| 1. |
- Nilsson, Jan, et al.
(författare)
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Immunomodulation of Atherosclerosis. Implications for Vaccine Development.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:1, s. 18-28
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Forskningsöversikt (refereegranskat)abstract
- A number of studies have shown activation of the immune system throughout various stages of atherosclerosis. Recent observations have suggested that activation of immune responses may promote atherosclerosis on one hand by inducing and perpetuating arterial inflammation, whereas on the other hand, selective activation of certain immune functions may inhibit atherosclerosis and arterial inflammation. These observations suggest the possibility that selective suppression of proatherogenic immune responses or selective activation of antiatherogenic immune responses may provide new approaches for atherosclerosis prevention and treatment. Several antigens activating immune responses affecting development of atherosclerosis have been identified. These immune responses may be modulated by presenting the antigens together with different types of adjuvants as well as through the route of administration. In this review, we summarize recent experimental studies using immunomodulatory approaches for treatment of atherosclerosis.
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| 2. |
- Chyu, Kuang-Yuh, et al.
(författare)
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Active and passive immunization for atherosclerosis
- 2007
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Ingår i: Current Opinion in Molecular Therapeutics. - 2040-3445. ; 9:2, s. 176-182
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Forskningsöversikt (refereegranskat)abstract
- This review summarizes experimental findings that highlight the role of immune mechanisms in atherosclerosis and the potential atheroprotective effects of active or passive immunization strategies. Immunomodulation therapy appears to be feasible and effective, suggesting that a vaccine for atherosclerosis can be developed for clinical testing. Given the increasing number of patients with atherosclerotic disease on current therapy, a new therapy is needed and an immunization strategy could provide such a possibility. Several questions regarding this approach remain unanswered, however, such as choice of optimal antigens, choice of most effective adjuvants, the optimal route of administration, durability of effects and safety, but cautious optimism remains that a vaccine-based approach has the potential to become a part of the armamentarium for atherosclerotic vascular disease.
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| 3. |
- Chyu, Kuang-Yuh, et al.
(författare)
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Immunization for atherosclerosis
- 2007
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Ingår i: Current Atherosclerosis Reports. - : Springer Science and Business Media LLC. - 1523-3804 .- 1534-6242. ; 9:2, s. 104-109
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Forskningsöversikt (refereegranskat)abstract
- This review summarizes experimental findings that highlight the complex roles of the immune system in atherogenesis. Immune activation can have either proatherogenic or atheroprotective effects. Immune-modulation therapy via an active or passive immunization strategy aims to exploit the atheroprotective aspects of the immune system to modulate atherosclerosis. Several experimental studies have demonstrated that such an approach is feasible and effective, raising the tantalizing possibility that an atheroprotective vaccine can be developed for clinical testing. Several potential immunogens have been identified and tested for their atheroprotective efficacy with variable results. Although several questions such as choice of optimal antigens, choice of most effective adjuvants, the optimal route of administration, durability of effects, and safety remain to be answered, we believe that a vaccine-based approach to manage atherosclerotic cardiovascular disease is a potentially viable paradigm.
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| 4. |
- Crisby, Milita, et al.
(författare)
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Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques - Implications for plaque stabilization
- 2001
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 1524-4539 .- 0009-7322. ; 103:7, s. 926-933
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Tidskriftsartikel (refereegranskat)abstract
- Background--The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results--Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid Plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2 +/-8.4% versus 23.9 +/- 21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.33.6% versus 22.0 +/-6.5%, P<0.001), fewer macrophages (15.010.2% versus 25.3 +/- 12.5%, P<0.05), fewer T cells (11.29.3% versus 24.3 +/- 13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.63.9% versus 8.4 +/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.06.2% versus 3.1 +/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.43.1% versus 7.5 +/-3.5%, P<0.005), Cell death by TUNEL staining was reduced in the pravastatin group (17.77.8% versus 32.0 +/- 12.6%, P<0.05). Conclusions--Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.
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| 5. |
- Dimayuga, Paul C, et al.
(författare)
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T Cell Modulation of Intimal Thickening After Vascular Injury. The Bimodal Role of IFN-{gamma} in Immune Deficiency.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:Oct 13, s. 2528-2534
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Tidskriftsartikel (refereegranskat)abstract
- Background - Immune deficiency results in exuberant intimal thickening after arterial injury. The mechanisms involved are not well defined. We investigated the role of T cells and IFN-gamma in the response to injury in normal and immune-deficient Rag-1KO mice. Methods and Results - Carotid arterial injury was induced in wild-type (WT), Rag-1KO mice, and Rag-1KO mice reconstituted with T cell-enriched splenocytes. The exuberant intimal thickening in Rag-1KO mice compared with WT mice 21 days after injury was reduced by T cell transfer (P < 0.01). Exogenous IFN-gamma starting on the day of injury inhibited intimal thickening in Rag-1KO mice. However, antibody neutralization of endogenous IFN-gamma in Rag-1KO mice starting 7 days after injury decreased intimal thickening, indicating that late presence of IFN-gamma promoted intimal thickening in Rag-1KO mice. Results further suggest that the effect of late IFN-gamma in Rag-1KO mice is mediated in part by increased IRF-1 and iNOS expression, coupled with low SOCS1 expression. Conclusion - T cells inhibit intimal thickening in the early stages of the response to injury through basal IFN-gamma secretion. In the Rag-1KO mice, late IFN-gamma expression promotes intimal thickening. These findings add novel insight to conditions of immune deficiency that affect intimal thickening.
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| 6. |
- Dimayuga, Paul, et al.
(författare)
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Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.
- 2002
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636 .- 1079-5642. ; 22:4, s. 644-649
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effect of B-cell reconstitution in immune-deficient Rag-1 knockout (KO) mice subjected to arterial injury. After 21 days, injury induced a 4- to 5-fold increase in neointimal formation in Rag-1 KO mice fed normal chow compared with wild-type (WT) mice (0.020+/-0.0160 [n=8] versus 0.0049+/-0.0022 [n=8] mm(2), respectively; P<0.05) and in western-type diet-fed Rag-1 KO mice compared with WT mice (0.0312+/-0.0174 [n=7] versus 0.0050+/-0.0028 [n=6] mm(2), respectively; P<0.05). To investigate the role of B cells in response to injury, Rag-1 KO mice were reconstituted with B cells derived from the spleens of WT mice, with donors and recipients on the same diet. Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed normal chow) reduced neointimal formation compared with the effect in unreconstituted Rag-1 KO mice (0.0076+/-0.0039 [n=9] versus 0.020+/-0.0160 [n=8] mm(2), respectively; P<0.05). Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed a western diet) reduced neointimal formation compared the effect in Rag-1 KO mice (0.0087+/-0.0037 [n=8] versus 0.0312+/-0.0174 [n=7] mm(2), respectively; P<0.05). Injured carotid arteries from reconstituted Rag-1 KO mice had detectable IgM and IgG, indicating viable transfer of B cells. The results suggest that B cells modulate the response to arterial injury.
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| 7. |
- Engelbertsen, Daniel, et al.
(författare)
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High levels of IgM against methylglyoxal-modified apolipoprotein B100 is associated with less coronary artery calcification in patients with type 2 diabetes.
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 271:1, s. 82-89
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Advanced glycation end products (AGE) have been implicated in diabetic vascular complications through activation of pro-inflammatory genes. AGE-modified proteins are also targeted by the immune system resulting in the generation of AGE-specific autoantibodies, but the association of these immune responses with diabetic vasculopathy remains to be fully elucidated. The aim of this study was to determine whether antibodies against apolipoprotein B100 modified by methylglyoxal (MGO-apoB100) are associated with coronary atherosclerosis in patients with type 2 diabetes. Methods. We measured antibodies against MGO-apoB100 in plasma from 497 type 2 diabetic patients without clinical signs of cardiovascular disease. Severity of coronary disease was assessed as coronary artery calcium (CAC) imaging. Immunoglobulin (Ig)M and IgG levels recognizing MGO-apoB100 were determined by enzyme-linked immunosorbent assay. Results. Anti-MGO-apoB100 IgM antibody levels were higher in subjects with a low to moderate CAC score (≤400 Agatston units) than in subjects with a high score (>400 Agatston units; 136.8 ± 4.4 vs. 101.6 ± 7.4 arbitrary units (AU), P < 0.0001) and in subjects demonstrating no progression of CAC during 30 months of follow-up (136.4 ± 5.7 vs. 113.9 ± 6.2 AU in subjects with progression, P < 0.0001). Subjects with a family history of premature myocardial infarction had lower levels of anti-MGO-apoB100 IgM. Female subjects had higher levels of anti-MGO-apoB100 antibodies and lower CAC than men. Accordingly, high levels of IgM against MGO-apoB100 are associated with less severe and a lower risk of progression of coronary disease in subjects with type 2 diabetes. Conclusions. Although conclusions regarding causal relationships based on epidemiological observations need to be made with caution, our findings suggest the possibility that anti-MGO-apoB100 IgM may be protective in diabetic vasculopathy.
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| 8. |
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| 9. |
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| 10. |
- Nilsson, Jan, et al.
(författare)
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Oxidized LDL antibodies in treatment and risk assessment of atherosclerosis and associated cardiovascular disease.
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128. ; 13:10, s. 1021-1030
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Forskningsöversikt (refereegranskat)abstract
- Immune responses against oxidized forms of LDL play a critical role in activation and regulation of the inflammatory process that characterizes all stages of atherosclerosis. In humans oxidized LDL is targeted by both IgM and IgG autoantibodies. Immunization of hypercholesterolemic animals with oxidized LDL has been shown to inhibit atherosclerosis demonstrating that at least some of these immune responses have a protective effect. The identification of the structures in oxidized LDL that are responsible for activation of immunity has made it possible to develop novel therapeutic approaches for treatment of atherosclerosis based on active (vaccines) and passive (antibodies) immunization. Studies performed in atherosclerosis-prone mice demonstrate that both peptide-based vaccines and recombinant IgG targeting epitopes in oxidized LDL significantly reduce atherosclerosis. There is also evidence antibodies against oxidized LDL could also be used for imaging atherosclerosis.
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| 11. |
- Nilsson, Jan, et al.
(författare)
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Oxidized lipoprotein autoimmunity: an emerging drug target in cardiovascular disease
- 2006
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Ingår i: Future Lipidology. - : Informa UK Limited. - 1746-0875. ; 1:3, s. 321-330
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Forskningsöversikt (refereegranskat)abstract
- Oxidative modification of low-density lipoprotein (LDL) in the arterial wall is believed to be one of the most important mechanisms involved in the development of atherosclerosis. It is well established that oxidized (Ox)-LDL uptake is responsible for the formation of macrophage foam cells, one of the most characteristic hallmarks of the atherosclerotic plaque, and that the proinflammatory and cytotoxic effects of Ox-LDL play an important role in vascular inflammation and lesion development. More recently, it has become apparent that Ox-LDL is also recognized by the immune system, thus resulting in innate and adaptive immune reactions modulating both Ox-LDL clearance and the vascular inflammatory response. The finding that some of these immune responses have a protective effect against plaque development has focused attention on the potential to develop novel therapies for the prevention and treatment of cardiovascular disease based on the selective activation of this protective immunity by vaccines, or mimicking them directly by using Ox-LDL-specific antibodies.
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| 12. |
- Nilsson, Jan, et al.
(författare)
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Promoting athero-protective immunity by vaccination with low density lipoprotein-derived antigens
- 2021
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 335, s. 89-97
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Forskningsöversikt (refereegranskat)abstract
- Immune responses activated by LDL particles that have been trapped and oxidized in the arterial wall play an important role in atherosclerosis. Some of these immune responses are protective by facilitating the removal of pro-inflammatory and toxic lipid species formed as result of LDL oxidation. However, should these protective immune responses be insufficient, other more potent pro-inflammatory immune responses instead contributing to disease progression will gradually become dominant. The importance of the balance between protective and pathogenic immunity is particularly apparent when it comes to the adaptive immune system where pro-inflammatory T helper 1 (Th1) type T cells aggravate atherosclerosis, while regulatory T cells (Tregs) have an opposing role. As oxidized LDL is a key autoantigen in atherosclerosis, it has become an interesting possibility that immune-modulatory therapy that favors the activity of apolipoprotein B peptide-specific Tregs could be developed into a novel treatment strategy for prevention/stabilization of atherosclerosis and ischemic cardiovascular events. Indeed, several such oxidized LDL tolerance vaccines have shown promising results in animal models of atherosclerosis. This review will discuss the experimental background for development of atherosclerosis vaccines based on LDL-derived antigens as well as the challenges involved in translating these findings into clinical application.
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| 13. |
- Nilsson, Jan, et al.
(författare)
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Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis.
- 2009
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Ingår i: Trends in Cardiovascular Medicine. - : Elsevier BV. - 1873-2615 .- 1050-1738. ; 19:8, s. 272-276
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Tidskriftsartikel (refereegranskat)abstract
- It has long been recognized that arterial inflammation plays a key role in the development of atherosclerosis. More recent evidence has suggested that this inflammation is modulated by autoimmune responses against modified self-antigens, such as oxidized low-density lipoprotein, in the vascular wall. However, the role of the immune system in atherosclerosis appears to be more complex than in classic autoimmune diseases; and a number of protective immune responses have also been identified. One of the most important of these is carried out by the regulatory T cells. Regulatory T cells inhibit the development of autoimmunity by controlling the activity of autoreactive T cells. If the function of regulatory T cells is compromised in hypercholesterolemic mouse models of atherosclerosis, the development of disease becomes much more aggressive. In this review, we will discuss the possibility that the inflammatory activity in atherosclerotic lesions depends on the balance between plaque antigen-specific proinflammatory Th1-type T cells and anti-inflammatory regulatory T cells specific for the same antigen. We will also discuss the role of hypercholesterolemia in generation of these modified self-antigens as well as ongoing research aiming to develop novel immune-modulating therapy for prevention of cardiovascular disease by targeting these processes.
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| 14. |
- Nilsson, Jan, et al.
(författare)
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Vaccines against atherosclerosis.
- 2013
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1744-8395 .- 1476-0584. ; 12:3, s. 311-321
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Forskningsöversikt (refereegranskat)abstract
- Atherosclerosis is the primary cause of acute myocardial infarction and stroke. It is well established that arterial inflammation in response to accumulation and oxidation of lipoproteins in the vascular wall is the major factor responsible for the development of atherosclerosis. During recent years, it has become apparent that this vascular inflammation is modulated by a complex array of autoimmune responses against modified self-antigens in the atherosclerotic plaque and that both protective and pathogenic immune responses become activated as part of the disease process. Studies of hypercholesterolemia-induced immune activation in mouse models of atherosclerosis have demonstrated that Th1 cells contribute to disease progression while regulatory T cells are protective. It has been suggested that antigen presentation of modified self-antigens in the inflammatory environment of atherosclerotic plaques favors generation of antigen-specific Th1 cells over that of regulatory T cells, resulting in a local loss of tolerance. This concept has stimulated the development of plaque-antigen tolerogenic vaccines to dampen plaque inflammation and disease progression. A first generation of atherosclerosis vaccines based on peptides derived from apoB100 and heat shock proteins have demonstrated promising results in animal studies and are now approaching clinical testing.
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| 15. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Association between IgM against an aldehyde-modified peptide in apo B-100 and progression of carotid disease.
- 2007
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Ingår i: Stroke. - : Lippincott Williams & Wilkins. - 0039-2499 .- 1524-4628. ; 38, s. 1495-1500
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose— Autoantibodies against antigens in oxidized low-density lipoprotein are common in people; experimental studies suggest that these immune responses have a functional role in the disease process. The aim of this study was to evaluate the relationship between the immune response against one defined oxidized low-density lipoprotein antigen, the aldehyde-modified peptide corresponding amino acids 3136 and 3155 (MDA-p210) in apolipoprotein (apo) B-100, and progression of carotid intima media thickness (IMT).Methods— IgM and IgG against MDA-p210 were determined by enzyme-linked immunosorbent assay at baseline and after 12 months of treatment with placebo, metoprolol, fluvastatin, or metoprolol/fluvastatin in 751 individuals participating in the BCAPS. Carotid IMT was assessed by ultrasonography at baseline and after 18 and 36 months of treatment.Results— Antibody levels did not change in response to treatment, but high baseline MDA-p210 IgM levels were associated with a more rapid progression of carotid disease both at 18 (r=0.09, P<0.05) and 36 months (r=0.12, P<0.005). At 36 months, the difference in IMT progression rate per year between those with high MDA-p210 IgM levels and those with low was 0.011 mm (95% CI=0.005 to 0.018 mm, P<0.0001). Treatment with fluvastatin markedly decreased the progression of IMT among subjects with high but not with low MDA-p210 IgM levels. There was no association between MDA-p210 IgG and carotid IMT progression.Conclusions— IgM against the aldehyde-modified peptide corresponding amino acids 3136 and 3155 in apo B-100 is common in subjects with asymptomatic carotid disease, and high levels are associated with a more rapid progression of carotid IMT. The observation that the effect of fluvastatin was restricted to subjects with high MDA-p210 IgM levels may reflect the increased rate of disease progression in this group.
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| 16. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Association between IgM against an aldehyde-modified peptide in apolipoprotein B-100 and progression of carotid disease
- 2007
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 38:5, s. 1495-1500
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose - Autoantibodies against antigens in oxidized low-density lipoprotein are common in people; experimental studies suggest that these immune responses have a functional role in the disease process. The aim of this study was to evaluate the relationship between the immune response against one defined oxidized low-density lipoprotein antigen, the aldehyde-modified peptide corresponding amino acids 3136 and 3155 (MDA-p210) in apolipoprotein (apo) B-100, and progression of carotid intima media thickness (IMT). Methods - IgM and IgG against MDA-p210 were determined by enzyme-linked immunosorbent assay at baseline and after 12 months of treatment with placebo, metoprolol, fluvastatin, or metoprolol/ fluvastatin in 751 individuals participating in the BCAPS. Carotid IMT was assessed by ultrasonography at baseline and after 18 and 36 months of treatment. Results - Antibody levels did not change in response to treatment, but high baseline MDA-p210 IgM levels were associated with a more rapid progression of carotid disease both at 18 ( r = 0.09, P < 0.05) and 36 months ( r = 0.12, P < 0.005). At 36 months, the difference in IMT progression rate per year between those with high MDA-p210 IgM levels and those with low was 0.011 mm ( 95% CI = 0.005 to 0.018 mm, P < 0.0001). Treatment with fluvastatin markedly decreased the progression of IMT among subjects with high but not with low MDA-p210 IgM levels. There was no association between MDA-p210 IgG and carotid IMT progression. Conclusions - IgM against the aldehyde-modified peptide corresponding amino acids 3136 and 3155 in apo B-100 is common in subjects with asymptomatic carotid disease, and high levels are associated with a more rapid progression of carotid IMT. The observation that the effect of fluvastatin was restricted to subjects with high MDA-p210 IgM levels may reflect the increased rate of disease progression in this group.
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| 17. |
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| 18. |
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| 19. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Autoimmune responses against the apo B-100 LDL receptor-binding site protect against arterial accumulation of lipids in LDL receptor deficient mice.
- 2007
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:2, s. 122-130
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxidation of LDL is associated with generation of autoantibodies against a large number of different aldehyde-modified peptide sequences in apo B-100. Autoantibodies recognizing peptide sequences in the LDL receptor-binding region of apo B-100 could potentially affect both cholesterol metabolism and atherosclerosis. The aim of the present study was to determine physiological effects of induction of immune responses against the apo B-100 LDL receptor-binding site in mice deficient for the LDL receptor. Methods and results: Mice received three immunizations, beginning at 6 weeks of age, with aldehyde-modified or nonmodified peptides corresponding to the amino acid sequence of the LDL receptor-binding site. Analysis of antibody response by ELISA unexpectedly revealed high titers of pre-existing IgG against both native and aldehyde-modified binding site sequences in non-immunized mice. Immunization with aldehyde-modified binding site sequences resulted in an almost complete down-regulation of this autoimmune response. It was also associated with a rapid increase in lipid-rich plaques in the aorta and a substantial depletion of the lipid content of the liver, whereas plasma lipid and apo B values were similar in all groups. Conclusions: These observations demonstrate existence of an endogenous T cell-dependent autoimmune response against the LDL receptor-binding site in LDL receptor(-/-) mice and suggest that this may help to prevent accumulation of lipoprotein lipids in the artery wall, whereas immunization with the corresponding aldehyde modified sequence down-regulates this response and induces substantial atherosclerotic development.
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| 20. |
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| 21. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Identification of autoantibodies in human plasma recognizing an apoB-100 LDL receptor binding site peptide
- 2006
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Ingår i: Journal of Lipid Research. - 1539-7262 .- 0022-2275. ; 47:9, s. 2049-2054
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to test the hypothesis that autoantibodies recognize amino acid sequences in the LDL receptor binding region of apolipoprotein B-100 (apoB-100). Autoantibodies against an unmodified or malondialdehyde (MDA)-modified LDL receptor binding site peptide were determined by ELISA in baseline plasma samples of 78 cases with coronary events and 149 matched controls recruited from the prospective Malmo Diet Cancer Study. IgG and IgM recognizing this peptide were detected in all subjects but did not differ between cases and controls. Inverse associations were observed between IgG against the native binding site and plasma oxidized LDL (r = -0.21, P < 0.005), but there were no significant associations with total or LDL cholesterol levels. In univariate analyses, inverse associations were found between baseline carotid intima-media thickness and IgG against the MDA-modified binding site (r = -0.14, P < 0.05), but this association was lost when controlling for other major cardiovascular risk factors. Specificity studies demonstrated that the binding of autoantibodies to these sequences could be inhibited by oxidized but not by native LDL. Autoantibodies recognizing the LDL receptor binding site in apoB-100 are frequently expressed. Their association with plasma oxidized LDL suggests that they have been generated in response to breakdown products of LDL oxidation, but their influence on cholesterol metabolism and the development of atherosclerosis appears limited.
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| 22. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease.
- 2003
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : The Assoc.. - 1524-4636 .- 1079-5642. ; 23:5, s. 872-878
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Tidskriftsartikel (refereegranskat)abstract
- Objective— Atherosclerosis is associated with an immune response against oxidized LDL, which modulates the progression of the disease process. Methods and Results— Using a library of polypeptides covering the complete sequence of apoB-100, the only major protein of LDL, we have identified over 100 different human antibodies reacting against aldehyde-modified apoB-100 sequences. IgM antibody titer levels decreased with age and were associated with the intima-media thickness of the carotid artery in subjects younger than 60 years. There were also inverse associations between IgM levels and oxidized LDL in plasma. In prospective clinical studies, antibody levels against several aldehyde-modified apoB-100 sites were associated with cardiovascular disease in this age group. Whether this immune response is adaptive (protective) or maladaptive (causal) in atherosclerosis requires further investigation. Conclusions— We have characterized a large number of epitopes within the apoB-100 component of oxidized LDL that provoke an immune response in humans. These findings will make it possible to study the role of immune responses against specific sites in oxidized LDL and to determine whether these immune responses influence the risk for future cardiac events.
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| 23. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences.
- 2003
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : The Assoc.. - 1524-4636 .- 1079-5642. ; 23:5, s. 879-884
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Tidskriftsartikel (refereegranskat)abstract
- Objective - LDL oxidation is believed to play an important role in the development of atherosclerosis, and oxidized LDL particles have been shown to become targets for the immune system. Immunization of animals with oxidized LDL results in reduction of atherosclerosis, suggesting an atheroprotective effect of this immune response. Methods and Results - Using a polypeptide library covering the complete sequence of apoB-100, a large number of native and malondialdehyde-modified peptide sequences in apoB-100 that are recognized by antibodies in human plasma were identified. We report here that immunization with apoB-100 peptide sequences, against which high levels of IgG and IgM antibodies are present in healthy human controls, reduce atherosclerosis in apoE-null mice by about 60%. Immunizations with these peptides were also found to increase the collagen content of subvalvular lesions. Conclusions - These studies have identified peptide sequences in apoB-100 that induce immune responses, which inhibits atherosclerosis. This suggests a way of developing an immunization therapy for coronary heart disease.
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| 24. |
- Pitts, Reynaria, et al.
(författare)
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Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure
- 2017
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Ingår i: Journal of the American Heart Association. - : WILEY-BLACKWELL. - 2047-9980. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background- Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. Methods and Results- To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF amp;lt; 40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates. Conclusions- In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events.
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| 25. |
- Salahuddin, Taufiq, et al.
(författare)
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Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial
- 2020
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Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 221, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Background High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). Methods The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. Results Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P =.81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. Conclusions Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.
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| 26. |
- Schiopu, Alexandru, et al.
(författare)
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Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.
- 2007
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 50:24, s. 2313-2318
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence. RESULTS: At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes. CONCLUSIONS: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.
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| 27. |
- Schwartz, Gregory G., et al.
(författare)
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Association of Lipoprotein(a) With Risk of Recurrent Ischemic Events Following Acute Coronary Syndrome Analysis of the dal-Outcomes Randomized Clinical Trial
- 2018
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Ingår i: JAMA cardiology. - : AMER MEDICAL ASSOC. - 2380-6583 .- 2380-6591. ; 3:2, s. 164-168
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). OBJECTIVE To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS This nested case-cohort analysis was performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina ormyocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. INTERVENTIONS Patients were randomly assigned to receive treatment with dalcetrapib, 600 mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. MAIN OUTCOMES AND MEASURES Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. RESULTS The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9) mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95% CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. CONCLUSIONS AND RELEVANCE For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS.
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| 28. |
- Schwartz, Gregory G., et al.
(författare)
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Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease
- 2020
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Ingår i: Diabetes Care. - : AMER DIABETES ASSOC. - 0149-5992 .- 1935-5548. ; 43:5, s. 1077-1084
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A(1c) and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A(1c) >= 6.5%, or a combination of at least two measurements of serum glucose >= 7.0 mmol/L (fasting) or >= 11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.
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| 29. |
- Schwartz, Gregory G, et al.
(författare)
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Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:22, s. 2089-2099
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND less thanbrgreater than less thanbrgreater thanIn observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanWe randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanAt the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (Pandlt;0.001 for both comparisons). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanIn patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.)
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| 30. |
- Schwartz, Gregory G, et al.
(författare)
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Rationale and design of the dal-OUTCOMES trial: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome
- 2009
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 158:6, s. 896-U34
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite contemporary therapies for acute coronary syndrome (ACS), morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and may contribute to ongoing risk. Strategies that raise levels of HDL cholesterol, such as inhibition of cholesterol ester transfer protein (CETP), might reduce risk after ACS. Dal-OUTCOMES is a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces cardiovascular morbidity and mortality in patients with recent ACS. Design The study will randomize approximately 15,600 patients to receive daily doses of dalcetrapib 600 mg or matching placebo, beginning 4 to 12 weeks after an index ACS event. There are no prespecified boundaries for HDL cholesterol levels at entry. Other elements of care, including management of low-density lipoprotein cholesterol, are to follow best evidence-based practice. The primary efficacy measure is time to first occurrence of coronary heart disease death, nonfatal acute myocardial infarction, unstable angina requiring hospital admission, resuscitated cardiac arrest, or atherothrombotic stroke. The trial will continue until 1,600 primary end point events have occurred, all evaluable subjects have been followed for at least 2 years, and 80% of evaluable subjects have been followed for at least 2.5 years. Summary Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.
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| 31. |
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| 32. |
- Shah, Prediman K., et al.
(författare)
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Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins - An idea whose time for testing is coming, Part II
- 2001
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 1524-4539 .- 0009-7322. ; 104:20, s. 2498-2502
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Tidskriftsartikel (refereegranskat)abstract
- Despite the benefits of currently available preventative and therapeutic interventions, atherosclerotic vascular disease continues to be a major cause of morbidity and mortality in much of the Western World. This emphasize,,, the need for additional preventive and therapeutic interventions exploiting new targets to compliment and augment the results of LDL lowering and other current strategies. One such potential target is HDL and its apolipoproteins, A large body of experimental evidence suggests that augmenting the levels and/or function of HDL and its apolipoproteins can have major vascular protective effects ranging from prevention to stabilization and regression, independent of total or non-HDL cholesterol levels. Therefore, we think that the time is ripe for the development and clinical testing of this new frontier in antiatherogenic strategy. In the present article, We will review the structure/function of HDL and explore means of enhancing the levels and/or function of HDL and its apolipoproteins for vascular protection.
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| 33. |
- Shah, Prediman K, et al.
(författare)
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Vaccination for atherosclerosis: a novel therapeutic paradigm
- 2004
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1744-8395 .- 1476-0584. ; 3:6, s. 711-716
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have identified a role for the innate and adaptive immune response in atherosclerosis; both pro- and antiatherogenic roles for the immune responses have been demonstrated. Common autoantigens against which an immune response has been identified in experimental and human models of atherosclerosis include oxidized low-density lipopoteins, beta2 glycoprotein 1 and heat shock protein 60. Activation of atheroprotective adaptive immune responses have been demonstrated for oxidized low-density lipoprotein-related antigens. Conversely, atheroprotection has been demonstrated with the induction of immune tolerance through activation of mucosal immunity to heat shock protein 65/60 and beta2 glycoprotein 1. Recent identification of specific immunoreactive antigenic epitopes in the apolipoprotein B-100 component of low density lipoproetin and early experimental observations have provided proof of concept that active vaccination using specific apolipoprotein B-100-related antigens may emerge as a novel immunomodulating atheroprotective strategy.
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| 34. |
- Shah, Prediman K, et al.
(författare)
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Vaccine for Atherosclerosis.
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 64:25, s. 2779-2791
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Forskningsöversikt (refereegranskat)abstract
- Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immunomodulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis. This review discusses: 1) the complex role of important components of the innate and adaptive immune systems in atherogenesis; 2) the nature of many antigens that have been tested successfully in vaccine formulations to reduce atherosclerosis in pre-clinical experimental models; and 3) the potential opportunities and challenges for clinical application of vaccination for atherosclerosis in the future.
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| 35. |
- Venuraju, Shreenidhi M., et al.
(författare)
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Association of Epicardial Fat Volume With the Extent of Coronary Atherosclerosis and Cardiovascular Adverse Events in Asymptomatic Patients With Diabetes
- 2021
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Ingår i: Angiology. - : SAGE Publications. - 0003-3197 .- 1940-1574. ; 72:5, s. 442-450
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Tidskriftsartikel (refereegranskat)abstract
- Epicardial adipose tissue has a paracrine effect, enhancing coronary artery atherosclerotic plaque development. This study evaluated epicardial fat volume (EFV), adipokines, coronary atherosclerosis, and adverse cardiovascular events in a cohort of asymptomatic patients with type 2 diabetes mellitus (T2DM). Epicardial fat volume was calculated using data from computed tomography coronary angiograms. Adipokines and inflammatory cytokines were also assayed and correlated with EFV. Epicardial fat volume was also assessed as a predictor of coronary artery calcium (CAC) score, number of coronary artery plaques, and significant plaque (>50% luminal stenosis). Data from the EFV analysis were available for 221 (85.7%) participants. Median EFV was 97.4 cm3, mean body mass index was 28.1 kg/m2, and mean duration of T2DM was 13 years. Statistically significant, but weak, correlations were observed between several adipokines, inflammatory cytokines, and EFV. Epicardial fat volume was a significant univariate (P =.01), but not multivariate, predictor of the number of coronary plaques, but not of CAC score or significant plaque. After a mean follow-up of 22.8 months, 12 adverse cardiovascular events were reported, exclusively in participants with EFV >97.4 cm3. Epicardial fat volume has limited utility as a marker of coronary artery plaque in patients with T2DM and is weakly correlated with adipokine expression.
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| 36. |
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