|
1
|
Tani S, Imatake K, Suzuki Y, Yagi T, Takahashi A. Association of aerobic exercise habits with higher albumin-globulin ratio and lower cellular immune-inflammatory markers: implication of the preventive effect of aerobic exercise on atherosclerotic cardiovascular disease. Heart Vessels 2025; 40:509-522. [PMID: 39625493 DOI: 10.1007/s00380-024-02490-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 11/20/2024] [Indexed: 05/19/2025]
Abstract
Aerobic exercise habits have shown promising potential in reducing inflammation. Several studies have suggested that a higher albumin-globulin ratio (AGR), a key indicator of the immune-inflammatory response, could potentially suppress the progression of atherosclerosis. In this study, we investigated the relationship between aerobic exercise and atherosclerotic cardiovascular disease (ASCVD) predictors, specifically, AGR and cellular immune-inflammatory markers. We conducted a cross-sectional study involving 8381 participants (average age, 46.7 ± 13.0 years; 59% men) with no history of ASCVD registered at the Health Planning Center, Nihon University Hospital between 2019 and 2020. We defined aerobic exercise habits as 30 min of sweating at least twice a week for over a year, per the guideline for conducting specific health examinations according to Japan's Ministry of Health, Labour and Welfare. Participants who engaged in habitual aerobic exercise (n = 2159) had a significantly higher AGR than those who did not (n = 6220) [1.70 (1.55/1.86) vs. 1.67 (1.53/1.84), P < 0.0001]. Cellular immune-inflammatory markers, including neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and systemic immune-inflammation index (neutrophil/lymphocyte × platelet count), were significantly lower in participants who engaged in habitual aerobic exercise than in those who did not (all P < 0.0001). Furthermore, lower cellular immune-inflammatory markers were associated with a higher AGR. Causal mediation analysis revealed that cellular immune-inflammatory markers partially mediated the association between aerobic exercise and AGR. In conclusion, aerobic exercise habits may be associated with a higher AGR and lower cellular immune-inflammatory markers. Moreover, the lower immune-inflammatory response related to aerobic exercise may partially mediate the higher AGR. These associations may explain the attenuating effects of aerobic exercise on the risk of ASCVD.
Collapse
Affiliation(s)
- Shigemasa Tani
- Department of Health Planning Center, Nihon University Hospital, Tokyo, Japan.
- Department of Cardiology, Nihon University Hospital, Tokyo, Japan.
- Division of Cardiology, Department Medicine, The Nippon Dental University School of Life Dentistry, 2-3-16 Fujimicho, Chiyoda-Ku, Tokyo, 102-8158, Japan.
| | - Kazuhiro Imatake
- Department of Health Planning Center, Nihon University Hospital, Tokyo, Japan
| | - Yasuyuki Suzuki
- Department of Health Planning Center, Nihon University Hospital, Tokyo, Japan
- Department of Cardiology, Nihon University Hospital, Tokyo, Japan
| | - Tsukasa Yagi
- Department of Health Planning Center, Nihon University Hospital, Tokyo, Japan
- Department of Cardiology, Nihon University Hospital, Tokyo, Japan
| | - Atsuhiko Takahashi
- Department of Health Planning Center, Nihon University Hospital, Tokyo, Japan
| |
Collapse
|
|
2
|
Toso A, Leoncini M, Maioli M, Villani S, Bellandi F. Biomarkers of residual risk and all-cause mortality after acute coronary syndrome. Am J Prev Cardiol 2025; 21:100934. [PMID: 39896052 PMCID: PMC11787588 DOI: 10.1016/j.ajpc.2025.100934] [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: 09/30/2024] [Revised: 01/09/2025] [Accepted: 01/13/2025] [Indexed: 02/04/2025] Open
Abstract
Background Adverse cardiovascular events often recur after acute coronary syndrome (ACS), despite secondary prevention measures. Residual risk involves various inflammatory, metabolic and renal factors as well as lipid and thrombotic processes. This cohort study investigates the relationship between four risk biomarkers at 1 month after ACS and all-cause death within 3 years in patients treated with early invasive strategy and high-intensity statins from admission. Methods Levels of residual risk for the biomarkers were: low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dl; high-sensitivity C reactive protein (hs-CRP) ≥ 2 mg/l; glycosylated hemoglobin (HbA1c) ≥ 7% in diabetic and ≥ 5.7% in non-diabetic patients; decrease in estimated glomerular filtration rate (eGFR) ≥ 25% compared to baseline. The association between the four biomarkers and all-cause death within 3 years was evaluated with Cox proportional analysis. Results This study included 1099 patients (68±12 years; 70.3% males). At 1 month the majority of patients had levels of LDL-C, hs-CRP and/or HbA1c above the risk cut-points, and only 7% of cases presented reduced eGFR. Reduced eGFR and hs-CRP ≥ 2 mg/l at 1 month were the sole independent biomarker predictors of 3-year mortality (adjusted hazard ratios 3.03 and 2.66, respectively). Conclusions In this population on high-intensity statin therapy only hsCRP and eGFR were independently associated with medium-term mortality. Diversification of secondary preventive measures based on routine evaluations of inflammation and kidney function markers, not only LDL-C, could lead to better targeted reduction of residual risk after ACS.
Collapse
Affiliation(s)
- Anna Toso
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Mario Leoncini
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Mauro Maioli
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| | - Simona Villani
- Section of Biostatistics and Clinical Epidemiology, Department of Public Health, Experimental and Forensic Medicine, Pavia University, Pavia, Italy
| | - Francesco Bellandi
- Cardiology Unit, Department of Medical Specialties, Azienda USL Toscana Centro, Prato, Italy
| |
Collapse
|
|
3
|
Thorp EB, Filipp M. Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction. ANNUAL REVIEW OF PATHOLOGY 2025; 20:143-167. [PMID: 39357068 DOI: 10.1146/annurev-pathmechdis-111523-023405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.
Collapse
Affiliation(s)
- Edward B Thorp
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; ,
| | - Mallory Filipp
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; ,
| |
Collapse
|
|
4
|
Wilkinson MJ, Shapiro MD. Immune-Mediated Inflammatory Diseases, Dyslipidemia, and Cardiovascular Risk: A Complex Interplay. Arterioscler Thromb Vasc Biol 2024; 44:2396-2406. [PMID: 39479765 PMCID: PMC11602385 DOI: 10.1161/atvbaha.124.319983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Individuals with autoimmune inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, are at increased risk for cardiovascular disease. While these diseases share common features of systemic inflammation, the impact of individual autoimmune inflammatory conditions on circulating lipids and lipoproteins varies by specific disease, disease activity, and the immune-suppressing medications used to treat these conditions. A common feature observed in many autoimmune inflammatory diseases is the development of a proatherogenic dyslipidemic state, characterized by dysfunctional HDLs (high-density lipoproteins) and increased oxidation of LDLs (low-density lipoproteins). Various disease-modifying antirheumatic drugs also have complex and variable effects on lipids, and it is critical to take this into consideration when evaluating lipid-related risk in individuals with immune-mediated inflammatory conditions. This review aims to critically evaluate the current understanding of the relationship between immune-mediated inflammatory diseases and dyslipidemia, the underlying mechanisms contributing to atherogenesis, and the impact of various pharmacotherapies on lipid profiles and cardiovascular risk. We also discuss the role of lipid-lowering therapies, particularly statins, in managing residual risk in this high-risk population and explore the potential of emerging therapies with complementary anti-inflammatory and lipid-lowering effects.
Collapse
Affiliation(s)
- Michael J. Wilkinson
- Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Michael D. Shapiro
- Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| |
Collapse
|
|
5
|
Datta S, Pasham S, Inavolu S, Boini KM, Koka S. Role of Gut Microbial Metabolites in Cardiovascular Diseases-Current Insights and the Road Ahead. Int J Mol Sci 2024; 25:10208. [PMID: 39337693 PMCID: PMC11432476 DOI: 10.3390/ijms251810208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.
Collapse
Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Sindhura Pasham
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Sriram Inavolu
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| |
Collapse
|
|
6
|
Zubirán R, Neufeld EB, Dasseux A, Remaley AT, Sorokin AV. Recent Advances in Targeted Management of Inflammation In Atherosclerosis: A Narrative Review. Cardiol Ther 2024; 13:465-491. [PMID: 39031302 PMCID: PMC11333429 DOI: 10.1007/s40119-024-00376-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/26/2024] [Indexed: 07/22/2024] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite effective low-density lipoprotein cholesterol-targeted therapies. This review explores the crucial role of inflammation in the residual risk of ASCVD, emphasizing its impact on atherosclerosis progression and plaque stability. Evidence suggests that high-sensitivity C-reactive protein (hsCRP), and potentially other inflammatory biomarkers, can be used to identify the inflammatory residual ASCVD risk phenotype and may serve as future targets for the development of more efficacious therapeutic approaches. We review the biological basis for the association of inflammation with ASCVD, propose new therapeutic strategies for the use of inflammation-targeted treatments, and discuss current challenges in the implementation of this new treatment paradigm for ASCVD.
Collapse
Affiliation(s)
- Rafael Zubirán
- Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Edward B Neufeld
- Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Amaury Dasseux
- Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alan T Remaley
- Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alexander V Sorokin
- Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Section of Inflammation and Cardiometabolic Diseases, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Section of Lipoprotein Metabolism, Clinical Research Center, National Heart, Lung and Blood Institute, 9000 Rockville Pike, Bldg 10, Room 5-5150, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
7
|
Della Corte V, Todaro F, Cataldi M, Tuttolomondo A. Atherosclerosis and Its Related Laboratory Biomarkers. Int J Mol Sci 2023; 24:15546. [PMID: 37958528 PMCID: PMC10649778 DOI: 10.3390/ijms242115546] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/18/2023] [Accepted: 10/22/2023] [Indexed: 11/15/2023] Open
Abstract
Atherosclerosis constitutes a persistent inflammatory ailment, serving as the predominant underlying condition for coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease. The progressive buildup of plaques within the walls of medium- and large-caliber arteries characterizes the atherosclerotic process. This accumulation results in significant narrowing that impedes blood flow, leading to critical tissue oxygen deficiency. Spontaneous blockage of thrombotic vessels can precipitate stroke and myocardial infarction, which are complications representing the primary global causes of mortality. Present-day models for predicting cardiovascular risk incorporate conventional risk factors to gauge the likelihood of cardiovascular events over a ten-year span. In recent times, researchers have identified serum biomarkers associated with an elevated risk of atherosclerotic events. Many of these biomarkers, whether used individually or in combination, have been integrated into risk prediction models to assess whether their inclusion enhances predictive accuracy. In this review, we have conducted a comprehensive analysis of the most recently published literature concerning serum biomarkers associated with atherosclerosis. We have explored the potential utility of incorporating these markers in guiding clinical decisions.
Collapse
|
|
8
|
Papastamos C, Antonopoulos AS, Simantiris S, Koumallos N, Sagris M, Theofilis P, Oikonomou E, Siasos G, Tsioufis K, Tousoulis D. Interleukin-6 Signaling in Atherosclerosis: From Molecular Mechanisms To Clinical Outcomes. Curr Top Med Chem 2023; 23:2172-2183. [PMID: 37464827 DOI: 10.2174/1568026623666230718141235] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 07/20/2023]
Abstract
Interleukin-6 (IL-6) is a cytokine centrally involved in several immune responses and it has been recognized as a driver of enhanced atherothrombotic risk. Immunity and inflammation are intrinsically involved in atherosclerosis progression. This generated 'inflammation hypothesis', which is now validated in large-scale clinical trials. Abundant evidence supports the distinctive role of IL-6 in coronary artery disease. The focus on this cytokine stems from epidemiological studies linking high plasma concentrations of IL-6 with greater risk for adverse cardiovascular events, genetic studies which implicate a causative role of IL-6 in atherosclerosis and murine data which support the involvement of IL-6 in various pathophysiological cascades of atherothrombosis. The fact that high IL-6 levels are equivalent to increased cardiovascular risk created an unmet need to address those who are at 'residual inflammatory risk'. Moreover, the opposing effects of IL-6 underlined the importance of deciphering specific signaling cascades, which may be responsible for different effects. Finally, murine data and some small clinical trials highlighted the possibility of reversing the pro-atherogenic effects of IL-6 by directly targeting it. While IL-1 blockage was proved effective, it is reasonable to examine if moving more downstream in the inflammation cascade could be more selective and effective than other anti-inflammatory therapies. In the present review, we examine the role of IL-6 as a biomarker of 'residual inflammatory risk', its vital role in the pathophysiology of atherosclerosis progression and the possibility of targeting it to stall coronary artery disease progression.
Collapse
Affiliation(s)
- Charalampos Papastamos
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Alexios S Antonopoulos
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Spyridon Simantiris
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Nikolaos Koumallos
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Marios Sagris
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Panagiotis Theofilis
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens, Greece
| | - Gerasimos Siasos
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens, Greece
| | - Konstantinos Tsioufis
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| |
Collapse
|
|
9
|
Pacinella G, Ciaccio AM, Tuttolomondo A. Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases. Int J Mol Sci 2022; 23:15722. [PMID: 36555364 PMCID: PMC9779461 DOI: 10.3390/ijms232415722] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.
Collapse
Affiliation(s)
| | | | - Antonino Tuttolomondo
- Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D’Alessandro, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy
| |
Collapse
|
|
10
|
Pinto LCS, Mello APQ, Izar MCO, Damasceno NRT, Neto AMF, França CN, Caixeta A, Bianco HT, Póvoa RMS, Moreira FT, Bacchin ASF, Fonseca FA. Main differences between two highly effective lipid-lowering therapies in subclasses of lipoproteins in patients with acute myocardial infarction. Lipids Health Dis 2021; 20:124. [PMID: 34587943 PMCID: PMC8482657 DOI: 10.1186/s12944-021-01559-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/13/2021] [Indexed: 11/26/2022] Open
Abstract
Background Large observational studies have shown that small, dense LDL subfractions are related to atherosclerotic cardiovascular disease. This study assessed the effects of two highly effective lipid-lowering therapies in the atherogenic subclasses of lipoproteins in subjects with ST-segment elevation myocardial infarction (STEMI). Methods Patients of both sexes admitted with their first myocardial infarction and submitted to pharmacoinvasive strategy (N = 101) were included and randomized using a central computerized system to receive a daily dose of simvastatin 40 mg plus ezetimibe 10 mg or rosuvastatin 20 mg for 30 days. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) subfractions were analysed by polyacrylamide gel electrophoresis (Lipoprint System) on the first (D1) and 30th days (D30) of lipid-lowering therapy. Changes in LDL and IDL subfractions between D1 and D30 were compared between the lipid-lowering therapies (Mann-Whitney U test). Results The classic lipid profile was similar in both therapy arms at D1 and D30. At D30, the achievement of lipid goals was comparable between lipid-lowering therapies. Cholesterol content in atherogenic subclasses of LDL (p = 0.043) and IDL (p = 0.047) decreased more efficiently with simvastatin plus ezetimibe than with rosuvastatin. Conclusions Lipid-lowering therapy with simvastatin plus ezetimibe was associated with a better pattern of lipoprotein subfractions than rosuvastatin monotherapy. This finding was noted despite similar effects in the classic lipid profile and may contribute to residual cardiovascular risk. Trial registration ClinicalTrials.gov, NCT02428374, registered on 28/09/2014.
Collapse
Affiliation(s)
- Leticia C S Pinto
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Ana P Q Mello
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Maria C O Izar
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | | | - Antonio M F Neto
- Instituto de Física, Universidade de São Paulo, USP, São Paulo, Brazil
| | | | - Adriano Caixeta
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Henrique T Bianco
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Rui M S Póvoa
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Flavio T Moreira
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Amanda S F Bacchin
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil
| | - Francisco A Fonseca
- Escola Paulista de Medicina, Setor de Lípides, Aterosclerose e Biologia Vascular, Universidade Federal de São Paulo, UNIFESP, Rua Loefgren 1350, São Paulo, SP, 04040-001, Brazil.
| |
Collapse
|
|
11
|
Yetmar ZA, Chesdachai S, Kashour T, Riaz M, Gerberi DJ, Badley AD, Berbari EF, Tleyjeh IM. Prior Statin Use and Risk of Mortality and Severe Disease From Coronavirus Disease 2019: A Systematic Review and Meta-analysis. Open Forum Infect Dis 2021; 8:ofab284. [PMID: 34258316 PMCID: PMC8244756 DOI: 10.1093/ofid/ofab284] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/26/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Statins up-regulate angiotensin-converting enzyme 2, the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while also exhibiting pleiotropic antiviral, antithrombotic, and anti-inflammatory properties. Uncertainties exist about their effect on the course of SARS-CoV-2 infection. We sought to systematically review the literature and perform a meta-analysis to examine the association between prior statin use and outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS We searched Ovid Medline, Web of Science, Scopus, and the preprint server medRxiv from inception to December 2020. We assessed the quality of eligible studies with the Newcastle-Ottawa quality scale. We pooled adjusted relative risk (aRRs) of the association between prior statin use and outcomes of patients with COVID-19 using the DerSimonian-Laird random-effects model and assessed heterogeneity using the I 2 index. RESULTS Overall, 19 (16 cohorts and 3 case-control) studies were eligible, with a total of 395 513 patients. Sixteen of 19 studies had low or moderate risk of bias. Among 109 080 patients enrolled in 13 separate studies, prior statin use was associated with a lower risk of mortality (pooled aRR, 0.65 [95% confidence interval {CI}, .56-.77], I 2 = 84.1%) and a reduced risk of severe COVID-19 was also observed in 48 110 patients enrolled in 9 studies (pooled aRR, 0.73 [95% CI, .57-.94], I 2 = 82.8%), with no evidence of publication bias. CONCLUSIONS Cumulative evidence suggests that prior statin use is associated with lower risks of mortality or severe disease in patients with COVID-19. These data support the continued use of statins medications in patients with an indication for lipid-lowering therapy during the COVID-19 pandemic.
Collapse
Affiliation(s)
- Zachary A Yetmar
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Tarek Kashour
- Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Muhammad Riaz
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | | | - Andrew D Badley
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Elie F Berbari
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Imad M Tleyjeh
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
- Infectious Diseases Section, Department of Medical Specialties, King Fahad Medical City, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| |
Collapse
|
|
12
|
A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV. AIDS 2021; 35:1041-1050. [PMID: 33587443 PMCID: PMC8916096 DOI: 10.1097/qad.0000000000002845] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH. DESIGN This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks. METHODS Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks. RESULTS Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo. CONCLUSIONS In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis.
Collapse
|
|
13
|
Denegri A, Boriani G. High Sensitivity C-reactive Protein (hsCRP) and its Implications in Cardiovascular Outcomes. Curr Pharm Des 2021; 27:263-275. [PMID: 32679014 DOI: 10.2174/1381612826666200717090334] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 05/20/2020] [Indexed: 11/22/2022]
Abstract
Atherosclerosis and its fearsome complications represent the first cause of morbidity and mortality worldwide. Over the last two decades, several pieces of evidence have been accumulated, suggesting a central role of inflammation in atheroma development. High sensitivity C-reactive protein (hsCRP) is a well-established marker of cardiovascular (CV) disease; high levels of hsCRP have been associated with adverse CV outcome after acute coronary syndrome (ACS) and, despite some controversy, an active role for hsCRP in initiation and development of the atherosclerotic plaque has been also proposed. Randomized clinical trials focusing on hsCRP have been crucial in elucidating the anti-inflammatory effects of statin therapy. Thus, hsCRP has been progressively considered a real CV risk factor likewise to low-density lipoprotein cholesterol (LDL-C), expanding the concept of residual CV inflammatory risk. Subsequent research has been designed to investigate potential new targets of atherothrombotic protection. Despite the fact that the clinical usefulness of hsCRP is widely recognized, hsCRP may not represent the ideal target of specific anti-inflammatory therapies. Clinical investigations, therefore, have also focused on other inflammatory mediators, restricting hsCRP to an indicator rather than a therapeutic target. The aim of the present review is to provide an illustrative overview of the current knowledge of atherosclerosis and inflammation, highlighting the most representative clinical studies of lipid-lowering and antiinflammatory therapies focused on hsCRP in CV diseases.
Collapse
Affiliation(s)
- Andrea Denegri
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Largo del Pozzo, 71, 41125, Modena, Italy
| | - Giuseppe Boriani
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Largo del Pozzo, 71, 41125, Modena, Italy
| |
Collapse
|
|
14
|
Hong LZ, Xue Q, Shao H. Inflammatory Markers Related to Innate and Adaptive Immunity in Atherosclerosis: Implications for Disease Prediction and Prospective Therapeutics. J Inflamm Res 2021; 14:379-392. [PMID: 33628042 PMCID: PMC7897977 DOI: 10.2147/jir.s294809] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/21/2021] [Indexed: 12/20/2022] Open
Abstract
Several lines of evidence have linked a dysregulated inflammatory setting to the pathogenesis of atherosclerosis, which is a form of chronic vascular inflammation. Various inflammatory biomarkers have been associated with inflammation and are recognized as potential tools to monitor the progression of atherosclerosis. A well-studied inflammatory marker in the context of cardiovascular diseases is C-reactive protein (CRP) or, more accurately, highly sensitive-CRP (hs-CRP), which has been established as an inflammatory biomarker for atherosclerotic events. In addition, a growing body of investigations has attempted to disclose the potential of inflammatory cytokines, enzymes, and genetic polymorphisms related to innate and adaptive immunity as biomarkers for predicting the development of atherosclerosis. In this review article, we clarify both traditional and novel inflammatory biomarkers related to components of the innate and adaptive immune system that may mirror the progression or phases of atherosclerotic inflammation/lesions. Furthermore, the contribution of the inflammatory biomarkers in developing potential therapeutics against atherosclerotic treatment will be discussed.
Collapse
Affiliation(s)
- Ling-Zhi Hong
- Emergency Department, Chun’an First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, 311700, Zhejiang Province, People’s Republic of China
| | - Qi Xue
- Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People’s Republic of China
| | - Hong Shao
- Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People’s Republic of China
| |
Collapse
|
|
15
|
Kashour T, Halwani R, Arabi YM, Sohail MR, O'Horo JC, Badley AD, Tleyjeh IM. Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility. Immunopharmacol Immunotoxicol 2021; 43:37-50. [PMID: 33406943 DOI: 10.1080/08923973.2020.1863984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has infected millions of individuals and has claimed hundreds of thousands of human lives worldwide. Patients with underlying cardiovascular conditions are at high risk for SARS-CoV-2 infection, and COVID-19 patients have high incidence of cardiovascular complications such as acute cardiac injury, arrhythmias, heart failure, and thromboembolism. The disease has no approved proven effective therapy and hence repurposing of existing approved drugs has been considered as the fastest treatment approach. Statins have been shown to exhibit lipid lowering dependent and independent cardiovascular protective effects as well as favorable effects in various other pathophysiological states. These beneficial properties of statins are a result of their multiple pleotropic effects that include, anti-inflammatory, immunomodulatory, antithrombotic and antimicrobial properties. In this review, we provide a comprehensive description of the mechanisms of the pleotropic effects of statins, the relevant pre-clinical and clinical data pertinent to their role in infections and acute lung injury, the possible cardiovascular benefits of statins in COVID-19, and the implications of the therapeutic potential of statins in COVID-19 disease. We conclude with the rationale for conducting randomized controlled trials of statins in COVID-19 disease.
Collapse
Affiliation(s)
- Tarek Kashour
- Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, UAE
| | - Yaseen M Arabi
- Intensive Care Department, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - M Rizwan Sohail
- Section of Infectious Diseases, Baylor College of Medicine Houston, TX, USA.,Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - John C O'Horo
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Andrew D Badley
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Department of Molecular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Imad M Tleyjeh
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Department of Medical Specialties, Infectious Diseases Section, King Fahad Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| |
Collapse
|
|
16
|
Cakir SS, Ozcan L, Polat EC, Besiroglu H, Kocaaslan R, Ötunctemur A, Ozbek E. Statins are effective in the treatment of benign prostatic hyperplasia with metabolic syndrome. Aging Male 2020; 23:538-543. [PMID: 30463466 DOI: 10.1080/13685538.2018.1541979] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE To compare the efficacy of statins and ɑ blockers drug therapies for benign prostatic hyperplasia (BPH) in patients with metabolic syndrome (MetS). MATERIALS AND METHOD A total of three hundred patients were randomly distributed into three groups of one hundred patients each. Group 1 received only ɑ-adrenoceptor antagonist (ɑ-blocker, AB) (Tamsulosin), group 2 received only statin (atorvastatin), and group 3 received AB plus statin (Tamsulosin + Atorvastatin). The efficacy measurement was assessed by analyzing the changes from baseline in the total International Prostate Symptom Score (IPSS), disease-specific QoL question score and maximum urinary flow rate at the end of 6 months in each group and between the three groups. RESULTS Pre-treatment and post-treatment value of triglycerides (TG), high-density lipoprotein (HDL), and prostate volüme (PV) were not significantly different in AB group, while TG and PV were significantly lower in patients taking statin and combined therapy. The significant decrease was demonstrated in maximum urinary flow rate (Qmax) in three groups. However, the most significant decrease was observed in the combination therapy group. IPSS, postvoid residual urine volüme (PVR), and Quality of Life score (QoL) significantly changed in three groups. CONCLUSION We recommend of the use of statins in those men with BPH accompanied by MetS in which AB is ineffective alone.
Collapse
Affiliation(s)
- Suleyman Sami Cakir
- Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Levent Ozcan
- Department of Urology, Derince Training and Research Hospital, Kocaeli, Turkey
| | - Emre Can Polat
- Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | | | - Ramazan Kocaaslan
- Department of Urology, Kafkas University School of Medicine, Kars, Turkey
| | - Alper Ötunctemur
- Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Emin Ozbek
- Department of Urology, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
| |
Collapse
|
|
17
|
Alfaddagh A, Martin SS, Leucker TM, Michos ED, Blaha MJ, Lowenstein CJ, Jones SR, Toth PP. Inflammation and cardiovascular disease: From mechanisms to therapeutics. Am J Prev Cardiol 2020; 4:100130. [PMID: 34327481 PMCID: PMC8315628 DOI: 10.1016/j.ajpc.2020.100130] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/14/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as “the fire within,” is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.
Collapse
Affiliation(s)
- Abdulhamied Alfaddagh
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Seth S Martin
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thorsten M Leucker
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Erin D Michos
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael J Blaha
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Charles J Lowenstein
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Steven R Jones
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter P Toth
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
18
|
Shakour N, Ruscica M, Hadizadeh F, Cirtori C, Banach M, Jamialahmadi T, Sahebkar A. Statins and C-reactive protein: in silico evidence on direct interaction. Arch Med Sci 2020; 16:1432-1439. [PMID: 33224343 PMCID: PMC7667423 DOI: 10.5114/aoms.2020.100304] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 02/27/2018] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Statins are known to lower CRP, and this reduction has been suggested to contribute to the established efficacy of these drugs in reducing cardiovascular events and outcomes. However, the exact mechanism underlying the CRP-lowering effect of statins remains elusive. METHODS In order to test the possibility of direct interaction, we performed an in silico study by testing the orientation of the respective ligands (statins) and phosphorylcholine (the standard ligand of CRP) in the CRP active site using Molecular Operating Environment (MOE) software. RESULTS Docking experiments showed that all statins could directly interact with CRP. Among statins, rosuvastatin had the strongest interaction with CRP (pKi = 16.14), followed by fluvastatin (pKi = 15.58), pitavastatin (pKi = 15.26), atorvastatin (pKi = 14.68), pravastatin (pKi = 13.95), simvastatin (pKi = 7.98) and lovastatin (pKi = 7.10). According to the above-mentioned results, rosuvastatin, fluvastatin, pitavastatin and atorvastatin were found to have stronger binding to CRP compared with the standard ligand phosphocholine (pKi = 14.55). CONCLUSIONS This finding suggests a new mechanism of interaction between statins and CRP that could be independent of the putative cholesterol-lowering activity of statins.
Collapse
Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Farzin Hadizadeh
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Cesare Cirtori
- Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital, Medical University of Lodz, Lodz, Poland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Halal Research Center of IRI, FDA, Tehran, Iran
| |
Collapse
|
|
19
|
Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur Heart J 2020; 41:2974-2982. [PMID: 32006431 PMCID: PMC7453832 DOI: 10.1093/eurheartj/ehz961] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/10/2019] [Accepted: 01/09/2020] [Indexed: 12/12/2022] Open
Abstract
The ongoing worldwide increase in life expectancy portends a rising prevalence of age-related cardiovascular (CV) diseases in the coming decades that demands a deeper understanding of their molecular mechanisms. Inflammation has recently emerged as an important contributor for CV disease development. Indeed, a state of chronic sterile low-grade inflammation characterizes older organisms (also known as inflamm-ageing) and participates pivotally in the development of frailty, disability, and most chronic degenerative diseases including age-related CV and cerebrovascular afflictions. Due to chronic activation of inflammasomes and to reduced endogenous anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, endothelial, and vascular smooth muscle cells, thus accelerating vascular ageing and atherosclerosis. Furthermore, inflamm-ageing promotes the development of catastrophic athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for health care systems worldwide. Here, we discuss recent findings in the pathophysiology of inflamm-ageing, the impact of these processes on the development of age-related CV diseases, results from clinical trials targeting its components and the potential implementation of these advances into daily clinical practice.
Collapse
Affiliation(s)
- Luca Liberale
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren CH-8952, Switzerland
- Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, v.le Benedetto XV 10, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- IRCCS Ospedale Policlinico San Martino Genoa – Italian Cardiovascular Network, L.go Rosanna Benzi 10, 16132 Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, v.le Benedetto XV 10, 16132 Genoa, Italy
| | - Jean-Claude Tardif
- Montreal Heart Institute, Université de Montreal, Rue Bélanger 5000, Montreal, QC H1T 1C8, Canada
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Francis Street 75, Boston, MA 02115, USA
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren CH-8952, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
| |
Collapse
|
|
20
|
Role of Heat Shock Protein 27 in Modulating Atherosclerotic Inflammation. J Cardiovasc Transl Res 2020; 14:3-12. [PMID: 32661980 DOI: 10.1007/s12265-020-10000-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/01/2020] [Indexed: 12/20/2022]
Abstract
Atherosclerosis is the primary cause of heart attacks, and while efforts to prevent its development or progression have historically focused largely on reducing cholesterol levels, there is now important proof-of-principle data that supports the role that inflammation plays in atherogenesis. Heat shock protein 27 (HSP27) is a novel biomarker of atherosclerosis that is also atheroprotective. Through a series of murine and in vitro experiments, an iterative narrative is emerging that demonstrates how HSP27 can act as an extracellular mediator that reduces plaque inflammation-either directly via transcriptional pathways, or indirectly via important effects on macrophage biology. While there is much more to learn about the biology of HSP27, we now review the strong foundation of knowledge that highlights the potential anti-inflammatory role of HSP27 as a novel therapeutic for not only atherosclerosis but potentially other inflammatory disorders.
Collapse
|
|
21
|
Ruscica M, Corsini A, Ferri N, Banach M, Sirtori CR. Clinical approach to the inflammatory etiology of cardiovascular diseases. Pharmacol Res 2020; 159:104916. [PMID: 32445957 PMCID: PMC7238995 DOI: 10.1016/j.phrs.2020.104916] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 02/06/2023]
Abstract
Inflammation is an obligatory marker of arterial disease, both stemming from the inflammatory activity of cholesterol itself and from well-established molecular mechanisms. Raised progenitor cell recruitment after major events and clonal hematopoiesis related mechanisms have provided an improved understanding of factors regulating inflammatory phenomena. Trials with inflammation antagonists have led to an extensive evaluation of biomarkers such as the high sensitivity C reactive protein (hsCRP), not exerting a causative role, but frequently indicative of the individual cardiovascular (CV) risk. Aim of this review is to provide indication on the anti-inflammatory profile of agents of general use in CV prevention, i.e. affecting lipids, blood pressure, diabetes as well nutraceuticals such as n-3 fatty acids. A crucial issue in the evaluation of the benefit of the anti-inflammatory activity is the frequent discordance between a beneficial activity on a major risk factor and associated changes of hsCRP, as in the case of statins vs PCSK9 antagonists. In hypertension, angiotensin converting enzyme inhibitors exert an optimal anti-inflammatory activity, vs the case of sartans. The remarkable preventive activity of SLGT-2 inhibitors in heart failure is not associated with a clear anti-inflammatory mechanism. Finally, icosapent ethyl has been shown to reduce the CV risk in hypertriglyceridemia, with a 27 % reduction of hsCRP. The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals.
Collapse
Affiliation(s)
- Massimiliano Ruscica
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy; Multimedica IRCCS, Milano, Italy
| | - Nicola Ferri
- Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
| | - Cesare R Sirtori
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
22
|
Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, Blonde L, Bush MA, DeFronzo RA, Garber JR, Garvey WT, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Perreault L, Rosenblit PD, Samson S, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2020 EXECUTIVE SUMMARY. Endocr Pract 2020; 26:107-139. [PMID: 32022600 DOI: 10.4158/cs-2019-0472] [Citation(s) in RCA: 383] [Impact Index Per Article: 76.6] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
23
|
Quispe R, Michos ED, Martin SS, Puri R, Toth PP, Al Suwaidi J, Banach M, Virani SS, Blumenthal RS, Jones SR, Elshazly MB. High-Sensitivity C-Reactive Protein Discordance With Atherogenic Lipid Measures and Incidence of Atherosclerotic Cardiovascular Disease in Primary Prevention: The ARIC Study. J Am Heart Assoc 2020; 9:e013600. [PMID: 32013698 PMCID: PMC7033866 DOI: 10.1161/jaha.119.013600] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background Inflammation is an independent causal risk factor for atherosclerotic cardiovascular diseases (ASCVDs). However, whether hsCRP (high-sensitivity C-reactive protein) is prognostic across various levels of atherogenic lipid measures such as low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B and total cholesterol/high-density lipoprotein cholesterol in primary prevention is unknown. Methods and Results We studied 9748 ARIC (Atherosclerosis Risk in Communities) study participants who were free of ASCVD at baseline (visit 4, 1996-1998) and had measurements of lipids, apolipoprotein B, and hsCRP. We used multivariable adjusted Cox models to estimate the risk of incident ASCVD events associated with hsCRP levels (less than/greater than or equal to median) in individuals where triple lipid measures combined (low-density lipoprotein cholesterol + non-high-density lipoprotein cholesterol + apolipoprotein B) or quadruple measures combined [triple + total cholesterol/high-density lipoprotein cholesterol] were less than versus greater than or equal to median cut points. Mean age of participants was 62.6±5.6 years; 59% women, 22% black. There were 1574 ASCVD events over median (interquartile range) follow-up of 18.4 (12.8-19.5) years, and discordance between hsCRP and lipid measures was prevalent in 50% of the population. hsCRP greater than or equal to median (2.4 mg/L), compared with less than median, was associated with an increased risk of ASCVD in individuals with less than median levels of the triple (adjusted hazard ratio, 1.33; 95% CI, 1.09-1.60) and quadruple (adjusted hazard ratio,1.47; 95% CI, 1.18-1.85) lipid measures. Such increased risk was consistent among individuals with low (<7.5%) or high (≥7.5%) estimated risk by the pooled cohort equation. There were no interactions by sex, diabetes mellitus, or statin use. Conclusions Our findings suggest that inflammation is independently associated with ASCVD regardless of atherogenic lipid levels and pooled cohort equation risk score in individuals without known ASCVD.
Collapse
Affiliation(s)
- Renato Quispe
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD
| | - Erin D Michos
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD
| | - Seth S Martin
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD
| | - Rishi Puri
- Department of Cardiovascular Medicine, Heart and Vascular Institute Cleveland Clinic Cleveland OH
| | - Peter P Toth
- Department of Preventive Cardiology CGH Medical Center Sterling IL.,University of Illinois College of Medicine Peoria IL
| | - Jassim Al Suwaidi
- Division of Cardiology Department of Medicine Weill Cornell Medical College-Qatar Doha Qatar.,Department of Cardiology Heart Hospital HMC Doha Qatar
| | - Maciej Banach
- Department of Hypertension Medical University of Lodz Lodz Poland
| | - Salim S Virani
- Michael E. DeBakey Veterans Affairs Medical Center and Section of Cardiovascular Research Department of Medicine Baylor College of Medicine Houston TX
| | - Roger S Blumenthal
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD
| | - Steven R Jones
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD
| | - Mohamed B Elshazly
- Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins School of Medicine Baltimore MD.,Department of Cardiovascular Medicine, Heart and Vascular Institute Cleveland Clinic Cleveland OH.,Department of Cardiology Heart Hospital HMC Doha Qatar
| |
Collapse
|
|
24
|
Ma C, Gurol ME, Huang Z, Lichtenstein AH, Wang X, Wang Y, Neumann S, Wu S, Gao X. Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study. Neurology 2019; 93:e445-e457. [PMID: 31266905 PMCID: PMC6693427 DOI: 10.1212/wnl.0000000000007853] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/13/2019] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE To prospectively examine the association between low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations and intracerebral hemorrhage (ICH) risk. METHODS The current cohort study included 96,043 participants (mean age 51.3 years) who were free of stroke, myocardial infarction, and cancer at baseline (2006). Serum LDL-C concentrations were assessed in 2006, 2008, 2010, and 2012. Cumulative average LDL-C concentrations were calculated from all available LDL-C data during that period. Incident ICH was confirmed by review of medical records. RESULTS We identified 753 incident ICH cases during 9 years of follow-up. The ICH risk was similar among participants with LDL concentrations of 70 to 99 mg/dL and those with LDL-C concentrations ≥100 mg/dL. In contrast, participants with LDL-C concentrations <70 mg/dL had a significantly higher risk of developing ICH than those with LDL-C concentrations of 70 to 99 mg/dL; adjusted hazard ratios were 1.65 (95% confidence interval [CI] 1.32-2.05) for LDL-C concentrations of 50 to 69 mg/dL and 2.69 (95% CI 2.03-3.57) for LDL-C concentrations <50 mg/dL. CONCLUSIONS We observed a significant association between lower LDL-C and higher risk of ICH when LDL-C was <70 mg/dL, and the association became nonsignificant when LDL-C ≥70 mg/dL. These data can help determination of the ideal LDL range in patients who are at increased risk of both atherosclerotic disease and hemorrhagic stroke and guide planning of future lipid-lowering studies.
Collapse
Affiliation(s)
- Chaoran Ma
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - M Edip Gurol
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Zhe Huang
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Alice H Lichtenstein
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Xiuyan Wang
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Yuzhen Wang
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Samantha Neumann
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA
| | - Shouling Wu
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA.
| | - Xiang Gao
- From the Department of Nutritional Sciences (C.M.), Eberly College of Science (S.N.), and Department of Nutritional Sciences (X.G.), Pennsylvania State University, University Park; Hemorrhagic Stroke Research Program (M.E.G.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Cardiology (Z.H., S.W.) and Neurology (X.W., Y.W.), Kailuan General Hospital, Tangshan, China; and Jean Mayer USDA Human Nutrition Research Center on Aging (A.H.L.), Tufts University, Boston, MA.
| |
Collapse
|
|
25
|
Ruscica M, Tokgözoğlu L, Corsini A, Sirtori CR. PCSK9 inhibition and inflammation: A narrative review. Atherosclerosis 2019; 288:146-155. [PMID: 31404822 DOI: 10.1016/j.atherosclerosis.2019.07.015] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/06/2019] [Accepted: 07/17/2019] [Indexed: 12/21/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite excellent pharmacological and revascularization approaches. Low-density lipoproteins (LDL) are undoubtedly the most significant biochemical variables associated with atheroma, however, compelling data identify inflammation as critical for the maintenance of the atherosclerotic process, underlying some of the most feared vascular complications. Although its causal role is questionable, high-sensitivity C-reactive protein (hs-CRP) represents a major biomarker of inflammation and associated risk in CVD. While statin-associated reduced risk may be related to the lowering of both LDL-C and hs-CRP, PCSK9 inhibitors leading to dramatic LDL-C reductions do no alter hs-CRP levels. On the other hand, hs-CRP levels identify groups of patients with a high risk of CV disease achieving better ASCVD prevention in response to PCSK9 inhibition. In the FOURIER study, even in patients with extremely low levels of LDL-C, there was a stepwise risk increment according to the values of hs-CRP: +9% (<1 mg/L), +10.8% (1-3 mg/L) and +13.1% (>3 mg/L). Likewise, in the SPIRE-1 and -2 studies, bococizumab patients with hs-CRP> 3 mg/L had a 60% greater risk of future CV events. Most of the patients enrolled in the PCSK9 trials were on maximally tolerated statin therapy at baseline, and an elevated hs-CRP may reflect residual inflammatory risk after standard LDL-C lowering therapy. Moreover, data on changes in inflammation markers in carriers of PCSK9 loss-of-function mutations are scanty and not conclusive, thus, evidence from the effects of anti-inflammatory molecules on PCSK9 levels might help unravel this hitherto complex tangle.
Collapse
Affiliation(s)
- Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
| | - Lale Tokgözoğlu
- Department of Cardiology, Hacettepe University, Ankara, Turkey
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; Multimedica IRCCS, Milan, Italy
| | - Cesare R Sirtori
- Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
| |
Collapse
|
|
26
|
Tawakol A, Jaffer F. Imaging the Intersection of Oxidative Stress, Lipids, and Inflammation: Progress Toward Personalized Care of Atherosclerosis. J Am Coll Cardiol 2019; 71:336-338. [PMID: 29348026 DOI: 10.1016/j.jacc.2017.11.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Ahmed Tawakol
- Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Farouc Jaffer
- Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
27
|
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2019 EXECUTIVE SUMMARY. Endocr Pract 2019; 25:69-100. [PMID: 30742570 DOI: 10.4158/cs-2018-0535] [Citation(s) in RCA: 217] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
28
|
Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract 2019; 23:1-87. [PMID: 28437620 DOI: 10.4158/ep171764.appgl] [Citation(s) in RCA: 669] [Impact Index Per Article: 111.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. RESULTS The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). CONCLUSION This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. ABBREVIATIONS 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative.
Collapse
|
|
29
|
Aday AW, Ridker PM. Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease. Front Cardiovasc Med 2019; 6:16. [PMID: 30873416 PMCID: PMC6403155 DOI: 10.3389/fcvm.2019.00016] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/11/2019] [Indexed: 12/21/2022] Open
Abstract
As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This "residual inflammatory risk" has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.
Collapse
Affiliation(s)
- Aaron W Aday
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Paul M Ridker
- Divisions of Preventive Medicine and Cardiovascular Medicine, Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
30
|
Katsiki N, Mikhailidis DP. Lipids: a personal view of the past decade. Hormones (Athens) 2018; 17:461-478. [PMID: 30229482 DOI: 10.1007/s42000-018-0058-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 08/31/2018] [Indexed: 12/27/2022]
Abstract
The past decade has witnessed considerable progress in the field of lipids. New drugs have been "rapidly" developed and some of these drugs have already been evaluated in event-based large trials. This evidence has led to the guidelines recommending new, more aggressive treatment goals for low-density lipoprotein cholesterol (LDL-C) levels. Although LDL-C remains the principal goal for cardiovascular disease (CVD) risk reduction, there has also been considerable interest in other lipid variables, such as high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Statin intolerance is now considered a very important topic in daily clinical practice. This has resulted in more attention focusing on non-statin drugs [e.g., ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors] and statin-related side effects. The latter mainly involve muscles, but there is also a need to consider other adverse effects associated with statin use (e.g., new onset diabetes). New specific areas of statin use have attracted interest. For example, statin-loading before procedures (e.g., coronary stenting), the prevention of stroke, and the treatment of non-alcoholic fatty liver disease (NAFLD). Statins will remain the most widely used drugs to treat dyslipidaemia and decrease CVD risk. However, we also need to briefly consider some other lipid-lowering drugs, including those that may become available in the future.
Collapse
Affiliation(s)
- Niki Katsiki
- Second Department of Propaedeutic Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London, NW3 2QG, UK.
| |
Collapse
|
|
31
|
Koskinas KC, Windecker S, Buhayer A, Gencer B, Pedrazzini G, Mueller C, Cook S, Muller O, Matter CM, Räber L, Heg D, Mach F. Design of the randomized, placebo-controlled evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial. Clin Cardiol 2018; 41:1513-1520. [PMID: 30421481 DOI: 10.1002/clc.23112] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/26/2018] [Accepted: 11/08/2018] [Indexed: 12/14/2022] Open
Abstract
Statins lower low-density lipoprotein cholesterol (LDL-C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL-C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9)-inhibitor resulting in rapid, marked LDL-C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL-cholesterol levels in patients with ACS (EVOPACS), a phase-3, multicenter, randomized, double-blind, placebo-controlled trial to assess the feasibility, safety, and LDL-C-lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL-C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL-C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C-reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast-induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub-study will investigate the change from baseline in the lipid core burden index in non-culprit lesions, as assessed by serial near-infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned.
Collapse
Affiliation(s)
| | - Stephan Windecker
- Department of Cardiology, Bern University Hospital, Bern, Switzerland
| | | | - Baris Gencer
- Department of Cardiology, Geneva University Hospital, Geneva, Switzerland
| | | | - Christian Mueller
- Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland
| | - Stephan Cook
- Department of Cardiology, Fribourg Hospital and University, Fribourg, Switzerland
| | - Olivier Muller
- Service of Cardiology, Lausanne University Hospital, Lausanne, Switzerland
| | - Christian M Matter
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Lorenz Räber
- Department of Cardiology, Bern University Hospital, Bern, Switzerland
| | - Dik Heg
- CTU Bern, University of Bern, Bern, Switzerland
| | - François Mach
- Department of Cardiology, Geneva University Hospital, Geneva, Switzerland
| | | |
Collapse
|
|
32
|
Balanova YA, Kontsevaya AV, Imaeva AE, Karpov OI, Khudyakov MB. Economic losses due to low coverage of lipid-lowering therapy in patients with cardiovascular diseases in the Russian Federation. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2018. [DOI: 10.20996/1819-6446-2018-14-5-716-724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
| | | | - A. E. Imaeva
- National Medical Research Center for Preventive Medicine
| | | | | |
Collapse
|
|
33
|
Ruscica M, Ferri N, Macchi C, Corsini A, Sirtori CR. Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes? Ann Med 2018; 50:461-484. [PMID: 29976096 DOI: 10.1080/07853890.2018.1498118] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.
Collapse
Affiliation(s)
- M Ruscica
- a Dipartimento di Scienze Farmacologiche e Biomolecolari , Università degli Studi di Milano , Milan , Italy
| | - N Ferri
- b Dipartimento di Scienze del Farmaco , Università degli Studi di Padova , Padova , Italy
| | - C Macchi
- a Dipartimento di Scienze Farmacologiche e Biomolecolari , Università degli Studi di Milano , Milan , Italy
| | - A Corsini
- a Dipartimento di Scienze Farmacologiche e Biomolecolari , Università degli Studi di Milano , Milan , Italy
| | - C R Sirtori
- c Centro Dislipidemie , A.S.S.T. Grande Ospedale Metropolitano Niguarda , Milan , Italy
| |
Collapse
|
|
34
|
Aday AW, Ridker PM. Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond. Front Cardiovasc Med 2018; 5:62. [PMID: 29922680 PMCID: PMC5996084 DOI: 10.3389/fcvm.2018.00062] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/16/2018] [Indexed: 01/13/2023] Open
Abstract
Inflammation is a critical pathway in the pathogenesis of atherosclerosis. Previous studies have shown that plasma levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, are associated with cardiovascular disease independent of traditional risk factors. Randomized trial data have also shown that statins reduce not only hsCRP but also cardiovascular event rates independent of their effect on low-density lipoprotein cholesterol (LDL-C) level. More recently, the CANTOS trial showed that directly reducing inflammation with canakinumab, an interleukin (IL)-1β neutralizing monoclonal antibody, could also reduce cardiovascular event rates. These mark the first phase 3 trial results validating inflammation as a viable target for preventing cardiovascular disease. In this review, we recap the role of inflammation in cardiovascular disease and highlight previous trial data showing its modulation with statins and other agents. We also detail the CANTOS trial results and discuss its implications for clinicians as well as future directions for anti-inflammatory therapy in the prevention of cardiovascular disease.
Collapse
Affiliation(s)
- Aaron W Aday
- Divisions of Preventive Medicine and Cardiovascular Medicine, Department of Medicine, Center for Cardiovascular Disease Prevention, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States
| | - Paul M Ridker
- Divisions of Preventive Medicine and Cardiovascular Medicine, Department of Medicine, Center for Cardiovascular Disease Prevention, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States
| |
Collapse
|
|
35
|
Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018; 391:319-328. [PMID: 29146124 DOI: 10.1016/s0140-6736(17)32814-3] [Citation(s) in RCA: 615] [Impact Index Per Article: 87.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 10/29/2017] [Accepted: 10/30/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients. METHODS The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846. FINDINGS Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration. INTERPRETATION The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab. FUNDING Novartis Pharmaceuticals.
Collapse
Affiliation(s)
- Paul M Ridker
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Jean G MacFadyen
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Brendan M Everett
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Peter Libby
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tom Thuren
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; Novartis Pharmaceutical Corporation, Basel, Switzerland
| | - Robert J Glynn
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
36
|
Ghasemzadeh N, Brooks MM, Vlachos H, Hardison R, Sikora S, Sperling L, Quyyumi AA, Epstein SE. An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes). J Am Heart Assoc 2017; 6:JAHA.116.003587. [PMID: 28673897 PMCID: PMC5586254 DOI: 10.1161/jaha.116.003587] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background In a previous study, we found that a biomarker risk score (BRS) comprised of C‐reactive protein, fibrin‐degradation products, and heat shock protein‐70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. Methods and Results Two thousand thirty‐two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut‐off values (C‐reactive protein >3 mg/L, heat shock protein‐70 >0.313 ng/mL, and fibrin‐degradation products >1 μg/mL). After adjustment for covariates, those with a BRS of 3 had a 4‐fold increased risk of all‐cause death and a 6.8‐fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9–16.0; P<0.0001). All individual biomarkers decreased by 1 year, with ≈80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1‐year BRS of 2 to 3 had a 4‐year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P<0.0001). Conclusions Our results validate the ability of the BRS to identify coronary artery disease patients at very high near‐term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.
Collapse
Affiliation(s)
| | - Maria M Brooks
- Graduate School of Public Health, University of Pittsburgh, PA
| | - Helen Vlachos
- Graduate School of Public Health, University of Pittsburgh, PA
| | - Regina Hardison
- Graduate School of Public Health, University of Pittsburgh, PA
| | | | | | | | - Stephen E Epstein
- MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC
| |
Collapse
|
|
37
|
Wu CK, Yeh CF, Chiang JY, Lin TT, Wu YF, Chiang CK, Kao TW, Hung KY, Huang JW. Effects of atorvastatin treatment on left ventricular diastolic function in peritoneal dialysis patients—The ALEVENT clinical trial. J Clin Lipidol 2017; 11:657-666. [DOI: 10.1016/j.jacl.2017.02.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/12/2017] [Accepted: 02/28/2017] [Indexed: 12/31/2022]
|
|
38
|
Lin CJ, Liao WC, Chen YA, Lin HJ, Feng CL, Lin CL, Lin YJ, Kao MC, Huang MZ, Lai CH, Kao CH. Statin Therapy Is Associated with Reduced Risk of Peptic Ulcer Disease in the Taiwanese Population. Front Pharmacol 2017; 8:210. [PMID: 28503146 PMCID: PMC5408271 DOI: 10.3389/fphar.2017.00210] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/05/2017] [Indexed: 12/17/2022] Open
Abstract
Although statin use may affect the severity of chronic gastritis and gastric cancer, no data exists about the relationship between statin therapy and risk of peptic ulcer disease (PUD) in patients. We investigated the effect of statin use and the incidence of PUD from the Taiwan National Health Insurance Research Database (NHIRD). A total of 35,194 patients records for medical claims were enrolled. We performed a population-based case-control analysis to compare the incidence of PUD in patients who were prescribed statins and that in patients who were not. In the univariate logistic analysis, we found that statin was not significant risk of PUD. However, a multivariate model indicates that satin use was significantly associated with a reduced risk of PUD (adjusted odds ratio [aOR] = 0.87, 95% CI = 0.82-0.93, P < 0.001). The cumulative defined daily dose (DDD) was analyzed. Patients who prescribed fluvastatin ≥280 DDD, atorvastatin ≥200 DDD, and pravastatin ≥130 DDD dramatically decreased risk for PUD (aOR = 0.58, 0.67, and 0.71; 95% CI = 0.46-0.74, 0.57-0.78, and 0.56-0.91, respectively). Our results showed that statin therapy reduced the risk of PUD and this was associated with the high cumulative DDD of prescribed statins. This study reveals that active use of statins to be associated with decreased risk for PUD.
Collapse
Affiliation(s)
- Chun-Jung Lin
- Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA.,Graduate Institute of Clinical Medical Science, China Medical UniversityTaichung, Taiwan
| | - Wei-Chih Liao
- Graduate Institute of Clinical Medical Science, China Medical UniversityTaichung, Taiwan.,Department of Pulmonary and Critical Care Medicine, China Medical University HospitalTaichung, Taiwan
| | - Yu-An Chen
- School of Medicine, Graduate Institute of Basic Medical Science, China Medical UniversityTaichung, Taiwan
| | - Hwai-Jeng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho HospitalNew Taipei, Taiwan
| | - Chun-Lung Feng
- Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University HospitalTaichung, Taiwan.,College of Medicine, China Medical UniversityTaichung, Taiwan
| | - Ying-Ju Lin
- Genetic Center, Department of Medical Research, School of Chinese Medicine, China Medical University and HospitalTaichung, Taiwan
| | - Min-Chuan Kao
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung UniversityTaoyuan, Taiwan
| | - Mei-Zi Huang
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung UniversityTaoyuan, Taiwan
| | - Chih-Ho Lai
- School of Medicine, Graduate Institute of Basic Medical Science, China Medical UniversityTaichung, Taiwan.,Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung UniversityTaoyuan, Taiwan.,Department of Nursing, Asia UniversityTaichung, Taiwan.,Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial HospitalTaoyuan, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Clinical Medical Science, China Medical UniversityTaichung, Taiwan.,Department of Bioinformatics and Medical Engineering, Asia UniversityTaichung, Taiwan.,Department of Nuclear Medicine, PET Center, China Medical University HospitalTaichung, Taiwan
| |
Collapse
|
|
39
|
Sandhu K, Mamas M, Butler R. Endothelial progenitor cells: Exploring the pleiotropic effects of statins. World J Cardiol 2017; 9:1-13. [PMID: 28163831 PMCID: PMC5253189 DOI: 10.4330/wjc.v9.i1.1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/29/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023] Open
Abstract
Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction, prior to any significant change in lipid profile. Therefore, pleiotropic mechanisms, other than lowering lipid profile alone, must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell (EPC) identification, role in vascular repair, factors affecting EPC numbers, the role of statins in current medical practice and their effects on EPC number.
Collapse
|
|
40
|
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2017 EXECUTIVE SUMMARY. Endocr Pract 2017; 23:207-238. [PMID: 28095040 DOI: 10.4158/ep161682.cs] [Citation(s) in RCA: 331] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
41
|
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Henry RR, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY. Endocr Pract 2016; 22:84-113. [PMID: 26731084 DOI: 10.4158/ep151126.cs] [Citation(s) in RCA: 335] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
42
|
Tani S, Nagao K, Hirayama A. Association of systemic inflammation with the serum apolipoprotein A-1 level: A cross-sectional pilot study. J Cardiol 2016; 68:168-77. [DOI: 10.1016/j.jjcc.2015.08.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 08/06/2015] [Accepted: 08/27/2015] [Indexed: 12/18/2022]
|
|
43
|
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2015 EXECUTIVE SUMMARY. Endocr Pract 2016; 21:1403-14. [PMID: 26642101 DOI: 10.4158/ep151063.cs] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.
Collapse
|
|
44
|
Radojkovic J, Sikanic N, Bukumiric Z, Tadic M, Kostic N, Babic R. Improvement of Glycemic Control in Insulin-Dependent Diabetics with Depression by Concomitant Treatment with Antidepressants. Med Sci Monit 2016; 22:2133-43. [PMID: 27329213 PMCID: PMC4920101 DOI: 10.12659/msm.899571] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background It is still disputable whether negative effects of comorbid depression in diabetics can be diminished by successful treatment of depression. The primary aim of this study was to assess whether addition of antidepressants to existing insulin treatment would further improve glycemic control in these patients. A secondary objective was to assess whether such treatment impairs their lipid and inflammatory status. Material/Methods Total of 192 patients with poorly controlled diabetes (defined as HbA1c ≥8%) in the absence of any uncontrolled medical condition entered the 6-month run-in phase with optimization of diabetic therapy. Depression status was screened at the end of this phase by BDI-II depression testing. Patients with BDI-II ≥14 and psychiatric confirmation of depression (58 patients) entered the 6-month interventional phase with SSRI class antidepressants. Results Fifty patients completed the study. During the run-in phase, HbA1c dropped from 10.0±1.8% to 8.5±1.2% (p<0.001), and during the interventional phase it dropped from 8.5±1.2% to 7.7±0.7% (p<0.001). BDI-II scores improved significantly from 30.4±13.2 to 23.5±11.0 (p=0.02) during the interventional phase. A positive linear correlation between improvement in depression scale and improvement in glycemic control was observed (R2=0.139, p=0.008). Lipid profile and inflammatory status did not change significantly during the interventional phase. Conclusions Patients with poorly controlled diabetes and comorbid depression might benefit from screening and treatment of depression with SSRI antidepressants by achieving an incremental effect on glycoregulation. This therapy did not have any adverse effects on lipid profile or inflammatory status.
Collapse
Affiliation(s)
- Jana Radojkovic
- Department of Clinical Endocrinology, Clinical Center "Dr Dragisa Misovic", Belgrade, Serbia
| | - Natasa Sikanic
- Department of Clinical Psychiatry, Clinical Center "Dr Dragisa Misovic", Belgrade, Serbia
| | - Zoran Bukumiric
- Department of Medical Statistics, University School of Medicine, Belgrade, Serbia
| | - Marijana Tadic
- Department of Internal Medicine, University School of Medicine, Belgrade, Serbia
| | - Nada Kostic
- Department of Clinical Endocrinology, Clinical Center "Dr Dragisa Misovic", Belgrade, Serbia
| | - Rade Babic
- Department of Internal Medicine, University School of Medicine, Belgrade, Serbia
| |
Collapse
|
|
45
|
Kamath DY, Xavier D, Sigamani A, Pais P. High sensitivity C-reactive protein (hsCRP) & cardiovascular disease: An Indian perspective. Indian J Med Res 2016; 142:261-8. [PMID: 26458341 PMCID: PMC4669860 DOI: 10.4103/0971-5916.166582] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The role of low grade systemic inflammation as evidenced by elevated high sensitivity C-reactive protein (hsCRP) levels in the pathogenesis of atherosclerotic vascular disease has been intensely investigated through observational studies and clinical trials in the past two decades. On the basis of evidence that has accrued, hsCRP measurement has been integrated into the Reynolds risk scoring system to predict cardiovascular risk. The JUPITER trial proved the benefit of statins in cardiovascular risk reduction in patients with low grades of systemic inflammation and ‘normal’ cholesterol levels. However, substantial evidence has been generated from western studies. We, therefore, conducted a scoping review for studies done in India with a view to identify gaps in evidence and make further recommendations. Most Indian studies had small sample sizes and short term follow ups. There were no large population based prospective studies where patients were followed up for long periods of time for major cardiovascular end points. An analysis of the hsCRP level from the control arms of case-control studies derived a mean hsCRP value of 1.88 mg/l, which is higher than the western population where values < 1 mg/l are classified as low cardiovascular risk. Further large prospective cohort studies with longer term follow ups are essential before we can make further recommendations to integrate hsCRP into risk prediction models for cardiovascular disease prevention.
Collapse
Affiliation(s)
| | | | | | - Prem Pais
- Division of Clinical Research & Training, St. John's Research Institute, St. John's National Academy of Health Sciences, Bengaluru, India
| |
Collapse
|
|
46
|
Fonseca FAH, de Oliveira Izar MC. High-Sensitivity C-Reactive Protein and Cardiovascular Disease Across Countries and Ethnicities. Clinics (Sao Paulo) 2016; 71:235-42. [PMID: 27166776 PMCID: PMC4825196 DOI: 10.6061/clinics/2016(04)11] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 02/12/2016] [Indexed: 12/22/2022] Open
Abstract
Despite substantial differences in ethnicities, habits, cultures, the prevalence of traditional cardiovascular risk factors and affordable therapies, atherosclerosis remains the major cause of death in developing and developed countries. However, irrespective of these differences, inflammation is currently recognized as the common pathway for the major complications of atherosclerosis, stroke, and ischemic heart disease. A PubMed search was conducted for "high-sensitivity C-reactive protein" (hs-CRP) in combination with the terms race, ethnicity, gender, prevalence, geographic, epidemiology, cardiovascular, obesity, diabetes, hypertension, cholesterol, smoking, ischemic heart disease, stroke, and mortality. This review includes the articles that pertained to the topic and additional articles identified from the reference lists of relevant publications. This review describes the marked differences in cardiovascular mortality across countries and ethnicities, which may be attributed to inequalities in the prevalence of the classic risk factors and the stage of cardiovascular epidemiological transition. However, hs-CRP appears to contribute to the prognostic information regarding cardiovascular risk and mortality even after multiple adjustments. Considering the perception of cardiovascular disease as an inflammatory disease, the more widespread use of hs-CRP appears to represent a valid tool to identify people at risk, independent of their ancestry or geographic region. In conclusion, this review reports that the complications associated with vulnerable atherosclerotic plaques are triggered by the major mechanisms of dyslipidemia and inflammation; whereas both mechanisms are influenced by classic risk factors, hs-CRP contributes additional information regarding cardiovascular events and mortality.
Collapse
|
|
47
|
Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res 2016; 118:145-56. [PMID: 26837745 PMCID: PMC4793711 DOI: 10.1161/circresaha.115.306656] [Citation(s) in RCA: 675] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 10/01/2015] [Indexed: 12/23/2022]
Abstract
Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.
Collapse
Affiliation(s)
- Paul M Ridker
- From the Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
| |
Collapse
|
|
48
|
Michos ED, Martin SS, Blumenthal RS. Bringing back targets to "IMPROVE" atherosclerotic cardiovascular disease outcomes: the duel for dual goals; are two targets better than one? Circulation 2015; 132:1218-20. [PMID: 26330413 DOI: 10.1161/circulationaha.115.018511] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Erin D Michos
- From Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Seth S Martin
- From Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Roger S Blumenthal
- From Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD.
| |
Collapse
|
|
49
|
MacNamara J, Eapen DJ, Quyyumi A, Sperling L. Novel biomarkers for cardiovascular risk assessment: current status and future directions. Future Cardiol 2015; 11:597-613. [DOI: 10.2217/fca.15.39] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in the modern world. Traditional risk algorithms may miss up to 20% of CVD events. Therefore, there is a need for new cardiac biomarkers. Many fields of research are dedicated to improving cardiac risk prediction, including genomics, transcriptomics and proteomics. To date, even the most promising biomarkers have only demonstrated modest associations and predictive ability. Few have undergone randomized control trials. A number of biomarkers are targets to new therapies aimed to reduce cardiovascular risk. Currently, some of the most promising risk prediction has been demonstrated with panels of multiple biomarkers. This article reviews the current state and future of proteomic biomarkers and aggregate biomarker panels.
Collapse
Affiliation(s)
- James MacNamara
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Danny J Eapen
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Arshed Quyyumi
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| | - Laurence Sperling
- Emory University School of Medicine, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA 30322, USA
| |
Collapse
|
|
50
|
Abstract
Coronary artery disease (CAD) is the leading cause of death in the United States. Although CAD was formerly considered a lipid accumulation-mediated disease, it has now been clearly shown to involve an ongoing inflammatory response. Advances in basic science research have established the crucial role of inflammation in mediating all stages of CAD. Today, there is convincing evidence that multiple interrelated immune mechanisms interact with metabolic risk factors to initiate, promote, and ultimately activate lesions in the coronary arteries. This review aims to provide current evidence pertaining to the role of inflammation in the pathogenesis of CAD and discusses the impact of inflammatory markers and their modification on clinical outcomes.
Collapse
|