| 1. |
- Asciutto, Giuseppe, et al.
(författare)
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Treatment with beta-blockers is associated with lower levels of Lp-PLA2 and suPAR in carotid plaques.
- 2013
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Ingår i: Cardiovascular Pathology. - : Elsevier BV. - 1879-1336 .- 1054-8807. ; 22:6, s. 438-443
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To determine whether a long-term treatment with beta-blockers influences the inflammatory activity in carotid artery disease by reducing the carotid plaque levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), its enzymatic products lysophosphatidylcholine (lysoPCs), and of soluble urokinase plasminogen activator receptor (suPAR). MATERIALS AND METHODS: One hundred and thirty-four patients with significant symptomatic or asymptomatic carotid stenosis undergoing surgery were prospectively included and divided into two groups (Group A or B) based on the absence or presence of an on-going long-term oral treatment with beta-blockers. The harvested carotid plaques were analyzed for the levels of lysoPCs using mass spectrometry and Lp-PLA2 and suPAR by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Plaques of patients on long-term treatment with beta-blockers revealed lower levels of Lp-PLA2 (Group A 0.752±0.393 ug/g vs. Group B 0.644±0.445 ug/g, P=.049) as well as suPAR (Group A 0.044±0.024 μg/g vs. Group B 0.036±0.025 μg/g, P=.028). Levels of Lp-PLA2 and suPAR were positively correlated (r=.637, P<.0001). Lp-PLA2 and suPAR levels were also correlated (P<.0001) with the three lysoPC species tested (lysoPC 16:0, lysoPC 18:0. lysoPC 18:1). All the above-mentioned findings were confirmed after correction for age, gender, hypertension, coronary artery disease, and statin usage. CONCLUSIONS: The reduced levels of Lp-PLA2 and suPAR in human carotid plaques of subjects on long-term treatment with beta-blockers suggest their possible protective role in plaque inflammation. Our findings support an even more selective Lp-PLA2 and suPAR inhibition as a possible strategy for the prevention of cardiovascular disease.
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| 2. |
- Edsfeldt, Andreas
(författare)
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Detecting the Vulnerable Plaque
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Myocardial infarction and stroke, mainly caused by a rupture of an atherosclerotic plaque, are two of the most common causes of mortality and morbidity in the world. Previous studies have pointed out inflammation, driven by inflammatory lipids, as the keystone in the formation of the rupture prone vulnerable plaque. The risk for a plaque rupture is greatly enhanced in the diabetic population and increased inflammation has been suggested as the contributing factor. However, the mechanism remains unknown. One of the current greatest challenges in the atherosclerotic field is to identify subjects with plaques that are vulnerable before the occurrence of a plaque rupture. In this thesis we provide evidence that the enzyme lipoprotein associated phospholipase A2 (LpPLA2) and the lipids lysophosphatidylcholines and sphingolipids (ceramides, lactosylceramides, glucosylceramides) contribute to the inflammatory process and that they are associated with the vulnerable plaque. This suggests that the synthesis of these lipids may be possible therapeutic targets. We also show that the inflammatory process in the plaque is reflected in the peripheral blood, as measured by cytokines, whereas no association was found for soluble urokinase-type plasminogen activator receptor. The inflammatory cytokines MIP-1β, TNF-α and fractalkine predict the inflammatory plaque with high sensitivity and specificity, proposing that these inflammatory cytokines could be used as plasma markers for plaque inflammation. Finally, we provide novel data regarding the biology of the diabetic plaque. According to our data the inflammatory activity is not increased in the diabetic plaque tissue. Diabetic plaques contained less stabilizing extracellular matrix proteins (collagen and elastin). Additionally the plaque levels of the inflammation regulating cytokine IL-10 and the growth factor platelet derived growth factor as well as the smooth muscle cell stimulating matrix metalloproteinase 2 were significantly decreased in diabetic plaque tissue. These findings were independent of the presence of symptoms. In summary, this thesis shows that lipids as LysoPCs and glycosphingolipids are important inducers of plaque inflammation and may be possible therapeutic targets. In the general population the inflammatory activity is an important factor for the formation of a vulnerable plaque and this inflammatory process is reflected in blood, hinting a role for fractalkine, MIP-1β and TNF-α as future biomarkers. In the diabetic population, however, an impaired tissue repair mechanism seems to be the keystone of plaque vulnerability, rather than inflammation, emphasizing the need for new therapeutic approaches for diabetics.
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| 3. |
- Edsfeldt, Andreas, et al.
(författare)
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Impaired Fibrous Repair: A Possible Contributor to Atherosclerotic Plaque Vulnerability in Patients With Type II Diabetes.
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 34:9, s. 2143-2150
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II.
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| 4. |
- Edsfeldt, Andreas, et al.
(författare)
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Low carotid calcium score is associated with higher levels of glycosaminoglycans, tumor necrosis factor-alpha, and parathyroid hormone in human carotid plaques.
- 2011
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 42:10, s. 458-2966
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Computed tomography (CT) is used to study coronary artery plaques, but little is known about its potential to characterize plaque composition. This study assesses the relation between carotid calcium score (CCS) by CT and plaque composition, namely extracellular matrix, inflammatory mediators, and calcium metabolites. METHODS: Thirty patients with significant carotid stenosis underwent preoperative CT. CCS was quantified by Agaston calcium score. Plaque components were studied histologically and biochemically (collagen, elastin, and glycosaminoglycans). Fraktalkine, interferon-γ, interleukin-10, interleukin-12 p70, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, platelet-derived growth factor-AB/BB, RANTES and tumor necrosis factor-α, and parathyroid hormone were measured using Luminex technology. RESULTS: Plaques with CCS ≥400 had more calcium (P=0.012), less glycosaminoglycan (P=0.002), tumor necrosis factor-α (P=0.013), and parathyroid hormone (P=0.028) than those with CCS <400. CCS correlated with plaque content of calcium (r=0.62; P<0.001) and inversely with glycosaminoglycan (r=-0.49; P=0.006) and tumor necrosis factor-α (r=-0.56; P=0.001). CONCLUSIONS: Human carotid plaques with high CCS are richer in calcium and have lower amounts of glycosaminoglycan, parathyroid hormone, and tumor necrosis factor-α, which is one of the main proinflammatory cytokines involved in atherosclerosis. This suggests that CCS not only reflects the degree of calcification, but also other important biological components relevant for stability such as inflammation.
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| 5. |
- Edsfeldt, Andreas, et al.
(författare)
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Soluble Urokinase Plasminogen Activator Receptor is Associated With Inflammation in the Vulnerable Human Atherosclerotic Plaque.
- 2012
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:12, s. 3305-3312
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Tidskriftsartikel (refereegranskat)abstract
- Recently, plasma soluble urokinase plasminogen activator receptor (suPAR) has gained interest as a marker of cardiovascular risk. suPAR is released through the cleavage of urokinase plasminogen activator receptor (uPAR), which is found in monocytes, activated T-lymphocytes and endothelial cells, all involved in atherosclerosis. suPAR levels have been well studied in plasma, but no studies have focused on suPAR in human atherosclerotic plaques. The aim of this study was to determine whether suPAR measured in the plaque is associated with symptomatic plaques and plaque inflammation.
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| 6. |
- Goncalves, Isabel, et al.
(författare)
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Evidence Supporting a Key Role of Lp-PLA2-Generated Lysophosphatidylcholine in Human Atherosclerotic Plaque Inflammation.
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 32:6, s. 1505-1505
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp-PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein-oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. METHODS AND RESULTS: Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among lysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 in plaques. LysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 correlated with interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-α in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16:0, 18:0, and 18:1, but not LPA were higher in symptomatic than in asymptomatic plaques. CONCLUSIONS: The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease.
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| 7. |
- Grufman, Helena, et al.
(författare)
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Evidence for altered inflammatory and repair responses in symptomatic carotid plaques from elderly patients.
- 2014
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 237:1, s. 177-182
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Tidskriftsartikel (refereegranskat)abstract
- Most acute cardiovascular events are caused by rupture of an atherosclerotic plaque. The incidence of cardiovascular events increases with age and inflammation is generally considered to be the main cause of increased plaque vulnerability. However, the relationship between age and plaque inflammation has not yet been fully clarified. The aim of our study was to determine if age-dependent plaque vulnerability is associated with increased plaque inflammation.
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| 8. |
- Grufman, Helena, et al.
(författare)
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Plasma levels of high-sensitive C-reactive protein do not correlate with inflammatory activity in carotid atherosclerotic plaques.
- 2014
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 275:2, s. 127-133
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that subjects with moderately elevated plasma levels of C-reactive protein (CRP) have an increased risk of development of cardiovascular events. As atherosclerosis is a disease characterized by chronic arterial inflammation, it is possible that moderate increases in CRP level reflect the presence of plaque inflammation. To investigate this possibility we compared plasma levels of hsCRP the day before carotid endarterectomy with the degree of inflammation in the excised plaque tissue.
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