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Carbon-14 Dating to Determine Carotid Plaque Age: Carbon-14 Dating of Carotid Plaques
Linköping University, Department of Physics, Chemistry and Biology, Computational Biology . Linköping University, The Institute of Technology.
Ion Physics, Angström Laboratory, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden.
From the Computational Medicine Group, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
From the Computational Medicine Group, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Rationale: The exact nature of atherosclerotic plaque development and the molecular mechanisms that lead to clinical manifestations of carotid stenosis are unclear. After nuclear bomb tests in the 1950s, atmospheric 14C concentrations rapidly increased. Since then, the concentrations have been declining, and the curve of declination can be used to date biological samples synthesized during the last five to six decades.

Objective: To investigate plaque age as a novel characteristic of atherosclerotic plaques in patients with carotid stenosis.

Methods and Results: Carotid plaques from 29 well-characterized endarterectomy patients with symptomatic carotid stenosis were analyzed by accelerator mass spectrometry, and global gene expression of 25 plaque samples was profiled with HG-U133 Plus 2.0 arrays. The average plaque age was 9.3 years, and inter- and intrasample standard variations were low (1–3.5 years); thus, most of the plaques were generated 5–15 years before surgery. Plaque age was not associated with patient age or plaque size, determined by intima-media thickness, but was inversely related to plasma insulin levels (P=0.0014). A cluster of functionally related genes enriched with genes involved in immune responses was activated in plaques with low plaque age, as were oxidative phosphorylation genes.

Conclusion: Patients with mild insulin resistance have increased immune and inflammatory gene activity in their carotid plaques causing them to become instable, rapidly progressing into clinical manifestations at a relatively young age. These results show that plaque age, determined by 14C dating, is a novel and important characteristic of atherosclerotic plaques that will improve our understanding of the clinical significance and molecular underpinnings of atherosclerosis.

Keyword [en]
gene expression profiling, carotid stenosis, atherosclerosis, 14C dating, insulin resistance
National Category
Other Biological Topics
URN: urn:nbn:se:liu:diva-51917OAI: diva2:278120
Available from: 2009-12-03 Created: 2009-11-24 Last updated: 2009-12-03Bibliographically approved
In thesis
1. Gene Expression Profiling of Human Atherosclerosis
Open this publication in new window or tab >>Gene Expression Profiling of Human Atherosclerosis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis is a progressive inflammatory disease that causes lipid accumulation in the arterial wall, leading to the formation of plaques. The clinical manifestations of plaque rupture—stroke and myocardial infarction—are increasing worldwide and pose an enormous economic burden for society. Atherosclerosis development reflects a complex interaction between environmental exposures and genetic predisposition. To understand this complexity, we hypothesized that a top-down approach—one in which all molecular activities that drive atherosclerosis are examined simultaneously—is necessary to highlight those that are clinically relevant. To this end, we performed whole-genome expression profiling in multiple tissues isolated from patients with coronary artery disease (CAD).

In the Stockholm Atherosclerosis Gene Expression (STAGE) study, biopsies of five tissues (arterial wall with and without atherosclerotic lesions, liver, skeletal muscle and visceral fat) were isolated from 124 CAD patients undergoing coronary artery bypass grafting surgery (CABG) at the Karolinska University Hospital, Solna and carotid lesions from 39 patients undergoing carotid artery surgery at Stockholm Söder Hospital. Detailed clinical characteristics of these patients were assembled together with a total of 303 global gene expression profiles obtained with the Affymetrix GeneChip platform.

In paper 1, a two-way clustering analysis of the data identified 60 tissue clusters of functionally related genes. One cluster, partly present in both visceral fat and atherosclerotic lesions, related to atherosclerosis severity as judged by coronary angiograms. Many of the genes in that cluster were also present in a carotid lesion cluster relating to intima-media thickness (IMT) in the carotid patients. The union of all three clusters relating to extent of atherosclerosis—referred to as the “A-module”—was overrepresented with genes belonging to the transendothelial migration of leukocyte (TEML) pathway. The transcription co-factor, Lim domain binding 2 (LDB2), was identified as putative regulator of the A-module and TEML pathway in validation studies including Ldb2-/- mice.

In paper 2, we investigated the increased incidence of postoperative complications in CABG patients with diabetes. Using the STAGE compendium, we identified an anti-inflammatory marker, dual-specificity phosphatase 1 (DUSP1), as a novel preoperative blood marker of risk for a prolonged hospital stay after CABG.

In paper 3, plaque age was determined with C14-dating in the carotid patients. Interestingly, the strongest correlation with plaque age was not the age of the patients or IMT. Rather, the strongest correlations were with plasma insulin levels and inflammatory gene expression.

Taken together, the findings in this thesis show that a top-down approach using multi-tissue gene expression profiling in CAD and C14-dating of plaques can contribute to a better understanding of the molecular processes underlying atherosclerosis development and to the identification of clinically useful biomarkers.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 43 p.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1282
National Category
Natural Sciences
urn:nbn:se:liu:diva-52085 (URN)978-91-7393-502-9 (ISBN)
Public defence
2009-12-18, Thoraxaulan, Karolinska Universitetssjukhuset, Solna, N2:U1, Stockholm, 09:00 (English)
Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved

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