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Al-Kuraishy HM, Sulaiman GM, Mohsin MH, Mohammed HA, Dawood RA, Albuhadily AK, Al-Gareeb AI, Albukhaty S, Abomughaid MM. Targeting of AMPK/MTOR signaling in the management of atherosclerosis: Outmost leveraging. Int J Biol Macromol 2025; 309:142933. [PMID: 40203916 DOI: 10.1016/j.ijbiomac.2025.142933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Atherosclerosis (AS) is a chronic vascular disorder that is characterized by the thickening and narrowing of arteries due to the development of atherosclerotic plaques. The traditional risk factors involved in AS are obesity, type 2 diabetes (T2D), dyslipidemia, hypertension, and smoking. Furthermore, non-traditional risk factors for AS, such as inflammation, sleep disturbances, physical inactivity, air pollution, and alterations of gut microbiota, gained attention in relation to the pathogenesis of AS. Interestingly, the pathogenesis of AS, is complex and related to different abnormalities of cellular and sub-cellular signaling pathways. It has been illustrated that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (MTOR) pathways are involved in AS pathogenesis. Mounting evidence indicated that AMPK plays a critical role in attenuating the development of AS by activating autophagy, which is impaired during atherogenesis. AMPK has a vasculoprotective effect by reducing lipid accumulation, inflammatory cell proliferation, and the release of pro-inflammatory cytokines, as well as decreasing inflammatory cell adhesion to the vascular endothelium. AMPK activation by metformin inhibits the migration of vascular smooth muscle cells (VSMCs) and AS development. However, the MTOR pathway contributes to AS by inhibiting autophagy, highlighting autophagy as a crucial link between the AMPK and MTOR pathways in AS pathogenesis. The MTOR is a key inducer of endothelial dysfunction and is involved in the development of AS. Therefore, both the AMPK and MTOR pathways play a crucial role in the pathogenesis of AS. However, the exact role of AMPK and MTOR pathways in the pathogenesis of AS is not fully clarified. Therefore, this review aims to discuss the potential role of the AMPK/MTOR signaling pathway in AS, and how AMPK activators and MTOR inhibitors influence the development and progression of AS. In conclusion, AMPK activators and MTOR inhibitors have vasculoprotective effects against the development and progression of AS.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ghassan M Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad, Iraq.
| | - Mayyadah H Mohsin
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Retaj A Dawood
- Department of Biology, College of Science, Al-Mustaqbal University, Hilla 51001, Iraq
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir ibn Hayyan Medical University, Al-Ameer Qu, PO.Box13 Kufa, Najaf, Iraq
| | | | - Mosleh M Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Bisha 67714, Saudi Arabia
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Frühwald L, Fasching P, Dobrev D, Kaski JC, Borghi C, Wassmann S, Huber K, Semb AG, Agewall S, Drexel H. Management of dyslipidaemia in patients with comorbidities-facing the challenge. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2025; 11:164-173. [PMID: 39719399 PMCID: PMC12063584 DOI: 10.1093/ehjcvp/pvae095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/28/2024] [Accepted: 12/23/2024] [Indexed: 12/26/2024]
Abstract
This review aims to examine the evidence on the benefits and risks of lipid-lowering drugs in patients with liver disease. Elevated liver enzyme levels often lead to cautious discontinuation of these drugs, potentially withholding from patients their benefit in reducing cardiovascular disease morbidity and mortality. Using a literature search of PubMed, we examine the efficacy and safety profiles of various lipid-lowering agents, including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, fibrates, and icosapent ethyl, focusing particularly on their potential side effects related to liver health. A major challenge in the assessment of drug-induced hepatotoxicity is the fact that it relies heavily on case reports rather than real-world evidence. There is currently a lack of robust evidence on lipid-lowering therapy in people with pre-existing liver disease. Nevertheless, we have attempted to summarize the available data for all the drugs mentioned in order to provide guidance for the treatment of patients with liver dysfunction. This review highlights the need for further research to optimize treatment strategies for patients with coexisting liver and cardiovascular disease.
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Affiliation(s)
- Lisa Frühwald
- 5th Medical Department with Endocrinology, Rheumatology and Acute-Geriatrics, Vienna Health Association, Ottakring Clinic, Montleartstraße 37, 1160 Vienna, Austria
- Verein zur Förderung der Wissenschaftlichen Forschung am Wilhelminenspital der Stadt Wien FWFW, Montleartstraße 37, 1160 Wien, Österreich
| | - Peter Fasching
- 5th Medical Department with Endocrinology, Rheumatology and Acute-Geriatrics, Vienna Health Association, Ottakring Clinic, Montleartstraße 37, 1160 Vienna, Austria
- Verein zur Förderung der Wissenschaftlichen Forschung am Wilhelminenspital der Stadt Wien FWFW, Montleartstraße 37, 1160 Wien, Österreich
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Rue Bélanger, QC H1T 1C8 Montréal, Canada
- Department of Integrative Physiology, Baylor College of Medicine, One Baylor Placa, 77030 Housten, Texas, USA
| | - Juan Carlos Kaski
- Division of Cardiovascular Medicine, Molecular and Clinical Sciences Research Institute, St George's University of London, London SW17 0RE, UK
| | - Claudio Borghi
- Department of Cardiovascular Medicine, University of Bologna-IRCCS AOU S, 10138 Orsola, Bologna, Italy
| | - Sven Wassmann
- Cardiology Pasing, Faculty of Medicine, Munich and University of the Saarland, 66123 Homburg/Saar, Germany
| | - Kurt Huber
- Ludwig Boltzmann Institute of Interventional Cardiology and Rhythmology, Clinic Ottakring, Montleartstraße 37, 1160 Vienna, Austria
- Sigmund Freud University, Faculty of Medicine, Freudplatz 3, 1020 Vienna, Austria
| | - Anne Grete Semb
- Preventive Cardio-Rheuma Clinic, Division of Research and Innovation, REMEDY Centre, Diakonhjemmet Hospital, Oslo, Norway
| | - Stefan Agewall
- Institute of Clinical Sciences, Karolinska Institute of Danderyd, 171 77 Stockholm, Sweden
| | - Heinz Drexel
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Carinagasse 47, 6800 Feldkirch, Austria
- Private University in the Principality of Liechtenstein, Dorfstraße 24, 9495 Triesen, Liechtenstein
- Vorarlberger Landeskrankenhausbetriebsgesellschaft, Carinagasse 47, 6800 Feldkirch, Austria
- Drexel University College of Medicine, 2900 Queen Ln, Philadelphia PA 19129, USA
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Bashir B, Schofield J, Downie P, France M, Ashcroft DM, Wright AK, Romeo S, Gouni-Berthold I, Maan A, Durrington PN, Soran H. Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape-focus on hypertriglyceridaemia. Front Cardiovasc Med 2024; 11:1389106. [PMID: 39171323 PMCID: PMC11335737 DOI: 10.3389/fcvm.2024.1389106] [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: 02/20/2024] [Accepted: 07/08/2024] [Indexed: 08/23/2024] Open
Abstract
Aims Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors. Findings Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors. Implications Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.
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Affiliation(s)
- Bilal Bashir
- Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Jonathan Schofield
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Paul Downie
- Department of Clinical Biochemistry, Bristol Royal Infirmary, Bristol, United Kingdom
| | - Michael France
- Department of Clinical Biochemistry, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom
| | - Darren M. Ashcroft
- Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
- Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Alison K. Wright
- Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
- Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ioanna Gouni-Berthold
- Centre for Endocrinology, Diabetes and Preventive Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Akhlaq Maan
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Paul N. Durrington
- Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Handrean Soran
- Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
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Yang XH, Tu QM, Li L, Guo YP, Wang NS, Jin HM. Triglyceride-lowering therapy for the prevention of cardiovascular events, stroke, and mortality in patients with diabetes: A meta-analysis of randomized controlled trials. Atherosclerosis 2024; 394:117187. [PMID: 37527961 DOI: 10.1016/j.atherosclerosis.2023.117187] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND AND AIMS Triglyceride (TG)-lowering therapy is efficient for the prevention of cardiovascular disease (CVD) in the general population; however, for diabetic individuals, it is more controversial. The purpose of this study was to pool the results from randomized controlled trials (RCTs) to clarify whether the lowering of TG is beneficial for the prevention of CVD events, stroke, and mortality in subjects with diabetes. METHODS MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Controlled Trials were searched to identify the relevant literature. We included randomized controlled trials (RCTs) to assess the association of triglyceride-lowering therapy with the prevention of CVD events, stroke, and mortality in diabetic patients. RESULTS Overall, 19 studies were included in this meta-analysis. Compared with the control groups, TG lowering was associated with a decreased risk of CVD events (RR = 0.91, 95% CI 0.87-0.95, p = 0.000) and CVD mortality (RR = 0.93, 95% CI 0.86-1.00, p = 0.047). There was no significant correlation between TG-lowering therapy and the incidence of stroke and all-cause mortality (RR = 0.93, 95% CI 0.86-1.02, p = 0.129 and RR = 0.97, 95% CI 0.93-1.01, p = 0.107, respectively). Subgroup analysis showed that the decreased CVD risk resulting from TG-lowering therapy was independent of age, sex, region, duration of follow-up, degree of TG reduction and glycemic control. CONCLUSIONS TG-lowering therapy is associated with a reduction in CVD events and cardiovascular-specific mortality, but not in stroke and all-cause mortality. Future large, multicenter RCTs will further confirm these conclusions.
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Affiliation(s)
- Xiu Hong Yang
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China; Department of Nephrology, Affiliated the Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Ming Tu
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China
| | - Li Li
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China
| | - Yong Ping Guo
- Department of Nephrology, Affiliated the Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Nian Song Wang
- Department of Nephrology, Affiliated the Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Hui Min Jin
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China; Department of Nephrology, The People's Hospital of Wenshan Prefecture, Yunnan Province, China.
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Nicholls SJ, Nelson AJ. New targets and mechanisms of action for lipid-lowering and anti-inflammatory therapies in atherosclerosis: where does the field stand? Expert Opin Ther Targets 2024; 28:375-384. [PMID: 38815057 DOI: 10.1080/14728222.2024.2362644] [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: 12/20/2023] [Accepted: 05/29/2024] [Indexed: 06/01/2024]
Abstract
INTRODUCTION Atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality worldwide, despite widespread use of statins. There is a need to develop additional therapeutic strategies that will complement statins to achieve more effective reductions in cardiovascular risk. AREAS COVERED This review provides a comprehensive summary of current areas of therapeutic development targeting both lipid and inflammatory factors implicated in the pathogenesis of atherosclerosis. In addition to develop of novel approaches that will produce more effective lowering of low-density lipoprotein cholesterol, clinical trials are currently evaluating the potential to target other atherogenic lipid parameters such as triglyceride-rich lipoproteins and Lp(a), in addition to promoting the biological properties of high-density lipoproteins. Targeting inflammation within the vascular wall has emerged as a new frontier in cardiovascular prevention, with early evidence that use of anti-inflammatory agents have the potential to reduce cardiovascular risk. EXPERT OPINION Clinical practice has an increasing array of therapeutic tools to achieve more effective lowering of low-density lipoprotein cholesterol for high-risk patients. In addition, clinical trials have the potential to deliver a range of additional agents to the clinic, that target alternative lipid and inflammatory mediators. This will permit the potential to personalize cardiovascular prevention.
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Affiliation(s)
| | - Adam J Nelson
- Victorian Heart Institute, Monash University, Melbourne, Australia
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6
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Ahmed R, de Souza RJ, Li V, Banfield L, Anand SS. Twenty years of participation of racialised groups in type 2 diabetes randomised clinical trials: a meta-epidemiological review. Diabetologia 2024; 67:443-458. [PMID: 38177564 PMCID: PMC10844363 DOI: 10.1007/s00125-023-06052-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/16/2023] [Indexed: 01/06/2024]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes mellitus prevalence is increasing globally and the greatest burden is borne by racialised people. However, there are concerns that the enrolment of racialised people into RCTs is limited, resulting in a lack of ethnic and racial diversity. This may differ depending whether an RCT is government funded or industry funded. The aim of this study was to review the proportions of racialised and white participants included in large RCTs of type 2 diabetes pharmacotherapies relative to the disease burden of type 2 diabetes in these groups. METHODS The Ovid MEDLINE database was searched from 1 January 2000 to 31 December 2020. English language reports of RCTs of type 2 diabetes pharmacotherapies published in select medical journals were included. Studies were included in this review if they had a sample size of at least 100 participants and all participants were adults with type 2 diabetes. Industry-funded trials must have recruited participants from at least two countries. Government-funded trials were not held to the same standard because they are typically conducted in a single country. Data including the numbers and proportions of participants by ethnicity and race were extracted from trial reports. The participation-to-prevalence ratio (PPR) was calculated for each trial by dividing the percentage of white and racialised participants in each trial by the percentage of white and racialised participants with type 2 diabetes, respectively, for the regions of recruitment. A random-effects meta-analysis was used to generate the pooled PPRs and 95% CIs across study types. A PPR <0.80 indicates under-representation and a PPR >1.20 indicates over-representation. Risk of bias assessments were not conducted for this study as the objective was to examine recruitment of racialised and white participants rather than evaluate the trustworthiness of clinical trial outcomes. RESULTS A total of 83 trials were included, involving 283,122 participants, of which 15 were government-funded and 68 were industry-funded trials. In government-funded trials, the PPR for white participants was 1.11 (95% CI 0.99, 1.24) and the PPR for racialised participants was 0.72 (95% CI 0.60, 0.86). In industry-funded trials, the PPR for white participants was 1.95 (95% CI 1.74, 2.18) and the PPR for racialised participants was 0.36 (95% CI 0.32, 0.42). The limitations of this study include the reliance on investigator-reported ethnicity and race to classify participants as 'white' or 'racialised', the use of estimates for type 2 diabetes prevalence and demographic data, and the high levels of heterogeneity of pooled estimates. However, despite these limitations, the results were consistent with respect to direction. CONCLUSIONS/INTERPRETATION Racialised participants are under-represented in government- and industry-funded type 2 diabetes trials. Strategies to improve recruitment and enrolment of racialised participants into RCTs should be developed. REGISTRATION Open Science Framework registration no. f59mk ( https://osf.io/f59mk ) FUNDING: The authors received no financial support for this research or authorship of the article.
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Affiliation(s)
- Rabeeyah Ahmed
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada
| | - Russell J de Souza
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
| | - Vincent Li
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Laura Banfield
- Health Sciences Library, McMaster University, Hamilton, ON, Canada
| | - Sonia S Anand
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada.
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.
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Yin J, Fu X, Luo Y, Leng Y, Ao L, Xie C. A Narrative Review of Diabetic Macroangiopathy: From Molecular Mechanism to Therapeutic Approaches. Diabetes Ther 2024; 15:585-609. [PMID: 38302838 PMCID: PMC10942953 DOI: 10.1007/s13300-024-01532-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/11/2024] [Indexed: 02/03/2024] Open
Abstract
Diabetic macroangiopathy, a prevalent and severe complication of diabetes mellitus, significantly contributes to the increased morbidity and mortality rates among affected individuals. This complex disorder involves multifaceted molecular mechanisms that lead to the dysfunction and damage of large blood vessels, including atherosclerosis (AS) and peripheral arterial disease. Understanding the intricate pathways underlying the development and progression of diabetic macroangiopathy is crucial for the development of effective therapeutic interventions. This review aims to shed light on the molecular mechanism implicated in the pathogenesis of diabetic macroangiopathy. We delve into the intricate interplay of chronic inflammation, oxidative stress, endothelial dysfunction, and dysregulated angiogenesis, all of which contribute to the vascular complications observed in this disorder. By exploring the molecular mechanism involved in the disease we provide insight into potential therapeutic targets and strategies. Moreover, we discuss the current therapeutic approaches used for treating diabetic macroangiopathy, including glycemic control, lipid-lowering agents, and vascular interventions.
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Affiliation(s)
- Jiacheng Yin
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoxu Fu
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yue Luo
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yuling Leng
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Lianjun Ao
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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Abrahams T, Nicholls SJ. Perspectives on the success of plasma lipidomics in cardiovascular drug discovery and future challenges. Expert Opin Drug Discov 2024; 19:281-290. [PMID: 38402906 DOI: 10.1080/17460441.2023.2292039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 12/04/2023] [Indexed: 02/27/2024]
Abstract
INTRODUCTION Plasma lipidomics has emerged as a powerful tool in cardiovascular drug discovery by providing insights into disease mechanisms, identifying potential biomarkers for diagnosis and prognosis, and discovering novel targets for drug development. Widespread application of plasma lipidomics is hampered by technological limitations and standardization and requires a collaborative approach to maximize its use in cardiovascular drug discovery. AREAS COVERED This review provides an overview of the utility of plasma lipidomics in cardiovascular drug discovery and discusses the challenges and future perspectives of this rapidly evolving field. The authors discuss the role of lipidomics in understanding the molecular mechanisms of CVD, identifying novel biomarkers for diagnosis and prognosis, and discovering new therapeutic targets for drug development. Furthermore, they highlight the challenges faced in data analysis, standardization, and integration with other omics approaches and propose future directions for the field. EXPERT OPINION Plasma lipidomics holds great promise for improving the diagnosis, treatment, and prevention of CVD. While challenges remain in standardization and technology, ongoing research and collaboration among scientists and clinicians will undoubtedly help overcome these obstacles. As lipidomics evolves, its impact on cardiovascular drug discovery and clinical practice is expected to grow, ultimately benefiting patients and healthcare systems worldwide.
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Affiliation(s)
- Timothy Abrahams
- From the Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Stephen J Nicholls
- From the Victorian Heart Institute, Monash University, Melbourne, Australia
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9
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Zhu B, Wu H, Li KS, Eisa-Beygi S, Singh B, Bielenberg DR, Huang W, Chen H. Two sides of the same coin: Non-alcoholic fatty liver disease and atherosclerosis. Vascul Pharmacol 2024; 154:107249. [PMID: 38070759 DOI: 10.1016/j.vph.2023.107249] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/20/2023] [Accepted: 11/25/2023] [Indexed: 02/03/2024]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis remain high, which is primarily due to widespread adoption of a western diet and sedentary lifestyle. NAFLD, together with advanced forms of this disease such as non-alcoholic steatohepatitis (NASH) and cirrhosis, are closely associated with atherosclerotic-cardiovascular disease (ASCVD). In this review, we discussed the association between NAFLD and atherosclerosis and expounded on the common molecular biomarkers underpinning the pathogenesis of both NAFLD and atherosclerosis. Furthermore, we have summarized the mode of function and potential clinical utility of existing drugs in the context of these diseases.
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Affiliation(s)
- Bo Zhu
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Hao Wu
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Kathryn S Li
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Shahram Eisa-Beygi
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Bandana Singh
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Diane R Bielenberg
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolic Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, United States of America
| | - Hong Chen
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America.
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Kim KA, Kim NJ, Choo EH. The effect of fibrates on lowering low-density lipoprotein cholesterol and cardiovascular risk reduction: a systemic review and meta-analysis. Eur J Prev Cardiol 2024; 31:291-301. [PMID: 37855457 DOI: 10.1093/eurjpc/zwad331] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/14/2023] [Accepted: 10/17/2023] [Indexed: 10/20/2023]
Abstract
AIMS The effect of fibrate treatment on cardiovascular risk is inconsistent. This meta-analysis aimed to assess the effect of fibrates on major adverse cardiovascular outcome (MACE) reduction. METHODS AND RESULTS PubMed, Embase, and Cochrane library databases were searched up to February 2023 for randomized controlled trials comparing fibrate therapy against placebo and reporting cardiovascular outcomes and lipid profile changes. The primary outcome was the clinical outcomes of each trial that most closely corresponding to MACE, a composite of cardiovascular death, acute myocardial infarction, stroke, and coronary revascularization. A pre-specified meta-regression analysis to examine the relationship between the changes in lipid levels after fibrate treatment and the risk of MACE was also performed. Twelve trials were selected for final analysis, with 25 781 patients and 2741 MACEs in the fibrate group and 27 450 patients and 3754 MACEs in the control group. Overall, fibrate therapy was associated with decreased risk of MACE [RR 0.87, 95% confidence interval (CI) 0.81-0.94] with moderate heterogeneity (I2 = 47%). In meta-regression analysis, each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) after fibrate treatment reduced MACE (RR 0.71, 95% CI 0.49-0.94, P = 0.01), while triglyceride level changes did not show a significant association (RR per 1mmol/L reduction 0.96, 95% CI 0.53-1.40, P = 0.86). A sensitivity analysis with the composite outcome of cardiovascular death or acute myocardial infarction produced similar results. CONCLUSION Treatment with fibrates was associated with decreased risk of MACE. The reduction in MACE risk with fibrate therapy appears to be attributable to LDL-C reduction rather than a decrease in triglyceride levels.
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Affiliation(s)
- Kyung An Kim
- Division of Cardiology, Department of Internal Medicine, Seoul St.Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
| | - Na Jin Kim
- Medical Library, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
| | - Eun Ho Choo
- Division of Cardiology, Department of Internal Medicine, Seoul St.Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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11
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Mohsin SN, Saleem F, Humayun A, Tanweer A, Muddassir A. Prospective Nutraceutical Effects of Cinnamon Derivatives Against Insulin Resistance in Type II Diabetes Mellitus-Evidence From the Literature. Dose Response 2023; 21:15593258231200527. [PMID: 37701673 PMCID: PMC10494518 DOI: 10.1177/15593258231200527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
Apart from advances in pharmaceutical antidiabetic agents, efforts are being made toward hypoglycemic agents derived from natural sources. Cinnamon has been reported to have significant benefits for human health, particularly as an anti-inflammatory, antidiabetic, and anti-hypertriglyceridemic agent. The phytochemicals in cinnamon can be extracted from different parts of plant by distillation and solvent extraction. These chemicals help in decreasing insulin resistance and can act against hyperglycemia and dyslipidemia, inflammation and oxidative stress, obesity, overweight, and abnormal glycation of proteins. Cinnamon has shown to improve all of these conditions in in vitro, animal, and/or human studies. However, the mechanism of action of active ingredients found in cinnamon remains unclear. The current review presents the outstanding ability of cinnamon derivatives to control diabetes by various pathways modulating insulin release and insulin receptor signaling. It was also found that the type and dosage of cinnamon as well as subject characteristics including drug interactions are likely to affect the response to cinnamon. Future research directions based on this review include the synergistic usage of various cinnamon derivatives in managing and/or preventing diabetes and possible other relevant chronic diseases.
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Affiliation(s)
- Saima Naz Mohsin
- NIH, HRI, Research Center NHRC, Shaikh Zayed Post Graduate Medical Institute, Lahore, Pakistan
| | - Faiza Saleem
- Department of Biotechnology, Lahore College for Women University, Lahore, Pakistan
| | - Ayesha Humayun
- Department of Public Health and Community Medicine, Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan
| | - Afifa Tanweer
- Department of Nutrition & Dietetics, School of Health Sciences, University of Management and Technology, Lahore, Pakistan
| | - Ambreen Muddassir
- Department of Medicine, Shaikh Zayed Post Graduate Medical Institute, Lahore, Pakistan
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12
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Rodriguez-Gutierrez R, Garcia-Leal M, Raygoza-Cortez K, Flores-Rodríguez A, Moreno-Alvarado M, Heredia-Martínez EM, Vazquez-Baquerizo B, Guerra-Espiricueta R, Muñoz-Silva V, Gonzalez-Gonzalez JG. Benefits and harms of fibrate therapy in patients with type 2 diabetes: a systematic review and meta-analysis. Endocrine 2023:10.1007/s12020-023-03401-y. [PMID: 37247046 DOI: 10.1007/s12020-023-03401-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/13/2023] [Indexed: 05/30/2023]
Abstract
PURPOSE This systematic review aimed to evaluate the benefits and harms of fibrate therapy, alone or in combination with statins, in adult patients with type 2 diabetes (T2D). METHODS A comprehensive search was conducted in six databases, from inception to January 27, 2022. Clinical trials that compared fibrate therapy with other lipid-lowering interventions or placebo were included. Outcomes of interest comprised cardiovascular (CV) events, complications of T2D, metabolic profile, and adverse events. Random-effects meta-analyses were performed to estimate mean differences (MD) and risk ratios (RR), alongside 95% confidence intervals (CI). RESULTS A total of 25 studies were included, six comparing fibrates against statins, 11 against placebo, and eight evaluating the combination of fibrates with statins. Overall risk of bias was rated as moderate, and most outcomes rendered low confidence per GRADE approach. Fibrates showed reduction of serum triglycerides (TGs) (MD -17.81, CI -33.92 to -1.69) and a marginal increase of high-density lipoprotein cholesterol (HDL-c) (MD: 1.60, CI 0.29 to 2.90) in adults with T2D, but no differences were found in CV events when compared to statin therapy (RR 0.99, CI 0.76 to 1.09). When used in combination with statins, no major differences were exhibited regarding lipid profile and CV outcomes. Adverse events were comparable between fibrate and statin monotherapies (e.g., RR of 1.03 for rhabdomyolysis, and 0.90 for gastrointestinal events). CONCLUSIONS Fibrate therapy in patients with T2D results in a marginal improvement of TGs and HDL-c but without reducing the risk of CV events and mortality. Their use should be reserved for very specific scenarios after a deliberative dialogue between patients and clinicians regarding their benefits and harms.
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Affiliation(s)
- Rene Rodriguez-Gutierrez
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
- Knowledge and Evaluation Research Unit (KER Unit), Mayo Clinic, Rochester, MN, USA.
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
| | - Mariana Garcia-Leal
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Karina Raygoza-Cortez
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Andrea Flores-Rodríguez
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Marcela Moreno-Alvarado
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - E Maximiliano Heredia-Martínez
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Briana Vazquez-Baquerizo
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Raul Guerra-Espiricueta
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Valeria Muñoz-Silva
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Jose Gerardo Gonzalez-Gonzalez
- Plataforma INVEST UANL-KER Unit Mayo Clinic (KER Unit Mexico), School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
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13
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Chandra A, Kaur P, Sahu SK, Mittal A. A new insight into the treatment of diabetes by means of pan PPAR agonists. Chem Biol Drug Des 2022; 100:947-967. [PMID: 34990085 DOI: 10.1111/cbdd.14020] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 01/25/2023]
Abstract
PPARs stand for 'peroxisome proliferator-activated receptors' and are ligand-activated transcription factors of nuclear hormone receptor superfamily. A list of the most commonly used single receptor PPAR agonists, that is α (alpha) PPAR agonists, β/δ(beta/delta) PPAR agonists, γ(gamma) PPAR agonists, along with pan PPAR agents, that are being researched on, are marketed, are in clinical trials or are being studied for further derivative findings, has been listed. Type 2 diabetes constitutes about 90% of total diabetes cases. Pan PPAR ligands could very well pave the foundation for a new class of agents, that can act on all 3 PPAR receptors, and produce better effects in general, than the individual receptor-acting ligands or dual combination ligands (α/ γ). In this review paper, we have detailed various pan PPAR agonists that can be used to treat type 2 diabetes, which can generate potential derivatives as well.
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Affiliation(s)
- Avik Chandra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Paranjeet Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Amit Mittal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
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14
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Abstract
INTRODUCTION Dyslipidemia therapeutics have primarily focused on lowering levels of low-density lipoprotein cholesterol. However, many patients continue to experience cardiovascular events, despite effective lowering of LDL-C. This has prompted efforts to target additional risk factors to achieve more effective prevention of cardiovascular disease. Emerging evidence suggests that triglyceride rich lipoproteins play a causal role in atherosclerosis, highlighting the potential for specific therapeutic lowering. AREAS COVERED (1) Evidence to support the causal role of triglyceride rich lipoproteins in atherosclerotic cardiovascular disease. (2) Use of existing lipid modifying therapies to target triglyceride rich lipoproteins. (3) Development of novel therapeutic agents that target triglyceride rich lipoproteins and their potential impact on cardiovascular risk. EXPERT OPINION/COMMENTARY Evidence from preclinical, observational and genetic studies highlight the role of triglyceride rich lipoproteins in the causal pathway of atherosclerotic cardiovascular disease. A number of existing agents have the potential to reduce residual cardiovascular risk associated with hypertriglyceridemia. However, emerging agents have the potential to substantially and preferentially lower triglyceride levels beyond contemporary therapeutics. How they will modulate cardiovascular risk will ultimately be determined by large clinical outcomes trials. They do provide the opportunity to substantially influence the way we target dyslipidemia in the prevention of cardiovascular disease.
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Affiliation(s)
- Kristen J Bubb
- Biomedicine Discovery Institute, Clayto, VIC, Australia.,Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia
| | - Adam J Nelson
- Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia
| | - Stephen J Nicholls
- Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia
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15
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Iwata H, Osborn EA, Ughi GJ, Murakami K, Goettsch C, Hutcheson JD, Mauskapf A, Mattson PC, Libby P, Singh SA, Matamalas J, Aikawa E, Tearney GJ, Aikawa M, Jaffer FA. Highly Selective PPARα (Peroxisome Proliferator-Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular-Microstructural Imaging. J Am Heart Assoc 2021; 10:e020834. [PMID: 34632804 PMCID: PMC8751880 DOI: 10.1161/jaha.121.020834] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator‐activated receptor α) agonist, suppresses coronary stent‐induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2–4 per animal; 44 stents total). On day 7, intracoronary molecular‐structural near‐infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent‐induced inflammatory protease activity (near‐infrared fluorescence target‐to‐background ratio: pemafibrate, median [25th‐75th percentile]: 2.8 [2.5–3.3] versus control, 4.1 [3.3–4.3], P=0.02). At day 28, animals underwent repeat near‐infrared fluorescence–optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7–54.1] mm3 versus control, 54.2 [41.2–81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent‐induced cellular inflammation and neointima expression of the inflammatory mediators TNF‐α (tumor necrosis factor‐α) and MMP‐9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)–myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.
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Affiliation(s)
- Hiroshi Iwata
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA.,Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Eric A Osborn
- Cardiovascular Research CenterCardiology DivisionMassachusetts General HospitalHarvard Medical School Boston MA.,Cardiology Division Beth Israel Deaconess Medical CenterHarvard Medical School Boston MA
| | - Giovanni J Ughi
- Wellman Center for Photomedicine Massachusetts General HospitalHarvard Medical School Boston MA
| | - Kentaro Murakami
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Claudia Goettsch
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Joshua D Hutcheson
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Adam Mauskapf
- Cardiovascular Research CenterCardiology DivisionMassachusetts General HospitalHarvard Medical School Boston MA
| | - Peter C Mattson
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Peter Libby
- Center for Excellence in Vascular Biology Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Sasha A Singh
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Joan Matamalas
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA
| | - Elena Aikawa
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA.,Center for Excellence in Vascular Biology Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA.,Department of Human Pathology I.M. Sechenov First Moscow State Medical University of the Ministry of Health Moscow Russian Federation
| | - Guillermo J Tearney
- Wellman Center for Photomedicine Massachusetts General HospitalHarvard Medical School Boston MA.,Department of Pathology Massachusetts General HospitalHarvard Medical School Boston MA
| | - Masanori Aikawa
- Center for Interdisciplinary Cardiovascular Sciences Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA.,Center for Excellence in Vascular Biology Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston MA.,Channing Division of Network Medicine Brigham and Women's HospitalHarvard Medical School Boston MA
| | - Farouc A Jaffer
- Cardiovascular Research CenterCardiology DivisionMassachusetts General HospitalHarvard Medical School Boston MA.,Wellman Center for Photomedicine Massachusetts General HospitalHarvard Medical School Boston MA
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16
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Tomlinson B, Patil NG, Fok M, Lam CWK. Managing dyslipidemia in patients with Type 2 diabetes. Expert Opin Pharmacother 2021; 22:2221-2234. [PMID: 33823719 DOI: 10.1080/14656566.2021.1912734] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Type 2 diabetes mellitus (T2DM) is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) which is partly related to atherogenic dyslipidemia with raised triglycerides, reduced high-density lipoprotein cholesterol levels, and accompanying lipid changes. Treatment of this dyslipidemia is regarded as a priority to reduce the ASCVD risk in T2DM. AREAS COVERED This article reviews the relevant studies and guidelines from the publications related to this area. EXPERT OPINION Lifestyle modification should always be encouraged, and statin treatment is indicated in most patients with T2DM based on the outcome of randomized controlled trials. If LDL-C goals are not achieved, first, ezetimibe and subsequently proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors should be added. Patients with T2DM derive greater benefits from ezetimibe and PCSK9 inhibitors due to their higher absolute ASCVD risk compared to patients without T2DM. If triglyceride levels remain elevated, a high dose of eicosapentaenoic acid ethyl ester should be added. Fibrates should be used for severe hypertriglyceridemia to prevent acute pancreatitis. Novel treatments including pemafibrate and inclisiran are undergoing cardiovascular outcome trials, and RNA-based therapies may help to target residual hypertriglyceridemia and high lipoprotein(a) with the long acting treatments offering potential improved adherence to therapy.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau China
| | | | - Manson Fok
- Faculty of Medicine, Macau University of Science and Technology, Macau China
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17
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Jeong H, Yang D, Zhao J, Seo JH, Shin DG, Cha JD, Lim CW, Kim JW, Kim B. Ethanol Extract of Orostachys japonicus A. Berger (Crassulaceae) Protects Against Type 2 Diabetes by Reducing Insulin Resistance and Hepatic Inflammation in Mice. J Med Food 2021; 24:464-478. [PMID: 34009023 DOI: 10.1089/jmf.2020.4790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes (T2D) is a threaten human health problem, and accompanied by hyperglycemia and disorder of insulin secretion, is a major cause of abnormalities in maintaining blood glucose homeostasis. Also, low-grade inflammation, as well as insulin resistance (IR), is a common feature in patients with T2D. Numerous causes of the outbreak of T2D have been suggested by researchers, who indicate that genetic background and epigenetic predisposition, such as overnutrition and deficient physical activity, hasten the promotion of T2D milieu. Orostachys japonicus A. Berger (O. japonicus) is a herbal and remedial plant whose various activities include hemostatic, antidotal, febrile, and anti-inflammatory. Hence, we designed to evaluate the antidiabetic efficacy of ethanol extracts of O. japonicus (OJE). Six-week-old C57BL/Ksj-db/db (db/db) mice were used. The results showed that mice given various concentrations of OJE (0, 50, 100, and 200 mg/kg per day) for 8 weeks showed significantly reduced hyperglycemia, IR, and liver injury, confirmed by measuring diabetic parameters, serum, and hepatic biochemicals. Furthermore, the treatment of OJE markedly decreased the mRNA levels of proinflammatory cytokines, lipid accumulation, and gluconeogenesis-related genes. Consistently, western blot analysis indicated that mice treated with OJE showed increased levels of phospho-c-Jun N-terminal kinase, phospho-Akt, glucose transporters 2 and 4 (GLUT2 and GLUT4) in T2D mice. Likewise, much the same results were obtained in in vitro experiments. Taken together, OJE had hopeful advantage in sustaining the glucose homeostasis and diminishing IR, and could be a safe alternative remedy for treating T2D.
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Affiliation(s)
- Hyuneui Jeong
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
| | - Daram Yang
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
| | - Jing Zhao
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
| | - Jeong Hun Seo
- Research & Development Center of General Bio Co., Ltd, Namwon-si, Jeollabuk-do, Korea
| | - Dong Gue Shin
- Research & Development Center of General Bio Co., Ltd, Namwon-si, Jeollabuk-do, Korea
| | - Jeong-Dan Cha
- Research & Development Center of General Bio Co., Ltd, Namwon-si, Jeollabuk-do, Korea
| | - Chae Woong Lim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
| | - Jong-Won Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Korea
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18
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Tian Q, Leung FP, Chen FM, Tian XY, Chen Z, Tse G, Ma S, Wong WT. Butyrate protects endothelial function through PPARδ/miR-181b signaling. Pharmacol Res 2021; 169:105681. [PMID: 34019979 DOI: 10.1016/j.phrs.2021.105681] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/21/2021] [Accepted: 05/14/2021] [Indexed: 01/06/2023]
Abstract
Reports of the beneficial roles of butyrate in cardiovascular diseases, such as atherosclerosis and ischemic stroke, are becoming increasingly abundant. However, the mechanisms of its bioactivities remain largely unknown. In this study, we explored the effects of butyrate on endothelial dysfunction and its potential underlying mechanism. In our study, ApoE-/- mice were fed with high-fat diet (HFD) for ten weeks to produce atherosclerosis models and concurrently treated with or without sodium butyrate daily. Thoracic aortas were subsequently isolated from C57BL/6 wild-type (WT), PPARδ-/-, endothelial-specific PPARδ wild-type (EC-specific PPARδ WT) and endothelial-specific PPARδ knockout (EC-specific PPARδ KO) mice were stimulated with interleukin (IL)-1β with or without butyrate ex vivo. Our results demonstrated that butyrate treatment rescued the impaired endothelium-dependent relaxations (EDRs) in thoracic aortas of HFD-fed ApoE-/- mice. Butyrate also rescued impaired EDRs in IL-1β-treated thoracic aorta ring ex vivo. Global and endothelial-specific knockout of PPARδ eliminated the protective effects of butyrate against IL-1β-induced impairment to EDRs. Butyrate abolished IL-1β-induced reactive oxygen species (ROS) production in endothelial cells while the inhibitory effect was incapacitated by genetic deletion of PPARδ or pharmacological inhibition of PPARδ. IL-1β increased NADPH oxidase 2 (NOX2) mRNA and protein expressions in endothelial cells, which were prevented by butyrate treatment, and the effects of butyrate were blunted following pharmacological inhibition of PPARδ. Importantly, butyrate treatment upregulated the miR-181b expression in atherosclerotic aortas and IL-1β-treated endothelial cells. Moreover, transfection of endothelial cells with miR-181b inhibitor abolished the suppressive effects of butyrate on NOX2 expressions and ROS generation in endothelial cells. To conclude, butyrate prevents endothelial dysfunction in atherosclerosis by reducing endothelial NOX2 expression and ROS production via the PPARδ/miR-181b pathway.
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Affiliation(s)
- Qinqin Tian
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Fung Ping Leung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Francis M Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Zhenyu Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Gary Tse
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shuangtao Ma
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MICH, USA
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
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19
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Xue Y, Chen H, Zhang S, Bao L, Chen B, Gong H, Zhao Y, Qi R. Resveratrol Confers Vascular Protection by Suppressing TLR4/Syk/NLRP3 Signaling in Oxidized Low-Density Lipoprotein-Activated Platelets. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8819231. [PMID: 33728029 PMCID: PMC7935581 DOI: 10.1155/2021/8819231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 02/04/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022]
Abstract
This study investigated the effect of resveratrol on Toll-like receptor 4- (TLR4-) mediated matrix metalloproteinase 3 (MMP3) and MMP9 expression in oxidized low-density lipoprotein- (ox-LDL-) activated platelets and the potential molecule mechanism. Human platelets were used in the present study. The results showed that resveratrol suppressed TLR4, MMP3, and MMP9 expression in ox-LDL-activated platelets. The TLR4 inhibitor CLI-095 also inhibited MMP3 and MMP9 expression and secretion in ox-LDL- and lipopolysaccharide- (LPS-) activated platelets. The combination of resveratrol and CLI-095 synergistically suppressed MMP3 and MMP9 expression in ox-LDL- and LPS-activated platelets. These findings suggest that the resveratrol-induced inhibition of MMP3 and MMP9 expression is linked to the suppression of TLR4 activation. Resveratrol also suppressed spleen tyrosine kinase (Syk) phosphorylation and nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) expression and IL-1β secretion in ox-LDL- and LPS-treated platelets. The coimmunoprecipitation results showed that resveratrol inhibited the binding of Syk and NLRP3. Finally, resveratrol reduced vascular senescence cells and the expression of TLR4, MMP3, and MMP9 and prevented alterations of vascular structure in 52-week-old mice. Our findings demonstrated that resveratrol decreased inflammatory protein expression and improved vascular structure in aged mice. Resveratrol inhibited the expression of TLR4 and secretion of MMP3, MMP9, and IL-1β. The mechanism of action of resveratrol appears to be associated with the inhibition of TLR4/Syk/NLRP3 activation in ox-LDL-activated platelets.
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Affiliation(s)
- Yun Xue
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Huilian Chen
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Shenghao Zhang
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Li Bao
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Beidong Chen
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Huan Gong
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Yanyang Zhao
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Ruomei Qi
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
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20
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Li B, Jiang HY, Wang ZH, Ma YC, Bao YN, Jin Y. Effect of fenofibrate on proliferation of SMMC-7721 cells via regulating cell cycle. Hum Exp Toxicol 2021; 40:1208-1221. [PMID: 33538198 DOI: 10.1177/0960327121991901] [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
Liver cancer is a malignant cancer with great harmfulness. Fenofibrate is a peroxisome proliferation activated receptor (PPARα) agonist widely used in the treatment of dyslipidemia. Previous studies have shown that fenofibrate may promote cell proliferation, but the underlying mechanism has not been fully characterized. The aim of this study was to investigate the role of PPARα agonist fenofibrate in cell proliferation of SMMC-7721 cells compared with that of THLE-2 cells. SMMC-7721 and THLE-2 cells were treated with different concentrations of fenofibrate. Cell proliferation was analyzed by MTT, using flow cytometry for cell cycle analysis, and CyclinD1, Cyclin-dependent kinases2 (CDK2) and Proliferating Cell Nuclear Antigen (PCNA) were analyzed by Western blotting. RT-qPCR method was used to assess CDK2, CyclinD1 and PCNA mRNA levels. The results showed that 10-9-10-4 mol/L fenofibrate could induce cell growth and 10-4, 10-5, 10-6 mol/L fenofibrate could reduce the number of G0/G1 phase cells and increased in the number of cells in S and G2/M phase of cell cycle in SMMC-7721 cells. Furthermore, fenofibrate could significantly increase the expression of cell cycle related protein (CyclinD1, CDK2)and cell proliferation related proteins (PCNA). The use of PPARα inhibitor MT886 inhibited cell cycle progression and promote tumor cell apoptosis. But fenofibrate had no obvious effect on THLE-2 cells. These results revealed the effect of fenofibrate on the cell cycle of liver cancer cells, and provided a reasonable explanation for studying how fenofibrate promotes cell proliferation.
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Affiliation(s)
- B Li
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
| | - H-Y Jiang
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
| | - Z-H Wang
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
| | - Y-C Ma
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
| | - Y-N Bao
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
| | - Y Jin
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, 12485Anhui Medical University, Hefei, China.,Institute for Liver Diseases of 12485Anhui Medical University, Hefei, China
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21
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Li JJ, Yeo KK, Tan K, Ako J, Krittayaphong R, Tan RS, Aylward PE, Lam C, Baek SH, Dalal J, Fong A, Li YH, O’Brien RC, Koh SYN, Scherer DJ, Tada H, Kang V, Butters J, Nicholls SJ. Tackling cardiometabolic risk in the Asia Pacific region. Am J Prev Cardiol 2020; 4:100096. [PMID: 34327472 PMCID: PMC8315619 DOI: 10.1016/j.ajpc.2020.100096] [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: 06/17/2020] [Revised: 09/28/2020] [Accepted: 10/10/2020] [Indexed: 12/17/2022] Open
Abstract
With the global spread of abdominal obesity, cardiovascular disease continues to spread to all countries of the world. Given the large population, the challenges presented by cardiometabolic risk in the Asia Pacific region are considerable. In addition to the clinical consequences of cardiovascular disease, in terms of its morbidity and mortality, the diversity of the Asia Pacific region brings heterogeneity in approaches to prevention, diagnosis and treatment of cardiometabolic risk. In this manuscript, we will review the current state of knowledge of cardiometabolic risk in Asia Pacific and highlight the needs moving forward to tackle this public health challenge.
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Affiliation(s)
- Jian-Jun Li
- State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Khung Keong Yeo
- National Heart Centre Singapore and Duke-NUS Medical School, Singapore
| | - Kathyrn Tan
- Department of Medicine, University of Hong Kong; Kitasato University, Sagamihara, Japan
| | - Junya Ako
- Kitasato University, Sagamihara, Japan
| | - Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ru San Tan
- National Heart Centre Singapore and Duke-NUS Medical School, Singapore
| | - Philip E. Aylward
- South Australian Health and Medical Research Institute and Flinders University, Adelaide, Australia
| | - CarolynS.P. Lam
- National Heart Centre Singapore and Duke-NUS Medical School, Singapore
| | - Sang Hong Baek
- Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | | | - Alan Fong
- Department of Cardiology, Sarawak Heart Centre; and Clinical Research Centre, Sarawak General Hospital, Kuching, Malaysia
| | - Yi-Heng Li
- National Cheng Kung University Hospital, Tainan, Taiwan
| | | | - Si Ya Natalie Koh
- National Heart Centre Singapore and Duke-NUS Medical School, Singapore
| | | | - Hayato Tada
- Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | | | - Julie Butters
- Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Stephen J. Nicholls
- Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, Australia
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22
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La Fountaine MF, Cirnigliaro CM, Hobson JC, Lombard AT, Specht AF, Dyson-Hudson TA, Bauman WA. Fenofibrate therapy to lower serum triglyceride concentrations in persons with spinal cord injury: A preliminary analysis of its safety profile. J Spinal Cord Med 2020; 43:704-709. [PMID: 30870136 PMCID: PMC7534379 DOI: 10.1080/10790268.2019.1581694] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Context: Fenofibrate is used to treat elevated serum triglyceride (TG) concentrations (e.g. ≥150 mg/dl). The lipoprotein profile of most individuals with spinal cord injury (SCI) would not satisfy conventional criteria to initiate lipid-lowering therapies. Serum TG concentrations of 115 and 137 mg/dl were recently identified as potential intervention thresholds for persons with a SCI proximal to the 4th and below the 5th thoracic vertebrae, respectively. Fenofibrate therapy has not been tested for safety in persons with SCI. Methods: An open-label trial was performed in 15 persons with SCI to determine the safety profile of 4 months of once-daily fenofibrate (145 mg tablet) treatment when initiated using modified intervention thresholds. Fasting blood tests and a review of systems were performed monthly to determine changes in liver and kidney function, as well as overall health status. Results: Fifteen subjects participated and 4 had an adverse event (e.g. 2 with gastrointestinal distress; 2 with elevated liver enzymes). Three subjects discontinued the trial within the first month and one participant remained in the trial with no further adverse events. Two participants were discontinued from fenofibrate after 2 months after not responding to treatment, as per protocol, and 10 participants completed the 4-month trial without experiencing an adverse event. Conclusion: In persons with SCI, 4 months of fenofibrate therapy initiated at lower threshold serum TG concentrations did not result in an increased incidence of adverse events compared to that reported in the general population. Fenofibrate therapy appears to be well tolerated in persons with SCI.
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Affiliation(s)
- Michael F. La Fountaine
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Department of Physical Therapy, School of Health and Medical Sciences, Seton Hall University, South Orange, New Jersey, USA,Departments of Medical Sciences and Neurology, Seton Hall-Hackensack Meridian School of Medicine, South Orange, New Jersey, USA,The Institute for Advanced Study of Rehabilitation and Sports Science, School of Health and Medical Sciences, Seton Hall University, South Orange, New Jersey, USA,Correspondence to: Michael F. La Fountaine, National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY10468, USA; Ph: (718) 584-9000, ext. 3121.
| | - Christopher M. Cirnigliaro
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Joshua C. Hobson
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware, USA
| | - Alexander T. Lombard
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Adam F. Specht
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Trevor A. Dyson-Hudson
- Kessler Foundation, West Orange, New Jersey, USA,Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - William A. Bauman
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Departments of Medicine and Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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23
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Srivastava RAK, Cefalu AB, Srivastava NS, Averna M. NPC1L1 and ABCG5/8 induction explain synergistic fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists. Mol Cell Biochem 2020; 473:247-262. [DOI: 10.1007/s11010-020-03826-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/04/2020] [Indexed: 12/15/2022]
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24
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int 2020; 11:165-223. [PMID: 32802702 PMCID: PMC7387396 DOI: 10.1007/s13340-020-00439-5] [Citation(s) in RCA: 280] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 01/09/2023]
Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Ichikawa, Japan
| | - Hiroshi Noto
- Division of Endocrinology and Metabolism, St. Luke’s International Hospital, Tokyo, Japan
| | - Hideki Origasa
- Department of Biostatistics and Clinical Epidemiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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25
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. J Diabetes Investig 2020; 11:1020-1076. [PMID: 33021749 PMCID: PMC7378414 DOI: 10.1111/jdi.13306] [Citation(s) in RCA: 197] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 01/09/2023] Open
Affiliation(s)
- Eiichi Araki
- Department of Metabolic MedicineFaculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Atsushi Goto
- Department of Health Data ScienceGraduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and EndocrinologyIchikawa HospitalInternational University of Health and WelfareIchikawaJapan
| | - Hiroshi Noto
- Division of Endocrinology and MetabolismSt. Luke's International HospitalTokyoJapan
| | - Hideki Origasa
- Department of Biostatistics and Clinical EpidemiologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular GeneticsEhime University Graduate School of MedicineToonJapan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Kazuyuki Tobe
- First Department of Internal MedicineGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
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26
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Lakshmanan S, Shekar C, Kinninger A, Dahal S, Onuegbu A, Cai AN, Hamal S, Birudaraju D, Cherukuri L, Flores F, Dailing C, Roy SK, Bhatt DL, Nelson JR, Budoff MJ. Association of high-density lipoprotein levels with baseline coronary plaque volumes by coronary CTA in the EVAPORATE trial. Atherosclerosis 2020; 305:34-41. [PMID: 32615321 DOI: 10.1016/j.atherosclerosis.2020.05.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/24/2020] [Accepted: 05/20/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS Dyslipidemia with elevated triglycerides (TGL) and low high-density lipoprotein cholesterol (HDL-C) predicts residual cardiovascular risk, despite goal LDL-C levels and optimal statin therapy. Coronary plaque characterization by CCTA can provide mechanistic understanding of coronary artery disease and associated prognosis. The role of HDL-C in the pathogenesis of atherosclerosis is not well understood in statin-treated patients with elevated TGL. We sought to examine the association of HDL-C levels with baseline coronary plaque volumes, namely total plaque (TP) and total non-calcified plaque (TNCP) volumes by CCTA in participants enrolled in the EVAPORATE trial. METHODS We analyzed 80 participants who were enrolled in the trial. Linear regression analysis as a univariate and multivariate model adjusted for significant cardiovascular risk factors was performed to evaluate independent association of HDL-C and baseline coronary plaque volumes. In an exploratory analysis, stratified by sex, we compared the association of serum HDL-C levels with baseline coronary plaque volumes in males and females. RESULTS Mean (SD) age of participants (n = 80) was 57.1 (8.6) years and 43% were male. Median (Inter Quartile Range/IQR) log-TNCP volume was 83.0 (0.1-7.3) mm3 and median (IQR) log-TP volume was 144.8 (0.1-7.1) mm3. After adjustment for relevant clinical covariates including age, gender, BMI, hypertension, diabetes, past smoking and baseline TGL levels, increasing levels of HDL-C remain independently associated with lower baseline log-TNCP volumes (β: 0.043 ± 0.021, p = 0.042) and baseline log-TP volumes (β: 0.046 ± 0.022, p = 0.035) on CCTA. On stratifying by sex in a multivariable regression analysis, HDL-C levels were inversely associated with baseline log-TNCP volumes (β: 0.066 ± 0.026, p = 0.018) and log-TP volumes (β: 0.077 ± 0.025, p = 0.004) in females, but not in males (log-TNCP volumes β: 0.038 ± 0.034, p = 0.282) and log-TP volumes (β: -0.033 ± 0.036, p = 0.364). CONCLUSIONS In a cohort of statin treated patients with known atherosclerosis and residually elevated TGL, there was a significant inverse relationship between HDL-C levels and baseline coronary plaque, TP and TNCP volumes on CCTA. Our findings provide more detailed mechanistic evidence regarding the protective role of HDL-C in coronary atherosclerosis in a high-risk cohort. Further investigation to evaluate the interaction of HDL-C levels and coronary plaque volumes on differential CVD risk in statin-treated patients with elevated TGL levels is warranted.
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Affiliation(s)
- Suvasini Lakshmanan
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | | | - April Kinninger
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Suraj Dahal
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Afiachukwu Onuegbu
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Andrew N Cai
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Sajad Hamal
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Divya Birudaraju
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Lavanya Cherukuri
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Ferdinand Flores
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Christopher Dailing
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Sion K Roy
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - John R Nelson
- Department of Cardiology, California Cardiovascular Institute, Fresno, CA, USA
| | - Matthew J Budoff
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA.
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27
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Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, Gao H, Lovato L, Prudente S, Pandolfi A, Pezzolesi MG, Sigal RJ, Paré G, Marcovina SM, Rotroff DM, Patorno E, Mercuri L, Trischitta V, Chew EY, Kraft P, Buse JB, Wagner MJ, Cresci S, Gerstein HC, Ginsberg HN, Mychaleckyj JC, Doria A. PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid. Diabetes 2020; 69:771-783. [PMID: 31974142 PMCID: PMC7085251 DOI: 10.2337/db19-0973] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/21/2020] [Indexed: 02/06/2023]
Abstract
The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes (P interaction = 3.7 × 10-4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
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Affiliation(s)
- Mario Luca Morieri
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
- Department of Medicine, University of Padova, Padova, Italy
| | - Hetal S Shah
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jennifer Sjaarda
- McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada
| | - Petra A Lenzini
- Department of Genetics, Washington University School of Medicine, St. Louis, MO
| | - Hannah Campbell
- Department of Genetics, Washington University School of Medicine, St. Louis, MO
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Alison A Motsinger-Reif
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC
| | - He Gao
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Laura Lovato
- Wake Forest School of Medicine, Winston Salem, NC
| | - Sabrina Prudente
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio," Chieti, Italy
| | - Marcus G Pezzolesi
- Division of Nephrology and Hypertension and Diabetes and Metabolism Center, University of Utah, Salt Lake City, UT
| | - Ronald J Sigal
- Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Cumming School of Medicine, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada
| | - Guillaume Paré
- McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada
| | - Santica M Marcovina
- Department of Medicine, University of Washington, and Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, WA
| | - Daniel M Rotroff
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Luana Mercuri
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Vincenzo Trischitta
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Experimental Medicine, "Sapienza" University, Rome, Italy
| | - Emily Y Chew
- Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Peter Kraft
- Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Michael J Wagner
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Sharon Cresci
- Department of Genetics, Washington University School of Medicine, St. Louis, MO
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Hertzel C Gerstein
- McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada
| | - Henry N Ginsberg
- Irving Institute for Clinical and Translational Research, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Josyf C Mychaleckyj
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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28
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Koshelskaya OA, Suslova TE, Kologrivova IV, Margolis NY, Zhuravleva OA, Kharitonova OA, Vinnitskaya IV. Metabolic, Inflammatory and Imaging Biomarkers in Evaluation of Coronary Arteries Anatomical Stenosis in Patients with Stable Coronary Artery Disease. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2020. [DOI: 10.20996/1819-6446-2020-01-01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Aim. To reveal the statistically significant determinants of the coronary artery (CA) stenosis ≥70% in patients with chronic stable CA disease receiving drug therapy.Material and methods. The study included 68 patients (aged 59.6±6.4 years) with stable CA disease and optimal cardioactive therapy. Coronary angiography was performed in all patients. Basic serum parameters of carbohydrate and lipid metabolism were evaluated; serum concentration of cytokines, adipokines and high sensitive C-reactive protein (hsCRP) were determined by ELISA. The epicardial adipose tissue (EAT) thickness was measured by B-mode echocardiography.Results. The patients’ classification model was created. It allowed to determine probability P for CA stenosis of 70% or more for each patient using formula Р, where L=0.89-1.09×gender+ 0.51×triglycerides–0.28×HDL+0.24×hsCRP (HDL – high density lipoproteins). If calculated P value falls into interval (0; 0.228) the patient should be classified into the group with the risk of CA stenosis ≥70%, while if calculated P value falls into interval (0.228; 1), the patient should be classified into group with CA stenosis below 70%. Even though EAT thickness was indistinguishable determinant of CA stenosis ≥70% in our study, its inclusion into the model as a fifth variable allowed to increase the model quality: area under ROC-curve (AUC) in the model without EAT thickness constituted 0.708 (p=0.009), and increased up to 0.879 (p=0.011) after EAT thickness inclusion.Conclusions. Male sex, level of triglycerides, HDL and hsCRP are statistically significant determinants of CA stenosis ≥70%. The presence of the triglycerides level in the created model underscores an important contribution of this lipid fraction, even when elevated only up to the moderate values, into modulation of the residual cardiovascular risk in patients receiving statins.
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Affiliation(s)
- O. A. Koshelskaya
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
| | - T. E. Suslova
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
| | - I. V. Kologrivova
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
| | | | - O. A. Zhuravleva
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
| | - O. A. Kharitonova
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
| | - I. V. Vinnitskaya
- Tomsk National Research Medical Center, Russian Academy of Science, Cardiology Research Institute
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La Fountaine MF, Cirnigliaro CM, Hobson JC, Lombard AT, Specht AF, Dyson-Hudson TA, Kirshblum SC, Bauman WA. A Four Month Randomized Controlled Trial on the Efficacy of Once-daily Fenofibrate Monotherapy in Persons with Spinal Cord Injury. Sci Rep 2019; 9:17166. [PMID: 31748594 PMCID: PMC6868213 DOI: 10.1038/s41598-019-53753-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/05/2019] [Indexed: 11/24/2022] Open
Abstract
An open-label, randomized clinical trial of once-daily fenofibrate monotherapy administered for 2- (Mo2) and 4- (Mo4) months using modified intervention thresholds for triglyceride (TG) was performed in persons with chronic spinal cord injury (SCI). Fenofibrate (145 mg tablet) was self-administered daily in 10 persons with SCI for 4 months with monthly blood testing to quantify the lipoprotein profile (e.g., serum TG, LDL-C, and HDL-C concentrations). Eight SCI participants were control subjects. In comparison to the control group, the treatment group at Mo2 had a 40% (±12%; p < 0.05) reduction in serum TG concentration, a 28% (±21%; p < 0.05) increase in HDL-C and 14% (±20%; p < 0.05) decline in LDL-C. In the same comparison at Mo4, the treatment group maintained a 40% (±20%; p < 0.05) reduction in serum TG concentration, had an 18% in reduction in LDL-C (±12%; p < 0.05) and a 23% (±23%; p < 0.05) increase in HDL-C. Fenofibrate monotherapy for Mo2 and Mo4 initiated in persons with SCI resulted in a robust and favorable change in the serum lipoprotein profile and ratios, suggesting reduced risk for cardiovascular disease.
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Affiliation(s)
- Michael F La Fountaine
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
- Department of Physical Therapy, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
- Departments of Medical Sciences and Neurology, Seton Hall-Hackensack Meridian School of Medicine, Nutley, NJ, USA.
- The Institute for Advanced Study of Rehabilitation and Sports Science, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
| | - Christopher M Cirnigliaro
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
| | - Joshua C Hobson
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, USA
| | - Alexander T Lombard
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
| | - Adam F Specht
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
| | - Trevor A Dyson-Hudson
- Kessler Foundation, West Orange, NJ, USA
- Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Steven C Kirshblum
- Kessler Foundation, West Orange, NJ, USA
- Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ, USA
- Kessler Institute for Rehabilitation, West Orange, NJ, USA
| | - William A Bauman
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
- Departments of Medicine and Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Zhou Q, Ren D, Xiao Y, Yi L, Zhou Z. Plasma fatty acid metabolic profiling coupled with clinical research reveals the risk factors for atherosclerosis development in type 2 diabetes mellitus. RSC Adv 2019; 9:36162-36170. [PMID: 35540605 PMCID: PMC9074937 DOI: 10.1039/c9ra07634d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 10/17/2019] [Indexed: 11/30/2022] Open
Abstract
Many publications have reported that the incidence of atherosclerotic cardiovascular diseases is higher in patients with type 2 diabetes mellitus (T2DM) than in the non-diabetic population; however, until now, the reason has been unclear. In this study, 25 males (25/64, 39.06%) and 19 females (19/54, 35.19%) had complications with atherosclerosis after two years. To reveal the risk factors for developing atherosclerosis in patients with T2DM, plasma fatty acid metabolic profiling based on gas chromatography-mass spectrometry was combined with the analysis of clinical biochemical indices. The results of partial least squares-discriminant and canonical correlation analyses suggested that C20:0, C22:6n-3, glycosylated hemoglobin, waist circumference, and waist-to-hip ratio are likely to be closely related to T2DM complicated with atherosclerosis. Metabolomic information is a beneficial supplement to existing clinical indices and is useful in predicting the development of a patient's disease and optimizing the treatment.
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Affiliation(s)
- Qianyu Zhou
- Faculty of Agriculture and Food, Kunming University of Science and Technology Kunming Yunnan 650500 China +86 871 65920302
| | - Dabing Ren
- Faculty of Agriculture and Food, Kunming University of Science and Technology Kunming Yunnan 650500 China +86 871 65920302
- Yunnan Food Safety Research Institute, Kunming University of Science and Technology Kunming Yunnan 650500 China
| | - Yang Xiao
- Diabetes Center, Institute of Metabolism and Endocrinology, Department of Endocrinology, The Second Xiangya Hospital, Central South University Changsha Hunan 410011 China
| | - Lunzhao Yi
- Faculty of Agriculture and Food, Kunming University of Science and Technology Kunming Yunnan 650500 China +86 871 65920302
- Yunnan Food Safety Research Institute, Kunming University of Science and Technology Kunming Yunnan 650500 China
| | - Zhiguang Zhou
- Diabetes Center, Institute of Metabolism and Endocrinology, Department of Endocrinology, The Second Xiangya Hospital, Central South University Changsha Hunan 410011 China
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Marston NA, Giugliano RP, Im K, Silverman MG, O'Donoghue ML, Wiviott SD, Ference BA, Sabatine MS. Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials. Circulation 2019; 140:1308-1317. [PMID: 31530008 PMCID: PMC6791781 DOI: 10.1161/circulationaha.119.041998] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/08/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. METHODS We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. RESULTS A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]). CONCLUSIONS In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.
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Affiliation(s)
- Nicholas A Marston
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
| | - Robert P Giugliano
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
| | - KyungAh Im
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
| | | | - Michelle L O'Donoghue
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
| | - Stephen D Wiviott
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
| | - Brian A Ference
- Centre for Naturally Randomized Trials, University of Cambridge, UK (B.A.F.)
| | - Marc S Sabatine
- Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., R.P.G., K.I., M.L.O., S.D.W., M.S.S.)
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Gupta M, Tummala R, Ghosh RK, Blumenthal C, Philip K, Bandyopadhyay D, Ventura H, Deedwania P. An update on pharmacotherapies in diabetic dyslipidemia. Prog Cardiovasc Dis 2019; 62:334-341. [PMID: 31442512 DOI: 10.1016/j.pcad.2019.07.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 07/28/2019] [Indexed: 01/08/2023]
Abstract
Hyperlipidemia plays a crucial role in the underlying pathogenesis of multiple cardiovascular diseases (CVD), including coronary artery disease, peripheral arterial disease, carotid stenosis, and heart failure. The risk of developing such diseases in the diabetic population is relatively high. Diabetes mellitus (DM) is an independent risk factor for premature atherosclerosis. The hallmark of DM dyslipidemia is a demonstrably high level of atherogenic triglyceride rich lipids including very low-density lipoprotein, chylomicrons, and small dense low-density lipoprotein (LDL). Moderate to high intensity statins, targeting LDL cholesterol reduction, remain the cornerstone in the management of this unique disorder. Many 'non-statin' drugs have recently been studied in the DM patients who were either on a 'maximally tolerated statin' or 'statin intolerant'. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are particularly important and were incorporated in the recent guidelines by the European Society of Cardiology, American College of Cardiology, American Heart Association, and American Diabetes Association. Icosapent Ethyl has garnered huge interest this year following publication of the REDUCE-IT trial. There are several newer hypolipidemic drugs, including Bempedoic acid, Inclisiran and RVX-208, that are in different phases of clinical trials. In this article, we review the underlying pathophysiology of DM dyslipidemia, existing guidelines related to its management, and the potential of newer hypolipidemic and anti-inflammatory drugs being incorporated in the management of DM.
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Affiliation(s)
- Manasvi Gupta
- Department of Internal Medicine, University of Connecticut, Hartford, CT, USA
| | | | - Raktim K Ghosh
- MedStar Heart and Vascular Institute, Union Memorial Hospital, Baltimore, MD, USA.
| | - Colin Blumenthal
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Karan Philip
- Department of Neurology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Dhrubajyoti Bandyopadhyay
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/Mount Sinai St Luke's Roosevelt Hospital, New York, NY, USA
| | - Hector Ventura
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, USA
| | - Prakash Deedwania
- Department of Cardiology/Internal Medicine, University of California at San Francisco School of Medicine, San Francisco, CA, USA
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Abstract
Dyslipidemia is one of the major cardiovascular risk factors, but beyond statin treatment-which represents the cornerstone of therapy-a relevant practical uncertainty regards the use of fibrate derivatives. In the lack of successful results from the main cardiovascular trials, guidelines recommend the use of peroxisome proliferator-activated receptor agonists in selected cases, i.e. patients with true atherogenic dyslipidemia. However, recent observations indicate that fenofibrate treatment may provide a reliable complementary support against residual cardiovascular risk. We therefore summarize current evidence on fenofibrate, seeking to provide an updated interpretation of recent studies in the field.
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Comparative Evaluation of Gemcabene and Peroxisome Proliferator-Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease. J Cardiovasc Pharmacol 2019; 72:3-10. [PMID: 29621036 PMCID: PMC6039382 DOI: 10.1097/fjc.0000000000000580] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator-activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-α transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-α of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-α in a concentration-dependent manner. The known PPAR-δ agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (300 μM) showed no response in mouse and rat and a marginal response against human PPAR-δ receptors (3.2-fold). For PPAR-γ, gemcabene showed no agonist activity against all 3 species at 100 μM and marginal activity (3.6- to 5-fold) at 300 μM. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-γ receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-α, PPAR-γ, and PPAR-δ receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene.
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Arutyunov GP, Boytsov SA, Voyevoda MI, Gurevich VS, Drapkina OM, Kukharchuk VV, Martynov AI, Sergiyenko IV, Shestakova MV, Aliyeva AS, Akhmedzhanov NM, Bubnova MG, Galyavich АS, Gordeyev IG, Ezhov MV, Karpov YA, Konstantinov VO, Nedogoda SV, Nifontov EM, Orlova YA, Panov AV, Sayganov SA, Skibitskiy VV, Tarlovskaya EI, Urazgildeyeva SA, Khalimov YS. Correction of Hypertriglyceridemia as the Way to Reduce Residual Risk in Diseases Caused by Atherosclerosis. Conclusion of the Advisory Board of the Russian Society of Cardiology, the Russian Scientific Medical Society of Therapists, the Eurasian Association of Therapists, the Russian National Atherosclerosis Society, the Russian Association of Endocrinologists, and the National League of Cardiologic Genetics. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2019. [DOI: 10.20996/1819-6446-2019-15-2-282-288] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Streja E, Streja DA, Soohoo M, Kleine CE, Hsiung JT, Park C, Moradi H. Precision Medicine and Personalized Management of Lipoprotein and Lipid Disorders in Chronic and End-Stage Kidney Disease. Semin Nephrol 2019; 38:369-382. [PMID: 30082057 DOI: 10.1016/j.semnephrol.2018.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Precision medicine is an emerging field that calls for individualization of treatment strategies based on characteristics unique to each patient. In lipid management, current guidelines are driven mainly by clinical trial results that presently indicate that patients with non-dialysis-dependent chronic kidney disease (CKD) should be treated with a β-hydroxy β-methylglutaryl-CoA reductase inhibitor, also known as statin therapy. For patients with end-stage kidney disease (ESKD) being treated with hemodialysis, statin therapy has not been shown to successfully reduce poor outcomes in trials and therefore is not recommended. The two major guidelines dissent on whether statin therapy should be of moderate or high intensity in non-dialysis-dependent CKD patients, but often leave the prescribing clinician to make that decision. These decisions often are complicated by the increased concerns for adverse events such as myopathies in patients with advanced kidney disease and ESKD. In the future, there may be an opportunity to further identify CKD and ESKD patients who are more likely to benefit from lipid-modifying therapy as opposed to those who likely will suffer from its side effects using precision medicine tools. For now, data from genetics studies and subgroup analyses may provide insight for future research directions in this field and we review some of the work that has been published in this regard.
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Affiliation(s)
- Elani Streja
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA..
| | - Dan A Streja
- Division of Endocrinology, Diabetes and Metabolism, West Los Angeles VA Medical Center, Greater Los Angeles VA Healthcare System, Los Angeles, CA
| | - Melissa Soohoo
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
| | - Carola-Ellen Kleine
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
| | - Jui-Ting Hsiung
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
| | - Christina Park
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
| | - Hamid Moradi
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA.; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
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Shih CM, Lin FY, Yeh JS, Lin YW, Loh SH, Tsao NW, Nakagami H, Morishita R, Sawamura T, Li CY, Lin CY, Huang CY. Dysfunctional high density lipoprotein failed to rescue the function of oxidized low density lipoprotein-treated endothelial progenitor cells: a novel index for the prediction of HDL functionality. Transl Res 2019; 205:17-32. [PMID: 30720435 DOI: 10.1016/j.trsl.2018.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 09/09/2018] [Accepted: 09/28/2018] [Indexed: 10/28/2022]
Abstract
Lipid metabolic disorders play critical roles in atherogenesis. Traditionally, it has been suggested that reduced high density lipoprotein (HDL) levels might be an important morbidity indicator for cardiovascular diseases. Therefore, it has been argued that therapeutically raising HDL levels may reduce atherogenesis in patients with dyslipidemia. However, recent clinical trials to elevate serum HDL levels by pharmacologic approaches failed to demonstrate clinical efficacy. Thus, to investigate the functionality of HDL and to explore the possible clinical relevance as well as to define an effective indicator that can represent HDL function may provide another key and reference to disclose the clinical treatment of dyslipidemia. We analyzed the association between the data of dichlorofluorescein assay (assay the functionality of HDL), the effect of HDL on oxidized low density lipoprotein (oxLDL)-stimulated endothelial progenitor cells (EPCs) in vitro, levels of circulating EPCs, and ex vitro EPC colony forming units of each case, we defined the indicator (relative HDL index (RHDL index) = dichlorofluorescein assay result of each subject/dichlorofluorescein assay reading of our young healthy controls) that may represent functionality of HDL. HDL from healthy adults protected oxLDL-treated EPCs by modulating p38 mitogen-activated protein kinase and Rho activation and by promoting nitric oxide production. HDL from subject with RHDL index ≧2 also failed to restore the functionality of oxLDL-treated EPCs via cell-signaling pathways in vitro. The RHDL index significantly correlated with patients' circulating EPC number or EPC colony forming units ex vivo. In conclusions, we explored the RHDL index as a score to predict a patient's EPC functions in vivo and ex vitro.
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Affiliation(s)
- Chun-Ming Shih
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Feng-Yen Lin
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Jong-Shiuan Yeh
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei, Taiwan
| | - Yi-Wen Lin
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Hurng Loh
- Department and Graduate Institute of Pharmacology, Defense Medical Center, Taipei, Taiwan
| | - Nai-Wen Tsao
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Hironori Nakagami
- Division of Vascular Medicine and Epigenetic, Osaka University, Osaka, Japan
| | | | - Tatsuya Sawamura
- Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan
| | - Chi-Yuan Li
- Department of Anesthesiology and Graduate Institute of Clinical Medical Science, China Medical University and Hospital, Taichung, Taiwan
| | - Cheng-Yen Lin
- Department of Marketing Management, Takming University of Science and Technology, Taipei, Taiwan; Healthcare Information and Management Department, Ming Chuan University, Taoyuan, Taiwan
| | - Chun-Yao Huang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
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Nicholls SJ, Nelson AJ. HDL and cardiovascular disease. Pathology 2019; 51:142-147. [PMID: 30612759 DOI: 10.1016/j.pathol.2018.10.017] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/28/2018] [Accepted: 10/28/2018] [Indexed: 12/31/2022]
Abstract
High-density lipoprotein (HDL) has received increasing interest due to observations of an inverse relationship between its systemic levels and cardiovascular risk and targeted interventions in animal models that have had favourable effects on atherosclerotic plaque. In addition to its pivotal role in reverse cholesterol transport, HDL has been reported to possess a range of functional properties, which may exert a protective influence on inflammation, oxidation, angiogenesis and glucose homeostasis. This has led to the development of a range of HDL targeted therapeutics, which have undergone evaluation in clinical trials. The current state of HDL in cardiovascular prevention will be reviewed.
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Affiliation(s)
- Stephen J Nicholls
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Monash University, Adelaide, SA, Australia.
| | - Adam J Nelson
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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D'Aronco S, Crotti S, Agostini M, Traldi P, Chilelli NC, Lapolla A. The role of mass spectrometry in studies of glycation processes and diabetes management. MASS SPECTROMETRY REVIEWS 2019; 38:112-146. [PMID: 30423209 DOI: 10.1002/mas.21576] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/03/2018] [Indexed: 06/09/2023]
Abstract
In the last decade, mass spectrometry has been widely employed in the study of diabetes. This was mainly due to the development of new, highly sensitive, and specific methods representing powerful tools to go deep into the biochemical and pathogenetic processes typical of the disease. The aim of this review is to give a panorama of the scientifically valid results obtained in this contest. The recent studies on glycation processes, in particular those devoted to the mechanism of production and to the reactivity of advanced glycation end products (AGEs, AGE peptides, glyoxal, methylglyoxal, dicarbonyl compounds) allowed to obtain a different view on short and long term complications of diabetes. These results have been employed in the research of effective markers and mass spectrometry represented a precious tool allowing the monitoring of diabetic nephropathy, cardiovascular complications, and gestational diabetes. The same approaches have been employed to monitor the non-insulinic diabetes pharmacological treatments, as well as in the discovery and characterization of antidiabetic agents from natural products. © 2018 Wiley Periodicals, Inc. Mass Spec Rev 38:112-146, 2019.
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Affiliation(s)
- Sara D'Aronco
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Sara Crotti
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Marco Agostini
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Pietro Traldi
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
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Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies. Nutrients 2018; 10:nu10111789. [PMID: 30453617 PMCID: PMC6266080 DOI: 10.3390/nu10111789] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 11/06/2018] [Accepted: 11/14/2018] [Indexed: 12/14/2022] Open
Abstract
Lipoproteins are a major risk factor for atherosclerotic cardiovascular diseases (ASCVD). Among the lipoproteins, low-density lipoproteins (LDL) have been shown to be causally associated with ASCVD development. In contrast, triglycerides or triglyceride-rich lipoproteins receive less attention than LDL because there is little definite evidence from randomized controlled trials. A Mendelian randomization study has recently been published in which a causal association could be estimated with observational datasets. Using such Mendelian randomization studies, ranging from common to rare genetic variations, triglycerides seem to be causally associated with ASCVD outcomes independent of LDL. Although the “causal association” of serum triglycerides and ASCVD is difficult to assert, accumulated evidence from clinical and Mendelian randomization studies, using common and rare genetic variations, strongly supports such an association. In this article, we provide a summary of investigations focusing on important causal associations between serum triglycerides and ASCVD from the clinical point of view.
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Belenkov YN, Privalova EV, Kaplunova VY, Zektser VY, Vinogradova NN, Ilgisonis IS, Shakaryants GA, Kozhevnikova MV, Lishuta AS. Metabolic Syndrome: Development of the Issue, Main Diagnostic Criteria. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2018. [DOI: 10.20996/1819-6446-2018-14-5-757-764] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Yu. N. Belenkov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. V. Privalova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. Y. Kaplunova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. Y. Zektser
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | - I. S. Ilgisonis
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - G. A. Shakaryants
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - M. V. Kozhevnikova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - A. S. Lishuta
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Nicholls SJ, Lincoff AM, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Pedersen TR, Ridker PM, Ray K, Karlson BW, Lundström T, Wolski K, Nissen SE. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol 2018; 41:1281-1288. [PMID: 30125052 DOI: 10.1002/clc.23055] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 01/11/2023] Open
Abstract
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.
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Affiliation(s)
- Stephen J Nicholls
- South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia
| | - A Michael Lincoff
- Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio
| | - Dianna Bash
- Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio
| | | | | | | | | | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Darren K McGuire
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Dariush Mozaffarian
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
| | | | | | | | - Björn W Karlson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,AstraZeneca Pharmaceuticals, Gothenburg, Sweden
| | - Torbjörn Lundström
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,AstraZeneca Pharmaceuticals, Gothenburg, Sweden
| | - Kathy Wolski
- Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio
| | - Steven E Nissen
- Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio
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Srivastava N, Cefalu AB, Averna M, Srivastava RAK. Lack of Correlation of Plasma HDL With Fecal Cholesterol and Plasma Cholesterol Efflux Capacity Suggests Importance of HDL Functionality in Attenuation of Atherosclerosis. Front Physiol 2018; 9:1222. [PMID: 30271349 PMCID: PMC6142045 DOI: 10.3389/fphys.2018.01222] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/14/2018] [Indexed: 11/13/2022] Open
Abstract
A number of clinical findings suggested HDL-raising as a plausible approach to treat residual risk of CVD. However, lack of CVD risk reduction by elevated HDL cholesterol (HDL-C) through cholesterol ester transfer protein (CETP) inhibition and enhanced risk reduction in apolipoprotein A-I Milano (apoAI-M) individuals with low HDL-C shifted the focus from HDL-C level to HDL function. In the present study, we investigated correlations between HDL-C, HDL function, fecal cholesterol excretion, and ex vivo plasma cholesterol efflux capacity (CEC) in animal models using two HDL modulators, LXR and PPAR-α agonists. In C57Bl mice, LXR agonist, T1317, raised HDL-C by 30%, while PPAR-α agonist, fenofibrate, reduced HDL-C by 30%, but fecal cholesterol showed twofold increase in both cases. CEC showed a 30–40% increase. Combination of LXR and PPAR-α agonists showed no changes in HDL-C, but, interestingly, fecal cholesterol increased by 4.5-fold, and CEC by 40%, suggesting existence of additional pathway for fecal cholesterol excretion. Regression analysis showed a lack of correlation between HDL-C and fecal cholesterol and CEC, while fecal cholesterol showed significant correlation with CEC, a measure of HDL function. ABCA1 and G1, the two important players in RCT showed greater induction with LXR agonist than PPAR-α agonist. HDL-C increased by 40 and 80% in LXR and PPAR-α treated apoA-I transgenic mice, respectively, with 80% increase in fecal cholesterol. A fivefold increase in fecal cholesterol with no correlation with either plasma HDL-C or CEC following co-treatment with LXR and PPAR-α agonists suggested existence of an HDL-independent pathway for body cholesterol elimination. In hyperlipidemic diabetic ob/ob mice also combination of LXR and PPAR-α agonists showed marked increases in fecal cholesterol content (10–20-fold), while HDL-C rise was only 40%, further suggesting HDL-independent elimination of body cholesterol in mice treated with combination of LXR and PPAR-α agonists. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr-deficient mice was associated with increased fecal cholesterol, but not HDL-C. However, fecal cholesterol counts showed inverse correlation with aortic cholesteryl ester content. These data suggest: (a) lack of correlation between HDL-C and fecal or aortic cholesterol content; (b) HDL function (CEC) correlated with fecal cholesterol content; (c) association of reduced aortic lipids in LDLr−/− mice with increased fecal cholesterol, but not with HDL-C, and (d) existence of an HDL-independent pathway for fecal cholesterol excretion following co-treatment with LXR and PPAR-α agonists.
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Affiliation(s)
- Neelam Srivastava
- Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Angelo B Cefalu
- Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Maurizio Averna
- Department of Internal Medicine, University of Palermo, Palermo, Italy
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Di Bartolo BA, Psaltis PJ, Bursill CA, Nicholls SJ. Translating Evidence of HDL and Plaque Regression. Arterioscler Thromb Vasc Biol 2018; 38:1961-1968. [DOI: 10.1161/atvbaha.118.307026] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Considerable evidence from preclinical and population studies suggests that HDLs (high-density lipoproteins) possess atheroprotective properties. Reports from HDL infusion studies in animals and early clinical imaging trials reported evidence of plaque regression. These findings have stimulated further interest in developing new agents targeting HDL. However, the results of more recent imaging studies in the setting of high-intensity statin use have been disappointing. As the concept of plaque changes with HDL therapeutics evolves and imaging technology to evaluate these effects advances, there will become increasing opportunity to determine the effects of HDL agents on atherosclerotic plaque (Graphic Abstract).
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Affiliation(s)
- Belinda A. Di Bartolo
- From the South Australian Health and Medical Research Institute, University of Adelaide
| | - Peter J. Psaltis
- From the South Australian Health and Medical Research Institute, University of Adelaide
| | - Christina A. Bursill
- From the South Australian Health and Medical Research Institute, University of Adelaide
| | - Stephen J. Nicholls
- From the South Australian Health and Medical Research Institute, University of Adelaide
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Araki M, Nakagawa Y, Oishi A, Han SI, Wang Y, Kumagai K, Ohno H, Mizunoe Y, Iwasaki H, Sekiya M, Matsuzaka T, Shimano H. The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice. Int J Mol Sci 2018; 19:ijms19072148. [PMID: 30041488 PMCID: PMC6073532 DOI: 10.3390/ijms19072148] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/13/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.
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Affiliation(s)
- Masaya Araki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Asayo Oishi
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Song-Iee Han
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Yunong Wang
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Kae Kumagai
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Hiroshi Ohno
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Yuhei Mizunoe
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Hitoshi Iwasaki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Motohiro Sekiya
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Takashi Matsuzaka
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
- Japan Agency for Medical Research and Development⁻Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-1004, Japan.
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Li J, Liu YP. The roles of PPARs in human diseases. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2018; 37:361-382. [PMID: 30036119 DOI: 10.1080/15257770.2018.1475673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs), as members of nuclear hormone receptor superfamily, can be activated by binding natural or synthetic ligands. The use of related ligands has revealed many potential roles for PPARs in the pathogenesis of some human metabolic disorders and inflammatory-related disease. Based on the previous studies, this review primarily concluded the current progress of knowledge regarding the specific biological activity of PPARs in cancers, atherosclerosis, and type 2 diabetes mellitus, providing a foundation for the potential therapeutic use of PPAR ligands in human diseases.
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Affiliation(s)
- Jingjing Li
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
| | - Yi-Ping Liu
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
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Abstract
PURPOSE OF REVIEW Type 2 diabetes mellitus (T2DM) is associated with increased coronary heart disease (CHD) morbidity and mortality. These patients are also more prone to heart failure, arrhythmias and sudden cardiac death. Furthermore, coronary interventions performed in such high-risk patients have worse outcomes. In this narrative review, we discuss the role of diabetic dyslipidaemia on the risk of CHD in patients with T2DM. The effects of hypolipidaemic, antihypertensive and antidiabetic drugs on lipid and glucose metabolism in T2DM are also considered. RECENT FINDINGS Among CHD risk factors, diabetic dyslipidaemia characterized by moderately elevated low-density lipoprotein (LDL) cholesterol, increased triglycerides and small, dense LDL particles as well as decreased high-density lipoprotein cholesterol levels may contribute to the increased CHD risk associated with T2DM. Hypolipidaemic, antihypertensive and antidiabetic drugs can affect lipid and glucose parameters thus potentially influencing CHD risk. Such drugs may improve not only the quantity, but also the quality of LDL as well as postprandial lipaemia. SUMMARY Current data highlight the importance of treating diabetic dyslipidaemia in order to minimize CHD risk. Both fasting and postprandial lipids are influenced by drugs in patients with T2DM; physicians should take this into consideration in clinical decision making.
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Abstract
PURPOSE OF REVIEW Despite the benefits of surgical coronary revascularization, patients continue to be at risk for ischemic events in the years that follow coronary artery bypass graft surgery (CABG), mandating the role for postoperative secondary preventive therapy. The purpose of this review was to present a summary on the subject of secondary prevention after CABG, including an overview of a recently published scientific statement, and highlight the newest studies in the field. RECENT FINDINGS Aspirin and statin therapy continue to be the mainstay of secondary prevention after CABG, although newer antiplatelet and lipid-lowering medicines are being actively studied for their potential benefits. Other important elements to secondary prevention after CABG include the aggressive management of hypertension, smoking cessation, and the initiation of cardiac rehabilitation. SUMMARY Secondary prevention is an essential component of postoperative care after CABG. Instituting preventive therapies after surgery optimizes graft patency and helps patients achieve the highest level of physical health and quality of life following CABG.
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Oikonomou E, Mourouzis K, Fountoulakis P, Papamikroulis GA, Siasos G, Antonopoulos A, Vogiatzi G, Tsalamadris S, Vavuranakis M, Tousoulis D. Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance. Heart Fail Rev 2018; 23:389-408. [PMID: 29453696 DOI: 10.1007/s10741-018-9682-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Heart failure (HF) is a common cardiac syndrome, whose pathophysiology involves complex mechanisms, some of which remain unknown. Diabetes mellitus (DM) constitutes not only a glucose metabolic disorder accompanied by insulin resistance but also a risk factor for cardiovascular disease and HF. During the last years though emerging data set up, a bidirectional interrelationship between these two entities. In the case of DM impaired calcium homeostasis, free fatty acid metabolism, redox state, and advance glycation end products may accelerate cardiac dysfunction. On the other hand, when HF exists, hypoperfusion of the liver and pancreas, b-blocker and diuretic treatment, and autonomic nervous system dysfunction may cause impairment of glucose metabolism. These molecular pathways may be used as therapeutic targets for novel antidiabetic agents. Peroxisome proliferator-activated receptors (PPARs) not only improve insulin resistance and glucose and lipid metabolism but also manifest a diversity of actions directly or indirectly associated with systolic or diastolic performance of left ventricle and symptoms of HF. Interestingly, they may beneficially affect remodeling of the left ventricle, fibrosis, and diastolic performance but they may cause impaired water handing, sodium retention, and decompensation of HF which should be taken into consideration in the management of patients with DM. In this review article, we present the pathophysiological data linking HF with DM and we focus on the molecular mechanisms of PPARs agonists in left ventricle systolic and diastolic performance providing useful insights in the molecular mechanism of this class of metabolically active regiments.
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Affiliation(s)
- Evangelos Oikonomou
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece.
| | - Konstantinos Mourouzis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Petros Fountoulakis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Georgios Angelos Papamikroulis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Gerasimos Siasos
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Alexis Antonopoulos
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Georgia Vogiatzi
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Sotiris Tsalamadris
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Manolis Vavuranakis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Dimitris Tousoulis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
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