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1
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Wańczura P, Aebisher D, Iwański MA, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D. The Essence of Lipoproteins in Cardiovascular Health and Diseases Treated by Photodynamic Therapy. Biomedicines 2024; 12:961. [PMID: 38790923 PMCID: PMC11117957 DOI: 10.3390/biomedicines12050961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
Lipids, together with lipoprotein particles, are the cause of atherosclerosis, which is a pathology of the cardiovascular system. In addition, it affects inflammatory processes and affects the vessels and heart. In pharmaceutical answer to this, statins are considered a first-stage treatment method to block cholesterol synthesis. Many times, additional drugs are also used with this method to lower lipid concentrations in order to achieve certain values of low-density lipoprotein (LDL) cholesterol. Recent advances in photodynamic therapy (PDT) as a new cancer treatment have gained the therapy much attention as a minimally invasive and highly selective method. Photodynamic therapy has been proven more effective than chemotherapy, radiotherapy, and immunotherapy alone in numerous studies. Consequently, photodynamic therapy research has expanded in many fields of medicine due to its increased therapeutic effects and reduced side effects. Currently, PDT is the most commonly used therapy for treating age-related macular degeneration, as well as inflammatory diseases, and skin infections. The effectiveness of photodynamic therapy against a number of pathogens has also been demonstrated in various studies. Also, PDT has been used in the treatment of cardiovascular diseases, such as atherosclerosis and hyperplasia of the arterial intima. This review evaluates the effectiveness and usefulness of photodynamic therapy in cardiovascular diseases. According to the analysis, photodynamic therapy is a promising approach for treating cardiovascular diseases and may lead to new clinical trials and management standards. Our review addresses the used therapeutic strategies and also describes new therapeutic strategies to reduce the cardiovascular burden that is induced by lipids.
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Affiliation(s)
- Piotr Wańczura
- Department of Cardiology, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
| | - Mateusz A Iwański
- English Division Science Club, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland
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Abstract
PURPOSE OF REVIEW Aortic valve disease is a leading global cause of morbidity and mortality, posing an increasing burden on society. Advances in next-generation technologies and disease models over the last decade have further delineated the genetic and molecular factors that might be exploited in development of therapeutics for affected patients. This review describes several advances in the molecular and genetic understanding of AVD, focusing on bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). RECENT FINDINGS Genomic studies have identified a myriad of genes implicated in the development of BAV, including NOTCH1 , SMAD6 and ADAMTS19 , along with members of the GATA and ROBO gene families. Similarly, several genes associated with the initiation and progression of CAVD, including NOTCH1 , LPA , PALMD , IL6 and FADS1/2 , serve as the launching point for emerging clinical trials. SUMMARY These new insights into the genetic contributors of AVD have offered new avenues for translational disease investigation, bridging molecular discoveries to emergent pharmacotherapeutic options. Future studies aimed at uncovering new genetic associations and further defining implicated molecular pathways are fuelling the new wave of drug discovery.
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Affiliation(s)
- Ruth L. Ackah
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Jun Yasuhara
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Vidu Garg
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
- Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, USA
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3
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Zhang SS, Hu WY, Li YJ, Yu J, Sang S, Alsalman ZM, Xie DQ. Lipoprotein (a) variability is associated with mean follow-up C-reactive protein in patients with coronary artery disease following percutaneous coronary intervention. World J Clin Cases 2022; 10:12909-12919. [PMID: 36569022 PMCID: PMC9782931 DOI: 10.12998/wjcc.v10.i35.12909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/12/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Increased lipoprotein (a) [lp (a)] has proinflammatory effects, which increase the risk of coronary artery disease. However, the association between lp (a) variability and follow-up C-reactive protein (CRP) level in patients undergoing percutaneous coronary intervention (PCI) has not been investigated.
AIM To explore the association between lp (a) variability and mean CRP levels within the 1st year post-PCI.
METHODS Results of lp (a) and CRP measurements from at least three follow-up visits of patients who had received PCI were retrospectively analyzed. Standard deviation (SD), coefficient of variation (CV), and variability independent of the mean (VIM) are presented for the variability for lp (a) and linear regression analysis was conducted to correlate lp (a) variability and mean follow-up CRP level. The relationship of lp (a) variability and inflammation status was analyzed by restricted cubic spline analysis. Finally, exploratory analysis was performed to test the consistency of results in different populations.
RESULTS A total of 2712 patients were enrolled. Patients with higher variability of lp (a) had a higher level of mean follow-up CRP (P < 0.001). lp (a) variability was positively correlated with the mean follow-up CRP (SD: β = 0.023, P < 0.001; CV: β = 0.929, P < 0.001; VIM: β = 1.648, P < 0.001) by multivariable linear regression analysis. Exploratory analysis showed that the positive association remained consistent in most subpopulations.
CONCLUSION Lp (a) variability correlated with mean follow-up CRP level and high variability could be considered an independent risk factor for increased post-PCI CRP level.
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Affiliation(s)
- Si-Si Zhang
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Wen-Yi Hu
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Yi-Jing Li
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Juan Yu
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Shang Sang
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Zakareya M Alsalman
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
| | - Da-Qi Xie
- Department of Cardiology, Ningbo Ninth Hospital, Ningbo 315300, Zhejiang Province, China
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Ugovšek S, Zupan J, Rehberger Likozar A, Šebeštjen M. Influence of lipid-lowering drugs on inflammation: what is yet to be done? Arch Med Sci 2022; 18:855-869. [PMID: 35832698 PMCID: PMC9266870 DOI: 10.5114/aoms/133936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/04/2021] [Indexed: 12/17/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that is associated with risk of cardiovascular events. The best-characterised and well-standardised clinical indicator of inflammation is C-reactive protein. Current evidence-based drug therapies for prevention and treatment of cardiovascular diseases are mainly focused on reduction of low-density lipoprotein cholesterol. However, these drugs do not provide sufficient protection against recurrent cardiovascular events. One of the possible mechanisms behind this recurrence might be the persistence of residual inflammation. For the most commonly used lipid-lowering drugs, the statins, their reduction of cardiovascular events goes beyond lowering of low-density lipoprotein cholesterol. Here, we review the effects of these lipid-lowering drugs on inflammation, considering statins, ezetimibe, fibrates, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, ethyl eicosapentaenoic acid and antisense oligonucleotides. We focus in particular on C-reactive protein, and discuss how the effects of the statins might be related to reduced rates of cardiovascular events.
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Affiliation(s)
- Sabina Ugovšek
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Janja Zupan
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | | | - Miran Šebeštjen
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Vascular Diseases, University Medical Centre, Ljubljana, Slovenia
- University Medical Centre Ljubljana, Department of Cardiology, Slovenia
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Lombardo B, Izzo V, Terracciano D, Ranieri A, Mazzaccara C, Fimiani F, Cesaro A, Gentile L, Leggiero E, Pero R, Izzo B, D'Alicandro AC, Ercolini D, D'Alicandro G, Frisso G, Pastore L, Calabrò P, Scudiero O. Laboratory medicine: health evaluation in elite athletes. Clin Chem Lab Med 2020; 57:1450-1473. [PMID: 30835249 DOI: 10.1515/cclm-2018-1107] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/24/2019] [Indexed: 02/06/2023]
Abstract
The need to evaluate the health status of an athlete represents a crucial aim in preventive and protective sports science in order to identify the best diagnostic strategy to improve performance and reduce risks related to physical exercise. In the present review we aim to define the main biochemical and haematological markers that vary significantly during and after sports training to identify risk factors, at competitive and professional levels and to highlight the set up of a specific parameter's panel for elite athletes. Moreover, we also intend to consider additional biomarkers, still under investigation, which could further contribute to laboratory sports medicine and provide reliable data that can be used by athlete's competent staff in order to establish personal attitudes and prevent sports injuries.
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Affiliation(s)
- Barbara Lombardo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy
| | - Viviana Izzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
| | - Daniela Terracciano
- Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Annaluisa Ranieri
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy
| | - Cristina Mazzaccara
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy
| | - Fabio Fimiani
- Division of Cardiology, Department of Cardio-Thoracic and Respiratory Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Arturo Cesaro
- Division of Cardiology, Department of Cardio-Thoracic and Respiratory Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | | | | | - Raffaela Pero
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,Task Force on Microbiome Studies, University of Naples "Federico II", Naples, Italy
| | - Barbara Izzo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | | | - Danilo Ercolini
- Task Force on Microbiome Studies, University of Naples "Federico II", Naples, Italy.,Division of Microbiology, Department of Agricultural Sciences, University of Naples "Federico II", Naples, Italy
| | - Giovanni D'Alicandro
- Department of Neuroscience and Rehabilitation, Center of Sports Medicine and Disability, AORN, Santobono-Pausillipon, Naples, Italy
| | - Giulia Frisso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy
| | - Lucio Pastore
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy.,Task Force on Microbiome Studies, University of Naples "Federico II", Naples, Italy
| | - Paolo Calabrò
- Division of Cardiology, Department of Cardio-Thoracic and Respiratory Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Olga Scudiero
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.,CEINGE Advanced Biotechnologies, Naples, Italy.,Task Force on Microbiome Studies, University of Naples "Federico II", Naples, Italy
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Parish S, Hopewell JC, Hill MR, Marcovina S, Valdes-Marquez E, Haynes R, Offer A, Pedersen TR, Baigent C, Collins R, Landray M, Armitage J. Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e001696. [PMID: 29449329 PMCID: PMC5841847 DOI: 10.1161/circgen.117.001696] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 12/01/2017] [Indexed: 12/28/2022]
Abstract
Supplemental Digital Content is available in the text. Background: Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear. Methods: HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin–laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified. Results: Allocation to niacin–laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin–laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (PTrend=4×10−29) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels. Conclusions: Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin–laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a). Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.
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Affiliation(s)
- Sarah Parish
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13.
| | - Jemma C Hopewell
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Michael R Hill
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Santica Marcovina
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Elsa Valdes-Marquez
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Richard Haynes
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Alison Offer
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Terje R Pedersen
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Colin Baigent
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Rory Collins
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Martin Landray
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
| | - Jane Armitage
- From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13
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Sathiyakumar V, Kapoor K, Jones SR, Banach M, Martin SS, Toth PP. Novel Therapeutic Targets for Managing Dyslipidemia. Trends Pharmacol Sci 2018; 39:733-747. [PMID: 29970260 DOI: 10.1016/j.tips.2018.06.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/31/2018] [Accepted: 06/01/2018] [Indexed: 11/16/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results.
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Affiliation(s)
- Vasanth Sathiyakumar
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Karan Kapoor
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Steven R Jones
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland
| | - Seth S Martin
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Peter P Toth
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, CGH Medical Center, Sterling, IL, USA.
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8
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Sun D, Li S, Zhao X, Wu NQ, Zhu CG, Guo YL, Gao Y, Qing P, Cui CJ, Liu G, Sun J, Dong Q, Li JJ. Association between lipoprotein (a) and proprotein convertase substilisin/kexin type 9 in patients with heterozygous familial hypercholesterolemia: A case-control study. Metabolism 2018; 79:33-41. [PMID: 29129821 DOI: 10.1016/j.metabol.2017.11.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 10/27/2017] [Accepted: 11/06/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Recent data have suggested an important role of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) in the development of atherosclerotic cardiovascular disease (ASCVD) in both general population and family hypercholesterolemia (FH), while the relation of Lp(a) to PCSK9 has not been examined. OBJECTIVE The aim of the present study was to investigate the association between plasma PCSK9 and Lp(a)in patients with heterozygous FH (HeFH). METHODS Two hundred and fifty-five molecularly confirmed patients with HeFH were compared to 255 age- and gender-matched non-FH controls. Plasma PCSK9 and Lp(a) concentrations were measured using ELISA and immunoturbidimetric method respectively, and finally their association was assessed. RESULTS Both plasma PCSK9 and Lp(a) levels were significantly higher in patients with HeFH compared to control group (p<0.001). Besides, the Lp(a) concentration and percentage of Lp(a)≥300mg/L were increased by PCSK9 tertiles in HeFH group (both p<0.05) while not in control group. In partial correlation analysis, Lp(a) was associated with PCSK9 (r=0.254, p<0.001) in HeFH group but not in control, which were further confirmed by multivariable linear regression analysis. Furthermore, significant associations between Lp(a) and PCSK9 were also found in subgroups of HeFH group irrespective of definite or probable FH, with and without coronary artery disease (CAD), and with statin or not. CONCLUSIONS Plasma Lp(a) level was associated with PCSK9 in patients with HeFH alone, suggesting that much about the interaction of PCSK9 with Lp(a) in FH need further explorations.
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Affiliation(s)
- Di Sun
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Sha Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Xi Zhao
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Na-Qiong Wu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Cheng-Gang Zhu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Yuan-Lin Guo
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Ying Gao
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Ping Qing
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Chuan-Jue Cui
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Geng Liu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Jing Sun
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Qian Dong
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Jian-Jun Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China.
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Abstract
PURPOSE OF REVIEW Genetic dyslipidemias contribute to the prevalence of ischemic heart disease. The field of genetic dyslipidemias and their influence on atherosclerotic heart disease is rapidly developing and accumulating increasing evidence. The purpose of this review is to describe the current state of knowledge in regard to inherited atherogenic dyslipidemias. The disorders of familial hypercholesterolemia (FH) and elevated lipoprotein(a) will be detailed. Genetic technology has made rapid advancements, leading to new discoveries in inherited atherogenic dyslipidemias, which will be explored in this review, as well as a description of possible future developments. Increasing attention has come upon the genetic disorders of familial hypercholesterolemia and elevated lipoprotein(a). RECENT FINDINGS This review includes new knowledge of these disorders including description of these disorders, their method of diagnosis, their prevalence, their genetic underpinnings, and their effect on the development of cardiovascular disease. In addition, it discusses major advances in genetic technology, including the completion of the human genome sequence, next-generation sequencing, and genome-wide association studies. Also discussed are rare variant studies with specific genetic mechanisms involved in inherited dyslipidemias, such as in the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. The field of genetics of dyslipidemia and cardiovascular disease is rapidly growing, which will result in a bright future of novel mechanisms of action and new therapeutics.
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Affiliation(s)
- Kavita Sharma
- Ohio Health Heart and Vascular Physicians, 765 North Hamilton Road, Suite 120, Gahanna, OH, 43230, USA
| | - Ragavendra R Baliga
- The Ohio State University Wexner Medical Center, Suite 200, 473 West 12th Avenue, Columbus, OH, 43210, USA.
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10
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Ma X, Liu Y, Tan Y, Qu K, He X, Zhang H, Wang Z. Diallyl disulphide inhibits apolipoprotein(a) expression in HepG2 cells through the MEK1-ERK1/2-ELK-1 pathway. Lipids Health Dis 2017; 16:223. [PMID: 29178936 PMCID: PMC5702159 DOI: 10.1186/s12944-017-0616-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/16/2017] [Indexed: 11/24/2022] Open
Abstract
Background Lipoprotein(a) [LP(a)] is implicated as a common and independent risk factor for cardiovascular diseases. The therapeutic options currently available for reducing plasma LP(a) concentrations are limited. Diallyl disulphide (DADS), the main component of garlic, regulates lipid metabolism in hepatocytes and adipocytes through ERK1/2 signalling. This study aimed to assess the effect of DADS on apolipoprotein(a) [apo(a)] in HepG2 cells. We also determined the effects of DADS on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. Methods We examined the role of DADS on apo(a) expression in HepG2 cells by treating cell with different concentrations of DADS (10, 20, 40 and 80 μg/mL) for 24 h or treating cells with 40 μg/mL DADS for 0, 6, 12, 24 and 48 h. Then we used quantitative real-time PCR to analysis apo(a) mRNA levels, used Western blot to analysis apo(a) protein levels and used enzyme-linked immunosorbent assay to test apo(a) secreted levels. To farther determined the role of DADS, we applied Transfection of small interfering RNA to knockdown ELK-1levels and applied PD98059, a specific inhibitor of ERK1/2, to block ERK1/2 signal. Results The results show DADS inhibited apo(a) at both the mRNA and protein levels in HepG2 cells in a dose-dependent manner. DADS-mediated inhibition of apoa(a) expression in HepG2 cells was attenuated when the cells were cultured in medium containing PD98059 (ERK1/2 inhibitor) or were transfected with siRNAs against MEK1 or ELK-1. Overexpression of apo(a) yielded similar results. Conclusions This study reveals that DADS can downregulate apo(a) expression in a dose-dependent manner via the MEK-ERK12-ELK-1 pathway.
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Affiliation(s)
- Xiaofeng Ma
- Department of Cardiology, Affiliated Nanhua Hospital of University of South China, Hengyang, 421001, China.,Institute of Cardiovascular disease, Key Laboratory for Atherosclerology of Human Province, University of South China, Hengyang, 421001, China
| | - Yami Liu
- Institute of Cardiovascular disease, Key Laboratory for Atherosclerology of Human Province, University of South China, Hengyang, 421001, China
| | - Yanmei Tan
- Department of Pathology, Changde Vocational Technical College, Changde, 415000, China
| | - Kai Qu
- Institute of Cardiovascular disease, Key Laboratory for Atherosclerology of Human Province, University of South China, Hengyang, 421001, China
| | - Xinglan He
- Women and Children Healthcare Hospital of Zhu zhou, Zhuzhou, 412000, China
| | - Hai Zhang
- Department of Pathology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China.
| | - Zuo Wang
- Institute of Cardiovascular disease, Key Laboratory for Atherosclerology of Human Province, University of South China, Hengyang, 421001, China.
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11
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Suwa S, Ogita M, Miyauchi K, Sonoda T, Konishi H, Tsuboi S, Wada H, Naito R, Dohi T, Kasai T, Okazaki S, Isoda K, Daida H. Impact of Lipoprotein (a) on Long-Term Outcomes in Patients with Coronary Artery Disease Treated with Statin After a First Percutaneous Coronary Intervention. J Atheroscler Thromb 2017; 24:1125-1131. [PMID: 28321012 PMCID: PMC5684478 DOI: 10.5551/jat.38794] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/07/2017] [Indexed: 01/04/2023] Open
Abstract
AIMS Cardiovascular risk persists despite intensive lipid lowering therapy using statins. Serum levels of lipoprotein (a) [Lp(a)] can be a residual cardiovascular risk for adverse events. Aim of the present study was to evaluate the impact of Lp(a) on long-term clinical outcomes in patients treated with statin after percutaneous coronary intervention. METHODS We prospectively enrolled 3507 consecutive CAD patients who underwent a first percutaneous coronary intervention (PCI) between 1997 and 2011 at our institution. We identified 1768 patients (50.4%) who had treated with statin during PCI. Eligible 1336 patients were stratified to two groups according to Lp(a) levels (median Lp (a) 21.5 mg/dL). The primary outcome was major adverse cardiac events (MACE) including cardiac death and non-fatal acute coronary syndrome. RESULTS MACE occurred 144 (10.8%) including 34 (2.5%) cardiac death and 110 (8.7%) non-fatal ACS during median follow-up period of 1920 days. The cumulative rate of MACE was significantly higher in group with high Lp(a) group (log-rank p=0.0460). Multivariate Cox regression analysis showed a significant correlation between Lp (a) levels treated as a natural logarithm-transformed continuous variable and increased MACE (adjusted HR for MACE 1.28, 95%CI 1.04-1.58, p=0.0184)Conclusion: Elevated levels of Lp(a) is significantly associated with long-term adverse clinical outcomes among CAD patients who received statin therapy after PCI.
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Affiliation(s)
- Satoru Suwa
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Manabu Ogita
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Katsumi Miyauchi
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Taketo Sonoda
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Hirokazu Konishi
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Shuta Tsuboi
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Hideki Wada
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryo Naito
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tomotaka Dohi
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takatoshi Kasai
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shinya Okazaki
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kikuo Isoda
- Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Hiroyuki Daida
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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12
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Lipid Metabolism and Emerging Targets for Lipid-Lowering Therapy. Can J Cardiol 2017; 33:872-882. [DOI: 10.1016/j.cjca.2016.12.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/12/2016] [Accepted: 12/26/2016] [Indexed: 12/25/2022] Open
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13
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Kelly E, Hemphill L. Lipoprotein(a): A Lipoprotein Whose Time Has Come. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2017; 19:48. [DOI: 10.1007/s11936-017-0549-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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14
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Sahebkar A, Simental-Mendía LE, Watts GF, Serban MC, Banach M. Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials. BMC Med 2017; 15:22. [PMID: 28153024 PMCID: PMC5290642 DOI: 10.1186/s12916-017-0787-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 01/07/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Raised plasma lipoprotein(a) (Lp(a)) concentration is an independent and causal risk factor for atherosclerotic cardiovascular disease. Several types of pharmacological approaches are under evaluation for their potential to reduce plasma Lp(a) levels. There is suggestive evidence that statins and fibrates, two frequently employed lipid-lowering drugs, can lower plasma Lp(a). The present study aims to compare the efficacy of fibrates and statins in reducing plasma concentrations of Lp(a) using a meta-analysis of randomized head-to-head trials. METHODS Medline and Scopus databases were searched to identify randomized head-to-head comparative trials investigating the efficacy of fibrates versus statins in reducing plasma Lp(a) levels. Meta-analysis was performed using a random-effects model, with inverse variance weighted mean differences (WMDs) and 95% confidence intervals (CIs) as summary statistics. The impact of putative confounders on the estimated effect size was explored using random effects meta-regression. RESULTS Sixteen head-to-head comparative trials with a total of 1388 subjects met the eligibility criteria and were selected for this meta-analysis. Meta-analysis revealed a significantly greater effect of fibrates versus statins in reducing plasma Lp(a) concentrations (WMD, -2.70 mg/dL; 95% CI, -4.56 to -0.84; P = 0.004). Combination therapy with fibrates and statins had a significantly greater effect compared with statin monotherapy (WMD, -1.60 mg/dL; 95% CI, -2.93 to -0.26; P = 0.019) but not fibrate monotherapy (WMD, -1.76 mg/dL; 95% CI, -5.44 to +1.92; P = 0.349) in reducing plasma Lp(a) concentrations. The impact of fibrates versus statins in reducing plasma Lp(a) concentrations was not found to be significantly associated with treatment duration (P = 0.788). CONCLUSIONS Fibrates have a significantly greater effect in reducing plasma Lp(a) concentrations than statins. Addition of fibrates to statins can enhance the Lp(a)-lowering effect of statins.
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Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- School of Medicine, University of Western Australia, Perth, Australia.
| | | | - Gerald F Watts
- School of Medicine, University of Western Australia, Perth, Australia
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia
| | - Maria-Corina Serban
- Department of Functional Sciences, Discipline of Pathophysiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland
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15
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Kotani K, Banach M. Lipoprotein(a) and inhibitors of proprotein convertase subtilisin/kexin type 9. J Thorac Dis 2017; 9:E78-E82. [PMID: 28203441 DOI: 10.21037/jtd.2017.01.40] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Lipoprotein(a) [Lp(a)] has been identified as a risk factor for cardiovascular disease. Lp(a) levels are also high under certain clinical conditions, including familial hypercholesterolemia and high blood low-density lipoprotein (LDL) cholesterol levels. Few effective generic therapies for modulating Lp(a) have been developed. However, new therapies involving inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) using monoclonal antibodies have markedly reduced the blood LDL levels-and the Lp(a) levels as well. Much attention has therefore been focused on this therapy and its utility. The mechanism by which PCSK9 inhibitors reduce the Lp(a) levels remains unclear. We here describe the effects of PCSK9 inhibitors on Lp(a) and discuss potential mechanisms and perspectives of this topic.
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Affiliation(s)
- Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland
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17
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Bucci M, Tana C, Giamberardino MA, Cipollone F. Lp(a) and cardiovascular risk: Investigating the hidden side of the moon. Nutr Metab Cardiovasc Dis 2016; 26:980-986. [PMID: 27514608 DOI: 10.1016/j.numecd.2016.07.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/21/2016] [Accepted: 07/06/2016] [Indexed: 12/21/2022]
Abstract
AIMS This article reports current evidence on the association between Lp(a) and cardiovascular (CV) disease and on pathophysiological mechanisms. The available information on therapy for reduction of lipoprotein(a) is also discussed. DATA SYNTHESIS Although some evidence is conflicting, Lp(a) seems to increase CV risk through stimulation of platelet aggregation, inhibition of tissue factor pathway inhibitor, alteration of fibrin clot structure and promotion of endothelial dysfunction and phospholipid oxidation. Lp(a) 3.5-fold higher than normal increases the risk of coronary heart disease and general CV events, particularly in those with LDL cholesterol ≥ 130 mg/dl. High Lp(a) values represent also an independent risk factor for ischemic stroke (more relevant in young stroke patients), peripheral artery disease (PAD) and aortic and mitral stenosis. Furthermore, high Lp(a) levels seem to be associated with increased risk of cardiovascular events in patients with chronic kidney disease, particularly in those undergoing percutaneous coronary intervention. CONCLUSIONS Lipoprotein (a) (Lp[a]) seems to significantly influence the risk of cardiovascular events. The effects of statins and fibrates on Lp(a) are limited and extremely variable. Nicotinic acid was shown effective in reducing Lp(a) but, due to its side effects and serious adverse events during clinical trials, it is no longer considered a possible option for treatment. To date, the treatment of choice for high levels of Lp(a) in high CV risk patients is represented by LDL-Apheresis. Thanks to innovative technologies, new selectively inhibiting LPA drugs are being developed and tested.
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Affiliation(s)
- M Bucci
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, "SS Annunziata" Hospital - ASL Chieti, Italy; Ce.S.I.-Met, "G. D'Annunzio" University of Chieti, Italy
| | - C Tana
- Internal Medicine Unit, Guastalla Hospital, AUSL Reggio Emilia, Italy
| | - M A Giamberardino
- Ce.S.I.-Met, "G. D'Annunzio" University of Chieti, Italy; Geriatrics Clinic, Department of Medicine and Science of Aging, "G. D'Annunzio" University of Chieti, Italy
| | - F Cipollone
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, "SS Annunziata" Hospital - ASL Chieti, Italy; Ce.S.I.-Met, "G. D'Annunzio" University of Chieti, Italy; Geriatrics Clinic, Department of Medicine and Science of Aging, "G. D'Annunzio" University of Chieti, Italy.
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18
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Sahebkar A, Reiner Ž, Simental-Mendía LE, Ferretti G, Cicero AFG. Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials. Metabolism 2016; 65:1664-1678. [PMID: 27733255 DOI: 10.1016/j.metabol.2016.08.007] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 08/20/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023]
Abstract
AIM Lipoprotein(a) (Lp(a)) is a proatherogenic and prothrombotic lipoprotein. Our aim was to quantify the extended-release nicotinic acid Lp(a) reducing effect with a meta-analysis of the available randomized clinical trials. METHODS A meta-analysis and random-effects meta-regression were performed on data pooled from 14 randomized placebo-controlled clinical trials published between 1998 and 2015, comprising 17 treatment arms, which included 9013 subjects, with 5362 in the niacin arm. RESULTS The impact of ER niacin on plasma Lp(a) concentrations was reported in 17 treatment arms. Meta-analysis suggested a significant reduction of Lp(a) levels following ER niacin treatment (weighted mean difference - WMD: -22.90%, 95% CI: -27.32, -18.48, p<0.001). Results also remained similar when the meta-analysis was repeated with standardized mean difference as summary statistic (WMD: -0.66, 95% CI: -0.82, -0.50, p<0.001). When the studies were categorized according to the administered dose, there was a comparable effect between the subsets of studies with administered doses of <2000mg/day (WMD: -21.85%, 95% CI: -30.61, -13.10, p<0.001) and ≥2000mg/day (WMD: -23.21%, 95% CI: -28.41, -18.01, p<0.001). The results of the random-effects meta-regression did not suggest any significant association between the changes in plasma concentrations of Lp(a) with dose (slope: -0.0001; 95% CI: -0.01, 0.01; p=0.983), treatment duration (slope: -0.40; 95% CI: -0.97, 0.17; p=0.166), and percentage change in plasma HDL-C concentrations (slope: 0.44; 95% CI: -0.48, 1.36; p=0.350). CONCLUSION In this meta-analysis of randomized placebo-controlled clinical trials, treatment with nicotinic acid was associated with a significant reduction in Lp(a) levels.
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Affiliation(s)
- Amirhosssein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran; Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
| | - Željko Reiner
- University Hospital Center Zagreb, Department of Internal medicine, Kišpatićeva 12, Zagreb, Croatia
| | | | - Gianna Ferretti
- Dipartimento di Scienze cliniche Specialistiche ed Odontostomatologiche (DISCO), Università Politecnica delle Marche, Italy
| | - Arrigo F G Cicero
- Medicine and Surgery Sciences Dept., Alma Mater Studiorum University of Bologna, Italy.
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Tarantino G, Finelli C, Gioa S, Citro V, La Sala N, Gentile M. Serum levels of Lp(a) are related to waist circumference in NAFLD patients with low prevalence of co-morbidities. Scand J Clin Lab Invest 2016; 76:544-552. [PMID: 27433943 DOI: 10.1080/00365513.2016.1207249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 06/26/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Novel evidence suggests a relationship between circulating Lp(a) levels and the presence of cardiovascular events independently from the cardio-metabolic profile. METHODS AND RESULTS The purpose of this study was to investigate serum Lp(a) concentrations in relation to carotid intima-media thickness (IMT), anthropometric measures, lipid profile, assessment of insulin resistance, and other parameters conventionally used to predict CVD risk, in obese patients suffering from hepatic steatosis (HS), the well-known nonalcoholic fatty liver disease (NAFLD). Evidencing the key-points of this research, firstly, serum Lp(a) concentrations were not associated with carotid IMT in this selected population or, consequently, with early atherosclerosis, at least as evaluated by IMT. Secondly, carotid IMT was not predicted by HS severity, as evaluated by ultrasound. Finally, in the adjusted model, Lp(a) was positively predicted by waist circumference (WC) (β = 0.25, t = 2.3, p = 0.02) and negatively by central adiposity, assessed as visceral adipose tissue at US (β = -0.33, t = -3.0, p = 0.003). CONCLUSION Serum Lp(a) values may not play a direct role in increasing IMT, albeit associated with WC.
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Affiliation(s)
- Giovanni Tarantino
- a Department of Clinical Medicine and Surgery , Federico II University Medical School of Naples , Italy
- b Centro Ricerche Oncologiche Di Mercogliano , Istituto Nazionale per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale", IRCCS , Italy
| | - Carmine Finelli
- c Center of Obesity and Eating Disorders , Stella Maris Mediterraneum Foundation , C/Da S. Lucia , Chiaromonte , Potenza , Italy
| | - Saverio Gioa
- c Center of Obesity and Eating Disorders , Stella Maris Mediterraneum Foundation , C/Da S. Lucia , Chiaromonte , Potenza , Italy
| | - Vincenzo Citro
- d Department of Internal Medicine , Umberto I Hospital , Nocera Inferiore , Salerno , Italy
| | - Nicolina La Sala
- c Center of Obesity and Eating Disorders , Stella Maris Mediterraneum Foundation , C/Da S. Lucia , Chiaromonte , Potenza , Italy
| | - Marco Gentile
- a Department of Clinical Medicine and Surgery , Federico II University Medical School of Naples , Italy
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20
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van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LAB, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ESG. Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation 2016; 134:611-24. [PMID: 27496857 DOI: 10.1161/circulationaha.116.020838] [Citation(s) in RCA: 404] [Impact Index Per Article: 44.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 06/22/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway. METHODS In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity. RESULTS We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a). CONCLUSIONS These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. CLINICAL TRIAL REGISTRATION URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study).
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Affiliation(s)
- Fleur M van der Valk
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Siroon Bekkering
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Jeffrey Kroon
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Calvin Yeang
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Jan Van den Bossche
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Jaap D van Buul
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Amir Ravandi
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Aart J Nederveen
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Hein J Verberne
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Corey Scipione
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Max Nieuwdorp
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Leo A B Joosten
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Mihai G Netea
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Marlys L Koschinsky
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Joseph L Witztum
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Sotirios Tsimikas
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Niels P Riksen
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.)
| | - Erik S G Stroes
- From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.).
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Ellis KL, Hooper AJ, Burnett JR, Watts GF. Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism. Nat Rev Endocrinol 2016; 12:467-84. [PMID: 27199287 DOI: 10.1038/nrendo.2016.69] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Familial hypercholesterolaemia, familial combined hyperlipidaemia (FCH) and elevated lipoprotein(a) are common, inherited disorders of apolipoprotein B metabolism that markedly accelerate the onset of atherosclerotic cardiovascular disease (ASCVD). These disorders are frequently encountered in clinical lipidology and need to be accurately identified and treated in both index patients and their family members, to prevent the development of premature ASCVD. The optimal screening strategies depend on the patterns of heritability for each condition. Established therapies are widely used along with lifestyle interventions to regulate levels of circulating lipoproteins. New therapeutic strategies are becoming available, and could supplement traditional approaches in the most severe cases, but their long-term cost-effectiveness and safety have yet to be confirmed. We review contemporary developments in the understanding, detection and care of these highly atherogenic disorders of apolipoprotein B metabolism.
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Affiliation(s)
- Katrina L Ellis
- School of Medicine and Pharmacology, The University of Western Australia, PO Box X2213, Perth, Western Australia 6847, Australia
- Centre for Genetic Origins of Health and Disease, The University of Western Australia and Curtin University, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia
| | - Amanda J Hooper
- School of Medicine and Pharmacology, The University of Western Australia, PO Box X2213, Perth, Western Australia 6847, Australia
- PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia
- School of Pathology and Laboratory Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia
| | - John R Burnett
- School of Medicine and Pharmacology, The University of Western Australia, PO Box X2213, Perth, Western Australia 6847, Australia
- PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Wellington Street Perth, Western Australia, Australia
| | - Gerald F Watts
- School of Medicine and Pharmacology, The University of Western Australia, PO Box X2213, Perth, Western Australia 6847, Australia
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Wellington Street Perth, Western Australia, Australia
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Langsted A, Kamstrup PR, Benn M, Tybjærg-Hansen A, Nordestgaard BG. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol 2016; 4:577-87. [PMID: 27185354 DOI: 10.1016/s2213-8587(16)30042-0] [Citation(s) in RCA: 220] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 04/08/2016] [Accepted: 04/08/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA risk genotypes are a possible cause of clinical familial hypercholesterolaemia, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction. METHODS We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein(a) cholesterol-adjusted analyses, total cholesterol and LDL cholesterol were adjusted for the lipoprotein(a) cholesterol content by subtracting 30% of the individuals' lipoprotein(a) total mass before total and LDL cholesterol were used for diagnosis of clinical familial hypercholesterolaemia. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria to clinically diagnose familial hypercholesterolaemia. Cox proportional hazard regression calculated hazard ratios (95% CI) of myocardial infarction. FINDINGS Using unadjusted LDL cholesterol, mean lipoprotein(a) concentrations were 23 mg/dL in individuals unlikely to have familial hypercholesterolaemia, 32 mg/dL in those with possible familial hypercholesterolaemia, and 35 mg/dL in those with probable or definite familial hypercholesterolaemia (ptrend<0·0001). However, when adjusting LDL cholesterol for lipoprotein(a) cholesterol content the corresponding values were 24 mg/dL for individuals unlikely to have familial hypercholesterolaemia, 22 mg/dL for those with possible familial hypercholesterolaemia, and 21 mg/dL for those with probable or definite familial hypercholesterolaemia (ptrend=0·46). High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia and LPA risk genotypes were more frequent in clinical familial hypercholesterolaemia, whereas lipoprotein(a) concentrations were similar in those with and without familial hypercholesterolaemia mutations. The hazard ratios (HRs) for myocardial infarction compared with individuals unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less were 1·4 (95% CI 1·1-1·7) in those unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentrations of more than 50 mg/dL, 3·2 (2·5-4·1) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less, and 5·3 (3·6-7·6) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of more than 50 mg/dL. In analyses using Simon Broome or MEDPED criteria, results were similar to those using DLCN criteria to diagnose clinical familial hypercholesterolaemia. INTERPRETATION High lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction. FUNDING Danish Heart Association and IMK General Fund, Denmark.
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Affiliation(s)
- Anne Langsted
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pia R Kamstrup
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Benn
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Tybjærg-Hansen
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Ajufo E, Rader DJ. Recent advances in the pharmacological management of hypercholesterolaemia. Lancet Diabetes Endocrinol 2016; 4:436-46. [PMID: 27012540 DOI: 10.1016/s2213-8587(16)00074-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/28/2016] [Accepted: 02/15/2016] [Indexed: 12/27/2022]
Abstract
The recent developments in pharmacological interventions that reduce LDL cholesterol have been remarkable, coming more than a decade after the approval of the last LDL-cholesterol-lowering drug, the cholesterol absorption inhibitor ezetimibe. Within just a few years, four new LDL-cholesterol-lowering agents have received regulatory approval. Lomitapide and mipomersen inhibit the production of LDL, but also increase hepatic fat and are licensed specifically for homozygous familial hypercholesterolaemia. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by about 50-60%. These drugs are approved for use in patients with cardiovascular disease or familial hypercholesterolaemia whose LDL cholesterol levels are insufficiently controlled on standard agents. Although definitive clinical efficacy and long-term safety data are still needed, antibody-based PCSK9 inhibitors promise to meet much of the unmet medical need in the treatment of raised LDL cholesterol. However, several additional approaches to inhibiting PCSK9, as well as other classes of LDL-lowering therapies, are in clinical development. Here we summarise the science behind the development of the newly approved LDL-cholesterol-lowering drugs and critically review their efficacy and safety data, highlighting unanswered research questions. Finally, we discuss emerging LDL-lowering therapies in clinical development.
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Affiliation(s)
- Ezim Ajufo
- Department of Medicine and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel J Rader
- Department of Medicine and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Sahebkar A, Simental-Mendía LE, Stefanutti C, Pirro M. Supplementation with coenzyme Q10 reduces plasma lipoprotein(a) concentrations but not other lipid indices: A systematic review and meta-analysis. Pharmacol Res 2016; 105:198-209. [PMID: 26836888 DOI: 10.1016/j.phrs.2016.01.030] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 01/25/2016] [Accepted: 01/27/2016] [Indexed: 12/17/2022]
Abstract
Plasma lipoprotein(a) [Lp(a)] elevations are associated with increased cardiovascular risk. Coenzyme Q10 (CoQ10) is a member of the mitochondrial respiratory chain with a prominent role as a potent gene regulator. The Lp(a)-lowering efficacy of CoQ10 has been investigated in different clinical settings with contrasting results. A systematic literature search in Medline, SCOPUS, Web of Science and Google Scholar databases was conducted to identify controlled trials investigating the efficacy of CoQ10 supplementation on plasma Lp(a) levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in Lp(a) levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma Lp(a) levels. Seven randomized controlled trials with a total of 409 subjects (206 in the CoQ10 arm and 203 in the control arm) met the eligibility criteria. Overall, CoQ10 supplementation was paralleled by a slight but significant reduction of plasma Lp(a) levels (WMD: -3.54 mg/dL, 95% CI: -5.50, -1.58; p<0.001), this effect being more robust in those trials with higher baseline Lp(a) levels (slope: -0.44; 95% CI: -0.80, -0.08; p=0.018). Reduction of plasma Lp(a) levels was consistent across different CoQ10 doses, with an inverse association between administered CoQ10 dose and Lp(a) lowering (slope: 0.04; 95% CI: 0.01, 0.07; p=0.004). Neither total cholesterol and cholesterol subfractions, nor triglyceride levels were affected by CoQ10 supplementation. In conclusion, CoQ10 supplementation, in the tested range of doses, reduces plasma Lp(a) concentrations, particularly in patients with Lp(a)≥ 30 mg/dL. Other lipid indices were not altered by CoQ10 supplementation.
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Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
| | | | - Claudia Stefanutti
- Extracorporeal Therapeutic Techniques Unit-Immunohematology and Transfusion Medicine, Department of Molecular Medicine, University of Rome Sapienza, Umberto I Hospital, 155 Viale del Policlinico, I-00161 Rome, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Hospital "Santa Maria della Misericordia", Piazzale Menghini, 1-06156 Perugia, Italy.
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Reith C, Armitage J. Management of residual risk after statin therapy. Atherosclerosis 2016; 245:161-70. [DOI: 10.1016/j.atherosclerosis.2015.12.018] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 12/10/2015] [Accepted: 12/12/2015] [Indexed: 01/19/2023]
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Abstract
The armamentarium for the treatment of dyslipidemia today comprises six different modes of action with overall around 24 different drugs. The treatment of lipid disorders was revolutionized with the introduction of statins which have become the most important therapeutic option available today to reduce and prevent atherosclerosis and its detrimental consequences like cardiovascular diseases and stroke. With and optimized reduction of elevated LDL levels with statins, the risk for cardiovascular diseases (CVD) can be reduced by 30%, indicating a residual remaining risk of 70% for the development and progression of CVD notifying still a high medical need for more effective antilipidemic drugs. Consequently, the search for novel lipid-modifying drugs is still one of the most active areas in research and development in the pharmaceutical industry. Major focus lies on approaches to LDL-lowering drugs superior to statins with regard to efficacy, safety, and patient compliance and on approaches modifying plasma levels and functionality of HDL particles based on the clinically validated inverse relationship between high-plasma HDL levels and the risk for CVD. The available drugs today for the treatment of dyslipidemia are small organic molecules or nonabsorbable polymers for binding of bile acids to be applied orally. Besides small molecules for novel targets, biological drugs such as monoclonal antibodies, antisense or gene-silencing oligonucleotides, peptidomimetics, reconstituted synthetic HDL particles and therapeutic proteins are novel approaches in clinical development are which have to be applied by injection or infusion. The promising clinical results of several novel drug candidates, particularly for LDL cholesterol lowering with monoclonal antibodies raised against PCSK9, may indicate more than a decade after the statins, the entrance of new breakthrough therapies to treat lipid disorders.
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Affiliation(s)
- Werner Kramer
- Institute of Biochemistry, Biocenter, Goethe-Universität Frankfurt, Max-von-Laue-Str. 9, Frankfurt, Germany.
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van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein (a). J Lipid Res 2015; 57:1612-8. [PMID: 26637277 DOI: 10.1194/jlr.r053066] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Indexed: 01/21/2023] Open
Abstract
Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with apoB and an additional glycoprotein, called apo(a). Ever since the strong association between elevated levels of Lp(a) and an increased risk for CVD was recognized, interest in the therapeutic modulation of Lp(a) levels has increased. Here, the past and present therapies aiming to lower Lp(a) levels will be reviewed, demonstrating that these agents have had varying degrees of success. The next challenge will be to prove that Lp(a) lowering also leads to cardiovascular benefit in patients with elevated Lp(a) levels. Therefore, highly specific and potent Lp(a)-lowering strategies are awaited urgently.
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Affiliation(s)
| | - Fleur M van der Valk
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Erik S G Stroes
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
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Man LC, Kelly E, Duffy D. Targeting lipoprotein (a): an evolving therapeutic landscape. Curr Atheroscler Rep 2015; 17:502. [PMID: 25736345 DOI: 10.1007/s11883-015-0502-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Robust epidemiologic and genetic studies have solidified the role of lipoprotein (a) [Lp(a)] as an independent and causal risk factor for cardiovascular disease. The increased cardiovascular risk of Lp(a) is mediated through both proatherogenic and prothrombotic/antifibrinolytic mechanisms. Several societies recommend Lp(a) screening for patients with high cardiovascular risk, although no consensus exists on the management of patients with elevated Lp(a). However, numerous pharmacologic approaches are being evaluated that have the potential to reduce Lp(a) and will be the focus of this review. The majority of these interventions have been developed for other lipid-lowering indications, but also lower Lp(a). There are also novel therapies in development that specifically target Lp(a). The efficacy of these therapies varies, and their role in the evolving lipoprotein therapeutic landscape has yet to be determined. Nevertheless, targeted Lp(a) reduction is certainly intriguing and will likely continue to be an active area of investigation in the future.
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Affiliation(s)
- Lillian C Man
- Department of Medicine, Thomas Jefferson University Hospital, 1025 Walnut Street, Room 805, Philadelphia, PA, 19107, USA,
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Abstract
Cardiovascular disease (CVD) is the most common cause of death and disability worldwide. Therefore, great importance has been placed on the discovery of novel risk factors and metabolic pathways relevant in the prevention and management of CVD. Such research is ongoing and may continue to lead to better risk stratification of individuals and/or the development of new intervention targets and treatment options. This review highlights emerging biomarkers related to lipid metabolism, glycemia, inflammation, and cardiac damage, some of which show promising associations with CVD risk and provide further understanding of the underlying pathophysiology. However, their measurement methodology and assays will require validation and standardization, and it will take time to accumulate evidence of their role in CVD in various population settings in order to fully assess their clinical utility. Several of the novel biomarkers represent intriguing, potentially game-changing targets for therapy.
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Affiliation(s)
- Leah E Cahill
- Department of Medicine, Dalhousie University, 5790 University Ave, Halifax, NS, B3H 1V7, Canada.
- Department of Nutrition, Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA.
| | - Monica L Bertoia
- Department of Nutrition, Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA.
| | - Sarah A Aroner
- Department of Nutrition, Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA.
| | - Kenneth J Mukamal
- Beth Israel Deaconess Medical Center, 1309 Beacon Street, 2nd Floor, Brookline, Boston, MA, USA.
| | - Majken K Jensen
- Department of Nutrition, Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA.
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Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K, Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M. Tibolone decreases Lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients. Atherosclerosis 2015; 242:87-96. [DOI: 10.1016/j.atherosclerosis.2015.06.056] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 06/28/2015] [Accepted: 06/29/2015] [Indexed: 10/23/2022]
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MacNamara J, Eapen DJ, Quyyumi A, Sperling L. Novel biomarkers for cardiovascular risk assessment: current status and future directions. Future Cardiol 2015; 11:597-613. [DOI: 10.2217/fca.15.39] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in the modern world. Traditional risk algorithms may miss up to 20% of CVD events. Therefore, there is a need for new cardiac biomarkers. Many fields of research are dedicated to improving cardiac risk prediction, including genomics, transcriptomics and proteomics. To date, even the most promising biomarkers have only demonstrated modest associations and predictive ability. Few have undergone randomized control trials. A number of biomarkers are targets to new therapies aimed to reduce cardiovascular risk. Currently, some of the most promising risk prediction has been demonstrated with panels of multiple biomarkers. This article reviews the current state and future of proteomic biomarkers and aggregate biomarker panels.
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Affiliation(s)
- James MacNamara
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Danny J Eapen
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Arshed Quyyumi
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Laurence Sperling
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
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McNeal CJ. Lipoprotein(a): Its relevance to the pediatric population. J Clin Lipidol 2015; 9:S57-66. [PMID: 26343213 DOI: 10.1016/j.jacl.2015.07.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 06/09/2015] [Accepted: 07/14/2015] [Indexed: 11/26/2022]
Abstract
Lipoprotein(a) (Lp(a)) is a highly atherogenic and heterogeneous lipoprotein that is inherited in an autosomal codominant trait. A unique aspect of this lipoprotein is that it is fully expressed by the first or second year of life in children, a pattern that is distinctly different from other lipoproteins, which typically only reach adult levels after adolescence. Despite decades of research, Lp(a) metabolism is still poorly understood but what is abundantly clear is that it is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents does not recommend measuring Lp(a) levels as part of routine screening except in youth with an ischemic or hemorrhagic stroke or youth with a parental history of ASCVD not explained by classical risk factors. One of the reasons that both the pediatric and adult guidelines fail to include this lipoprotein as part of routine lipid screening is the absence of data to show that lowering Lp(a) will reduce current or future ASCVD risk independently of low-density lipoprotein cholesterol (LDL-C) lowering. The cholesterol carried by Lp(a) is included in the low-density lipoprotein cholesterol measurement, but a separate test is used to measure the lipoprotein mass and/or cholesterol carried only by Lp(a). Because levels seem to be largely under genetic control, studies of lifestyle modification have been inconclusive although one study in obese children showed a decrease in the Lp(a) level comparable with the favorable effect on other lipids. The most compelling data regarding the importance of Lp(a) in the pediatric population are the increased risk associated with arterial ischemic stroke, a risk that is comparable with that associated with antiphospholipid antibodies or protein C deficiency. Although no specific pharmaceutical treatments are recommended to lower Lp(a) levels in youth, it is vitally important to educate youth and their parents about the excessive risk associated with this lipoprotein and the need to avoid the acquisition of other lifestyle-related risk factors such as smoking, excess weight, and physical inactivity to preserve more ideal cardiovascular health in adulthood.
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Affiliation(s)
- Catherine J McNeal
- Division of Cardiology, Department of Internal Medicine, Baylor Scott & White Health, Temple, TX, USA.
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Kassner U, Schlabs T, Rosada A, Steinhagen-Thiessen E. Lipoprotein(a) – An independent causal risk factor for cardiovascular disease and current therapeutic options. ATHEROSCLEROSIS SUPP 2015; 18:263-7. [DOI: 10.1016/j.atherosclerosissup.2015.02.039] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol 2015; 35:689-99. [PMID: 25614280 PMCID: PMC4344404 DOI: 10.1161/atvbaha.114.304549] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 01/03/2015] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH). APPROACH AND RESULTS In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (-26.4 [-42.8, -5.4] versus -0.0 [-10.7, 15.3]; P<0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ≤30 or ≤50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (r=0.43; P<0.001) and low-density lipoprotein cholesterol and Lp(a) (r=0.36; P<0.001) plasma levels. CONCLUSIONS Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.
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Affiliation(s)
- Raul D Santos
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.)
| | - Frederick J Raal
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.)
| | - Alberico L Catapano
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.)
| | - Joseph L Witztum
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.)
| | - Elisabeth Steinhagen-Thiessen
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.)
| | - Sotirios Tsimikas
- From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of California San Diego, La Jolla (J.L.W., S.T.).
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Hung MY, Tsimikas S. What is the ultimate test that lowering lipoprotein(a) is beneficial for cardiovascular disease and aortic stenosis? Curr Opin Lipidol 2014; 25:423-30. [PMID: 25340480 DOI: 10.1097/mol.0000000000000131] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
PURPOSE OF REVIEW Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD) and calcific aortic valve stenosis. We review recent studies that highlight Lp(a) in CVD and calcific aortic valve stenosis and propose pathways to clinical registration of Lp(a)-lowering agents. RECENT FINDINGS Over the last few years, almost irrefutable evidence has accumulated that Lp(a) is a causal, independent, genetic risk factor for CVD. Most recently, new data have emerged that elevated Lp(a) is causally associated with calcific aortic valve stenosis and the need for aortic valve replacement. Three levels of evidence to support these findings: epidemiological studies, Mendelian randomization studies and genetic association studies. A dedicated Lp(a)-lowering trial has not been performed to date. Emerging Lp(a)-lowering therapies with specific and potent lowering of Lp(a) are in phase II clinical trials and provide a tool to test the hypothesis that lowering Lp(a) plasma levels will lead to clinical benefit. SUMMARY We provide a rationale for the potential clinical use of Lp(a)-lowering therapies in high-risk patients or patients with established CVD whose major risk factor is elevated Lp(a) levels and propose clinical studies and trials to demonstrate that lowering Lp(a) levels will effectively reduce the risk of calcific aortic valve stenosis and CVD.
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Affiliation(s)
- Ming-Yow Hung
- aDivision of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City bDepartment of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan cSchool of Medicine, University of California San Diego, La Jolla, California, USA
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Jensen MK, Bertoia ML, Cahill LE, Agarwal I, Rimm EB, Mukamal KJ. Novel metabolic biomarkers of cardiovascular disease. Nat Rev Endocrinol 2014; 10:659-72. [PMID: 25178732 DOI: 10.1038/nrendo.2014.155] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Coronary heart disease (CHD) accounts for one in every six deaths in US individuals. Great advances have been made in identifying important risk factors for CHD, such as hypertension, diabetes mellitus, smoking and hypercholesterolaemia, which have led to major developments in therapy. In particular, statins represent one of the greatest successes in the prevention of CHD. While these standard risk factors are important, an obvious opportunity exists to take advantage of ongoing scientific research to better risk-stratify individuals and to identify new treatment targets. In this Review, we summarize ongoing scientific research in a number of metabolic molecules or features, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. We evaluate the current state of the research and the strength of evidence supporting each emerging biomarker. We also discuss whether the associations with CHD are strong and consistent enough to improve current risk stratification metrics, and whether these markers enhance our understanding of the underlying biology of CHD and thus point towards new treatment options.
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Affiliation(s)
- Majken K Jensen
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, 02115 Boston, MA, USA
| | - Monica L Bertoia
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, 02115 Boston, MA, USA
| | - Leah E Cahill
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, 02115 Boston, MA, USA
| | - Isha Agarwal
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, 02115 Boston, MA, USA
| | - Eric B Rimm
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, 02115 Boston, MA, USA
| | - Kenneth J Mukamal
- Department of Medicine, Beth Israel Deaconess Medical Centre, 1309 Beacon Street, 02446 Brookline, MA, USA
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Marzano L, Colussi G, Del Torre M, Sechi LA, Catena C. Relationships of plasma lipoprotein(a) levels with insulin resistance in hypertensive patients. Metabolism 2014; 63:1439-46. [PMID: 25212579 DOI: 10.1016/j.metabol.2014.08.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 08/12/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Lipoprotein(a) [Lp(a)] is an emergent cardiovascular risk factor that is related to the presence and severity of cardiovascular damage in hypertensive patients. In these patients, insulin resistance is frequently detected but its relationship with plasma Lp(a) is not clear. The aim of this study was to examine the relationships between Lp(a) and variables of glucose metabolism in hypertension. METHODS In 527 consecutive, non-diabetic, middle-aged hypertensive patients we measured anthropometric indexes, 24-hour creatinine clearance, lipid profile including Lp(a) levels, fasting glucose, insulin and C-peptide, and calculated the Homeostatic Model Assessment (HOMA) index. RESULTS Lp(a) levels were significantly and progressively lower with increasing HOMA-index values. Lp(a) was inversely related to fasting glucose, insulin, and C-peptide, HOMA-index, and creatinine clearance and directly related to LDL-cholesterol. Multiple regression analysis adjusted for age, sex, body mass index, blood pressure, smoking habit, alcohol intake, renal function, lipid profile, history of cardiovascular events, and drug use showed that HOMA-index and creatinine clearance were inversely and independently associated to Lp(a) levels. CONCLUSIONS Insulin resistance and higher fasting insulin levels are associated with lower plasma Lp(a) in hypertensive patients. This association might be relevant in the assessment of cardiovascular risk in these patients.
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Affiliation(s)
- Luigi Marzano
- Clinica Medica, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100, Udine, Italy
| | - GianLuca Colussi
- Clinica Medica, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100, Udine, Italy
| | - Martina Del Torre
- Clinica Medica, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100, Udine, Italy
| | - Leonardo A Sechi
- Clinica Medica, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100, Udine, Italy
| | - Cristiana Catena
- Clinica Medica, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100, Udine, Italy.
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Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014; 64:851-60. [PMID: 25169167 DOI: 10.1016/j.jacc.2014.03.061] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 03/04/2014] [Accepted: 03/11/2014] [Indexed: 01/07/2023]
Abstract
BACKGROUND Recent studies showed that lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease (CVD). However, whether Lp(a) modifies clinical risk assessment was not established. OBJECTIVES This study was conducted to determine whether Lp(a) improves CVD risk prediction. METHODS In 1995, Lp(a) was measured in 826 men and women (age range, 45 to 84 years) from the general community. Incidence of CVD was recorded over 15 years of follow-up. RESULTS In models adjusted for Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) variables, the hazard ratio (HR) for incident CVD was 1.37 per 1-SD higher Lp(a) level (SD = 32 mg/dl) and 2.37 when comparing the top fifth quintile with other quintiles. The addition of Lp(a) to the RRS increased the C-index by 0.016. Of the 502 subjects who remained free of CVD, 82 were correctly reclassified to a lower risk category and 49 were reclassified to a higher risk category (predicted 15-year categories: <7.5%, 7.5% to <15%, 15% to <30%, ≥30%) (p < 0.001). Of the 148 subjects who developed CVD, 18 were correctly reclassified to a higher risk category and 17 were reclassified to a lower risk category. In subjects at intermediate risk (15% to <30%), the net reclassification improvement afforded by Lp(a) was 22.5% for noncases, 17.1% for cases, and 39.6% overall. Allele-specific Lp(a) levels did not add to the predictive ability of the FRS or RRS or to Lp(a). CONCLUSIONS Elevated Lp(a) predicts 15-year CVD outcomes and improves CVD risk prediction. These findings suggest that Lp(a) levels may be used in risk assessment of subjects in the general community, particularly in intermediate-risk groups.
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Eckel RH, Cornier MA. Update on the NCEP ATP-III emerging cardiometabolic risk factors. BMC Med 2014; 12:115. [PMID: 25154373 PMCID: PMC4283079 DOI: 10.1186/1741-7015-12-115] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/20/2014] [Indexed: 12/31/2022] Open
Abstract
The intent of this review is to update the science of emerging cardiometabolic risk factors that were listed in the National Cholesterol Education Program (NCEP) Adult Treatment Panel-III (ATP-III) report of 2001 (updated in 2004). At the time these guidelines were published, the evidence was felt to be insufficient to recommend these risk factors for routine screening of cardiovascular disease risk. However, the panel felt that prudent use of these biomarkers for patients at intermediate risk of a major cardiovascular event over the subsequent 10 years might help identify patients who needed more aggressive low density lipoprotein (LDL) or non-high density lipoprotein (HDL) cholesterol lowering therapy. While a number of other emerging risk factors have been identified, this review will be limited to assessing the data and recommendations for the use of apolipoprotein B, lipoprotein (a), homocysteine, pro-thrombotic factors, inflammatory factors, impaired glucose metabolism, and measures of subclinical atherosclerotic cardiovascular disease for further cardiovascular disease risk stratification.
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Affiliation(s)
- Robert H Eckel
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Anschutz Medical Campus, Mail Stop 8106, 12801 E 17th Ave, Aurora, CO 80045 USA
| | - Marc-Andre Cornier
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Anschutz Medical Campus, Mail Stop 8106, 12801 E 17th Ave, Aurora, CO 80045 USA
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Boffa MB, Koschinsky ML. Update on lipoprotein(a) as a cardiovascular risk factor and mediator. Curr Atheroscler Rep 2014; 15:360. [PMID: 23990263 DOI: 10.1007/s11883-013-0360-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Recent genetic studies have put the spotlight back onto lipoprotein(a) [Lp(a)] as a causal risk factor for coronary heart disease. However, there remain significant gaps in our knowledge with respect to how the Lp(a) particle is assembled, the route of its catabolism, and the mechanism(s) of Lp(a) pathogenicity. It has long been speculated that the effects of Lp(a) in the vasculature can be attributed to both its low-density lipoprotein moiety and the unique apolipoprotein(a) component, which is strikingly similar to the kringle-containing fibrinolytic zymogen plasminogen. However, the ability of Lp(a) to modulate either purely thrombotic or purely atherothrombotic processes in vivo remains unclear. The presence of oxidized phospholipid on Lp(a) may underlie many of the proatherosclerotic effects of Lp(a) that have been identified both in cell models and in animal models, and provides a possible avenue for identifying therapeutics aimed at mitigating the effects of Lp(a) in the vasculature. However, the beneficial effects of targeted Lp(a) therapeutics, designed to either lower Lp(a) concentrations or interfere with its effects, on cardiovascular outcomes remains to be determined.
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Affiliation(s)
- Michael B Boffa
- Department of Chemistry & Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, ON, Canada.
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Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA. Reduction in Lipoprotein(a) With PCSK9 Monoclonal Antibody Evolocumab (AMG 145). J Am Coll Cardiol 2014; 63:1278-1288. [DOI: 10.1016/j.jacc.2014.01.006] [Citation(s) in RCA: 276] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 12/29/2013] [Accepted: 01/06/2014] [Indexed: 11/30/2022]
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Beyond the Standard Lipid Profile: What is Known about Apolipoproteins, Lp(a), and Lipoprotein Particle Distributions in Children. CURRENT CARDIOVASCULAR RISK REPORTS 2014. [DOI: 10.1007/s12170-014-0381-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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O'Donoghue ML, Morrow DA, Tsimikas S, Sloan S, Ren AF, Hoffman EB, Desai NR, Solomon SD, Domanski M, Arai K, Chiuve SE, Cannon CP, Sacks FM, Sabatine MS. Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol 2013; 63:520-7. [PMID: 24161323 DOI: 10.1016/j.jacc.2013.09.042] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 09/13/2013] [Accepted: 09/24/2013] [Indexed: 10/26/2022]
Abstract
OBJECTIVES The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.
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Affiliation(s)
- Michelle L O'Donoghue
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
| | - David A Morrow
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Sotirios Tsimikas
- Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California
| | - Sarah Sloan
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Angela F Ren
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Elaine B Hoffman
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Nihar R Desai
- Section of Cardiovascular Medicine, Department of Medicine, Yale School of Medicine; Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, Connecticut
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Domanski
- Mount Sinai School of Medicine, Cardiovascular Division, New York, New York
| | - Kiyohito Arai
- Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California; Division of Cardiology, Tokyo Women's Medical University, Tokyo, Japan
| | - Stephanie E Chiuve
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Christopher P Cannon
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Frank M Sacks
- Channing Laboratory and Cardiology Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Marc S Sabatine
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
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Miller YI, Tsimikas S. Oxidation-specific epitopes as targets for biotheranostic applications in humans: biomarkers, molecular imaging and therapeutics. Curr Opin Lipidol 2013; 24:426-37. [PMID: 23995232 PMCID: PMC4085330 DOI: 10.1097/mol.0b013e328364e85a] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
PURPOSE OF REVIEW Emerging data demonstrate the potential of translational applications of antibodies directed against oxidation-specific epitopes (OSEs). 'Biotheranostics' as used in this context in cardiovascular disease (CVD) describes targeting of OSEs for biomarker, therapeutic and molecular imaging diagnostic applications. RECENT FINDINGS Atherogenesis can be viewed as a chronic, maladaptive inflammatory response to OSE and related antigens. Lipid oxidation collectively yields a large variety of OSE, such as oxidized phospholipids (OxPL) and malondialdehyde epitopes. OSEs are immunogenic, proinflammatory, proatherogenic and plaque destabilizing and represent danger-associated molecular patterns (DAMPs). DAMPs are recognized by the innate immune system via pattern recognition receptors, including scavenger receptors, IgM natural antibodies and complement factor H, which bind, neutralize and/or facilitate their clearance. Biomarker assays measuring OxPL present on apolipoprotein B-100 lipoproteins, and particularly on lipoprotein (a), predict the development of CVD events. In contrast, OxPL on plasminogen facilitate fibrinolysis and may reduce atherothrombosis. Oxidation-specific antibodies attached to magnetic nanoparticles image lipid-rich, oxidation-rich plaques. Infusion or overexpression of oxidation-specific antibodies reduces the progression of atherosclerosis by potentially neutralizing and clearing OSE and preventing foam cell formation, suggesting similar applications in humans. SUMMARY Using the accelerating knowledge base and improved understanding of the interplay of oxidation, inflammation and innate and adaptive immunity in atherogenesis, emerging clinical applications of oxidation-specific antibodies may identify, monitor and treat CVD in humans.
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Affiliation(s)
- Yury I Miller
- Department of Medicine, University of California San Diego, La Jolla, California, USA
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Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, Zhou J, Hoffman EB, Huang F, Rogers WJ, Wasserman SM, Scott R, Sabatine MS. AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy. Circulation 2013; 128:962-9. [DOI: 10.1161/circulationaha.113.001969] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background—
Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a).
Methods and Results—
As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (
P
<0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (
P
<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33,
P
<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values.
Conclusions—
AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient’s atherogenic lipid profile.
Clinical Trial Registration—
URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01380730.
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Affiliation(s)
- Nihar R. Desai
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Payal Kohli
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Robert P. Giugliano
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Michelle L. O’Donoghue
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Ransi Somaratne
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Jing Zhou
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Elaine B. Hoffman
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Fannie Huang
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - William J. Rogers
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Scott M. Wasserman
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Robert Scott
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
| | - Marc S. Sabatine
- From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (N.R.D., P.K., R.P.G., M.L.O’D., J.Z., E.B.H., M.S.S.); Amgen, Inc, Thousand Oaks, CA (R. Somaratne, F.H., S.M.W., R. Scott); and University of Alabama at Birmingham (W.J.R.)
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Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, Yang X, Dennis E, Witztum JL, Koschinsky ML, Tsimikas S. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res 2013; 54:2815-30. [PMID: 23828779 DOI: 10.1194/jlr.m040733] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Oxidized phospholipids (OxPLs) are present on apolipoprotein (a) [apo(a)] and lipoprotein (a) [Lp(a)] but the determinants influencing their binding are not known. The presence of OxPLs on apo(a)/Lp(a) was evaluated in plasma from healthy humans, apes, monkeys, apo(a)/Lp(a) transgenic mice, lysine binding site (LBS) mutant apo(a)/Lp(a) mice with Asp(55/57)→Ala(55/57) substitution of kringle (K)IV10)], and a variety of recombinant apo(a) [r-apo(a)] constructs. Using antibody E06, which binds the phosphocholine (PC) headgroup of OxPLs, Western and ELISA formats revealed that OxPLs were only present in apo(a) with an intact KIV10 LBS. Lipid extracts of purified human Lp(a) contained both E06- and nonE06-detectable OxPLs by tandem liquid chromatography-mass spectrometry (LC-MS/MS). Trypsin digestion of 17K r-apo(a) showed PC-containing OxPLs covalently bound to apo(a) fragments by LC-MS/MS that could be saponified by ammonium hydroxide. Interestingly, PC-containing OxPLs were also present in 17K r-apo(a) with Asp(57)→Ala(57) substitution in KIV10 that lacked E06 immunoreactivity. In conclusion, E06- and nonE06-detectable OxPLs are present in the lipid phase of Lp(a) and covalently bound to apo(a). E06 immunoreactivity, reflecting pro-inflammatory OxPLs accessible to the immune system, is strongly influenced by KIV10 LBS and is unique to human apo(a), which may explain Lp(a)'s pro-atherogenic potential.
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Affiliation(s)
- Gregor Leibundgut
- Departments of Medicine, University of California, San Diego, La Jolla, CA
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Kei A, Liberopoulos E, Tellis K, Rizzo M, Elisaf M, Tselepis A. Effect of hypolipidemic treatment on emerging risk factors in mixed dyslipidemia: a randomized pilot trial. Eur J Clin Invest 2013; 43:698-707. [PMID: 23600368 DOI: 10.1111/eci.12095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 03/19/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND The effects of different hypolipidemic treatment strategies on emerging atherosclerosis risk factors remain unknown. MATERIALS AND METHODS This is a prespecified analysis of a prospective, randomized, open-label, blinded end point (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (n = 100) with mixed dyslipidaemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronized fenofibrate for a total of 3 months. RESULTS Following 3 months of treatment, low-density lipoprotein (LDL) particle size increased equally in all groups. Similarly, all treatments were associated with comparable small dense LDL cholesterol reduction. Apolipoprotein B levels decreased by 15%, 7% and 4% in the rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively (P < 0.01 for all compared with baseline, P < 0.01 for all comparisons between groups). Only add-on ER-NA/LRPT was associated with lipoprotein (a) reduction (26%, P < 0.01 compared with baseline). Rosuvastatin monotherapy and add-on ER-NA/LRPT groups were associated with 56% and 24% reduction in high-sensitivity C-reactive protein levels (hsCRP), respectively (P < 0.01 compared with baseline), while add-on fenofibrate was not associated with changes in hsCRP concentration. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity decreased similarly in both rosuvastatin and add-on fenofibrate groups, while add-on ER-NA/LRPT was associated with a more pronounced Lp-PLA2 activity reduction. ER-NA/LRPT was associated with more side effects compared with rosuvastatin and add-on fenofibrate. CONCLUSIONS Add-on ER-NA/LRPT followed by switch to the highest dose rosuvastatin were associated with more pronounced beneficial modifications in emerging cardiovascular risk factors compared with add-on fenofibrate in patients with mixed dyslipidaemia.
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Affiliation(s)
- Anastazia Kei
- Department of Internal Medicine, University of Ioannina Medical School, Ioannina, Greece
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Leibundgut G, Witztum JL, Tsimikas S. Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis. Curr Opin Pharmacol 2013; 13:168-79. [PMID: 23541680 DOI: 10.1016/j.coph.2013.02.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 02/18/2013] [Accepted: 02/18/2013] [Indexed: 01/22/2023]
Abstract
Oxidation-specific epitopes (OSE), present on oxidized LDL (OxLDL), apoptotic cells, cell debris and modified proteins in the vessel wall, accumulate in response to hypercholesterolemia, and generate potent pro-inflammatory, disease-specific antigens. They represent an important class of 'danger associated molecular patterns' (DAMPs), against which a concerted innate immune response is directed. OSE are recognized by innate 'pattern recognition receptors', such as scavenger receptors present on dendritic cells and monocyte/macrophages, as well as by innate proteins, such as IgM natural antibodies and soluble proteins, such as C-reactive protein and complement factor H. These innate immune responses provide a first line of defense against atherosclerosis-specific DAMPs, and engage adaptive immune responses, provided by T and B-2 cells, which provide a more specific and definitive response. Such immune responses are ordinarily directed to remove foreign pathogens, such as those found on microbial pathogens, but when persistent or maladaptive, lead to host damage. In this context, atherosclerosis can be considered as a systemic chronic inflammatory disease initiated by the accumulation of OSE type DAMPs and perpetuated by maladaptive response of the innate and adaptive immune system. Understanding this paradigm leads to new approaches to defining cardiovascular risk and suggests new modes of therapy. Therefore, OSE have become potential targets of diagnostic and therapeutic agents. Human and murine OSE-targeting antibodies have been developed and are now being used as biomarkers in human studies and experimentally in translational applications of non-invasive molecular imaging of oxidation-rich plaques and immunotherapeutics.
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Affiliation(s)
- Gregor Leibundgut
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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