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Romeo S, Vidal-Puig A, Husain M, Ahima R, Arca M, Bhatt DL, Diehl AM, Fontana L, Foo R, Frühbeck G, Kozlitina J, Lonn E, Pattou F, Plat J, Quaggin SE, Ridker PM, Rydén M, Segata N, Tuttle KR, Verma S, Roeters van Lennep J, Benn M, Binder CJ, Jamialahmadi O, Perkins R, Catapano AL, Tokgözoğlu L, Ray KK. Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement. Eur Heart J 2025:ehaf314. [PMID: 40331343 DOI: 10.1093/eurheartj/ehaf314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2025] Open
Abstract
Obesity rates have surged since 1990 worldwide. This rise is paralleled by increases in pathological processes affecting organs such as the heart, liver, and kidneys, here termed systemic metabolic disorders (SMDs). For clinical management of SMD, the European Atherosclerosis Society proposes a pathophysiology-based system comprising three stages: Stage 1, where metabolic abnormalities such as dysfunctional adiposity and dyslipidaemia occur without detectable organ damage; Stage 2, which involves early organ damage manifested as Type 2 diabetes, asymptomatic diastolic dysfunction, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage affecting multiple organs. Various forms of high-risk obesity, driven by maintained positive energy balance, are the most common cause of SMD, leading to ectopic lipid accumulation and insulin resistance. This progression affects various organs, promoting comorbidities such as hypertension and atherogenic dyslipidaemia. Genetic factors influence SMD susceptibility, and ethnic disparities in SMD are attributable to genetic and socioeconomic factors. Key SMD features include insulin resistance, inflammation, pre-diabetes, Type 2 diabetes, MASH, hypertension, CKD, atherogenic dyslipidaemia, and heart failure. Management strategies involve lifestyle changes, pharmacotherapy, and metabolic surgery in severe cases, with emerging treatments focusing on genetic approaches. The staging system provides a structured approach to understanding and addressing the multi-faceted nature of SMD, which is crucial for improving health outcomes. Categorization of SMD abnormalities by presence and progression is aimed to improve awareness of a multi-system trait and encourage a tailored and global approach to treatment, ultimately aiming to reduce the burden of obesity-related comorbidities.
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Affiliation(s)
- Stefano Romeo
- Department of Medicine, H7 Medicin, Huddinge, H7 Endokrinologi och Diabetes Romeo, Karolinska Institutet, 171 77 Stockholm, Sweden
- Department of Endocrinology, Karolinska University Hospital Huddinge, 141 57 Huddinge, Stockholm, Sweden
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Cardiology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Viale Europa, 88100 Catanzaro, Italy
| | - Antonio Vidal-Puig
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
- Centro de Investigacion Principe Felipe, C/ d'Eduardo Primo Yufera, 3, 46012 Valencia, Spain
- Cambridge University Nanjing Centre of Technology and Innovation, No. 23, Rongyue Road, Jiangbei New Area, Nanjing, Jiangsu, China
| | - Mansoor Husain
- Ted Rogers Centre for Heart Research, Department of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, Canada M5G 1M1
| | - Rexford Ahima
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
- Unit of Internal Medicine and Metabolic Diseases, Hospital Policlinico Umberto I, Rome, Italy
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA
| | - Luigi Fontana
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
- Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Roger Foo
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Singapore
- Cardiovascular Metabolic Disease Translational Research Programme, National University Health Systems, Singapore
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain
- Metabolic Research Laboratory, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
| | - Julia Kozlitina
- The Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Eva Lonn
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Francois Pattou
- Department of Endocrine and Metabolic Surgery, CHU Lille, University of Lille, Inserm, Institut Pasteur Lille, Lille, France
| | - Jogchum Plat
- Department of Nutrition and Movement Sciences, NUTRIM School of Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Susan E Quaggin
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Paul M Ridker
- Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Nicola Segata
- Department CIBIO, University of Trento, Trento, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Katherine R Tuttle
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
| | - Subodh Verma
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Jeanine Roeters van Lennep
- Department of Internal Medicine, Cardiovascular Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marianne Benn
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Rosie Perkins
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Alberico L Catapano
- Center for the Study of Atherosclerosis, IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Lale Tokgözoğlu
- Department of Cardiology, Hacettepe University Medical Faculty, Ankara, Turkey
| | - Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK
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Wang Y, Chen Z, Huo Z, Qin H, Fu P, Wu K, Zheng H, Cai Z, Wu W, Lan Y, He Z, Wu S, Chen Y. Metabolic Syndrome Evolution and Cardio-Kidney-Metabolic Multimorbidity: Implications for Targeted Prevention. JACC. ADVANCES 2025:101778. [PMID: 40402123 DOI: 10.1016/j.jacadv.2025.101778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/27/2025] [Accepted: 03/10/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Metabolic syndrome (MetS) is an important criterion for clinicians in assessing cardio-kidney-metabolic diseases, yet the association between longitudinal evolution of MetS and cardio-kidney-metabolic disease multimorbidity remains unclear. OBJECTIVES The purpose of this study was to investigate the extent of increased multimorbidity risk in individuals recovered from MetS and investigate the mediation of Life's Essential 8 (LE8) score on MetS transition patterns and risk of multimorbidity. METHODS A cohort study using data from the Kailuan study (2006-2010) was conducted. Cox regression models were used to assess the association of MetS evolution with multimorbidity and its components. Survival mediation analysis was used to calculate the mediation proportion. RESULTS A total of 36,201 participants were included. During a median follow-up of 12.02 years, 930 participants developed a multimorbidity. Not only the persistent metabolic disorder group (HR: 2.95 [95% CI: 2.41-3.60]) and the MetS progression group (HR: 1.70 [95% CI: 1.39-2.06]) but also the MetS recovery group (HR: 1.87 [95% CI: 1.48-2.36]) were associated with an elevated risk compared with the sustained metabolic health group. LE8 score mediated the association between MetS progress, MetS recover, and persistent MetS and incident cardio-kidney-metabolic multimorbidity, accounting for 24.1% (95% CI: 11.4-44.0), 25.7% (95% CI: 16.4-37.7), and 19.5% (95% CI: 13.7-26.9) of the proportion mediated, respectively. CONCLUSIONS Both current MetS and a history of metabolic disorder, even in the absence of current MetS, may increase the risk of multimorbidity. Prevention targeting the LE8 may help reduce the risk and provide new perspectives for early intervention.
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Affiliation(s)
- Yuxian Wang
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zekai Chen
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Zhenyu Huo
- School of Public Health, North China University of Science and Technology, Tangshan, China; Department of Cardiology, Kailuan General Hospital, Tangshan, China
| | - Hailun Qin
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Peng Fu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Kuangyi Wu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Huancong Zheng
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zefeng Cai
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Weiqiang Wu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yulong Lan
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhen He
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Shouling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, China.
| | - Youren Chen
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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Crespo-Masip M, Goodluck HA, Kim YC, Oe Y, Roach AM, Kanoo S, Lopez N, Zhang H, Badal SS, Vallon V. ASK1 limits kidney glucose reabsorption, growth, and mid-late proximal tubule KIM-1 induction when diabetes and Western diet are combined with SGLT2 inhibition. Am J Physiol Renal Physiol 2025; 328:F662-F675. [PMID: 40152436 DOI: 10.1152/ajprenal.00031.2025] [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: 01/23/2025] [Revised: 02/18/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025] Open
Abstract
Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor (ASK1i) that attenuated the decline in creatinine-based estimated GFR in humans with type 2 diabetes and kidney disease but increased the rate of acute kidney injury. This study explored the individual and combined kidney effects of selonsertib and the antihyperglycemic sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in Western diet-fed male Akita mice, a murine model of early type 1 diabetes mellitus showing signs of systemic but no kidney inflammation. ASK1i reduced elevated plasma levels of proinflammatory cytokines/chemokines (IL-6, MCP1/CCL2, KC/CXCL1, and IP-10/CXCL10) without significantly changing hyperglycemia, glomerular hyperfiltration, and albuminuria or affecting the blood glucose and glomerular hyperfiltration-lowering effect of SGLT2i. A potential sign of tubular stress, SGLT2i modestly upregulated kidney cortex transcription of proinflammatory and profibrotic genes and distal tubule injury marker Ngal. Adding ASK1i to SGLT2i lowered the transcription of many of these genes, including Ngal. However, ASK1i enhanced kidney glucose reabsorption independent of SGLT2i, and combined ASK1i + SGLT2i increased kidney weight by 30%. This was associated with and positively correlated with the upregulation of the tubular stress/injury marker KIM-1, primarily in the mid-to-late proximal tubule. Combined ASK1i + SGLT2i increased the tubular injury score but not signs of kidney inflammation or fibrosis beyond a robust increase in kidney mRNA expression of Il6, Ccl2 (Mcp1), and Timp1, associated with increased plasma IL-6 levels. The data support the hypothesis that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.NEW & NOTEWORTHY Selonsertib is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor that attenuated creatinine-based eGFR decline in humans with type 2 diabetes and kidney disease but increased acute kidney injury rates. Here, we report evidence in a murine model of early type 1 diabetes mellitus that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.
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MESH Headings
- Animals
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Male
- Kidney Tubules, Proximal/drug effects
- Kidney Tubules, Proximal/metabolism
- Kidney Tubules, Proximal/pathology
- Kidney Tubules, Proximal/enzymology
- MAP Kinase Kinase Kinase 5/metabolism
- MAP Kinase Kinase Kinase 5/antagonists & inhibitors
- Hepatitis A Virus Cellular Receptor 1/metabolism
- Diet, Western/adverse effects
- Benzhydryl Compounds/pharmacology
- Glucosides/pharmacology
- Mice, Inbred C57BL
- Diabetic Nephropathies/enzymology
- Mice
- Blood Glucose/metabolism
- Blood Glucose/drug effects
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/enzymology
- Diabetes Mellitus, Type 1/genetics
- Renal Reabsorption/drug effects
- Disease Models, Animal
- Glucose/metabolism
- Sodium-Glucose Transporter 2
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Affiliation(s)
- Maria Crespo-Masip
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Helen A Goodluck
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Young Chul Kim
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Yuji Oe
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Allie M Roach
- Gilead Sciences, Inc., Foster City, California, United States
| | - Sadhana Kanoo
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Natalia Lopez
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Haiyan Zhang
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
| | - Shawn S Badal
- Gilead Sciences, Inc., Foster City, California, United States
| | - Volker Vallon
- Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California San Diego, California, United States
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Lin Y, Yi C, Cao P, Lin J, Chen W, Mao H, Yang X, Guo Q. Visit-to-visit blood pressure variability and clinical outcomes in peritoneal dialysis - based on machine learning algorithms. Hypertens Res 2025; 48:1702-1715. [PMID: 39984751 DOI: 10.1038/s41440-025-02142-x] [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: 05/09/2024] [Revised: 01/03/2025] [Accepted: 01/24/2025] [Indexed: 02/23/2025]
Abstract
This study aims to investigate the association between visit-to-visit blood pressure variability (VVV) in early stage of continuous ambulatory peritoneal dialysis (CAPD) and long-term clinical outcomes, utilizing machine learning algorithms. Patients who initiated CAPD therapy between January 1, 2006, and December 31, 2009 were enrolled. VVV parameters were collected during the first six months of CAPD therapy. Patient follow-up extended to December 31, 2021, for up to 15.8 years. The primary outcome was the occurrence of a three-point major adverse cardiovascular event (MACE). Four machine learning algorithms and competing risk regression analysis were applied to construct predictive models. A total of 666 participants were included in the analysis with a mean age of 47.9 years. One of the six VVV parameters, standard deviation of diastolic blood pressure (SDDBP), was finally enrolled into the MACE predicting model and mortality predicting model. In the MACE predicting model, higher SDDBP was associated with 99% higher MACE risk. The association between SDDBP and MACE risk was attenuated by better residual renal function (p for interaction <0.001). In the mortality predicting model, higher SDDBP was associated with 46% higher mortality risk. This cohort study discerned that high SDDBP in early stage of CAPD indicated increased long-term MACE and mortality risks.
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Affiliation(s)
- Yan Lin
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
- Yunkang School of Medicine and Health, Nanfang College, Guangzhou, China
| | - Chunyan Yi
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
| | - Peiyi Cao
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
| | - Jianxiong Lin
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China
| | - Xiao Yang
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
| | - Qunying Guo
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University and Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
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Ren Y, Chen Y, Zheng W, Kong W, Liao Y, Zhang J, Wang M, Zeng T. The effect of GLP-1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta-analysis. Diabetes Obes Metab 2025. [PMID: 40230207 DOI: 10.1111/dom.16366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 04/16/2025]
Abstract
AIM To investigate whether the antidiabetic agent glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can exert anti-inflammatory effects while lowering blood glucose, we performed a meta-analysis and systematic review. METHODS We searched 4 online databases (Medline, Embase, Cochrane Library and the Web of Science) for randomised controlled trials (RCTs) that examined changes after GLP-1RAs intervention in commonly accepted biomarkers of inflammation: C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1(MCP-1) and advanced glycation end products (AGEs). RESULTS This meta-analysis included 52 eligible RCTs (n = 4734) with a median follow-up of 24 weeks, a mean age of 54.13 years, 44.46% females, body mass index (BMI) 29.80 kg/m2, glycated haemoglobin (HbA1c) 8.28% and diabetes duration 7.27 years. GLP-1 RAs treatment, compared to placebo or conventional diabetes therapies (including oral medicine and insulin), resulted in significant reductions in CRP, TNF-α, IL-6, IL-1β and leptin (standard mean difference [SMD] -0.63 [-1.03, -0.23]; SMD -0.92 [-1.57, -0.27]; SMD -0.76 [-1.32, -0.20], SMD -3.89 [-6.56, -1.22], SMD -0.67 [-1.09, -0.26], respectively), as well as significant increases in adiponectin (SMD 0.69 [0.19, 1.19]). CONCLUSIONS Our meta-analysis demonstrates that GLP-1 RAs exert significant anti-inflammatory effects in patients with T2DM. Our findings provide important insights that may guide the therapeutic application of GLP-1 RAs and inform the development of related therapies.
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Affiliation(s)
- Yifan Ren
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Yuzhang Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Wenbin Zheng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Yunfei Liao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Jiaoyue Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Meng Wang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Tianshu Zeng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
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6
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Schepanski S, Ngoumou GB, Koch AK, Schröter M, Roehle R, Seifert G. Mind-body therapies and their interplay with the immune system in children and adolescents: a protocol for a systematic review and meta-analysis. Syst Rev 2025; 14:78. [PMID: 40186267 PMCID: PMC11969903 DOI: 10.1186/s13643-025-02812-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/11/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Chronic inflammation is a critical public health concern that, in children and adolescents, increases the long-term risk of a variety of different health issues. While mind-body therapies like yoga, meditation, and acupuncture have shown promise in modulating immune responses in adults, their safety and effectiveness in pediatric populations remain underexplored. This protocol outlines the methodology for a systematic review and meta-analysis aimed at evaluating the effects of mind-body therapies on immune modulation in children and adolescents. METHODS This systematic review and meta-analysis will follow PRISMA 2020 guidelines. We will include randomized controlled trials, non-randomized controlled trials, cohort studies, and case-control studies that examine the relationship between mind-body therapies and immune markers in pediatric populations. Electronic searches will be conducted in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and the Cochrane Library, supplemented by trial registries. Risk of bias will be assessed using the Cochrane Risk of Bias Tool (RoB 1), the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I), and the Newcastle-Ottawa Scale (NOS). Two independent reviewers will screen studies, extract data, and assess study quality, with a third reviewer resolving any discrepancies. Results will be synthesized both narratively and through meta-analysis using R software. DISCUSSION The review will evaluate the effectiveness and safety of mind-body therapies on immune markers in children and adolescents. The synthesized evidence will guide clinical practice and public health policies in integrating mind-body therapies into pediatric care. The findings will also provide a foundation for future research and policymaking in this area. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42024546585.
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Affiliation(s)
- Steven Schepanski
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charité Competence Center for Traditional and Integrative Medicine (CCCTIM), Berlin, Germany.
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatrics, Division of Oncology and Hematology, Berlin, Germany.
| | - Gonza B Ngoumou
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charité Competence Center for Traditional and Integrative Medicine (CCCTIM), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatrics, Division of Oncology and Hematology, Berlin, Germany
| | - Anna Katharina Koch
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charité Competence Center for Traditional and Integrative Medicine (CCCTIM), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatrics, Division of Oncology and Hematology, Berlin, Germany
| | - Marleen Schröter
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charité Competence Center for Traditional and Integrative Medicine (CCCTIM), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatrics, Division of Oncology and Hematology, Berlin, Germany
| | - Robert Roehle
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute for Biometry and Clinical Epidemiology, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Clinical Trial Office, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Georg Seifert
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charité Competence Center for Traditional and Integrative Medicine (CCCTIM), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatrics, Division of Oncology and Hematology, Berlin, Germany
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7
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Duan Y, Qiu M, Na K, Liu D, Zhou S, Xu Y, Qi Z, Liu H, Xu K, Wang X, Li J, Li Y, Han Y. Inflammatory and Bleeding Risks on Clinical Outcomes in Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention. Thromb Haemost 2025. [PMID: 39904360 DOI: 10.1055/a-2531-3268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
This study aimed to evaluate the impact of systemic inflammation burden using high-sensitivity C-reactive protein (hsCRP) and long-term prognosis in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) stratified by bleeding risk status.Consecutive patients admitted for ACS and who received PCI between March 2016 and March 2022 were enrolled in the analysis. Elevated systemic inflammation was defined as hsCRP >2 mg/L, and high bleeding risk (HBR) was defined the Academic Research Consortium (ARC)-HBR criteria. The primary outcome was ischemic events at 12 months, composed of cardiac death, myocardial infarction, and/or stroke. The main secondary outcomes included all-cause death, and Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding and types 3 and 5 bleeding.Of 15,013 patients, 4,606 (30.7%) were qualified as HBR and 8,395 (55.9%) had hsCRP >2 mg/L. Elevated hsCRP was consistently associated with higher risk of ischemic events in both HBR (adjusted hazard ratio [aHR]: 1.20; 95% confidence interval [CI]: 0.91-1.58) and non-HBR (aHR: 1.34; 95% CI: 1.01-1.78) subgroups (P interaction = 0.755). Although the incidence of bleeding events was higher in HBR patients, an elevated hsCRP level was not associated with bleeding events regardless of HBR status. Restricted cubic spline regression represented an inverse J-shaped relation between hsCRP and non-HBR for ischemic events (P nonlinearity <0.001) and all-cause death (P nonlinearity = 0.003).Regardless of HBR status, high levels of hsCRP were associated with an increased risk of ischemic events and all-cause death in ACS patients following PCI, but not for bleeding.
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Affiliation(s)
- Yixuan Duan
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
- The Department of Cardiology, Air Force Medical University, Xijing Hospital, Xi'an, Shaanxi, China
| | - Miaohan Qiu
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Kun Na
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Daoshen Liu
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
- The Department of Cardiology, Air Force Medical University, Xijing Hospital, Xi'an, Shaanxi, China
| | - Shangxun Zhou
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
- The Department of Cardiology, Air Force Medical University, Xijing Hospital, Xi'an, Shaanxi, China
| | - Ying Xu
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Zizhao Qi
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Haiwei Liu
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Kai Xu
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Xiaozeng Wang
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Jing Li
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Yi Li
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
| | - Yaling Han
- Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, Shenyang, China
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8
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Pesce G, Gusto G, Johansen P, Khachatryan A, Lopez-Ledesma B, Vukmirica J, Cases A. Systemic inflammation prevalence in patients with atherosclerotic cardiovascular disease and chronic kidney disease: a population-based study using a nationwide primary care database in Spain. Front Cardiovasc Med 2025; 12:1538466. [PMID: 40104140 PMCID: PMC11913838 DOI: 10.3389/fcvm.2025.1538466] [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] [Received: 12/02/2024] [Accepted: 02/04/2025] [Indexed: 03/20/2025] Open
Abstract
Introduction Systemic inflammation is recognised as a critical driver of atherosclerotic cardiovascular disease (ASCVD), especially in patients with comorbid chronic kidney disease (CKD). This study aims to assess the prevalence of systemic inflammation in the ASCVD population in Spain. Methods Outpatient electronic medical records from The Health Improvement Network (THIN®) database were used to identify patients with ASCVD and a C-reactive protein (CRP) measurement ≥1 between January 2014 and July 2023 in Spain. The proportion of patients with systemic inflammation (defined as CRP ≥ 2 mg/L) was estimated at the first CRP measurement (index date) and at the end of the study. The patients' characteristics, comorbidities, and drug dispensation in the prior 12 months were reported by systemic inflammation status at the index date. Results Overall, 15,798 patients with ASCVD were included in the study (mean age: 71.1 years; 57% men), of whom 34% had CKD. The proportion of patients with systemic inflammation at the index date was 58% (65% among CKD patients) and 56% (62% among CKD patients) at the end of the study. Patients with systemic inflammation were more frequently smokers, obese, with comorbidities, and had higher low-density lipoprotein cholesterol and triglycerides levels than patients without systemic inflammation. Overall, patients with ASCVD and systemic inflammation used statins and aspirin less frequently compared to patients without systemic inflammation, while they used antibiotics, anticoagulants, and antihypertensives more frequently. Conclusion Systemic inflammation prevalence is high among patients with ASCVD in Spain, especially among patients with comorbid CKD. Therapeutic strategies focused on targeting systemic inflammation may have beneficial effects in reducing the burden of ASCVD.
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Affiliation(s)
- Giancarlo Pesce
- Real-World Evidence & Modeling Solutions, Certara, Milan, Italy
| | - Gaelle Gusto
- Real-World Evidence & Modeling Solutions, Certara, Paris, France
| | | | - Artak Khachatryan
- Real-World Evidence & Modeling Solutions, Certara, London, United Kingdom
| | | | | | - Aleix Cases
- Servicio de Nefrologia, Hospital Clínic, Barcelona, Spain
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9
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Kanbay M, Copur S, Yilmaz ZY, Mallamaci F, Zoccali C. Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope? J Nephrol 2025; 38:403-414. [PMID: 39453604 DOI: 10.1007/s40620-024-02117-0] [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: 03/12/2024] [Accepted: 09/17/2024] [Indexed: 10/26/2024]
Abstract
Anemia of chronic kidney disease is a multifactorial condition secondary to various etiologies, including nutritional deficiencies, chronic inflammation, erythropoietin deficiency or resistance, bone marrow suppression, iron deficiency and adverse drug effects. The major therapeutic intervention for anemia among chronic kidney disease patients is erythropoiesis-stimulating agents. However, a limitation of erythropoiesis-stimulating agents is the risk for thromboembolic events, hypertension, seizures, solid organ malignancies and hyporesponsiveness. A novel interleukin-6 monoclonal antibody, ziltivekimab, has been evaluated for managing anemia in chronic kidney disease patients in pilot clinical trials with promising outcomes, including an improvement in hemoglobin levels and reduction of inflammatory parameters. These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. Furthermore, potentially beneficial effects on serum lipid profile have been reported, leading to the hypothesis of a favorable impact of the drug on atherosclerotic complications. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, 34010, Istanbul, Turkey.
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Zeynep Y Yilmaz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Francesca Mallamaci
- Nephrology, Dialysis and Transplantation Unit Azienda Ospedaliera "Bianchi-Melacrino-Morelli" & CNR-IFC, Institute of Clinical Physiology, Research Unit of Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Reggio Calabria, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, NY, USA
- Associazione Ipertensione Nefrologia Trapianto Renal (IPNET), C/O Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
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10
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Toso A, Leoncini M, Maioli M, Villani S, Bellandi F. Biomarkers of residual risk and all-cause mortality after acute coronary syndrome. Am J Prev Cardiol 2025; 21:100934. [PMID: 39896052 PMCID: PMC11787588 DOI: 10.1016/j.ajpc.2025.100934] [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: 09/30/2024] [Revised: 01/09/2025] [Accepted: 01/13/2025] [Indexed: 02/04/2025] Open
Abstract
Background Adverse cardiovascular events often recur after acute coronary syndrome (ACS), despite secondary prevention measures. Residual risk involves various inflammatory, metabolic and renal factors as well as lipid and thrombotic processes. This cohort study investigates the relationship between four risk biomarkers at 1 month after ACS and all-cause death within 3 years in patients treated with early invasive strategy and high-intensity statins from admission. Methods Levels of residual risk for the biomarkers were: low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dl; high-sensitivity C reactive protein (hs-CRP) ≥ 2 mg/l; glycosylated hemoglobin (HbA1c) ≥ 7% in diabetic and ≥ 5.7% in non-diabetic patients; decrease in estimated glomerular filtration rate (eGFR) ≥ 25% compared to baseline. The association between the four biomarkers and all-cause death within 3 years was evaluated with Cox proportional analysis. Results This study included 1099 patients (68±12 years; 70.3% males). At 1 month the majority of patients had levels of LDL-C, hs-CRP and/or HbA1c above the risk cut-points, and only 7% of cases presented reduced eGFR. Reduced eGFR and hs-CRP ≥ 2 mg/l at 1 month were the sole independent biomarker predictors of 3-year mortality (adjusted hazard ratios 3.03 and 2.66, respectively). Conclusions In this population on high-intensity statin therapy only hsCRP and eGFR were independently associated with medium-term mortality. Diversification of secondary preventive measures based on routine evaluations of inflammation and kidney function markers, not only LDL-C, could lead to better targeted reduction of residual risk after ACS.
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Affiliation(s)
- Anna Toso
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Mario Leoncini
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Mauro Maioli
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Simona Villani
- Section of Biostatistics and Clinical Epidemiology, Department of Public Health, Experimental and Forensic Medicine, Pavia University, Pavia, Italy
| | - Francesco Bellandi
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
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11
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Wu Q, Zeng Y, Geng K, Guo M, Teng FY, Yan PJ, Lei Y, Long Y, Jiang ZZ, Law BYK, Xu Y. The role of IL-1 family cytokines in diabetic cardiomyopathy. Metabolism 2025; 163:156083. [PMID: 39603339 DOI: 10.1016/j.metabol.2024.156083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.
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Affiliation(s)
- Qi Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Pathology, and Luzhou Key Laboratory of Precision Pathology Diagnosis for Serious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yan Zeng
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Kang Geng
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Department of Plastic and burns surgery, National Key Clinical Construction Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Man Guo
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Fang-Yuan Teng
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Pi-Jun Yan
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yi Lei
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yang Long
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Zong-Zhe Jiang
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Yong Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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12
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Kurts C, von Vietinghoff S, Krebs CF, Panzer U. Kidney immunology from pathophysiology to clinical translation. Nat Rev Immunol 2025:10.1038/s41577-025-01131-y. [PMID: 39885266 DOI: 10.1038/s41577-025-01131-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/02/2025] [Indexed: 02/01/2025]
Abstract
Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the identification of distinct intrarenal immunological niches and characterization of kidney disease endotypes according to the underlying molecular immunopathology, as well as a better understanding of the pathological roles for T cells, mononuclear phagocytes and B cells and the renal elements they target. These insights have improved the diagnosis of kidney disease. Here, we discuss new developments in our understanding of kidney immunology, focusing on immune mechanisms of disease and their translational implications for the diagnosis and treatment of kidney disease. We also describe the immune-mediated crosstalk between the kidney and other organs that influences kidney disease and extrarenal inflammation.
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Affiliation(s)
- Christian Kurts
- Institute of Molecular Medicine and Experimental Immunology, University Hospital, Bonn, Germany.
- Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
| | - Sibylle von Vietinghoff
- Nephrology Section, University Hospital Bonn, Medical Clinic and Polyclinic I, Bonn, Germany
| | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf Panzer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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13
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Razi B, Imani D, Aslani S, Reiner Z, Sahebkar A. Statin Therapy and C-reactive Protein in Patients with Kidney Disease: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Curr Drug Targets 2025; 26:132-145. [PMID: 39318006 DOI: 10.2174/0113894501302428240909150925] [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: 03/27/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Increased levels of inflammation markers in patients with kidney disease, particularly chronic kidney disease (CKD) is an important risk factor. This study explored whether the effect of more potent statins on inflammation in CKD patients is dose-dependent, whether there is any difference between the hydrophilic and lipophilic statins concerning their effects on inflammation markers in patients with CKD, and whether the duration of treatment with statins has any effect on markers of inflammation in these patients. METHODS A systematic literature search of Scopus, PubMed, and ISI Web of Science databases from inception to August 2022 was performed. Eligible studies were stratified based on a target population, intervention duration, dosage and type of statins (high intensity statin and moderate/ low intensity), and solubility of statins. Publication bias was evaluated using Begg's regression asymmetry test for visual inspection of funnel plots. Non-linear effects of dosage of statins and treatment duration were also examined by fractional polynomial modeling. RESULTS Meta-analysis of 10 RCTs (12 studies) on 264 patients with kidney disease and 254 controls showed a significant hs-CRP lowering effect of the dose of statin. Both hydrophilic and lipophilic statins had significant hs-CRP lowering effects. Meta-analysis of 6 publications (7 studies) evaluating the impact of statins on CRP in 235 patients and 197 control subjects showed a significant negative association between treatment with statins group and CRP levels. CONCLUSION Statin treatment decreases significantly the levels of CRP and hs-CRP in patients with kidney disease.
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Affiliation(s)
- Bahman Razi
- Department of Laboratory Sciences and Hematology, Faculty of Paramedicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Danyal Imani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Zeljko Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, University of Zagreb, Kišpatićeva 12, Zagreb, Croatia
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Liu Y, Li Z, Xu Y, Mao H, Huang N. Uric Acid and Atherosclerosis in Patients with Chronic Kidney Disease: Recent Progress, Mechanisms, and Prospect. KIDNEY DISEASES (BASEL, SWITZERLAND) 2025; 11:112-127. [PMID: 40124130 PMCID: PMC11928073 DOI: 10.1159/000543781] [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: 10/04/2024] [Accepted: 01/16/2025] [Indexed: 03/25/2025]
Abstract
Background Chronic kidney disease (CKD) is a prevalent global health concern, significantly linked to increased cardiovascular morbidity and mortality. Among various risk factors, uric acid (UA) has emerged as a potentially modifiable contributor to cardiovascular complications in CKD patients. Summary Elevated serum uric acid levels frequently occur in individuals with CKD and are associated with the development of atherosclerosis (AS). Uric acid has been demonstrated to exacerbate inflammatory processes, promote oxidative stress, and cause endothelial dysfunction, which are critical factors that drive the formation of atherosclerotic plaques. Furthermore, high uric acid levels can worsen renal function, establishing a detrimental cycle that amplifies cardiovascular risk. Key Messages This review investigates the complex interconnection between UA and AS in patients with CKD, highlighting the underlying mechanisms and therapeutic considerations. A more profound comprehension of this relationship is essential for enhancing cardiovascular health and outcomes in this vulnerable population.
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Affiliation(s)
- Yuchu Liu
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Zeyu Li
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yuanwen Xu
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Naya Huang
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
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15
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Cortada E, Yao J, Xia Y, Dündar F, Zumbo P, Yang B, Rubio-Navarro A, Perder B, Qiu M, Pettinato AM, Homan EA, Stoll L, Betel D, Cao J, Lo JC. Cross-species single-cell RNA-seq analysis reveals disparate and conserved cardiac and extracardiac inflammatory responses upon heart injury. Commun Biol 2024; 7:1611. [PMID: 39627536 PMCID: PMC11615278 DOI: 10.1038/s42003-024-07315-x] [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: 08/12/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
The immune system coordinates the response to cardiac injury and controls regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Adult mice and humans lack the ability to fully recover while adult zebrafish spontaneously regenerate after heart injury. Here we profile the inflammatory response to heart cryoinjury in zebrafish and coronary artery ligation in mouse using single cell transcriptomics. We interrogate the extracardiac reaction to cardiomyocyte necrosis to assess the specific peripheral tissue and immune cell reaction to chronic stress. Cardiac macrophages play a critical role in determining tissue homeostasis by healing versus scarring. We identify distinct transcriptional clusters of monocytes/macrophages (mono/Mϕ) in each species and find analogous pairs in zebrafish and mice. However, the reaction to myocardial injury is largely disparate between mice and zebrafish. The dichotomous response to heart damage between the murine and zebrafish mono/Mϕ and/or the presence of distinct zebrafish mono/Mϕ subtypes may underlie the impaired regenerative process in adult mammals and humans. Our study furnishes a direct cross-species comparison of immune responses between regenerative and profibrotic myocardial injury models, providing a useful resource to the fields of regenerative biology and cardiovascular research.
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Affiliation(s)
- Eric Cortada
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Jun Yao
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Yu Xia
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Friederike Dündar
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Paul Zumbo
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Boris Yang
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Alfonso Rubio-Navarro
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Björn Perder
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Miaoyan Qiu
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Anthony M Pettinato
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
| | - Edwin A Homan
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Lisa Stoll
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Doron Betel
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
- Institute for Computational Biomedicine, Division of Hematology and Medical, Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
| | - Jingli Cao
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA.
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.
| | - James C Lo
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA.
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA.
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16
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Heerspink HJ, Perkovic V, Tuttle KR, Pergola PE, Mahaffey KW, Patel UD, Ishida JH, Kuo A, Chen F, Kustra R, Petrovic V, Rossing P, Kashihara N, Chertow GM. Selonsertib in Patients with Diabetic Kidney Disease: A Phase 2b Randomized Active Run-In Clinical Trial. J Am Soc Nephrol 2024; 35:1726-1736. [PMID: 39018154 PMCID: PMC11617472 DOI: 10.1681/asn.0000000000000444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 07/11/2024] [Indexed: 07/19/2024] Open
Abstract
Key Points In a randomized, placebo-controlled, phase 2b study, we compared the effects of selonsertib with placebo on eGFR decline in people with type 2 diabetes and CKD. Patients taking selonsertib had slower eGFR decline but were more likely to reach a composite kidney outcome and report AKI. A larger trial with longer-term follow-up would more precisely assess the relative benefits and risks of selonsertib in this setting. Background Selonsertib is an apoptosis signal–regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. Methods We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min per 1.73 m2 with urine albumin-creatinine ratio 150–5000 mg/g on maximum tolerated dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. To account for an acute selonsertib-related decrease in serum creatinine–based eGFR (eGFRcr), patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFRcr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks of follow-up. The primary efficacy outcome was the difference in eGFRcr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided P = 0.30. We also evaluated kidney clinical events (eGFRcr ≥40% decline from pre–run-in baseline, kidney failure, or death due to kidney disease) and adverse events. Results In total, 310 patients were randomized (selonsertib n =154, placebo n =156; 68% male, mean age 65 years, mean baseline eGFRcr 35 ml/min per 1.73 m2). Mean difference between selonsertib and placebo eGFRcr slopes at week 84 was 1.20 ml/min per 1.73 m2 per year (95% confidence interval, −0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% confidence interval, −6.3% to 15.9%). The most common investigator-reported adverse event was AKI (selonsertib 11.0/100 and placebo 5.9/100 patient-years). Conclusions Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported AKI. Clinical Trial registry name and registration number: Study to Evaluate the Efficacy and Safety of Selonsertib in Participants With Moderate to Advanced Diabetic Kidney Disease (MOSAIC), NCT04026165 .
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Affiliation(s)
- Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center, University of Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, New South Wales, Australia
- UNSW Sydney, Sydney, New South Wales, Australia
| | | | - Katherine R. Tuttle
- Nephrology Division, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, Washington
| | | | - Kenneth W. Mahaffey
- Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California
| | - Uptal D. Patel
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Julie H. Ishida
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Albert Kuo
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Fang Chen
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Robert Kustra
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Vladimir Petrovic
- Department of Clinical Development, Gilead Sciences, Inc., Foster City, California
| | - Peter Rossing
- Complications Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - Glenn M. Chertow
- Departments of Medicine, Epidemiology and Population Health, and Health Policy, Stanford University School of Medicine, Stanford, California
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Elías-López D, Vedel-Krogh S, Kobylecki CJ, Wadström BN, Nordestgaard BG. Impaired Renal Function With Higher Remnant Cholesterol Related to Risk of Atherosclerotic Cardiovascular Disease: A Cohort Study. Arterioscler Thromb Vasc Biol 2024; 44:2647-2658. [PMID: 39445427 DOI: 10.1161/atvbaha.124.321387] [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: 06/13/2024] [Accepted: 10/01/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Chronic kidney disease confers a high risk of atherosclerotic cardiovascular disease (ASCVD), partly due to hyperlipidemia. Although statins reduce the risk of ASCVD in chronic kidney disease, residual risk persists. We investigated whether higher remnant cholesterol is associated with an increased risk of ASCVD in statin users and nonusers with impaired renal function. METHODS We included 107 925 individuals from CGPS (Copenhagen General Population Study) initiated in 2003 to 2015, of whom 10 427 had impaired renal function (estimated glomerular filtration rate, <60 mL/min per 1.73 m2). Remnant cholesterol was calculated from a standard lipid profile. ASCVD was myocardial infarction, coronary heart disease death, ischemic stroke, coronary artery bypass graft, or percutaneous coronary intervention extracted from Danish nationwide health registries from baseline through 2018; individuals with events before the start of follow-up were excluded from relevant analysis. RESULTS In individuals with impaired renal function during up to 15 years of follow-up, 597 were diagnosed with myocardial infarction, 618 with ischemic stroke, and 1182 with ASCVD. In these individuals, a 1-mmol/L (39 mg/dL) higher remnant cholesterol level was associated with multivariable-adjusted hazard ratios of 1.22 (95% CI, 1.05-1.42) for myocardial infarction, 1.16 (95% CI, 0.97-1.38) for ischemic stroke, and 1.21 (95% CI, 1.08-1.36) for ASCVD. Corresponding hazard ratios for ASCVD were 1.40 (95% CI, 1.07-1.83) in statin users and 1.16 (95% CI, 1.01-1.34) in nonusers. Of the 1.36-fold excess risk of ASCVD in impaired versus normal renal function, elevated remnant cholesterol and elevated LDL (low-density lipoprotein) cholesterol explained 25% (95% CI, 2.5%-47%) and 0% in statin users and 8.3% (95% CI, 2.4%-14%) and 14% (95% CI, 6.4%-22%) in nonusers, respectively. CONCLUSIONS Our results suggest that higher remnant cholesterol is a good marker of increased risk of ASCVD in individuals with impaired renal function, while higher LDL cholesterol may not be. Patients with chronic kidney disease who have high levels of remnant cholesterol are identifiable through higher non-HDL (high-density lipoprotein) cholesterol or apoB levels.
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Affiliation(s)
- Daniel Elías-López
- Department of Clinical Biochemistry (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- The Copenhagen General Population Study (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- Department of Endocrinology and Metabolism and Research Center of Metabolic Diseases, National Institute of Medical Sciences and Nutrition Salvador Zubirán, México City, México (D.E.-L.)
| | - Signe Vedel-Krogh
- Department of Clinical Biochemistry (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- The Copenhagen General Population Study (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (S.V.-K., B.N.W., B.G.N.)
| | - Camilla Jannie Kobylecki
- Department of Clinical Biochemistry (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- The Copenhagen General Population Study (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
| | - Benjamin Nilsson Wadström
- Department of Clinical Biochemistry (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- The Copenhagen General Population Study (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (S.V.-K., B.N.W., B.G.N.)
| | - Børge Grønne Nordestgaard
- Department of Clinical Biochemistry (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- The Copenhagen General Population Study (D.E.-L., S.V.-K., C.J.K., B.N.W., B.G.N.), Copenhagen University Hospital, Herlev Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (S.V.-K., B.N.W., B.G.N.)
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18
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Chermiti R, Burtey S, Dou L. Role of Uremic Toxins in Vascular Inflammation Associated with Chronic Kidney Disease. J Clin Med 2024; 13:7149. [PMID: 39685608 DOI: 10.3390/jcm13237149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Cardiovascular disease (CVD) is a major complication of chronic kidney disease (CKD), despite improvements in patient care. Vascular inflammation is a crucial process in the pathogenesis of CVD and a critical factor in the cardiovascular complications in CKD patients. CKD promotes a pro-inflammatory environment that impacts the vascular wall, leading to endothelial dysfunction, increased oxidative stress, and vascular remodeling. The uremic toxins that accumulate as kidney function declines are key contributors to vascular inflammatory processes. Our review will examine how CKD leads to vascular inflammation, paving the way to CVD. We will provide an overview of the mechanisms of vascular inflammation induced by uremic toxins, with a particular focus on those derived from tryptophan metabolism. These toxins, along with their receptor, the aryl hydrocarbon receptor (AHR), have emerged as key players linking inflammation and thrombosis. A deeper understanding of the mechanisms underlying inflammation in CKD, particularly those driven by uremic toxins, could reveal valuable therapeutic targets to alleviate the burden of CVD in CKD patients.
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Affiliation(s)
- Rania Chermiti
- C2VN, Aix-Marseille University, INSERM, INRAE, 13005 Marseille, France
| | - Stéphane Burtey
- C2VN, Aix-Marseille University, INSERM, INRAE, 13005 Marseille, France
- Centre de Néphrologie et Transplantation Rénale, APHM, Hôpital Conception, 13005 Marseille, France
| | - Laetitia Dou
- C2VN, Aix-Marseille University, INSERM, INRAE, 13005 Marseille, France
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19
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Crea F. Focus on the evolving methodologies of trials, on inflammation in atherosclerotic cardiovascular disease, and on abdominal aortic aneurysms. Eur Heart J 2024; 45:4671-4675. [PMID: 39566898 DOI: 10.1093/eurheartj/ehae789] [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: 11/22/2024] Open
Affiliation(s)
- Filippo Crea
- Center of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
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Caturano A, Galiero R, Rocco M, Tagliaferri G, Piacevole A, Nilo D, Di Lorenzo G, Sardu C, Russo V, Vetrano E, Monda M, Marfella R, Rinaldi L, Sasso FC. The Dual Burden: Exploring Cardiovascular Complications in Chronic Kidney Disease. Biomolecules 2024; 14:1393. [PMID: 39595570 PMCID: PMC11591570 DOI: 10.3390/biom14111393] [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: 10/01/2024] [Revised: 10/18/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Chronic kidney disease (CKD) represents a significant global health challenge, affecting millions of individuals and leading to substantial morbidity and mortality. This review aims to explore the epidemiology, cardiovascular complications, and management strategies associated with CKD, emphasizing the importance of preventing cardiovascular disease and early intervention. CKD is primarily driven by conditions such as diabetes mellitus, hypertension, and cardiovascular diseases, which often coexist and exacerbate renal impairment. Effective management requires a multifaceted approach, including lifestyle modifications, pharmacological interventions, and regular monitoring. Dietary changes, such as sodium restriction and a controlled intake of phosphorus and potassium, play a vital role in preserving renal function. Pharmacological therapies, particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and emerging agents like SGLT2 inhibitors, have shown efficacy in slowing disease progression and improving patient outcomes. Furthermore, patients undergoing dialysis face increased cardiovascular risk, necessitating comprehensive management strategies to address both renal and cardiac health. As the landscape of CKD treatment evolves, ongoing research into novel therapeutic options and personalized medical approaches are essential. This review underscores the urgent need for awareness, education, and effective preventive measures to mitigate the burden of CKD and enhance the quality of life for affected individuals.
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Affiliation(s)
- Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy;
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Maria Rocco
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Giuseppina Tagliaferri
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Alessia Piacevole
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Davide Nilo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Giovanni Di Lorenzo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Vincenzo Russo
- Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy;
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Marcellino Monda
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
| | - Luca Rinaldi
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, Università degli Studi del Molise, 86100 Campobasso, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (M.R.); (G.T.); (A.P.); (D.N.); (G.D.L.); (C.S.); (E.V.); (R.M.)
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21
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Verma S, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, Shah SJ, Rönnbäck C, Abildstrøm SZ, Liisberg K, Wolf D, von Lewinski D, Lelonek M, Melenovsky V, Senni M, Kosiborod MN. Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program. J Am Coll Cardiol 2024; 84:1646-1662. [PMID: 39217564 DOI: 10.1016/j.jacc.2024.08.028] [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: 08/06/2024] [Revised: 08/15/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. OBJECTIVES This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. METHODS This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). RESULTS In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). CONCLUSIONS Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).
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Affiliation(s)
- Subodh Verma
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Mark C Petrie
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom
| | - Barry A Borlaug
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi, Jackson, Mississippi, USA
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Biomedical Research Centre, Leicester, United Kingdom
| | - Dalane W Kitzman
- Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Sanjiv J Shah
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | | | | | | | - Dennis Wolf
- Cardiology and Angiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Malgorzata Lelonek
- Department of Noninvasive Cardiology, Medical University of Łódź, Łódź, Poland
| | - Vojtech Melenovsky
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Michele Senni
- University of Milano-Bicocca, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Mikhail N Kosiborod
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
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Martí-Carvajal AJ, Gemmato-Valecillos MA, Monge Martín D, Dayer M, Alegría-Barrero E, De Sanctis JB, Parise Vasco JM, Riera Lizardo RJ, Nicola S, Martí-Amarista CE, Correa-Pérez A. Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev 2024; 9:CD014741. [PMID: 39297531 PMCID: PMC11411914 DOI: 10.1002/14651858.cd014741.pub2] [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] [Indexed: 09/21/2024]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.
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Key Words
- humans
- angina, unstable
- angina, unstable/mortality
- angina, unstable/prevention & control
- antibodies, monoclonal, humanized
- antibodies, monoclonal, humanized/administration & dosage
- antibodies, monoclonal, humanized/adverse effects
- atherosclerosis
- atherosclerosis/mortality
- atherosclerosis/prevention & control
- bias
- cause of death
- myocardial infarction
- myocardial infarction/mortality
- myocardial infarction/prevention & control
- primary prevention
- primary prevention/methods
- randomized controlled trials as topic
- receptors, interleukin-1
- receptors, interleukin-1/antagonists & inhibitors
- secondary prevention
- secondary prevention/methods
- tumor necrosis factor-alpha
- tumor necrosis factor-alpha/antagonists & inhibitors
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Affiliation(s)
- Arturo J Martí-Carvajal
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
- Facultad de Medicina (Centro Cochrane Madrid), Universidad Francisco de Vitoria, Madrid, Spain
- Cátedra Rectoral de Medicina Basada en la Evidencia, Universidad de Carabobo, Valencia , Venezuela
| | - Mario A Gemmato-Valecillos
- Icahn School of Medicine at Mount Sinai/ NYCHH Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, New York 11373, USA
| | | | - Mark Dayer
- Cardiovascular Research Institute, Mater Private Network, Dublin, Ireland
- Faculty of Health, University of Plymouth, Plymouth, UK
| | | | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Palacky University, Faculty of Medicine and Dentistry, Olomouc, Czech Republic
| | - Juan Marcos Parise Vasco
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
| | - Ricardo J Riera Lizardo
- Cátedra Rectoral de Medicina Basada en la Evidencia, Universidad de Carabobo, Valencia, Venezuela
| | - Susana Nicola
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
| | | | - Andrea Correa-Pérez
- Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
- Hospital Pharmacy and Medical Devices Department, Hospital Central de la Defensa "Gómez Ulla" CSVE, Madrid, Spain
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23
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Corken AL, Ong V, Kore R, Ghanta SN, Karaduta O, Pathak R, Rose S, Porter C, Jain N. Platelets, inflammation, and purinergic receptors in chronic kidney disease. Kidney Int 2024; 106:392-399. [PMID: 38821448 PMCID: PMC11343655 DOI: 10.1016/j.kint.2024.03.033] [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: 02/13/2024] [Revised: 02/29/2024] [Accepted: 03/08/2024] [Indexed: 06/02/2024]
Abstract
Platelets are anucleated cells that circulate in the bloodstream. Historically, platelets were thought to perform a singular function-stop bleeding via clotting. Although platelets do play a key role in hemostasis and thrombosis, recent studies indicate that platelets also modulate inflammation, and this platelet-induced inflammation contributes to the pathophysiology of various diseases such as atherosclerosis and diabetes mellitus. Thus, in recent years, our understanding of platelet function has broadened. In this review, we revisit the classic role of platelets in hemostasis and thrombosis and describe the newly recognized function of platelets in modulating inflammation. We cover the potential use of purinergic receptor antagonists to prevent platelet-modulated inflammation, particularly in patients with chronic kidney disease, and finally, we define key questions that must be addressed to understand how platelet-modulated inflammation contributes to the pathophysiology of chronic kidney disease.
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Affiliation(s)
- Adam L Corken
- Department of Pediatrics, Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Vincz Ong
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Rajshekhar Kore
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Sai N Ghanta
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Oleg Karaduta
- Department of Physician Assistant Studies, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Rupak Pathak
- Department of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Shannon Rose
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Department of Pediatrics, Arkansas Children's Research Institute, Little Rock, Arkansas, USA
| | - Craig Porter
- Department of Pediatrics, Arkansas Children's Research Institute, Little Rock, Arkansas, USA
| | - Nishank Jain
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
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24
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Yu YM, Jin GH, Zhong C, Qian H, Wang L, Zhan F. Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study. World J Psychiatry 2024; 14:1244-1253. [PMID: 39165549 PMCID: PMC11331385 DOI: 10.5498/wjp.v14.i8.1244] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND The interplay between inflammation, immune dysregulation, and the onset of neurological disorders, including epilepsy, has become increasingly recognized. Interleukin (IL)-6, a pro-inflammatory cytokine, is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients. The role of IL-6 receptor (IL6R) blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes. AIM To explore the potential of IL6R blockade in reducing the risk of epilepsy and investigate whether this pathway might also influence associated psychiatric and neuropsychiatric conditions due to neuroinflammation. METHODS Mendelian randomization (MR) analysis employing single nucleotide polymorphisms (SNPs) in the vicinity of the IL6R gene (total individuals = 408225) was used to evaluate the putative causal relationship between IL6R blockade and epilepsy (total cases/controls = 12891/312803), focal epilepsy (cases/controls = 7526/399290), and generalized epilepsy (cases/controls = 1413/399287). SNP weights were determined by their effect on C-reactive protein (CRP) levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects. To address potential outlier and pleiotropic influences, sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions. RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk [inverse variance weighting: Odds ratio (OR): 0.827; 95% confidence interval (CI): 0.685-1.000; P = 0.05]. Subtype analysis showed variability, with no significant effect observed in generalized, focal, or specific childhood and juvenile epilepsy forms. Beyond the primary inflammatory marker CRP, the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy, hinting at possible links to neuroinflammation, psychiatric symptoms, and associated mental disorders. CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence, likely mediated via complex neuroinflammatory pathways. These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy. The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.
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Affiliation(s)
- Yan-Mei Yu
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Gui-Hong Jin
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Chong Zhong
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Hao Qian
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Lei Wang
- Department of Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang Province, China
| | - Feng Zhan
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
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25
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Chertow GM, Chang AM, Felker GM, Heise M, Velkoska E, Fellström B, Charytan DM, Clementi R, Gibson CM, Goodman SG, Jardine M, Levin A, Lokhnygina Y, Mears J, Mehran R, Stenvinkel P, Wang AYM, Wheeler DC, Zoccali C, Ridker PM, Mahaffey KW, Tricoci P, Wolf M. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nat Med 2024; 30:2328-2336. [PMID: 38796655 PMCID: PMC11333272 DOI: 10.1038/s41591-024-03043-1] [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: 04/04/2024] [Accepted: 05/02/2024] [Indexed: 05/28/2024]
Abstract
Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg l-1 at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l-1 was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961 .
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Shaun G Goodman
- University of Toronto and University of Alberta, Edmonton, Alberta, Canada
| | - Meg Jardine
- University of Sydney, Sydney, New South Wales, Australia
| | - Adeera Levin
- University of British Columbia, Vancouver, British Columbia, Canada
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26
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Crea F. Focus on acute myocardial infarction, sex-related differences in coronary bypass surgery, inflammation in heart failure, and infective endocarditis in prosthetic valves. Eur Heart J 2024; 45:2463-2467. [PMID: 39032925 DOI: 10.1093/eurheartj/ehae450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/23/2024] Open
Affiliation(s)
- Filippo Crea
- Center of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
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27
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Kane J, Vos WG, Bosmans LA, van Os BW, den Toom M, Hoeksema‐Hackmann S, Moen‐de Wit D, Gijbels MJ, Beckers L, Grefhorst A, Levels JHM, Jakulj L, Vervloet MG, Lutgens E, Eringa EC. Peritoneal Dialysis Aggravates and Accelerates Atherosclerosis in Uremic ApoE-/- Mice. J Am Heart Assoc 2024; 13:e034066. [PMID: 38979792 PMCID: PMC11292770 DOI: 10.1161/jaha.123.034066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/29/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND Atherosclerosis is highly prevalent in people with chronic kidney disease (CKD), including those receiving peritoneal dialysis (PD). Although it is lifesaving, PD induces profound systemic inflammation, which may aggravate atherosclerosis. Therefore, the hypothesis is that this PD-induced inflammation aggravates atherosclerosis via immune cell activation. METHODS AND RESULTS ApoE-/- mice were subjected to a 5/6 nephrectomy to induce CKD. Three weeks later, mice were fed a high-cholesterol diet. Half of the nephrectomized mice then received daily peritoneal infusions of 3.86% Physioneal for 67 further days (CKD+PD) until the end of the experiment, and were compared with mice without CKD. Sham operated and PD-only mice were additional controls. CKD+PD mice displayed more severe atherosclerotic disease than control mice. Plaque area increased, and plaques were more advanced with a vulnerable phenotype typified by decreased collagen content and decreased fibrous cap thickness. Increased CD3+ T-cell numbers were present in plaques and perivascular adipose tissue of CKD and CKD+PD mice. Plaques of CKD+PD mice contained more iNOS+ immune cells. Spleens of CKD+PD mice showed more CD4+ central memory, terminally differentiated type 1 T-helper (Th1), Th17, and CX3C motif chemokine receptor 1+ (CX3CR1) CD4+ T-cells with less regulatory and effector T-cells. CONCLUSIONS PD-fluid exposure in uremic mice potentiates systemic and vascular T-cell-driven inflammation and aggravates atherosclerosis. PD polarized CD4+ T-cells toward an inflammatory Th1/Th17 phenotype, and increased CX3CR1+ CD4+ T-cells, which are associated with vascular homing in CKD-associated atherosclerosis. Targeting CD4+ T-cell activation and CX3CR1+ polarization has the potential to attenuate atherosclerosis in PD patients.
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Affiliation(s)
- Jamie Kane
- Department of Nephrology, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of Physiology, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Winnie G. Vos
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Laura A. Bosmans
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of Experimental Vascular Medicine, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Bram W. van Os
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Myrthe den Toom
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
| | | | - Denise Moen‐de Wit
- Animal Research Institute AMCAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Marion J. Gijbels
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM)Maastricht University Medical CentreMaastrichtthe Netherlands
| | - Linda Beckers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Immunity and InfectionAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Aldo Grefhorst
- Department of Experimental Vascular Medicine, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Johannes H. M. Levels
- Department of Experimental Vascular Medicine, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
| | - Lily Jakulj
- Department of Nephrology, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
- Dianet Dialysis Centre AmsterdamAmsterdamthe Netherlands
| | - Marc G. Vervloet
- Department of Nephrology, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of NephrologyRadboud University Medical CentreNijmegenthe Netherlands
| | - Esther Lutgens
- Department of Cardiovascular Medicine and ImmunologyMayo ClinicRochesterMN
| | - Etto C. Eringa
- Department of Physiology, Amsterdam Cardiovascular SciencesAmsterdam University Medical CentreAmsterdamthe Netherlands
- Department of PhysiologyMaastricht UniversityMaastrichtthe Netherlands
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28
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Fisher A, Fisher L, Srikusalanukul W. Prediction of Osteoporotic Hip Fracture Outcome: Comparative Accuracy of 27 Immune-Inflammatory-Metabolic Markers and Related Conceptual Issues. J Clin Med 2024; 13:3969. [PMID: 38999533 PMCID: PMC11242639 DOI: 10.3390/jcm13133969] [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: 06/11/2024] [Revised: 06/26/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
Objectives: This study, based on the concept of immuno-inflammatory-metabolic (IIM) dysregulation, investigated and compared the prognostic impact of 27 indices at admission for prediction of postoperative myocardial injury (PMI) and/or hospital death in hip fracture (HF) patients. Methods: In consecutive HF patient (n = 1273, mean age 82.9 ± 8.7 years, 73.5% females) demographics, medical history, laboratory parameters, and outcomes were recorded prospectively. Multiple logistic regression and receiver-operating characteristic analyses (the area under the curve, AUC) were used to establish the predictive role for each biomarker. Results: Among 27 IIM biomarkers, 10 indices were significantly associated with development of PMI and 16 were indicative of a fatal outcome; in the subset of patients aged >80 years with ischaemic heart disease (IHD, the highest risk group: 90.2% of all deaths), the corresponding figures were 26 and 20. In the latter group, the five strongest preoperative predictors for PMI were anaemia (AUC 0.7879), monocyte/eosinophil ratio > 13.0 (AUC 0.7814), neutrophil/lymphocyte ratio > 7.5 (AUC 0.7784), eosinophil count < 1.1 × 109/L (AUC 0.7780), and neutrophil/albumin × 10 > 2.4 (AUC 0.7732); additionally, sensitivity was 83.1-75.4% and specificity was 82.1-75.0%. The highest predictors of in-hospital death were platelet/lymphocyte ratio > 280.0 (AUC 0.8390), lymphocyte/monocyte ratio < 1.1 (AUC 0.8375), albumin < 33 g/L (AUC 0.7889), red cell distribution width > 14.5% (AUC 0.7739), and anaemia (AUC 0.7604), sensitivity 88.2% and above, and specificity 85.1-79.3%. Internal validation confirmed the predictive value of the models. Conclusions: Comparison of 27 IIM indices in HF patients identified several simple, widely available, and inexpensive parameters highly predictive for PMI and/or in-hospital death. The applicability of IIM biomarkers to diagnose and predict risks for chronic diseases, including OP/OF, in the preclinical stages is discussed.
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Affiliation(s)
- Alexander Fisher
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia
- Department of Orthopaedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia
- Medical School, Australian National University, Canberra 2601, Australia
| | - Leon Fisher
- Frankston Hospital, Peninsula Health, Melbourne 3199, Australia
| | - Wichat Srikusalanukul
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia
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29
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孙 丽, 霍 醒, 贾 珊, 陈 晓. [Association Between the Aggregate Index of Systemic Inflammation and Albuminuria: A Cross-Sectional Study of National Health and Nutrition Examination Survey 2007-2018]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:671-679. [PMID: 38948283 PMCID: PMC11211792 DOI: 10.12182/20240560108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Indexed: 07/02/2024]
Abstract
Objective Prior studies have established a connection between albuminuria and various inflammatory reactions, highlighting that an increase in C-reactive protein by 1 mg/L increases the likelihood of albuminuria by 2%. Recent investigations indicate a positive correlation between the systemic immune-inflammation index (SII) and increased urinary protein excretion. In addition, elevated levels of the systemic inflammatory response index (SIRI) also correlate with a higher prevalence of albuminuria. The aggregate index of systemic inflammation (AISI) offers a more comprehensive indicator of inflammation, providing an extensive assessment of systemic inflammatory status compared to SII and SIRI. Yet, the specific relationship between AISI and albuminuria remains unclear. This study aims to explore this association in U.S. adults. Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) for 2007-2018, excluding pregnant women and individuals under 18. Cases with missing data on AISI, urinary albumin concentration, and other covariates were also excluded. AISI was computed using the formula: AISI=(platelet count×neutrophil count×monocyte count)/lymphocyte count. Albuminuria was defined as the urinary albumin-to-creatinine ratio exceeding 30 mg/g. Continuous variables were presented in the form of the mean±standard error, and categorical variables in percentages. We utilized weighted t-tests and chi-square tests for baseline comparisons. We applied weighted multivariable logistic regression and generalized additive models (GAM) to explore the association between AISI and albuminuria and to assess potential nonlinear relationships. Results The study included 32273 participants, with an average age of (46.75±0.24) years old. The cohort comprised 48.73% males and 51.27% females. The prevalence of albuminuria was 9.64%. The average logarithmic value of log2AISI was 7.95±0.01, and were categorized into tertiles as follows: Quartile 1 (Q1) (4.94 to 7.49), Q2 (7.49 to 8.29), and Q3 (8.29 to 10.85). As log2AISI increased, so did the prevalence of hypertension, diabetes, congestive heart failure, and albuminuria, all showing statistically significant increases (P<0.001). Similarly, the use of antihypertensive, lipid-lowering, and hypoglycemic drugs was also more prevalent (P<0.001). Statistically significant differences were observed across the three groups concerning age, race and ethnicity, formal education, alcohol consumption, smoking status, systolic and diastolic blood pressures, body mass index, estimated glomerular filtration rate, HbA1c, alanine aminotransferase, aspartate aminotransferase, albumin, creatinine, uric acid, and high-density lipoprotein cholesterol (P<0.05). However, no significant differences were noted in the total cholesterol or the sex ratios among the groups. The association between log2AISI and albuminuria was assessed using weighted multivariable logistic regression, and the detailed results are presented in Table 2. In model 1, without adjusting for covariates, each unit increase in log2AISI was associated with a 32% increase in the risk of albuminuria (odds ratio [OR]=1.32, 95% confidence interval [CI]: 1.27-1.38, P<0.001). Model 2 was adjusted for age, gender, race, and education level, and showed a similar trend, with each unit increase in log2AISI associated with a 31% increased risk (OR=1.31, 95% CI: 1.26-1.37, P<0.001). Model 3, which was further adjusted for all covariates, revealed that each unit increase in log2AISI was associated with a 20% increase in the risk of albuminuria (OR=1.20, 95% CI: 1.15-1.26, P<0.001). The study also transformed log2AISI from a continuous to a categorical variable for analysis. Compared with Q1, the risk of albuminuria in Q3, after adjusting for all covariates, significantly increased (OR=1.37, 95% CI: 1.22-1.55, P<0.001). Q2 also demonstrated a higher risk compared with Q1 (OR=1.13, 95% CI: 1.06-1.36, P=0.004). The trend test indicated a dose-effect relationship between increasing log2AISI and the rising risk of albuminuria. GAM revealed a nonlinear relationship between log2AISI and albuminuria, with distinct trends noted between sexes. Segmented regression based on turning points showed significant effects among women, although the slope difference between the segments was not significant. In men, a significant threshold effect was observed; below the log2AISI of 7.25, increases in log2AISI did not enhance the risk of albuminuria, but above this threshold, the risk significantly increased. As part of a sensitivity analysis, weighted multivariable logistic regression was performed by changing the outcome variable to macroalbuminuria and adjusting for all covariates. The analysis showed that for every unit increase in log2AISI, the risk of developing macroalbuminuria increased by 31% (OR=1.31, 95% CI: 1.15-1.49, P<0.001). Compared with Q1, the risk of albuminuria in Q3 increased by 69% (OR=1.69, 95% CI: 1.27-2.25, P<0.001), and in Q2, it increased by 40% (OR=1.40, 95% CI: 1.03-1.92, P=0.030). Subgroup analysis and interaction results showed that the positive association between AISI and proteinuria risk was stronger in men than in women. Similarly, the association was stronger in people with hypertension compared with those with normal blood pressure, and higher in overweight people compared with those of normal weight. Furthermore, smokers and drinkers showed a stronger positive association between AISI and the risk of proteinuria than non-smokers and non-drinkers do. These results suggest that sex, blood pressure, body mass index, smoking, and alcohol consumption interact with AISI to influence the risk of proteinuria. Conclusion There is a robust positive association between AISI and increased risks of albuminuria in US adults. As log2AISI increases, so does the risk of albuminuria. However, further validation of this conclusion through large-scale prospective studies is warranted.
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Affiliation(s)
- 丽荣 孙
- 四川大学华西医院 心内科 (成都 610041)Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
- 西藏民族大学附属医院 (咸阳 712000)Affiliated Hospital of Xizang Minzu University, Xianyang 712000, China
| | - 醒伟 霍
- 四川大学华西医院 心内科 (成都 610041)Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 珊珊 贾
- 四川大学华西医院 心内科 (成都 610041)Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 晓平 陈
- 四川大学华西医院 心内科 (成都 610041)Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
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30
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Crea F. Focus on ischaemic heart disease: prevention with colchicine, role of the brain-heart axis, new therapeutic targets for ischaemia-reperfusion injury. Eur Heart J 2024; 45:1577-1581. [PMID: 38738301 DOI: 10.1093/eurheartj/ehae270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/14/2024] Open
Affiliation(s)
- Filippo Crea
- Centre of Excellence of Cardiovascular Sciences, Gemelli Isola Hospital, Rome, Italy
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31
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Crea F. Non-traditional risk factors: built environment assessed by Google Street View, syphilis, and rheumatoid arthritis. Eur Heart J 2024; 45:1489-1493. [PMID: 38713840 DOI: 10.1093/eurheartj/ehae261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2024] Open
Affiliation(s)
- Filippo Crea
- Centre of Excellence of Cardiovascular Sciences, Gemelli Isola Hospital, Rome, Italy
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32
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Qu S, Fang J, Zhao S, Wang Y, Gao W, Li Z, Xu H, Zhang Y, Shi S, Cheng X, Liu Z, Jin L, Yao Y. Associations of dietary inflammatory index with low estimated glomerular filtration rate, albuminuria and chronic kidney disease in U.S adults: Results from the NHANES 2011-2018. Nutr Metab Cardiovasc Dis 2024; 34:1036-1045. [PMID: 38267324 DOI: 10.1016/j.numecd.2023.11.006] [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: 06/11/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND AND AIMS Chronic Kidney Disease (CKD) is characterized by a high inflammation status with ever-increasing prevalence, and defined as low estimated glomerular filtration rate (eGFR) or albuminuria. Both low eGFR and albuminuria can have independent effects on the body. The dietary inflammatory index (DII) is a validated tool used to assess the inflammatory potential of the diet. We aim to explore not only the association between DII and CKD, but also the associations of DII with low eGFR and albuminuria, respectively. In addition, their associations in different subgroups remain to be explored. METHODS AND RESULTS 18,070 participants from the 2011-2018 NHANES with complete data of dietary intake and laboratory data were involved in our study. The data of 24-hour dietary recall interview was used to calculate DII, CKD could be reflected by laboratory data of creatinine and albumin. Then weighted multivariate logistic regression models and subgroup analyses were performed. The prevalence of low eGFR, albuminuria and CKD were 6.8%, 9.8% and 14.5%, respectively. A positive association between DII and low eGFR was observed (OR=1.12, 95%CI: 1.05-1.21), Q2, Q3 and Q4 are positively associated with a significant 39%, 65% and 71% increased risk of low eGFR compared with Q1 (P for trend<0.05). DII was also associated with CKD (OR=1.06, 95%CI: 1.01-1.11). CONCLUSION Significant positive associations of DII with CKD and low eGFR were observed. But we didn't find such association between DII and albuminuria.
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Affiliation(s)
- Shifang Qu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Jiaxin Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Saisai Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Yuxiang Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Wenhui Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Zhiyao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Han Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Yuan Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Shunyao Shi
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Xiaowei Cheng
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Zhigang Liu
- Osteopathic Center, The Second Hospital of Jilin University, No.4026, Yatai Street, Nanguan District, Changchun, Jilin, China.
| | - Lina Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Yan Yao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
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Kovalik ME, Dacanay MA, Crowley SD, Hall G. Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome. Biomedicines 2024; 12:738. [PMID: 38672094 PMCID: PMC11048099 DOI: 10.3390/biomedicines12040738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 04/28/2024] Open
Abstract
Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.
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Affiliation(s)
- Maria E. Kovalik
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Monique A. Dacanay
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Steven D. Crowley
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
| | - Gentzon Hall
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
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Elías-López D, Doi T, Nordestgaard BG, Kobylecki CJ. Remnant cholesterol and low-grade inflammation jointly in atherosclerotic cardiovascular disease: implications for clinical trials. Curr Opin Clin Nutr Metab Care 2024; 27:125-135. [PMID: 38320159 DOI: 10.1097/mco.0000000000000999] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
PURPOSE OF REVIEW Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death despite the development of effective treatments. Recently, elevated remnant cholesterol and low-grade inflammation have emerged as factors explaining part of the residual ASCVD risk. Interestingly, the coexistence of both high remnant cholesterol and low-grade inflammation can further increase the risk of ASCVD. The aim of this review is to describe the role of elevated remnant cholesterol and low-grade inflammation, separately and combined, in ASCVD. RECENT FINDINGS Results from recently published studies, including observational and genetic Mendelian randomization studies, support a causal relationship between elevated remnant cholesterol and low-grade inflammation on risk of ASCVD in both primary and secondary prevention settings. In addition, current evidence from observational studies suggests that the coexistence of elevated remnant cholesterol and low-grade inflammation further increases the risk of ASCVD. SUMMARY Recent observational studies suggest that high remnant cholesterol combined with low-grade inflammation may confer a particular high risk for ASCVD. Attention on the dual threat from high remnant cholesterol and low-grade inflammation is necessary, and further research in this field is warranted. The effect of remnant cholesterol-lowering drugs and anti-inflammatory drugs on ASCVD risk alone and combined remains to be elucidated. VIDEO ABSTRACT http://links.lww.com/COCN/A20.
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Affiliation(s)
- Daniel Elías-López
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte
- The Copenhagen General Population Study, Copenhagen University Hospital - Herlev Gentofte, Herlev, Denmark
- Department of Endocrinology and Metabolism and Research Center of Metabolic Diseases, National Institute of Medical Sciences and Nutrition Salvador Zubirán, México City, México
| | - Takahito Doi
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte
- The Copenhagen General Population Study, Copenhagen University Hospital - Herlev Gentofte, Herlev, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte
- The Copenhagen General Population Study, Copenhagen University Hospital - Herlev Gentofte, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Camilla J Kobylecki
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte
- The Copenhagen General Population Study, Copenhagen University Hospital - Herlev Gentofte, Herlev, Denmark
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Xu C, Tsihlis G, Chau K, Trinh K, Rogers NM, Julovi SM. Novel Perspectives in Chronic Kidney Disease-Specific Cardiovascular Disease. Int J Mol Sci 2024; 25:2658. [PMID: 38473905 PMCID: PMC10931927 DOI: 10.3390/ijms25052658] [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: 01/19/2024] [Revised: 02/18/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Chronic kidney disease (CKD) affects > 10% of the global adult population and significantly increases the risk of cardiovascular disease (CVD), which remains the leading cause of death in this population. The development and progression of CVD-compared to the general population-is premature and accelerated, manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. CKD and CV disease combine to cause multimorbid cardiorenal syndrome (CRS) due to contributions from shared risk factors, including systolic hypertension, diabetes mellitus, obesity, and dyslipidemia. Additional neurohormonal activation, innate immunity, and inflammation contribute to progressive cardiac and renal deterioration, reflecting the strong bidirectional interaction between these organ systems. A shared molecular pathophysiology-including inflammation, oxidative stress, senescence, and hemodynamic fluctuations characterise all types of CRS. This review highlights the evolving paradigm and recent advances in our understanding of the molecular biology of CRS, outlining the potential for disease-specific therapies and biomarker disease detection.
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Affiliation(s)
- Cuicui Xu
- Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, 176 Hawkesbury Road, Westmead, NSW 2145, Australia; (C.X.); (K.T.)
| | - George Tsihlis
- Renal and Transplantation Medicine, Westmead Hospital, Westmead, NSW 2145, Australia;
| | - Katrina Chau
- Department of Renal Services, Blacktown Hospital, Blacktown, NSW 2148, Australia;
- Blacktown Clinical School, School of Medicine, Western Sydney University, Sydney, NSW 2148, Australia
| | - Katie Trinh
- Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, 176 Hawkesbury Road, Westmead, NSW 2145, Australia; (C.X.); (K.T.)
- Department of Renal Services, Blacktown Hospital, Blacktown, NSW 2148, Australia;
| | - Natasha M. Rogers
- Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, 176 Hawkesbury Road, Westmead, NSW 2145, Australia; (C.X.); (K.T.)
- Renal and Transplantation Medicine, Westmead Hospital, Westmead, NSW 2145, Australia;
- Faculty of Medicine and Health, The University of Sydney, Science Rd., Camperdown, NSW 2050, Australia
| | - Sohel M. Julovi
- Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, 176 Hawkesbury Road, Westmead, NSW 2145, Australia; (C.X.); (K.T.)
- Faculty of Medicine and Health, The University of Sydney, Science Rd., Camperdown, NSW 2050, Australia
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36
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Chen M, Hao G, Hu S, Chen C, Tao Q, Xu J, Geng Y, Wang X, Hu C. Lesion-specific pericoronary adipose tissue CT attenuation improves risk prediction of major adverse cardiovascular events in coronary artery disease. Br J Radiol 2024; 97:258-266. [PMID: 38263819 PMCID: PMC11651292 DOI: 10.1093/bjr/tqad017] [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: 04/16/2023] [Revised: 10/10/2023] [Accepted: 11/02/2023] [Indexed: 01/25/2024] Open
Abstract
OBJECTIVES To determine whether lesion-specific pericoronary adipose tissue CT attenuation (PCATa) is superior to PCATa around the proximal right coronary artery (PCATa-RCA) and left anterior descending artery (PCATa-LAD) for major adverse cardiovascular events (MACE) prediction in coronary artery disease (CAD). METHODS Six hundred and eight CAD patients who underwent coronary CTA from January 2014 to December 2018 were retrospectively included, with clinical risk factors, plaque features, lesion-specific PCATa, PCATa-RCA, and PCATa-LAD collected. MACE was defined as cardiovascular death, non-fatal myocardial infarction, unplanned revascularization, and hospitalization for unstable angina. Four models were established, encapsulating traditional factors (Model A), traditional factors and PCATa-RCA (Model B), traditional factors and PCATa-LAD (Model C), and traditional factors and lesion-specific PCATa (Model D). Prognostic performance was evaluated with C-statistic, area under receiver operator characteristic curve (AUC), and net reclassification index (NRI). RESULTS Lesion-specific PCATa was an independent predictor for MACE (adjusted hazard ratio = 1.108, P < .001). The C-statistic increased from 0.750 for model A to 0.762 for model B (P = .078), 0.773 for model C (P = .046), and 0.791 for model D (P = .005). The AUC increased from 0.770 for model A to 0.793 for model B (P = .027), 0.793 for model C (P = .387), and 0.820 for model D (P = .019). Compared with model A, the NRIs for models B, C, and D were 0.243 (-0.323 to 0.792, P = .392), 0.428 (-0.012 to 0.835, P = .048), and 0.708 (0.152-1.016, P = .001), respectively. CONCLUSIONS Lesion-specific PCATa improves risk prediction of MACE in CAD, which is better than PCATa-RCA and PCATa-LAD. ADVANCES IN KNOWLEDGE Lesion-specific PCATa was superior to PCATa-RCA and PCATa-LAD for MACE prediction.
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Affiliation(s)
- Meng Chen
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Guangyu Hao
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Su Hu
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Can Chen
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Qing Tao
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Jialiang Xu
- Department of Cardiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Yayuan Geng
- Department of Research and Development, ShuKun Technology Co.,
Ltd, Beijing 100102, China
| | - Ximing Wang
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
| | - Chunhong Hu
- Department of Radiology, The First Affiliated Hospital of Soochow
University, Suzhou, Jiangsu 215006, China
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Crea F. Strengths and limitations of risk scores in cardiovascular prevention. Eur Heart J 2024; 45:75-78. [PMID: 38184761 DOI: 10.1093/eurheartj/ehad850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2024] Open
Affiliation(s)
- Filippo Crea
- Centre of Excellence of Cardiovascular Sciences, Gemelli Isola Hospital, Rome, Italy
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Endo Y, Sasaki K, Ikewaki K. Residual Cardiovascular Risk Determined through Posthoc Analysis of the REAL-CAD Trial. J Atheroscler Thromb 2024; 31:21-22. [PMID: 37853635 PMCID: PMC10776336 DOI: 10.5551/jat.ed245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Affiliation(s)
- Yasuhiro Endo
- Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
- Division of Environmental Medicine, National Defense Medical College Research Institute, Saitama, Japan
| | - Kei Sasaki
- Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Katsunori Ikewaki
- Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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Crea F. New inflammatory predictors of cardiovascular events and the role of Mendelian randomizations. Eur Heart J 2023; 44:4897-4901. [PMID: 38093458 DOI: 10.1093/eurheartj/ehad804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023] Open
Affiliation(s)
- Filippo Crea
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
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Ismail A, Hayek SS. Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease. Curr Cardiol Rep 2023; 25:1797-1810. [PMID: 37948017 DOI: 10.1007/s11886-023-01991-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
PURPOSE OF REVIEW Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR's role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target. RECENT FINDINGS Clinical, genetic, and experimental evidence supports suPAR's role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling. Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.
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Affiliation(s)
- Anis Ismail
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E Medical Center Dr, CVC #2709, Ann Arbor, 48109, MI, USA
| | - Salim S Hayek
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E Medical Center Dr, CVC #2709, Ann Arbor, 48109, MI, USA.
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Makris A, Barkas F, Sfikakis PP, Liberopoulos E, Filippatos TD, Ray KK, Agouridis AP. Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association? ATHEROSCLEROSIS PLUS 2023; 54:1-6. [PMID: 37720252 PMCID: PMC10500445 DOI: 10.1016/j.athplu.2023.09.001] [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: 06/20/2023] [Revised: 08/09/2023] [Accepted: 09/06/2023] [Indexed: 09/19/2023]
Abstract
Background and aims Lipoprotein(a) [Lp(a)] and interleuking-6 (IL-6), an inflammation biomarker, have been established as distinct targets of the residual atherosclerotic cardiovascular disease (ASCVD) risk. We aimed to investigate the association between them, and the potential clinical implications in ASCVD prevention. Methods A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords. Results Elevated lipoprotein(a) [Lp(a)] levels constitute the most common inherited lipid disorder associated with ASCVD. Although Lp(a) levels are mostly determined genetically by the LPA gene locus, they may be altered by acute conditions of stress and chronic inflammatory diseases. Considering its resemblance with low-density lipoproteins, Lp(a) is involved in atherosclerosis, but it also exerts oxidative, thrombotic, antifibrinolytic and inflammatory properties. The cardiovascular efficacy of therapies lowering Lp(a) by >90% is currently investigated. On the other hand, interleukin (IL)-1b/IL-6 pathway also plays a pivotal role in atherosclerosis and residual ASCVD risk. IL-6 receptor inhibitors [IL-6(R)i] lower Lp(a) by 16-41%, whereas ongoing trials are investigating their potential anti-atherosclerotic effect. The Lp(a)-lowering effect of IL-6(R)i might be attributed to the inhibition of the IL-6 response elements in the promoter region of the LPA gene. Conclusions Although the effect of IL-6(R)i on Lp(a) levels is inferior to that of available Lp(a)-lowering therapies, the dual effect of the former on both inflammation and apolipoprotein (a) synthesis may prove of equal or even greater significance when it comes ASCVD outcomes. More trials are required to establish IL-6(R)i in ASCVD prevention and elucidate their interplay with Lp(a) as well as its clinical significance.
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Affiliation(s)
- Anastasios Makris
- School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Fotios Barkas
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
| | - Petros P. Sfikakis
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Evangelos Liberopoulos
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | | | - Kausik K. Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
| | - Aris P. Agouridis
- School of Medicine, European University Cyprus, Nicosia, Cyprus
- Department of Internal Medicine, German Oncology Center, Limassol, Cyprus
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Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, Coresh J, Baker-Smith CM, Carnethon MR, Després JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV, Rangaswami J. A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation 2023; 148:1636-1664. [PMID: 37807920 DOI: 10.1161/cir.0000000000001186] [Citation(s) in RCA: 191] [Impact Index Per Article: 95.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.
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Tokuda K, Tanaka A, Tobe A, Shirai Y, Kurobe M, Kubota Y, Kunieda T, Miyazaki T, Mizutani K, Furusawa K, Ishii H, Murohara T. Impact of C-Reactive Protein on Long-Term Cardiac Events in Stable Coronary Artery Disease Patients with Chronic Kidney Disease. J Atheroscler Thromb 2023; 30:1635-1643. [PMID: 36908149 PMCID: PMC10627763 DOI: 10.5551/jat.64047] [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: 11/05/2022] [Accepted: 02/21/2023] [Indexed: 03/13/2023] Open
Abstract
AIM Chronic inflammation is associated with atherosclerosis development. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular events and is associated with chronic inflammation. We aimed to investigate the influence of C-reactive protein (CRP), an important marker of inflammation, on the clinical outcomes of patients with CKD and stable coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). METHODS Among patients with stable CAD and CKD who underwent PCI, 516 patients whose CRP levels were available before the PCI procedure were identified. The patients were divided into two groups according to the CRP levels: those with CRP ≥ 2.0 mg/L (high-CRP group) and those with CRP <2.0 mg/L (low-CRP group). The primary endpoint of this study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, and unplanned revascularization. RESULTS Overall, the mean age of the patients was 72.5±9.7 years, and 20.7% were female. The median CRP level was 1.43 mg/L (0.6-4.9 mg/L). The median follow-up period was 3.6 years. The occurrence of MACE was significantly higher in the high-CRP group than in the low-CRP group (log-rank p<0.001). Notably, the incidence rate of cardiac death was significantly higher in the high-CRP group (log-rank p<0.001). According to the multivariable analysis, CRP level ≥ 2.0 mg/L was found to be a significant predictor of MACE (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.04-2.28, p=0.003), as well as estimated glomerular filtration rate (HR: 0.98, 95% CI: 0.97-0.99, p<0.01). CONCLUSION High-CRP levels adversely affect long-term cardiac events in patients with stable CAD and CKD.
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Affiliation(s)
- Kotaro Tokuda
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Akihito Tanaka
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Akihiro Tobe
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Yoshinori Shirai
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Masanari Kurobe
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Yoshiaki Kubota
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Takeshige Kunieda
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Tatsuya Miyazaki
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Koji Mizutani
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Kenji Furusawa
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
| | - Hideki Ishii
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
- Department of Cardiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University graduate school of medicine, Nagoya, Japan
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Sarakpi T, Mesic A, Speer T. Leukocyte-endothelial interaction in CKD. Clin Kidney J 2023; 16:1845-1860. [PMID: 37915921 PMCID: PMC10616504 DOI: 10.1093/ckj/sfad135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Indexed: 11/03/2023] Open
Abstract
Chronic kidney disease (CKD) represents an independent risk factor for cardiovascular diseases (CVD). Accordingly, CKD patients show a substantial increased risk of cardiovascular mortality. Inflammation represents an important link between CKD and CVD. The interaction between endothelial cells and effector cells of the innate immune system plays a central role in the development and progression of inflammation. Vascular injury causes endothelial dysfunction, leading to augmented oxidative stress, increased expression of leukocyte adhesion molecules and chronic inflammation. CKD induces numerous metabolic changes, creating a uremic milieu resulting in the accumulation of various uremic toxins. These toxins lead to vascular injury, endothelial dysfunction and activation of the innate immune system. Recent studies describe CKD-dependent changes in monocytes that promote endothelial dysfunction and thus CKD progression and CKD-associated CVD. The NLR family pyrin domain containing 3-interleukin-1β-interleukin-6 (NLRP3-IL-1β-IL-6) signaling pathway plays a pivotal role in the development and progression of CVD and CKD alike. Several clinical trials are investigating targeted inhibition of this pathway indicating that anti-inflammatory therapeutic strategies may emerge as novel approaches in patients at high cardiovascular risk and nonresolving inflammation. CKD patients in particular would benefit from targeted anti-inflammatory therapy, since conventional therapeutic regimens have limited efficacy in this population.
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Affiliation(s)
- Tamim Sarakpi
- Department of Internal Medicine 4 – Nephrology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Else Kröner-Fresenius-Zentrum for Nephrological Research, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Armir Mesic
- Department of Internal Medicine 4 – Nephrology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Else Kröner-Fresenius-Zentrum for Nephrological Research, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Thimoteus Speer
- Department of Internal Medicine 4 – Nephrology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Else Kröner-Fresenius-Zentrum for Nephrological Research, Goethe University Frankfurt, Frankfurt am Main, Germany
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Reijnders E, van der Laarse A, Jukema JW, Cobbaert CM. High residual cardiovascular risk after lipid-lowering: prime time for Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive medicine. Front Cardiovasc Med 2023; 10:1264319. [PMID: 37908502 PMCID: PMC10613690 DOI: 10.3389/fcvm.2023.1264319] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/03/2023] [Indexed: 11/02/2023] Open
Abstract
As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on "residual cardiovascular disease risk". During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual's CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches.
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Affiliation(s)
- E. Reijnders
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - A. van der Laarse
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - J. W. Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
- Netherlands Heart Institute, Utrecht, Netherlands
| | - C. M. Cobbaert
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands
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Mazzarino M, Cetin E, Bartosova M, Marinovic I, Ipseiz N, Hughes TR, Schmitt CP, Ramji DP, Labéta MO, Raby AC. Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology. Front Immunol 2023; 14:1240679. [PMID: 37849759 PMCID: PMC10577224 DOI: 10.3389/fimmu.2023.1240679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/08/2023] [Indexed: 10/19/2023] Open
Abstract
Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients' plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients' plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.
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Affiliation(s)
- Morgane Mazzarino
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
- Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Esra Cetin
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
- Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Maria Bartosova
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Iva Marinovic
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Natacha Ipseiz
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
| | - Timothy R. Hughes
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
| | - Claus Peter Schmitt
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Dipak P. Ramji
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Mario O. Labéta
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
- Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Anne-Catherine Raby
- Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom
- Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Roger E, Chadjichristos CE, Kavvadas P, Price GW, Cliff CL, Hadjadj S, Renciot J, Squires PE, Hills CE. Connexin-43 hemichannels orchestrate NOD-like receptor protein-3 (NLRP3) inflammasome activation and sterile inflammation in tubular injury. Cell Commun Signal 2023; 21:263. [PMID: 37770948 PMCID: PMC10536814 DOI: 10.1186/s12964-023-01245-7] [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: 05/26/2023] [Accepted: 07/23/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Without a viable cure, chronic kidney disease is a global health concern. Inflammatory damage in and around the renal tubules dictates disease severity and is contributed to by multiple cell types. Activated in response to danger associated molecular patterns (DAMPs) including ATP, the NOD-like receptor protein-3 (NLRP3) inflammasome is integral to this inflammation. In vivo, we have previously observed that increased expression of Connexin 43 (Cx43) is linked to inflammation in chronic kidney disease (CKD) whilst in vitro studies in human proximal tubule cells highlight a role for aberrant Cx43 hemichannel mediated ATP release in tubule injury. A role for Cx43 hemichannels in priming and activation of the NLRP3 inflammasome in tubule epithelial cells remains to be determined. METHODS Using the Nephroseq database, analysis of unpublished transcriptomic data, examined gene expression and correlation in human CKD. The unilateral ureteral obstruction (UUO) mouse model was combined with genetic (tubule-specific Cx43 knockout) and specific pharmacological blockade of Cx43 (Peptide5), to explore a role for Cx43-hemichannels in tubule damage. Human primary tubule epithelial cells were used as an in vitro model of CKD. RESULTS Increased Cx43 and NLRP3 expression correlates with declining glomerular filtration rate and increased proteinuria in biopsies isolated from patients with CKD. Connexin 43-tubule deletion prior to UUO protected against tubular injury, increased expression of proinflammatory molecules, and significantly reduced NLRP3 expression and downstream signalling mediators. Accompanied by a reduction in F4/80 macrophages and fibroblast specific protein (FSP1+) fibroblasts, Cx43 specific hemichannel blocker Peptide5 conferred similar protection in UUO mice. In vitro, Peptide5 determined that increased Cx43-hemichannel activity primes and activates the NLRP3 inflammasome via ATP-P2X7 receptor signalling culminating in increased secretion of chemokines and cytokines, each of which are elevated in individuals with CKD. Inhibition of NLRP3 and caspase 1 similarly decreased markers of tubular injury, whilst preventing the perpetual increase in Cx43-hemichannel activity. CONCLUSION Aberrant Cx43-hemichannel activity in kidney tubule cells contributes to tubule inflammation via activation of the NLRP3 inflammasome and downstream paracrine mediated cell signalling. Use of hemichannel blockers in targeting Cx43-hemichannels is an attractive future therapeutic target to slow or prevent disease progression in CKD. Video Abstract.
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Affiliation(s)
- Elena Roger
- Batiment Recherche, INSERM, UMR-S1155, Tenon Hospital, 4 Rue de la Chine, Paris, 75020, France
- Faculty of Medicine, Sorbonne University, Paris, 75013, France
| | - Christos E Chadjichristos
- Batiment Recherche, INSERM, UMR-S1155, Tenon Hospital, 4 Rue de la Chine, Paris, 75020, France
- Faculty of Medicine, Sorbonne University, Paris, 75013, France
| | - Panagiotis Kavvadas
- Batiment Recherche, INSERM, UMR-S1155, Tenon Hospital, 4 Rue de la Chine, Paris, 75020, France
- Faculty of Medicine, Sorbonne University, Paris, 75013, France
| | - Gareth W Price
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - Chelsy L Cliff
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - Safia Hadjadj
- Batiment Recherche, INSERM, UMR-S1155, Tenon Hospital, 4 Rue de la Chine, Paris, 75020, France
- Faculty of Medicine, Sorbonne University, Paris, 75013, France
| | - Jessy Renciot
- Batiment Recherche, INSERM, UMR-S1155, Tenon Hospital, 4 Rue de la Chine, Paris, 75020, France
- Faculty of Medicine, Sorbonne University, Paris, 75013, France
| | - Paul E Squires
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - Claire E Hills
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK.
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Zoccali C, Mallamaci F, Adamczak M, de Oliveira RB, Massy ZA, Sarafidis P, Agarwal R, Mark PB, Kotanko P, Ferro CJ, Wanner C, Burnier M, Vanholder R, Wiecek A. Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association. Cardiovasc Res 2023; 119:2017-2032. [PMID: 37249051 PMCID: PMC10478756 DOI: 10.1093/cvr/cvad083] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/29/2022] [Accepted: 01/09/2023] [Indexed: 05/31/2023] Open
Abstract
Chronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Cardiovascular complications are the most common causes of death in patients with kidney failure (stage G5) who are maintained on regular dialysis treatment. Because of the high death rate attributable to cardiovascular (CV) disease, most patients with progressive CKD die before reaching kidney failure. Classical risk factors implicated in CV disease are involved in the early stages of CKD. In intermediate and late stages, non-traditional risk factors, including iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders, accumulation of a class of endogenous compounds called 'uremic toxins', and a variety of hormonal disorders are the main factors that accelerate the progression of CV disease in these patients. Arterial disease in CKD patients is characterized by an almost unique propensity to calcification and vascular stiffness. Left ventricular hypertrophy, a major risk factor for heart failure, occurs early in CKD and reaches a prevalence of 70-80% in patients with kidney failure. Recent clinical trials have shown the potential benefits of hypoxia-inducible factor prolyl hydroxylase inhibitors, especially as an oral agent in CKD patients. Likewise, the value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown. Sodium/glucose cotransporter-2 inhibitors are now fully emerged as a class of drugs that substantially reduces the risk for CV complications in patients who are already being treated with adequate doses of inhibitors of the renin-angiotensin system. Concerted efforts are being made by major scientific societies to advance basic and clinical research on CV disease in patients with CKD, a research area that remains insufficiently explored.
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Affiliation(s)
- Carmine Zoccali
- Renal Research Institute, 315 E, 62nd St., New York, NY 10065, USA
- Associazione Ipertensione Nefrologia e Trapianto Renale (IPNET) c/o Nefrologia e CNR, Grande Ospedale Metropolitano, Contrada Camporeale, 83031 Ariano Irpino Avellino, Italy
| | - Francesca Mallamaci
- Nephrology and Transplantation Unit, Grande Ospedale Metropolitano Reggio Cal and CNR-IFC, Via Giuseppe Melacrino 21, 89124 Reggio Calabria, Italy
| | - Marcin Adamczak
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice, Francuska 20-24 St. 40-027 Katowice, Poland
| | - Rodrigo Bueno de Oliveira
- Department of Internal Medicine (Nephrology), School of Medical Sciences, University of Campinas (Unicamp), Campinas, Brazil
| | - Ziad A Massy
- Ambroise Paré University Hospital, APHP, Boulogne Billancourt/Paris, and INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP), Equipe 5, Paris-Saclay University (PSU) and University of Paris Ouest-Versailles-Saint-Quentin-en-Yvelines (UVSQ), FCRIN INI-CRCT, Villejuif, France
| | - Pantelis Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Rajiv Agarwal
- Indiana University School of Medicine and Richard L. Roudebush VA Medical Center, 1481 W 10th St, Indianapolis, IN 46202, USA
| | - Patrick B Mark
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Peter Kotanko
- Renal Research Institute, LLC Icahn School of Medicine at Mount Sinai, 315 East 62nd Street, 3rd Floor, New York, NY 10065, USA
| | - Charles J Ferro
- Department of Renal Medicine, University Hospitals Birmingham, Birmingham, UK
| | - Christoph Wanner
- Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany
| | - Michel Burnier
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Raymond Vanholder
- Nephrology Section, Department of Internal Medicine and Pediatrics, University Hospital, Ghent, Belgium
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice, Francuska 20-24 St. 40-027 Katowice, Poland
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Li L, Liu S, Zhang Z, Zhou L, Zhang Z, Xiong Y, Hu Z, Yao Y. Prognostic value of high-sensitivity C-reactive protein in patients undergoing percutaneous coronary intervention with different glycemic metabolism status. Cardiovasc Diabetol 2023; 22:223. [PMID: 37620818 PMCID: PMC10463538 DOI: 10.1186/s12933-023-01932-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/20/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). METHODS In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. RESULTS After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29-2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05-1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. CONCLUSION Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status.
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Affiliation(s)
- Le Li
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Shangyu Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhuxin Zhang
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Likun Zhou
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Zhenhao Zhang
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Yulong Xiong
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Zhao Hu
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China
| | - Yan Yao
- Chinese Academy of Medical Sciences, Peking Union Medical College, National Center for Cardiovascular Diseases, Fu Wai Hospital, Beijing, China.
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Crea F. Focus on translational vascular biology: new therapeutic targets in hypertension, aortic aneurysm, and atherosclerosis. Eur Heart J 2023; 44:2645-2649. [PMID: 37527405 DOI: 10.1093/eurheartj/ehad481] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/03/2023] Open
Affiliation(s)
- Filippo Crea
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
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