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Martin SS, Aday AW, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Bansal N, Beaton AZ, Commodore-Mensah Y, Currie ME, Elkind MSV, Fan W, Generoso G, Gibbs BB, Heard DG, Hiremath S, Johansen MC, Kazi DS, Ko D, Leppert MH, Magnani JW, Michos ED, Mussolino ME, Parikh NI, Perman SM, Rezk-Hanna M, Roth GA, Shah NS, Springer MV, St-Onge MP, Thacker EL, Urbut SM, Van Spall HGC, Voeks JH, Whelton SP, Wong ND, Wong SS, Yaffe K, Palaniappan LP. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2025; 151:e41-e660. [PMID: 39866113 DOI: 10.1161/cir.0000000000001303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
BACKGROUND The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2025 AHA Statistical Update is the product of a full year's worth of effort in 2024 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. This year's edition includes a continued focus on health equity across several key domains and enhanced global data that reflect improved methods and incorporation of ≈3000 new data sources since last year's Statistical Update. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Hu Y, Li W, Cheng X, Yang H, She ZG, Cai J, Li H, Zhang XJ. Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases. Circ Res 2024; 135:222-260. [PMID: 38900855 DOI: 10.1161/circresaha.124.324383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway-mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.
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Affiliation(s)
- Yufeng Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Wei Li
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
| | - Xu Cheng
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Hailong Yang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Zhi-Gang She
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
| | - Jingjing Cai
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China (J.C.)
| | - Hongliang Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China (H.L.)
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- School of Basic Medical Sciences, Wuhan University, China (X.-J.Z.)
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Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, Commodore-Mensah Y, Currie ME, Elkind MSV, Evenson KR, Generoso G, Heard DG, Hiremath S, Johansen MC, Kalani R, Kazi DS, Ko D, Liu J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Perman SM, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, Tsao CW, Urbut SM, Van Spall HGC, Voeks JH, Wang NY, Wong ND, Wong SS, Yaffe K, Palaniappan LP. 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2024; 149:e347-e913. [PMID: 38264914 DOI: 10.1161/cir.0000000000001209] [Citation(s) in RCA: 826] [Impact Index Per Article: 826.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
BACKGROUND The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year's worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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McGowan NG, Zhong JH, Trasande L, Hellmann J, Heffron SP. A randomized, placebo-controlled crossover trial to assess the influence of body weight on aspirin-triggered specialized pro-resolving mediators: Protocol for the DISCOVER Study. INTERNATIONAL JOURNAL OF CLINICAL TRIALS 2024; 11:53-60. [PMID: 38585621 PMCID: PMC10997378 DOI: 10.18203/2349-3259.ijct20240043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Background Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. Methods To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Results Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Conclusions Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin's role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight.
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Affiliation(s)
- Natalie G McGowan
- Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Judy H Zhong
- Department of Population Health, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Leonardo Trasande
- Department of Population Health, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- Department of Pediatrics, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- Department of Environmental Medicine, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Jason Hellmann
- Christina Lee Brown Envirome Institute, Diabetes and Obesity Center, Division of Environmental Medicine, University of Louisville School of Medicine, 500 S Preston St, Louisville, KY 40202 USA
| | - Sean P Heffron
- Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
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5
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Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Beaton AZ, Boehme AK, Buxton AE, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Fugar S, Generoso G, Heard DG, Hiremath S, Ho JE, Kalani R, Kazi DS, Ko D, Levine DA, Liu J, Ma J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, Virani SS, Voeks JH, Wang NY, Wong ND, Wong SS, Yaffe K, Martin SS. Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association. Circulation 2023; 147:e93-e621. [PMID: 36695182 DOI: 10.1161/cir.0000000000001123] [Citation(s) in RCA: 2286] [Impact Index Per Article: 1143.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Heffron SP, Windheim J, Barrett TJ, Voora D, Berger JS. Platelet inhibition by low-dose aspirin is not influenced by body mass or weight. Platelets 2022; 33:1208-1213. [PMID: 35768902 PMCID: PMC9976777 DOI: 10.1080/09537104.2022.2087868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/24/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023]
Abstract
Aspirin's clinical efficacy may be influenced by body weight and mass. Although inadequate platelet inhibition by aspirin is suggested as responsible, evidence for this in non-diabetic patients is sparse. We investigated the influence of body weight and mass on aspirin's inhibition of platelet aggregation in healthy adults without diabetes. Cohort one (NYU, n = 84) had light transmission aggregometry (LTA) of platelet-rich plasma to submaximal adenosine diphosphate (ADP) and arachidonic acid (AA) before and following 1 week of daily 81 mg non-enteric coated aspirin. Subjects in the validation cohort (Duke, n = 66) were randomized to 81 mg or 325 mg non-enteric coated aspirin for 4 weeks, immediately followed by 4 weeks of the other dose, with LTA to submaximal collagen, ADP, and AA before and after each dosage period. Body mass index (BMI) range was 18.0-57.5 kg/m2 and 25% were obese. Inhibition of platelet aggregation was similar irrespective of BMI, body weight and aspirin dose. There was no correlation between platelet aggregation before or after aspirin with BMI or body weight. Our data demonstrate that aspirin produces potent inhibition of direct and indirect COX1-mediated platelet aggregation in healthy adults without diabetes regardless of body weight or mass - suggesting that other mechanisms explain lower preventive efficacy of low-dose aspirin with increasing body weight/mass.
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Affiliation(s)
- Sean P. Heffron
- NYU Grossman School of Medicine, Leon H. Charney Division of Cardiology, New York, NY
- NYU Grossman School of Medicine, NYU Center for the Prevention of Cardiovascular Disease, New York, NY
| | - Joseph Windheim
- NYU Grossman School of Medicine, Leon H. Charney Division of Cardiology, New York, NY
| | - Tessa J. Barrett
- NYU Grossman School of Medicine, Leon H. Charney Division of Cardiology, New York, NY
| | - Deepak Voora
- Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, Durham, NC
| | - Jeffrey S. Berger
- NYU Grossman School of Medicine, Leon H. Charney Division of Cardiology, New York, NY
- NYU Grossman School of Medicine, NYU Center for the Prevention of Cardiovascular Disease, New York, NY
- NYU Grossman School of Medicine, Department of Surgery, New York, NY
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Cofer LB, Barrett TJ, Berger JS. Aspirin for the Primary Prevention of Cardiovascular Disease: Time for a Platelet-Guided Approach. Arterioscler Thromb Vasc Biol 2022; 42:1207-1216. [PMID: 36047408 PMCID: PMC9484763 DOI: 10.1161/atvbaha.122.318020] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022]
Abstract
Aspirin protects against atherothrombosis while increasing the risk of major bleeding. Although it is widely used to prevent cardiovascular disease (CVD), its benefit does not outweigh its risk for primary CVD prevention in large population settings. The recent United States Preventive Services Task Force guidelines on aspirin use to prevent CVD reflect this clinical tradeoff as well as the persistent struggle to define a population that would benefit from prophylactic aspirin therapy. Past clinical trials of primary CVD prevention with aspirin have not included consideration of a biomarker relevant to aspirin's mechanism of action, platelet inhibition. This approach is at odds with the paradigm used in other key areas of pharmacological CVD prevention, including antihypertensive and statin therapy, which combine cardiovascular risk assessment with the measurement of mechanistic biomarkers (eg, blood pressure and LDL [low-density lipoprotein]-cholesterol). Reliable methods for quantifying platelet activity, including light transmission aggregometry and platelet transcriptomics, exist and should be considered to identify individuals at elevated cardiovascular risk due to a hyperreactive platelet phenotype. Therefore, we propose a new, platelet-guided approach to the study of prophylactic aspirin therapy. We think that this new approach will reveal a population with hyperreactive platelets who will benefit most from primary CVD prevention with aspirin and usher in a new era of precision-guided antiplatelet therapy.
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8
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Elshafei MN, Imam Y, Alsaud AE, Chandra P, Parray A, Abdelmoneim MS, Obeidat K, Saeid R, Ali M, Ayadathil R, Mohamed MFH, Abdallah IM, Mohammed S, Akhtar N, Danjuma MIM. The impact of enteric coating of aspirin on aspirin responsiveness in patients with suspected or newly diagnosed ischemic stroke: prospective cohort study: results from the (ECASIS) study. Eur J Clin Pharmacol 2022; 78:1801-1811. [PMID: 36121499 PMCID: PMC9546947 DOI: 10.1007/s00228-022-03391-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 08/22/2022] [Indexed: 11/25/2022]
Abstract
Background and purpose Uncertainty remains regarding the impact of enteric-coated aspirin (EC-ASA) on secondary prevention of ischemic stroke compared to plain aspirin (P-ASA). Hence, this study was designed to investigate the effect of EC formulation on ASA response via evaluating thromboxane B2 (TXB2) levels in patients with suspected or newly diagnosed stroke. Methods A prospective cohort study on suspected or newly diagnosed ischemic stroke patients who are aspirin-naive was conducted. Patients were received either EC aspirin or plain aspirin for at least 3 days. The primary outcome was the proportion of aspirin non-responsiveness between two groups (level of residual serum TXB2 associated with elevated thrombotic risk (< 99.0% inhibition or TXB2 > 3.1 ng/ml) within 72 h after three daily aspirin doses, while secondary outcomes were the incidence of early gastrointestinal tract (GIT) bleeding with the various aspirin preparations. (Trial registration: Clinicaltrials.gov NCT04330872 registered on 02 April 2020). Results Of 42 patients, ischemic strokes were confirmed in both P-ASA (81%) and EC-ASA (67%) arms. ASA non-responsiveness showed no significant difference between the two formulations (P-ASA vs. EC-ASA; 28.6% vs 23.8%; P = 0.726). Univariate and multivariate logistic regression analysis showed that patients treated with EC-ASA were more likely to have a lower rate of non-responders compared to P-ASA (unadjusted OR 0.78; 95% CI 0.20, 3.11); with the risk highest in type 2 diabetic patients with HBA1c > 6.5% (adjusted OR 6; 95% CI 1.02, 35.27; P = 0.047). No incidence of GIT bleeding observed throughout the study. Conclusion A significant proportion of ASA non-responsiveness was recorded regardless of ASA formulation administered. The increased risk of ASA non-responsiveness in diabetic patients needs further exploration by larger prospective studies.
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Affiliation(s)
- Mohamed Nabil Elshafei
- Clinical Pharmacy Department, Hamad General Hospital, Hamad Medical Corporation, P.O. 3050, Doha, Qatar.
| | - Yahia Imam
- Neurology Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Arwa Ebrahim Alsaud
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Prem Chandra
- Biostatstics Section, Medical Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Aijaz Parray
- The Neuroscience Institute, Academic Health Systems, Hamad Medical Corporation, Doha, Qatar
| | - Mohamed S Abdelmoneim
- Neurology Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.,The Neuroscience Institute, Academic Health Systems, Hamad Medical Corporation, Doha, Qatar
| | - Khaldun Obeidat
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Razan Saeid
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Ali
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Raheem Ayadathil
- The Neuroscience Institute, Academic Health Systems, Hamad Medical Corporation, Doha, Qatar
| | - Mouhand F H Mohamed
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Ibtihal M Abdallah
- Clinical Pharmacy Department, Hamad General Hospital, Hamad Medical Corporation, P.O. 3050, Doha, Qatar
| | - Shaban Mohammed
- Department of Pharmacy, Hamad Medical Corporation, Doha, Qatar
| | - Naveed Akhtar
- Neurology Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Mohammed Ibn-Masoud Danjuma
- Internal Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.,College of Medicine, Qatar University, Doha, Qatar
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Overview of Nutraceuticals and Cardiometabolic Diseases following Socio-Economic Analysis. ENDOCRINES 2022. [DOI: 10.3390/endocrines3020023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The importance of functional food and nutraceutical products to deal with cardiometabolic diseases (CMDs) and metabolic syndrome (MetS) has gained attention in the past few years. The aim of this narrative review is to highlight the potential and effectiveness of nutraceutical in the improvement of CMDs and MetS biomarkers, alongside their burden of disease and economic health expenditure. A science database search was conducted between May and June 2021. A total of 35 studies were included in this paper. We included male and female subjects, children, and adults, in good health or with cardiovascular or metabolic disease. CMDs and MetS have gradually become worldwide health problems, becoming two of the major causes of morbidity and mortality in western countries. The results indicate a positive link between daily consumption of nutraceutical products and an improvement in cardiometabolic and anthropometric biomarkers. In this paper we included a wide range of nutraceutical products. Most of them showed promising data, indicating that nutraceuticals could provide a new therapeutic treatment to reduce prevalence and pharmaceutical expenditures attributed to CMDs and MetS. Unfortunately, there is a huge vacuum of data on nutraceutical usage, savings, and burden reduction. Therefore, further clinical and pharmaco-economic research in the field is highly required.
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10
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Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Ferguson JF, Generoso G, Ho JE, Kalani R, Khan SS, Kissela BM, Knutson KL, Levine DA, Lewis TT, Liu J, Loop MS, Ma J, Mussolino ME, Navaneethan SD, Perak AM, Poudel R, Rezk-Hanna M, Roth GA, Schroeder EB, Shah SH, Thacker EL, VanWagner LB, Virani SS, Voecks JH, Wang NY, Yaffe K, Martin SS. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation 2022; 145:e153-e639. [PMID: 35078371 DOI: 10.1161/cir.0000000000001052] [Citation(s) in RCA: 3161] [Impact Index Per Article: 1053.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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11
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Fries S, Grosser T. Mechanism of Variability in the Response to Low Dose Aspirin. Clin Pharmacol Ther 2022; 111:740-742. [PMID: 35167713 DOI: 10.1002/cpt.2550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/31/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Susanne Fries
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tilo Grosser
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Translational Pharmacology, Bielefeld University, Bielefeld, Germany
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12
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Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021; 143:e254-e743. [PMID: 33501848 DOI: 10.1161/cir.0000000000000950] [Citation(s) in RCA: 3534] [Impact Index Per Article: 883.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Abstract
BACKGROUND Metabolic syndrome is associated with increases in both inflammation and aspirin resistance, but effectiveness of aspirin in improving reproductive health among women with metabolic syndrome is unknown. We evaluated the effectiveness of low-dose aspirin in improving reproductive outcomes across metabolic syndrome score. METHODS The EAGeR trial randomly assigned 1228 women with a history of pregnancy loss to receive 81 mg aspirin or placebo for up to six menstrual cycles of attempting pregnancy and, if they became pregnant, throughout pregnancy. We assessed components of metabolic syndrome at enrollment, including: waist circumference ≥88 cm, triglycerides ≥150 mg/dl, high-density lipoprotein ≤50 mg/dl, blood pressure ≥130 mmHg systolic or ≥85 mmHg diastolic, and glucose ≥100 mg/dl. We summed components to calculate metabolic syndrome score. RESULTS A total of 229 participants (20%) met full criteria for metabolic syndrome, 207 (18%) had two components, 366 (31%) one component, and 372 (32%) no components. Among those without any component of metabolic syndrome, aspirin was associated with 10.7 [95% confidence interval (CI) = 1.2, 20.2] more pregnancies and 13.7 (95% CI = 3.3, 24.0) more live births per 100 couples. Effects were attenuated as metabolic syndrome score increased and we observed no clear effect of aspirin on pregnancy or live birth among women with metabolic syndrome. CONCLUSIONS Low-dose aspirin is most effective in increasing pregnancy and live birth among women with no or few components of metabolic syndrome. Reduced effectiveness among women with metabolic syndrome may be due to differences in effective dose or aspirin resistance.
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Olgar Y, Tuncay E, Billur D, Durak A, Ozdemir S, Turan B. Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes. Mol Cell Biochem 2020; 469:97-107. [PMID: 32301059 DOI: 10.1007/s11010-020-03731-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 04/07/2020] [Indexed: 12/20/2022]
Abstract
Ticagrelor, a P2Y12-receptor inhibitor, and a non-thienopyridine agent are used to treat diabetic patients via its effects on off-target mechanisms. However, the exact sub-cellular mechanisms by which ticagrelor exerts those effects remains to be elucidated. Accordingly, the present study aimed to examine whether ticagrelor influences directly the cardiomyocytes function under insulin resistance through affecting mitochondria-sarco(endo)plasmic reticulum (SER) cross-talk. Therefore, we analyzed the function and ultrastructure of mitochondria and SER in insulin resistance-mimicked (50-μM palmitic acid for 24-h) H9c2 cardiomyocytes in the presence or absence of ticagrelor (1-µM for 24-h). We found that ticagrelor treatment significantly prevented depolarization of mitochondrial membrane potential and increases in reactive oxygen species with a marked increase in the ATP level in insulin-resistant H9c2 cells. Ticagrelor treatment also reversed the increases in the resting level of free Ca2+ and mRNA level of P2Y12 receptors as well as preserved ER stress and apoptosis in insulin-resistant H9c2 cells. Furthermore, we determined marked repression with ticagrelor treatment in the increased number of autophagosomes and degeneration of mitochondrion, including swelling and loss of crista besides recoveries in enlargement and irregularity seen in SER in insulin-resistant H9c2 cells. Moreover, ticagrelor treatment could prevent the altered mRNA levels of Becklin-1 and type 1 equilibrative nucleoside transporter (ENT1), which are parallel to the preservation of ultrastructural ones. Our overall data demonstrated that ticagrelor can directly affect cardiomyocytes and provide marked protection against ER stress and dramatic induction of autophagosomes, and therefore, can alleviate the ER stress-induced oxidative stress increase and cell apoptosis during insulin resistance.
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Affiliation(s)
- Yusuf Olgar
- Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Erkan Tuncay
- Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Deniz Billur
- Departments of Histology-Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Aysegul Durak
- Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Semir Ozdemir
- Departments of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey.
| | - Belma Turan
- Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
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15
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Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation 2020; 141:e139-e596. [PMID: 31992061 DOI: 10.1161/cir.0000000000000757] [Citation(s) in RCA: 5393] [Impact Index Per Article: 1078.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. RESULTS Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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16
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Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 2019; 139:e56-e528. [PMID: 30700139 DOI: 10.1161/cir.0000000000000659] [Citation(s) in RCA: 5812] [Impact Index Per Article: 968.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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17
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Patrono C, Rocca B. Measurement of Thromboxane Biosynthesis in Health and Disease. Front Pharmacol 2019; 10:1244. [PMID: 31736753 PMCID: PMC6832017 DOI: 10.3389/fphar.2019.01244] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 09/27/2019] [Indexed: 12/17/2022] Open
Abstract
Thromboxane (TX) A2 is a chemically unstable lipid mediator involved in several pathophysiologic processes, including primary hemostasis, atherothrombosis, inflammation, and cancer. In human platelets, TXA2 is the major arachidonic acid derivative via the cyclooxygenase (COX)-1 pathway. Assessment of platelet TXA2 biosynthesis can be performed ex vivo through measurement of serum TXB2, an index of platelet COX-1 activity, as well as in vivo through measurement of urinary enzymatic metabolites, a non-invasive index of platelet activation. This article reviews the main findings of four decades of clinical investigation based on these analytical approaches, focusing on the measurement of TXA2 metabolites to characterize the pathophysiologic role of transiently or persistently enhanced platelet activation and to describe the clinical pharmacology of COX-1 inhibition in health and disease.
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Affiliation(s)
- Carlo Patrono
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - Bianca Rocca
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
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18
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Crescente M, Menke L, Chan MV, Armstrong PC, Warner TD. Eicosanoids in platelets and the effect of their modulation by aspirin in the cardiovascular system (and beyond). Br J Pharmacol 2018; 176:988-999. [PMID: 29512148 PMCID: PMC6451075 DOI: 10.1111/bph.14196] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 02/21/2018] [Accepted: 02/22/2018] [Indexed: 12/21/2022] Open
Abstract
Platelets are important players in thrombosis and haemostasis with their function being modulated by mediators in the blood and the vascular wall. Among these, eicosanoids can both stimulate and inhibit platelet reactivity. Platelet Cyclooxygenase (COX)-1-generated Thromboxane (TX)A2 is the primary prostanoid that stimulates platelet aggregation; its action is counter-balanced by prostacyclin, a product of vascular COX. Prostaglandin (PG)D2 , PGE2 and 12-hydroxyeicosatraenoic acid (HETE), or 15-HETE, are other prostanoid modulators of platelet activity, but some also play a role in carcinogenesis. Aspirin permanently inhibits platelet COX-1, underlying its anti-thrombotic and anti-cancer action. While the use of aspirin as an anti-cancer drug is increasingly encouraged, its continued use in addition to P2 Y12 receptor antagonists for the treatment of cardiovascular diseases is currently debated. Aspirin not only suppresses TXA2 but also prevents the synthesis of both known and unknown antiplatelet eicosanoid pathways, potentially lessening the efficacy of dual antiplatelet therapies. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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Affiliation(s)
- Marilena Crescente
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Laura Menke
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Melissa V Chan
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Paul C Armstrong
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Timothy D Warner
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation 2018; 137:e67-e492. [PMID: 29386200 DOI: 10.1161/cir.0000000000000558] [Citation(s) in RCA: 4768] [Impact Index Per Article: 681.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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Sharma A, Garg A, Elmariah S, Drachman D, Obiagwu C, Vallakati A, Sharma SK, Lavie CJ, Mukherjee D, Waksman R, Stefanini GG, Feres F, Marmur JD, Helft G. Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Diabetic and Non-Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Prog Cardiovasc Dis 2017; 60:500-507. [PMID: 29277295 DOI: 10.1016/j.pcad.2017.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Accepted: 12/17/2017] [Indexed: 01/19/2023]
Abstract
BACKGROUND Diabetic patients account for an increasing number of patients undergoing percutaneous coronary intervention (PCI). However, diabetes mellitus (DM) is associated with increased residual platelet activity during dual antiplatelet treatment (DAPT) and DM patients have worse clinical outcomes after PCI as compared to non-DM. OBJECTIVE To evaluate efficacy and safety of short duration DAPT (S-DAPT) and long duration DAPT (L-DAPT) after drug eluting stent (DES) implantation in DM and non-DM patients. METHODS We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the effect of S-DAPT versus L-DAPT after DES implantation in DM and non-DM patients. Efficacy endpoints were all-cause mortality, cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), target vessel revascularization (TVR), and composite end point of net adverse clinical events (NACE) (all-cause mortality, cardiac mortality, MI, ST, TVR, stroke, major bleeding). Safety endpoints were major bleeding and stroke. Event rates were compared using a forest plot of relative risk using a random effects model. RESULTS We included eight RCTs that randomized 28,318 patients to S-DAPT versus L-DAPT (8234 DM and 20,084 non-DM). S-DAPT was associated with an increased rate of ST in non-DM patients [3.67 (2.04, 6.59)]. There was no significant difference in the rate of all-cause mortality, cardiac mortality, ST, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in DM patients [1.19 (0.72-1.95); 1.25 (0.69, 2.25); 1.52 (0.70, 3.29); 1.33 (0.88, 2.01); 1.39 (0.89, 2.17); 0.92 (0.19, 4.42); 0.98 (0.29, 3.28); and 0.94 (0.57, 1.54) respectively]. Further, there was no significant difference in the rate of all-cause mortality, cardiac mortality, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in non-DM patients [0.93 (0.58, 1.48); 0.75 (0.42, 1.35); 1.52 (0.81, 2.83); 0.99 (0.71, 1.39); 0.72 (0.28, 1.84); 1.01 (0.40, 2.56); and 1.01 (0.77, 1.32) respectively]. CONCLUSION Compared to L-DAPT, S-DAPT was associated with significant increase in rate of ST in non-DM patients. Duration of DAPT had no significant impact on rates of all-cause mortality, cardiac mortality, MI, ST and TVR among DM patients.
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Affiliation(s)
- Abhishek Sharma
- Division of Cardiovascular Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Institute of Cardiovascular Science and Technology, Brooklyn, NY, USA.
| | - Aakash Garg
- Institute of Cardiovascular Science and Technology, Brooklyn, NY, USA; Division of Cardiology, Newark Beth Israel Medical Center, Newark, NJ, USA
| | - Sammy Elmariah
- Division of Cardiovascular Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Harvard Clinical Research Institute, Boston, USA
| | - Douglas Drachman
- Division of Cardiovascular Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Chukwudi Obiagwu
- Department of Cardiovascular Medicine, Maimonides Medical Center, Brooklyn, NY, USA
| | - Ajay Vallakati
- Division of Cardiology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Samin K Sharma
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Carl J Lavie
- Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School-the University of Queensland School of Medicine, New Orleans, LA, USA
| | | | - Ron Waksman
- Division of Cardiology, MedStar Washington Hospital Center, Washington, DC, USA
| | - Giulio G Stefanini
- Cardiovascular Department, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Fausto Feres
- Instituto Dante Pazzanese de Cardiologia, Ave Dante Pazzanense, 500, Ibirapuera, São Paulo, São Paulo, Brazil
| | - Jonathan D Marmur
- Division of Cardiovascular Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Gérard Helft
- Institut de Cardiologie, Hôpital Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, boulevard de l'Hôpital, Paris, France; Institute of Cardiometabolism and Nutrition, Hôpital Pitié-Salpétrière, Paris, France
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21
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Wang N, Vendrov KC, Simmons BP, Schuck RN, Stouffer GA, Lee CR. Urinary 11-dehydro-thromboxane B2 levels are associated with vascular inflammation and prognosis in atherosclerotic cardiovascular disease. Prostaglandins Other Lipid Mediat 2017; 134:24-31. [PMID: 29155368 DOI: 10.1016/j.prostaglandins.2017.11.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 10/09/2017] [Accepted: 11/14/2017] [Indexed: 01/20/2023]
Abstract
Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy. Urinary TxA2-M levels were significantly correlated with circulating P-selectin (r=0.319, p<0.001) and E-selectin (r=0.245, p=0.007) levels, and associated with higher risk of MACE (p=0.043). In contrast, PGI2-M levels were not significantly associated with CAM levels or MACE. These results provide insight into the contribution of TxA2 biosynthesis to ASCVD progression in humans, and suggest that patients with elevated TxA2-M levels may be predisposed to advanced platelet and endothelial activation and higher risk of adverse cardiovascular outcomes.
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Affiliation(s)
- Nan Wang
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kimberly C Vendrov
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Brian P Simmons
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Robert N Schuck
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - George A Stouffer
- Division of Cardiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Craig R Lee
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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23
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Murata K, Deguchi T, Yasuda M, Endo R, Fujita T, Matsumura S, Yoshioka Y, Matsuda H. Improvement of Blood Rheology by Extract of Asana, Pterocarpus marsupium -Suppression of Platelet Aggregation Activity and Pterostilbene, as a Main Stilbene in the Extract. Nat Prod Commun 2017. [DOI: 10.1177/1934578x1701200722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The decoction from a tumbler made of heartwood of the Indian kino tree (Asana, Pterocarpus marsupium, PM) was a remedy for diabetes mellitus in Ayurveda. Diabetes mellitus is a one of the lifestyle-related diseases that finally leads to the induction of fatal diseases such as arterial sclerosis and cerebral infarction. In this study, effects on blood fluidity was investigated using extract obtained from the heartwood of PM. Oral administration of the extract reduced passage time of the blood obtained from disseminated intravascular coagulation model rats. In addition, the extract inhibited the reduction of platelets, which suggests that this attributed to the inhibition of platelet aggregation. The extract also demonstrated suppressive effects on both collagen- and arachidonic acid-induced platelet aggregation. Moreover, the extract showed inhibition against cyclooxygenase. The active principle was determined to be pterostilbene by collagen-induced platelet aggregation inhibitory activity-guided purification. Pterostilbene is a derivative of resveratrol, which is known to be in red wine and to possess beneficial effects for prevention of life-style related diseases. Pterostilbene exhibited 56 and 57% inhibition on both collagen- and arachidonic acid-induced platelet aggregation at 20 μM, respectively. These results demonstrate that the extract of PM heartwood may be a promising candidate as a multifunctional agent for treating lifestyle-related diseases.
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Affiliation(s)
- Kazuya Murata
- Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Takahiro Deguchi
- Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Masayuki Yasuda
- Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Ryutaro Endo
- Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Takanori Fujita
- JAPAN TABLET CO., LTD, 149-1 Mekawa, Makishimacho, Uji, Kyoto 611-0041, Japan
| | - Shinichi Matsumura
- INABATA KORYO CO., LTD, 3-5-20 Tagawa, Yodogawaku, Osaka 532-0027, Japan
| | - Yuri Yoshioka
- INABATA KORYO CO., LTD, 3-5-20 Tagawa, Yodogawaku, Osaka 532-0027, Japan
| | - Hideaki Matsuda
- Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
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Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017; 135:e146-e603. [PMID: 28122885 PMCID: PMC5408160 DOI: 10.1161/cir.0000000000000485] [Citation(s) in RCA: 6361] [Impact Index Per Article: 795.1] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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25
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Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol 2017; 69:603-612. [DOI: 10.1016/j.jacc.2016.11.050] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/24/2016] [Accepted: 11/07/2016] [Indexed: 12/11/2022]
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Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2015; 133:e38-360. [PMID: 26673558 DOI: 10.1161/cir.0000000000000350] [Citation(s) in RCA: 3803] [Impact Index Per Article: 380.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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27
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Ruzov M, Rimon G, Pikovsky O, Stepensky D. Celecoxib interferes to a limited extent with aspirin-mediated inhibition of platelets aggregation. Br J Clin Pharmacol 2015; 81:316-26. [PMID: 26456703 DOI: 10.1111/bcp.12801] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 09/17/2015] [Accepted: 10/09/2015] [Indexed: 01/18/2023] Open
Abstract
AIMS The aim of the study was to analyze the interaction between celecoxib and low dose aspirin for COX-1 binding and its consequences on the aspirin-mediated antiplatelet effects. METHODS We investigated ex vivo the interaction between celecoxib and aspirin for COX-1 binding and measured the resulting antiplatelet effects. We applied mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modelling to analyze these data and to predict in vivo platelet aggregation for different doses and administration schedules of aspirin and celecoxib. RESULTS The predictions of the PK-PD model were consistent with results from previous studies that investigated interaction between aspirin and celecoxib. The modelling results indicate that celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. The extent of this interaction can be substantial (up to 15% increase in platelet aggregation by 200 mg day(-1) celecoxib when combined with low dose aspirin) during the first days of aspirin administration in patients who are already treated with celecoxib, and it cannot be prevented by separate administration of the interacting drugs. CONCLUSIONS At the recommended therapeutic doses, celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. Patients receiving a combination of low dose aspirin and the recommended doses of celecoxib were not identified to have increased risk of cardiovascular and cerebrovascular events due to competition between these drugs for COX-1 binding. Interaction between low dose aspirin and other COX-2 inhibitors and its clinical consequences requires further investigation.
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Affiliation(s)
- Mark Ruzov
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva
| | - Gilad Rimon
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva
| | - Oleg Pikovsky
- Blood Bank & Hematology Institute, Soroka University Medical Center, Beer Sheva, Israel
| | - David Stepensky
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva
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28
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Patrono C. The Multifaceted Clinical Readouts of Platelet Inhibition by Low-Dose Aspirin. J Am Coll Cardiol 2015; 66:74-85. [PMID: 26139061 DOI: 10.1016/j.jacc.2015.05.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/21/2015] [Accepted: 05/05/2015] [Indexed: 12/14/2022]
Abstract
Inactivation of platelet cyclooxygenase (COX)-1 by low-dose aspirin leads to long-lasting suppression of thromboxane (TX) A2 production and TXA2-mediated platelet activation and aggregation. This effect is necessary and sufficient to explain aspirin's unique (among other COX-1 inhibitors) effectiveness in preventing atherothrombosis, as well as its shared (with other antiplatelet agents) bleeding liability. However, different mechanisms of action have been suggested to explain other beneficial effects of aspirin, such as prevention of venous thromboembolism, chemoprevention of colorectal (and other) cancers, and reduced risk of dementia. These mechanisms include acetylation of other proteins in blood coagulation, inhibition of COX-2 activity, and other COX-independent mechanisms. The intent of this review is to develop the concept that the multifaceted therapeutic effects of low-dose aspirin may reflect pleiotropic consequences of platelet inhibition on pathophysiological tissue repair processes. Furthermore, the clinical implications of this concept will be discussed in terms of current clinical practice and future research.
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Affiliation(s)
- Carlo Patrono
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
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29
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Zagol-Ikapite I, Sosa IR, Oram D, Judd A, Amarnath K, Amarnath V, Stec D, Oates JA, Boutaud O. Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers. J Lipid Res 2015; 56:2196-205. [PMID: 26378094 DOI: 10.1194/jlr.p063271] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Indexed: 12/25/2022] Open
Abstract
The thromboxane synthase converts prostaglandin H(2) to thromboxane A(2) and malondialdehyde (MDA) in approximately equimolar amounts. A reactive dicarbonyl, MDA forms covalent adducts of amino groups, including the ε-amine of lysine, but the importance of this reaction in platelets was unknown. Utilizing a novel LC/MS/MS method for analysis of one of the MDA adducts, the dilysyl-MDA cross-link, we demonstrated that dilysyl-MDA cross-links in human platelets are formed following platelet activation via the cyclooxygenase (COX)-1/thromboxane synthase pathway. Salicylamine and analogs of salicylamine were shown to react with MDA preferentially, thereby preventing formation of lysine adducts. Dilysyl-MDA cross-links were measured in two diseases known to be associated with increased platelet activation. Levels of platelet dilysyl-MDA cross-links were increased by 2-fold in metabolic syndrome relative to healthy subjects, and by 1.9-fold in sickle cell disease (SCD). In patients with SCD, the reduction of platelet dilysyl-MDA cross-links following administration of nonsteroidal anti-inflammatory drug provided evidence that MDA modifications of platelet proteins in this disease are derived from the COX pathway. In summary, MDA adducts of platelet proteins that cross-link lysines are formed on platelet activation and are increased in diseases associated with platelet activation. These protein modifications can be prevented by salicylamine-related scavengers.
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Affiliation(s)
| | - Iberia R Sosa
- Department of Medicine, Vanderbilt University, Nashville, TN
| | - Denise Oram
- Department of Medicine, Vanderbilt University, Nashville, TN
| | - Audra Judd
- Department of Medicine, Vanderbilt University, Nashville, TN
| | - Kalyani Amarnath
- Department of Pharmacology, Vanderbilt University, Nashville, TN
| | - Venkataraman Amarnath
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN
| | - Donald Stec
- Department of Chemistry, Vanderbilt University, Nashville, TN
| | - John A Oates
- Department of Medicine, Vanderbilt University, Nashville, TN Department of Pharmacology, Vanderbilt University, Nashville, TN
| | - Olivier Boutaud
- Department of Pharmacology, Vanderbilt University, Nashville, TN
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30
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Bliden KP, Patrick J, Pennell AT, Tantry US, Gurbel PA. Drug delivery and therapeutic impact of extended-release acetylsalicylic acid. Future Cardiol 2015; 12:45-58. [PMID: 26356085 DOI: 10.2217/fca.15.60] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Current treatment guidelines recommend once-daily, low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention of cardiovascular events. However, the anti-thrombotic benefits of traditional ASA formulations may not extend over a 24-h period, especially in patients at high risk for a recurrent cardiovascular event. A next-generation, extended-release ASA formulation (ER-ASA) has been developed to provide 24-h anti-thrombotic coverage with once-daily dosing. The pharmacokinetics of ER-ASA indicates slower absorption and prolonged ASA release versus immediate-release ASA, with a favorable safety profile. ER-ASA minimizes systemic ASA absorption and provides sustained antiplatelet effects over a 24-h period.
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Affiliation(s)
- Kevin P Bliden
- Sinai Center for Thrombosis Research, Baltimore, MD, USA
| | - Jeff Patrick
- New Haven Pharmaceuticals, Inc., North Haven, CT, USA
| | | | - Udaya S Tantry
- Sinai Center for Thrombosis Research, Baltimore, MD, USA
| | - Paul A Gurbel
- Sinai Center for Thrombosis Research, Baltimore, MD, USA
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31
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Hoefer T, Armstrong PC, Finsterbusch M, Chan MV, Kirkby NS, Warner TD. Drug-Free Platelets Can Act as Seeds for Aggregate Formation During Antiplatelet Therapy. Arterioscler Thromb Vasc Biol 2015; 35:2122-33. [PMID: 26272940 PMCID: PMC4587545 DOI: 10.1161/atvbaha.115.306219] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 07/30/2015] [Indexed: 12/27/2022]
Abstract
Supplemental Digital Content is available in the text. Objective— Reduced antiplatelet drug efficacy occurs in conditions of increased platelet turnover, associated with increased proportions of drug-free, that is, uninhibited, platelets. Here, we detail mechanisms by which drug-free platelets promote platelet aggregation in the face of standard antiplatelet therapy. Approach and Results— To model standard antiplatelet therapy, platelets were treated in vitro with aspirin, the P2Y12 receptor blocker prasugrel active metabolite, or aspirin plus prasugrel active metabolite. Different proportions of uninhibited platelets were then introduced. Light transmission aggregometry analysis demonstrated clear positive associations between proportions of drug-free platelets and percentage platelet aggregation in response to a range of platelet agonists. Using differential platelet labeling coupled with advanced flow cytometry and confocal imaging we found aggregates formed in mixtures of aspirin-inhibited platelets together with drug-free platelets were characterized by intermingled platelet populations. This distribution is in accordance with the ability of drug-free platelets to generate thromboxane A2 and so drive secondary platelet activation. Conversely, aggregates formed in mixtures of prasugrel active metabolite–inhibited or aspirin plus prasugrel active metabolite–inhibited platelets together with drug-free platelets were characterized by distinct cores of drug-free platelets. This distribution is consistent with the ability of drug-free platelets to respond to the secondary activator ADP. Conclusions— These experiments are the first to image the interactions of inhibited and uninhibited platelets in the formation of platelet aggregates. They demonstrate that a general population of platelets can contain subpopulations that respond strikingly differently to overall stimulation of the population and so act as the seed for platelet aggregation.
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Affiliation(s)
- Thomas Hoefer
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.)
| | - Paul C Armstrong
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.)
| | - Michaela Finsterbusch
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.)
| | - Melissa V Chan
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.)
| | - Nicholas S Kirkby
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.)
| | - Timothy D Warner
- From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.).
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32
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Santilli F, Pignatelli P, Violi F, Davì G. Aspirin for primary prevention in diabetes mellitus: from the calculation of cardiovascular risk and risk/benefit profile to personalised treatment. Thromb Haemost 2015; 114:876-82. [PMID: 26245672 DOI: 10.1160/th15-03-0202] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 05/29/2015] [Indexed: 01/23/2023]
Abstract
Type 2 diabetes mellitus is characterised by persistent thromboxane (TX)-dependent platelet activation, regardless of disease duration. Low-dose aspirin, that induces a permanent inactivation of platelet cyclooxygenase (COX)-1, thus inhibiting TXA2 biosynthesis, should be theoretically considered the drug of choice. The most up-to-date meta-analysis of aspirin prophylaxis in this setting, which includes three trials conducted in patients with diabetes and six other trials in which such patients represent a subgroup within a broader population, reported that aspirin is associated with a non-significant decrease in the risk of vascular events, although the limited amount of available data precludes a precise estimate of the effect size. An increasing body of evidence supports the concept that less-than-expected response to aspirin may underlie mechanisms related to residual platelet hyper-reactivity despite anti-platelet treatment, at least in a fraction of patients. Among the proposed mechanisms, the variable turnover rate of the drug target (platelet COX-1) appears to represent the most convincing determinant of the inter-individual variability in aspirin response. This review intends to develop the idea that the understanding of the determinants of less-than-adequate response to aspirin in certain individuals, although not changing the paradigm of the indication to low-dose aspirin prescription in primary prevention, may help identifying, in terms of easily detectable clinical or biochemical characteristics, individuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged.
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Affiliation(s)
| | | | | | - Giovanni Davì
- Giovanni Davì, Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Luigi Polacchi 11, 66013 Chieti, Italy, Tel: +39 0871 541312, Fax: +39 0871 541261, E-mail:
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33
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Kirkby NS, Reed DM, Edin ML, Rauzi F, Mataragka S, Vojnovic I, Bishop-Bailey D, Milne GL, Longhurst H, Zeldin DC, Mitchell JA, Warner TD. Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation. FASEB J 2015; 29:4568-78. [PMID: 26183771 PMCID: PMC4608906 DOI: 10.1096/fj.15-275065] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/06/2015] [Indexed: 12/25/2022]
Abstract
Eicosanoids are important vascular regulators, but the phospholipase A2
(PLA2) isoforms supporting their production within the cardiovascular
system are not fully understood. To address this, we have studied platelets,
endothelial cells, and leukocytes from 2 siblings with a homozygous loss-of-function
mutation in group IVA cytosolic phospholipase A2
(cPLA2α). Chromatography/mass spectrometry was used to determine
levels of a broad range of eicosanoids produced by isolated vascular cells, and in
plasma and urine. Eicosanoid release data were paired with studies of cellular
function. Absence of cPLA2α almost abolished eicosanoid synthesis
in platelets (e.g., thromboxane A2, control 20.5 ±
1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes
[e.g., prostaglandin E2 (PGE2), control
21.9 ± 7.4 ng/ml vs. patient 1.9 ng/ml], and this was
associated with impaired platelet activation and enhanced inflammatory responses.
cPLA2α-deficient endothelial cells showed reduced, but not
absent, formation of prostaglandin I2 (prostacyclin; control 956 ±
422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation.
In the urine, prostaglandin metabolites were selectively influenced by
cPLA2α deficiency. For example, prostacyclin metabolites were
strongly reduced (18.4% of control) in patients lacking cPLA2α,
whereas PGE2 metabolites (77.8% of control) were similar to healthy
volunteer levels. These studies constitute a definitive account, demonstrating the
fundamental role of cPLA2α to eicosanoid formation and cellular
responses within the human circulation.—Kirkby, N. S., Reed, D. M., Edin, M.
L., Rauzi, F., Mataragka, S., Vojnovic, I., Bishop-Bailey, D., Milne, G. L.,
Longhurst, H., Zeldin, D. C., Mitchell, J. A., Warner, T. D. Inherited human group
IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial,
and leucocyte eicosanoid generation.
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Affiliation(s)
- Nicholas S Kirkby
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Daniel M Reed
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Matthew L Edin
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Francesca Rauzi
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Stefania Mataragka
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Ivana Vojnovic
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - David Bishop-Bailey
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Ginger L Milne
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Hilary Longhurst
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Darryl C Zeldin
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Jane A Mitchell
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
| | - Timothy D Warner
- *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom
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Santilli F, Lapenna D, La Barba S, Davì G. Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus. Free Radic Biol Med 2015; 80:101-10. [PMID: 25530150 DOI: 10.1016/j.freeradbiomed.2014.12.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 12/05/2014] [Accepted: 12/05/2014] [Indexed: 01/19/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk. A large body of evidence supports the contention that oxidative stress, which characterizes DM, may be responsible, at least in part, for less-than-expected response to aspirin, with multiple mechanisms acting at several levels. This review discusses the pathophysiological mechanisms related to oxidative stress and contributing to suboptimal aspirin action or responsiveness. These include: (1) mechanisms counteracting the antiplatelet effect of aspirin, such as reduced platelet sensitivity to the antiaggregating effects of NO, due to high-glucose-mediated oxidative stress; (2) mechanisms interfering with COX acetylation especially at the platelet level, e.g., lipid hydroperoxide-dependent impaired acetylating effects of aspirin; (3) mechanisms favoring platelet priming (lipid hydroperoxides) or activation (F2-isoprostanes, acting as partial agonists of thromboxane receptor), or aldose-reductase pathway-mediated oxidative stress, leading to enhanced platelet thromboxane A2 generation or thromboxane receptor activation; (4) mechanisms favoring platelet recruitment, such as aspirin-induced platelet isoprostane formation; (5) modulation of megakaryocyte generation and thrombopoiesis by oxidative HO-1 inhibition; and (6) aspirin-iron interactions, eventually resulting in impaired pharmacological activity of aspirin, lipoperoxide burden, and enhanced generation of hydroxyl radicals capable of promoting protein kinase C activation and platelet aggregation. Acknowledgment of oxidative stress as a major contributor, not only of vascular complications, but also of suboptimal response to antiplatelet agents in T2DM, may open the way to designing and testing novel antithrombotic strategies, specifically targeting oxidative stress-mediated mechanisms of less-than-expected response to aspirin.
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Affiliation(s)
- Francesca Santilli
- Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy.
| | - Domenico Lapenna
- Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy
| | - Sara La Barba
- Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy
| | - Giovanni Davì
- Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy
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35
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Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation 2014; 131:e29-322. [PMID: 25520374 DOI: 10.1161/cir.0000000000000152] [Citation(s) in RCA: 4521] [Impact Index Per Article: 411.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Patrono C. Role of Clinical Pharmacology in the Development of Antiplatelet Drugs. Clin Ther 2014; 36:2096-2111. [DOI: 10.1016/j.clinthera.2014.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/15/2014] [Accepted: 10/20/2014] [Indexed: 10/24/2022]
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37
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Lopez LR, Guyer KE, Torre IGDL, Pitts KR, Matsuura E, Ames PRJ. Platelet thromboxane (11-dehydro-Thromboxane B 2) and aspirin response in patients with diabetes and coronary artery disease. World J Diabetes 2014; 5:115-127. [PMID: 24748925 PMCID: PMC3990310 DOI: 10.4239/wjd.v5.i2.115] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 02/25/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023] Open
Abstract
Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on thromboxane generation was evaluated in patients with diabetes (DM) and cardiovascular disease. Thromboxane inhibition was assessed by measuring the urinary excretion of 11-dehydro-thromboxane B2 (11dhTxB2), a stable metabolite of thromboxane A2. The mean baseline urinary 11dhTxB2 of DM was 69.6% higher than healthy controls (P = 0.024): female subjects (DM and controls) had 50.9% higher baseline 11dhTxB2 than males (P = 0.0004), while age or disease duration had no influence. Daily ASA ingestion inhibited urinary 11dhTxB2 in both DM (71.7%) and controls (75.1%, P < 0.0001). Using a pre-established cut-off of 1500 pg/mg of urinary 11dhTxB2, there were twice as many ASA poor responders (ASA “resistant”) in DM than in controls (14.8% and 8.4%, respectively). The rate of ASA poor responders in two populations of acute coronary syndrome (ACS) patients was 28.6 and 28.7%, in spite of a significant (81.6%) inhibition of urinary 11dhTxB2 (P < 0.0001). Both baseline 11dhTxB2 levels and rate of poor ASA responders were significantly higher in DM and ACS compared to controls. Underlying systemic oxidative inflammation may maintain platelet function in atherosclerotic cardiovascular disease irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.
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Kawai VK, Avalos I, Oeser A, Oates JA, Milne GL, Solus JF, Chung CP, Stein CM. Suboptimal inhibition of platelet cyclooxygenase 1 by aspirin in systemic lupus erythematosus: association with metabolic syndrome. Arthritis Care Res (Hoboken) 2014; 66:285-92. [PMID: 24022862 DOI: 10.1002/acr.22169] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 09/03/2013] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Low-dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2 ) synthesis. However, in some individuals TXA2 suppression by aspirin is impaired, indicating suboptimal inhibition of platelet cyclooxygenase 1 (COX-1) by aspirin. Because patients with systemic lupus erythematosus (SLE) have increased risk of thrombotic events, many receive aspirin; however, the efficacy of aspirin in SLE has not been determined. We examined the hypothesis that aspirin response is impaired in SLE. METHODS We assessed the effect of aspirin by measuring concentrations of the stable metabolite of TXA2 , serum thromboxane B2 (sTXB2 ), before and after treatment with daily aspirin (81 mg) for 7 days in 34 patients with SLE and 36 control subjects. The inability to suppress sTXB2 synthesis to <10 ng/ml represents suboptimal inhibition of platelet COX-1 by aspirin. RESULTS Aspirin almost completely suppressed sTXB2 in control subjects to median 1.5 ng/ml (interquartile range [IQR] 0.8-2.7) but had less effect in patients with SLE (median 3.1 ng/ml [IQR 2.2-5.3]) (P = 0.002). A suboptimal effect of aspirin was present in 15% (5 of 34) of the patients with SLE but not in control subjects (0 of 36) (P = 0.023). Incomplete responders were more likely to have metabolic syndrome (P = 0.048), obesity (P = 0.048), and higher concentrations of C-reactive protein (CRP) (P = 0.018). CONCLUSION The pharmacologic effect of aspirin is suboptimal in 15% of patients with SLE but in none of the control subjects, and the suboptimal response was associated with metabolic syndrome, obesity, and higher CRP concentrations.
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Affiliation(s)
- Vivian K Kawai
- Vanderbilt University School of Medicine, Nashville, Tennessee
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Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129:e28-e292. [PMID: 24352519 PMCID: PMC5408159 DOI: 10.1161/01.cir.0000441139.02102.80] [Citation(s) in RCA: 3572] [Impact Index Per Article: 324.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Good RIS, McGarrity A, Sheehan R, James TE, Miller H, Stephens J, Watkins S, McConnachie A, Goodall AH, Oldroyd KG. Variation in thromboxane B2 concentrations in serum and plasma in patients taking regular aspirin before and after clopidogrel therapy. Platelets 2014; 26:17-24. [PMID: 24433337 DOI: 10.3109/09537104.2013.870334] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Dual antiplatelet therapy with aspirin and a P2Y12 antagonist is widely prescribed for the prevention of thrombotic events in patients with an acute coronary syndrome or undergoing percutaneous coronary intervention (PCI). It is recognised that there is inter-individual variation in the antiplatelet effects of both drugs. Recent data also suggest that P2Y12 antagonists can affect the response to aspirin. A direct indicator of the effect of aspirin on platelets is their ability to generate thromboxane, which if measured as the difference between the level of thromboxane B2 in serum and plasma ([TxB2]S-P) avoids the confounding effect of endogenous TxB2 production from other cells. We therefore analysed [TxB2]S-P as a measure of aspirin response in a group of 123 patients undergoing elective PCI before and after the introduction of clopidogrel. In a subgroup of 40 patients taking aspirin alone, we compared [TxB2]S-P and VerifyNow Aspirin for the assessment of aspirin response. There was a wide variation in plasma and serum TxB2 concentrations both before and after clopidogrel therapy but only 3.5% of patients had residual serum concentration of TxB2 > 10 ng/ml. There was a strong correlation between the pre and post clopidogrel levels of TxB2 (r ≥ 0.78; p = 0.001) and no significant difference in [TxB2]S-P. There was no correlation between the magnitude of response to clopidogrel response and the generation of thromboxane B2. Correlation between [TxB2]S-P and VerifyNow Aspirin was poor. We conclude that the use of a P2Y12 antagonist does not influence the effect of aspirin on the ability of platelets to generate thromboxane. Therefore, measurement of TxB2 levels in serum, after subtracting the contribution from plasma, provides a measure of the response to aspirin in patients taking dual antiplatelet therapy.
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Affiliation(s)
- Richard I S Good
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow , Glasgow , UK
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Santos MT, Madrid I, Moscardo A, Latorre AM, Bonastre J, Ruano M, Valles J. The administration of a loading dose of aspirin to patients presenting with acute myocardial infarction while receiving chronic aspirin treatment reduces thromboxane A2-dependent platelet reactivity. Platelets 2013; 25:268-73. [PMID: 23909754 DOI: 10.3109/09537104.2013.816671] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Abstract The optimal dose of aspirin for patients presenting with acute myocardial infarction (AMI) while receiving chronic aspirin therapy has not been clearly established. We evaluated whether continued treatment with 100 mg of aspirin or a loading dose (200-500 mg) influences thromboxane A2 (TX) suppression or platelet reactivity. Sixty-four consecutive patients with AMI and 98 healthy subjects (82 aspirin-free and 16 receiving 100 mg daily for a week) were evaluated. Treatment was at the discretion of the attending physician. Collagen (1 µg/ml)-induced TX synthesis, (14)C-serotonin-release, platelet aggregation, and the PFA-100 assay were evaluated. The platelet TX synthesis of patients receiving a loading dose of aspirin was sixfold lower than that of patients receiving 100 mg of aspirin (p<0.005). This was associated with marked reductions in (14)C-serotonin-release and arachidonic-acid-induced aggregation and an increase in the PFA-100 closure time (p<0.01). Categorization of patients according to their TX synthesis (<95% or ≥ 95% inhibition vs. healthy aspirin-free subjects) revealed that 8% of the patients treated with loading doses had a poor response (<95% inhibition) vs. 53% of those treated with 100 mg (p<0.001). Patients with lower TX inhibition had higher serum NT-Pro-BNP (p<0.005), a marker of poor left ventricular systolic function. Administration of a loading dose of aspirin to patients with AMI during existing chronic aspirin treatment induced greater reductions in platelet TX synthesis and TX-dependent platelet reactivity than the continued treatment alone.
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Kirkby NS, Chan MV, Lundberg MH, Massey KA, Edmands WMB, MacKenzie LS, Holmes E, Nicolaou A, Warner TD, Mitchell JA. Aspirin-triggered 15-epi-lipoxin A4 predicts cyclooxygenase-2 in the lungs of LPS-treated mice but not in the circulation: implications for a clinical test. FASEB J 2013; 27:3938-46. [PMID: 23792301 PMCID: PMC3973905 DOI: 10.1096/fj.12-215533] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Inhibition of cyclooxygenase (COX)-2 increases cardiovascular deaths. Identifying a biomarker of COX-2 is desirable but difficult, since COX-1 and COX-2 ordinarily catalyze formation of an identical product, prostaglandin H2. When acetylated by aspirin, however, COX-2 (but not COX-1) can form 15(R)-HETE, which is metabolized to aspirin-triggered lipoxin (ATL), 15-epi-lipoxin A4. Here we have used COX-1- and COX-2-knockout mice to establish whether plasma ATL could be used as a biomarker of vascular COX-2 in vivo. Vascular COX-2 was low but increased by LPS (10 mg/kg; i.p). Aspirin (10 mg/kg; i.v.) inhibited COX-1, measured as blood thromboxane and COX-2, measured as lung PGE2. Aspirin also increased the levels of ATL in the lungs of LPS-treated wild-type C57Bl6 mice (vehicle: 25.5±9.3 ng/ml; 100 mg/kg: 112.0±7.4 ng/ml; P<0.05). Despite this, ATL was unchanged in plasma after LPS and aspirin. This was true in wild-type as well as COX-1−/− and COX-2−/− mice. Thus, in mice in which COX-2 has been induced by LPS treatment, aspirin triggers detectable 15-epi-lipoxin A4 in lung tissue, but not in plasma. This important study is the first to demonstrate that while ATL can be measured in tissue, plasma ATL is not a biomarker of vascular COX-2 expression.—Kirkby, N. S., Chan, M. V., Lundberg, M. H., Massey, K. A., Edmands, W. M. B., MacKenzie, L. S., Holmes, E., Nicolaou, A., Warner, T. D., Mitchell, J. A. Aspirin-triggered 15-epi-lipoxin A4 predicts cyclooxygenase-2 in the lungs of LPS-treated mice but not in the circulation: implications for a clinical test.
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Affiliation(s)
- Nicholas S Kirkby
- 1Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, Dovehouse St., London SW3 6LY, UK. J.A.M.,
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Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J 2013; 34:3403-11. [DOI: 10.1093/eurheartj/eht058] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Abstract
Abstract
Persistently enhanced platelet activation has been characterized in polycythemia vera (PV) and essential thrombocythemia (ET) and shown to contribute to a higher risk of both arterial and venous thrombotic complications. The incidence of major bleeding complications is also somewhat higher in PV and ET than in the general population. Although its efficacy and safety was assessed in just 1 relatively small trial in PV, low-dose aspirin is currently recommended in practically all PV and ET patients. Although for most patients with a thrombosis history the benefit/risk profile of antiplatelet therapy is likely to be favorable, in those with no such history this balance will depend critically on the level of thrombotic and hemorrhagic risks of the individual patient. Recent evidence for a chemopreventive effect of low-dose aspirin may tilt the balance of benefits and harm in favor of using aspirin more broadly, but the potential for additional benefits needs regulatory scrutiny and novel treatment guidelines. A clear pharmacodynamic rationale and analytical tools are available for a personalized approach to antiplatelet therapy in ET, and an improved regimen of low-dose aspirin therapy should be tested in a properly sized randomized trial.
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Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. Proc Natl Acad Sci U S A 2012; 109:17597-602. [PMID: 23045674 DOI: 10.1073/pnas.1209192109] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
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Rocca B, Santilli F, Pitocco D, Mucci L, Petrucci G, Vitacolonna E, Lattanzio S, Mattoscio D, Zaccardi F, Liani R, Vazzana N, Del Ponte A, Ferrante E, Martini F, Cardillo C, Morosetti R, Mirabella M, Ghirlanda G, Davì G, Patrono C. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost 2012; 10:1220-30. [PMID: 22471290 DOI: 10.1111/j.1538-7836.2012.04723.x] [Citation(s) in RCA: 187] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Interindividual variability in response to aspirin has been popularized as 'resistance'. We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane (TX) inhibition during the 24-h dosing interval. OBJECTIVE To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated diabetic and non-diabetic patients. PATIENTS/METHODS One hundred type 2 diabetic and 73 non-diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB(2) was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase-1 recovery. Patients with the fastest TXB(2) recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB(2) recovery was reassessed. RESULTS AND CONCLUSIONS Platelet TXB(2) production was profoundly suppressed at 12 h in both groups. Serum TXB(2) recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL(-1) h(-1) ) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non-diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB(2) recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low-dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.
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Affiliation(s)
- B Rocca
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
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Sethi SS, Akl EG, Farkouh ME. Diabetes mellitus and acute coronary syndrome: lessons from randomized clinical trials. Curr Diab Rep 2012; 12:294-304. [PMID: 22528594 DOI: 10.1007/s11892-012-0272-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Diabetes mellitus is a major independent risk factor for acute coronary syndrome (ACS). In addition, diabetic patients with ACS suffer from increased mortality compared to their nondiabetic peers. Driven by multiple pathophysiological disturbances, such patients are predisposed to a proinflammatory, prothrombotic state, which may lead to plaque rupture. To counteract this more complex biology, several therapies and strategies have emerged, with some having unique preferential benefits in this population. Antiplatelet agents such as aspirin and clopidogrel have long been standard of care. Dose adjustment of these therapies remains the subject of continued research. Along with medical therapy, ACS diabetic patients preferentially benefit from primary percutaneous intervention compared to fibrinolysis. However, with advances in reperfusion techniques, the optimal strategy has yet to be determined. With these differences in ACS treatment responses, diabetic individuals may not just be a high-risk group, but may actually constitute a fundamentally different population, requiring dedicated clinical trials and individualized treatment regimens.
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Affiliation(s)
- Sanjum S Sethi
- Zena and Michael A. Weiner Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
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