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Zhang L, Zhou J, Kong W. Extracellular matrix in vascular homeostasis and disease. Nat Rev Cardiol 2025; 22:333-353. [PMID: 39743560 DOI: 10.1038/s41569-024-01103-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 01/04/2025]
Abstract
The extracellular matrix is an essential component and constitutes a dynamic microenvironment of the vessel wall with an indispensable role in vascular homeostasis and disease. From early development through to ageing, the vascular extracellular matrix undergoes various biochemical and biomechanical alterations in response to diverse environmental cues and exerts precise regulatory control over vessel remodelling. Advances in novel technologies that enable the comprehensive evaluation of extracellular matrix components and cell-matrix interactions have led to the emergence of therapeutic strategies that specifically target this fine-tuned network. In this Review, we explore various aspects of extracellular matrix biology in vascular development, disorders and ageing, emphasizing the effect of the extracellular matrix on disease initiation and progression. Additionally, we provide an overview of the potential therapeutic implications of targeting the extracellular matrix microenvironment in vascular diseases.
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Affiliation(s)
- Lu Zhang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
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Chen J, Hu L, Liu Z. Medical treatments for abdominal aortic aneurysm: an overview of clinical trials. Expert Opin Investig Drugs 2024; 33:979-992. [PMID: 38978286 DOI: 10.1080/13543784.2024.2377747] [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: 01/29/2024] [Accepted: 07/04/2024] [Indexed: 07/10/2024]
Abstract
INTRODUCTION Abdominal aortic aneurysm is a progressive, segmental, abdominal aortic dilation associated with a high mortality rate. Abdominal aortic aneurysms with diameters larger than 55 mm are associated with a high risk of rupture, and the most effective treatment options are surgical repair. Close observation and lifestyle adjustments are recommended for smaller abdominal aortic aneurysms with lower rupture risk. The development of medical therapies that limit or prevent the progression, expansion, and eventual rupture of abdominal aortic aneurysms remains an unmet clinical need. AREAS COVERED This review provides an overview of completed and ongoing clinical trials examining the efficacies of various drug classes, including antibiotics, antihypertensive drugs, hypolipidemic drugs, hypoglycemic drugs, and other potential therapies for abdominal aortic aneurysms. A search of PubMed, Web of Science, Clinical Trials, and another six clinical trial registries was conducted in January 2024. EXPERT OPINION None of the drugs have enough evidence to indicate that they can effectively inhibit the dilation of abdominal aortic aneurysm. More clinical trial data is required to support the efficacy of propranolol. Future research should also explore different drug delivery mechanisms, such as nanoparticles, to elevate drug concentration at the aneurysm wall.
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Affiliation(s)
- Jinyi Chen
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lanting Hu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenjie Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Chao CL, Applewhite B, Reddy NK, Matiuto N, Dang C, Jiang B. Advances and challenges in regenerative therapies for abdominal aortic aneurysm. Front Cardiovasc Med 2024; 11:1369785. [PMID: 38895536 PMCID: PMC11183335 DOI: 10.3389/fcvm.2024.1369785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Abdominal aortic aneurysm (AAA) is a significant source of mortality worldwide and carries a mortality of greater than 80% after rupture. Despite extensive efforts to develop pharmacological treatments, there is currently no effective agent to prevent aneurysm growth and rupture. Current treatment paradigms only rely on the identification and surveillance of small aneurysms, prior to ultimate open surgical or endovascular repair. Recently, regenerative therapies have emerged as promising avenues to address the degenerative changes observed in AAA. This review briefly outlines current clinical management principles, characteristics, and pharmaceutical targets of AAA. Subsequently, a thorough discussion of regenerative approaches is provided. These include cellular approaches (vascular smooth muscle cells, endothelial cells, and mesenchymal stem cells) as well as the delivery of therapeutic molecules, gene therapies, and regenerative biomaterials. Lastly, additional barriers and considerations for clinical translation are provided. In conclusion, regenerative approaches hold significant promise for in situ reversal of tissue damages in AAA, necessitating sustained research and innovation to achieve successful and translatable therapies in a new era in AAA management.
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Affiliation(s)
- Calvin L. Chao
- Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Brandon Applewhite
- Department of Biomedical Engineering, Northwestern University McCormick School of Engineering, Chicago, IL, United States
| | - Nidhi K. Reddy
- Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Natalia Matiuto
- Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Caitlyn Dang
- Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Bin Jiang
- Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Biomedical Engineering, Northwestern University McCormick School of Engineering, Chicago, IL, United States
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Skovbo Kristensen JS, Krasniqi L, Obel LM, Kavaliunaite E, Liisberg M, Lindholt JS. Exploring Drug Re-Purposing for Treatment of Abdominal Aortic Aneurysms: a Systematic Review and Meta-analysis. Eur J Vasc Endovasc Surg 2024; 67:570-582. [PMID: 38013062 DOI: 10.1016/j.ejvs.2023.11.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 10/26/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Abstract
OBJECTIVE Large abdominal aortic aneurysms (AAAs) present a significant mortality risk. While numerous medical interventions have been proposed, no drugs have convincingly reduced AAA progression, rupture rates, or repair risk. This systematic review and meta-analysis aimed to assess the impact of re-purposed drugs or dietary supplements on slowing expansion rates, reducing the risk of rupture, or minimising the risk of repair for individuals with AAA. METHODS A systematic search was conducted in five databases. Both observational studies and randomised controlled trials were included. Unpublished data from two screening trials were incorporated. Risk of bias was assessed using the Newcastle-Ottawa scale and revised Cochrane risk of bias tool. Meta-analyses were performed for each identified drug subclass and were stratified by overall risk of bias. Results were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS Of 7 484 screened studies, 39 met the inclusion criteria. No studies on dietary supplements were included. A total of 84 cohorts were derived from the included studies, and twelve distinct drug groups underwent meta-analyses. Two drug groups, metformin and statins, were statistically significant in slowing AAA growth. No low risk of bias studies were included for these two drug groups, and the results had very high heterogeneity (I2 > 80%). Both groups had a GRADE certainty of very low. Metformin, excluding high risk of bias studies, presented an estimated mean growth difference of AAA diameter between users and non-users of -0.73 mm/year, whilst statins had an overall estimated mean difference of -0.84 mm/year. CONCLUSION This systematic review and meta-analysis suggests that metformin and statins may provide some effect in slowing AAA progression. However, no definitive evidence was found for any of the investigated drugs included in this study. Further research is needed to identify effective medical treatments for AAA progression with more robust methodology.
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Affiliation(s)
- Joachim S Skovbo Kristensen
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark.
| | - Lytfi Krasniqi
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Lasse M Obel
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Egle Kavaliunaite
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Mads Liisberg
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Jes S Lindholt
- Department of Cardiac, Thoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark
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Hu J, Xu J, Zhao J, Liu Y, Huang R, Yao D, Xie J, Lei Y. Colchicine ameliorates short-term abdominal aortic aneurysms by inhibiting the expression of NLRP3 inflammasome components in mice. Eur J Pharmacol 2024; 964:176297. [PMID: 38135264 DOI: 10.1016/j.ejphar.2023.176297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND Abdominal aortic aneurysms (AAA) are often associated with chronic inflammation and pose a significant risk to affected individuals. Colchicine, known for its anti-inflammatory properties, has shown promise in managing cardiovascular diseases. However, its specific role in the development of AAA remains poorly understood. METHODS AND RESULTS In this study, we employed a short-term AAA model induced by angiotensin II (Ang II, 1000 ng/kg/min) and calcium chloride (CaCl2, 0.5 mol/l) in male ApoE-/- and C57BL/6 mice (8-12 weeks old) to investigate the effects of colchicine on AAA progression. Colchicine (0.4 mg/kg) was administered orally once daily, starting on the same day as AAA induction. After a 4-week duration, we observed a significant reduction in AAA diameter, degradation of elastic fibers, and expression of components related to the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome in the vessel wall of colchicine-treated mice compared to the saline group. Mechanistically, colchicine (5 μm/l, for 24h) inhibited the expression of NLRP3 inflammasome components through the P38-ERK/MicroRNA145-toll-like receptor 4 (TLR4) pathway in RAW264.7 cells. CONCLUSIONS Our study demonstrates the effectiveness of colchicine in suppressing NLRP3 inflammasome components, thereby delaying AAA progression in the Ang II and CaCl2-induced short-term model. These findings suggest the potential of colchicine as a pharmacological treatment option for AAA.
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Affiliation(s)
- Jiaxin Hu
- Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China; Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China
| | - Jiamin Xu
- Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jiling Zhao
- Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China
| | - Yuwei Liu
- Department of Medical Ultrasound, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China
| | - Rui Huang
- Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China
| | - Dejiang Yao
- Surgical Division III, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China
| | - Jun Xie
- Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Anhui, China.
| | - Yuhua Lei
- Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China.
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Waitayangkoon P, Moon SJ, Ponnusamy JJT, Zeng L, Driban J, McAlindon T. Long-Term Safety Profiles of Macrolides and Tetracyclines: A Systematic Review and Meta-Analysis. J Clin Pharmacol 2024; 64:164-177. [PMID: 37751595 PMCID: PMC11949418 DOI: 10.1002/jcph.2358] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 09/17/2023] [Indexed: 09/28/2023]
Abstract
Macrolides and tetracyclines are antibiotics that have a range of anti-inflammatory properties beyond their microbial capabilities. Although these antibiotics have been in widespread use, the long-term safety profiles are limited. We performed a systematic review and meta-analysis of randomized clinical trials that compared macrolides or tetracyclines with placeboes to provide long-term safety information. We searched Medline and EMBASE from inception to October 2022 and identified studies that reported study drug-related death, serious adverse events (SAEs), or withdrawal rates, and common adverse effects of each drug. Relative risk (RR) and number needed to harm were calculated. Of the 52 randomized clinical trials included, there are 3151 participants on doxycycline, 2519 participants on minocycline, 3049 participants on azithromycin, 763 participants on clarithromycin, 262 participants on erythromycin, and 100 participants on roxithromycin. There was no death related to any study drugs and rates of SAE were not significantly different from placebo in any drug. Overall withdrawal rates were slightly higher than placebo in doxycycline (RR, 1.30; 95% CI, 1.12-1.52) and minocycline (RR, 1.29; 95% CI, 1.15-1.46). Withdrawal rates due to adverse events were higher in doxycycline (RR, 2.82; 95% CI, 1.88-4.22), minocycline (RR, 1.48; 95% CI, 1.09-1.98), and azithromycin (RR, 1.53; 95% CI, 1.13-2.08). Gastrointestinal disturbances are the most common tolerable adverse effects for every drug. Photosensitivity and rash are the second most common adverse effects for doxycycline and minocycline. We found no evidence that long-term use up to 2 years of macrolides or tetracyclines was associated with increased risk of SAEs.
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Affiliation(s)
- Palapun Waitayangkoon
- Department of Medicine, MetroWest Medical Center, Tufts University School of Medicine, Framingham, MA, USA
| | - Soo Jin Moon
- Department of Medicine, MetroWest Medical Center, Tufts University School of Medicine, Framingham, MA, USA
| | | | - Li Zeng
- Department of Immunology, Tufts University School of Medicine, Boston, MA, USA
| | - Jeffrey Driban
- Division of Rheumatology, Allergy & Immunology, Tufts Medical Center, Boston, MA, USA
| | - Timothy McAlindon
- Division of Rheumatology, Allergy & Immunology, Tufts Medical Center, Boston, MA, USA
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Wanhainen A, Van Herzeele I, Bastos Goncalves F, Bellmunt Montoya S, Berard X, Boyle JR, D'Oria M, Prendes CF, Karkos CD, Kazimierczak A, Koelemay MJW, Kölbel T, Mani K, Melissano G, Powell JT, Trimarchi S, Tsilimparis N, Antoniou GA, Björck M, Coscas R, Dias NV, Kolh P, Lepidi S, Mees BME, Resch TA, Ricco JB, Tulamo R, Twine CP, Branzan D, Cheng SWK, Dalman RL, Dick F, Golledge J, Haulon S, van Herwaarden JA, Ilic NS, Jawien A, Mastracci TM, Oderich GS, Verzini F, Yeung KK. Editor's Choice -- European Society for Vascular Surgery (ESVS) 2024 Clinical Practice Guidelines on the Management of Abdominal Aorto-Iliac Artery Aneurysms. Eur J Vasc Endovasc Surg 2024; 67:192-331. [PMID: 38307694 DOI: 10.1016/j.ejvs.2023.11.002] [Citation(s) in RCA: 338] [Impact Index Per Article: 338.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 02/04/2024]
Abstract
OBJECTIVE The European Society for Vascular Surgery (ESVS) has developed clinical practice guidelines for the care of patients with aneurysms of the abdominal aorta and iliac arteries in succession to the 2011 and 2019 versions, with the aim of assisting physicians and patients in selecting the best management strategy. METHODS The guideline is based on scientific evidence completed with expert opinion on the matter. By summarising and evaluating the best available evidence, recommendations for the evaluation and treatment of patients have been formulated. The recommendations are graded according to a modified European Society of Cardiology grading system, where the strength (class) of each recommendation is graded from I to III and the letters A to C mark the level of evidence. RESULTS A total of 160 recommendations have been issued on the following topics: Service standards, including surgical volume and training; Epidemiology, diagnosis, and screening; Management of patients with small abdominal aortic aneurysm (AAA), including surveillance, cardiovascular risk reduction, and indication for repair; Elective AAA repair, including operative risk assessment, open and endovascular repair, and early complications; Ruptured and symptomatic AAA, including peri-operative management, such as permissive hypotension and use of aortic occlusion balloon, open and endovascular repair, and early complications, such as abdominal compartment syndrome and colonic ischaemia; Long term outcome and follow up after AAA repair, including graft infection, endoleaks and follow up routines; Management of complex AAA, including open and endovascular repair; Management of iliac artery aneurysm, including indication for repair and open and endovascular repair; and Miscellaneous aortic problems, including mycotic, inflammatory, and saccular aortic aneurysm. In addition, Shared decision making is being addressed, with supporting information for patients, and Unresolved issues are discussed. CONCLUSION The ESVS Clinical Practice Guidelines provide the most comprehensive, up to date, and unbiased advice to clinicians and patients on the management of abdominal aorto-iliac artery aneurysms.
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Han Q, Qiao L, Yin L, Sui X, Shao W, Wang Q. The effect of exercise training intervention for patients with abdominal aortic aneurysm on cardiovascular and cardiorespiratory variables: an updated meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2024; 24:80. [PMID: 38291355 PMCID: PMC10829311 DOI: 10.1186/s12872-024-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/22/2024] [Indexed: 02/01/2024] Open
Abstract
OBJECTIVE The purpose of this meta-analysis was to evaluate the effect of exercise training intervention in patients with abdominal aortic aneurysm (AAA). METHODS Eight randomized controlled trials (RCTs) that recruited 588 AAA patients were extracted using 4 databases (PubMed, Embase, Wanfang Data, and Cochrane Library). Physiological and biochemistry parameters that included in this study are high-sensitivity C-reactive protein (hs-CRP), respiratory peak oxygen uptake rate (VO2peak), triglyceride (TG), total cholesterol (TC), anaerobic threshold (AT), the diameter of AAA, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), and matrix metalloproteinase-9 (MMP-9). Standard mean difference (SMD) was used to assess the between group effect. RESULTS This meta-analysis was synthesized with findings from RCTs and found that hs-CRP (SMD, - 0.56 mg/dL; 95% CI: - 0.90 to 0.22; P = 0.001), VO2peak (SMD, 0.4 mL/kg/min; 95% CI, 0.21 to 0.60; P < 0.001), TG (SMD, - 0.39 mg/dL; 95% CI: - 0.02 to 0.77; P = 0.04), and AT (SMD, 0.75 mL/kg/min; 95% CI, 0.54 to 0.96; P < 0.001) were significantly improved in the exercise groups, while the size of AAA (SMD, - 0.15; 95% CI: - 0.36 to 0.06; P = 0.15), TC (SMD, 0.16 mg/dL; 95% CI: - 0.10 to 0.42; P = 0.23), HDL/LDL ratio (SMD, - 0.06; 95% CI: - 0.32 to 0.20; P = 0.64), HDL (SMD, - 0.09; 95% CI: - 0.39 to 0.20; P = 0.54), LDL (SMD, 0.08; 95% CI: - 0.21 to 0.38; P = 0.59), and MMP-9 (SMD, - 0.23 mg/dL; 95% CI: - 0.53 to 0.06; P = 0.12) did not differ in the exercise groups compared with the controls. CONCLUSION Exercise intervention improved some of the CVD risk factors but not all, hs-CRP, VO2peak and AT were significantly improved after exercise intervention, while, changes of MMP-9, the size of AAA, and the overall lipids profile were not. Exercise intervention provides an additional solution for improving cardiorespiratory capacity and health status among AAA patients, and might lead to a delay of AAA progression.
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Affiliation(s)
- Qi Han
- Sports Nutrition Center, National Institute of Sports Medicine, Beijing, 100029, China
- Beijing Sport University, Beijing, 100084, China
| | - Li Qiao
- Beijing Competitor Sports Nutrition Research Institute, Beijing, 100029, China
| | - Li Yin
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310020, China
- Department of Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Xuemei Sui
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA
| | - Wenjuan Shao
- Beijing Sport University, Beijing, 100084, China
- Minzu University of China, Beijing, 100081, China
| | - Qirong Wang
- Sports Nutrition Center, National Institute of Sports Medicine, Beijing, 100029, China.
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Rossi PJ. The continued pursuit of the holy grail - a novel method for reducing the risk of aortic aneurysm growth. J Vasc Surg 2023; 78:936. [PMID: 37739746 DOI: 10.1016/j.jvs.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 09/24/2023]
Affiliation(s)
- Peter J Rossi
- Division of Vascular and Endovascular Surgery, Medical College of Wisconsin, Milwaukee, WI
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10
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Atkinson G, Bianco R, Di Gregoli K, Johnson JL. The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms. Front Cardiovasc Med 2023; 10:1248561. [PMID: 37799778 PMCID: PMC10549934 DOI: 10.3389/fcvm.2023.1248561] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/07/2023] [Indexed: 10/07/2023] Open
Abstract
Abdominal aortic aneurysms (AAAs) account for up to 8% of deaths in men aged 65 years and over and 2.2% of women. Patients with AAAs often have atherosclerosis, and intimal atherosclerosis is generally present in AAAs. Accordingly, AAAs are considered a form of atherosclerosis and are frequently referred to as atherosclerotic aneurysms. Pathological observations advocate inflammatory cell infiltration alongside adverse extracellular matrix degradation as key contributing factors to the formation of human atherosclerotic AAAs. Therefore, macrophage production of proteolytic enzymes is deemed responsible for the damaging loss of ECM proteins, especially elastin and fibrillar collagens, which characterise AAA progression and rupture. Matrix metalloproteinases (MMPs) and their regulation by tissue inhibitors metalloproteinases (TIMPs) can orchestrate not only ECM remodelling, but also moderate the proliferation, migration, and apoptosis of resident aortic cells, alongside the recruitment and subsequent behaviour of inflammatory cells. Accordingly, MMPs are thought to play a central regulatory role in the development, progression, and eventual rupture of abdominal aortic aneurysms (AAAs). Together, clinical and animal studies have shed light on the complex and often diverse effects MMPs and TIMPs impart during the development of AAAs. This dichotomy is underlined from evidence utilising broad-spectrum MMP inhibition in animal models and clinical trials which have failed to provide consistent protection from AAA progression, although more encouraging results have been observed through deployment of selective inhibitors. This review provides a summary of the supporting evidence connecting the contribution of individual MMPs to AAA development, progression, and eventual rupture. Topics discussed include structural, functional, and cell-specific diversity of MMP members; evidence from animal models of AAA and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the advances in identifying aberrant MMP activity. As evidenced, our developing understanding of the multifaceted roles individual MMPs perform during the progression and rupture of AAAs, should motivate clinical trials assessing the therapeutic potential of selective MMP inhibitors, which could restrict AAA-related morbidity and mortality worldwide.
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Affiliation(s)
| | | | | | - Jason L. Johnson
- Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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Puertas-Umbert L, Almendra-Pegueros R, Jiménez-Altayó F, Sirvent M, Galán M, Martínez-González J, Rodríguez C. Novel pharmacological approaches in abdominal aortic aneurysm. Clin Sci (Lond) 2023; 137:1167-1194. [PMID: 37559446 PMCID: PMC10415166 DOI: 10.1042/cs20220795] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/05/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.
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Affiliation(s)
- Lídia Puertas-Umbert
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
| | | | - Francesc Jiménez-Altayó
- Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marc Sirvent
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Angiología y Cirugía Vascular del Hospital Universitari General de Granollers, Granollers, Barcelona, Spain
| | - María Galán
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain
| | - José Martínez-González
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain
| | - Cristina Rodríguez
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
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Golledge J, Thanigaimani S, Powell JT, Tsao PS. Pathogenesis and management of abdominal aortic aneurysm. Eur Heart J 2023:ehad386. [PMID: 37387260 PMCID: PMC10393073 DOI: 10.1093/eurheartj/ehad386] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/16/2023] [Accepted: 05/29/2023] [Indexed: 07/01/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have been limited by small sample sizes, limited drug adherence, poor participant retention, and over-optimistic AAA growth reduction targets. Data from some large observational cohorts suggest that blood pressure reduction, particularly by angiotensin-converting enzyme inhibitors, could limit aneurysm rupture, but this has not been evaluated in randomized trials. Some observational studies suggest metformin may limit AAA growth, and this is currently being tested in randomized trials. In conclusion, no drug therapy has been shown to convincingly limit AAA growth in randomized controlled trials. Further large prospective studies on other targets are needed.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Australian Institute of Tropical Health and Medicine, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Department of Vascular and Endovascular Surgery, Townsville University Hospital, 100 Angus Smith Drive, Douglas, QLD, Australia
| | - Shivshankar Thanigaimani
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
- Australian Institute of Tropical Health and Medicine, James Cook University, 1 James Cook Drive, Douglas, Townsville, QLD, Australia
| | - Janet T Powell
- Department of Surgery & Cancer, Imperial College London, Fulham Palace Road, London, UK
| | - Phil S Tsao
- Department of Cardiovascular Medicine, Stanford University, 450 Serra Mall, Stanford, CA, USA
- VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, USA
- Stanford Cardiovascular Institute, Stanford University, 450 Serra Mall, Stanford, CA, USA
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Bian H, Wang Y, Wu P, Han N, Wang L, Li X, Zhang X, Cho K, Zhang Y, Yin J, Jiang B. Rosmarinic Acid Suppresses Abdominal Aortic Aneurysm Progression in Apolipoprotein E-deficient Mice. PLANTA MEDICA 2022; 88:899-912. [PMID: 34741296 DOI: 10.1055/a-1659-3908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice via infusion of angiotensin II for 4 wks. Rosmarinic acid, salvianolic acid C, salvianolic acid B, or doxycycline as a positive control was provided daily through intraperitoneal injection. Administration of rosmarinic acid was found to decrease the thickness of the aortic wall, as determined by histopathological assay. Rosmarinic acid also exhibited protection against elastin fragmentation in aortic media and down-regulated cell apoptosis and proliferation in the aortic adventitia. Infiltration of macrophages, T lymphocytes, and neutrophils in aortic aneurysms was found, especially at the aortic adventitia. Rosmarinic acid, salvianolic acid C, or salvianolic acid B inhibited the infiltration on macrophages specifically, but these compounds did not influence T lymphocytes and neutrophils. Expression of matrix metalloproteinase 9 and macrophage migration inhibitory factor significantly increased in aortic aneurysms. Rosmarinic acid and salvianolic acid C decreased the expression of matrix metalloproteinase-9 in media, and rosmarinic acid also tended to reduce migration inhibitory factor expression. Further then, partial least squares-discriminate analysis was used to classify metabolic changes among different treatments. Rosmarinic acid affected most of the metabolites in the biosynthesis of the citrate cycle, fatty acid pathway significantly. Our present study on mice demonstrated that rosmarinic acid inhibited multiple pathological processes, which were the key features important in abdominal aortic aneurysm formation. Further study on rosmarinic acid, the novel candidate for aneurysmal therapy, should be undertaken to determine its potential for clinical use.
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Affiliation(s)
- Huimiao Bian
- Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yang Wang
- West Yunnan University of Applied Sciences, Jinghong, Yunnan, China
- Metabo-Profile Biotechnology (Shanghai) Co. Ltd., Shanghai, China
| | - Peng Wu
- Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Na Han
- Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang, China
| | - Linlin Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xue Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - XianJing Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Kenka Cho
- Takarazuka University of Medical and Health Care, Hanayashiki-Midorigaoka, Takarazuka-city, Japan
| | - Yongyu Zhang
- West Yunnan University of Applied Sciences, Jinghong, Yunnan, China
| | - Jun Yin
- Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang, China
| | - Baohong Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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14
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Weaver LM, Loftin CD, Zhan CG. Development of pharmacotherapies for abdominal aortic aneurysms. Biomed Pharmacother 2022; 153:113340. [PMID: 35780618 PMCID: PMC9514980 DOI: 10.1016/j.biopha.2022.113340] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 11/23/2022] Open
Abstract
The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.
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Affiliation(s)
- Lauren M Weaver
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
| | - Charles D Loftin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
| | - Chang-Guo Zhan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
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15
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Bacterial Infections and Atherosclerosis – A Mini Review. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2022. [DOI: 10.22207/jpam.16.3.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Atherosclerosis is the most challenging subsets of coronary artery disease in humans, in which risk factors emerge from childhood, and its prevalence increases with age. Experimental research demonstrates that infections due to bacteria stimulate atherogenic events. Atherosclerosis has complex pathophysiology that is linked with several bacterial infections by damaging the inner arterial wall and heart muscles directly and indirectly by provoking a systemic pro-inflammation and acute-phase protein. Repeated bacterial infections trigger an inflammatory cascade that triggers immunological responses that negatively impact cardiovascular biomarkers includes triglycerides, high-density lipoprotein, C-reactive protein, heat shock proteins, cytokines, fibrinogen, and leukocyte count. Herein, we intended to share the role of bacterial infection in atherosclerosis and evaluate existing evidence of animal and human trials on the association between bacterial infections and atherosclerosis on update.
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Kessler V, Klopf J, Eilenberg W, Neumayer C, Brostjan C. AAA Revisited: A Comprehensive Review of Risk Factors, Management, and Hallmarks of Pathogenesis. Biomedicines 2022; 10:94. [PMID: 35052774 PMCID: PMC8773452 DOI: 10.3390/biomedicines10010094] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/30/2021] [Indexed: 01/27/2023] Open
Abstract
Despite declining incidence and mortality rates in many countries, the abdominal aortic aneurysm (AAA) continues to represent a life-threatening cardiovascular condition with an overall prevalence of about 2-3% in the industrialized world. While the risk of AAA development is considerably higher for men of advanced age with a history of smoking, screening programs serve to detect the often asymptomatic condition and prevent aortic rupture with an associated death rate of up to 80%. This review summarizes the current knowledge on identified risk factors, the multifactorial process of pathogenesis, as well as the latest advances in medical treatment and surgical repair to provide a perspective for AAA management.
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Affiliation(s)
| | | | | | | | - Christine Brostjan
- Department of General Surgery, Division of Vascular Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (V.K.); (J.K.); (W.E.); (C.N.)
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17
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Chiu HH. An update of medical care in Marfan syndrome. Tzu Chi Med J 2022; 34:44-48. [PMID: 35233355 PMCID: PMC8830539 DOI: 10.4103/tcmj.tcmj_95_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/11/2020] [Accepted: 06/25/2021] [Indexed: 11/14/2022] Open
Abstract
Marfan syndrome (MFS), a multisystemic connective disorder, caused by fibrillin 1 gene mutations with autosomal dominant inheritance. The disease spectrum is wide and the major causes of death are related to aortic root aneurysm or dissection. The purposes of medical treatment are to reduce structural changes in the aortic wall and slow aortic root dilatation. Advance in medical researches have provided new insights into the pathogenesis of disease and opened up new horizons for treatments. Several medications such as angiotensin II type I receptor blockers, β-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, tetracyclines, and statins have been studied for the purpose. Currently, the life expectancy of Marfan patients improves significantly and is closes to the general population with proper treatment. In this article, we review and update the medical treatments for patients with MFS.
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18
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Su Z, Guo J, Gu Y. Pharmacotherapy in Clinical Trials for Abdominal Aortic Aneurysms: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost 2022; 28:10760296221120423. [PMID: 36083182 PMCID: PMC9465599 DOI: 10.1177/10760296221120423] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE There is no medical treatment proven to limit abdominal aortic aneurysm (AAA) progression. This systematic review aimed to summarise available trial evidence on the efficacy of pharmacotherapy in limiting AAA growth and AAA-related events. METHODS A systematic literature search was performed to examine the efficacy of pharmacotherapy in reducing AAA growth and AAA-related events. Pubmed, Embase (Excerpta Medica Database), and the Cochrane library were searched from March, 1999 to March 29, 2022. AAA growth (mm/year) in the intervention and control groups was expressed as mean and standard deviation (SD). The results of AAA growth were expressed as mean difference (MD) and its 95% confidence interval (95% CI). Odds ratios (ORs) were calculated for the AAA-related events.Heterogeneity was quantified using the I2 statistic. Forest plots were created to show the pooled results of each outcome. OUTCOMES A total of 1373 articles were found in different databases according to the search strategy, and 10 articles were identified by hand searching. A total of 26 articles were included in our systematic review after the screening. For the studies of metformin, the meta-analysis demonstrated that metformin use was associated with a lower AAA growth rate (MD: -0.81 mm/y, 95% CI: -1.19 to -0.42, P < 0.0001, I2 = 87%), Metformin use also was related to the lower rates of AAA-related events (OR: 0.53, 95% CI: 0.36 to 0.76, P = 0.0007, I2 = 60%). The hypotensive drugs of the studies mainly included angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), and propranolol. The overall meta-analysis of blood pressure-lowering drugs reported no significant effect in limiting the AAA growth (MD: 0.31mm/year, 95%CI: -0.03 to 0.65, P = 0.07, I2 = 66%) and AAA-related events (OR: 1.33, 95%CI: 0.76 to 2.32, P = 0.32, I2 = 98%), In the subgroup analysis of the hypotensive drugs, the ACEI/ARB and propranolol also showed no significant in reducing the AAA growth and AAA-related events. The meta-analysis of the antibiotics demonstrated that the antibiotics were not associated with a lower AAA growth rate (MD: -0.27 mm/y, 95% CI: -0.88 to 0.34, P = 0.39, I2 = 77%) and AAA-related events (OR: 0.94, 95%CI: 0.65 to 1.35, P = 0.72, I2 = 0%). The results of statins also showed no significant effect in limiting AAA growth (MD: -1.11mm/year, 95%CI: -2.38 to 0.16, P = 0.09, I2 = 96%) and AAA-related events (OR: 0.53, 95%CI: 0.26 to 1.06, P = 0.07, I2 = 92%). CONCLUSION In conclusion, effective pharmacotherapy for AAA was still lacking. Although the meta-analysis showed that metformin use was associated with lower AAA growth and AAA-related events, all of the included studies about metformin were cohort studies or case-control studies. More randomized controlled trials (RCTs) are needed for further verification.
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Affiliation(s)
- Zhixiang Su
- Vascular Surgery Department, 71044Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jianming Guo
- Vascular Surgery Department, 71044Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yongquan Gu
- Vascular Surgery Department, 71044Xuanwu Hospital, Capital Medical University, Beijing, China
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19
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Golledge J, Arnott C, Moxon J, Monaghan H, Norman R, Morris D, Li Q, Jones G, Roake J, Bown M, Neal B. Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm. Trials 2021; 22:962. [PMID: 34961561 PMCID: PMC8710921 DOI: 10.1186/s13063-021-05915-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/03/2021] [Indexed: 11/10/2022] Open
Abstract
Background Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. Methods MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). Discussion Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design. Trial registration Australian Clinical Trials ACTRN12618001707257. Registered on 16 October 2018
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, 4811, Australia. .,The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia. .,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia. .,George Institute Australia, Sydney, New South Wales, Australia.
| | - Clare Arnott
- George Institute Australia, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Joseph Moxon
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, 4811, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Helen Monaghan
- George Institute Australia, Sydney, New South Wales, Australia
| | - Richard Norman
- Curtin School of Population Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia
| | - Dylan Morris
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, 4811, Australia
| | - Qiang Li
- George Institute Australia, Sydney, New South Wales, Australia
| | - Greg Jones
- Department of Surgical Sciences, Division of Health Sciences, University of Otago, Dunedin, New Zealand
| | - Justin Roake
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Matt Bown
- Department of Cardiovascular Services, University of Leicester, Leicester, UK
| | - Bruce Neal
- George Institute Australia, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
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20
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Shirasu T, Takagi H, Yasuhara J, Kuno T, Kent KC, Clouse WD. Smaller size is more suitable for pharmacotherapy among undersized abdominal aortic aneurysm: a systematic review and meta-analysis. Vasc Med 2021; 27:261-268. [PMID: 34930052 DOI: 10.1177/1358863x211061603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background: Pharmacotherapy for undersized abdominal aortic aneurysm (AAA) is a clinical unmet need. Randomized controlled trials (RCTs) have failed to show effectiveness despite countless promising data in preclinical studies. We aimed to identify the population with undersized AAAs (30-54 mm) who potentially benefit from pharmacotherapy. Methods: In accordance with the PRISMA statement, we conducted a systematic review and meta-analysis of placebo-controlled RCTs. The primary outcome was mean difference (MD) in annual growth rate (< 0 favors pharmacotherapy), and the secondary outcome was aneurysm-related events (diameters ⩾ 55 mm, ruptures, or referral to surgery). Results: Our search strategy identified eight RCTs (six trials on antibiotics [ABx], two on renin-angiotensin system inhibitors [RAS-I]) with a total of 1325 patients. The mean of baseline diameters ranged from 33.1 mm to 43.1 mm. Neither ABx nor RAS-I showed significant differences in MD. Multivariable random-effects restricted maximum likelihood meta-regression revealed a statistically significant linear relationship between baseline diameter and MD (coefficient 0.15 [95% CI 0.0011, 0.30], p = 0.049) but not for the follow-up period (p = 0.28) and duration of treatment (p = 0.11). In line with this result, ABx with baseline diameter < 40 mm significantly reduced MD (-1.03 mm/year [95% CI -1.64, -0.42], p = 0.001) and a borderline significant difference in aneurysm-related events (HR 0.53 [95% CI 0.28, 1.00], p = 0.05), whereas the other groups ⩾ 40 mm never demonstrated effectiveness. Fixed-effect models did not change the results. No evidence of publication bias was detected. Conclusion: Undersized AAAs < 40 mm can potentially benefit from pharmacotherapy. Future RCTs should consider preferentially including undersized AAA with smaller diameters.
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Affiliation(s)
- Takuro Shirasu
- Division of Vascular & Endovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Hisato Takagi
- Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan
| | - Jun Yasuhara
- Center for Cardiovascular Research, The Abigail Wexner Research Institute and The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA
| | - Toshiki Kuno
- Department of Cardiology, Montefiore Medical Center, Albert Einstein Medical College, New York, NY, USA
| | - K Craig Kent
- Division of Vascular & Endovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - W Darrin Clouse
- Division of Vascular & Endovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA
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21
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The Development of Third-Generation Tetracycline Antibiotics and New Perspectives. Pharmaceutics 2021; 13:pharmaceutics13122085. [PMID: 34959366 PMCID: PMC8707899 DOI: 10.3390/pharmaceutics13122085] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 01/04/2023] Open
Abstract
The tetracycline antibiotic class has acquired new valuable members due to the optimisation of the chemical structure. The first modern tetracycline introduced into therapy was tigecycline, followed by omadacycline, eravacycline, and sarecycline (the third generation). Structural and physicochemical key elements which led to the discovery of modern tetracyclines are approached. Thus, several chemical subgroups are distinguished, such as glycylcyclines, aminomethylcyclines, and fluorocyclines, which have excellent development potential. The antibacterial spectrum comprises several resistant bacteria, including those resistant to old tetracyclines. Sarecycline, a narrow-spectrum tetracycline, is notable for being very effective against Cutinebacterium acnes. The mechanism of antibacterial action from the perspective of the new compound is approached. Several severe bacterial infections are treated with tigecycline, omadacycline, and eravacycline (with parenteral or oral formulations). In addition, sarecycline is very useful in treating acne vulgaris. Tetracyclines also have other non-antibiotic properties that require in-depth studies, such as the anti-inflammatory effect effect of sarecycline. The main side effects of modern tetracyclines are described in accordance with published clinical studies. Undoubtedly, this class of antibiotics continues to arouse the interest of researchers. As a result, new derivatives are developed and studied primarily for the antibiotic effect and other biological effects.
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22
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Mosquera‐Sulbaran JA, Pedreañez A, Carrero Y, Callejas D. C-reactive protein as an effector molecule in Covid-19 pathogenesis. Rev Med Virol 2021; 31:e2221. [PMID: 34773448 PMCID: PMC7995022 DOI: 10.1002/rmv.2221] [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] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 01/08/2023]
Abstract
The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.
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Affiliation(s)
- Jesús A. Mosquera‐Sulbaran
- Instituto de Investigaciones Clinicas “Dr. Americo Negrette”Facultad de MedicinaUniversidad del ZuliaMaracaiboVenezuela
| | - Adriana Pedreañez
- Catedra de InmunologiaEscuela de BioanalisisFacultad de MedicinaUniversidad del ZuliaMaracaiboVenezuela
| | - Yenddy Carrero
- Facultad de Ciencias de la SaludCarrera de MedicinaUniversidad Tecnica de AmbatoAmbatoEcuador
| | - Diana Callejas
- Facultad de Ciencias de la SaludDepartamento de Ciencias BiologicasUniversidad Tecnica de ManabiPortoviejoEcuador
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23
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Weininger G, Chan SM, Zafar M, Ziganshin BA, Elefteriades JA. Risk reduction and pharmacological strategies to prevent progression of aortic aneurysms. Expert Rev Cardiovasc Ther 2021; 19:619-631. [PMID: 34102944 DOI: 10.1080/14779072.2021.1940958] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION While size thresholds exist to determine when aortic aneurysms warrant surgical intervention, there is no consensus on how best to treat this disease before aneurysms reach the threshold for intervention. Since a landmark study in 1994 first suggested ß-blockers may be useful in preventing aortic aneurysm growth, there has been a surge in research investigating different pharmacologic therapies for aortic aneurysms - with very mixed results. AREAS COVERED We have reviewed the existing literature on medical therapies used for thoracic and abdominal aortic aneurysms in humans. These include ß-blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors as well as miscellaneous drugs such as tetracyclines, macrolides, statins, and anti-platelet medications. EXPERT OPINION While multiple classes of drugs have been explored for risk reduction in aneurysm disease, with few exceptions results have been disappointing with an abundance of contradictory findings. The vast majority of studies have been done in patients with abdominal aortic aneurysms or thoracic aortic aneurysm patients with Marfan Syndrome. There exists a striking gap in the literature when it comes to pharmacologic management of non-Marfan Syndrome patients with thoracic aortic aneurysms. Given the differences in pathogenesis, this is an important future direction for aortic aneurysm research.
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Affiliation(s)
- Gabe Weininger
- Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA
| | - Shin Mei Chan
- Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA
| | - Mohammad Zafar
- Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA
| | - Bulat A Ziganshin
- Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA
| | - John A Elefteriades
- Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA
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24
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Paghdar S, Khan TM, Patel NP, Chandrasekaran S, De Sousa JFM, Tsouklidis N. Doxycycline Therapy for Abdominal Aortic Aneurysm: Inhibitory Effect on Matrix Metalloproteinases. Cureus 2021; 13:e14966. [PMID: 34123662 PMCID: PMC8191685 DOI: 10.7759/cureus.14966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening condition associated with smoking, aging, atherosclerosis, and destruction of the connective tissue in the abdominal aortic wall. Disturbances in the synthesis and degradation of matrix metalloproteinase (MMP) have been known to contribute to the development of AAAs. The only available treatment of AAA is surgical repair. Doxycycline, a tetracycline analog, is thought to have an inhibitory effect on MMPs. Knowing the effect of doxycycline, there may be some favorable effects of the drug to reduce the growth of small AAAs and avoid the need for invasive treatment. This article aims to determine the relationship between doxycycline and the MMPs to prevent the growth of small AAAs. We conducted our review using online resources such as PubMed, Google Scholar, The Journal of Vascular Surgery, and ResearchGate. The result of our study supports the effect of doxycycline in preventing the growth of small AAAs. We conclude that therapeutic treatment with doxycycline in patients with small AAAs can prevent the growth of aneurysms, life-threatening aneurysm rupture, and reduce the need for expensive, invasive treatment.
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Affiliation(s)
- Smit Paghdar
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Surat Municipal Institute of Medical Education and Research (SMIMER), Surat, IND
| | - Taheseen M Khan
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nishant P Patel
- Internal Medicine, Government Medical College, Surat, Surat, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Savitri Chandrasekaran
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Joaquim Francisco Maria De Sousa
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Surgery, S.S. Institute of Medical Sciences and Research Centre, Davangere, IND.,Emergency Medicine, Healthway Hospital, Panaji, IND
| | - Nicholas Tsouklidis
- Health Care Administration, University of Cincinnati Health, Cincinnati, USA.,Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Medicine, Atlantic University School of Medicine, Gros Islet, LCA
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25
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Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model. CONTRAST MEDIA & MOLECULAR IMAGING 2021; 2021:9999847. [PMID: 34007253 PMCID: PMC8099506 DOI: 10.1155/2021/9999847] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/12/2021] [Accepted: 04/19/2021] [Indexed: 11/18/2022]
Abstract
Background Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE-/- model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment. Methods Nine ApoE-/- mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE-/- animals without doxycycline treatment. Differences in mortality were also investigated between these groups. Results In a previous study, we found that approximately 25% of angiotensin II-infused ApoE-/- mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE-/- mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE-/- mice showed significantly lower contrast-to-noise (CNR) values (p=0.017) in MRI compared to ApoE-/- mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R 2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment. Conclusion The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.
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Gouveia E Melo R, Rodrigues M, Caldeira D, Alves M, Fernandes E Fernandes R, Mendes Pedro L. Doxycycline is not Effective in Reducing Abdominal Aortic Aneurysm Growth: A Mini Systematic Review and Meta-Analysis of Randomised Controlled Trials. Eur J Vasc Endovasc Surg 2021; 61:863-864. [PMID: 33674154 DOI: 10.1016/j.ejvs.2021.01.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/23/2020] [Accepted: 01/14/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Ryan Gouveia E Melo
- Lisbon Medical Academic Centre (Centro Académico de Medicina de Lisboa - CAML), Lisbon, Portugal.
| | - Marta Rodrigues
- Lisbon Medical Academic Centre (Centro Académico de Medicina de Lisboa - CAML), Lisbon, Portugal
| | - Daniel Caldeira
- Lisbon Medical Academic Centre (Centro Académico de Medicina de Lisboa - CAML), Lisbon, Portugal
| | - Mariana Alves
- Lisbon Medical Academic Centre (Centro Académico de Medicina de Lisboa - CAML), Lisbon, Portugal
| | | | - Luís Mendes Pedro
- Lisbon Medical Academic Centre (Centro Académico de Medicina de Lisboa - CAML), Lisbon, Portugal
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27
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Dalhoff A. Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks? Infection 2021; 49:29-56. [PMID: 33367978 PMCID: PMC7851017 DOI: 10.1007/s15010-020-01536-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
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Affiliation(s)
- Axel Dalhoff
- Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
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28
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Tedjawirja VN, Nieuwdorp M, Yeung KK, Balm R, de Waard V. A Novel Hypothesis: A Role for Follicle Stimulating Hormone in Abdominal Aortic Aneurysm Development in Postmenopausal Women. Front Endocrinol (Lausanne) 2021; 12:726107. [PMID: 34721292 PMCID: PMC8548664 DOI: 10.3389/fendo.2021.726107] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/02/2021] [Indexed: 12/24/2022] Open
Abstract
An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta, which can potentially be fatal due to exsanguination following rupture. Although AAA is less prevalent in women, women with AAA have a more severe AAA progression compared to men as reflected by enhanced aneurysm growth rates and a higher rupture risk. Women are diagnosed with AAA at an older age than men, and in line with increased osteoporosis and cardiovascular events, the delayed AAA onset has been attributed to the reduction of the protective effect of oestrogens during the menopausal transition. However, new insights have shown that a high follicle stimulating hormone (FSH) level during menopause may also play a key role in those diseases. In this report we hypothesize that FSH may aggravate AAA development and progression in postmenopausal women via a direct and/or indirect role, promoting aorta pathology. Since FSH receptors (FSHR) are reported on many other cell types than granulosa cells in the ovaries, it is feasible that FSH stimulation of FSHR-bearing cells such as aortic endothelial cells or inflammatory cells, could promote AAA formation directly. Indirectly, AAA progression may be influenced by an FSH-mediated increase in osteoporosis, which is associated with aortic calcification. Also, an FSH-mediated decrease in cholesterol uptake by the liver and an increase in cholesterol biosynthesis will increase the cholesterol level in the circulation, and subsequently promote aortic atherosclerosis and inflammation. Lastly, FSH-induced adipogenesis may lead to obesity-mediated dysfunction of the microvasculature of the aorta and/or modulation of the periaortic adipose tissue. Thus the long term increased plasma FSH levels during the menopausal transition may contribute to enhanced AAA disease in menopausal women and could be a potential novel target for treatment to lower AAA-related events in women.
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Affiliation(s)
- Victoria N. Tedjawirja
- Department of Surgery, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
- *Correspondence: Victoria N. Tedjawirja,
| | - Max Nieuwdorp
- Departments of Internal and Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Kak Khee Yeung
- Department of Surgery, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
| | - Ron Balm
- Department of Surgery, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
| | - Vivian de Waard
- Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
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29
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Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Taruya A, Furuta M, Mukaida N, Kondo T. Prevention of CaCl 2-induced aortic inflammation and subsequent aneurysm formation by the CCL3-CCR5 axis. Nat Commun 2020; 11:5994. [PMID: 33239616 PMCID: PMC7688638 DOI: 10.1038/s41467-020-19763-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 10/29/2020] [Indexed: 11/27/2022] Open
Abstract
Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3-/- mice and Ccr5-/- but not Ccr1-/- mice exhibit exaggerated CaCl2-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl2-treated Ccl3-/- mice. On the contrary, CCL3 treatment attenuates CaCl2-induced AAA in both wild-type and Ccl3-/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl2-induced AAA by suppressing MMP-9 expression.
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MESH Headings
- Angiotensin II/toxicity
- Animals
- Anti-Inflammatory Agents/metabolism
- Aorta, Abdominal/drug effects
- Aorta, Abdominal/immunology
- Aorta, Abdominal/pathology
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/immunology
- Aortic Aneurysm, Abdominal/pathology
- Calcium Chloride/toxicity
- Chemokine CCL3/genetics
- Chemokine CCL3/metabolism
- Disease Models, Animal
- Humans
- Inflammation Mediators/metabolism
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Matrix Metalloproteinase 9/metabolism
- Mice
- Mice, Knockout
- Receptors, CCR1/genetics
- Receptors, CCR1/metabolism
- Receptors, CCR5/genetics
- Receptors, CCR5/metabolism
- Signal Transduction/genetics
- Signal Transduction/immunology
- Specific Pathogen-Free Organisms
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yumi Kuninaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mizuho Nosaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akihiko Kimura
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Taruya
- Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan
| | - Machi Furuta
- Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
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30
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Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases. Antioxidants (Basel) 2020; 9:antiox9111150. [PMID: 33228202 PMCID: PMC7699558 DOI: 10.3390/antiox9111150] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA) are serious arterial diseases in the aorta and brain, respectively. AAA and IA are associated with old age in males and females, respectively, and if rupture occurs, they carry high morbidity and mortality. Aneurysmal subarachnoid hemorrhage (SAH) due to IA rupture has a high rate of complication and fatality. Despite these severe clinical outcomes, preventing or treating these devastating diseases remains an unmet medical need. Inflammation and oxidative stress are shared pathologies of these vascular diseases. Therefore, therapeutic strategies have focused on reducing inflammation and reactive oxygen species levels. Interestingly, in response to cellular stress, the inducible heme oxygenase-1 (HO-1) is highly upregulated and protects against tissue injury. HO-1 degrades the prooxidant heme and generates molecules with antioxidative and anti-inflammatory properties, resulting in decreased oxidative stress and inflammation. Therefore, increasing HO-1 activity is an attractive option for therapy. Several HO-1 inducers have been identified and tested in animal models for preventing or alleviating AAA, IA, and SAH. However, clinical trials have shown conflicting results. Further research and the development of highly selective HO-1 regulators may be needed to prevent the initiation and progression of AAA, IA, or SAH.
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31
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Golledge J, Singh TP. Effect of blood pressure lowering drugs and antibiotics on abdominal aortic aneurysm growth: a systematic review and meta-analysis. Heart 2020; 107:1465-1471. [PMID: 33199361 DOI: 10.1136/heartjnl-2020-318192] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE There is currently no medical treatment proven to limit abdominal aortic aneurysm (AAA) progression. The aim of this systematic review and meta-analysis was to pool data from previous randomised controlled trials assessing the efficacy of blood pressure-lowering and antibiotic medications in limiting AAA growth and AAA-related events, that is, rupture or repair. METHODS A systematic literature search was performed to identify randomised controlled trials that examined the efficacy of blood pressure-lowering medications or antibiotics in reducing AAA growth and AAA-related events. AAA growth (mm/year) was measured by ultrasound or computed tomography imaging. Meta-analyses were performed using random effects models. A subanalysis was conducted including trials that investigated tetracycline or macrolide antibiotics. RESULTS Ten randomised controlled trials including 2045 participants with an asymptomatic AAA were included. Follow-up was between 18 and 63 months. Neither blood pressure-lowering medications (mean growth±SD 2.0±2.4 vs 2.3±2.7 mm/year; standardised mean difference (SMD) -0.07, 95% CI -0.19 to 0.06; p=0.288) or antibiotics (mean growth±SD 2.6±2.1 vs 2.6±2.5 mm/year; SMD -0.11, 95% CI -0.38 to 0.16; p=0.418) reduced AAA growth or AAA-related events (blood pressure-lowering medications: 92 vs 95 events; risk ratio (RR) 0.86, 95% CI 0.66 to 1.11; p=0.244; and antibiotics: 69 vs 73 events; RR 0.93, 95% CI 0.69 to 1.25; p=0.614). The subanalysis of antibiotics showed similar results. CONCLUSIONS This meta-analysis suggests that neither blood pressure-lowering medications or antibiotics limit growth or clinically relevant events in people with AAAs.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia .,Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, Queensland, Australia
| | - Tejas P Singh
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
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32
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Golledge J, Krishna SM, Wang Y. Mouse models for abdominal aortic aneurysm. Br J Pharmacol 2020; 179:792-810. [PMID: 32914434 DOI: 10.1111/bph.15260] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/25/2020] [Accepted: 09/03/2020] [Indexed: 12/21/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Smriti Murali Krishna
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Yutang Wang
- Discipline of Life Sciences, School of Health and Life Sciences, Federation University Australia, Ballarat, Victoria, Australia
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33
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Golledge J, Moxon JV, Singh TP, Bown MJ, Mani K, Wanhainen A. Lack of an effective drug therapy for abdominal aortic aneurysm. J Intern Med 2020; 288:6-22. [PMID: 31278799 DOI: 10.1111/joim.12958] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, P = 0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregation inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.
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Affiliation(s)
- J Golledge
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Qld, Australia.,Centre for Molecular Therapeutics, The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Qld, Australia
| | - J V Moxon
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,Centre for Molecular Therapeutics, The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Qld, Australia
| | - T P Singh
- From the, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Qld, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Qld, Australia
| | - M J Bown
- Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK
| | - K Mani
- Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - A Wanhainen
- Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
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34
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Baxter BT, Matsumura J, Curci JA, McBride R, Larson L, Blackwelder W, Lam D, Wijesinha M, Terrin M. Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms: A Randomized Clinical Trial. JAMA 2020; 323:2029-2038. [PMID: 32453369 PMCID: PMC7251450 DOI: 10.1001/jama.2020.5230] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
IMPORTANCE Abdominal aortic aneurysms affect more than 3% of US older adults. OBJECTIVE To test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter. DESIGN, SETTING, AND PARTICIPANTS Parallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018. INTERVENTIONS Patients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128). MAIN OUTCOMES AND MEASURES The primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores"). RESULTS Of 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo. CONCLUSIONS AND RELEVANCE Among patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01756833.
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Affiliation(s)
- B. Timothy Baxter
- Department of Surgery, University of Nebraska School of Medicine, Omaha
| | - Jon Matsumura
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison
| | - John A. Curci
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - LuAnn Larson
- Department of Surgery, University of Nebraska School of Medicine, Omaha
| | - William Blackwelder
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore
| | | | - Marniker Wijesinha
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore
| | - Michael Terrin
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore
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Li Y, Wang W, Li L, Khalil RA. MMPs and ADAMs/ADAMTS inhibition therapy of abdominal aortic aneurysm. Life Sci 2020; 253:117659. [PMID: 32283055 DOI: 10.1016/j.lfs.2020.117659] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Abdominal aortic aneurysm (AAA) is a chronic vascular degenerative disease featured by progressive dilation and remodeling of the vascular wall, which may lead to aortic rupture and high mortality. The occurrence and development of AAA involve multiple mechanisms, including extracellular matrix degradation, chronic inflammation, oxidative stress, apoptosis of vascular smooth muscle cells and innate immunity. Extracellular matrix degradation is considered as the most important mechanism causing AAA. Matrix metalloproteinases (MMPs) are key factors in this process, contributing greatly to the occurrence and development of AAA. But whether the zinc-dependent endopeptidases (ADAM/ADAMTS) are involved in this process is very little known. This study is a review about the role of MMPs and ADAM/ADAMT as well as the existing MMP inhibitors in abdominal aortic aneurysm, with the purpose of providing reference for the clinical treatment of abdominal aortic aneurysm.
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Affiliation(s)
- Yongqi Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | - Weicheng Wang
- Emergency Center, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Lei Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Dahal S, Swaminathan G, Carney S, Broekelmann T, Mecham R, Ramamurthi A. Pro-elastogenic effects of mesenchymal stem cell derived smooth muscle cells in a 3D collagenous milieu. Acta Biomater 2020; 105:180-190. [PMID: 31982591 DOI: 10.1016/j.actbio.2020.01.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/17/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023]
Abstract
Intrinsically poor auto-regenerative repair of proteolytically-disrupted elastic matrix structures by resident SMCs in the wall of abdominal aortic aneurysms (AAAs) prevents growth arrest and regression of these wall expansions. Supporting their possible future use in a regenerative cell therapy for AAAs, in a prior study, we showed that bone marrow mesenchymal stem cell-derived Smooth Muscle Cells (BM-SMCs) secrete biological factors that have significant pro-elastogenic and anti-proteolytic effects on aneurysmal rat aortic SMCs (EaRASMCs) in non-contact co-cultures. We also identified one stable BM-SMC phenotype (cBM-SMC) generated by differentiating BM-MSCs on a 2D fibronectin substrate in the presence of PDGF (Platelet Derived Growth Factor) and TGF-β1 (Transforming Growth Factor-β1) that exhibited superior elastogenicity and pro-elastogenic/anti-proteolytic properties. In this study, we further investigated the ability of these cBM-SMCs to maintain these superior elastogenic properties in a 3D collagenous milieu alone and in co-culture with EaRASMC to evaluate their potential as an alternative cell source for cell therapy in AAA. Some of our key observations were higher contractility and greater amount of structurally intact elastin production in both standalone culture of cBM-SMCs as well as co-culture of cBM-SMCs with EaRASMCs as shown by VVG (Verhoeff-Van Gieson) staining and Pontamine Sky Blue labeling and lower MMP-9 protein expression in standalone culture in 3D collagenous environment. Our overall result indicates that cBM-SMCs possess the ability to provide elastogenic impetus in a 3D collagenous AAA milieu which is otherwise not conducive to elastogenesis. Therefore our study strongly suggest the utility of cBM-SMCs as a potential cell source for cell therapy to augment elastic matrix neo-assembly and fiber formation and attenuate proteolysis in a collagenous milieu that is evocative of the de-elasticized aneurysmal wall. STATEMENT OF SIGNIFICANCE: Abdominal aortic aneurysm (AAA) or ballooning of the aorta is one of the leading causes of cardiovascular disease (CVD) related death caused by significantly increased proteolytic activity in the aortic wall. Reversing pathophysiology of this condition is challenging due to intrinsically poor regeneration of elastin by aortic smooth muscle cells. Current management of AAA is limited to passive monitoring of the disease until it becomes large enough to receive surgical intervention and no drug based therapy currently exists. Cell based therapy can be a potential alternative treatment in this scenario because it provides elastogenic impetus to the aneurysmal SMCs, compensates for the dead SMCs and serves as a robust source of elastin while being delivered with minimal invasiveness. Hence this work will have significant impact in the field of tissue engineering and regenerative medicine.
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Grant JS, Stafylis C, Celum C, Grennan T, Haire B, Kaldor J, Luetkemeyer AF, Saunders JM, Molina JM, Klausner JD. Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections. Clin Infect Dis 2020; 70:1247-1253. [PMID: 31504345 PMCID: PMC7319058 DOI: 10.1093/cid/ciz866] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 08/29/2019] [Indexed: 02/04/2023] Open
Abstract
Bacterial sexually transmitted infections (STIs) have been increasing over the past 2 decades in gay, bisexual, and other men who have sex with men. With the widespread use of early human immunodeficiency virus (HIV) treatment, which virtually eliminates transmission risk, and the availability of HIV pre-exposure prophylaxis, there have been attitudinal changes regarding HIV infection with resultant increases in sexual contact and declines in condom use. Doxycycline is used for primary prophylaxis in a number of infectious diseases. We conducted a state-of-the-art review to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis and other STIs. International academic and government experts met in March 2019 to frame the initial inquiry, which was supplemented by focused literature searches. Two small short-term randomized controlled trials examining doxycycline prophylaxis found high efficacy. Five additional clinical studies are underway or in development. Studies differed in design, population, outcomes, and safety measures. Doxycycline prophylaxis for bacterial STIs shows promise. Better and more robust data are needed on efficacy; target population; community acceptability; behavioral risk compensation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness; and risk-benefit.
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Affiliation(s)
| | - Chrysovalantis Stafylis
- Division of Infectious Diseases, University of California–Los Angeles (UCLA) David Geffen School of Medicine, Los Angeles, California, USA
| | - Connie Celum
- Department of Global Health, University of Washington, Seattle, Washington DC, USA
- Department of Medicine, University of Washington, Seattle, Washington DC, USA
- Department of Epidemiology, University of Washington, Seattle, Washington DC, USA
| | - Troy Grennan
- British Columbia Centre for Disease Control and Division of Infectious Diseases, University of British Columbia, Vancouver, Canada
| | - Bridget Haire
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - John Kaldor
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Anne F Luetkemeyer
- Zuckerberg San Francisco General, University of California, San Francisco, California, USA
| | - John M Saunders
- Blood Safety, Hepatitis, STI, and HIV Division, National Infection Service, Public Health England, London, United Kingdom
| | - Jean-Michel Molina
- Department of Infectious Diseases, St-Louis Hospital, University of Paris Diderot, Paris, France
- INSERM U944, Paris, France
| | - Jeffrey D Klausner
- Division of Infectious Diseases, University of California–Los Angeles (UCLA) David Geffen School of Medicine, Los Angeles, California, USA
- Department of Epidemiology, University of California–Los Angeles (UCLA), Los Angeles, California, USA
- Fielding School of Public Health, University of California–Los Angeles (UCLA), Los Angeles, California, USA
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Liu B, Granville DJ, Golledge J, Kassiri Z. Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm. Am J Physiol Heart Circ Physiol 2020; 318:H652-H670. [PMID: 32083977 PMCID: PMC7099451 DOI: 10.1152/ajpheart.00621.2019] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/13/2020] [Accepted: 02/13/2020] [Indexed: 12/14/2022]
Abstract
Aortic aneurysm is a permanent focal dilation of the aorta. It is usually an asymptomatic disease but can lead to sudden death due to aortic rupture. Aortic aneurysm-related mortalities are estimated at ∼200,000 deaths per year worldwide. Because no pharmacological treatment has been found to be effective so far, surgical repair remains the only treatment for aortic aneurysm. Aortic aneurysm results from changes in the aortic wall structure due to loss of smooth muscle cells and degradation of the extracellular matrix and can form in different regions of the aorta. Research over the past decade has identified novel contributors to aneurysm formation and progression. The present review provides an overview of cellular and noncellular factors as well as enzymes that process extracellular matrix and regulate cellular functions (e.g., matrix metalloproteinases, granzymes, and cathepsins) in the context of aneurysm pathogenesis. An update of clinical trials focusing on therapeutic strategies to slow abdominal aortic aneurysm growth and efforts underway to develop effective pharmacological treatments is also provided.
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Affiliation(s)
- Bo Liu
- University of Wisconsin, Madison, Department of Surgery, Madison Wisconsin
| | - David J Granville
- International Collaboration on Repair Discoveries Centre and University of British Columbia Centre for Heart Lung Innovation, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jonathan Golledge
- The Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Department of Vascular and Endovascular Surgery, Townsville Hospital and Health Services, Townsville, Queensland, Australia
| | - Zamaneh Kassiri
- University of Alberta, Department of Physiology, Cardiovascular Research Center, Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada
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Provenzano M, Andreucci M, Garofalo C, Faga T, Michael A, Ielapi N, Grande R, Sapienza P, de Franciscis S, Mastroroberto P, Serra R. The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel? Biomolecules 2020; 10:E154. [PMID: 31963569 PMCID: PMC7022805 DOI: 10.3390/biom10010154] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 12/11/2022] Open
Abstract
: Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.
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Affiliation(s)
- Michele Provenzano
- Department of Health Sciences, Renal Unit, “Magna Graecia” University, 88100 Catanzaro, Italy; (M.P.); (M.A.); (T.F.); (A.M.)
| | - Michele Andreucci
- Department of Health Sciences, Renal Unit, “Magna Graecia” University, 88100 Catanzaro, Italy; (M.P.); (M.A.); (T.F.); (A.M.)
| | - Carlo Garofalo
- Division of Nephrology, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy;
| | - Teresa Faga
- Department of Health Sciences, Renal Unit, “Magna Graecia” University, 88100 Catanzaro, Italy; (M.P.); (M.A.); (T.F.); (A.M.)
| | - Ashour Michael
- Department of Health Sciences, Renal Unit, “Magna Graecia” University, 88100 Catanzaro, Italy; (M.P.); (M.A.); (T.F.); (A.M.)
| | - Nicola Ielapi
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy; (N.I.); (S.d.F.)
- Department of Public Health and Infectious Disease, “Sapienza” University of Rome, 00185 Rome, Italy
- Department of Radiology, Vibo Valentia Hospital, 89900 Vibo Valentia, Italy
| | - Raffaele Grande
- Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, 00161 Rome, Italy; (R.G.); (P.S.)
| | - Paolo Sapienza
- Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, 00161 Rome, Italy; (R.G.); (P.S.)
| | - Stefano de Franciscis
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy; (N.I.); (S.d.F.)
- Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Pasquale Mastroroberto
- Department of Experimental and Clinical Medicine, “Magna Graecia” University, 88100 Catanzaro, Italy;
| | - Raffaele Serra
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy; (N.I.); (S.d.F.)
- Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy
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Guirguis-Blake JM, Beil TL, Senger CA, Coppola EL. Primary Care Screening for Abdominal Aortic Aneurysm: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2019; 322:2219-2238. [PMID: 31821436 DOI: 10.1001/jama.2019.17021] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
IMPORTANCE Ruptured abdominal aortic aneurysms (AAAs) have mortality estimated at 81%. OBJECTIVE To systematically review the evidence on benefits and harms of AAA screening and small aneurysm treatment to inform the US Preventive Services Task Force. DATA SOURCES MEDLINE, PubMed (publisher supplied only), Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials for relevant English-language studies published through September 2018. Surveillance continued through July 2019. STUDY SELECTION Trials of AAA screening benefits and harms; trials and cohort studies of small (3.0-5.4 cm) AAA treatment benefits and harms. DATA EXTRACTION AND SYNTHESIS Two investigators independently reviewed abstracts and full-text articles and extracted data. The Peto method was used to pool odds ratios (ORs) for AAA-related mortality, rupture, and operations; the DerSimonian and Laird random-effects model was used to pool calculated risk ratios for all-cause mortality. MAIN OUTCOMES AND MEASURES AAA and all-cause mortality; AAA rupture; treatment complications. RESULTS Fifty studies (N = 323 279) met inclusion criteria. Meta-analysis of population-based randomized clinical trials (RCTs) estimated that a screening invitation to men 65 years or older was associated with a reduction in AAA-related mortality over 12 to 15 years (OR, 0.65 [95% CI, 0.57-0.74]; 4 RCTs [n = 124 926]), AAA-related ruptures over 12 to 15 years (OR, 0.62 [95% CI, 0.55-0.70]; 4 RCTs [n = 124 929]), and emergency surgical procedures over 4 to 15 years (OR, 0.57 [95% CI, 0.48-0.68]; 5 RCTS [n = 175 085]). In contrast, no significant association with all-cause mortality benefit was seen at 12- to 15-year follow-up (relative risk, 0.99 [95% CI 0.98-1.00]; 4 RCTs [n = 124 929]). One-time screening was associated with significantly more procedures over 4 to 15 years in the invited group compared with the control group (OR, 1.44 [95% CI, 1.34-1.55]; 5 RCTs [n = 175 085]). Four trials (n = 3314) of small aneurysm surgical treatment demonstrated no significant difference in AAA-related mortality or all-cause mortality compared with surveillance over 1.7 to 12 years. These 4 early surgery trials showed a substantial increase in procedures in the early surgery group. For small aneurysm treatment, registry data (3 studies [n = 14 424]) showed that women had higher surgical complications and postoperative mortality compared with men. CONCLUSIONS AND RELEVANCE One-time AAA screening in men 65 years or older was associated with decreased AAA-related mortality and rupture rates but was not associated with all-cause mortality benefit. Higher rates of elective surgery but no long-term differences in quality of life resulted from screening.
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Affiliation(s)
- Janelle M Guirguis-Blake
- Department of Family Medicine, University of Washington, Tacoma
- Kaiser Permanente Research Affiliates Evidence-based Practice Center, Kaiser Permanente Center for Health Research, Portland, Oregon
| | - Tracy L Beil
- Kaiser Permanente Research Affiliates Evidence-based Practice Center, Kaiser Permanente Center for Health Research, Portland, Oregon
| | - Caitlyn A Senger
- Kaiser Permanente Research Affiliates Evidence-based Practice Center, Kaiser Permanente Center for Health Research, Portland, Oregon
| | - Erin L Coppola
- Kaiser Permanente Research Affiliates Evidence-based Practice Center, Kaiser Permanente Center for Health Research, Portland, Oregon
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Yoshimura K, Morikage N, Nishino-Fujimoto S, Furutani A, Shirasawa B, Hamano K. Current Status and Perspectives on Pharmacologic Therapy for Abdominal Aortic Aneurysm. Curr Drug Targets 2019; 19:1265-1275. [PMID: 29284386 PMCID: PMC6182934 DOI: 10.2174/1389450119666171227223331] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/13/2017] [Accepted: 12/13/2017] [Indexed: 01/16/2023]
Abstract
Background: Abdominal aortic aneurysm (AAA), a common disease involving the segmen-tal expansion and rupture of the aorta, has a high mortality rate. Therapeutic options for AAA are cur-rently limited to surgical repair to prevent catastrophic rupture. Non-surgical approaches, particularly pharmacotherapy, are lacking for the treatment of AAA. Objective: We review both basic and clinical studies and discuss the current challenges to developing medical therapy that reduces AAA progression. Results: Studies using animal models of AAA progression and human AAA explant cultures have identified several potential targets for preventing AAA growth. However, no clinical studies have con-vincingly confirmed the efficacy of any pharmacologic treatment against the growth of AAA. Thus, there is as yet no strong recommendation regarding pharmacotherapy to reduce the risk of AAA pro-gression and rupture. Conclusion: This review identifies concerns that need to be addressed for the field to progress and dis-cusses the challenges that must be overcome in order to develop effective pharmacotherapy to reduce AAA progression in the future.
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Affiliation(s)
- Koichi Yoshimura
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan.,Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi, 753-8502, Japan
| | - Noriyasu Morikage
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan
| | - Shizuka Nishino-Fujimoto
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan
| | - Akira Furutani
- Department of Surgery, Yamaguchi Rosai Hospital, Sanyo-Onoda, 756-0095, Japan
| | - Bungo Shirasawa
- Department of Medical Education, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan
| | - Kimikazu Hamano
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan
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Abstract
Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm identified hundreds of candidate strategies for stabilization, and data from preoperative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome-related aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field.
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Affiliation(s)
- Jan H. Lindeman
- Dept. Vascular Surgery, Leiden University Medical Center, The Netherlands
| | - Jon S. Matsumura
- Division of Vascular Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
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Patnaik SS, Simionescu DT, Goergen CJ, Hoyt K, Sirsi S, Finol EA. Pentagalloyl Glucose and Its Functional Role in Vascular Health: Biomechanics and Drug-Delivery Characteristics. Ann Biomed Eng 2019; 47:39-59. [PMID: 30298373 PMCID: PMC6318003 DOI: 10.1007/s10439-018-02145-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 09/28/2018] [Indexed: 02/08/2023]
Abstract
Pentagalloyl glucose (PGG) is an elastin-stabilizing polyphenolic compound that has significant biomedical benefits, such as being a free radical sink, an anti-inflammatory agent, anti-diabetic agent, enzymatic resistant properties, etc. This review article focuses on the important benefits of PGG on vascular health, including its role in tissue mechanics, the different modes of pharmacological administration (e.g., oral, intravenous and endovascular route, intraperitoneal route, subcutaneous route, and nanoparticle based delivery and microbubble-based delivery), and its potential therapeutic role in vascular diseases such as abdominal aortic aneurysms (AAA). In particular, the use of PGG for AAA suppression and prevention has been demonstrated to be effective only in the calcium chloride rat AAA model. Therefore, in this critical review we address the challenges that lie ahead for the clinical translation of PGG as an AAA growth suppressor.
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Affiliation(s)
- Sourav S Patnaik
- Vascular Biomechanics and Biofluids Laboratory, Department of Mechanical Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249-0670, USA
| | - Dan T Simionescu
- Department of Bioengineering, Clemson University, Clemson, SC, USA
| | - Craig J Goergen
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Kenneth Hoyt
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX, USA
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shashank Sirsi
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX, USA
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ender A Finol
- Vascular Biomechanics and Biofluids Laboratory, Department of Mechanical Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249-0670, USA.
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Atturu G, Gooneratne T. Introduction to translational research in vascular surgery/medicine. INDIAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY 2019. [DOI: 10.4103/ijves.ijves_30_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Torres-Fonseca M, Galan M, Martinez-Lopez D, Cañes L, Roldan-Montero R, Alonso J, Reyero-Postigo T, Orriols M, Mendez-Barbero N, Sirvent M, Blanco-Colio LM, Martínez J, Martin-Ventura JL, Rodríguez C. Pathophisiology of abdominal aortic aneurysm: biomarkers and novel therapeutic targets. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2018; 31:166-177. [PMID: 30528271 DOI: 10.1016/j.arteri.2018.10.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/14/2018] [Indexed: 01/01/2023]
Abstract
Abdominal aortic aneurysm (AAA) is a vascular pathology with a high rate of morbidity and mortality and a prevalence that, in men over 65 years, can reach around 8%. In this disease, usually asymptomatic, there is a progressive dilatation of the vascular wall that can lead to its rupture, a fatal phenomenon in more than 80% of cases. The treatment of patients with asymptomatic aneurysms is limited to periodic monitoring with imaging tests, control of cardiovascular risk factors and treatment with statins and antiplatelet therapy. There is no effective pharmacological treatment capable of limiting AAA progression or avoiding their rupture. At present, the aortic diameter is the only marker of risk of rupture and determines the need for surgical repair when it reaches values greater than 5.5cm. This review addresses the main aspects related to epidemiology, risk factors, diagnosis and clinical management of AAA, exposes the difficulties to have good biomarkers of this pathology and describes the strategies for the identification of new therapeutic targets and biomarkers in AAA.
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Affiliation(s)
- Monica Torres-Fonseca
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - María Galan
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, España
| | - Diego Martinez-Lopez
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Laia Cañes
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España; Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), IIB-Sant Pau, Barcelona, España
| | - Raquel Roldan-Montero
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Judit Alonso
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Teresa Reyero-Postigo
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Mar Orriols
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Nerea Mendez-Barbero
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - Marc Sirvent
- Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España
| | - Luis Miguel Blanco-Colio
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España; CIBER de Enfermedades Cardiovasculares (CIBERCV), España
| | - José Martínez
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España; Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), IIB-Sant Pau, Barcelona, España
| | - Jose Luis Martin-Ventura
- Vascular Research Lab, Instituto de Investigación Sanitaria, Hospital Universitario Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, España.
| | - Cristina Rodríguez
- CIBER de Enfermedades Cardiovasculares (CIBERCV), España; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, España.
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46
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Mennander AA. The dark side of fluoroquinolones. J Thorac Cardiovasc Surg 2018; 157:122-123. [PMID: 30482528 DOI: 10.1016/j.jtcvs.2018.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 09/06/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Ari A Mennander
- Division of Cardiothoracic Surgery, Tampere University Heart Hospital, Tampere, Finland; Tampere University, Tampere, Finland.
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47
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Thibault PK. Neck vein obstruction: Diagnosis and the role of chronic persistent Chlamydophila pneumoniae infection. Phlebology 2018; 34:372-379. [PMID: 30360684 DOI: 10.1177/0268355518804379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Background The objective of this review is to describe the diagnosis of neck vein obstruction and the possible role of chronic persistent Chlamydophila pneumoniae infection in producing the syndrome of chronic cerebrospinal venous obstruction. Method The normal patterns of flow in the neck veins are described and guidelines for interpretation of the quantitative duplex ultrasound examination of the extracranial neck veins are developed. Result An infective cause of neck vein obstruction is proposed and from a literature search of the role of the obligate intracellular bacterium Chlamydophila pneumoniae in vascular and chronic diseases, a diagnostic protocol for confirming chronic persistent Chlamydophila pneumoniae infection, which includes the quantitative duplex ultrasound examination and specific blood tests are suggested. Conclusion Further research to validate this diagnostic protocol is required.
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48
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Sakalihasan N, Michel JB, Katsargyris A, Kuivaniemi H, Defraigne JO, Nchimi A, Powell JT, Yoshimura K, Hultgren R. Abdominal aortic aneurysms. Nat Rev Dis Primers 2018; 4:34. [PMID: 30337540 DOI: 10.1038/s41572-018-0030-7] [Citation(s) in RCA: 380] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
An abdominal aortic aneurysm (AAA) is a localized dilatation of the infrarenal aorta. AAA is a multifactorial disease, and genetic and environmental factors play a part; smoking, male sex and a positive family history are the most important risk factors, and AAA is most common in men >65 years of age. AAA results from changes in the aortic wall structure, including thinning of the media and adventitia due to the loss of vascular smooth muscle cells and degradation of the extracellular matrix. If the mechanical stress of the blood pressure acting on the wall exceeds the wall strength, the AAA ruptures, causing life-threatening intra-abdominal haemorrhage - the mortality for patients with ruptured AAA is 65-85%. Although AAAs of any size can rupture, the risk of rupture increases with diameter. Intact AAAs are typically asymptomatic, and in settings where screening programmes with ultrasonography are not implemented, most cases are diagnosed incidentally. Modern functional imaging techniques (PET, CT and MRI) may help to assess rupture risk. Elective repair of AAA with open surgery or endovascular aortic repair (EVAR) should be considered to prevent AAA rupture, although the morbidity and mortality associated with both techniques remain non-negligible.
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Affiliation(s)
- Natzi Sakalihasan
- Department of Cardiovascular and Thoracic Surgery, CHU Liège, University of Liège, Liège, Belgium. .,Surgical Research Center, GIGA-Cardiovascular Science Unit, University of Liège, Liège, Belgium.
| | - Jean-Baptiste Michel
- UMR 1148, INSERM Paris 7, Denis Diderot University, Xavier Bichat Hospital, Paris, France
| | - Athanasios Katsargyris
- Department of Vascular and Endovascular Surgery, Paracelsus Medical University, Nuremberg, Germany
| | - Helena Kuivaniemi
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Jean-Olivier Defraigne
- Department of Cardiovascular and Thoracic Surgery, CHU Liège, University of Liège, Liège, Belgium.,Surgical Research Center, GIGA-Cardiovascular Science Unit, University of Liège, Liège, Belgium
| | - Alain Nchimi
- Surgical Research Center, GIGA-Cardiovascular Science Unit, University of Liège, Liège, Belgium.,Department of Medical Imaging, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - Janet T Powell
- Vascular Surgery Research Group, Imperial College London, London, UK
| | - Koichi Yoshimura
- Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi, Japan.,Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Rebecka Hultgren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden
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49
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Carino D, Sarac TP, Ziganshin BA, Elefteriades JA. Abdominal Aortic Aneurysm: Evolving Controversies and Uncertainties. Int J Angiol 2018; 27:58-80. [PMID: 29896039 PMCID: PMC5995687 DOI: 10.1055/s-0038-1657771] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is defined as a permanent dilatation of the abdominal aorta that exceeds 3 cm. Most AAAs arise in the portion of abdominal aorta distal to the renal arteries and are defined as infrarenal. Most AAAs are totally asymptomatic until catastrophic rupture. The strongest predictor of AAA rupture is the diameter. Surgery is indicated to prevent rupture when the risk of rupture exceeds the risk of surgery. In this review, we aim to analyze this disease comprehensively, starting from an epidemiological perspective, exploring etiology and pathophysiology, and concluding with surgical controversies. We will pursue these goals by addressing eight specific questions regarding AAA: (1) Is the incidence of AAA increasing? (2) Are ultrasound screening programs for AAA effective? (3) What causes AAA: Genes versus environment? (4) Animal models: Are they really relevant? (5) What pathophysiology leads to AAA? (6) Indications for AAA surgery: Are surgeons over-eager to operate? (7) Elective AAA repair: Open or endovascular? (8) Emergency AAA repair: Open or endovascular?
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Affiliation(s)
- Davide Carino
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
| | - Timur P. Sarac
- Section of Vascular and Endovascular Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
| | - Bulat A. Ziganshin
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
- Department of Surgical Diseases # 2, Kazan State Medical University, Kazan, Russia
| | - John A. Elefteriades
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
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50
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Seto SW, Chang D, Kiat H, Wang N, Bensoussan A. Chinese Herbal Medicine as a Potential Treatment of Abdominal Aortic Aneurysm. Front Cardiovasc Med 2018; 5:33. [PMID: 29732374 PMCID: PMC5919947 DOI: 10.3389/fcvm.2018.00033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 03/20/2018] [Indexed: 12/19/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is an irreversible condition where the abdominal aorta is dilated leading to potentially fatal consequence of aortic rupture. Multiple mechanisms are involved in the development and progression of AAA, including chronic inflammation, oxidative stress, vascular smooth muscle (VSMC) apoptosis, immune cell infiltration and extracellular matrix (ECM) degradation. Currently surgical therapies, including minimally invasive endovascular aneurysm repair (EVAR), are the only viable interventions for AAAs. However, these treatments are not appropriate for the majority of AAAs, which measure <50 mm. Substantial effort has been invested to identify and develop pharmaceutical treatments such as statins and doxycycline for this potentially lethal condition but these interventions failed to offer a cure or to retard the progression of AAA. Chinese herbal medicine (CHM) has been used for the management of cardiovascular diseases for thousands of years in China and other Asian countries. The unique multi-component and multi-target property of CHMs makes it a potentially ideal therapy for multifactorial diseases such as AAA. In this review, we review the current scientific evidence to support the use of CHMs for the treatment of AAA. Mechanisms of action underlying the effects of CHMs on AAA are also discussed.
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Affiliation(s)
- Sai Wang Seto
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
| | - Hosen Kiat
- Faculty of Medicine, University of New South Wales, Sydney, Australia.,School of Medicine, Western Sydney University, Penrith, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
| | - Ning Wang
- NICM Health Research Institute, Western Sydney University, Penrith, Australia.,Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.,College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Alan Bensoussan
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
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