ettore Seregni
- Nuclear Medical Division, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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41
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Bianco M, Gasparri A, Generoso L, Assi E, Colombo B, Scarfò L, Bertilaccio MTS, Scielzo C, Ranghetti P, Dondossola E, Ponzoni M, Caligaris-Cappio F, Ghia P, Corti A. Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models. Oncotarget 2018; 7:41725-41736. [PMID: 27203389 PMCID: PMC5173091 DOI: 10.18632/oncotarget.9407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 04/26/2016] [Indexed: 01/12/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.3 μg, i.v., or 1.5 μg/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Eμ-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2−/−γc−/− mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro, CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA1-373), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.
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Affiliation(s)
- Mimma Bianco
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Anna Gasparri
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Luca Generoso
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Emma Assi
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Barbara Colombo
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Lydia Scarfò
- B Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.,Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy.,San Raffaele Vita-Salute University, Milan 20132, Italy
| | - Maria T S Bertilaccio
- Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Cristina Scielzo
- Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Pamela Ranghetti
- Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Eleonora Dondossola
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Maurilio Ponzoni
- Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy
| | - Federico Caligaris-Cappio
- Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy.,San Raffaele Vita-Salute University, Milan 20132, Italy.,Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Paolo Ghia
- B Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.,Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy.,San Raffaele Vita-Salute University, Milan 20132, Italy
| | - Angelo Corti
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.,San Raffaele Vita-Salute University, Milan 20132, Italy
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Secretoneurin suppresses cardiac hypertrophy through suppression of oxidant stress. Eur J Pharmacol 2018; 822:13-24. [PMID: 29337195 DOI: 10.1016/j.ejphar.2018.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/25/2017] [Accepted: 01/10/2018] [Indexed: 02/05/2023]
Abstract
The neuropeptide secretoneurin (SN) plays protective roles in myocardial ischemia. In the present study, the effect of SN in cardiac hypertrophy was investigated. We observed that, in isoproterenol (ISO) treatment induced cardiac or cardiomyocytes hypertrophy, a marked increase in the expression of endogenous SN in mouse plasma, myocardium and primary-cultured cardiomyocytes occurs. In hypertrophic mice, the heart size, heart weight/body weight (HW/BW) ratio, cardiomyocyte size, and atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression were significantly higher than those in controls but were effectively suppressed by SN gene therapy. Similarly, the protective effects of SN were also observed in cultured cardiomyocytes following ISO treatment. SN significantly increased the activity of catalase and superoxide dismutase (SOD) in parallel with the decrease in reactive oxygen species levels in cardiomyocytes. We observed that SN evoked the activation of all of the AMPK, P38/MAPK and ERK/MAPK pathways in cardiomyocytes, but pretreatment with only AMPK inhibitor (compound C) and ERK1/2/MAPK inhibitor (PD98059) counteracted the protective effects of SN against cardiomyocyte hypertrophy and the suppressive effects of SN on oxidant stress in cardiomyocytes. These results indicated that endogenous SN is induced in hypertrophic cardiomyocytes, and may play a protective role in the pathogenesis of cardiac hypertrophy. These results suggest that exogenous SN supplementation protects the cardiac hypertrophy induced by ISO treatment through the activation of AMPK and ERK/MAPK pathways, thus upregulating antioxidants and suppressing oxidative stress.
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Chan DL, Moody L, Segelov E, Metz DC, Strosberg JR, Pavlakis N, Singh S. Follow-Up for Resected Gastroenteropancreatic Neuroendocrine Tumours: A Practice Survey of the Commonwealth Neuroendocrine Tumour Collaboration (CommNETS) and the North American Neuroendocrine Tumor Society (NANETS). Neuroendocrinology 2018. [PMID: 29539613 DOI: 10.1159/000488394] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES There is no consensus regarding optimal follow-up in resected gastroenteropancreatic neuroendocrine tumours (NETs). We aimed to perform a practice survey to ascertain follow-up patterns by health care practitioners and highlight areas of variation that may benefit from further quantitative research. METHODS A Web-based survey targeted at NET health care providers in Australia, New Zealand, Canada, and the USA was developed by a steering committee of medical oncologists and a research methodologist. Thirty-seven questions elicited information regarding adherence to guidelines, the influence of risk factors on follow-up, and the frequency and choice of modality in follow-up. RESULTS There were 163 respondents: 59 from Australia, 25 from New Zealand, 46 from Canada, and 33 from the USA (50% medical oncology, 23% surgery, 13% nuclear medicine, and 15% other). Thirty-eight percent of the respondents were "very familiar" with the NCCN NET guidelines, 33% with the ENETS guidelines, and 17% with the ESMO guidelines; however, only 15, 27, and 10%, respectively, found them "very useful"; 63% reported not using guidelines at their institution. The commonest investigations used were CT scans (66%) and chromogranin A (86%). The US respondents were more likely to follow patients up past 5 years, and the Australian respondents utilized more functional and less cross-sectional imaging. When poor prognostic factors were introduced, the respondents recommended more visits and tests. CONCLUSIONS This large international survey highlights variation in current follow-up practices not well addressed by the current guidelines. More quantitative research is required to inform the development of evidence-based guidelines tailored to the pattern of recurrence in NETs.
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Affiliation(s)
- David L Chan
- Department of Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
| | - Lesley Moody
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Eva Segelov
- Department of Oncology, Monash Health and Monash University, Melbourne, Victoria, Australia
| | - David C Metz
- Division of Gastroenterology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jonathan R Strosberg
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Nick Pavlakis
- Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Simron Singh
- Department of Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A, Faggiano A. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer 2018; 25:R11-R29. [PMID: 29066503 DOI: 10.1530/erc-17-0269] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.
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Affiliation(s)
- Vincenzo Marotta
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Maria Rosaria Ambrosio
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Marta Bondanelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy
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Heidrich FM, Melz C, Buechau MS, Pfluecke C, Quick S, Speiser U, Poitz DM, Augstein A, Ruf T, Wässnig NK, Youssef A, Strasser RH, Wiedemann S. Regulation of circulating chromogranin B levels in heart failure. Biomarkers 2017; 23:78-87. [PMID: 29098879 DOI: 10.1080/1354750x.2017.1395079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF. METHODS AND RESULTS We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair. CONCLUSION CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.
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Affiliation(s)
- Felix M Heidrich
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Carolin Melz
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Mimi S Buechau
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Christian Pfluecke
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Silvio Quick
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Uwe Speiser
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - David M Poitz
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Antje Augstein
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Tobias Ruf
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Nadine K Wässnig
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Akram Youssef
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Ruth H Strasser
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
| | - Stephan Wiedemann
- a Technische Universität Dresden , Heart Center Dresden University Hospital , Dresden , Germany
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Corti A, Marcucci F, Bachetti T. Circulating chromogranin A and its fragments as diagnostic and prognostic disease markers. Pflugers Arch 2017; 470:199-210. [PMID: 29018988 DOI: 10.1007/s00424-017-2030-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 12/19/2022]
Abstract
Chromogranin A (CgA), a secretory protein released in the blood by neuroendocrine cells and neurons, is the precursor of various bioactive fragments involved in the regulation of the cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair. After the original demonstration that circulating CgA can serve as a biomarker for a wide range of neuroendocrine tumors, several studies have shown that increased levels of CgA can be present also in the blood of patients with cardiovascular, gastrointestinal, and inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. Considering the high structural and functional heterogeneity of the CgA system, comprising precursor and fragments, it is not surprising that the different immunoassays used in these studies led, in some cases, to discrepant results. Here, we review these notions and we discuss the importance of measuring total-CgA, full-length CgA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system.
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Affiliation(s)
- Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. .,Vita-Salute San Raffaele University, Milan, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Tiziana Bachetti
- Clinical Trials Centre, Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Pavia, Italy
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Lackermair K, Clauss S, Voigt T, Klier I, Summo C, Hildebrand B, Nickel T, Estner HL, Kääb S, Wakili R, Wilbert-Lampen U. Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation. PLoS One 2017; 12:e0184337. [PMID: 28886122 PMCID: PMC5590904 DOI: 10.1371/journal.pone.0184337] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 08/22/2017] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). METHODS 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference. RESULTS Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI. CONCLUSION Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.
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Affiliation(s)
- K. Lackermair
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - S. Clauss
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner site Munich, Munich Heart Alliance, Munich, Germany
| | - T. Voigt
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - I. Klier
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - C. Summo
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - B. Hildebrand
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - T. Nickel
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - H. L. Estner
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - S. Kääb
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
| | - R. Wakili
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner site Munich, Munich Heart Alliance, Munich, Germany
- Department of Cardiology and Vascular Medicine, West-German Heart and Vascular Center Essen, University of Essen Medical School, University Duisburg-Essen, Essen, Germany
- * E-mail:
| | - U. Wilbert-Lampen
- Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Munich, Germany
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Hansen LH, Darkner S, Svendsen JH, Henningsen K, Pehrson S, Chen X, Vakhrushev SY, Schjoldager KT, Goetze JP. Chromogranin A in the mammalian heart: expression without secretion. Biomark Med 2017; 11:541-545. [PMID: 28685598 DOI: 10.2217/bmm-2017-0052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM To investigate whether chromogranin A (CgA) is secreted from the heart into circulation. MATERIALS & METHODS Porcine cardiac tissue was analyzed for the presence of CgA-derived glycopeptides using a global O-glycoproteomic strategy. Blood was sampled from the femoral vein, right atrium, coronary sinus and the left atrium from patients with predominantly atrial disease. The local concentration of proatrial natriuretic peptide and CgA was measured with immunoassays. RESULTS We identified CgA-derived glycopeptides exclusively in the atrial tissue. Proatrial natriuretic peptide is secreted from the heart (coronary sinus [795 pmol/l] vs left atrium [678 pmol/l]; p < 0.01) whereas no CgA gradient across the heart could be established (p = 0.6366). CONCLUSION The cardiac atria express but do not secrete CgA into circulation in patients with atrial disease.
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Affiliation(s)
- Lasse H Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Stine Darkner
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jesper H Svendsen
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kristoffer Henningsen
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Steen Pehrson
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Xu Chen
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sergey Y Vakhrushev
- Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Katrine T Schjoldager
- Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jens P Goetze
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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