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Ji M, Dong J, Ye Z, Kang J, Han G, Hong X, Wei Y, Chen X, Sun W, Liu D. Endogenous HClO-Gated Cascade MicroRNA Imaging for Precise Diagnosis of Atherosclerosis In Vivo. J Am Chem Soc 2025; 147:7113-7126. [PMID: 39932706 DOI: 10.1021/jacs.5c00031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
Precise imaging of atherosclerotic plaques using biomarkers could prompt the diagnosis and clinical management of atherosclerosis (AS)-driven cardiovascular diseases. MicroRNA-155 (miR-155) plays a critical role in AS development, with its expression notably upregulated in foam cells within plaques. However, miRNA imaging methods for atherosclerotic plaques face significant challenges, including low specificity, inefficient delivery, and poor cell selectivity. Herein, we develop an endogenous hypochlorous acid (HClO)-gated cascade signal amplification strategy for precise miR-155 imaging in living foam cells, enabling accurate in vivo and ex vivo detection of atherosclerotic plaques. This strategy utilizes a phosphorothioate (PT)-modified hairpin probe that is specifically deprotected by HClO and uncaged by miR-155, triggering a catalytic hairpin assembly (CHA) to amplify fluorescence signals. The PT-CHA probes are encapsulated in lipid nanoparticles (LNs), followed by conjugating with phosphatidylserine (PS)-binding peptide (PBP) for selectively targeting foam cells, enabling in vivo miR-155 imaging in atherosclerotic plaques. The fluorescence intensity of PT-CHA@LN-PBP in the aorta region shows clear differentiation among AS-bearing mice, miR-155-/- mice, and healthy mice. Moreover, the fluorescence intensity strongly correlates with plaque area and AS progression and can discriminate plaque vulnerability risk with an area under the curve (AUC) of 0.94. Imaging of human aortic tissues further validates the probe's capacity to distinguish atherosclerotic plaques from normal endarterium. These findings establish PT-CHA@LN-PBP as a noninvasive, reliable diagnostic tool for precise assessment of AS.
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Affiliation(s)
- Moxuan Ji
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jiantong Dong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Zhuo Ye
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Jingjing Kang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Guimei Han
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xiaoqin Hong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yongchun Wei
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xin Chen
- Department of Cardiovascular Medicine, Tianjin First Center Hospital, Tianjin 300192, China
| | - Wei Sun
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Dingbin Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
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Sherafati A, Norland K, Naderian M, Schaid DJ, Kullo IJ. Polygenic Risk and Coronary Artery Disease Severity. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2024; 17:e004470. [PMID: 39114909 DOI: 10.1161/circgen.123.004470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 06/16/2024] [Indexed: 10/17/2024]
Abstract
BACKGROUND Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause. METHODS We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRSCHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRSCHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent coronary heart disease and incident myocardial infarction. RESULTS A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRSCHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRSCHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10-10), and the Gensini score mediated 90% of this association. CONCLUSIONS PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.
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Affiliation(s)
- Alborz Sherafati
- Department of Cardiovascular Medicine (A.S., K.N., M.N., I.J.K.)
| | - Kristjan Norland
- Department of Cardiovascular Medicine (A.S., K.N., M.N., I.J.K.)
| | | | | | - Iftikhar J Kullo
- Department of Cardiovascular Medicine (A.S., K.N., M.N., I.J.K.)
- Gonda Vascular Center, Mayo Clinic, Rochester, MN (I.J.K.)
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Le A, Peng H, Golinsky D, Di Scipio M, Lali R, Paré G. What Causes Premature Coronary Artery Disease? Curr Atheroscler Rep 2024; 26:189-203. [PMID: 38573470 DOI: 10.1007/s11883-024-01200-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
PURPOSE OF REVIEW This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD). RECENT FINDINGS pCAD refers to coronary artery disease (CAD) occurring before the age of 65 years in women and 55 years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research.
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Affiliation(s)
- Ann Le
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Helen Peng
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Danielle Golinsky
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- School of Nursing, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Matteo Di Scipio
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
- Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Ricky Lali
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Guillaume Paré
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
- Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada.
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Ji M, Wei Y, Ye Z, Hong X, Yu X, Du R, Li Q, Sun W, Liu D. In Vivo Fluorescent Labeling of Foam Cell-Derived Extracellular Vesicles as Circulating Biomarkers for In Vitro Detection of Atherosclerosis. J Am Chem Soc 2024; 146:10093-10102. [PMID: 38545938 DOI: 10.1021/jacs.4c01173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Real-time monitoring of the development of atherosclerosis (AS) is key to the management of cardiovascular disease (CVD). However, existing laboratory approaches lack sensitivity and specificity, mostly due to the dearth of reliable AS biomarkers. Herein, we developed an in vivo fluorescent labeling strategy that allows specific staining of the foam cell-derived extracellular vesicles (EVs) in atherosclerotic plaques, which are released into the blood as circulating biomarkers for in vitro detection of AS. This strategy relies on a self-assembled nanoprobe that could recognize foam cells specifically, where the probe is degraded by the intracellular HClO to produce a trifluoromethyl-bearing boron-dipyrromethene fluorophore (termed B-CF3), a lipophilic dye that can be transferred to the exosomal membranes. These circulating B-CF3-stained EVs can be detected directly on a fluorescence spectrometer or microplate reader without resorting to any sophisticated analytical method. This liquid-biopsy format enables early detection and real-time differentiation of lesion vulnerability during AS progression, facilitating effective CVD management.
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Affiliation(s)
- Moxuan Ji
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yongchun Wei
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Zhuo Ye
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Xiaoqin Hong
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xiaoxuan Yu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Rui Du
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Qiang Li
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Wei Sun
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Dingbin Liu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centers for Cell Responses and New Organic Matter, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
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NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF- κB/NLRP3 Inflammasome Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5217572. [PMID: 34956438 PMCID: PMC8702349 DOI: 10.1155/2021/5217572] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/11/2021] [Indexed: 12/18/2022]
Abstract
Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV-ERB α, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture-prone vulnerable plaque model in hypercholesterolemic ApoE−/− mice and NR1D1−/−ApoE−/− mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P = 0.0325) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P = 0.1392). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE−/− mice, NR1D1−/−ApoE−/− mice exhibited a significantly higher expression level of pyroptosis-related genes in macrophages within the plaque. Further investigation based on mice bone marrow-derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3-inflammasome-dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture-prone vulnerable plaques.
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Fang S, Sun S, Cai H, Zou X, Wang S, Hao X, Wan X, Tian J, Li Z, He Z, Huang W, Liang C, Zhang Z, Yang L, Tian J, Yu B, Sun B. IRGM/Irgm1 facilitates macrophage apoptosis through ROS generation and MAPK signal transduction: Irgm1 +/- mice display increases atherosclerotic plaque stability. Theranostics 2021; 11:9358-9375. [PMID: 34646375 PMCID: PMC8490524 DOI: 10.7150/thno.62797] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 09/02/2021] [Indexed: 02/04/2023] Open
Abstract
Rationale: Atherosclerosis plaque rupture (PR) is the pathological basis and chief culprit of most acute cardiovascular events and death. Given the complex and important role of macrophage apoptosis and autophagy in affecting plaque stability, an important unanswered question include is whether, and how, immunity-related GTPase family M protein (IRGM) and its mouse orthologue IRGM1 affect macrophage survival and atherosclerotic plaque stability. Methods: To investigate whether serum IRGM of ST-segment elevation myocardial infarction (STEMI) patients is related to plaque morphology, we divided 85 STEMI patients into those with and without plaque rupture (PR and non-PR, respectively) based on OCT image analysis, and quantified the patients' serum IRGM levels. Next, we engineered Irgm1 deficient mice (Irgm1+/-) and chimera mice with Irgm1 deficiency in the bone marrow on an ApoE-/- background, which were then fed a high-fat diet for 16 weeks. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. In addition, immunofluorescence, immunohistochemical staining and western blot were used to detect the apoptosis of macrophages in the plaques. In vitro, THP-1 and RAW264.7 cells were stimulated with ox-LDL to mimic the in vivo environment, and IRGM/IRGM1 expression were modified by specific siRNA (knockdown) or IRGM plasmid (knocked-in). The effect of IRGM/Irgm1 on autophagy and apoptosis of macrophages induced by ox-LDL was then evaluated. In addition, we introduced inhibitors of the JNK/p38/ERK signaling pathway to verify the specific mechanism by which Irgm1 regulates RAW264.7 cell apoptosis. Results: The serum IRGM levels of PR patients is significantly higher than that of non-PR patients and healthy volunteers, which may be an effective predictor of PR. On a high-fat diet, Irgm1-deficient mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis is inhibited in the plaques of Irgm1-deficient mice. In vitro, IRGM/Irgm1 deficiency rapidly inhibits ox-LDL-induced macrophage autophagy while inhibiting ox-LDL-induced macrophage apoptosis in late stages. Additionally, IRGM/Irgm1 deficiency suppresses reactive oxygen species (ROS) production in macrophages, while removal of ROS effectively inhibits macrophage apoptosis induced by IRGM overexpression. We further show that Irgm1 can affect macrophage apoptosis by regulating JNK/p38/ERK phosphorylation in the MAPK signaling pathway. Conclusions: Serum IRGM may be related to the process of PR in STEMI patients, and IRGM/Irgm1 deficiency increases plaque stability. In addition, IRGM/Irgm1 deficiency suppresses macrophage apoptosis by inhibiting ROS generation and MAPK signaling transduction. Cumulatively, these results suggest that targeting IRGM may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.
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Bhatt SP. Acute Exacerbations of Chronic Lung Disease: Cardiac Considerations. CARDIAC CONSIDERATIONS IN CHRONIC LUNG DISEASE 2020. [PMCID: PMC7282481 DOI: 10.1007/978-3-030-43435-9_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The importance of appropriately recognizing and managing patients with cardiovascular and pulmonary comorbidities is underscored by the poor outcomes described in complex comorbid patients. Patients with chronic obstructive pulmonary disease (COPD) have an increased risk, up to one-third greater than the general population, of cardiovascular comorbidities including hypertension and diabetes [1].
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Affiliation(s)
- Surya P. Bhatt
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL USA
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Aggarwal A, Srivastava S, Velmurugan M. Newer perspectives of coronary artery disease in young. World J Cardiol 2016; 8:728-734. [PMID: 28070240 PMCID: PMC5183972 DOI: 10.4330/wjc.v8.i12.728] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/03/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Coronary artery disease (CAD) occurring in less than 45 years of age is termed as young CAD. Recent studies show a prevalence of 1.2% of CAD cases in this age group. Ethnic wise south Asians especially Indians are more vulnerable to have CAD in young age group with a prevalence of 5% to 10%. Conventional risk factors such as smoking, diabetes, hypertension, obesity and family history seems to be as important as in older CAD subjects. But the prevalence of these risk factors seems to vary in younger subjects. By far the most commonly associated risk factor is smoking in young CAD. Several genes associated with lipoprotein metabolism are now found to be associated with young CAD like cholesterol ester transfer protein (CETP) gene, hepatic lipase gene, lipoprotein lipase gene, apo A1 gene, apo E gene and apo B. Biomarkers such as lipoprotein (a), fibrinogen, D-dimer, serum Wnt, gamma glutamyl transferase, vitamin D2 and osteocalcin are seems to be associated with premature CAD in some newer studies. In general CAD in young has better prognosis than older subjects. In terms of prognosis two risk factors obesity and current smoking are associated with poorer outcomes. Angiographic studies shows predominance of single vessel disease in young CAD patients. Like CAD in older person primary and secondary prevention plays an important role in prevention of new and further coronary events.
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Cope FO, Abbruzzese B, Sanders J, Metz W, Sturms K, Ralph D, Blue M, Zhang J, Bracci P, Bshara W, Behr S, Maurer T, Williams K, Walker J, Beverly A, Blay B, Damughatla A, Larsen M, Mountain C, Neylon E, Parcel K, Raghuraman K, Ricks K, Rose L, Sivakumar A, Streck N, Wang B, Wasco C, Schlesinger LS, Azad A, Rajaram MVS, Jarjour W, Young N, Rosol T, Williams A, McGrath M. The inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach. Nucl Med Biol 2016; 43:215-25. [PMID: 26924502 PMCID: PMC4794336 DOI: 10.1016/j.nucmedbio.2015.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 11/13/2015] [Accepted: 11/16/2015] [Indexed: 12/30/2022]
Abstract
In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. (99m)Tc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10(-11)M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), that the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 min to bind more tilmanocept (acting as intracellular "drug compilers" of tilmanocept into non-degraded vesicles), gives serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate (99m)Tc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy.
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Affiliation(s)
- Frederick O Cope
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017.
| | - Bonnie Abbruzzese
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - James Sanders
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - Wendy Metz
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - Kristyn Sturms
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - David Ralph
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - Michael Blue
- Navidea Biopharmaceuticals, Drug Development, 5600 Blazer Parkway, Dublin, OH 43017
| | - Jane Zhang
- The University of California San Francisco and the San Francisco General Hospital, AIDS and Cancer Specimen Resource Center, The Department of Pathology, 1001 Potrero Ave, Bldg. 3, Rm 207 San Francisco, CA 94110
| | - Paige Bracci
- The University of California San Francisco and the San Francisco General Hospital, AIDS and Cancer Specimen Resource Center, The Department of Pathology, 1001 Potrero Ave, Bldg. 3, Rm 207 San Francisco, CA 94110
| | - Wiam Bshara
- Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263
| | - Spencer Behr
- Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263
| | - Toby Maurer
- Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263
| | - Kenneth Williams
- Boston College, Department of Biology, 14 Commonwealth Ave, Chestnut Hill, Massachusetts 02467
| | - Joshua Walker
- Boston College, Department of Biology, 14 Commonwealth Ave, Chestnut Hill, Massachusetts 02467
| | - Allison Beverly
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Brooke Blay
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Anirudh Damughatla
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Mark Larsen
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Courtney Mountain
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Erin Neylon
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Kaeli Parcel
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Kapil Raghuraman
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Kevin Ricks
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Lucas Rose
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Akhilesh Sivakumar
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Nicholas Streck
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Bryan Wang
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Christopher Wasco
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | | | | | | | | | | | | | - Amifred Williams
- Navidea Biopharmaceuticals Drug Development Internship Program, 5600 Blazer Parkway, Dublin, OH 43017
| | - Michael McGrath
- The University of California San Francisco and the San Francisco General Hospital, AIDS and Cancer Specimen Resource Center, The Department of Pathology, 1001 Potrero Ave, Bldg. 3, Rm 207 San Francisco, CA 94110
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Ramirez A, Hu PP. Low High-Density Lipoprotein and Risk of Myocardial Infarction. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2015; 9:113-7. [PMID: 26692765 PMCID: PMC4670046 DOI: 10.4137/cmc.s26624] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 08/16/2015] [Accepted: 08/25/2015] [Indexed: 02/02/2023]
Abstract
Low HDL is an independent risk factor for myocardial infarction. This paper reviews our current understanding of HDL, HDL structure and function, HDL subclasses, the relationship of low HDL with myocardial infarction, HDL targeted therapy, and clinical trials and studies. Furthermore potential new agents, such as alirocumab (praluent) and evolocumab (repatha) are discussed.
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Affiliation(s)
- A Ramirez
- University of California, Riverside, School of Medicine, Riverside, CA, USA. ; Riverside Medical Clinic, Riverside, CA, USA
| | - P P Hu
- University of California, Riverside, School of Medicine, Riverside, CA, USA. ; Riverside Medical Clinic, Riverside, CA, USA
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12
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Choi YJ, Jung SC, Lee DH. Vessel Wall Imaging of the Intracranial and Cervical Carotid Arteries. J Stroke 2015; 17:238-55. [PMID: 26437991 PMCID: PMC4635720 DOI: 10.5853/jos.2015.17.3.238] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 08/19/2015] [Accepted: 08/31/2015] [Indexed: 12/05/2022] Open
Abstract
Vessel wall imaging can depict the morphologies of atherosclerotic plaques, arterial walls, and surrounding structures in the intracranial and cervical carotid arteries beyond the simple luminal changes that can be observed with traditional luminal evaluation. Differentiating vulnerable from stable plaques and characterizing atherosclerotic plaques are vital parts of the early diagnosis, prevention, and treatment of stroke and the neurological adverse effects of atherosclerosis. Various techniques for vessel wall imaging have been developed and introduced to differentiate and analyze atherosclerotic plaques in the cervical carotid artery. High-resolution magnetic resonance imaging (HR-MRI) is the most important and popular vessel wall imaging technique for directly evaluating the vascular wall and intracranial artery disease. Intracranial artery atherosclerosis, dissection, moyamoya disease, vasculitis, and reversible cerebral vasoconstriction syndrome can also be diagnosed and differentiated by using HR-MRI. Here, we review the radiologic features of intracranial artery disease and cervical carotid artery atherosclerosis on HR-MRI and various other vessel wall imaging techniques (e.g., ultrasound, computed tomography, magnetic resonance, and positron emission tomography-computed tomography).
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Affiliation(s)
- Young Jun Choi
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung Chai Jung
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Deok Hee Lee
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Diffuse calcifications protect carotid plaques regardless of the amount of neoangiogenesis and related histological complications. BIOMED RESEARCH INTERNATIONAL 2015; 2015:795672. [PMID: 25883974 PMCID: PMC4389976 DOI: 10.1155/2015/795672] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/16/2014] [Accepted: 01/13/2015] [Indexed: 01/25/2023]
Abstract
Background. Neoangiogenesis is crucial in plaque progression and instability. Previous data from our group showed that Nestin-positive intraplaque neovessels correlated with histological complications. The aim of the present work is to evaluate the relationship between neoangiogenesis, plaque morphology, and clinical instability of the plaque. Materials and Methods. Seventy-three patients (53 males and 20 females, mean age 71 years) were consecutively enrolled. Clinical data and 14 histological variables, including intraplaque hemorrhage and calcifications, were collected. Immunohistochemistry for CD34 and Nestin was performed. RT-PCR was performed to evaluate Nestin mRNA (including 5 healthy arteries as controls). Results. Diffusely calcified plaques (13/73) were found predominantly in females (P = 0.017), with a significantly lower incidence of symptoms (TIA/stroke (P = 0.019) than noncalcified plaques but with the same incidence of histological complications (P = 0.156)). Accordingly, calcified and noncalcified plaques showed similar mean densities of positivity for CD34 and Nestin. Nestin density, but not CD34, correlated with the occurrence of intraplaque hemorrhage. Conclusions. Plaques with massive calcifications show the same incidence of histological complications but without influencing symptomatology, especially in female patients, and regardless of the amount of neoangiogenesis. These results can be applied in a future presurgical identification of patients at major risk of developing symptoms.
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Kullo IJ, Trejo-Gutierrez JF, Lopez-Jimenez F, Thomas RJ, Allison TG, Mulvagh SL, Arruda-Olson AM, Hayes SN, Pollak AW, Kopecky SL, Hurst RT. A perspective on the New American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment. Mayo Clin Proc 2014; 89:1244-56. [PMID: 25131696 DOI: 10.1016/j.mayocp.2014.06.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/17/2014] [Accepted: 06/23/2014] [Indexed: 01/21/2023]
Abstract
The recently published American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for cardiovascular risk assessment provide equations to estimate the 10-year and lifetime atherosclerotic cardiovascular disease (ASCVD) risk in African Americans and non-Hispanic whites, include stroke as an adverse cardiovascular outcome, and emphasize shared decision making. The guidelines provide a valuable framework that can be adapted on the basis of clinical judgment and individual/institutional expertise. In this review, we provide a perspective on the new guidelines, highlighting what is new, what is controversial, and potential adaptations. We recommend obtaining family history of ASCVD at the time of estimating ASCVD risk and consideration of imaging to assess subclinical disease burden in patients at intermediate risk. In addition to the adjuncts for ASCVD risk estimation recommended in the guidelines, measures that may be useful in refining risk estimates include carotid ultrasonography, aortic pulse wave velocity, and serum lipoprotein(a) levels. Finally, we stress the need for research efforts to improve assessment of ASCVD risk given the suboptimal performance of available risk algorithms and suggest potential future directions in this regard.
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Affiliation(s)
- Iftikhar J Kullo
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
| | | | | | - Randal J Thomas
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | | | | | | | | | - Amy W Pollak
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | | | - R Todd Hurst
- Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ
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15
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Bang OY, Ovbiagele B, Kim JS. Evaluation of Cryptogenic Stroke With Advanced Diagnostic Techniques. Stroke 2014; 45:1186-94. [DOI: 10.1161/strokeaha.113.003720] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Oh Young Bang
- From the Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (O.Y.B.); Department of Neurosciences, Medical University of South Carolina, Charleston (B.O.); and Department of Neurology, Asan Medical Center, University of Ulsan, Seoul, South Korea (J.S.K.)
| | - Bruce Ovbiagele
- From the Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (O.Y.B.); Department of Neurosciences, Medical University of South Carolina, Charleston (B.O.); and Department of Neurology, Asan Medical Center, University of Ulsan, Seoul, South Korea (J.S.K.)
| | - Jong S. Kim
- From the Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (O.Y.B.); Department of Neurosciences, Medical University of South Carolina, Charleston (B.O.); and Department of Neurology, Asan Medical Center, University of Ulsan, Seoul, South Korea (J.S.K.)
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16
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Kuo YS, Kelle S, Lee C, Hinojar R, Nagel E, Botnar R, Puntmann VO. Contrast-enhanced cardiovascular magnetic resonance imaging of coronary vessel wall: state of art. Expert Rev Cardiovasc Ther 2014; 12:255-63. [PMID: 24417398 DOI: 10.1586/14779072.2014.877838] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Coronary wall imaging by cardiovascular magnetic resonance (CMR) emerges as a promising method to detect vascular injury and remodeling directly within the coronary vascular wall. In this review, the current evidence on coronary wall enhancement using CMR is presented and summarized, with particular focus on its ability to detect inflammation in atherosclerosis, Takayasu's arteritis, acute coronary syndromes and immune-mediated inflammatory vasculitides. The authors review the possible mechanisms of coronary wall contrast enhancement on CMR and discuss the technical considerations and limitations. Lastly, the potential clinical applications and possibilities for future research are proposed.
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Affiliation(s)
- Yen-Shu Kuo
- Department of Cardiovascular Imaging, The Rayne Institute, King's College London, London, UK
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17
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Using oxidized low-density lipoprotein autoantibodies to predict restenosis after balloon angioplasty in patients with acute myocardial infarction. PLoS One 2013; 8:e74726. [PMID: 24098346 PMCID: PMC3789725 DOI: 10.1371/journal.pone.0074726] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 08/05/2013] [Indexed: 12/22/2022] Open
Abstract
Objectives Oxidized low-density lipoproteins (oxLDL) and oxidized low-density lipoprotein autoantibodies (OLAB) have been detected in human plasma and atherosclerotic lesions. OLAB appear to play a role in the clearance of oxLDL from circulation. Higher levels of OLAB appear to be associated with a reduced risk of a wide range of cardiovascular diseases. We investigated the prognostic value of plasma oxLDL and OLAB in patients undergoing primary coronary balloon angioplasty for acute ST-elevation myocardial infarction (STEMI). Methods Plasma oxLDL and OLAB concentrations were measured in 56 patients with acute STEMI before primary angioplasty, and then 3 days, 7 days and 1 month after the acute event. Follow-up angiography was repeated 6 months later to detect the presence of restensosis (defined as >50% luminal diameter stenosis). The thrombolysis in myocardial infarction (TIMI) risk score was calculated to determine the relationship between OLAB/oxLDL ratio and TIMI risk scores. Results Of the 56 patients, 18 (31%) had angiographic evidence of restenosis. Plasma OLAB concentrations were significantly lower in the restenosis group before angioplasty (181±114 vs. 335±257 U/L, p = 0.003), and at day 3 (155±92 vs. 277±185 U/L, p<0.001) and day 7 (177±110 vs. 352±279 U/L, p<0.001) after the acute event. There was no difference in oxLDL concentration between the two groups. The ratio of OLAB/oxLDL positively correlated with TIMI risk scores before angioplasty (p for trend analysis, p = 0.004), at day 3 (p = 0.008) and day 7 (p<0.001) after STEMI. Significance A relative deficit of OLAB, and hence likely impaired clearance of oxLDL, is associated with the risk of arterial restenosis after primary angioplasty for acute STEMI.
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18
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Hingwala D, Kesavadas C, Sylaja PN, Thomas B, Kapilamoorthy TR. Multimodality imaging of carotid atherosclerotic plaque: Going beyond stenosis. Indian J Radiol Imaging 2013; 23:26-34. [PMID: 23986615 PMCID: PMC3737614 DOI: 10.4103/0971-3026.113616] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Apart from the degree of stenosis, the morphology of carotid atherosclerotic plaques and presence of neovascularization are important factors that may help to evaluate the risk and ‘vulnerability’ of plaques and may also influence the choice of treatment. In this article, we aim to describe the techniques and imaging findings on CTA, high resolution MRI and contrast enhanced ultrasound in the evaluation of carotid atherosclerotic plaques. We also discuss a few representative cases from our institute with the related clinical implications.
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Affiliation(s)
- Divyata Hingwala
- Department of Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
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Saba L, Anzidei M, Marincola BC, Piga M, Raz E, Bassareo PP, Napoli A, Mannelli L, Catalano C, Wintermark M. Imaging of the carotid artery vulnerable plaque. Cardiovasc Intervent Radiol 2013; 37:572-85. [PMID: 23912494 DOI: 10.1007/s00270-013-0711-2] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 07/03/2013] [Indexed: 11/28/2022]
Abstract
Atherosclerosis involving the carotid arteries has a high prevalence in the population worldwide. This condition is significant because accidents of the carotid artery plaque are associated with the development of cerebrovascular events. For this reason, carotid atherosclerotic disease needs to be diagnosed and those determinants that are associated to an increased risk of stroke need to be identified. The degree of stenosis typically has been considered the parameter of choice to determine the therapeutical approach, but several recently published investigations have demonstrated that the degree of luminal stenosis is only an indirect indicator of the atherosclerotic process and that direct assessment of the plaque structure and composition may be key to predict the development of future cerebrovascular ischemic events. The concept of "vulnerable plaque" was born, referring to those plaque's parameters that concur to the instability of the plaque making it more prone to the rupture and distal embolization. The purpose of this review is to describe the imaging characteristics of "vulnerable carotid plaques."
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Affiliation(s)
- Luca Saba
- Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari - Polo di Monserrato, s.s. 554, 09045, Monserrato, Cagliari, Italy,
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20
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Bozinovski S, Anthony D, Anderson GP, Irving LB, Levy BD, Vlahos R. Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways. Pharmacol Ther 2013; 140:280-9. [PMID: 23880288 DOI: 10.1016/j.pharmthera.2013.07.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 07/09/2013] [Indexed: 12/19/2022]
Abstract
Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. Here, we discuss new strategies to combat this inflammation in COPD by focusing on the anti-inflammatory role of ALX/FPR2 receptors. ALX/FPR2 is a promiscuous G-protein coupled receptor (GPCR) responding to lipid and peptide agonists that can either switch on acute inflammation or promote resolution of inflammation. We highlight this receptor as an emerging target in the pathogenesis of COPD because known ALX/FPR2 endogenous agonists are enriched in COPD. Serum Amyloid A (SAA) has recently been discovered to be abundantly expressed in COPD and is a potent ALX/FPR2 agonist that unlike almost all other inflammatory chemoattractants, is induced by glucocorticosteroids. SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms.
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Affiliation(s)
- Steven Bozinovski
- Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
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21
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Leban N, Jraba K, Chalghoum A, Hassine S, Elhayek D, Denden S, Lakhdhar R, Maatoug F, Gamra H, Braham H, Ben Chibani J, Khelil AH. Polymorphism of C3 complement in association with myocardial infarction in a sample of central Tunisia. Diagn Pathol 2013; 8:93. [PMID: 23764154 PMCID: PMC3931526 DOI: 10.1186/1746-1596-8-93] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 03/04/2013] [Indexed: 11/17/2022] Open
Abstract
Background Myocardial infarction (MI) is a major clinical problem because of its large contribution to mortality. The genetic bases of this disease have been widely studied in recent years to find a clear association with some genetic markers that increase the risk of its occurrence. In the present investigation, the correlation between MI and the C3 complement polymorphism was analyzed using a case–control study. Methods Our study ported on one hundred seventy survived myocardial infarction patients and ninety five healthy controls. The C3 allele identification was investigated using the amplification refractory mutation system PCR to determine the C3*S and the C3*F alleles of the C3 polymorphism. Results Frequencies of C3*S and C3*F in patients are 0.59 and 0.41 respectively. Fisher test results showed a significant increase of C3*F allele in the sample of patients (0.41; odds ratio: 2.616; C.I [1.738-3.938]) compared to controls (0.21; odds ratio: 0.382; 95% CI [0.254-0.575]), p = 2.742 × 10-6. Conclusion A strong positive correlation was found between C3 polymorphism and MI estimating that the risk of myocardial infarction is significantly increased among patients with C3*F allele of this polymorphism. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1190484203893646
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Affiliation(s)
- Nadia Leban
- Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy, Street Avicenne, 5019 Monastir, Tunisia.
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Takahashi K, Kakuta T, Yonetsu T, Lee T, Koura K, Hishikari K, Murai T, Iesaka Y, Isobe M. In vivo detection of lipid-rich plaque by using a 40-MHz intravascular ultrasound: a comparison with optical coherence tomography findings. Cardiovasc Interv Ther 2013; 28:333-43. [DOI: 10.1007/s12928-013-0177-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Accepted: 03/31/2013] [Indexed: 11/28/2022]
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Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. THE LANCET RESPIRATORY MEDICINE 2013; 1:73-83. [PMID: 24321806 DOI: 10.1016/s2213-2600(12)70060-7] [Citation(s) in RCA: 196] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensin-converting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of so-called spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.
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Affiliation(s)
- Marc Decramer
- Respiratory Division, University of Leuven, Leuven, Belgium.
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Wykrzykowska JJ, Diletti R, Gutierrez-Chico JL, van Geuns RJ, van der Giessen WJ, Ramcharitar S, Duckers HE, Schultz C, de Feyter P, van der Ent M, Regar E, de Jaegere P, Garcia-Garcia HM, Pawar R, Gonzalo N, Ligthart J, de Schepper J, van den Berg N, Milewski K, Granada JF, Serruys PW. Plaque sealing and passivation with a mechanical self-expanding low outward force nitinol vShield device for the treatment of IVUS and OCT-derived thin cap fibroatheromas (TCFAs) in native coronary arteries: report of the pilot study vShield Evaluated at Cardiac hospital in Rotterdam for Investigation and Treatment of TCFA (SECRITT). EUROINTERVENTION 2012; 8:945-54. [DOI: 10.4244/eijv8i8a144] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Li ZY, Howarth S, U-King-Im J, Gillard J. Atheroma: is Calcium Important or Not? A Modelling Study of Stress Within the Atheromatous Fibrous Cap in Relation to Position and Size of Calcium Deposits. CONFERENCE PROCEEDINGS : ... ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL CONFERENCE 2012; 2005:2236-9. [PMID: 17282677 DOI: 10.1109/iembs.2005.1616908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Atheromatous plaque rupture is the cause of the majority of strokes and heart attacks in the developed world. The role of calcium deposits and their contribution to plaque vulnerability are controversial. Some studies have suggested that calcified plaque tends to be more stable whereas others have suggested the opposite. This study uses a finite element model to evaluate the effect of calcium deposits on the stress within the fibrous cap by varying their location and size. Plaque fibrous cap, lipid pool and calcification were modeled as hyperelastic, isotropic, (nearly) incompressible materials with different properties for large deformation analysis by assigning time-dependent pressure loading on the lumen wall. The stress and strain contours were illustrated for each condition for comparison. Von Mises stress only increases up to 1.5% when varying the location of calcification in the lipid pool distant to the fibrous cap. Calcification in the fibrous cap leads to a 43% increase of Von Mises stress when compared with that in the lipid pool. An increase of 100% of calcification area leads to a 15% stress increase in the fibrous cap. Calcification in the lipid pool does not increase fibrous cap stress when it is distant to the fibrous cap, whilst large areas of calcification close to or in the fibrous cap may lead to a high stress concentration within the fibrous cap, which may cause plaque rupture.
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Affiliation(s)
- Zhi-Yong Li
- Department of Radiology, University of Cambridge and Addenbrooke's Hospital, Cambridge, UK
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26
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Van Eeden S, Leipsic J, Paul Man SF, Sin DD. The Relationship between Lung Inflammation and Cardiovascular Disease. Am J Respir Crit Care Med 2012; 186:11-6. [DOI: 10.1164/rccm.201203-0455pp] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Atherosclerosis: an integrative East-west medicine perspective. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:148413. [PMID: 22548116 PMCID: PMC3328236 DOI: 10.1155/2012/148413] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/16/2011] [Accepted: 01/24/2012] [Indexed: 11/30/2022]
Abstract
Recent understanding of atherosclerosis and coronary heart disease has shifted the focus from lumen stenosis to vulnerable plaque, from lipid deposit to inflammatory reaction, and from vulnerable plaque to vulnerable patient. This has led to a new direction of treatment consisting of intervening the inflammatory reaction, stabilizing the vulnerable plaque, inhibiting thrombosis after plaque rupture, and treating the vulnerable patient instead of treating lumen stenosis. This seems to mirror the traditional Chinese medicine (TCM) focus on prevention and on the vulnerable patient with treatment matched to the pattern dysfunction and dysregulation using the Chinese herbal medicine multitargeted approach. Given the convergence of both the East and the West conceptualization of atherosclerosis, it is hopeful that the integrative East-West approach will facilitate early detection and more effective treatment of the vulnerable patients with coronary heart disease.
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Pratap P, Gupta S, Berlowtiz M. Routine Invasive Versus Conservative Management Strategies in Acute Coronary Syndrome: Time for a “Hybrid” Approach. J Cardiovasc Transl Res 2011; 5:30-40. [DOI: 10.1007/s12265-011-9333-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 11/09/2011] [Indexed: 11/29/2022]
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Sarvazyan A, Hall TJ, Urban MW, Fatemi M, Aglyamov SR, Garra BS. AN OVERVIEW OF ELASTOGRAPHY - AN EMERGING BRANCH OF MEDICAL IMAGING. Curr Med Imaging 2011; 7:255-282. [PMID: 22308105 PMCID: PMC3269947 DOI: 10.2174/157340511798038684] [Citation(s) in RCA: 249] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
From times immemorial manual palpation served as a source of information on the state of soft tissues and allowed detection of various diseases accompanied by changes in tissue elasticity. During the last two decades, the ancient art of palpation gained new life due to numerous emerging elasticity imaging (EI) methods. Areas of applications of EI in medical diagnostics and treatment monitoring are steadily expanding. Elasticity imaging methods are emerging as commercial applications, a true testament to the progress and importance of the field.In this paper we present a brief history and theoretical basis of EI, describe various techniques of EI and, analyze their advantages and limitations, and overview main clinical applications. We present a classification of elasticity measurement and imaging techniques based on the methods used for generating a stress in the tissue (external mechanical force, internal ultrasound radiation force, or an internal endogenous force), and measurement of the tissue response. The measurement method can be performed using differing physical principles including magnetic resonance imaging (MRI), ultrasound imaging, X-ray imaging, optical and acoustic signals.Until recently, EI was largely a research method used by a few select institutions having the special equipment needed to perform the studies. Since 2005 however, increasing numbers of mainstream manufacturers have added EI to their ultrasound systems so that today the majority of manufacturers offer some sort of Elastography or tissue stiffness imaging on their clinical systems. Now it is safe to say that some sort of elasticity imaging may be performed on virtually all types of focal and diffuse disease. Most of the new applications are still in the early stages of research, but a few are becoming common applications in clinical practice.
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Abstract
In the study of carotid arteries, modern techniques of imaging allow to analyze various alterations beyond simple luminal narrowing, including the morphology of atherosclerotic plaques, the arterial wall and the surrounding structures. By using CTA and MRI it is possible to obtain three-dimensional rendering of anatomic structures with excellent detail for treatment planning. This paper will detail the role of various imaging methods for the assessment of carotid artery pathology with emphasis on the detection, analysis and characterization of carotid atherosclerosis.
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O'Sullivan JF, Martin K, Caplice NM. Microribonucleic acids for prevention of plaque rupture and in-stent restenosis: "a finger in the dam". J Am Coll Cardiol 2011; 57:383-9. [PMID: 21251577 DOI: 10.1016/j.jacc.2010.09.029] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Revised: 07/26/2010] [Accepted: 09/21/2010] [Indexed: 01/09/2023]
Abstract
Vascular smooth muscle cells (VSMCs), which make up the arterial medial layer, possess a phenotype switching capability. This modulation of VSMCs is important in the development of atherosclerotic vascular disease. It has been recognized that VSMCs may also have a stabilizing role in advanced atherosclerotic plaques. Moreover, reduction of the proliferative capacity of these cells may be of benefit in reducing neointimal hyperplasia following therapeutic percutaneous intervention. The biology of microribonucleic acids (miRNAs) and their ability to modify smooth muscle biology has recently emerged in a number of investigations. These studies elucidated the key role of miRNAs, miR-143 and miR-145, in particular, in the regulation of SMC homeostasis in vitro, in murine models of targeted gene deletion, and also in human vascular pathology. This review places this burgeoning knowledge within the wider context of atherosclerosis and restenosis and explores the therapeutic potential of miRNAs to change the fate of VSMCs within the plaque.
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Affiliation(s)
- John F O'Sullivan
- Centre for Research in Vascular Biology, Biosciences Institute, University College Cork, Cork, Ireland
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Saba L, Sanfilippo R, Montisci R, Mallarini G. Carotid artery stenosis at MSCT: is there a threshold in millimeters that determines clinical significance? Cardiovasc Intervent Radiol 2011; 35:49-58. [PMID: 21301843 DOI: 10.1007/s00270-011-0108-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Accepted: 01/10/2011] [Indexed: 11/30/2022]
Abstract
PURPOSE The purpose of this work was to determine whether it is possible to identify a reliable carotid stenosis threshold--measured in millimeters (mm)--that is associated with cerebrovascular symptoms. METHODS Written, informed consent was obtained for each patient; 149 consecutive patients (98 men; median age, 68 years) were studied for suspected pathology of the carotid arteries by using MDCTA. In each patient, carotid artery stenosis was quantified using the mm-method. Continuous data were described as the mean value ± standard deviation (SD), and they were compared by using the Student's t test. A ROC curve was calculated to test the study hypothesis and identify a specific mm-stenosis threshold. Logistic regression analysis was performed to include other MDCTA findings, such as plaque type and ulcerations. A P value < 0.05 was considered to indicate statistical significance. RESULTS Twenty-six patients were excluded. Of those remaining, 75 patients suffered cerebrovascular symptoms (61%). There was a statistically significant difference (P = 0.0046) in the mm-carotid stenosis between patients with symptoms (1.31 ± 0.64 mm SD) and without symptoms (1.68 ± 0.79 mm SD). Multiple logistic regression analysis confirmed that symptoms were associated with increased luminal stenosis (P = 0.013) and with the presence of fatty plaques (P = 0.0491). Moreover, the ROC curve (Az = 0.669; ±0.051 SD; P = 0.0009) indicated that a threshold of 1.6 mm stenosis was associated with a sensitivity to symptoms of 76%. CONCLUSIONS The results of our study suggest an association between luminal stenosis (measure in mm) and the presence of cerebrovascular symptoms. Luminal stenosis of 1.6 mm is associated, with a sensitivity of 76%, with cerebrovascular symptoms.
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Affiliation(s)
- Luca Saba
- Department of Radiology, Azienda Ospedaliero Universitaria, di Cagliari-Polo di Monserrato, s.s. 554, 09045 Monserrato, CA, Italy.
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Identification of carotid 'vulnerable plaque' by contrast-enhanced ultrasonography: correlation with plaque histology, symptoms and cerebral computed tomography. Eur J Vasc Endovasc Surg 2010; 41:238-48. [PMID: 21145266 DOI: 10.1016/j.ejvs.2010.11.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2010] [Accepted: 11/01/2010] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Indication to carotid revascularisation is commonly determined by percent of stenosis as well as neurological symptoms and clinical conditions. High plaque embolic potential is defined as 'vulnerability'; however, its characterisation is not universally used for carotid revascularisation. We investigated the role of contrast-enhanced ultrasonography (CEUS) to identify carotid vulnerable plaque. METHODS Patients undergoing carotid endarterectomy were preoperatively evaluated by cerebral computed tomography (CT) scan and CEUS. Contrast microbubbles detected within the plaque indicated neovascularisation and were quantified by decibel enhancement (dB-E). Plaques were histologically evaluated for five features: (microvessel density, fibrous cap thickness, extension of calcification, inflammatory infiltrate and lipid core) and blindly scored 1-5 to assess plaque vulnerability. Analysis of variance (ANOVA), Fisher's and Student's t-test were used to correlate patients' characteristics, histological features and dB-E. RESULTS In 22 patients, dB-E (range 2-7.8, mean 4.85 ± 1.9 SD) was significantly greater in symptomatic (7.40 ± 0.5) vs. asymptomatic (3.5 ± 1.4) patients (p = 0.002). A higher dB-E was significantly associated with thinner fibrous cap (<200 μm, 5.96 ± 1.5 vs. 3 ± 1, p = 0.01) and greater inflammatory infiltrate (3.2 ± 0.9 vs. 6.4 ± 1.2, p = 0.03). Plaques with vulnerability score of 5 had significantly higher dB-E compared with those with vulnerability score of 1 (7.6 ± 0.2 vs. 2.5 ± 0.6, respectively, p = 0.001). Preoperative ipsilateral embolic lesions at CT were correlated with higher dB-E (5.96 ± 1.5 vs. 3.0 ± 1.0, p = 0.01). CONCLUSION CEUS with dB-E is indicative of the extent of plaque neovascularisation. It can be used therefore as a marker for vulnerable plaque.
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Nguyen CM, Levy AJ. The mechanics of atherosclerotic plaque rupture by inclusion/matrix interfacial decohesion. J Biomech 2010; 43:2702-8. [DOI: 10.1016/j.jbiomech.2010.06.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 06/11/2010] [Accepted: 06/12/2010] [Indexed: 10/19/2022]
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Li F, McDermott MM, Li D, Carroll TJ, Hippe DS, Kramer CM, Fan Z, Zhao X, Hatsukami TS, Chu B, Wang J, Yuan C. The association of lesion eccentricity with plaque morphology and components in the superficial femoral artery: a high-spatial-resolution, multi-contrast weighted CMR study. J Cardiovasc Magn Reson 2010; 12:37. [PMID: 20591197 PMCID: PMC2904754 DOI: 10.1186/1532-429x-12-37] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Accepted: 07/01/2010] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Atherosclerotic plaque morphology and components are predictors of subsequent cardiovascular events. However, associations of plaque eccentricity with plaque morphology and plaque composition are unclear. This study investigated associations of plaque eccentricity with plaque components and morphology in the proximal superficial femoral artery using cardiovascular magnetic resonance (CMR). METHODS Twenty-eight subjects with an ankle-brachial index less than 1.00 were examined with 1.5 T high-spatial-resolution, multi-contrast weighted CMR. One hundred and eighty diseased locations of the proximal superficial femoral artery (about 40 mm) were analyzed. The eccentric lesion was defined as [(Maximum wall thickness- Minimum wall thickness)/Maximum wall thickness] >or= 0.5. The arterial morphology and plaque components were measured using semi-automatic image analysis software. RESULTS One hundred and fifteen locations were identified as eccentric lesions and sixty-five as concentric lesions. The eccentric lesions had larger wall but similar lumen areas, larger mean and maximum wall thicknesses, and more calcification and lipid rich necrotic core, compared to concentric lesions. For lesions with the same lumen area, the degree of eccentricity was associated with an increased wall area. Eccentricity (dichotomous as eccentric or concentric) was independently correlated with the prevalence of calcification (odds ratio 3.78, 95% CI 1.47-9.70) after adjustment for atherosclerotic risk factors and wall area. CONCLUSIONS Plaque eccentricity is associated with preserved lumen size and advanced plaque features such as larger plaque burden, more lipid content, and increased calcification in the superficial femoral artery.
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Affiliation(s)
- Feiyu Li
- Department of Radiology, Peking University First Hospital, Beijing, China
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Mary McGrae McDermott
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Debiao Li
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Timothy J Carroll
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Daniel S Hippe
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Christopher M Kramer
- Departments of Radiology and Medicine, University of Virginia, Charlottesville, VA, USA
| | - Zhaoyang Fan
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Xihai Zhao
- Department of Radiology, University of Washington, Seattle, WA, USA
| | | | - Baocheng Chu
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Jinnan Wang
- Clinical Sites Research Program, Philips Research North America, Briarcliff Manor, NY, USA
| | - Chun Yuan
- Department of Radiology, University of Washington, Seattle, WA, USA
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Abstract
Despite major advances in the management of acute coronary syndromes (ACS), 1 in 3 Canadians die from cardiovascular disease. In 1998, the total economic burden of cardiovascular illness in Canada was $159 434.5 million dollars — $83 953.9 million in direct costs and $75 479.6 in indirect costs. During the past 20 years, several pharmacologic adjuncts have been investigated with hopes of ameliorating the consequences of ACS. Notably, clopidogrel has become a common component of ACS therapeutic regimens since its introduction in 1998. Both new medications and those already accepted as standard treatment deserve critical evaluation to ensure they are safe and effective.
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Affiliation(s)
- Payal Patel
- Evidence-Based Prescribing Initiative, London Health Sciences Centre, London, Ontario, Canada.
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Ha EJ, Kim Y, Cheung JY, Shim SS. Coronary artery disease in asymptomatic young adults: its prevalence according to coronary artery disease risk stratification and the CT characteristics. Korean J Radiol 2010; 11:425-32. [PMID: 20592926 PMCID: PMC2893313 DOI: 10.3348/kjr.2010.11.4.425] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Accepted: 03/11/2010] [Indexed: 12/12/2022] Open
Abstract
Objective We aimed at evaluating the prevalence and CT characteristics of occult coronary artery disease (CAD) in young Korean adults under 40 years of age by performing coronary CT angiography (CCTA). Materials and Methods We retrospectively enrolled 112 consecutive asymptomatic subjects (90 men, mean age: 35.6 ± 3.7 years) who underwent CCTA as part of a general health evaluation. We classified the subjects into three National Cholesterol Education Program risk categories and we assessed the plaque characteristics on CCTA according to the number of involved vessels, the location and type of plaques and vascular remodeling. Results Twelve individuals had CAD (11%, 11 men). The prevalence of CAD was significantly higher in the subgroups with moderate (22%) or high (25%) risk than that in the low risk subgroup (5%) (p < 0.05). Nine patients had single-vessel disease and three patients had two-vessel disease. The most common location for plaque was the proximal left anterior descending coronary artery (60%). All the patients had non-significant stenosis and plaque, including the non-calcified (27%), mixed (47%) and calcified (27%) types. Positive vascular remodeling was identified in all the patients with non-calcified or mixed plaques. Conclusion The prevalence of occult CAD was not negligible in the asymptomatic young adults with moderate to high risk, and this suggests the importance of management and risk factor modification in this population. All the patients had non-significant stenosis, and one fourth of the plaques did not show calcification.
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Affiliation(s)
- Eun Ju Ha
- Department of Radiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea
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Saba L, Mallarin G. Window settings for the study of calcified carotid plaques with multidetector CT angiography. AJNR Am J Neuroradiol 2009; 30:1445-50. [PMID: 19299487 DOI: 10.3174/ajnr.a1509] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
SUMMARY CT angiography (CTA) shows high sensitivity in detecting calcified plaques, but sometimes a bias in the exact quantification of stenosis degree occurs, mainly caused by the high linear attenuation coefficient of the calcified plaques. The purpose of this technical study was to evaluate the most appropriate CT window parameters for the assessment of calcified plaques stating which of them can provide the best inter-observer agreement. Scatter-plots and regression results showed the correlation between both width and level respectively depending on intraluminal Hounsfield units (HU) value (width = intraluminal HU x 2.07; level = intraluminal HU x 0.72). Obtained data indicated that the presence of different stenosis degrees did not modify visualization parameters.
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Affiliation(s)
- L Saba
- Department of Science of the Images, Policlinico Universitario, Cagliari, Italy.
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40
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Saba L, Montisci R, Sanfilippo R, Mallarini G. Multidetector row CT of the brain and carotid artery: a correlative analysis. Clin Radiol 2009; 64:767-78. [PMID: 19589415 DOI: 10.1016/j.crad.2009.03.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2008] [Revised: 03/16/2009] [Accepted: 03/19/2009] [Indexed: 01/02/2023]
Abstract
AIM To evaluate the association between types of carotid plaque, the presence of prior ischaemic events detectable with CT, and patient's symptoms. MATERIALS AND METHODS Between January 2004 and May 2006, 112 patients were evaluated using multidetector row computed tomography angiography (MDCTA) of the carotid arteries and computed tomography (CT) of the brain. Carotid arteries were categorized by evaluating the degree of stenosis according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, the type of plaque, and the presence of plaque ulceration. The brain was assessed via CT for the presence, type, and position of lesions. Chi-square tests, Student's t test, and simple logistic regression analysis were performed and the Cohen kappa test was applied for interobserver variability measurement. RESULTS The Chi-square test indicated a statistically significant association between the presence of fatty plaques (p=0.005) and CT-detectable lesions in the brain (p=0.004). Moreover, the number of patients with CT-detectable brain lesions was greater in patients with >70% stenosis than in those with <70% stenosis (p=0.007). Logistic regression confirmed the association between fatty plaque and symptoms (p=0.001), between >70% stenosis and symptoms (p=0.041), and an inverse association between calcified plaque and symptoms (p=0.009). CONCLUSION MDCTA allows adequate evaluation of the type of plaque. The results of the present study indicate that there is an association between cerebral lesions, symptoms, and fatty plaque in the carotid artery. The degree of stenosis also correlated with cerebral lesions and symptoms. According to the obtained data, the type of carotid plaque should be included among primary parameters in the classification of patients' risk class.
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Affiliation(s)
- L Saba
- Department of Imaging Science, Policlinico Universitario, s.s. 554 Monserrato (Cagliari) 09045, Italy.
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41
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Nair D, Carrigan TP, Curtin RJ, Popovic ZB, Kuzmiak S, Schoenhagen P, Flamm SD, Desai MY. Association of Total Cholesterol/High-Density Lipoprotein Cholesterol Ratio With Proximal Coronary Atherosclerosis Detected by Multislice Computed Tomography. ACTA ACUST UNITED AC 2009; 12:19-26. [DOI: 10.1111/j.1751-7141.2008.00011.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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43
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3D flow study in a mildly stenotic coronary artery phantom using a whole volume PIV method. Med Eng Phys 2008; 30:1193-200. [DOI: 10.1016/j.medengphy.2008.02.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Revised: 02/26/2008] [Accepted: 02/26/2008] [Indexed: 11/15/2022]
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Kuge Y, Kume N, Ishino S, Takai N, Ogawa Y, Mukai T, Minami M, Shiomi M, Saji H. Prominent lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1) expression in atherosclerotic lesions is associated with tissue factor expression and apoptosis in hypercholesterolemic rabbits. Biol Pharm Bull 2008; 31:1475-82. [PMID: 18670075 DOI: 10.1248/bpb.31.1475] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Despite increasing in vitro evidence that lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL, is implicated in the atherogenesis and thrombus formation, its in vivo participation to the atherosclerotic plaque destabilization, rupture and thrombus formation remains unclear. Here, we compared the in vivo expression of LOX-1, with tissue factor (TF) expression and cell apoptosis, in atherosclerotic lesions of myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. METHODS AND RESULTS We prepared sixty series of cross sections in the aortic arch and the thoracic aorta from four WHHLMI rabbits. LOX-1 and TF expression, as well as apoptotic events were determined by immunohistochemical staining and TUNEL methods, respectively. LOX-1 expression was mainly observed in the macrophage-rich lipid areas of vulnerable plaque-like atheromatous lesions where TF expression and apoptotic events were prominent. LOX-1 expression was positively correlated with TF expression (r=0.53, p<0.0001), apoptotic events (r=0.52, p<0.0001) and morphological vulnerability (r=0.63, p<0.0001). CONCLUSIONS LOX-1 expression appears to be closely associated with TF expression, apoptotic events and the morphological vulnerability, suggesting the in vivo involvement of LOX-1 in the destabilization and rupture of atherosclerotic lesions and the subsequent thrombus formation. The present findings in hypercholesterolemic rabbits should help advance our understanding of the pathophysiology of atherosclerosis.
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Affiliation(s)
- Yuji Kuge
- Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
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Celik T, Iyisoy A, Yuksel UC. Mechanical plaque sealing in patients with acute coronary syndromes: a local solution for a systemic disease involving whole coronary arterial tree? Int J Cardiol 2008; 135:102-4; author reply 105-6. [PMID: 18499286 DOI: 10.1016/j.ijcard.2007.12.124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2007] [Accepted: 12/29/2007] [Indexed: 10/22/2022]
Abstract
Mechanical plaque sealing with coronary stents is an established way of treating culprit lesions in diseased coronary arteries. Even though coronary stents are invaluable tools for local treatment of the diseased coronary arteries, the high prevalence of pancoronary destabilization in patients with acute coronary syndromes (ACS) highlights the importance of the systemic approaches rather than the local treatment of the culprit lesion.
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46
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Contemporary Approach to the Diagnosis and Management of Non–ST-Segment Elevation Acute Coronary Syndromes. Prog Cardiovasc Dis 2008; 50:311-51. [DOI: 10.1016/j.pcad.2007.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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47
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48
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Ishino S, Mukai T, Kume N, Asano D, Ogawa M, Kuge Y, Minami M, Kita T, Shiomi M, Saji H. Lectin-like oxidized LDL receptor-1 (LOX-1) expression is associated with atherosclerotic plaque instability—analysis in hypercholesterolemic rabbits. Atherosclerosis 2007; 195:48-56. [PMID: 17239887 DOI: 10.1016/j.atherosclerosis.2006.11.031] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Revised: 10/30/2006] [Accepted: 11/21/2006] [Indexed: 10/23/2022]
Abstract
Lectin-like oxidized LDL receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL (Ox-LDL), has been implicated in vascular cell dysfunction related to atherosclerotic plaque instability, according to cell culture experiments. In the present study, we investigated the relationship between LOX-1 expression and plaque instability in hypercholesterolemic rabbits by immunohistological analyses in vivo. We prepared thirty series of cross sections of the thoracic aorta from six myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits (12-24 months), in which seventy atherosclerotic plaques were observed. LOX-1, matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1) expression, apoptotic events, plaque instability index (an index of the morphological destabilization of atherosclerotic plaques) and fibromuscular cap thickness in each atherosclerotic plaque were determined by immunohistochemical staining, TUNEL staining and Azan-Mallory staining. LOX-1 expression was positively correlated with the plaque instability index and MMP-9 expression. LOX-1 expression was more prominent in atherosclerotic plaques with thinner fibromuscular cap (<100 microm). Furthermore, LOX-1 expression was shown in the macrophage-rich lipid core area where MCP-1 expression and apoptotic events were prominent. These results indicate that enhanced LOX-1 expression was associated with histologically unstable atherosclerotic plaques in hypercholesterolemic rabbits, suggesting the involvement of LOX-1 in the destabilization of atherosclerotic plaques in vivo.
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Affiliation(s)
- Seigo Ishino
- Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
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Gállego J, Martínez Vila E, Muñoz R. Patients at high risk for ischemic stroke: identification and actions. Cerebrovasc Dis 2007; 24 Suppl 1:49-63. [PMID: 17971639 DOI: 10.1159/000107379] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Atherosclerosis is a disease of chronic inflammation. It is diffuse, multisystemic and affects the vascular, metabolic and immune systems. The traditional evaluation of risk is based on methods of clinical and biological assessments, and conventional imaging. The existence of symptomatic disease and the number of symptomatic sites of atherothrombosis are critical factors in predicting the recurrence of major vascular events. However, these methods are insufficient to predict near-future episodes, above all in the individual standard clinical practice. Active treatment of modifiable risk factors such as hypertension, dyslipidemia and atrial fibrillation can reduce the number of patients who develop a stroke. There is considerable evidence suggesting that a substantial proportion of the population with high blood pressure receives insufficient treatment. More active treatment of this condition is probably the most efficient single measure. Lifestyle factors such as smoking, diet, physical inactivity and obesity contribute to the relatively high incidence of stroke. There is a need to incorporate new systemic markers and new investigation techniques in the future so as to identify the individuals at risk in the population and to administer more individualized intervention therapies.
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Affiliation(s)
- Jaime Gállego
- Stroke Unit, Department of Neurology, Hospital de Navarra, Pamplona, Spain.
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50
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Otero-Viñas M, Llorente-Cortés V, Peña E, Padró T, Badimon L. Aggregated low density lipoproteins decrease metalloproteinase-9 expression and activity in human coronary smooth muscle cells. Atherosclerosis 2007; 194:326-33. [PMID: 17134708 DOI: 10.1016/j.atherosclerosis.2006.10.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2006] [Revised: 10/10/2006] [Accepted: 10/23/2006] [Indexed: 11/22/2022]
Abstract
Plaque stability largely depends on vascular smooth muscle cell (VSMC) function. VSMC secrete metalloproteinases (MMPs), matrix degrading endopeptidases, that regulate VSMC migration and function. Among them, gelatinase B or MMP-9 seems to have a protective effect by promoting a stable plaque phenotype. In macrophage foam cells oxidized LDL (oxLDL) uptake regulates MMP-9 expression. However, it is unknown whether VSMC-lipid loading by aggregated LDL (agLDL) internalization produces any effect on MMP-9 production by human resident vascular cells. In the present study, we analyzed the effect of lipid-internalization in MMP-9 and MMP-2 expression and activity and its consequences in VSMC migration. Our results show that agLDL-internalization down-regulates MMP-9 activity in a time-dependent manner up to 42% at 48h and in a dose-dependent manner up to 87% at 300 microg/mL. nLDL induced similar but not sustained decrease on MMP-9 activity. However, neither agLDL nor nLDL exerted any significant effect on MMP-2 and TIMP-1. VSMC regrowth after a scratch injury was significantly reduced by exposure to agLDL. We conclude that agLDL-lipid loading reduces MMP-9 activity and this effect is associated to inhibition of VSMC migration. Thus, agLDL internalization may have consequences on vascular remodeling after injury, and the stability of lipid-rich atherosclerotic plaques.
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