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Davaine JM, Denimal D, Treca P, Francon H, Phan F, Hartemann A, Bourron O. Medial arterial calcification of the lower limbs in diabetes: Time for awareness? A short narrative review. DIABETES & METABOLISM 2025; 51:101586. [PMID: 39521119 DOI: 10.1016/j.diabet.2024.101586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/02/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
In patients with diabetes, peripheral arterial disease, particularly below the knee, is associated with medial arterial calcification. This is a frequent and potentially serious complication, affecting all types of diabetes. In recent years, our understanding of the pathophysiology and clinical significance of medial arterial calcification has improved considerably. Here, we offer a short narrative review of the epidemiology, clinical consequences, and pathophysiology of this complication. Now that medial arterial calcification of the lower limbs is better understood, we also focus on the prospect of treatments targeting arterial calcification.
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Affiliation(s)
- Jean-Michel Davaine
- Sorbonne Université, Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Vascular Surgery, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Damien Denimal
- INSERM U1231, Center for Translational and Molecular Medicine, Dijon, France; Dijon Bourgogne University Hospital, Department of Clinical Biochemistry, Dijon, France
| | - Pauline Treca
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Diabetology, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France
| | - Hugo Francon
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Diabetology, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France
| | - Franck Phan
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Diabetology, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France
| | - Agnès Hartemann
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Diabetology, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France
| | - Olivier Bourron
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Assistance Publique‑Hôpitaux de Paris (APHP), Department of Diabetology, Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, France.
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Saunders SL, Chaudhri K, McOrist NS, Gladysz K, Gnanenthiran SR, Shalaby G. Do bisphosphonates and RANKL inhibitors alter the progression of coronary artery calcification? A systematic review. BMJ Open 2024; 14:e084516. [PMID: 39322597 PMCID: PMC11429268 DOI: 10.1136/bmjopen-2024-084516] [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: 01/21/2024] [Accepted: 08/09/2024] [Indexed: 09/27/2024] Open
Abstract
OBJECTIVES To determine whether bisphosphonates and NF-κB ligand (RANKL) inhibitors delay coronary artery calcification (CAC). DESIGN A systematic review was conducted. DATA SOURCES MEDLINE, EMBASE and CENTRAL. ELIGIBILITY CRITERIA Longitudinal studies investigating CAC progression in adults (>18 years) taking either a bisphosphonate or denosumab compared with those who did not. DATA EXTRACTION AND SYNTHESIS Study and participant characteristics, and primary outcome ( ∆ CAC from baseline to follow-up) were extracted. The Risk Of Bias In Non-Randomised Studies-of Interventions (ROBINS-I) and Risk-of-Bias Tool for Randomised Trials (RoB2) tools were used to assess the risk of bias for observational and randomised controlled trials (RCTs), respectively. Outcome measures were reported. RESULTS Four observational studies and one RCT (n=377) were included. Three studies solely reported the effect of bisphosphonates on ∆ CAC; one study (n=56) demonstrated a statistically significant CAC reduction in the intervention group (-372 mm3/year) compared with control (+159 mm3/year) (p<0.01). One study (n=14) demonstrated a difference in ∆ CAC between intervention (+880 mm3/year) versus control (+2220 mm3/year), however, no p value comparing groups was reported. One study (n=115) found no statistically significant difference between intervention and control.One study (n=42) exclusively investigated the effect of RANKL on ∆ CAC; there was a statistically significant reduction in CAC at 6-month follow-up between intervention (-133±124 modified Agatston unit (AU)) and control (+188±72 modified AU), p=0.03.One study (n=150) compared both bisphosphonates and denosumab to control and found no statistically significant difference between either intervention group and control over 24 months. Meta-analysis was not performed due to limited, heterogeneous studies. CONCLUSIONS There is insufficient evidence supporting the correlation between bisphosphonate or RANKL inhibitor use and CAC progression. Further research is warranted.
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Affiliation(s)
- Samantha Louise Saunders
- School of Medicine, The University of Notre Dame Australia, Darlinghurst, New South Wales, Australia
| | - Kanika Chaudhri
- Cardiovascular Division, The George Institute for Global Health, Newtown, New South Wales, Australia
| | - Nathan Scott McOrist
- School of Medicine, The University of Notre Dame Australia, Darlinghurst, New South Wales, Australia
| | - Karen Gladysz
- School of Medicine, The University of Notre Dame Australia, Darlinghurst, New South Wales, Australia
| | - Sonali R Gnanenthiran
- Cardiovascular Division, The George Institute for Global Health, Newtown, New South Wales, Australia
- Cardiology, Concord Hospital, Concord, New South Wales, Australia
| | - Grant Shalaby
- School of Medicine, The University of Notre Dame Australia, Darlinghurst, New South Wales, Australia
- Cardiology, Nepean Hospital, Kingswood, New South Wales, Australia
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Geers J, Bing R, Pawade TA, Doris MK, Daghem M, Fletcher AJ, White AC, Forsyth L, Evans E, Kwieciński J, Williams MC, van Beek EJR, Kwak S, Peeters FE, Tzolos E, Slomka PJ, Lucatelli C, Ralston SH, Prendergast B, Newby DE, Dweck MR. Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial. J Am Heart Assoc 2024; 13:e032571. [PMID: 39248270 PMCID: PMC11935633 DOI: 10.1161/jaha.123.032571] [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: 12/07/2023] [Accepted: 03/08/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. METHODS AND RESULTS In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. CONCLUSIONS Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. REGISTRATION https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
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Affiliation(s)
- Jolien Geers
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
- Department of CardiologyUniversitair Ziekenhuis Brussel (UZ Brussel)Vrije Universiteit Brussel (VUB)BrusselsBelgium
| | - Rong Bing
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Tania A. Pawade
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Mhairi K. Doris
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Marwa Daghem
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Alexander J. Fletcher
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
- Department of Child HealthUniversity of GlasgowGlasgowUK
| | - Audrey C. White
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Laura Forsyth
- Edinburgh Clinical Trials UnitUniversity of EdinburghEdinburghUK
| | - Emily Evans
- Edinburgh Clinical Research FacilityUniversity of EdinburghEdinburghUK
| | - Jacek Kwieciński
- Department of Interventional Cardiology and AngiologyInstitute of CardiologyWarsawPoland
| | - Michelle C. Williams
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
- Edinburgh ImagingUniversity of EdinburghEdinburghUK
| | - Edwin J. R. van Beek
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
- Edinburgh ImagingUniversity of EdinburghEdinburghUK
| | - Soongu Kwak
- Department of Internal MedicineSeoul National University HospitalSeoulSouth Korea
| | | | - Evangelos Tzolos
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Piotr J Slomka
- Departments of Biomedical Sciences and MedicineCedars‐Sinai Medical CenterBiomedical Imaging Research InstituteLos AngelesCAUSA
| | | | - Stuart H. Ralston
- Institute of Genetics and Molecular MedicineUniversity of EdinburghUK
| | | | - David E. Newby
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Marc R. Dweck
- BHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
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Diab DL, Watts NB. The use of denosumab in osteoporosis - an update on efficacy and drug safety. Expert Opin Drug Saf 2024; 23:1069-1077. [PMID: 39262109 DOI: 10.1080/14740338.2024.2386365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/03/2024] [Indexed: 09/13/2024]
Abstract
INTRODUCTION Denosumab (Prolia) is a fully human monoclonal antibody against the receptor activator of the nuclear factor kappaB ligand. It is a potent antiresorptive agent that reduces osteoclastogenesis. AREAS COVERED Denosumab has been shown to improve bone mineral density and reduce the incidence of new fractures in postmenopausal women and men. It is also used in the treatment of glucocorticoid-induced osteoporosis, as well as for the prevention of bone loss and reduction of fracture risk in men receiving androgen deprivation therapy for non-metastatic prostate cancer and women receiving adjuvant aromatase inhibitor therapy for breast cancer. Initial safety concerns included infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures; however, further study and experience provide reassurance on these issues. Anecdotal reports have raised concerns about an increased risk of multiple vertebral fractures following discontinuation of denosumab. EXPERT OPINION Although bisphosphonates are often selected as initial therapy for osteoporosis, denosumab may be an appropriate initial therapy in patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, as well as patients who are intolerant of, unresponsive to, or have contraindications to other therapies. Additional data is needed to address questions regarding treatment duration and discontinuation.
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Affiliation(s)
- Dima L Diab
- College of Medicine, Cincinnati VA Medical Center, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA
| | - Nelson B Watts
- Mercy Health Osteoporosis and Bone Health Services, Cincinnati, OH, USA
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Kobayashi T, Morimoto T, Ito K, Mawatari M, Shimazaki T. Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials. Osteoporos Int 2024; 35:1377-1393. [PMID: 38733394 DOI: 10.1007/s00198-024-07118-0] [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: 12/26/2023] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.
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Affiliation(s)
- Takaomi Kobayashi
- Department of Orthopaedic Surgery, Taku City Hospital, Saga, Japan.
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan.
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
- Department of Clinical Research, Amagi Chuo Hospital, Fukuoka, Japan.
| | - Tadatsugu Morimoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Koji Ito
- Department of Orthopaedic Surgery, Taku City Hospital, Saga, Japan
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Masaaki Mawatari
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Takafumi Shimazaki
- Department of Orthopaedic Surgery, Taku City Hospital, Saga, Japan
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
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Zhu Y, Lai Y, Hu Y, Fu Y, Zhang Z, Lin N, Huang W, Zheng L. The mechanisms underlying acute myocardial infarction in chronic kidney disease patients undergoing hemodialysis. Biomed Pharmacother 2024; 177:117050. [PMID: 38968794 DOI: 10.1016/j.biopha.2024.117050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024] Open
Abstract
Cardiovascular disease (CVD) is a leading cause of death in chronic kidney disease (CKD). Hemodialysis is one of the main treatments for patients with end-stage kidney disease. Epidemiological data has shown that acute myocardial infarction (AMI) accounts for the main reason for death in patients with CKD under hemodialysis therapy. Immune dysfunction and changes in metabolism (including a high level of inflammatory cytokines, a disorder of lipid and mineral ion homeostasis, accumulation of uremic toxins et al.) during CKD can deteriorate stability of atherosclerotic plaque and promote vascular calcification, which are exactly the pathophysiological mechanisms underlying the occurrence of AMI. Meanwhile, the hemodialysis itself also has adverse effects on lipoprotein, the immune system and hemodynamics, which contribute to the high incidence of AMI in these patients. This review aims to summarize the mechanisms and further promising methods of prevention and treatment of AMI in CKD patients undergoing hemodialysis, which can provide an excellent paradigm for exploring the crosstalk between the kidney and cardiovascular system.
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Affiliation(s)
- Yujie Zhu
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China
| | - Yuchen Lai
- School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yuxuan Hu
- Hubei University of Science and Technology, Xianning 437100, China
| | - Yiwen Fu
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China
| | - Zheng Zhang
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China
| | - Nan Lin
- Department of Cardiology, Fujian Provincial Hospital, Fuzhou 350013, China
| | - Wei Huang
- Department of Cardiology, General Hospital of Central Theater Command, No.627, Wuluo Road, Wuhan 430070, China.
| | - Lemin Zheng
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China; Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Beijing Institute of Brain Disorders, The Capital Medical University, Beijing 100050, China.
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Zheng J, He J, Li H. FAM19A5 in vascular aging and osteoporosis: Mechanisms and the "calcification paradox". Ageing Res Rev 2024; 99:102361. [PMID: 38821416 DOI: 10.1016/j.arr.2024.102361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/05/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
Aging induces a progressive decline in the vasculature's structure and function. Vascular aging is a determinant factor for vascular ailments in the elderly. FAM19A5, a recently identified adipokine, has demonstrated involvement in multiple vascular aging-related pathologies, including atherosclerosis, cardio-cerebral vascular diseases and cognitive deficits. This review summarizes the current understanding of FAM19A5' role and explores its putative regulatory mechanisms in various aging-related disorders, including cardiovascular diseases (CVDs), metabolic diseases, neurodegenerative diseases and malignancies. Importantly, we provide novel insights into the underlying therapeutic value of FAM19A5 in osteoporosis. Finally, we outline future perspectives on the diagnostic and therapeutic potential of FAM19A5 in vascular aging-related diseases.
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Affiliation(s)
- Jin Zheng
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Jieyu He
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Huahua Li
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
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Fernández-Villabrille S, Martín-Vírgala J, Martín-Carro B, Baena-Huerta F, González-García N, Gil-Peña H, Rodríguez-García M, Fernández-Gómez JM, Fernández-Martín JL, Alonso-Montes C, Naves-Díaz M, Carrillo-López N, Panizo S. RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction. Int J Mol Sci 2024; 25:5735. [PMID: 38891922 PMCID: PMC11172097 DOI: 10.3390/ijms25115735] [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: 04/23/2024] [Revised: 05/22/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.
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MESH Headings
- RANK Ligand/metabolism
- RANK Ligand/genetics
- Animals
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Rats
- Humans
- Male
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Osteoprotegerin/metabolism
- Osteoprotegerin/genetics
- Parathyroid Hormone/metabolism
- Cells, Cultured
- Rats, Sprague-Dawley
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Affiliation(s)
- Sara Fernández-Villabrille
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Julia Martín-Vírgala
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Beatriz Martín-Carro
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Francisco Baena-Huerta
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Nerea González-García
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Helena Gil-Peña
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- AGC de la Infancia y Adolescencia, Hospital Universitario Central de Asturias (HUCA), Instituto de Investigación Sanitaria del Princiado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Minerva Rodríguez-García
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | | | - José Luis Fernández-Martín
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Department of Medicine, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Cristina Alonso-Montes
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
| | - Manuel Naves-Díaz
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Department of Medicine, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Natalia Carrillo-López
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Department of Medicine, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Sara Panizo
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Department of Medicine, Universidad de Oviedo, 33006 Oviedo, Spain
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Dai GC, Wang H, Ming Z, Lu PP, Li YJ, Gao YC, Shi L, Cheng Z, Liu XY, Rui YF. Heterotopic mineralization (ossification or calcification) in aged musculoskeletal soft tissues: A new candidate marker for aging. Ageing Res Rev 2024; 95:102215. [PMID: 38325754 DOI: 10.1016/j.arr.2024.102215] [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: 11/19/2023] [Revised: 01/21/2024] [Accepted: 02/01/2024] [Indexed: 02/09/2024]
Abstract
Aging can lead to various disorders in organisms and with the escalating impact of population aging, the incidence of age-related diseases is steadily increasing. As a major risk factor for chronic illnesses in humans, the prevention and postponement of aging have become focal points of research among numerous scientists. Aging biomarkers, which mirror molecular alterations at diverse levels in organs, tissues, and cells, can be used to monitor and evaluate biological changes associated with aging. Currently, aging biomarkers are primarily categorized into physiological traits, imaging characteristics, histological features, cellular-level alterations, and molecular-level changes that encompass the secretion of aging-related factors. However, in the context of the musculoskeletal soft tissue system, aging-related biological indicators primarily involve microscopic parameters at the cellular and molecular levels, resulting in inconvenience and uncertainty in the assessment of musculoskeletal soft tissue aging. To identify convenient and effective indicators, we conducted a comprehensive literature review to investigate the correlation between ectopic mineralization and age-related changes in the musculoskeletal soft tissue system. Here, we introduce the concept of ectopic mineralization as a macroscopic, reliable, and convenient biomarker for musculoskeletal soft tissue aging and present novel targets and strategies for the future management of age-related musculoskeletal soft tissue disorders.
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Affiliation(s)
- Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Hao Wang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Zhang Ming
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Ying-Juan Li
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Yu-Cheng Gao
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Zhang Cheng
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Xiao-Yu Liu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China.
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10
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Fernández-Villabrille S, Martín-Carro B, Martín-Vírgala J, Rodríguez-Santamaria MDM, Baena-Huerta F, Muñoz-Castañeda JR, Fernández-Martín JL, Alonso-Montes C, Naves-Díaz M, Carrillo-López N, Panizo S. Novel Biomarkers of Bone Metabolism. Nutrients 2024; 16:605. [PMID: 38474734 DOI: 10.3390/nu16050605] [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: 01/23/2024] [Revised: 02/14/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
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Affiliation(s)
- Sara Fernández-Villabrille
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Beatriz Martín-Carro
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Julia Martín-Vírgala
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | | | - Francisco Baena-Huerta
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Juan Rafael Muñoz-Castañeda
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Nephrology Service, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain
| | - José Luis Fernández-Martín
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Cristina Alonso-Montes
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Manuel Naves-Díaz
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Natalia Carrillo-López
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Sara Panizo
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
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11
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Alarkawi D, Tran T, Chen W, March LM, Blyth FM, Blank RD, Bliuc D, Center JR. Denosumab and Mortality in a Real-World Setting: A Comparative Study. J Bone Miner Res 2023; 38:1757-1770. [PMID: 37915252 DOI: 10.1002/jbmr.4930] [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: 01/18/2023] [Revised: 10/13/2023] [Accepted: 10/21/2023] [Indexed: 11/03/2023]
Abstract
Denosumab (Dmab) is increasingly prescribed worldwide. Unlike bisphosphonates (BPs), its effect on mortality has yet to be well explored. This study examined the association between Dmab and all-cause mortality compared with no treatment in subjects with a fracture and BPs in subjects without a fracture. The study population was from the Sax Institute's 45 and Up Study (n = 267,357), a prospective population-based cohort with questionnaire data linked to hospital admissions (Admitted Patients Data Collection [APDC] data were linked by the Centre for Health Record Linkage), medication records (Pharmaceutical Benefits Scheme [PBS] provided by Services Australia), and stored securely (secure data access was provided through the Sax Institute's Secure Unified Research Environment [SURE]). The new-user cohort design with propensity-score (PS) matching was implemented. In the fracture cohort, Dmab and oral BP users were matched 1:2 to no treatment (Dmab: 617 women, 154 men; oral BPs: 615 women, 266 men). In the no-fracture cohort, Dmab users were matched 1:1 with oral BPs and zoledronic acid (Zol) users (Dmab:oral BPs: 479 men, 1534 women; Dmab:Zol: 280 men, 625 women). Mortality risk was measured using sex-specific pairwise multivariable Cox models. In the fracture cohort, compared with no treatment, Dmab was associated with 48% lower mortality in women (hazard ratio [HR] = 0.52, 95% confidence interval [CI] 0.36-0.72) but not in men. Oral BPs were associated with 44% lower mortality in both sexes (women HR = 0.56, 95% CI 0.42-0.77; men HR = 0.56, 95% CI 0.40-0.78). In the no-fracture cohort, compared with BPs, Dmab was associated with 1.5- to 2.5-fold higher mortality than oral BPs (women HR = 1.49, 95% CI 1.13-1.98; men HR = 2.74; 95% CI 1.82-4.11) but similar mortality to Zol. Dmab in women and oral BPs were associated with lower post-fracture mortality than no treatment. However, Dmab users had generally higher mortality than oral BP users in those without fractures. © 2023 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Dunia Alarkawi
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
| | - Thach Tran
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
| | - Weiwen Chen
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales, Sydney, Australia
| | - Lyn M March
- Institute of Bone and Joint Research, Kolling Institute, Sydney, Australia
- Clinical School, Royal North Shore Hospital, St Leonards, Australia
| | - Fiona M Blyth
- Clinical School, Concord Repatriation General Hospital, Sydney, Australia
| | - Robert D Blank
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
| | - Dana Bliuc
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
- School of Population Health, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia
| | - Jacqueline R Center
- Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales, Sydney, Australia
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12
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Di Costanzo A, Indolfi C, Franzone A, Esposito G, Spaccarotella CAM. Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA. Int J Mol Sci 2023; 24:14939. [PMID: 37834387 PMCID: PMC10573862 DOI: 10.3390/ijms241914939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85-90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.
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Affiliation(s)
- Assunta Di Costanzo
- Division of Cardiology, Cardiovascular Research Center, University Magna Graecia Catanzaro, 88100 Catanzaro, Italy;
| | - Ciro Indolfi
- Division of Cardiology, Cardiovascular Research Center, University Magna Graecia Catanzaro, 88100 Catanzaro, Italy;
| | - Anna Franzone
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
| | - Giovanni Esposito
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
| | - Carmen Anna Maria Spaccarotella
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
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13
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Tsai YL, Wu CH, Li CC, Shih CA, Chang YF, Hwang JS, Tai TW. Drug adherence and treatment duration for denosumab and mortality risk among hip fracture patients. Osteoporos Int 2023; 34:1783-1791. [PMID: 37466659 DOI: 10.1007/s00198-023-06845-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/28/2023] [Indexed: 07/20/2023]
Abstract
This study aimed to assess the impact of drug adherence and treatment duration for denosumab on mortality risk after hip fracture surgery. Lower all-cause mortality risk was associated with drug intervals of 7 months or less and longer treatment duration. The study highlights the importance of proper denosumab administration. PURPOSE Prescription of anti-osteoporotic medications (AOMs) after osteoporotic hip fracture may increase bone mineral density (BMD) and decrease mortality risk. However, few studies have been conducted on drug adherence and treatment duration for denosumab, a popular choice among AOMs. This study aimed to assess the impact of denosumab adherence and treatment duration on the mortality risk of hip fracture patients after surgery. METHODS We conducted a cohort study using nationwide population data from National Health Insurance Research Database (NHIRD) in Taiwan. Patients newly diagnosed with osteoporosis and hip fracture between 2008 and 2019 who used denosumab after surgery were included. We assessed drug adherence, treatment duration, and other parameters associated with patient outcomes. RESULTS A total of 21,316 patients diagnosed with osteoporotic hip fractures were included. Compared with a > 7-month drug interval for denosumab, an interval of ≤ 7 months led to lower all-cause mortality risk (hazard ratio (HR): 0.60, 95% confidence interval (CI): 0.57 ~ 0.64). Patients with denosumab treatment for over 1, 2, and 3 years had lower all-cause mortality risk (HR&CI: 0.68 (0.64 ~ 0.73), 0.48 (0.43 ~ 0.53), 0.29 (0.26 ~ 0.33)) than those with treatment duration < 1 year. Analysis after excluding short-term death yielded similar results. Analysis of causes of death also showed that good adherence and longer duration were associated with reduced mortality due to cancer and cardiovascular disease. CONCLUSION Better drug adherence and longer duration of denosumab treatment are associated with lower all-cause mortality risk among hip fracture patients after surgery. Our study highlights the benefits of a proper time interval of denosumab administration. These findings provide important insight into management of osteoporotic hip fractures and may inform clinical practice and development of guidelines.
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Affiliation(s)
- Yi-Lun Tsai
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Hsing Wu
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Chun Li
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-An Shih
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yin-Fan Chang
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jawl-Shan Hwang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Ta-Wei Tai
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Skeleton Materials and Biocompatibility Core Lab, Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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14
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Kanbay M, Copur S, Tanriover C, Yavuz F, Galassi A, Ciceri P, Cozzolino M. The pathophysiology and management of vascular calcification in chronic kidney disease patients. Expert Rev Cardiovasc Ther 2023; 21:75-85. [PMID: 36716079 DOI: 10.1080/14779072.2023.2174525] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Vascular calcification (VC) which is the pathological mineral deposition in the vascular system, predominantly at the intimal and medial layer of the vessel wall, is an important comorbidity in patients with chronic kidney disease (CKD) leading to significant morbidity and mortality while necessitating appropriate treatment. Our review aims to provide an in-depth analysis of the current understanding of VC. AREAS COVERED In this review, we first discuss the pathophysiology of VC in CKD patients, then we explain the methods to predict and assess VC. Afterwards, we provide the currently available as well as the potential therapeutic approaches of VC. We finally discuss our understanding regarding the current situation surrounding VC in our expert opinion section. EXPERT OPINION Predicting, assessing and treating VC is crucial and the future advances in the field of research surrounding VC will potentially occur in one or more of these three areas of clinical management. There is a current lack of evidence and consensus regarding specific therapeutic options for alleviating VC and this situation may not necessitate VC to be determined, detected, and documented before the available options are implemented. Regardless, the prediction and assessment of VC is still important and requires further improvement together with the developments in therapeutic alternatives. The future has the potential to bring better research which would guide and improve the management of this patient group. A more specialized approach consisting of targeted therapies and more tailored management plans for patients with CKD and VC is on the horizon.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.,Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Furkan Yavuz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Andrea Galassi
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Paola Ciceri
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
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15
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Denosumab Is Superior to Raloxifene in Lowering Risks of Mortality and Ischemic Stroke in Osteoporotic Women. Pharmaceuticals (Basel) 2023. [DOI: 10.3390/ph16020222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Both osteoporosis and cardiovascular disease (CVD) share similar pathways in pathophysiology and are intercorrelated with increased morbidity and mortality in elderly women. Although denosumab and raloxifene are the current guideline-based pharmacological treatments, their impacts on cardiovascular protection are yet to be examined. This study aimed to compare mortality rate and cardiovascular events between denosumab and raloxifene in osteoporotic women. Risks of CVD development and all-cause mortality were estimated using Cox proportional hazard regression. A total of 7972 (3986 in each group) women were recruited between January 2003 and December 2018. No significant difference between denosumab and raloxifene was observed in composite CVDs, myocardial infarction, or congestive heart failure. However, comparison of the propensity score matched cohorts revealed that patients with proportion of days covered (PDC) ≥60% had lower incidence of ischemic stroke in the denosumab group than that in the raloxifene group (aHR 0.68; 95% CI 0.47–0.98; p = 0.0399). In addition, all-cause mortality was lower in the denosumab group than in the raloxifene group (aHR 0.59; 95% CI 0.48–0.72; p = 0.001), except in patients aged <65 y/o in this cohort study. We concluded that denosumab is superior to raloxifene in lowering risks of all-cause mortality and certain ischemic strokes in osteoporotic women.
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Pan W, Jie W, Huang H. Vascular calcification: Molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e200. [PMID: 36620697 PMCID: PMC9811665 DOI: 10.1002/mco2.200] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 01/05/2023] Open
Abstract
Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life-threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin-angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.
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Affiliation(s)
- Wei Pan
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
| | - Wei Jie
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
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17
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Alhajri N, Rustom M, Adegbile A, Ahmed W, Kilidar S, Afify N. Deciphering the Basis of Molecular Biology of Selected Cardiovascular Diseases: A View on Network Medicine. Int J Mol Sci 2022; 23:ijms231911421. [PMID: 36232723 PMCID: PMC9569471 DOI: 10.3390/ijms231911421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death across the world. For decades, researchers have been studying the causes of cardiovascular disease, yet many of them remain undiscovered or poorly understood. Network medicine is a recently expanding, integrative field that attempts to elucidate this issue by conceiving of disease as the result of disruptive links between multiple interconnected biological components. Still in its nascent stages, this revolutionary application of network science facilitated a number of important discoveries in complex disease mechanisms. As methodologies become more advanced, network medicine harbors the potential to expound on the molecular and genetic complexities of disease to differentiate how these intricacies govern disease manifestations, prognosis, and therapy. This is of paramount importance for confronting the incredible challenges of current and future cardiovascular disease research. In this review, we summarize the principal molecular and genetic mechanisms of common cardiac pathophysiologies as well as discuss the existing knowledge on therapeutic strategies to prevent, halt, or reverse these pathologies.
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Affiliation(s)
- Noora Alhajri
- Department of Internal Medicine, Cleveland Clinic Abu Dhabi (CCAD), Abu Dhabi P.O. Box 112412, United Arab Emirates
- Correspondence:
| | - Mohammad Rustom
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
| | - Adedayo Adegbile
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
| | - Weshah Ahmed
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
| | - Salsabeel Kilidar
- Department of Emergency Medicine, Sheikh Shakhbout Medical City SSMC, Abu Dhabi P.O. Box 11001, United Arab Emirates
| | - Nariman Afify
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
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18
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Yamada S, Tsuruya K, Kitazono T, Nakano T. Emerging cross-talks between chronic kidney disease-mineral and bone disorder (CKD-MBD) and malnutrition-inflammation complex syndrome (MICS) in patients receiving dialysis. Clin Exp Nephrol 2022; 26:613-629. [PMID: 35353283 PMCID: PMC9203392 DOI: 10.1007/s10157-022-02216-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/22/2022] [Indexed: 12/14/2022]
Abstract
Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a systemic disorder that affects multiple organs and systems and increases the risk of morbidity and mortality in patients with CKD, especially those receiving dialysis therapy. CKD–MBD is highly prevalent in CKD patients, and its treatment is gaining attention from healthcare providers who manage these patients. Additional important pathologies often observed in CKD patients are chronic inflammation and malnutrition/protein-energy wasting (PEW). These two pathologies coexist to form a vicious cycle that accelerates the progression of various other pathologies in CKD patients. This concept is integrated into the term “malnutrition–inflammation–atherosclerosis syndrome” or “malnutrition–inflammation complex syndrome (MICS)”. Recent basic and clinical studies have shown that CKD–MBD directly induces inflammation as well as malnutrition/PEW. Indeed, higher circulating levels of inorganic phosphate, fibroblast growth factor 23, parathyroid hormone, and calciprotein particles, as markers for critical components and effectors of CKD–MBD, were shown to directly induce inflammatory responses, thereby leading to malnutrition/PEW, cardiovascular diseases, and clinically relevant complications. In this short review, we discuss the close interplay between CKD–MBD and MICS and emphasize the significance of simultaneous control of these two seemingly distinct pathologies in patients with CKD, especially those receiving dialysis therapy, for better management of the CKD/hemodialysis population.
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Affiliation(s)
- Shunsuke Yamada
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan.
| | | | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan
| | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan
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Lei J, Liu A, Ma Y, Shi G, Han F, Jiang W, Zhou Y, Zhang C, Liu Y, Huang X, Huang H, Chen J. Dexamethasone is Associated With a Lower Risk of the Progression of Thoracic Aortic Calcification in Breast Cancer Survivors. Front Pharmacol 2021; 12:740815. [PMID: 34955822 PMCID: PMC8709127 DOI: 10.3389/fphar.2021.740815] [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: 07/14/2021] [Accepted: 11/22/2021] [Indexed: 12/03/2022] Open
Abstract
Background and Purpose: Breast cancer survivors have an increased cardiovascular risk, and vascular calcification is the pathological basis of cardiovascular disease. Some factors that affect the progression of thoracic aortic calcification (TAC) in survivors are unclear, and this study aims to explore the relationship between dexamethasone or radiotherapy and the progression of TAC in survivors. Materials and Methods: This study included 189 female patients with breast cancer, and they were divided into the progression and non-progression TAC groups. Radiation or dexamethasone doses, and related laboratory parameters were collected. Results: The cumulative dose of dexamethasone was higher [40 (10–180) mg versus 180 (80–270) mg, p < 0.001], and the cycle was longer [4 (1–6) cycles versus 6 (4–8) cycles, p < 0.001] in the non-progression TAC group. The cumulative dose (r = −0.303, p < 0.001) and cycle (r = −0.357, p < 0.001) of dexamethasone were negatively correlated with the level of increased TAC Agatston scores in survivors. Logistic regression analysis showed that dexamethasone was a protective factor for the progression of TAC (p = 0.029, odds ratio = 0.263, 95% confidence interval = 0.08–0.872). However, there wasn’t significant relationship between radiotherapy, radiation dose, follow-up time and the progression of TAC (all p > 0.05). In addition, aorta volume was positively correlated with the level of increased TAC Agatston scores in intensity modulated radiation therapy (r = 0.460, p < 0.001). Conclusion: Dexamethasone is associated with a lower risk of the progression of TAC in breast cancer survivors, and there’s no correlation between radiotherapy and progression of TAC, but the aorta volume may be a predictor of the severity of progression of TAC.
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Affiliation(s)
- Juan Lei
- Department of Cardiovascular, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Aiting Liu
- Department of Cardiovascular, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yujia Ma
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guangzi Shi
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feng Han
- Department of Ultrasound, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Wenlong Jiang
- Department of Emergency, The Second People's Hospital of Huadu, Guangzhou, China
| | - Yongqiao Zhou
- Department of Cardiovascular, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chao Zhang
- Department of Cardiovascular, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yimin Liu
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaobo Huang
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Huang
- Department of Cardiovascular, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jie Chen
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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20
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Morselli F, McNally R, Nesti L, Liu B, Khan H, Thomson RJ, Stevenson A, Banerjee A, Ahmad M, Hanif M, Steeds R, Khan M. Pharmacological interventions for the treatment of aortic root and heart valve disease. Hippokratia 2021. [DOI: 10.1002/14651858.cd014767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Franca Morselli
- School of Cardiovascular Medicine and Sciences; King's College London; London UK
- Department of Cardiology; East Kent Hospitals Univestity NHS Foundation Trust; Kent UK
| | - Ryan McNally
- Department of Clinical Pharmacology; King's College London; London UK
| | - Lorenzo Nesti
- Department of Clinical and Experimental Medicine; University of Pisa; Pisa Italy
| | - Boyang Liu
- Department of Cardiology; University Hospitals Birmingham (Queen Elizabeth) NHS Foundation Trust; Birmingham UK
| | - Haris Khan
- Department of Renal Medicine; Guys and St Thomas NHS Foundation Trust; London UK
| | - Ross J Thomson
- William Harvey Research Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London; London UK
| | - Alex Stevenson
- Department of Acute Medicine; Royal Free NHS Foundation Trust; London UK
| | - Amitava Banerjee
- Institute of Health Informatics Research; University College London; London UK
| | - Mahmood Ahmad
- Department of Cardiology; Royal Free Hospital, Royal Free London NHS Foundation Trust; London UK
| | - Moghees Hanif
- William Harvey Research Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London; London UK
| | - Richard Steeds
- Department of Cardiology; University Hospitals Birmingham (Queen Elizabeth) NHS Foundation Trust; Birmingham UK
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21
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Afshar M, Yazdan-Ashoori S, Engert JC, Thanassoulis G. Drugs for Prevention and Treatment of Aortic Stenosis: How Close Are We? Can J Cardiol 2021; 37:1016-1026. [DOI: 10.1016/j.cjca.2021.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/18/2021] [Accepted: 02/25/2021] [Indexed: 12/25/2022] Open
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Carrillo-López N, Martínez-Arias L, Fernández-Villabrille S, Ruiz-Torres MP, Dusso A, Cannata-Andía JB, Naves-Díaz M, Panizo S. Role of the RANK/RANKL/OPG and Wnt/β-Catenin Systems in CKD Bone and Cardiovascular Disorders. Calcif Tissue Int 2021; 108:439-451. [PMID: 33586001 DOI: 10.1007/s00223-020-00803-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/19/2020] [Indexed: 12/23/2022]
Abstract
In the course of chronic kidney disease (CKD), alterations in the bone-vascular axis augment the risk of bone loss, fractures, vascular and soft tissue calcification, left ventricular hypertrophy, renal and myocardial fibrosis, which markedly increase morbidity and mortality rates. A major challenge to improve skeletal and cardiovascular outcomes in CKD patients requires a better understanding of the increasing complex interactions among the main modulators of the bone-vascular axis. Serum parathyroid hormone (PTH), phosphorus (P), calcium (Ca), fibroblast growth factor 23 (FGF23), calcidiol, calcitriol and Klotho are involved in this axis interact with RANK/RANKL/OPG system and the Wnt/β-catenin pathway. The RANK/RANKL/OPG system controls bone remodeling by inducing osteoblast synthesis of RANKL and downregulating OPG production and it is also implicated in vascular calcification. The complexity of this system has recently increased due the discovery of LGR4, a novel RANKL receptor involved in bone formation, but possibly also in vascular calcification. The Wnt/β-catenin pathway plays a key role in bone formation: when this pathway is activated, bone is formed, but when it is inhibited, bone formation is stopped. In the progression of CKD, a downregulation of the Wnt/β-catenin pathway has been described which occurs mainly through the not coincident elevations of sclerostin, Dickkopf1 (Dkk1) and the secreted Frizzled Related Proteins (sFRPs). This review analyzes the interactions of PTH, P, Ca, FGF23, calcidiol, calcitriol and Klotho with the RANKL/RANKL/OPG system and the Wnt/β-catenin, pathway and their implications in bone and cardiovascular disorders in CKD.
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Affiliation(s)
- Natalia Carrillo-López
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain
| | - Laura Martínez-Arias
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain
| | - Sara Fernández-Villabrille
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain
| | - María Piedad Ruiz-Torres
- Department of System Biology, Universidad de Alcalá, Retic REDinREN-ISCIII, Alcalá de Henares, Spain
| | - Adriana Dusso
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain
| | - Jorge B Cannata-Andía
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain.
| | - Manuel Naves-Díaz
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain
| | - Sara Panizo
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Universidad de Oviedo, Retic REDinREN-ISCIII, Avda. Roma, sn., 33011, Oviedo, Spain.
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Pimentel A, Ureña-Torres P, Bover J, Luis Fernandez-Martín J, Cohen-Solal M. Bone Fragility Fractures in CKD Patients. Calcif Tissue Int 2021; 108:539-550. [PMID: 33219822 PMCID: PMC8052229 DOI: 10.1007/s00223-020-00779-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022]
Abstract
Chronic kidney diseases (CKD) are associated with mineral and bone diseases (MBD), including pain, bone loss, and fractures. Bone fragility related to CKD includes the risk factors observed in osteoporosis in addition to those related to CKD, resulting in a higher risk of mortality related to fractures. Unawareness of such complications led to a poor management of fractures and a lack of preventive approaches. The current guidelines of the Kidney Disease Improving Global Outcomes (KDIGO) recommend the assessment of bone mineral density if results will impact treatment decision. In addition to bone density, circulating biomarkers of mineral, serum bone turnover markers, and imaging techniques are currently available to evaluate the fracture risk. The purpose of this review is to provide an overview of the epidemiology and pathogenesis of CKD-associated bone loss. The contribution of the current tools and other techniques in development are discussed. We here propose a current view of how to better predict bone fragility and the therapeutic options in CKD.
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Affiliation(s)
| | - Pablo Ureña-Torres
- AURA Paris-Nord, Saint-Ouen, France
- Necker Hospital, University of Paris Descartes, Department of Renal Physiology, Paris, France
| | - Jordi Bover
- Fundació Puigvert, Universitat Autònoma, IIB Sant Pau, REDinREN, Nephrology Department, Barcelona, Catalonia, Spain
| | - Jose Luis Fernandez-Martín
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), REDinREN del ISCIII, Hospital Universitario Central de Asturias. Universidad de Oviedo, Bone and Mineral Research Unit, Oviedo, Asturias, Spain
| | - Martine Cohen-Solal
- INSERM U1132 & Université de Paris, Hôpital Lariboisière, Department of Rheumatology, Paris, France.
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24
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Carrillo-López N, Martínez-Arias L, Alonso-Montes C, Martín-Carro B, Martín-Vírgala J, Ruiz-Ortega M, Fernández-Martín JL, Dusso AS, Rodriguez-García M, Naves-Díaz M, Cannata-Andía JB, Panizo S. The receptor activator of nuclear factor κΒ ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone-induced vascular calcification. Nephrol Dial Transplant 2021; 36:618-631. [PMID: 33367746 DOI: 10.1093/ndt/gfaa290] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 08/12/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND In chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone-vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH-driven VC. METHODS In vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1-34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10-7 versus 10-9 M PTH. RESULTS Rats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH-driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process. CONCLUSIONS High PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone's direct pro-calcifying actions involve PTH1R binding and PKA activation.
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Affiliation(s)
- Natalia Carrillo-López
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Laura Martínez-Arias
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Cristina Alonso-Montes
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Beatriz Martín-Carro
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Julia Martín-Vírgala
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Marta Ruiz-Ortega
- Vascular and Renal Laboratory Fundación Jimenez Díaz, Universidad Autónoma Madrid, REDinREN-ISCIII, Madrid, Spain
| | - José Luis Fernández-Martín
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Adriana S Dusso
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Minerva Rodriguez-García
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain.,Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Manuel Naves-Díaz
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
| | - Jorge B Cannata-Andía
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain.,Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Sara Panizo
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN-ISCIII, Oviedo, Spain
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Postmenopausal osteoporosis coexisting with other metabolic diseases: Treatment considerations. Maturitas 2021; 147:19-25. [PMID: 33832643 DOI: 10.1016/j.maturitas.2021.02.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/18/2021] [Accepted: 02/27/2021] [Indexed: 12/13/2022]
Abstract
In postmenopausal women, osteoporosis may coexist with other metabolic diseases, including, but not limited to, obesity, diabetes, nonalcoholic fatty liver disease (NAFLD), dyslipidemia and cardiovascular disease (CVD). This association may lie beyond simple coincidence owing to high prevalence of all these diseases, especially in the aging population, as common pathogenetic mechanisms between them and osteoporosis may exist. In this context, anti-osteoporotic medications may affect the pathogenesis of some of these metabolic diseases; this is an important consideration when selecting the most appropriate medication for osteoporotic patients with coexistent metabolic diseases. Conversely, some current or emerging medications for metabolic diseases adversely affect bone metabolism and, if possible, should be avoided in women with postmenopausal osteoporosis. The main aim of this review is to summarize the evidence on anti-osteoporotic treatment in postmenopausal women with concomitant metabolic diseases, i.e. obesity, diabetes, NAFLD, dyslipidemia and CVD. The secondary aim is to present data on the effect of current or emerging medication for metabolic diseases on bone metabolism of postmenopausal women. Deeper understanding of the underlying links between osteoporosis and metabolic diseases may have clinical implications. However, mechanistic studies are needed to elucidate the potential pathophysiological links, as well as clinical trials in women with postmenopausal osteoporosis coexisting with specific metabolic diseases; these may guide clinical practice in the future for the selection of the best anti-osteoporotic medication for each patient with specific metabolic diseases.
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Singh A, Tandon S, Tandon C. An update on vascular calcification and potential therapeutics. Mol Biol Rep 2021; 48:887-896. [PMID: 33394226 DOI: 10.1007/s11033-020-06086-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/12/2020] [Indexed: 02/07/2023]
Abstract
Pathological calcification is a major cause of cardiovascular morbidities primarily in population with chronic kidney disease (CKD), end stage renal diseases (ERSD) and metabolic disorders. Investigators have accepted the fact that vascular calcification is not a passive process but a highly complex, cell mediated, active process in patients with cardiovascular disease (CVD) resulting from, metabolic insults of bone fragility, diabetes, hypertension, dyslipidemia and atherosclerosis. Over the years, studies have revealed various mechanisms of vascular calcification like induction of bone formation, apoptosis, alteration in Ca-P balance and loss of inhibition. Novel clinical studies targeting cellular mechanisms of calcification provide promising and potential avenues for drug development. The interventions include phosphate binders, sodium thiosulphate, vitamin K, calcimimetics, vitamin D, bisphosphonates, Myoinositol hexaphosphate (IP6), Denosumab and TNAP inhibitors. Concurrently investigators are also working towards reversing or curing pathological calcification. This review focuses on the relationship of vascular calcification to clinical diseases, regulators and factors causing calcification including genetics which have been identified. At present, there is lack of any significant preventive measures for calcifications and hence this review explores further possibilities for drug development and treatment modalities.
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Affiliation(s)
- Anubha Singh
- Amity Institute of Biotechnology (AIB), Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
| | - Chanderdeep Tandon
- Amity Institute of Biotechnology (AIB), Amity University Uttar Pradesh, Noida, Uttar Pradesh, India.
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27
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Chen Y, Zhao X, Wu H. Transcriptional Programming in Arteriosclerotic Disease: A Multifaceted Function of the Runx2 (Runt-Related Transcription Factor 2). Arterioscler Thromb Vasc Biol 2021; 41:20-34. [PMID: 33115268 PMCID: PMC7770073 DOI: 10.1161/atvbaha.120.313791] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite successful therapeutic strategies in the prevention and treatment of arteriosclerosis, the cardiovascular complications remain a major clinical and societal issue worldwide. Increased vascular calcification promotes arterial stiffness and accelerates cardiovascular morbidity and mortality. Upregulation of the Runx2 (Runt-related transcription factor 2), an essential osteogenic transcription factor for bone formation, in the cardiovascular system has emerged as an important regulator for adverse cellular events that drive cardiovascular pathology. This review discusses the regulatory mechanisms that are critical for Runx2 expression and function and highlights the dynamic and complex cross talks of a wide variety of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and O-linked β-N-acetylglucosamine modification, in regulating Runx2 stability, cellular localization, and osteogenic transcriptional activity. How the activation of an array of signaling cascades by circulating and local microenvironmental factors upregulates Runx2 in vascular cells and promotes Runx2-mediated osteogenic transdifferentiation of vascular smooth muscle cells and expression of inflammatory cytokines that accelerate macrophage infiltration and vascular osteoclast formation is summarized. Furthermore, the increasing appreciation of a new role of Runx2 upregulation in promoting vascular smooth muscle cell phenotypic switch, and Runx2 modulated by O-linked β-N-acetylglucosamine modification and Runx2-dependent repression of smooth muscle cell-specific gene expression are discussed. Further exploring the regulation of this key osteogenic transcription factor and its new perspectives in the vasculature will provide novel insights into the transcriptional regulation of vascular smooth muscle cell phenotype switch, reprograming, and vascular inflammation that promote the pathogenesis of arteriosclerosis.
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Affiliation(s)
- Yabing Chen
- Department of Pathology, University of Alabama at Birmingham
- Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294
| | - Xinyang Zhao
- Department of Biochemistry, University of Alabama at Birmingham
| | - Hui Wu
- Department of Integrative Biomedical & Diagnostic Sciences, Oregon Health and Science University School of Dentistry, Portland, Oregon 97239
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28
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Cipriani C, Piemonte S, Colangelo L, De Martino V, Diacinti D, Ferrone F, Piazzolla V, Fassino V, Nieddu L, Minisola S, Pepe J. Inhibition of the RANKL with denosumab has no effect on circulating markers of atherosclerosis in women with postmenopausal osteoporosis: a pilot study. Endocrine 2021; 71:199-207. [PMID: 32897516 DOI: 10.1007/s12020-020-02483-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/26/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE We evaluated the early effect of denosumab on circulating markers of atherosclerosis in women with postmenopausal osteoporosis. METHODS Denosumab (60 mg) was administered subcutaneously every 6 months (m) in 27 women (mean age 75 ± 5 years) with postmenopausal osteoporosis and high cardiovascular risk for a total of 24 m. Zoledronic acid was administered in 6 age-matched women as a single intravenous dose. Serum levels of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E and P selectin, CD-40 ligand (CD40L), interleukin-6 (IL-6), matrix metalloproteinase (MMP) 1 and 9, monocyte chemoattractant protein-1 (MCP-1), fibrinogen (FBG), and high sensitivity C-reactive protein (hs-CRP) were measured at baseline, 15 days (d), 2, 6 and 12 m after dosing. In the denosumab group, observation was extended to 24 m as secondary endpoint. RESULTS Serum ICAM-1 levels showed significant increase in the zoledronic acid group (+18 ± 0.1%; p < 0.01) at 12 m. In the denosumab group, we observed a significant increase in serum CD40L (+2 ± 0.8%; p < 0.001), MMP-1 (+11 ± 0.4%, p < 0.02), and MMP-9 (+39.4 ± 0.8%, p < 0.01) at 24 m. There was a significant increase in serum FBG and hs-CRP in both groups at 12 m (denosumab:+2.2 ± 0.2% and +50.3 ± 1.6%; zoledronic acid: +9.4 ± 0.1 and +81.8 ± 0.8%; p < 0.01). No significant between-group differences were found. CONCLUSIONS 24-m treatment with denosumab has no effect on the circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Fluctuation of serum ICAM-1, CD40L, MMPs, FBG and hs-CRP can be ascribed to perturbation of immunological mechanisms stimulated by denosumab and zoledronic acid.
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Affiliation(s)
- Cristiana Cipriani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
| | - Sara Piemonte
- ASL ROMA 1, Distretto 2, via Tagliamento 19, 00198, Rome, Italy
| | - Luciano Colangelo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Viviana De Martino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Daniele Diacinti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Federica Ferrone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Valentina Piazzolla
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Valeria Fassino
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Luciano Nieddu
- Faculty of Economics, UNINT University, Via Cristoforo Colombo 200, 00147, Rome, Italy
| | - Salvatore Minisola
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Jessica Pepe
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
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29
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Kodumudi V, Jeha GM, Mydlo N, Kaye AD. Management of Cutaneous Calciphylaxis. Adv Ther 2020; 37:4797-4807. [PMID: 32997277 PMCID: PMC7595979 DOI: 10.1007/s12325-020-01504-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022]
Abstract
Calciphylaxis is a deadly, painful disease with a 1-year mortality of up to 50%. The disease is commonly associated with patients with end-stage kidney disease (ESKD), but it can manifest in non-uremic patients as well. In patients who are undergoing dialysis, the incidence of calciphylaxis can range from 0.04% to 4%. The progressive arterial calcification seen in calciphylaxis can affect multiple body organs, including the skin, brain, lungs, and muscle. In cutaneous calciphylaxis, painful and non-healing nodules, plaques, and ulcers may appear, increasing morbidity for patients. Diagnosis can be difficult, and the condition can clinically appear similar to other dermatological diseases, especially in non-uremic patients. Currently, skin biopsy with histological analysis is the most reliable method to help diagnose the condition. In certain cases, the use of medical imaging may be helpful. Treatment of pain in this condition can be difficult and should be multimodal and include wound care as well as modification of risk factors. Analgesic options include opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), as well as analgesic options that are targeted for specific patients. There are currently multiple clinical trials underway that are studying targeted therapies for this condition.
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30
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Donato M, Ferri N, Lupo MG, Faggin E, Rattazzi M. Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis. Int J Mol Sci 2020; 21:ijms21218263. [PMID: 33158204 PMCID: PMC7663524 DOI: 10.3390/ijms21218263] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/31/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Calcific aortic valve stenosis (CAVS), the most common heart valve disease, is characterized by the slow progressive fibro-calcific remodeling of the valve leaflets, leading to progressive obstruction to the blood flow. CAVS is an increasing health care burden and the development of an effective medical treatment is a major medical need. To date, no effective pharmacological therapies have proven to halt or delay its progression to the severe symptomatic stage and aortic valve replacement represents the only available option to improve clinical outcomes and to increase survival. In the present report, the current knowledge and latest advances in the medical management of patients with CAVS are summarized, placing emphasis on lipid-lowering agents, vasoactive drugs, and anti-calcific treatments. In addition, novel potential therapeutic targets recently identified and currently under investigation are reported.
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Affiliation(s)
- Maristella Donato
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (M.D.); (N.F.); (M.G.L.)
| | - Nicola Ferri
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (M.D.); (N.F.); (M.G.L.)
| | - Maria Giovanna Lupo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (M.D.); (N.F.); (M.G.L.)
| | - Elisabetta Faggin
- Department of Medicine—DIMED, University of Padova, 35122 Padova, Italy;
| | - Marcello Rattazzi
- Department of Medicine—DIMED, University of Padova, 35122 Padova, Italy;
- Correspondence: ; Tel.: +39-0498-211-867 or +39-0422-322-207
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31
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Bourron O, Phan F, Diallo MH, Hajage D, Aubert CE, Carlier A, Salem JE, Funck-Brentano C, Kemel S, Cluzel P, Redheuil A, Davaine JM, Massy Z, Mentaverri R, Bonnefont-Rousselot D, Gillery P, Jaisson S, Vermeer C, Lacorte JM, Bouziri N, Laroche S, Amouyal C, Hartemann A. Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study. Cardiovasc Diabetol 2020; 19:140. [PMID: 32948184 PMCID: PMC7501627 DOI: 10.1186/s12933-020-01122-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 09/12/2020] [Indexed: 12/15/2022] Open
Abstract
Background Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. Methods Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. Results At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (β coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00–1.04, p < 0.001), triglycerides (0.11, 0.03–0.20, p = 0.007), log(RANKL) (0.07, 0.02–0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15–0.57, p = 0.001), statin use (0.39, 0.06–0.72, p = 0.023) and duration of follow up (0.04, 0.01–0.06, p = 0.004). Conclusion In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234
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Affiliation(s)
- Olivier Bourron
- Sorbonne Université, Paris, France. .,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France. .,Institute of Cardiometabolism and Nutrition ICAN, Paris, France. .,INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 06, France. .,Diabetology Department, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, Paris, France.
| | - Franck Phan
- Sorbonne Université, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France.,INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 06, France
| | - Mamadou Hassimiou Diallo
- Unité de Recherche Clinique Salpêtrière - Charles Foix, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, 75013, Paris, France
| | - David Hajage
- Département de Santé, Centre de Pharmacoépidémiologie (Cephepi), CIC-1421, Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, 75013, Paris, France
| | - Carole-Elodie Aubert
- Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France
| | - Aurélie Carlier
- Sorbonne Université, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Joe-Elie Salem
- Sorbonne Université, Paris, France.,Department of Pharmacology and CIC-1421, AP-HP La Pitié Salpêtrière Charles Foix University Hospital, Paris, France.,INSERM, CIC-1901, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Christian Funck-Brentano
- Sorbonne Université, Paris, France.,Department of Pharmacology and CIC-1421, AP-HP La Pitié Salpêtrière Charles Foix University Hospital, Paris, France.,INSERM, CIC-1901, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Salim Kemel
- Sorbonne Université, Paris, France.,Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Department of Radiology, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France
| | - Philippe Cluzel
- Sorbonne Université, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France.,Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Department of Radiology, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France
| | - Alban Redheuil
- Sorbonne Université, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France.,Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Department of Radiology, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France
| | | | - Ziad Massy
- Division of Nephrology, Ambroise Paré Hospital, AP-HP, Université Paris-Saclay, Paris, France
| | - Romuald Mentaverri
- INSERM_1088, Centre Universitaire de Recherche en Santé, Université de Picardie Jules Verne, Amiens, France
| | - Dominique Bonnefont-Rousselot
- Department of Metabolic Biochemistry, La Pitié Salpêtrière-Charles Foix University Hospital (AP-HP), Paris, France.,UTCBS, CNRS UMR8258 - INSERM_1267, Faculty of Pharmacy of Paris, University of Paris, Paris, France
| | - Philippe Gillery
- University of Reims- Champagne-Ardenne, CNRS, MEDyC UMR 7369, Reims, France.,Laboratory of Biochemisry-Pharmacology-Toxicology, University Hospital of Reims, Maison Blanche Hospital, Reims, France
| | - Stéphane Jaisson
- University of Reims- Champagne-Ardenne, CNRS, MEDyC UMR 7369, Reims, France.,Laboratory of Biochemisry-Pharmacology-Toxicology, University Hospital of Reims, Maison Blanche Hospital, Reims, France
| | - Cees Vermeer
- Cardiovascular Research Institute CARIM, Maastricht University, Maastricht, The Netherlands
| | - Jean-Marc Lacorte
- Sorbonne Université, Paris, France.,Department of Endocrine and Oncologic Biochemistry, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.,INSERM U1166, Paris, France
| | - Nesrine Bouziri
- Sorbonne University, ACTION Study Group, INSERM, UMRS 1166, Institut de Cardiologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France
| | - Suzanne Laroche
- Sorbonne Université, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Chloé Amouyal
- Sorbonne Université, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Agnes Hartemann
- Sorbonne Université, Paris, France.,Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Paris, France.,Institute of Cardiometabolism and Nutrition ICAN, Paris, France.,INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 06, France
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Chen CL, Chen NC, Wu FZ, Wu MT. Impact of denosumab on cardiovascular calcification in patients with secondary hyperparathyroidism undergoing dialysis: a pilot study. Osteoporos Int 2020; 31:1507-1516. [PMID: 32246167 DOI: 10.1007/s00198-020-05391-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/13/2020] [Indexed: 11/25/2022]
Abstract
UNLABELLED The receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/osteoprotegerin system is dysregulated in hyperparathyroid bone diseases. The introduction of denosumab preceding elective surgery as an alternative option when surgery is not possible immediately. INTRODUCTION The effects of denosumab on vascular calcification in patients with chronic renal failure and low bone mass have been a subject of interest. Therefore, this investigation aimed to determine the short-term changes in vascular calcification after denosumab treatment using a serial electrocardiography-gated computed tomography (CT) to measure coronary artery calcification (CAC) in patients with secondary hyperparathyroidism (SHPT) and low bone mass. METHODS This 6-month study enrolled patients with SHPT and low bone mass (T-score < - 2.5) owing to dialysis. The 2 groups administered denosumab at a dose of 60 mg (denosumab group), and conventional treatment (control group) had 21 patients each. All patients underwent CT scans at baseline and at the follow-up examination at 6 months to determine the bone mineral density and CAC. RESULTS The control group demonstrated a significant increase in Agatston scores (187.79 ± 72.27) (P = 0.004). However, no significant change was noted in the denosumab group (P = 0.41). In the denosumab group, only the baseline serum alkaline phosphatase levels correlated negatively with changes in the CAC score (P = 0.01); the baseline alkaline phosphatase levels were the deciding biomarkers for non-responsive CAC scores by Berry Criteria after denosumab treatment (P = 0.02). The denosumab group demonstrated significantly increased bone mineral density in the femoral neck and lumbar spine (P < 0.01). CONCLUSION The findings provide evidence that denosumab may suppress the progression of CAC and also regress osseous calcification in severe cases of high bone turnover.
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Affiliation(s)
- C-L Chen
- Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - N-C Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - F-Z Wu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Radiology, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Rd., Kaohsiung, 813, Taiwan
| | - M-T Wu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
- Department of Radiology, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Rd., Kaohsiung, 813, Taiwan.
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33
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Pereira L, Frazão JM. The bone-vessel axis in chronic kidney disease: An update on biochemical players and its future role in laboratory medicine. Clin Chim Acta 2020; 508:221-227. [PMID: 32422129 DOI: 10.1016/j.cca.2020.05.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/31/2020] [Accepted: 05/11/2020] [Indexed: 12/16/2022]
Abstract
Vascular wall calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). In CKD, VC is more frequent and severe than in the general population and it is associated with increased cardiovascular mortality and morbidity. In the last years, laboratory and clinical evidence have drawn the attention to the relationship between bone disease and VC in CKD patients, leading to the concept of a bone-vessel or bone-vascular axis. It means that disorders of bone volume and bone turnover may influence the risk of VC and ultimately the high risk of cardiovascular mortality. In fact, a higher burden of VC has been associated to low bone volume and low bone turnover in hemodialysis (HD) patients with renal osteodystrophy characterized by histomorphometric evaluation of bone biopsies. The molecular mechanisms underlying the regulation of bone cells and vascular cells in CKD are poorly understood. In this review, we discuss relevant evidence linking bone disorders and VC in CKD and also rising molecular players involved in this bone-vascular axis. Indeed, accumulating data is available for two proposed systems: receptor activator for nuclear factor kB (RANK)/ RANK ligand (RANKL)/osteoprotegerin (OPG) system and inhibitors of Wnt signaling - mainly sclerostin. Although they are promising biochemical markers linking bone formation and bone reabsorption with VC, there is a long way to go as long evidence from laboratory studies is often divergent to the clinical data as will be discussed. Future prospective studies are needed in order to evaluate the role of these biochemical players as useful clinical markers for VC, bone volume and perhaps bone turnover.
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Affiliation(s)
- Luciano Pereira
- Institute of Investigation and Innovation in Health, University of Porto, Portugal; INEB - National Institute of Biomedical Engineering, University of Porto, Portugal; Department of Nephrology, São João Hospital Center, Porto, Portugal
| | - João M Frazão
- Institute of Investigation and Innovation in Health, University of Porto, Portugal; INEB - National Institute of Biomedical Engineering, University of Porto, Portugal; Department of Nephrology, São João Hospital Center, Porto, Portugal.
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34
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Alushi B, Curini L, Christopher MR, Grubitzch H, Landmesser U, Amedei A, Lauten A. Calcific Aortic Valve Disease-Natural History and Future Therapeutic Strategies. Front Pharmacol 2020; 11:685. [PMID: 32477143 PMCID: PMC7237871 DOI: 10.3389/fphar.2020.00685] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 04/27/2020] [Indexed: 12/20/2022] Open
Abstract
Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder. It is characterized by an active remodeling process accompanied with valve mineralization, that results in a progressive aortic valve narrowing, significant restriction of the valvular area, and impairment of blood flow.The pathophysiology of CAVD is a multifaceted process, involving genetic factors, chronic inflammation, lipid deposition, and valve mineralization. Mineralization is strictly related to the inflammatory process in which both, innate, and adaptive immunity are involved. The underlying pathophysiological pathways that go from inflammation to calcification and, finally lead to severe stenosis, remain, however, incompletely understood. Histopathological studies are limited to patients with severe CAVD and no samples are available for longitudinal studies of disease progression. Therefore, alternative routes should be explored to investigate the pathogenesis and progression of CAVD.Recently, increasing evidence suggests that epigenetic markers such as non-coding RNAs are implicated in the landscape of phenotypical changes occurring in CAVD. Furthermore, the microbiome, an essential player in several diseases, including the cardiovascular ones, has recently been linked to the inflammation process occurring in CAVD. In the present review, we analyze and discuss the CAVD pathophysiology and future therapeutic strategies, focusing on the real and putative role of inflammation, calcification, and microbiome.
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Affiliation(s)
- Brunilda Alushi
- Department of Cardiology, Charite´ Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- Department of General and Interventional Cardiology, Helios Klinikum Erfurt, Erfurt, Germany
| | - Lavinia Curini
- Department of Cardiology, Charite´ Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Mary Roxana Christopher
- Department of Cardiology, Charite´ Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK), Berlin, Germany
| | - Herko Grubitzch
- Berlin Institute of Health, Berlin, Germany
- Department of Cardiology, German Heart Centre Berlin (DHZB), Berlin, Germany
| | - Ulf Landmesser
- Department of Cardiology, Charite´ Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
- Sod of Interdisciplinary Internal Medicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Florence, Italy
| | - Alexander Lauten
- Department of Cardiology, Charite´ Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- Department of General and Interventional Cardiology, Helios Klinikum Erfurt, Erfurt, Germany
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35
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Himmelsbach A, Ciliox C, Goettsch C. Cardiovascular Calcification in Chronic Kidney Disease-Therapeutic Opportunities. Toxins (Basel) 2020; 12:toxins12030181. [PMID: 32183352 PMCID: PMC7150985 DOI: 10.3390/toxins12030181] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the 'point of no return'. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.
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Kim JM, Lee WS, Kim J. Therapeutic strategy for atherosclerosis based on bone-vascular axis hypothesis. Pharmacol Ther 2020; 206:107436. [DOI: 10.1016/j.pharmthera.2019.107436] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2019] [Indexed: 12/19/2022]
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Zheng KH, Tzolos E, Dweck MR. Pathophysiology of Aortic Stenosis and Future Perspectives for Medical Therapy. Cardiol Clin 2020; 38:1-12. [DOI: 10.1016/j.ccl.2019.09.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Thajudeen B, Murugapandian S, Roy-Chaudhury P. Emerging Therapies. CHRONIC RENAL DISEASE 2020:1189-1205. [DOI: 10.1016/b978-0-12-815876-0.00072-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
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Pharmacological and Nutritional Modulation of Vascular Calcification. Nutrients 2019; 12:nu12010100. [PMID: 31905884 PMCID: PMC7019601 DOI: 10.3390/nu12010100] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 12/15/2022] Open
Abstract
Vascular calcification is an independent predictor of cardiovascular disease, and therefore, inhibition or regression of this processes is of clinical importance. The standard care regarding prevention and treatment of cardiovascular disease at this moment mainly depends on drug therapy. In animal and preclinical studies, various forms of cardiovascular drug therapy seem to have a positive effect on vascular calcification. In particular, calcium channel blockers and inhibitors of the renin-angiotensin-aldosteron system slowed down arterial calcification in experimental animals. In humans, the results of trials with these drugs are far less pronounced and often contradictory. There is limited evidence that the development of new atherosclerotic lesions may be retarded in patients with coronary artery disease, but existing lesions can hardly be influenced. Although statin therapy has a proven role in the prevention and treatment of cardiovascular morbidity and mortality, it is associated with both regression and acceleration of the vascular calcification process. Recently, nutritional supplements have been recognized as a potential tool to reduce calcification. This is particularly true for vitamin K, which acts as an inhibitor of vascular calcification. In addition to vitamin K, other dietary supplements may also modulate vascular function. In this narrative review, we discuss the current state of knowledge regarding the pharmacological and nutritional possibilities to prevent the development and progression of vascular calcification.
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Skripnikova IA, Kosmatova OV, Kolchinа MA, Myagkova MA, Alikhanova NA. Atherosclerosis and Osteoporosis. Common Targets for the Effects of Cardiovascular and Anti-Osteoporotic Drugs (Part II). The Effect of Antiosteoporotic Drugs on the Vascular Wall State. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2019. [DOI: 10.20996/1819-6446-2019-15-3-359-367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
In the second part of the literature review, data are presented on the possible effect of anti-osteoporosis therapy on the vascular wall and the development of calcification. The discovery of common biological substances involved in the development of atherosclerosis, calcification of the vascular wall and osteoporosis attracts the attention of scientists in terms of targets for assessing the effects of already known drugs or developing new drugs that can simultaneously prevent or slow the progression of both atherosclerosis and osteoporosis. Currently, various groups of drugs for the treatment of osteoporosis have been studied to prevent or reduce the progression of subclinical atherosclerosis and calcification. Both antiresorptive drugs (bisphosphonates, monoclonal antibodies to RANKL, selective estrogen receptor modulators), and bone-anabolic therapy, which includes teriparatide, were studied. However, there are a few such studies and the most promising drugs that have a preventive effect in the early stages of atherosclerotic damage are bisphosphonates. Other classes of antiosteoporotic drugs did not reveal a positive effect on the vascular wall, and some of them increased the cardiovascular risk. Divergences in the results of experimental and clinical studies attract attention. If in the experiment almost all drugs for the treatment of osteoporosis had an atheroprotective effect and suppressed vascular calcification, then in clinical conditions only bisphosphonates confirmed the positive effect on the vascular wall.
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Affiliation(s)
| | | | - M. A. Kolchinа
- National Medical Research Center for Preventive Medicine
| | - M. A. Myagkova
- National Medical Research Center for Preventive Medicine
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Hsu TW, Hsu CN, Wang SW, Huang CC, Li LC. Comparison of the Effects of Denosumab and Alendronate on Cardiovascular and Renal Outcomes in Osteoporotic Patients. J Clin Med 2019; 8:jcm8070932. [PMID: 31261703 PMCID: PMC6678904 DOI: 10.3390/jcm8070932] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/24/2019] [Accepted: 06/25/2019] [Indexed: 02/06/2023] Open
Abstract
A correlation between impaired bone metabolism, chronic kidney disease, and cardiovascular diseases (CVD) has been suggested. This study aimed to compare the effects of denosumab and alendronate, two anti-resorptive agents, on cardiovascular and renal outcomes in osteoporotic patients. Propensity score-matched cohort study comparing denosumab to alendronate users between January 2005 and December 2017 was conducted from a large medical organization in Taiwan. Risks of CVD development and renal function decline were estimated using Cox proportional hazard regression. A total 2523 patients were recruited in each group. No significant difference in cardiovascular events was found between the two groups over a 5-year study period. Stratified analysis results showed that denosumab was likely to exert protective effects against composite CVD in patients with medication possession rate ≥60% (adjusted hazard ratio (AHR), 0.74; p = 0.0493) and myocardial infraction (AHR, 0.42; p = 0.0415). Denosumab was associated with increased risk of renal function decline in male patients (AHR, 1.78; p = 0.0132), patients with renal insufficiency (AHR, 1.5; p = 0.0132), and patients with acute kidney injury during the study period (AHR, 1.53; p = 0.0154). Conclusively, denosumab may exert cardiovascular benefits in patients with good adherence but may have renal disadvantages in certain conditions and thus must be used with caution.
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Affiliation(s)
- Tsuen-Wei Hsu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Shih-Wei Wang
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chiang-Chi Huang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Lung-Chih Li
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
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Iseri K, Watanabe M, Yoshikawa H, Mitsui H, Endo T, Yamamoto Y, Iyoda M, Ryu K, Inaba T, Shibata T. Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial. J Bone Miner Res 2019; 34:1014-1024. [PMID: 30690785 DOI: 10.1002/jbmr.3676] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 12/26/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022]
Abstract
Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Ken Iseri
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.,Nephrology Center, Makita General Hospital, Tokyo, Japan
| | - Makoto Watanabe
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.,Nephrology Center, Makita General Hospital, Tokyo, Japan
| | | | - Hisao Mitsui
- Hanedaoozora Dialysis Clinic, Tokyo, Japan.,Adachimotoki Jin Dialysis Clinic, Tokyo, Japan
| | | | | | - Masayuki Iyoda
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kakei Ryu
- Clinical Pharmacology, Pharmacology, Showa University School of Medicine, Tokyo, Japan
| | - Taro Inaba
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takanori Shibata
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Nie B, Zhang SY, Guan SM, Zhou SQ, Fang X. Role of Wnt/β-Catenin Pathway in the Arterial Medial Calcification and Its Effect on the OPG/RANKL System. Curr Med Sci 2019; 39:28-36. [DOI: 10.1007/s11596-019-1996-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/16/2018] [Indexed: 12/15/2022]
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Doris MK, Everett RJ, Shun-Shin M, Clavel MA, Dweck MR. The Role of Imaging in Measuring Disease Progression and Assessing Novel Therapies in Aortic Stenosis. JACC Cardiovasc Imaging 2019; 12:185-197. [PMID: 30621990 PMCID: PMC6323414 DOI: 10.1016/j.jcmg.2018.10.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 10/10/2018] [Accepted: 10/18/2018] [Indexed: 01/20/2023]
Abstract
Aortic stenosis represents a growing health care burden in high-income countries. Currently, the only definitive treatment is surgical or transcatheter valve intervention at the end stages of disease. As the understanding of the underlying pathophysiology evolves, many promising therapies are being investigated. These seek to both slow disease progression in the valve and delay the transition from hypertrophy to heart failure in the myocardium, with the ultimate aim of avoiding the need for valve replacement in the elderly patients afflicted by this condition. Noninvasive imaging has played a pivotal role in enhancing our understanding of the complex pathophysiology underlying aortic stenosis, as well as disease progression in both the valve and myocardium. In this review, the authors discuss the means by which contemporary imaging may be used to assess disease progression and how these approaches may be utilized, both in clinical practice and research trials exploring the clinical efficacy of novel therapies.
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Affiliation(s)
- Mhairi K Doris
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Russell J Everett
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Matthew Shun-Shin
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Marie-Annick Clavel
- Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec City, Québec, Canada
| | - Marc R Dweck
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
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Cucchiari D, Torregrosa JV. Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal. Nefrologia 2018; 38:579-586. [PMID: 30415999 DOI: 10.1016/j.nefro.2018.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/11/2018] [Accepted: 05/09/2018] [Indexed: 11/30/2022] Open
Abstract
Calciphylaxis, also known as calcific uraemic arteriolopathy, is a rare syndrome that typically causes skin necrosis and usually affects dialysis patients. Its pathogenesis is multifactorial and is the consequence of many factors causing ectopic calcifications in patients with chronic kidney disease, such as calcium-phosphate metabolism disorders, hyper- or hypo-parathyroidism, diabetes, obesity, systemic inflammation and the use of vitamin K antagonists, among others. From a clinical point of view, calciphylaxis may progress from painful purpura to extensive areas of skin necrosis that can potentially lead to superinfection and the death of the patient due to sepsis. Treatment is primarily based on managing the wounds, eliminating all the possible precipitating factors of ectopic calcification and administering agents which are capable of inhibiting the process of calcification.
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Affiliation(s)
- David Cucchiari
- Servicio de Nefrología y Trasplante Renal, Hospital Clínic, Barcelona, España; Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano, Italia
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Peeters FECM, Meex SJR, Dweck MR, Aikawa E, Crijns HJGM, Schurgers LJ, Kietselaer BLJH. Calcific aortic valve stenosis: hard disease in the heart: A biomolecular approach towards diagnosis and treatment. Eur Heart J 2018; 39:2618-2624. [PMID: 29136138 PMCID: PMC6055545 DOI: 10.1093/eurheartj/ehx653] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 10/05/2017] [Accepted: 10/27/2017] [Indexed: 12/19/2022] Open
Abstract
Calcific aortic valve stenosis (CAVS) is common in the ageing population and set to become an increasing economic and health burden. Once present, it inevitably progresses and has a poor prognosis in symptomatic patients. No medical therapies are proven to be effective in holding or reducing disease progression. Therefore, aortic valve replacement remains the only available treatment option. Improved knowledge of the mechanisms underlying disease progression has provided us with insights that CAVS is not a passive disease. Rather, CAVS is regulated by numerous mechanisms with a key role for calcification. Aortic valve calcification (AVC) is actively regulated involving cellular and humoral factors that may offer targets for diagnosis and intervention. The discovery that the vitamin K-dependent proteins are involved in the inhibition of AVC has boosted our mechanistic understanding of this process and has opened up novel avenues in disease exploration. This review discusses processes involved in CAVS progression, with an emphasis on recent insights into calcification, methods for imaging calcification activity, and potential therapeutic options.
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Affiliation(s)
| | - Steven J R Meex
- Department of Clinical Chemistry, MUMC+, P. Debyelaan 25, HX Maastricht, the Netherlands
| | - Marc R Dweck
- Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Elena Aikawa
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, USA
| | - Harry J G M Crijns
- Department of Cardiology, MUMC+ and CARIM, P. Debyelaan 25, HX Maastricht, the Netherlands
| | - Leon J Schurgers
- Department of Biochemistry and CARIM, Maastricht University, PO Box 616, MD Maastricht, The Netherlands
| | - Bas L J H Kietselaer
- Department of Cardiology, MUMC+ and CARIM, P. Debyelaan 25, HX Maastricht, the Netherlands
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The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function. Toxins (Basel) 2018; 10:toxins10060218. [PMID: 29844272 PMCID: PMC6024314 DOI: 10.3390/toxins10060218] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 05/26/2018] [Accepted: 05/27/2018] [Indexed: 12/18/2022] Open
Abstract
Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling.
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48
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The role of OPG/RANKL in the pathogenesis of diabetic cardiovascular disease. Cardiovasc Endocrinol Metab 2018; 7:28-33. [PMID: 31646276 DOI: 10.1097/xce.0000000000000144] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/21/2017] [Indexed: 11/25/2022]
Abstract
Cardiovascular (CV) disease is the leading cause of mortality in patients with type 2 diabetes mellitus. A major factor in the pathogenesis of CV disease is vascular calcification (VC), which is accelerated in type 2 diabetes mellitus. Calcification of the vessel wall contributes to vascular stiffness and left ventricular hypertrophy whereas intimal calcification may predispose to plaque rupture and CV death. The pathogenesis of VC is complex but appears to be regulated by the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) signaling pathway, which is involved in bone remodeling. Within the bone, OPG prevents RANKL from binding to receptor activator of nuclear factor-κB and inhibiting bone resorption. Outside of the bone, the clinical significance of OPG blocking RANKL is not well understood, but OPG knockout mice that lack OPG develop early and severe VC. This minireview outlines some of the research on OPG/RANKL in the pathogenesis of VC and discusses potential therapies, which may reduce VC and CV burden in humans.
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He L, He WY, A LT, Yang WL, Zhang AH. Lower Serum Irisin Levels Are Associated with Increased Vascular Calcification in Hemodialysis Patients. Kidney Blood Press Res 2018; 43:287-295. [DOI: 10.1159/000487689] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 02/15/2018] [Indexed: 11/19/2022] Open
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50
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Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C. The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases. Pharmacol Ther 2018; 182:115-132. [DOI: 10.1016/j.pharmthera.2017.08.015] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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