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von Känel R. Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration. Semin Thromb Hemost 2025; 51:381-400. [PMID: 38914118 DOI: 10.1055/s-0044-1787660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
By integrating findings from comprehensive reviews, meta-analyses, and cutting-edge genetic studies, this article illuminates the significance of stress-induced hypercoagulability in clinical medicine. In particular, the findings from numerous prospective cohort studies indicate that stress and hemostatic factors of a hypercoagulable state are associated with increased incident risk and poor prognosis for atherosclerotic cardiovascular disease and venous thromboembolism. Mendelian randomization studies suggest that these associations are partially causal. The review synthesizes extensive research on the link between acute and chronic stress and hypercoagulability, outlining a potential pathway from stress to thrombosis risk. Consistent with the allostatic load concept, acute stress-induced hypercoagulability, initially adaptive, can turn maladaptive under chronic stress or excessive acute stress, leading to arterial or venous thrombotic events. Individuals with predisposing factors, including atherosclerosis, thrombophilia, or immobilization, may exhibit an increased risk of thrombotic disease during stress. Contextual sociodemographic characteristics, the stress experience, and coping resources additionally modulate the extent of stress-induced hypercoagulability. Research into the neuroendocrine, cellular, and molecular bases reveals how stress influences platelet activation coagulation and fibrinolysis. The activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, along with vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are the central mechanisms involved. Hemoconcentration, inflammation, endothelial dysfunction, and thrombopoiesis additionally contribute to stress-induced hypercoagulability. Further research is needed to prove a causal link between chronic stress and hypercoagulability. This includes exploring its implications for the prevention and management of thrombotic diseases in stressed individuals, with a focus on developing effective psychosocial and pharmacological interventions.
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Affiliation(s)
- Roland von Känel
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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2
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Shah ASV, Keene SJ, Pennells L, Kaptoge S, Kimenai DM, Walker M, Halley JD, Rocha S, Hoogeveen RC, Gudnason V, Bakker SJL, Wannamethee SG, Pareek M, Eggers KM, Jukema JW, Hankey GJ, deLemos JA, Ford I, Omland T, Lyngbakken MN, Psaty BM, deFilippi CR, Wood AM, Danesh J, Welsh P, Sattar N, Mills NL, Di Angelantonio E. Cardiac Troponins and Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis. J Am Coll Cardiol 2025; 85:1471-1484. [PMID: 40204376 DOI: 10.1016/j.jacc.2025.02.016] [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: 10/23/2024] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND The extent to which high-sensitivity cardiac troponin can predict cardiovascular disease (CVD) is uncertain. OBJECTIVES We aimed to quantify the potential advantage of adding information on cardiac troponins to conventional risk factors in the prevention of CVD. METHODS We meta-analyzed individual-participant data from 15 cohorts, comprising 62,150 participants without prior CVD. We calculated HRs, measures of risk discrimination, and reclassification after adding cardiac troponin T (cTnT) or I (cTnI) to conventional risk factors. The primary outcome was first-onset CVD (ie, coronary heart disease or stroke). We then modeled the implications of initiating statin therapy using incidence rates from 2.1 million individuals from the United Kingdom. RESULTS Among participants with cTnT or cTnI measurements, 8,133 and 3,749 incident CVD events occurred during a median follow-up of 11.8 and 9.8 years, respectively. HRs for CVD per 1-SD higher concentration were 1.31 (95% CI: 1.25-1.37) for cTnT and 1.26 (95% CI: 1.19-1.33) for cTnI. Addition of cTnT or cTnI to conventional risk factors was associated with C-index increases of 0.015 (95% CI: 0.012-0.018) and 0.012 (95% CI: 0.009-0.015) and continuous net reclassification improvements of 6% and 5% in cases and 22% and 17% in noncases. One additional CVD event would be prevented for every 408 and 473 individuals screened based on statin therapy in those whose CVD risk is reclassified from intermediate to high risk after cTnT or cTnI measurement, respectively. CONCLUSIONS Measurement of cardiac troponin results in a modest improvement in the prediction of first-onset CVD that may translate into population health benefits if used at scale.
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Affiliation(s)
- Anoop S V Shah
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Cardiology, Imperial College NHS Trust, London, United Kingdom
| | - Spencer J Keene
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, United Kingdom.
| | - Lisa Pennells
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom
| | - Stephen Kaptoge
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom
| | - Dorien M Kimenai
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Matthew Walker
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom
| | - Julianne D Halley
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom
| | - Sara Rocha
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom
| | - Ron C Hoogeveen
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | | | - Manan Pareek
- Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
| | - Kai M Eggers
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands
| | - Graeme J Hankey
- Centre for Neuromuscular and Neurological Diseases, The University of Western Australia, Perth, Western Australia, Australia; Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia
| | - James A deLemos
- UT Southwestern Medical Center, Cardiology, Dallas, Texas, USA
| | - Ian Ford
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom
| | - Torbjørn Omland
- K. G. Jebsen Center for Cardiac Biomarkers, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Akershus University Hospital, Lørenskog, Norway
| | - Magnus Nakrem Lyngbakken
- K. G. Jebsen Center for Cardiac Biomarkers, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Akershus University Hospital, Lørenskog, Norway
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, Washington, USA
| | | | - Angela M Wood
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; Cambridge Centre of Artificial Intelligence in Medicine, Cambridge, United Kingdom; British Heart Foundation Data Science Centre, Health Data Research UK, London, United Kingdom
| | - John Danesh
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
| | - Paul Welsh
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom
| | - Nicholas L Mills
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Emanuele Di Angelantonio
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; Health Data Science Research Centre, Human Technopole, Milan, Italy
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Šoić D, Kifer D, Szavits-Nossan J, Blivajs A, Đerek L, Rudan D, Gornik O, Gudelj I, Keser T. High-Throughput Site-Specific N-Glycosylation Profiling of Human Fibrinogen in Atrial Fibrillation. J Proteome Res 2025; 24:2121-2134. [PMID: 40099449 PMCID: PMC11976851 DOI: 10.1021/acs.jproteome.5c00096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/19/2025]
Abstract
Fibrinogen is a major plasma glycoprotein involved in blood coagulation and inflammatory responses. Alterations in its glycosylation have been implicated in various pathological conditions; yet, its site-specific N-glycosylation profile remains largely unexplored in a clinical context. Here, we present a high-throughput LC-MS workflow for site-specific analysis of fibrinogen N-glycosylation using a cost-effective ethanol precipitation enrichment method. The method demonstrated good intra- and interplate repeatability (CV: 5% and 12%, respectively) and was validated through the first assessment of intraindividual temporal stability in healthy individuals, revealing consistent glycosylation patterns within individuals. Application to 181 atrial fibrillation (AF) patients and 52 healthy controls identified three gamma chain glycoforms significantly associated with AF. Most notably, increased levels of the asialylated N4H5, known to enhance fibrin bundle thickness and promote clot formation, suggest a potential mechanism linking glycosylation changes to the prothrombotic state in AF. Furthermore, fibrinogen sialylation showed strong associations with cardiovascular risk factors, including triglycerides, BMI, and glucose levels. Longitudinal analysis of 108 AF patients six months postcatheter ablation showed stability in the AF-associated glycan profile. Our findings establish fibrinogen glycosylation as a potential biomarker for cardiovascular conditions and demonstrate the utility of site-specific glycosylation analysis for clinical applications.
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Affiliation(s)
- Dinko Šoić
- Faculty
of Pharmacy and Biochemistry, University
of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
| | - Domagoj Kifer
- Faculty
of Pharmacy and Biochemistry, University
of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
| | - Janko Szavits-Nossan
- Magdalena
University Hospital for Cardiovascular Diseases, Radnička cesta 32, 10000 Zagreb, Croatia
- Faculty
of Dental Medicine and Health, J.J. Strossmayer
University in Osijek, Crkvena 21, 31000 Osijek, Croatia
- Faculty
of Medicine, J.J. Strossmayer University
of Osijek, Josipa Huttlera
4, 31000 Osijek, Croatia
| | - Aleksandar Blivajs
- Department
of Cardiology, University Hospital Dubrava, Avenija Gojka Šuška
6, 10000 Zagreb, Croatia
| | - Lovorka Đerek
- Clinical
Department for Laboratory Diagnostics, University
Hospital Dubrava, Avenija
Gojka Šuška 6, 10000 Zagreb, Croatia
| | - Diana Rudan
- Department
of Cardiology, University Hospital Dubrava, Avenija Gojka Šuška
6, 10000 Zagreb, Croatia
| | - Olga Gornik
- Faculty
of Pharmacy and Biochemistry, University
of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
| | - Ivan Gudelj
- Faculty
of Biotechnology and Drug Development, University
of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
| | - Toma Keser
- Faculty
of Pharmacy and Biochemistry, University
of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
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He L, Zhou J, Wang M, Chen J, Liu C, Shi J, Rui Y, Wu H. Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review. Int Urol Nephrol 2025; 57:517-533. [PMID: 39417966 PMCID: PMC11772542 DOI: 10.1007/s11255-024-04236-w] [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: 06/05/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024]
Abstract
PURPOSE We reported a confirmed case of Fibrinogen Aa-chain (AFib) amyloidosis and conducted systematic review of the genetic and protein mutation types, clinical manifestations, diagnostic methods and treatment for patients with this disease worldwide. METHODS We reported a case of AFib amyloidosis. Meanwhile, a systematic search was performed using defined terms and updated up to November 2023 in the Wanfang, China National Knowledge Infrastructure, VIP, PubMed, and Web of Science databases to identify reported cases of AFib renal amyloidosis worldwide, according to PRISMA guidelines. RESULTS A 46-year-old male patient was admitted for more than half a month because of oedematous lower limbs. Renal tissue mass spectrometry suggested an AFib type. Gene detection demonstrated that the patient carried the c.1673del (p.Lys558Argfs*10) locus heterozygous mutation of Fibrinogen Aα-chain gene (FGA). The patient was treated with haemodialysis because of uncontrollable hypertension. This systematic review comprised 46 cases. We found the onset age to be lower in women than in men (P < 0.05). All patients showed incipient symptoms including proteinuria; 10 (21.7%) patients progressed to end-stage renal disease (ESRD) or received renal replacement therapy (including dialysis and kidney transplantation) within 1 year; 18 (39.1%) patients progressed to ESRD or received renal replacement therapy within 1-5 years, and 4 (8.7%) patients did not progress to ESRD or received renal replacement therapy within 5 years. CONCLUSION AFib amyloidosis progresses rapidly. The diagnosis of this disease is primarily based on renal biopsy, mass spectrometry, and molecular gene detection. Reducing proteinuria is the main method of treating this disease. PROSPERO REGISTRATION NUMBER CRD42024516146.
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Affiliation(s)
- Linying He
- Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Jiahui Zhou
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Miner Wang
- Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Jianxiang Chen
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Chang Liu
- Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Jiazhen Shi
- Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Yanxia Rui
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China.
| | - Henglan Wu
- Department of Nephrology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China.
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Yang S, Pi J, Ma W, Gu W, Zhang H, Xu A, Liu Y, Shi T, Yang F, Chen L. Prognostic value of the fibrinogen-to-albumin ratio (FAR) in patients with chronic heart failure across the different ejection fraction spectrum. Libyan J Med 2024; 19:2309757. [PMID: 38290043 PMCID: PMC10829812 DOI: 10.1080/19932820.2024.2309757] [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: 11/14/2023] [Accepted: 01/19/2024] [Indexed: 02/01/2024] Open
Abstract
The ratio of fibrinogen to albumin (FAR) is considered a new inflammatory biomarker and a predictor of cardiovascular disease risk. However, its prognostic value for patients with chronic heart failure (CHF) with different ejection fractions (EFs) remains unclear. A total of 916 hospitalized patients with CHF from January 2017 to October 2021 in the First Affiliated Hospital of Kunming Medical University were included in the study. Death occurred in 417 (45.5%) patients out of 916 patients during a median follow-up time of 750 days. Among these patients, 381 patients suffered from HFrEF (LVEF <40%) and 535 patients suffered from HFpEF or HFmrEF (HFpEF plus HFmrEF, LVEF ≥ 40%). Patients were categorized into high-level FAR (FAR-H) and low-level FAR (FAR-L) groups based on the optimal cut-off value of FAR (9.06) obtained from receiver operating characteristic (ROC) curve analysis. Upon analysing the Kaplan - Meier plots, the incidence of death was significantly higher in all patients with FAR-H and patients in both HF subgroups (p < 0.001). The multivariate Cox proportional hazard analyses indicated that the FAR was an independent predictor of all-cause mortality, regardless of heart failure subtype. (HR 1.115, 95% CI 1.089-1.142, p < 0.001; HFpEF plus HFmrEF, HR 1.109, 95% CI 1.074-1.146, p < 0.0001; HFrEF, HR 1.138, 95% CI 1.094-1.183, p < 0.0001) The optimal cut-off value of FAR in predicting all-cause mortality was 9.06 with an area under the curve value of 0.720 (95% CI: 0.687-0.753, p < 0.001), a sensitivity of 68.8% and a specificity of 65.6%. After adjusting for the traditional indicators (LVEF, Lg BNP, etc.), the new model with the FAR had better prediction ability in patients with CHF. Elevated FAR is an independent predictor of death in CHF and is not related to the HF subtype.
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Affiliation(s)
- Sirui Yang
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Jiangyuan Pi
- Graduate School of Kunming Medical University, Kunming, China
| | - Wenfang Ma
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Wenyi Gu
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Hongxing Zhang
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Anyu Xu
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Yanqing Liu
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Tao Shi
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Fazhi Yang
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
| | - Lixing Chen
- Department of Cardiology, Kunming Medical University First Affiliated Hospital, Kunming, China
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Galli L, Sator A, Schauer S, Bräu K, Bernhard J, Hengstenberg C, Gangl C, Hemetsberger R, Roth C, Berger R, Krychtiuk KA, Speidl WS. Platelets, Biomarkers of Coagulation and Fibrinolysis, and Early Coronary Stent Thrombosis. J Clin Med 2024; 14:56. [PMID: 39797139 PMCID: PMC11721602 DOI: 10.3390/jcm14010056] [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: 11/23/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: Acute stent thrombosis (ST) is a rare yet severe complication following percutaneous coronary intervention (PCI). Herein, we investigated the possible association between routinely available coagulation and fibrinolysis markers with early ST. Methods: Within a single-center registry, we investigated the association between the preprocedural platelet count, plasma levels of fibrinogen and D-Dimer, and the incidence of early ST in the first 30 days after PCI. Results: Out of 10,714 consecutive patients who underwent PCI using drug-eluting stents (DESs), the preprocedural platelet count, fibrinogen, and D-Dimer measurements were available in 6337, 6155, and 956 patients, respectively. Fifty-eight patients (0.92%) experienced an early ST within 30 days after PCI. Compared with those without ST, patients with early ST showed significantly elevated preprocedural platelet counts (p < 0.05) and fibrinogen levels (p < 0.05). D-Dimer levels were not associated with early ST. Patients in the fifth quintile of platelet count had a significantly increased risk for early ST (HR 2.43; 95% CI 1.43-4.14; p = 0.001) compared with patients in the lower four quintiles. In addition, patients in the fifth quintile of fibrinogen also had a significantly increased risk for early ST (HR 1.86; 95% CI 1.07-3.26; p < 0.05) compared with patients in the lower four quintiles. These associations were independent of clinical risk factors, the number of stents, the presence of acute coronary syndromes, and white blood cell count. Conclusions: Preprocedural platelet counts and fibrinogen plasma levels can identify patients at elevated risk of early ST after implantation of DESs in addition to procedure-level and device-related risk factors.
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Affiliation(s)
- Lukas Galli
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
- Ludwig Boltzmann Institute for Cardiovascular Research, 1090 Vienna, Austria
| | - Alexander Sator
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Stephanie Schauer
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Konstantin Bräu
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Johannes Bernhard
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Christian Hengstenberg
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Clemens Gangl
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Rayyan Hemetsberger
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Christian Roth
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
| | - Rudolf Berger
- Department of Internal Medicine I, Cardiology and Nephrology, Hospital of St. John of God, 7000 Eisenstadt, Austria;
| | - Konstantin A. Krychtiuk
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
- Ludwig Boltzmann Institute for Cardiovascular Research, 1090 Vienna, Austria
| | - Walter S. Speidl
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (A.S.); (S.S.); (K.B.); (J.B.); (C.H.); (C.G.); (R.H.); (W.S.S.)
- Ludwig Boltzmann Institute for Cardiovascular Research, 1090 Vienna, Austria
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Huffman JE, Nicholas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessler J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BAT, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, Gao H, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJA, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MPM, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson PWF, Ben-Shlomo Y, et alHuffman JE, Nicholas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessler J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BAT, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, Gao H, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJA, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MPM, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson PWF, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia SLR, Lange LA, März W, Mathias RA, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner A, Ridker PM, Silverman EK, Spector TD, Völker U, Wareham NJ, Wilson JF, Yao J, VA Million Veteran Program, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Trégouët DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison AC, Smith NL. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. Blood 2024; 144:2248-2265. [PMID: 39226462 PMCID: PMC11600029 DOI: 10.1182/blood.2023022596] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 09/05/2024] Open
Abstract
ABSTRACT Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
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Affiliation(s)
- Jennifer E. Huffman
- Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA
- MAVERIC, VA Boston Healthcare System, Boston, MA
| | - Jayna Nicholas
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Julie Hahn
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
| | - Adam S. Heath
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
| | - Laura M. Raffield
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Lisa R. Yanek
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
| | - Florian Thibord
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
| | - Laura Almasy
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Traci M. Bartz
- Department of Biostatistics, University of Washington, Seattle, WA
| | - Lawrence F. Bielak
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
| | | | - Germán D. Carrasquilla
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Daniel I. Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Ming-Huei Chen
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
| | - David B. Emmert
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jeffrey Haessler
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Jouke-Jan Hottenga
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
| | - Marcus E. Kleber
- SYNLAB MVZ für Humangenetik Mannheim, Mannheim, Germany
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ngoc-Quynh Le
- Unit of Genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain
| | - Jiwon Lee
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Joshua P. Lewis
- Department of Medicine, University of Maryland, Baltimore, MD
| | - Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jian'an Luan
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Anni Malmberg
- Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
- National Institute for Health and Care Research Biomedical Research Centre, Guy’s and St Thomas’ Foundation Trust, London, United Kingdom
| | - Riccardo E. Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Angel Martinez-Perez
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
| | - Ozren Polasek
- Faculty of Medicine, University of Split, Split, Croatia
| | - Anne Richmond
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Benjamin A. T. Rodriguez
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
| | - Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
| | - Maristella Steri
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy
| | - Pierre Suchon
- Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France
- Laboratory of Haematology, La Timone Hospital, Marseille, France
| | - Stella Trompet
- Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany
| | - Marjan Zare
- Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Paul Auer
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI
| | - Michael H. Cho
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Paraskevi Christofidou
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
| | - Gail Davies
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Eco de Geus
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
| | - Jean-François Deleuze
- Centre National de Recherche en Génomique Humaine, Commissariat a l'Energie Atomique et aux Energies Alternatives, Université Paris-Saclay, Evry, France
| | - Graciela E. Delgado
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lynette Ekunwe
- Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS
| | - Nauder Faraday
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Martin Gögele
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Andreas Greinacher
- Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - He Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
| | - Tom Howard
- Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
| | - Peter K. Joshi
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | - Tuomas O. Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jari Lahti
- Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Allan Linneberg
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Silvia Naitza
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy
| | - Raymond Noordam
- Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands
| | - Ferran Paüls-Vergés
- Unit of Genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain
| | - Stephen S. Rich
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA
| | - Frits R. Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Igor Rudan
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | | | - Juan Carlos Souto
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Frank J. A. van Rooij
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Heming Wang
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI
| | - Lewis C. Becker
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew Beswick
- Translational Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Michael R. Brown
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
| | - Brian E. Cade
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Harry Campbell
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | - Kelly Cho
- MAVERIC, VA Boston Healthcare System, Boston, MA
- Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA
| | | | - Joanne E. Curran
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
| | - Moniek P. M. de Maat
- Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Margaret Doyle
- Department of Pathology and Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom
| | - James S. Floyd
- Departments of Medicine and Epidemiology, University of Washington, Seattle, WA
| | - Christian Fuchsberger
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
| | - Sarah E. Harris
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University, Chicago, IL
| | - Ivana Kolcic
- Faculty of Medicine, University of Split, Split, Croatia
| | - Charles Kooperberg
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Cristina Menni
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, German Center for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany, University Medicine Greifswald, Greifswald, Germany
| | | | - Valeria Orrù
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA
| | - Katri Räikkönen
- Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Jennifer A. Smith
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI
| | - Jose Manuel Soria
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - David J. Stott
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | | | - Hugh Watkins
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Gonneke Willemsen
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
| | - Peter W. F. Wilson
- VA Atlanta Healthcare System, Decatur, GA
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA
| | - Yoav Ben-Shlomo
- Poulation Health Sciences, University of Bristol, Bristol, United Kingdom
| | - John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
| | - Dorret Boomsma
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
| | - Simon R. Cox
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom
| | - Johan G. Eriksson
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Centre, Helsinki, Finland
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Edoardo Fiorillo
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - M. Arfan Ikram
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
| | - Sharon L. R. Kardia
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Leslie A. Lange
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Winfried März
- Synlab Academy, Synlab Holding Deutschland GmbH, and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Rasika A. Mathias
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Braxton D. Mitchell
- Department of Medicine, University of Maryland, Baltimore, MD
- Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD
| | - Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
| | - Pierre-Emmanuel Morange
- Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France
- Laboratory of Haematology, La Timone Hospital, Marseille, France
| | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter P. Pramstaller
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Susan Redline
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA
| | - Alexander Reiner
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Paul M. Ridker
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Edwin K. Silverman
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Tim D. Spector
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
| | - Uwe Völker
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany
| | - Nicholas J. Wareham
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - James F. Wilson
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | - Jie Yao
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
| | - VA Million Veteran Program
- Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA
- MAVERIC, VA Boston Healthcare System, Boston, MA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA
- Department of Biostatistics, University of Washington, Seattle, WA
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
- National Jewish Health, Denver, CO
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
- SYNLAB MVZ für Humangenetik Mannheim, Mannheim, Germany
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Unit of Genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Department of Medicine, University of Maryland, Baltimore, MD
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
- Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
- National Institute for Health and Care Research Biomedical Research Centre, Guy’s and St Thomas’ Foundation Trust, London, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
- Faculty of Medicine, University of Split, Split, Croatia
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy
- Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France
- Laboratory of Haematology, La Timone Hospital, Marseille, France
- Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany
- Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Centre National de Recherche en Génomique Humaine, Commissariat a l'Energie Atomique et aux Energies Alternatives, Université Paris-Saclay, Evry, France
- Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
- Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA
- Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI
- Translational Health Sciences, University of Bristol, Bristol, United Kingdom
- Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
- Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Department of Pathology and Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT
- United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom
- Departments of Medicine and Epidemiology, University of Washington, Seattle, WA
- Department of Preventive Medicine, Northwestern University, Chicago, IL
- Institute of Clinical Chemistry and Laboratory Medicine, German Center for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany, University Medicine Greifswald, Greifswald, Germany
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
- Department of Epidemiology, University of Washington, Seattle, WA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- VA Atlanta Healthcare System, Decatur, GA
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA
- Poulation Health Sciences, University of Bristol, Bristol, United Kingdom
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Centre, Helsinki, Finland
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
- Synlab Academy, Synlab Holding Deutschland GmbH, and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA
- Bordeaux Population Health Research Center, INSERM UMR 1219, University of Bordeaux, Bordeaux, France
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA
- Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA
| | - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA
- MAVERIC, VA Boston Healthcare System, Boston, MA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA
- Department of Biostatistics, University of Washington, Seattle, WA
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
- National Jewish Health, Denver, CO
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
- SYNLAB MVZ für Humangenetik Mannheim, Mannheim, Germany
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Unit of Genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Department of Medicine, University of Maryland, Baltimore, MD
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
- Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
- National Institute for Health and Care Research Biomedical Research Centre, Guy’s and St Thomas’ Foundation Trust, London, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
- Faculty of Medicine, University of Split, Split, Croatia
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy
- Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France
- Laboratory of Haematology, La Timone Hospital, Marseille, France
- Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany
- Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Centre National de Recherche en Génomique Humaine, Commissariat a l'Energie Atomique et aux Energies Alternatives, Université Paris-Saclay, Evry, France
- Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
- Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA
- Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI
- Translational Health Sciences, University of Bristol, Bristol, United Kingdom
- Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
- Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Department of Pathology and Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT
- United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom
- Departments of Medicine and Epidemiology, University of Washington, Seattle, WA
- Department of Preventive Medicine, Northwestern University, Chicago, IL
- Institute of Clinical Chemistry and Laboratory Medicine, German Center for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany, University Medicine Greifswald, Greifswald, Germany
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
- Department of Epidemiology, University of Washington, Seattle, WA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- VA Atlanta Healthcare System, Decatur, GA
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA
- Poulation Health Sciences, University of Bristol, Bristol, United Kingdom
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Centre, Helsinki, Finland
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
- Synlab Academy, Synlab Holding Deutschland GmbH, and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA
- Bordeaux Population Health Research Center, INSERM UMR 1219, University of Bordeaux, Bordeaux, France
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA
- Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA
| | - David-Alexandre Trégouët
- Bordeaux Population Health Research Center, INSERM UMR 1219, University of Bordeaux, Bordeaux, France
| | - Andrew D. Johnson
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA
| | - Alisa S. Wolberg
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Paul S. de Vries
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
| | - Maria Sabater-Lleal
- Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden
| | - Alanna C. Morrison
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
| | - Nicholas L. Smith
- Department of Epidemiology, University of Washington, Seattle, WA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA
- Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA
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Bruwer D, de Lange-Loots Z, Koschinsky ML, Boffa MB, Pieters M. Fibrinogen and plasma clot properties are associated with apolipoprotein B and apolipoprotein B-containing lipoproteins in Africans. J Clin Lipidol 2024; 18:e1002-e1014. [PMID: 39306544 DOI: 10.1016/j.jacl.2024.08.004] [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: 04/17/2024] [Revised: 07/15/2024] [Accepted: 08/06/2024] [Indexed: 03/03/2025]
Abstract
BACKGROUND Case-control, intervention and laboratory studies have demonstrated a link between apolipoprotein B (ApoB)-containing lipoproteins and clot structure and thrombosis. There is, however, limited evidence on a population level. OBJECTIVES We determined the cross-sectional relationship between lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB with fibrinogen and plasma clot properties in 1462 Black South Africans, a population with higher fibrinogen and Lp(a) levels compared with individuals of European descent. METHODS Data were obtained from participants in the South African arm of the Prospective Urban and Rural Epidemiology study. Clot properties analyzed included lag time, slope, maximum absorbance, and clot lysis time (turbidity). Lp(a) was measured in nM using particle-enhanced immunoturbidimetry. General linear models (GLM) were used to determine the associations between ApoB and ApoB-containing lipoproteins with fibrinogen and plasma clot properties. Stepwise regression was used to determine contributors to clot properties and Lp(a) variance. RESULTS GLM and regression results combined, indicated fibrinogen concentration and rate of clot formation (slope) had the strongest association with Lp(a); clot density associated positively with both Lp(a) and LDL-C; time to clot formation associated negatively with ApoB; and clot lysis time (CLT) demonstrated strong positive associations with both ApoB and LDL-C, while its association with Lp(a) was fibrinogen concentration dependent. CONCLUSION These findings suggest that ApoB and the lipoproteins carrying it contribute to prothrombotic clot properties in Africans on an epidemiological level and highlight potential novel prothrombotic roles for these (apo)lipoproteins to be considered for the development of targeted therapeutic approaches to address thrombotic conditions related to clot properties.
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Affiliation(s)
- Daniel Bruwer
- Centre of Excellence for Nutrition, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa (Drs Bruwer, de Lange-Loots and Pieters)
| | - Zelda de Lange-Loots
- Centre of Excellence for Nutrition, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa (Drs Bruwer, de Lange-Loots and Pieters); SAMRC Extramural Unit for Hypertension and Cardiovascular Disease, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa (Drs de Lange-Loots and Pieters). https://twitter.com/Zelda_dLL
| | - Marlys L Koschinsky
- Department of Physiology & Pharmacology and Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada (Dr Koschinsky). https://twitter.com/MarlysLPA
| | - Michael B Boffa
- Department of Biochemistry and Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Canada (Dr Boffa). https://twitter.com/MBBoffa
| | - Marlien Pieters
- Centre of Excellence for Nutrition, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa (Drs Bruwer, de Lange-Loots and Pieters); SAMRC Extramural Unit for Hypertension and Cardiovascular Disease, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa (Drs de Lange-Loots and Pieters).
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9
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Ferguson B, Doan V, Shoker A, Abdelrasoul A. A comprehensive exploration of chronic kidney disease and dialysis in Canada's Indigenous population: from epidemiology to genetic influences. Int Urol Nephrol 2024; 56:3545-3558. [PMID: 38898356 DOI: 10.1007/s11255-024-04122-5] [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: 03/10/2024] [Accepted: 06/13/2024] [Indexed: 06/21/2024]
Abstract
PURPOSE This study aims to review the escalating prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) among Canada's Indigenous population, focusing on risk factors, hospitalization and mortality rates, and disparities in kidney transplantation. The study explores how these factors contribute to the health outcomes of this population and examines the influence of genetic variations on CKD progression. METHODS The review synthesizes data on prevalence rates, hospitalization and mortality statistics, and transplantation disparities among Indigenous individuals. It also delves into the complexities of healthcare access, including geographical, socioeconomic, and psychological barriers. Additionally, the manuscript investigates the impact of racial factors on blood characteristics relevant to dialysis treatment and the genetic predispositions influencing disease progression in Indigenous populations. RESULTS Indigenous individuals exhibit a higher prevalence of CKD and ESRD risk factors such as diabetes and obesity, particularly in regions like Saskatchewan. These patients face a 77% higher risk of death compared to their non-Indigenous counterparts and are less likely to receive kidney transplants. Genetic analyses reveal significant associations between CKD and specific genomic variations. Through analyses, we found that healthy Indigenous individuals may have higher levels of circulating inflammatory markers, which could become further elevated for those with CKD. In particular, they may have higher levels of C-reactive protein (CRP) fibrinogen, as well as genomic variations that affect IL-6 production and the function of von Willebrand Factor (vWF) which has critical potential influence on the compatibility with dialysis membranes contributing to complications in dialysis. CONCLUSION Indigenous people in Canada are disproportionately burdened by CKD and ESRD due to socioeconomic factors and potential genetic predispositions. While significant efforts have been made to assess the socioeconomic conditions of the Indigenous population, the genetic factors and their potential critical influence on compatibility with dialysis membranes, contributing to treatment complications, remain understudied. Further investigation into these genetic predispositions is essential.
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Affiliation(s)
- Braiden Ferguson
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada
| | - Victoria Doan
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada
| | - Ahmed Shoker
- Saskatchewan Transplant Program, St. Paul's Hospital, 1702 20Th Street West, Saskatoon, SK, S7M 0Z9, Canada
- Nephrology Division, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Amira Abdelrasoul
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada.
- Department of Chemical and Biological Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada.
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10
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McCabe JJ, Walsh C, Gorey S, Harris K, Hervella P, Iglesias-Rey R, Jern C, Li L, Miyamoto N, Montaner J, Pedersen A, Purroy F, Rothwell PM, Sudlow C, Ueno Y, Vicente-Pascual M, Whiteley W, Woodward M, Kelly PJ. Plasma fibrinogen and risk of vascular recurrence after ischaemic stroke: An individual participant and summary-level data meta-analysis of 11 prospective studies. Eur Stroke J 2024; 9:704-713. [PMID: 38600679 PMCID: PMC11418456 DOI: 10.1177/23969873241246489] [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: 01/31/2024] [Accepted: 03/26/2024] [Indexed: 04/12/2024] Open
Abstract
INTRODUCTION Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear. MATERIALS AND METHODS We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event. RESULTS Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17-1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06-1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03-1.39), but not after adjustment (RR 1.11, 95% CI 0.94-1.31). The association with recurrent MACE was consistently observed in patients with post-acute (⩾14 days) fibrinogen measures (RR 1.29, 95% CI 1.16-1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82-1.18) (Pinteraction = 0.01). Similar associations were observed for recurrent stroke. DISCUSSION AND CONCLUSION Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after stroke.
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Affiliation(s)
- John J McCabe
- Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI), Dublin, Ireland
- School of Medicine, University College Dublin (UCD), Ireland
- Stroke Service, Department of Geriatric Medicine and Neurology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Cathal Walsh
- Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI), Dublin, Ireland
- Department of Biostatistics, Trinity College Dublin, Ireland
| | - Sarah Gorey
- Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI), Dublin, Ireland
- School of Medicine, University College Dublin (UCD), Ireland
- Stroke Service, Department of Geriatric Medicine and Neurology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Katie Harris
- George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
| | - Pablo Hervella
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela, Santiago De Compostela, Spain
| | - Ramon Iglesias-Rey
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela, Santiago De Compostela, Spain
| | - Christina Jern
- Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Department of Laboratory Medicine, Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden
| | - Linxin Li
- Wolfson Centre for the Prevention of Stroke and Dementia, University of Oxford, Oxford, UK
| | - Nobukazu Miyamoto
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Joan Montaner
- Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Neurology, Seville, Spain
- Department of Neurology, Virgen Macarena Hospital, Sevilla, Spain
- Neurovascular Research Laboratory, Vall d’Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Annie Pedersen
- Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Department of Laboratory Medicine, Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden
| | - Francisco Purroy
- Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain
- Department of Clinical Neurosciences, Institut Reserca Biomèdica Lleida, University of Lleida, Spain
| | - Peter M Rothwell
- Wolfson Centre for the Prevention of Stroke and Dementia, University of Oxford, Oxford, UK
| | - Catherine Sudlow
- Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Yuji Ueno
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Mikel Vicente-Pascual
- Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain
- Department of Clinical Neurosciences, Institut Reserca Biomèdica Lleida, University of Lleida, Spain
| | - William Whiteley
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Mark Woodward
- George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
- George Institute for Global Health, Imperial College London, London, UK
| | - Peter J Kelly
- Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI), Dublin, Ireland
- School of Medicine, University College Dublin (UCD), Ireland
- Stroke Service, Department of Geriatric Medicine and Neurology, Mater Misericordiae University Hospital, Dublin, Ireland
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11
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Dryer-Beers ER, Griffin J, Matthews PM, Frost GS. Higher Dietary Polyphenol Intake Is Associated With Lower Blood Inflammatory Markers. J Nutr 2024; 154:2470-2480. [PMID: 38740187 PMCID: PMC11375465 DOI: 10.1016/j.tjnut.2024.05.005] [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: 12/14/2022] [Revised: 04/27/2024] [Accepted: 05/01/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Evidence suggests a link between polyphenol intake and reduced incidence of several chronic diseases. This could arise through associations between polyphenol intake and reduced systemic oxidative stress and subsequent inflammation. However, confirming this association is difficult, as few large cohorts allow for comprehensive assessments of both polyphenol intake and markers of systemic inflammation. OBJECTIVES To address this, polyphenol intake was assessed in the UK-based Airwave cohort using 7-d diet diaries and data from Phenol-Explorer to test for associations between polyphenol intake and blood biomarkers of inflammation. METHODS Participants included 9008 males and females aged 17-74 y (median age: 42 y) whose data was included in a cross-sectional analysis. Phenol-Explorer was used to estimate individuals' polyphenol intake from diet data describing the consumption of 4104 unique food items. C-reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation. RESULTS There were 448 polyphenols found in reported diet items. Median total polyphenol intake was 1536 mg/d (1058-2092 mg/d). Phenolic acids and flavonoids were the main types of polyphenols, and nonalcoholic beverages, vegetables, and fruit were the primary sources. Variation in energy-adjusted polyphenol intake was explained by age, sex, salary, body mass index, education level, smoking, and alcohol consumption. Linear regressions showed inverse associations between total daily intake and both CRP (β: -0.00702; P < 0.001) and fibrinogen (β: -0.00221; P = 0.038). Associations with specific polyphenol compound groups were also found. Logistic regressions using total polyphenol intake quartiles showed stepwise reductions in the odds of elevated CRP with higher intake (6%, 23%, and 24% compared with quartile 1; P = 0.003), alongside 3% and 7% lower odds per unit of polyphenol consumption equivalent to 1 cup of tea or coffee per day. CONCLUSIONS This study describes polyphenol intake in a large, contemporary UK cohort. We observed associations between higher intake and lower CRP and fibrinogen. This contributes to evidence supporting the health benefits of dietary polyphenols.
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Affiliation(s)
- Elliot R Dryer-Beers
- Nutrition and Dietetics Research Group, Imperial College London, London, United Kingdom; UK Dementia Research Institute and Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Jennifer Griffin
- Nutrition and Dietetics Research Group, Imperial College London, London, United Kingdom
| | - Paul M Matthews
- UK Dementia Research Institute and Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Gary S Frost
- Nutrition and Dietetics Research Group, Imperial College London, London, United Kingdom.
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12
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Heleniak Z, Matusik PT, Undas A. Altered fibrin clot properties are associated with the progression of chronic kidney disease in atrial fibrillation. Thromb Res 2024; 236:14-21. [PMID: 38387299 DOI: 10.1016/j.thromres.2024.02.018] [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: 10/11/2023] [Revised: 02/05/2024] [Accepted: 02/15/2024] [Indexed: 02/24/2024]
Abstract
INTRODUCTION Formation of denser and resistant to lysis fibrin clot networks has been shown in chronic kidney disease (CKD) and atrial fibrillation (AF). We investigated whether such prothrombotic fibrin clot properties are associated with faster progression of CKD in AF patients. MATERIAL AND METHODS We recruited 265 AF patients (men 49.1 %, median age of 64.0 years, median estimated glomerular filtration rate [eGFR] of 77.0 ml/min/1.73 m2), including 137 patients on non-vitamin K antagonist oral anticoagulants (NOACs) (51.7 %) and 109 patients (41.1 %) on vitamin K antagonists (VKAs). At baseline while off anticoagulation, we determined fibrin clot permeability (Ks), and clot lysis time (CLT), along with plasminogen activator inhibitor-1 (PAI-1), endogenous thrombin potential (ETP), and von Willebrand factor (vWF). The kidney function was assessed at baseline and after a median follow-up of 50.0 months. RESULTS During follow-up, a median eGFR decreased by 8.0 (5.0-11.0) ml/min/1.73 m2, 1.8 ml/min/1.73 m2/year and this change correlated with age (R = 0.19, P = 0.002), Ks (R = 0.46, P < 0.0001), and CLT (R = -0.17, P = 0.005), but not ETP, fibrinogen, PAI-1 or vWF. A decrease in eGFR was lower in patients who used NOACs at baseline but not in those who started NOACs during follow-up (n = 101) as compared to the remaining patients. On multiple linear regression analysis, adjusted for age and fibrinogen, baseline Ks, eGFR, hypertension, and NOACs use independently predicted a decrease in eGFR. CONCLUSIONS This study is the first to show that more compact fibrin clot networks may contribute to faster progression of CKD in AF, indicating novel kidney-related harmful effects of prothrombotic clot properties in humans.
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Affiliation(s)
- Zbigniew Heleniak
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdańsk, Poland
| | - Paweł T Matusik
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | - Anetta Undas
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
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13
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Huffman JE, Nicolas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessle J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BA, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, He G, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJ, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MP, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson P, Ben-Shlomo Y, et alHuffman JE, Nicolas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessle J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BA, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, He G, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJ, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MP, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson P, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia SL, Lange LA, März W, Mathias RA, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner A, Ridker PM, Silverman EK, Spector TD, Völker U, Wareham N, Wilson JF, Yao J, Trégouët DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison AC, Smith NL. Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.06.07.23291095. [PMID: 37398003 PMCID: PMC10312878 DOI: 10.1101/2023.06.07.23291095] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. Key Points Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
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14
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Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne) 2023; 10:1011936. [PMID: 37064029 PMCID: PMC10103649 DOI: 10.3389/fmed.2023.1011936] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/27/2023] [Indexed: 04/03/2023] Open
Abstract
The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.
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Affiliation(s)
| | - Ryan J. Low
- Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom
- Sainsbury Wellcome Centre, University College London, London, United Kingdom
| | - Athena Akrami
- Sainsbury Wellcome Centre, University College London, London, United Kingdom
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15
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Garyfallogiannis K, Ramanujam RK, Litvinov RI, Yu T, Nagaswami C, Bassani JL, Weisel JW, Purohit PK, Tutwiler V. Fracture toughness of fibrin gels as a function of protein volume fraction: Mechanical origins. Acta Biomater 2023; 159:49-62. [PMID: 36642339 PMCID: PMC11824895 DOI: 10.1016/j.actbio.2022.12.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 01/15/2023]
Abstract
The mechanical stability of blood clots necessary for their functions is provided by fibrin, a fibrous gel. Rupture of clots leads to life-threatening thrombotic embolization, which is little understood. Here, we combine experiments and simulations to determine the toughness of plasma clots as a function of fibrin content and correlate toughness with fibrin network structure characterized by confocal and scanning electron microscopy. We develop fibrin constitutive laws that scale with fibrin concentration and capture the force-stretch response of cracked clot specimens using only a few material parameters. Toughness is calculated from the path-independent J* integral that includes dissipative effects due to fluid flow and uses only the constitutive model and overall stretch at crack propagation as input. We show that internal fluid motion, which is not directly measurable, contributes significantly to clot toughness, with its effect increasing as fibrin content increases, because the reduced gel porosity at higher density results in greater expense of energy in fluid motion. Increasing fibrin content (1→10mg/mL) results in a significant increase in clot toughness (3→15 N/m) in accordance with a power law relation reminiscent of cellular solids and elastomeric gels. These results provide a basis for understanding and predicting the tendency for thrombotic embolization. STATEMENT OF SIGNIFICANCE: Fibrin, a naturally occurring biomaterial, is the major determinant of the structural and mechanical integrity of blood clots. We determined that increasing the fibrin content in clots, as in some thrombi and fibrin-based anti-bleeding sealants, results in an increase in clot toughness. Toughness corresponds to the ability to resist rupturing in the presence of a defect. We couple bulk mechanical testing, microstructural measurements, and finite element modeling to capture the force-stretch response of fibrin clots and compute toughness. We show that increased fibrin content in clots reduces porosity and limits fluid motion and that fluid motion drastically alters the clot toughness. These results provide a fundamental understanding of blood clot rupture and could help in rational design of fibrin-containing biomaterials.
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Affiliation(s)
| | - Ranjini K Ramanujam
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Rustem I Litvinov
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Tony Yu
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | | | - John L Bassani
- Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA, USA
| | - John W Weisel
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Prashant K Purohit
- Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA, USA
| | - Valerie Tutwiler
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
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16
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Wang X, Hu Y, Luan H, Luo C, Kamila·Kamili, Zheng T, Tian G. Predictive impact of fibrinogen-to-albumin ratio (FAR) for left ventricular dysfunction in acute coronary syndrome: a cross-sectional study. Eur J Med Res 2023; 28:68. [PMID: 36755341 PMCID: PMC9906889 DOI: 10.1186/s40001-023-01029-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 01/22/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND The significantly prognostic value of fibrinogen-to-albumin ratio (FAR) has been proved in patients with coronary artery disease and different oncologic disorders. This study aimed to investigate the predictive value of FAR for left ventricular systolic dysfunction (LVSD) in acute coronary syndromes (ACS) patients. METHODS A total of 650 ACS patients after percutaneous coronary intervention (PCI) were eventually enrolled in the analysis. Participants were classified into three groups according to baseline FAR levels (T1: FAR < 73.00; T2: 73.00 ≤ FAR < 91.00; T3: FAR ≥ 91.00). The association between FAR and LVSD was assessed by binary logistic regression analysis. A nomogram to predict the risk of LVSD was constructed based on the output indices from multivariate regression analyses. RESULTS Patients with LVSD showed significantly higher FAR, monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without. FAR was an independent predictor of left ventricular dysfunction from the multivariate analyses (OR, 1.038; 95%CI, 1.020-1.057; P < 0.001). The area under receiver operating characteristic curve (AUC) of FAR predicting the occurrence of LVSD was 0.735. Meanwhile, FAR was the most powerful predictor than MLR, NLR, and PLR. Nomogram with the AUC reaching 0.906 showed a robust discrimination. CONCLUSIONS Admission FAR is independently and significantly associated with LVSD in patients with ACS undergoing PCI.
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Affiliation(s)
- Xuan Wang
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Hu
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hao Luan
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Chaodi Luo
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Kamila·Kamili
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Tingting Zheng
- grid.452438.c0000 0004 1760 8119Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Gang Tian
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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17
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Muacevic A, Adler JR, Mishra B, Guria RT, Kumar A, Birua H, Ray HN, Dungdung A, Kumar D, Maitra S. Association of Fibrinogen With Ischemic Stroke: A Systematic Review and Meta-Analysis. Cureus 2023; 15:e34335. [PMID: 36721710 PMCID: PMC9884496 DOI: 10.7759/cureus.34335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2023] [Indexed: 01/30/2023] Open
Abstract
Validation of a risk factor in a multifactorial disease like ischemic stroke is necessary to practice precision medicine. Many risk factors have been attributed to causing ischemic stroke but contribute very little to it. There are many risk factors that need to be validated, and fibrinogen is one such risk factor. Using a meta-analysis technique, we investigated fibrinogen as a risk factor for ischemic stroke. We searched the computerized databases such as PubMed, Google Scholar, and Cochrane to explore articles on ischemic stroke. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random effects model. A total of 10 case-control studies with 6877 cases and 7219 controls were included in the study that match inclusion and exclusion criteria. The Asiatic population was portrayed in four studies, whereas the Caucasian population was portrayed in six studies. Under the recessive model, an elevated level of serum fibrinogen is linked to an increased risk of ischemic stroke as shown by pooled odds ratio (OR: 1.47, 95% CI: 1.19-1.76, I2 = 78.3%, P = 0.000). Our meta-analysis concluded that a high level of fibrinogen is associated with an increased risk of ischemic stroke.
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18
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Pankratz N, Wei P, Brody JA, Chen MH, de Vries PS, Huffman JE, Stimson MR, Auer PL, Boerwinkle E, Cushman M, de Maat MPM, Folsom AR, Franco OH, Gibbs RA, Haagenson KK, Hofman A, Johnsen JM, Kovar CL, Kraaij R, McKnight B, Metcalf GA, Muzny D, Psaty BM, Tang W, Uitterlinden AG, van Rooij JGJ, Dehghan A, O'Donnell CJ, Reiner AP, Morrison AC, Smith NL. Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. Hum Mol Genet 2022; 31:3120-3132. [PMID: 35552711 PMCID: PMC9476613 DOI: 10.1093/hmg/ddac100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 04/27/2022] [Indexed: 11/12/2022] Open
Abstract
Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.
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Affiliation(s)
- Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Peng Wei
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Ming-Huei Chen
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
- Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
- Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Paul S de Vries
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jennifer E Huffman
- Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
- Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA
- Center for Population Genomics, MAVERIC, VA Boston Healthcare System, Boston, MA, USA
| | - Mary Rachel Stimson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Paul L Auer
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Eric Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Mary Cushman
- Departments of Medicine and Pathology, University of Vermont, Colchester, VT, USA
| | - Moniek P M de Maat
- Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Aaron R Folsom
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - Oscar H Franco
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Richard A Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Kelly K Haagenson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Albert Hofman
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jill M Johnsen
- Research Institute Bloodworks, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Christie L Kovar
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Robert Kraaij
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Barbara McKnight
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Ginger A Metcalf
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Donna Muzny
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Department of Health Services, University of Washington, Seattle, WA, USA
| | - Weihong Tang
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - André G Uitterlinden
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | | | - Abbas Dehghan
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
| | - Christopher J O'Donnell
- Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
- Cardiology Section, Department of Medicine, Boston Veterans Administration Healthcare, Harvard Medical School, Boston, MA, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alex P Reiner
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alanna C Morrison
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA, USA
- Seattle Epidemiologic Research and Information Center, Veterans Administration Office of Research and Development, Seattle, WA, USA
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19
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Choi S, Mazzeffi MA, Henderson R, Mondal S, Morita Y, Deshpande S, Tanaka KA. The
FIBTEM
paradox: Do coronary artery bypass grafting patients with high baseline
FIBTEM
clot firmness need more allogeneic blood transfusion? Transfusion 2022; 62:2020-2028. [DOI: 10.1111/trf.17065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/10/2022] [Accepted: 07/30/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Seung Choi
- Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA
| | - Michael A. Mazzeffi
- Department of Anesthesiology and Critical Care Medicine George Washington University School of Medicine and Health Sciences Washington District of Columbia USA
| | - Reney Henderson
- Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA
| | - Samhati Mondal
- Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA
| | - Yoshihisa Morita
- Department of Anesthesiology Thomas Jefferson University Philadelphia Pennsylvania USA
| | - Seema Deshpande
- Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA
| | - Kenichi A. Tanaka
- Department of Anesthesiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma USA
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20
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Sulimai NH, Brown J, Lominadze D. Fibrinogen, Fibrinogen-like 1 and Fibrinogen-like 2 Proteins, and Their Effects. Biomedicines 2022; 10:1712. [PMID: 35885017 PMCID: PMC9313381 DOI: 10.3390/biomedicines10071712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/05/2022] Open
Abstract
Fibrinogen (Fg) and its derivatives play a considerable role in many diseases. For example, increased levels of Fg have been found in many inflammatory diseases, such as Alzheimer's disease, multiple sclerosis, traumatic brain injury, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Although associations of Fg, Fg chains, and its derivatives with various diseases have been established, their specific effects and the mechanisms of actions involved are still unclear. The present review is the first attempt to discuss the role of Fg, Fg chains, its derivatives, and other members of Fg family proteins, such as Fg-like protein 1 and 2, in inflammatory diseases and their effects in immunomodulation.
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Affiliation(s)
- Nurul H. Sulimai
- Departments of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (N.H.S.); (J.B.)
| | - Jason Brown
- Departments of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (N.H.S.); (J.B.)
| | - David Lominadze
- Departments of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (N.H.S.); (J.B.)
- Departments of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
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21
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Lopardo V, Conti V, Montella F, Iannaccone T, Esposito RM, Sellitto C, Manzo V, Maciag A, Ricciardi R, Pagliano P, Puca AA, Filippelli A, Ciaglia E. Gender Differences Associated with the Prognostic Value of BPIFB4 in COVID-19 Patients: A Single-Center Preliminary Study. J Pers Med 2022; 12:1058. [PMID: 35887555 PMCID: PMC9319362 DOI: 10.3390/jpm12071058] [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: 05/30/2022] [Revised: 06/26/2022] [Accepted: 06/26/2022] [Indexed: 11/16/2022] Open
Abstract
In the ongoing global COVID-19 pandemic, male sex is a risk factor for severe disease and death, and the reasons for these clinical discrepancies are largely unknown. The aim of this work is to study the influence of sex on the course of infection and the differences in prognostic markers between genders in COVID-19 patients. Our cohort consisted of 64 adult patients (n = 34 men and n = 30 women) with PCR-proven SARS-CoV-2 infection. Further, a group of patients was characterized by a different severity degree (n = 8 high- and n = 8 low-grade individuals for both male and female patients). As expected, the serum concentrations of LDH, fibrinogen, CRP, and leucocyte count in men were significantly higher than in females. When serum concentrations of the inflammatory cytokines, including IL-6, IL-2, IP-10 and IL-4 and chemokines like MCP-1, were measured with multiplex ELISA, no significant differences between male and female patients were found. In COVID-19 patients, we recently attributed a new prognostic value to BPIFB4, a natural defensin against dysregulation of the immune responses. Here, we clarify that BPIFB4 is inversely related to the disease degree in men but not in women. Indeed, higher levels of BPIFB4 characterized low-grade male patients compared to high-grade ones. On the contrary, no significant difference was reported between low-grade female patients and high-grade ones. In conclusion, the identification of BPIFB4 as a biomarker of mild/moderate disease and its sex-specific activity would open an interesting field for research to underpin gender-related susceptibility to the disease.
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Affiliation(s)
- Valentina Lopardo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
| | - Valeria Conti
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy;
| | - Francesco Montella
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
| | - Teresa Iannaccone
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
| | - Roberta Maria Esposito
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
| | - Carmine Sellitto
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy;
| | - Valentina Manzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy;
| | - Anna Maciag
- Cardiovascular Research Unit, IRCCS MultiMedica, 20138 Milan, Italy;
| | - Rosaria Ricciardi
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy;
| | - Pasquale Pagliano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Infectious Diseases Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
| | - Annibale Alessandro Puca
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Cardiovascular Research Unit, IRCCS MultiMedica, 20138 Milan, Italy;
| | - Amelia Filippelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy;
| | - Elena Ciaglia
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy; (V.L.); (V.C.); (F.M.); (T.I.); (R.M.E.); (C.S.); (V.M.); (P.P.); (A.F.)
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22
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Zhang X, Ardeshirrouhanifard S, Li J, Li M, Dai H, Song Y. Associations of Nutritional, Environmental, and Metabolic Biomarkers with Diabetes-Related Mortality in U.S. Adults: The Third National Health and Nutrition Examination Surveys between 1988-1994 and 2016. Nutrients 2022; 14:nu14132629. [PMID: 35807807 PMCID: PMC9268621 DOI: 10.3390/nu14132629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Nutritional, environmental, and metabolic status may play a role in affecting the progression and prognosis of type 2 diabetes. However, results in identifying prognostic biomarkers among diabetic patients have been inconsistent and inconclusive. We aimed to evaluate the associations of nutritional, environmental, and metabolic status with disease progression and prognosis among diabetic patients. Methods: In a nationally representative sample in the NHANES III (The Third National Health and Nutrition Examination Survey, 1988−1994), we analyzed available data on 44 biomarkers among 2113 diabetic patients aged 20 to 90 years (mean age: 58.2 years) with mortality data followed up through 2016. A panel of 44 biomarkers from blood and urine specimens available from NHANES III were included in this study and the main outcomes as well as the measures are mortalities from all-causes. We performed weighted logistic regression analyses after controlling potential confounders. To assess incremental prognostic values of promising biomarkers beyond traditional risk factors, we compared c-statistics of the adjusted models with and without biomarkers, separately. Results: In total, 1387 (65.2%) deaths were documented between 1988 and 2016. We observed an increased risk of all-cause mortality associated with higher levels of serum C-reactive protein (p for trend = 0.0004), thyroid stimulating hormone (p for trend = 0.04), lactate dehydrogenase (p for trend = 0.02), gamma glutamyl transferase (p for trend = 0.02), and plasma fibrinogen (p for trend = 0.03), and urine albumin (p for trend < 0.0001). In contrast, higher levels of serum sodium (p for trend = 0.005), alpha carotene (p for trend = 0.006), and albumin (p for trend = 0.005) were associated with a decreased risk of all-cause mortality. In addition, these significant associations were not modified by age, sex, or race. Inclusion of thyroid stimulating hormone (p = 0.03), fibrinogen (p = 0.01), and urine albumin (p < 0.0001), separately, modestly improved the discriminatory ability for predicting all-cause mortality among diabetic patients. Conclusions: Our nationwide study findings provide strong evidence that some nutritional, environmental, and metabolic biomarkers were significant predictors of all-cause mortality among diabetic patients and may have potential clinical value for improving stratification of mortality risk.
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Affiliation(s)
- Xi Zhang
- Clinical Research Unit, Department of Pediatrics, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
| | - Shirin Ardeshirrouhanifard
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA; (S.A.); (M.L.)
| | - Jing Li
- Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA;
| | - Mingyue Li
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA; (S.A.); (M.L.)
| | - Hongji Dai
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin 300060, China
- Correspondence: (H.D.); (Y.S.); Tel.: +86-22-2337-2231 (H.D.); +1-317-274-3833 (Y.S.); Fax: +86-22-2337-2231 (H.D.); +1-317-274-3443 (Y.S.)
| | - Yiqing Song
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA; (S.A.); (M.L.)
- Correspondence: (H.D.); (Y.S.); Tel.: +86-22-2337-2231 (H.D.); +1-317-274-3833 (Y.S.); Fax: +86-22-2337-2231 (H.D.); +1-317-274-3443 (Y.S.)
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23
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Hsieh CT, Chien KL, Hsu HC, Lin HJ, Su TC, Chen MF, Lee YT. Associations between fibrinogen levels and the risk of cardiovascular disease and all-cause death: a cohort study from the Chin-Shan community in Taiwan. BMJ Open 2022; 12:e054638. [PMID: 35365526 PMCID: PMC8977805 DOI: 10.1136/bmjopen-2021-054638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVES Although several studies have investigated the association between fibrinogen level and the risk of cardiovascular disease (CVD), few studies have been conducted in Asia. SETTING We conducted a community-based prospective cohort study in the Chin-Shan community, Taiwan. PARTICIPANTS A total of 2222 participants (54.6±11.9 years, 53.4% women, and 22.4 years of follow-up) who underwent plasma fibrinogen measurements and were without CVD at baseline were recruited, among which 735 participants with available C reactive protein (CRP) were included in the joint analysis of the association of fibrinogen and CRP levels with the risk of CVD. PRIMARY AND SECONDARY OUTCOME MEASURES Fibrinogen and CRP levels were measured by clotting and high-sensitivity immunoturbidimetric assays, respectively. The study outcomes were CVD events and all-cause death. Our definition of CVD included both coronary artery disease (CAD) and stroke cases. Cox proportional hazards regression models were used to estimate the HRs and 95% CIs. RESULTS Compared with the lowest quartile, participants with higher fibrinogen levels tended to have a higher risk of CAD (adjusted HR for the highest quartile=1.48 (95% CI 0.90 to 2.44); test for trend p=0.037) regardless of CRP level (adjusted HR=2.12 (95% CI 1.24 to 3.63) and 2.17 (95% CI 1.06 to 4.44) for high fibrinogen/low CRP and high fibrinogen/high CRP, respectively). The association was not observed for stroke (adjusted HR for the highest quartile=0.99 (95% CI 0.62 to 1.60); test for trend p=0.99) and was only observed for all-cause death among participants <65 years of age (adjusted HR for the highest quartile=1.47 (95% CI 1.11 to 1.95); test for trend p=0.004). CONCLUSIONS Fibrinogen may be a potential risk factor for CAD but not for stroke. Further studies are necessary to clarify the differences in the role of fibrinogen levels on the risk of CVD between Asian and Western countries.
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Affiliation(s)
- Cheng-Tzu Hsieh
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Kuo-Liong Chien
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsiu-Ching Hsu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Ju Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ta-Chen Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Fong Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yuan-Teh Lee
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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24
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Williams PT. Quantile-specific heritability of plasma fibrinogen concentrations. PLoS One 2022; 17:e0262395. [PMID: 34995330 PMCID: PMC8741049 DOI: 10.1371/journal.pone.0262395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/21/2021] [Indexed: 11/30/2022] Open
Abstract
Background Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution. Purpose Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions. Methods Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP, h2 = 2βOP/(1+rspouse)) and full-sib regression slopes (βFS, h2 = {(1+8rspouseβFS)0.05–1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. Conclusion Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.
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Affiliation(s)
- Paul T. Williams
- Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division, Berkeley, CA, United States of America
- * E-mail:
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25
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Surma S, Banach M. Fibrinogen and Atherosclerotic Cardiovascular Diseases-Review of the Literature and Clinical Studies. Int J Mol Sci 2021; 23:ijms23010193. [PMID: 35008616 PMCID: PMC8745133 DOI: 10.3390/ijms23010193] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, represent a significant cause of premature death worldwide. Biomarkers, the evaluation of which would allow the detection of ASCVD at the earliest stage of development, are intensively sought. Moreover, from a clinical point of view, a valuable biomarker should also enable the assessment of the patient’s prognosis. It has been known for many years that the concentration of fibrinogen in plasma increases, inter alia, in patients with ASCVD. On the one hand, an increased plasma fibrinogen concentration may be the cause of the development of atherosclerotic lesions (increased risk of atherothrombosis); on the other hand, it may be a biomarker of ASCVD, as it is an acute phase protein. In addition, a number of genetic polymorphisms and post-translational modifications of fibrinogen were demonstrated that may contribute to the risk of ASCVD. This review summarizes the current data on the importance of fibrinogen as a biomarker of ASCVD, and also presents the relationship between molecular modifications of this protein in the context of ASCVD.
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Affiliation(s)
- Stanisław Surma
- Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-752 Katowice, Poland;
- Club of Young Hypertensiologists, Polish Society of Hypertension, 80-952 Gdansk, Poland
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, 93-338 Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, 65-417 Zielona Gora, Poland
- Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), 93-338 Lodz, Poland
- Correspondence: ; Tel.: +48-422-711-124
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26
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Tu M, Hu S, Lou Z. A high value of fibrinogen in immunoglobulin A nephropathy patients is associated with a worse renal tubular atrophy/interstitial fibrosis score. J Clin Lab Anal 2021; 36:e24120. [PMID: 34783399 PMCID: PMC8761457 DOI: 10.1002/jcla.24120] [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: 08/08/2021] [Revised: 11/03/2021] [Accepted: 11/07/2021] [Indexed: 12/01/2022] Open
Abstract
Purpose The purpose of our study was to investigate the relationship between serum fibrinogen value and renal tubular atrophy/interstitial fibrosis in immunoglobulin A nephropathy patients with eGFR ≥90 ml/min/1.73 m2. Patients and Methods Of 359 patients diagnosed with immunoglobulin A nephropathy after renal biopsy were enrolled in this retrospective study. Demographic, histopathological features, and clinical data were collected. The relationships among these factors were analyzed by using Student's t test, Mann‐Whitney U test, Kruskal‐Wallis test, Chi‐square test, or Fisher's exact test, where appropriate. The logistic regression analysis was performed to examine the independent risk factors. Results Of 176 immunoglobulin A nephropathy patients with eGFR ≥90 ml/min/1.73 m2 were included in this study, and patients were classified into low fibrinogen (fibrinogen <304.6 mg/dl) and high fibrinogen (fibrinogen ≥304.6 mg/dl) groups, respectively. High fibrinogen groups had advanced age, a higher classification of renal tubular atrophy/interstitial fibrosis, and higher levels of systolic pressure, D‐dimer, 24 h urine protein quantitation, nag enzyme. Multivariate logistic analysis showed that fibrinogen (OR = 1.018) was significantly associated with tubular atrophy/interstitial fibrosis. Conclusion Among patients with immunoglobulin A nephropathy, the higher levels of fibrinogen and uric acid may mean a higher score of tubular atrophy/interstitial fibrosis, which suggests the renal biopsy should be performed for these patients as early as possible to defined pathological classification, even though there is no obvious abnormal change in the test of renal function.
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Affiliation(s)
- Mengyun Tu
- Department of Clinical Laboratory, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Sipin Hu
- Department of Vascular Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Zhengqing Lou
- Department of Clinical Laboratory, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
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Anticoagulants and the Hemostatic System: A Primer for Occupational Stress Researchers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182010626. [PMID: 34682370 PMCID: PMC8535451 DOI: 10.3390/ijerph182010626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 12/02/2022]
Abstract
Anticoagulation, the body’s mechanism to prevent blood clotting, is an internal biomarker of an individual’s response to stress. Research has indicated that understanding the causes, processes, and consequences of anticoagulation can provide important insight into the experience of individuals facing emotional and occupational strain. Unfortunately, despite their importance, the mechanisms and implications of anticoagulation are unfamiliar to many researchers and practitioners working with trauma-exposed professionals. This paper provides an accessible primer on the topic of anticoagulation, including an overview of the biological process, the research connecting these processes with emotional and occupational functioning, as well as some potential methods for assessment.
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28
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Patoulias D, Stavropoulos K, Imprialos K, Athyros V, Grassos H, Doumas M, Faselis C. Inflammatory Markers in Cardiovascular Disease; Lessons Learned and Future Perspectives. Curr Vasc Pharmacol 2021; 19:323-342. [PMID: 32188386 DOI: 10.2174/1570161118666200318104434] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 02/24/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cardiovascular disease (CVD) still remains the leading cause of morbidity and mortality worldwide. It is now established that inflammation plays a crucial role in atherosclerosis and atherothrombosis, and thus, it is closely linked to cardiovascular disease. OBJECTIVE The aim of the present review is to summarize and critically appraise the most relevant evidence regarding the potential use of inflammatory markers in the field of CVD. METHODS We conducted a comprehensive research of the relevant literature, searching MEDLINE from its inception until November 2018, primarily for meta-analyses, randomized controlled trials and observational studies. RESULTS Established markers of inflammation, mainly C-reactive protein, have yielded significant results both for primary and secondary prevention of CVD. Newer markers, such as lipoprotein-associated phospholipase A2, lectin-like oxidized low-density lipoprotein receptor-1, cytokines, myeloperoxidase, cell adhesion molecules, matrix metalloproteinases, and the CD40/CD40 ligand system, have been largely evaluated in human studies, enrolling both individuals from the general population and patients with established CVD. Some markers have yielded conflicting results; however, others are now recognized not only as promising biomarkers of CVD, but also as potential therapeutic targets, establishing the role of anti-inflammatory and pleiotropic drugs in CVD. CONCLUSION There is significant evidence regarding the role of consolidated and novel inflammatory markers in the field of diagnosis and prognosis of CVD. However, multimarker model assessment, validation of cut-off values and cost-effectiveness analyses are required in order for those markers to be integrated into daily clinical practice.
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Affiliation(s)
- Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | | | - Konstantinos Imprialos
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Vasilios Athyros
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | | | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Charles Faselis
- VA Medical Center, and George Washington University, Washington, DC 20422, United States
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Yue W, Chen X, He S, Li N, Zhang L, Chen J. Exposure interval to ambient fine particulate matter (PM2.5) collected in Southwest China induced pulmonary damage through the Janus tyrosine protein kinase-2/signal transducer and activator of transcription-3 signaling pathway both in vivo and in vitro. J Appl Toxicol 2021; 41:2042-2054. [PMID: 34081793 DOI: 10.1002/jat.4196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/29/2021] [Accepted: 05/01/2021] [Indexed: 12/20/2022]
Abstract
PM2.5 is a well-known air pollutant threatening public health. Studies confirmed that exposure to the particles could impair pulmonary function, cause chronic obstructive pulmonary disease, and increase the incidence of lung cancer. The characteristic of PM2.5 varies across regions. The toxic function of PM2.5 in southwest China remains to be elucidated. This study aimed to investigate lung injury and its mechanisms induced by PM2.5 collected in Chengdu. Rats were administered with PM2.5 by intratracheal instillation for 4 weeks. Biochemical, cell count, and inflammation-related parameters were measured. Lung tissues were obtained for hematoxylin and eosin and Masson's trichrome staining. The expression levels of vascular endothelial growth factor (VEGF), Janus tyrosine protein kinase-2 (JAK-2), and signal transducer and activator of transcription-3 (STAT-3) were detected by immunohistochemistry assays. Meanwhile, A549 cells were treated with the PM2.5. The cell cycle, and apoptosis were measured by flow cytometry. mRNA and protein expressions of JAK-2, STAT-3, p-STAT-3, and VEGFA were detected using qPCR and Western blot analysis respectively. Results of in vivo study showed that PM2.5 induced lung pathological injury, aggravated the accumulation of inflammatory cells, and increased the serum levels of inflammatory factors. In vitro experiments showed that PM2.5 disrupted the cell growth cycle and increased cell apoptosis through the activation of the JAK-2/STAT-3 signaling pathway. Taken together, this study provided convincing experimental evidence that PM2.5 collected in southwest China could induce pulmonary injury as manifested by inflammatory response and lung fibrosis, possibly through the modulation of the JAK-2/STAT-3 signaling pathway.
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Affiliation(s)
- Wuyang Yue
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.,Department of Tuberculosis Institute Research, Chongqing Public Health Medical Center/Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Xuxi Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Sifu He
- Administration Department, Sichuan Kangchen Biotechnology Co., Chengdu, China
| | - Na Li
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Lishi Zhang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jinyao Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
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Lee J, Kim HS, Kim K, Bae DS, Kim BG, Choi CH. Metabolic syndrome and persistent cervical human papillomavirus infection. Gynecol Oncol 2021; 161:559-564. [PMID: 33676760 DOI: 10.1016/j.ygyno.2021.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 02/07/2021] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Few studies have been conducted on the relationship between metabolic syndrome (MetS) and persistent human papillomavirus (HPV) infection. We investigated whether MetS and associated factors can predict the persistence of HPV infection. PATIENTS AND METHODS We performed a retrospective cohort study of 80,993 female cases undergoing general medical screenings at Samsung Medical Center and 51,140 cases were included in final analysis. MetS and associated factors were used to develop a model predicting the persistence of HPV infection which was defined as HPV positivity for at least one year. The performance of the model was internally validated using bootstrapping and externally validated by testing the risk score against the test set. RESULTS Of the 51,140 cases, there were 5833 (11.4%) cases diagnosed with MetS and 7682 (15.0%) cases diagnosed with HPV infection at baseline. The 12- to 24-month persistence rates of HPV were 50.0% (2846/5691). MetS (OR 1.34, 95% CI 1.04-1.71), globulin (by quintile; OR 1.70, 95% CI 1.25-2.30), fibrinogen (x100 value by quintile; OR 1.07, 95% CI 1.02-1.14), total protein (by quintile; OR 0.91, 95% CI 0.84-0.99) and prothrombin time (by quintile; OR 0.94, 95% CI 0.89-0.99) were significantly associated with the persistence of HPV in multivariate analysis. For validation, a prediction model showed good performance for a range of risk scores and categorized cases into low-, intermediate- and high-risk, which were also correlated with HPV persistence (45.8%, 51.9%, and 60.2% respectively, P < 0.001). CONCLUSION MetS and associated factors were associated with an increased risk of persistent HPV infection.
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Affiliation(s)
- Jieun Lee
- Health Promotion Center, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, South Korea
| | - Hye Seung Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyunga Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Duk-Soo Bae
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byoung-Gie Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
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Richardson TG, Fang S, Mitchell RE, Holmes MV, Davey Smith G. Evaluating the effects of cardiometabolic exposures on circulating proteins which may contribute to severe SARS-CoV-2. EBioMedicine 2021; 64:103228. [PMID: 33548839 PMCID: PMC7857697 DOI: 10.1016/j.ebiom.2021.103228] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/14/2020] [Accepted: 01/13/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. METHODS We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. FINDINGS In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10-16) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 × 10-12). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 × 10-08, proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. INTERPRETATION Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. FUNDING The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.
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Affiliation(s)
- Tom G Richardson
- Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
| | - Si Fang
- Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom
| | - Ruth E Mitchell
- Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom
| | - Michael V Holmes
- Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom; Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom
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Sandrini L, Ieraci A, Amadio P, Zarà M, Barbieri SS. Impact of Acute and Chronic Stress on Thrombosis in Healthy Individuals and Cardiovascular Disease Patients. Int J Mol Sci 2020; 21:ijms21217818. [PMID: 33105629 PMCID: PMC7659944 DOI: 10.3390/ijms21217818] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/08/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
Psychological stress induces different alterations in the organism in order to maintain homeostasis, including changes in hematopoiesis and hemostasis. In particular, stress-induced hyper activation of the autonomic nervous system and hypothalamic–pituitary–adrenal axis can trigger cellular and molecular alterations in platelets, coagulation factors, endothelial function, redox balance, and sterile inflammatory response. For this reason, mental stress is reported to enhance the risk of cardiovascular disease (CVD). However, contrasting results are often found in the literature considering differences in the response to acute or chronic stress and the health condition of the population analyzed. Since thrombosis is the most common underlying pathology of CVDs, the comprehension of the mechanisms at the basis of the association between stress and this pathology is highly valuable. The aim of this work is to give a comprehensive review of the studies focused on the role of acute and chronic stress in both healthy individuals and CVD patients, focusing on the cellular and molecular mechanisms underlying the relationship between stress and thrombosis.
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Affiliation(s)
- Leonardo Sandrini
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (P.A.); (M.Z.)
- Correspondence: (L.S.); (S.S.B.); Tel.: +39-02-58002021 (L.S. & S.S.B.)
| | - Alessandro Ieraci
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Sezione di Fisiologia e Farmacologia, University of Milan, 20133 Milan, Italy;
| | - Patrizia Amadio
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (P.A.); (M.Z.)
| | - Marta Zarà
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (P.A.); (M.Z.)
| | - Silvia Stella Barbieri
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (P.A.); (M.Z.)
- Correspondence: (L.S.); (S.S.B.); Tel.: +39-02-58002021 (L.S. & S.S.B.)
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Nomura SO, Karger AB, Weir NL, Duprez DA, Tsai MY. Free fatty acids, cardiovascular disease, and mortality in the Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol 2020; 14:531-541. [PMID: 32651087 DOI: 10.1016/j.jacl.2020.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Fasting free fatty acid (FFA) levels may be associated with cardiovascular disease (CVD) and mortality, but research among generally healthy adults, females, and racially/ethnically diverse populations is lacking. OBJECTIVE The primary aim of this project was to investigate prospective associations between fasting FFAs and coronary heart disease (CHD) and CVD incidence and CVD-specific and all-cause mortality in a generally healthy age, sex, and racially/ethnically heterogeneous population. METHODS This study was conducted in the Multi-Ethnic Study of Atherosclerosis cohort using baseline (2000-2002) fasting FFAs and outcome data through 2015 (N = 6678). Cox proportional hazards regression was used to calculate hazard ratios for associations between FFAs and CHD, CVD, CVD-specific mortality, and all-cause mortality. Interactions by age, sex, race/ethnicity, and metabolic syndrome were evaluated by stratification and cross-product terms. A secondary analysis was conducted to evaluate associations between FFAs, and inflammatory and endothelial activation biomarkers were evaluated using linear regression (analytic N range: 964-6662). RESULTS FFA levels were not associated with CHD or CVD incidence. Higher FFAs were associated with CVD-specific and all-cause mortality, but associations were attenuated in fully adjusted models with a borderline significant association remaining only for all-cause mortality (fully adjusted, per standard deviation increase hazard ratio = 1.07, 95% confidence interval: 1.00-1.14). Associations did not differ by age, sex, race/ethnicity, or metabolic syndrome. CONCLUSIONS Fasting FFAs were not associated with CHD, CVD, or CVD-specific mortality and were modestly associated with all-cause mortality, regardless of age, sex, race/ethnicity, or metabolic syndrome status.
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Affiliation(s)
- Sarah O Nomura
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Amy B Karger
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Natalie L Weir
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Daniel A Duprez
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Michael Y Tsai
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
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Grafetstätter M, Pletsch-Borba L, Sookthai D, Karavasiloglou N, Johnson T, Katzke VA, Hoffmeister M, Bugert P, Kaaks R, Kühn T. Thrombomodulin and Thrombopoietin, Two Biomarkers of Hemostasis, Are Positively Associated with Adherence to the World Cancer Research Fund/American Institute for Cancer Research Recommendations for Cancer Prevention in a Population-Based Cross-Sectional Study. Nutrients 2019; 11:nu11092067. [PMID: 31484340 PMCID: PMC6770787 DOI: 10.3390/nu11092067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 08/22/2019] [Accepted: 08/27/2019] [Indexed: 01/08/2023] Open
Abstract
A pro-coagulative state is related to increased risk of cardiovascular diseases but also certain cancers. Since experimental and smaller human studies suggest that diet, physical activity, and body weight may all affect coagulation, we evaluated associations between these lifestyle factors and hemostatic biomarkers in a population-based study. Cross-sectional baseline data from 2267 randomly selected participants of EPIC-Heidelberg (age range 35–65 years) was used. Fibrinogen, glycoprotein IIb/IIIa, P-selectin, thrombomodulin (TM), and thrombopoietin (TPO) were measured in baseline plasma samples. A score reflecting adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations for cancer prevention was created. Associations between the WCRF/AICR score as well as its individual components and hemostatic biomarkers were analyzed by linear regression models. Multivariable-adjusted geometric means (95% confidence intervals) of TM and TPO were higher with greater adherence to the WCRF/AICR recommendations (TM, lowest vs. highest score category: 2.90 (2.7,3.1) vs. 3.10 (2.9,3.3) ng/mL, plinear trend = 0.0001; TPO: 328 (302,356) vs. 348 (321,378) pg/mL, plinear trend = 0.0007). These associations were driven by lower alcohol and meat consumption among persons with higher WCRF/AICR scores. Our results indicate that lifestyle factors favorably affect TM and TPO, two hemostatic factors implicated in chronic disease development.
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Affiliation(s)
- Mirja Grafetstätter
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
| | - Laura Pletsch-Borba
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Disorn Sookthai
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Nena Karavasiloglou
- Division of Chronic Disease Epidemiology, Institute for Epidemiology, Biostatistics and Prevention, University of Zürich, 8001 Zürich, Switzerland
| | - Theron Johnson
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Verena A Katzke
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Peter Bugert
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, and German Red Cross Blood Service, Friedrich-Ebert-Str. 107, 68167 Mannheim, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
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Relationship between fibrinogen levels and cardiovascular events in patients receiving percutaneous coronary intervention: a large single-center study. Chin Med J (Engl) 2019; 132:914-921. [PMID: 30958432 PMCID: PMC6595753 DOI: 10.1097/cm9.0000000000000181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: It is currently unclear if fibrinogen is a risk factor for adverse events in patients receiving percutaneous coronary intervention (PCI) or merely serves as a marker of pre-existing comorbidities and other causal factors. We therefore investigated the association between fibrinogen levels and 2-year all-cause mortality, and compared the additional predictive value of adding fibrinogen to a basic model including traditional risk factors in patients receiving contemporary PCI. Methods: A total of 6293 patients undergoing PCI with measured baseline fibrinogen levels were enrolled from January to December 2013 in Fuwai Hospital. Patients were divided into three groups according to tertiles of baseline fibrinogen levels: low fibrinogen, <2.98 g/L; medium fibrinogen, 2.98 to 3.58 g/L; and high fibrinogen, ≥3.58 g/L. Independent predictors of 2-year clinical outcomes were determined by multivariate Cox proportional hazards regression modeling. The increased discriminative value of fibrinogen for predicting all-cause mortality was assessed using the C-statistic and integrated discrimination improvement (IDI). Results: The 2-year all-cause mortality rate was 1.2%. It was significantly higher in the high fibrinogen compared with the low and medium fibrinogen groups according to Kaplan-Meier analyses (1.7% vs. 0.9% and 1.7% vs. 1.0%, respectively; log-rank, P = 0.022). Fibrinogen was significantly associated with all-cause mortality according to multivariate Cox regression (hazard ratio 1.339, 95% confidence interval: 1.109–1.763, P = 0.005), together with traditional risk factors including age, sex, diabetes mellitus, left ventricular ejection fraction, creatinine clearance, and low-density lipoprotein cholesterol. The area under the curve for all-cause mortality in the basic model including traditional risk factors was 0.776, and this value increased to 0.787 when fibrinogen was added to the model (IDI = 0.003, Z = 0.140, P = 0.889). Conclusions: Fibrinogen is associated with 2-year all-cause mortality in patients receiving PCI, but provides no additional information over a model including traditional risk factors.
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Association of overweight and obesity with cardiovascular risk factors in patients with atherosclerotic diseases. J Med Biochem 2019; 39:215-223. [PMID: 33033455 DOI: 10.2478/jomb-2019-0027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 05/04/2019] [Indexed: 01/29/2023] Open
Abstract
Background The aim of this study was to compare demographic, clinical and biochemical characteristics, including inflammatory markers, according to the nutritional status of patients with verified atherosclerotic disease. Methods This cross-sectional study involved 1045 consecutive patients with verified carotid disease or peripheral arterial disease (PAD). Anthropometric parameters and data on cardiovascular risk factors and therapy for hypertension and hyperlipidemia were collected for all participants. Results Carotid disease was positively and PAD was negatively associated with body mass index (BMI). Negative association between obesity and PAD was significant only in former smokers, not in current smokers or in patients who never smoked. Overweight and general obesity were significantly related to metabolic syndrome (p < 0.001), lower values of high - density lipoprotein cholesterol (p < 0.001), increased triglycerides (p < 0.001), hyperglycemia (p < 0.001), self-reported diabetes (p < 0.001), hypertension (p < 0.001), high serum uric acid (p < 0.001), increased high sensitivity C-reactive protein (p = 0.020) and former smoking (p = 0.005) after adjustment for age, gender and type of disease. Antihypertensive therapy seems to be less effective in patients who are overweight and obese. Conclusions In conclusion, overweight and general obesity were significantly related to several cardiovascular risk factors.
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Smith L, Yang L, Hamer M. Handgrip strength, inflammatory markers, and mortality. Scand J Med Sci Sports 2019; 29:1190-1196. [PMID: 30972827 DOI: 10.1111/sms.13433] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/22/2019] [Accepted: 04/04/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE To investigate the extent to which inflammatory markers explain the association between handgrip strength and mortality. METHODS Analyses of data from The English Longitudinal Study of Ageing. Handgrip strength and inflammatory marker data (C-reactive protein and fibrinogen) were collected at baseline (2004/5) and inflammatory marker data at follow-up (2012/13). Participant data were linked with death records. General linear models were used to explore associations between handgrip strength and inflammatory markers at follow-up. Cox proportional hazards regression models were used to examine associations between grip strength and risk of death. Models were estimated with the covariates age, sex, wealth, physical activity, smoking, depressive symptoms, long-standing illness, and adiposity. RESULTS The sample comprised of 5,240 participants (mean age 65.9 (SD 9.4) years; 53.8% female). Over an average 9.7 ± 1.4 years follow-up, there were 650 deaths. Inverse associations were evident between handgrip strength and change in inflammatory markers in women only. There was an association between grip strength and lower risk of mortality in women (hazard ratio = 0.85; 95% CI, 0.74, 0.98) after adjusting for age and wealth. The association was attenuated after adjustment for clinical and behavioral risk factors (0.92; 0.79, 1.07), and further attenuated after adjusting for inflammatory markers (0.95; 0.82, 1.11). CONCLUSION Higher grip strength is associated with lower levels of inflammation at 8-year follow-up, and inflammatory markers partly explained the association between handgrip strength and mortality.
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Affiliation(s)
- Lee Smith
- The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, UK
| | - Lin Yang
- Department of Epidemiology, Medical University of Vienna, Vienna, Austria
| | - Mark Hamer
- School Sport, Exercise Health Sciences, Loughborough University, Loughborough, UK
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Grafetstätter M, Hüsing A, González Maldonado S, Sookthai D, Johnson T, Pletsch-Borba L, Katzke VA, Hoffmeister M, Bugert P, Kaaks R, Kühn T. Plasma Fibrinogen and sP-Selectin are Associated with the Risk of Lung Cancer in a Prospective Study. Cancer Epidemiol Biomarkers Prev 2019; 28:1221-1227. [DOI: 10.1158/1055-9965.epi-18-1285] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/08/2019] [Accepted: 04/11/2019] [Indexed: 11/16/2022] Open
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Nilsson A, Bergens O, Kadi F. Physical Activity Alters Inflammation in Older Adults by Different Intensity Levels. Med Sci Sports Exerc 2019; 50:1502-1507. [PMID: 29462102 DOI: 10.1249/mss.0000000000001582] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE To examine the influence of reallocating time spent at different objectively measured physical activity (PA) behaviors on markers of systemic inflammation in older women with different levels of metabolic risk. METHODS Accelerometer-based monitoring of PA was conducted in a population of community-dwelling older women (n = 111; age, 65-70 yr) for determination of daily sedentary time, time in light PA (LPA) and moderate-to-vigorous PA (MVPA). Blood samples were collected for the assessment of the systemic inflammatory markers C-reactive protein (CRP), fibrinogen, and adiponectin. Metabolic risk was assessed by standardized procedures based on definitions for the metabolic syndrome. Data were analyzed by linear regression models based on isotemporal substitution analysis. RESULTS Reallocating 30 min of sedentary time with either time in LPA (β = -0.47; P < 0.05) or MVPA (β = -0.42; P < 0.05) was related to reduced fibrinogen level, whereas no corresponding effect was evident when shifting time in LPA with time in MVPA, while holding sedentary time constant. In contrast, reallocating a 30-min period in sedentary (β = -0.70; P < 0.01) or LPA (β = -0.71; P < 0.01) with MVPA was associated with a significant reduction in CRP level, whereas no impact on CRP was observed when a period of sedentary behavior was replaced with LPA. Importantly, all significant influences on fibrinogen and CRP by displacement of different PA behaviors remained after adjustment for metabolic risk status among participants. No significant associations with adiponectin were observed. CONCLUSIONS Altogether, this work supports the existence of different intensity thresholds mediating beneficial effects of PA on important clinical markers of systemic inflammation in older women across different stages of disease prevention.
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Affiliation(s)
- Andreas Nilsson
- School of Health Sciences, Örebro University, Örebro, SWEDEN
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Biomarkers of vascular injury in relation to myocardial infarction risk: A population-based study. Sci Rep 2019; 9:3004. [PMID: 30816120 PMCID: PMC6395643 DOI: 10.1038/s41598-018-38259-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/18/2018] [Indexed: 01/13/2023] Open
Abstract
Little is known about circulating biomarkers of vascular injury in relation to cardiovascular disease risk. Thus, we evaluated associations between six novel markers (E-Selectin, P-Selectin, thrombomodulin, thrombopoietin, intercellular adhesion molecule 3 and GPIIb/IIIa) and established cardiovascular risk factors as well as the risk of myocardial infarction (MI) in a population-based study. Biomarkers were measured in pre-diagnostic plasma samples of a case-cohort subset of EPIC-Heidelberg (incident MI cases: n = 369, random sub-cohort: n = 2,418). Generalized Linear models were used to analyse cross-sectional associations between biomarkers and cardiovascular risk factors. Multivariable Cox Regression analyses were carried out to obtain Hazard Ratios (HRs) of MI across quartiles of biomarkers levels. Cross-sectional analyses showed that sex, smoking, alcohol consumption, diabetes and exogenous hormone use were associated with biomarker levels. However, while fibrinogen was associated with MI risk (HR per standard deviation: 2.97 [95% confidence interval: 1.61, 5.46]), none of the six novel biomarkers was associated with MI risk after multivariable adjustment. In a population-based cohort, biomarkers of vascular injury were associated with established cardiovascular risk factors, but not MI risk. The tested biomarkers may reflect pathophysiological alterations in cardiovascular disease development rather than constituting independent MI risk factors.
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Amdur RL, Feldman HI, Dominic EA, Anderson AH, Beddhu S, Rahman M, Wolf M, Reilly M, Ojo A, Townsend RR, Go AS, He J, Xie D, Thompson S, Budoff M, Kasner S, Kimmel PL, Kusek JW, Raj DS. Use of Measures of Inflammation and Kidney Function for Prediction of Atherosclerotic Vascular Disease Events and Death in Patients With CKD: Findings From the CRIC Study. Am J Kidney Dis 2018; 73:344-353. [PMID: 30545708 DOI: 10.1053/j.ajkd.2018.09.012] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 09/18/2018] [Indexed: 12/19/2022]
Abstract
RATIONALE & OBJECTIVE Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD. STUDY DESIGN Observational cohort study. SETTING & PARTICIPANTS 2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry. PREDICTORS Baseline plasma levels of biomarkers of inflammation (interleukin 1β [IL-1β], IL-1 receptor antagonist, IL-6, tumor necrosis factor α [TNF-α], transforming growth factor β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate. OUTCOMES Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death. ANALYTICAL APPROACH Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR. RESULTS During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P<0.001), TNF-α (aHR, 1.09; 95% CI, 1.05-1.13; P<0.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<0.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<0.002) were independently associated with the composite ASVD-death outcome. A composite inflammation score (CIS) incorporating these 4 biomarkers was associated with a graded increase in risk for the composite outcome. The incidence of ASVD-death increased across the quintiles of risk derived from PCEP, kidney function, and CIS. The addition of eGFR, albuminuria, and CIS to PCEP improved (P=0.003) the area under the receiver operating characteristic curve for the composite outcome from 0.68 (95% CI, 0.66-0.71) to 0.73 (95% CI, 0.71-0.76). LIMITATIONS Data for cardiovascular death were not available. CONCLUSIONS Biomarkers of inflammation and measures of kidney function are independently associated with incident ASVD events and death in patients with CKD. Traditional cardiovascular risk estimates could be improved by adding markers of inflammation and measures of kidney function.
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Affiliation(s)
- Richard L Amdur
- Department of Surgery, George Washington University, Washington, DC
| | - Harold I Feldman
- Renal Electrolyte and Hypertension Division, University of Pennsylvania, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, PA
| | | | - Amanda H Anderson
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, PA
| | - Srinivasan Beddhu
- Division of Nephrology, University of Utah School of Medicine, Salt Lake City, UT
| | - Mahboob Rahman
- Division of Nephrology and Hypertension, Case Western Reserve University, OH
| | - Myles Wolf
- Division of Nephrology, Duke University, Durham, NC
| | - Muredach Reilly
- Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University College of Physician and Surgeon, New York, NY
| | - Akinlolu Ojo
- University of Arizona School of Medicine, Tucson, AZ
| | - Raymond R Townsend
- Renal Electrolyte and Hypertension Division, University of Pennsylvania, PA
| | - Alan S Go
- Kaiser Permanente Division of Research, Oakland, CA
| | - Jiang He
- Department of Epidemiology, Tulane University, LA
| | - Dawei Xie
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, PA
| | - Sally Thompson
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, PA
| | - Matthew Budoff
- Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA
| | - Scott Kasner
- Division of Vascular Neurology, University of Pennsylvania, PA
| | - Paul L Kimmel
- Division of Kidney Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - John W Kusek
- Division of Kidney Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Dominic S Raj
- Division of Kidney Diseases and Hypertension, George Washington University, Washington, DC.
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Affiliation(s)
- Ellen K Brinza
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
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Liberale L, Carbone F, Montecucco F, Gebhard C, Lüscher TF, Wegener S, Camici GG. Ischemic stroke across sexes: What is the status quo? Front Neuroendocrinol 2018; 50:3-17. [PMID: 29753797 DOI: 10.1016/j.yfrne.2018.05.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/11/2018] [Accepted: 05/06/2018] [Indexed: 12/15/2022]
Abstract
Stroke prevalence is expected to increase in the next decades due to the aging of the Western population. Ischemic stroke (IS) shows an age- and sex-dependent distribution in which men represent the most affected population within 65 years of age, being passed by post-menopausal women in older age groups. Furthermore, a sexual dimorphism concerning risk factors, presentation and treatment of IS has been widely recognized. In order to address these phenomena, a number of issue have been raised involving both socio-economical and biological factors. The latter can be either dependent on sex hormones or due to intrinsic factors. Although women have poorer outcomes and are more likely to die after a cerebrovascular event, they are still underrepresented in clinical trials and this is mirrored by the lack of sex-tailored therapies. A greater effort is needed in the future to ensure improved treatment and quality of life to both sexes.
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Affiliation(s)
- Luca Liberale
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy
| | - Cathérine Gebhard
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; Department of Nuclear Medicine, University Hospital Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; Cardiology, Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom
| | - Susanne Wegener
- Department of Neurology, University Hospital Zurich and University of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland.
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Sgambato JA, Jones BA, Caraway JW, Prasad G. Inflammatory profile analysis reveals differences in cytokine expression between smokers, moist snuff users, and dual users compared to non-tobacco consumers. Cytokine 2018; 107:43-51. [DOI: 10.1016/j.cyto.2017.11.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 11/16/2017] [Accepted: 11/18/2017] [Indexed: 12/21/2022]
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Liberale L, Carbone F, Montecucco F, Gebhard C, Lüscher TF, Wegener S, Camici GG. Ischemic stroke across sexes: what is the status quo? Front Neuroendocrinol 2018:S0091-3022(18)30040-2. [PMID: 29763641 DOI: 10.1016/j.yfrne.2018.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/13/2018] [Accepted: 04/16/2018] [Indexed: 12/14/2022]
Abstract
Stroke prevalence is expected to increase in the next decades due to the aging of the Western population. Ischemic stroke (IS) shows an age- and sex-dependent distribution in which men represent the most affected population within 65 years of age, being passed by post-menopausal women in older age groups. Furthermore, a sexual dimorphism concerning risk factors, presentation and treatment of IS has been widely recognized. In order to address these phenomena, a number of issue have been raised involving both socio-economical and biological factors. The latter can be either dependent on sex hormones or due to intrinsic factors. Although women have poorer outcomes and are more likely to die after a cerebrovascular event, they are still underrepresented in clinical trials and this is mirrored by the lack of sex-tailored therapies. A greater effort is needed in the future to ensure improved treatment and quality of life to both sexes.
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Affiliation(s)
- Luca Liberale
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy
| | - Cathérine Gebhard
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; Department of Nuclear Medicine, University Hospital Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland; Cardiology, Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom
| | - Susanne Wegener
- Department of Neurology, University Hospital Zurich and University of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, CH-8952 Schlieren, Switzerland.
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Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: A literature review. Regul Toxicol Pharmacol 2018; 94:203-233. [DOI: 10.1016/j.yrtph.2018.02.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 02/04/2018] [Accepted: 02/05/2018] [Indexed: 02/07/2023]
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The longitudinal relation of stress during the menopausal transition to fibrinogen concentrations: results from the Study of Women's Health Across the Nation. Menopause 2018; 23:518-27. [PMID: 26886885 DOI: 10.1097/gme.0000000000000579] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Life course theory suggests that exposures during critical or sensitive periods have particularly profound effects on health. Most research on this subject has focused on the occurrence of such windows early in life. We investigated whether perimenopause, a period of dramatic neuroendocrine changes at midlife, represents a sensitive period for response to stress by evaluating the relation of perceived stress to fibrinogen, a biomarker for inflammation. METHODS The study sample was composed of participants in the Study of Women's Health Across the Nation, a longitudinal study on women's health during the menopausal transition (n = 3,287). We fitted linear mixed effects models to estimate the longitudinal relationship between stress and menopausal stage and the association between stress and fibrinogen over the menopausal transition. RESULTS Women in early and late perimenopause reported perceiving higher levels of stress than premenopausal women (P < 0.05), adjusted for confounding variables. This increased perception of stress during perimenopause, however, was unrelated to changes in fibrinogen. CONCLUSIONS Although neuroendocrine changes during the menopausal transition may exacerbate the negative health effects of stress, the findings of this study do not suggest such interaction, as measured by changes in fibrinogen. The significant association observed between perceived stress and menopause status, however, may still have important implications, given prior literature linking perceived stress with numerous health outcomes.
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Lin T, Wang L, Guo J, Liu P, Chen L, Wei M, Li G. Association Between Serum LDL-C and ApoB and SYNTAX Score in Patients With Stable Coronary Artery Disease. Angiology 2018; 69:724-729. [PMID: 29310455 DOI: 10.1177/0003319717748771] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to examine the relationship between low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) B levels and the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) score (SS) in patients with stable angina pectoris. We enrolled 594 patients who were suspected to have coronary heart disease (CHD) and who underwent coronary angiography. Patients were divided into 4 groups based on the SS: normal (SS = 0, n = 154), low SS (SS ≤ 22, n = 210), intermediate SS (22 < SS < 32, n = 122), and high SS (SS ≥ 33, n = 63). Positive correlations between lipoprotein (a), LDL-C, ApoB, total cholesterol, and SS were significant ( r = 0.132, 0.632, 0.599, and 0.313, respectively; P < .01), whereas high-density lipoprotein cholesterol (HDL-C), ApoA1, and ApoA1/ApoB levels showed a significant negative correlation ( r = -0.29, -0.344, and -0.561, respectively; P < .01). Multivariate linear regression analysis revealed that LDL-C, ApoB, ApoA1/ApoB, fibrinogen (Fg), and HDL-C levels had an effect on SS (standardized regression coefficients were 0.41, 0.29, -0.12, 0.08, and -0.09, respectively; P < .05). In conclusion, LDL-C, ApoB, ApoA1/ApoB, Fg, and HDL-C levels affected the SS and were predictors of CHD complexity.
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Affiliation(s)
- Taiwu Lin
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Luzhao Wang
- 2 Department of Cardiology, Hanzhong Central Hospital, Hanzhong, China
| | - Jingbin Guo
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Liu
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Liheng Chen
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Mengqiu Wei
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Gongxin Li
- 1 Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Genetics of Atherosclerosis. Coron Artery Dis 2018. [DOI: 10.1016/b978-0-12-811908-2.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Hamer M, Malan NT, Scheepers K, Meiring M, Malan L, Känel RV. Procoagulant reactivity to laboratory acute mental stress in Africans and Caucasians, and its relation to depressive symptoms: The SABPA Study. Thromb Haemost 2017; 110:977-86. [DOI: 10.1160/th13-05-0383] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Accepted: 07/20/2013] [Indexed: 11/05/2022]
Abstract
SummaryThe risk of cardiovascular disease is dramatically increasing in Africans (black). The prothrombotic stress response contributes to atherothrombotic disease and is modulated by depressive symptoms. We examined coagulation reactivity to acute mental stress and its relation to psychological well-being in Africans relative to Caucasians (white). A total of 102 African and 165 Caucasian school teachers underwent the Stroop Color-Word Conflict test. Circulating levels of von Willebrand factor (VWF) antigen, fibrinogen, and D-dimer were measured before and after the Stroop. Cardiovascular reactivity measures were also obtained. All participants completed the Patient Health Questionnaire-9 and the General Health Questionnaire-28 for the assessment of depressive symptoms and total psychological distress, respectively. After controlling for covariates, resting levels of VWF, fibrinogen, and D-dimer were higher in Africans than in Caucasians (all p-values ≤0.006). Depressive symptoms and psychological distress were not significantly associated with resting coagulation measures. Stress reactivity in VWF (p<0.001) and fibrinogen (p=0.016), but not in D-dimer (p=0.27), were decreased in Africans relative to Caucasians with Africans showing greater reactivity of total peripheral resistance (p=0.017). Depressive symptoms, but not general psychological distress, were associated with greater VWF increase (p=0.029) and greater fibrinogen decrease (p=0.030) in Africans relative to Caucasians. In conclusion, Africans showed greater hypercoagulability at rest but diminished procoagulant reactivity to acute mental stress when compared with Caucasians. Ethnic differences in the vascular adrenergic stress response might partially explain this finding. Depressive symptoms were associated with exaggerated VWF reactivity in Africans relative to Caucasians. The clinical implications of these findings for Africans need further study.
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