| 1. |
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| 2. |
- Adner, Mikael, et al.
(author)
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Regional variation in appearance of vascular contractile endothelin-B receptors following organ culture
- 1998
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In: Cardiovascular Research. - 1755-3245. ; 37:1, s. 254-262
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study was to investigate the appearance of contractile endothelin (ET)-B receptors following organ culture in different vascular regions. METHOD: The contractile responses of vascular smooth muscle induced by ET-1 and the selective ETB receptor agonist sarafotoxin 6c (S6c) were investigated in circular segments representing eight vascular regions in the rat (aorta, femoral artery, mesenteric artery, branch of the mesenteric artery, proximal and distal parts of the caudal artery, femoral and mesenteric veins). To allow the ETB receptor to be expressed, the segments were placed in organ culture for 1 to 5 days. Pharmacological characterisation of the ET receptors was performed in mesenteric arterial segments. All contractile responses were measured in percentage of K(+)-induced contraction. RESULTS: ET-1 induced strong concentration-dependent contractions of all fresh (not cultured) segments. S6c had negligible effects on all fresh vessels with the exception of the mesenteric vein, where a small contraction was seen. After 1 day of organ culture all tested segments, with the exception of aorta and the proximal part of the caudal artery, showed concentration-dependent contractile responses to S6c which were further augmented after 5 days of culture. The ET-1-induced responses were only slightly affected by organ culture. Contractions induced by S6c were more enhanced in small arteries and veins than in larger arteries. Furthermore, the S6c-induced response was more pronounced in the mesenteric region as compared to the hindlimb. In fresh mesenteric arterial segments FR139317 (ETA receptor antagonist) and bosentan (ETA/ETB receptor antagonist) but not IRL 2500 (ETB receptor antagonist) shifted the ET-1-induced concentration-response curve in parallel to the right. In contrast, after organ culture the S6c-induced concentration-response curves were shifted parallel to the right in the following potency order: IRL 2500 > bosentan > FR139317. CONCLUSION: During normal conditions, the ETA receptor is the dominating mediator of endothelin-induced contraction in eight different vascular regions. Furthermore, this study indicates that most of the vessels have the ability to develop contractile ETB receptors and that this plasticity differs in vascular regions.
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| 3. |
- Alabas, Oras A., et al.
(author)
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Statistics on mortality following acute myocardial infarction in 842 897 Europeans
- 2020
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In: Cardiovascular Research. - : OXFORD UNIV PRESS. - 0008-6363 .- 1755-3245. ; 116:1, s. 149-157
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Journal article (peer-reviewed)abstract
- Aims: To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments.Methods and results: National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), beta-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4-8.5) vs. 6.7 (6.5-6.9)] and NSTEMI [6.8 (6.4-7.2) vs. 4.9 (4.7-5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5-3.3) vs. 2.3 (2.2-2.5)] and [21.4 (20.0-22.8) vs. 18.3 (17.6-19.0)], but was similar for STEMI [0.7 (0.4-1.0) vs. 0.9 (0.7-1.0)] and [8.4 (6.7-10.1) vs. 8.3 (7.5-9.1)].Conclusion: Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.
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| 4. |
- Alexander, Y, et al.
(author)
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Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis
- 2021
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 117:1, s. 29-42
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Journal article (peer-reviewed)abstract
- Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.
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| 5. |
- Andersson, Linda, 1973, et al.
(author)
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Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischemia
- 2015
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:4, s. 478-486
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Journal article (peer-reviewed)abstract
- In myocardial ischemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischemia/reperfusion injury.
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| 6. |
- Back, M, et al.
(author)
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From organic and inorganic phosphates to valvular and vascular calcifications
- 2021
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 117:9, s. 2016-2029
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Journal article (peer-reviewed)abstract
- Calcification of the arterial wall and valves is an important part of the pathophysiological process of peripheral and coronary atherosclerosis, aortic stenosis, ageing, diabetes, and chronic kidney disease. This review aims to better understand how extracellular phosphates and their ability to be retained as calcium phosphates on the extracellular matrix initiate the mineralization process of arteries and valves. In this context, the physiological process of bone mineralization remains a human model for pathological soft tissue mineralization. Soluble (ionized) calcium precipitation occurs on extracellular phosphates; either with inorganic or on exposed organic phosphates. Organic phosphates are classified as either structural (phospholipids, nucleic acids) or energetic (corresponding to phosphoryl transfer activities). Extracellular phosphates promote a phenotypic shift in vascular smooth muscle and valvular interstitial cells towards an osteoblast gene expression pattern, which provokes the active phase of mineralization. A line of defense systems protects arterial and valvular tissue calcifications. Given the major roles of phosphate in soft tissue calcification, phosphate mimetics, and/or prevention of phosphate dissipation represent novel potential therapeutic approaches for arterial and valvular calcification.
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| 7. |
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| 8. |
- Balogh, Johanna, et al.
(author)
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Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance.
- 2002
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In: Cardiovascular Research. - 1755-3245. ; 53:2, s. 439-450
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Desmin intermediate filaments are key structures in the cytoskeleton of cardiac muscle. Since they are associated with Z-discs and intercalated discs, they may have a role in sarcomere alignment or force transmission. We have explored the mechanical function of the desmin filaments in the cardiac wall by comparing desmin-deficient (Des-/-) and wild-type (Des+/+) mice. METHODS: The Langendorff technique was used to examine the contractility of the whole heart. Rate of force generation, Ca(2+)-sensitivity and force per cross-sectional area were measured in skinned ventricle muscle preparations. RESULTS: Des-/- mice have a cardiomyopathy with increased heart weight. Diastolic pressure was increased at all filling volumes in the Des-/- group. Since passive wall stress (i.e. force per area) was unchanged, the alteration in diastolic pressure is a consequence of the thicker ventricle wall. Developed pressure, rate of pressure increase and developed wall stress were significantly reduced, suggesting that active force generation of the contractile apparatus is reduced in Des-/-. Concentrations of actin and myosin in the ventricle were unaltered. Measurements in skinned muscle preparations showed a lower active force development with unaltered Ca(2+)-sensitivity and rate of tension development. CONCLUSION: It is suggested that the intermediate filaments have a role in active force generation of cardiac muscle, possibly by supporting sarcomere alignment or force transmission. The desmin filaments do not contribute the passive elasticity of the ventricle wall. Des-/- mice provide a model for genetic cardiomyopathy where the main factor contributing to altered cardiac performance is a decrease in active force generation, possibly in combination with a loss of functional contractile units.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Benz, Alexander P., et al.
(author)
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Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease
- 2021
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 118:1, s. 295-304
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Journal article (peer-reviewed)abstract
- Aims Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. Methods and results We analysed data of 15 400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrolment. A total of 1788 (11.6%) patients had RHD. These patients were younger (51.4 +/- 15.7 vs. 67.8 +/- 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA(2)DS(2)-VASc score (2.1 +/- 1.7 vs. 3.7 +/- 2.2) as compared to patients without RHD (all P<0.001). Significant mitral stenosis (average mean transmitral gradient 11.5 +/- 6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, P<0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA(2)DS(2)-VASc score was modest in both groups [stroke at 1 year, c-statistics 0.69, 95% confidence interval (CI) 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively]. In the overall cohort, advanced age, female sex, prior stroke, tobacco use, and non-use of anticoagulation were predictors for stroke (all P<0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, P=0.764). Conclusion The performance of the CHA(2)DS(2)-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.
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| 14. |
- Berg, Jonathan, et al.
(author)
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Mild hypothermia attenuates ischemia/reperfusion injury - insights from serial non-invasive pressure-volume loops
- 2023
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 119:12, s. 2230-2243
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Journal article (peer-reviewed)abstract
- BACKGROUND: Mild hypothermia, 32-35°C, reduces infarct size in experimental studies, potentially mediating reperfusion injuries, but human trials have been ambiguous. To elucidate the cardioprotective mechanisms of mild hypothermia, we analyzed cardiac performance in a porcine model of ischemia/reperfusion, with serial cardiovascular magnetic resonance (CMR) imaging throughout one week using non-invasive pressure-volume loops.METHODS AND RESULTS: Normothermia and Hypothermia groups sessions (n=7+7 pigs, nonrandom allocation) were imaged with CMR at baseline and subjected to 40 minutes of normothermic ischemia by catheter intervention. Thereafter, the Hypothermia group was rapidly cooled (mean 34.5°C) for 5 minutes before reperfusion. Additional CMR sessions at two hours, 24 hours, and seven days acquired ventricular volumes and ischemic injuries (unblinded analysis).Stroke volume (-24%; p=0.029; Friedmans test) and ejection fraction (-20%; p=0.068) were notably reduced at 24h in the Normothermia group compared to baseline. In contrast, the decreases were ameliorated in the Hypothermia group (stroke volume: -6%; p=0.77; ejection fraction: -6%; p=0.13). Mean arterial pressure remained stable in Normothermic animals (-3%, p=0.77) but dropped two hours post-reperfusion in hypothermic animals (-18%, p=0.007). Both groups experienced a decrease and partial recovery pattern for PV loop-derived variables over one week, but the adverse effects tended attenuated in the Hypothermia group. Infarct sizes were 10±8% in Hypothermic and 15±8% in Normothermic animals (p=0.32). Analysis of covariance at 24 hours indicated that hypothermia has cardioprotective properties incremental to reducing infarct size, such as higher external power (p=0.061) and lower arterial elastance (p=0.015).CONCLUSION: Using non-invasive pressure-volume loops by CMR, we observed that mild hypothermia at reperfusion alleviates the heart's work after ischemia/reperfusion injuries during the first week and preserves short-term cardiac performance. This hypothesis-generating study suggests hypothermia to have cardioprotective properties, incremental to reducing infarct size. The primary cardioprotective mechanism was likely an afterload reduction acutely unloading the left ventricle.
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| 15. |
- Berg, M, et al.
(author)
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3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:12, s. 1948-1957
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Journal article (peer-reviewed)abstract
- AimsAtherosclerosis is a chronic inflammatory disease involving immunological and metabolic processes. Metabolism of tryptophan (Trp) via the kynurenine pathway has shown immunomodulatory properties and the ability to modulate atherosclerosis. We identified 3-hydroxyanthranilic acid (3-HAA) as a key metabolite of Trp modulating vascular inflammation and lipid metabolism. The molecular mechanisms driven by 3-HAA in atherosclerosis have not been completely elucidated. In this study, we investigated whether two major signalling pathways, activation of SREBPs and inflammasome, are associated with the 3-HAA-dependent regulation of lipoprotein synthesis and inflammation in the atherogenesis process. Moreover, we examined whether inhibition of endogenous 3-HAA degradation affects hyperlipidaemia and plaque formation.Methods and resultsIn vitro, we showed that 3-HAA reduces SREBP-2 expression and nuclear translocation and apolipoprotein B secretion in HepG2 cell cultures, and inhibits inflammasome activation and IL-1β production by macrophages. Using Ldlr−/− mice, we showed that inhibition of 3-HAA 3,4-dioxygenase (HAAO), which increases the endogenous levels of 3-HAA, decreases plasma lipids and atherosclerosis. Notably, HAAO inhibition led to decreased hepatic SREBP-2 mRNA levels and lipid accumulation, and improved liver pathology scores.ConclusionsWe show that the activity of SREBP-2 and the inflammasome can be regulated by 3-HAA metabolism. Moreover, our study highlights that targeting HAAO is a promising strategy to prevent and treat hypercholesterolaemia and atherosclerosis.
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| 16. |
- Berglund, Lisa, et al.
(author)
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NFAT regulates the expression of AIF-1 and IRT-1: Yin and yang splice variants of neointima formation and atherosclerosis.
- 2012
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 93, s. 414-423
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Journal article (peer-reviewed)abstract
- Aims Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1). Here we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype.Methods and results Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity. Pharmacological inhibition of NFAT or targeting of NFATc3 with siRNA lowers the AIF-1/IRT-1 ratio and favors an anti-proliferative outcome. NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque.Conclusions Inhibition of NFAT signaling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis.
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| 17. |
- Bhattachariya, Anirban, et al.
(author)
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Expression of microRNAs is essential for arterial myogenic tone and pressure-induced activation of the PI3-kinase/Akt pathway.
- 2014
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 101:2, s. 288-296
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Journal article (peer-reviewed)abstract
- The myogenic response is the intrinsic ability of small arteries to constrict in response to increased intraluminal pressure. Although microRNAs have been shown to play a role in vascular smooth muscle function, their importance in the regulation of the myogenic response is not known. In this study, we investigate the role of microRNAs in the regulation of myogenic tone by using smooth muscle-specific and tamoxifen-inducible deletion of the endonuclease Dicer in mice.
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| 18. |
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| 19. |
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| 20. |
- Bosmans, Laura A., et al.
(author)
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Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages’ transition into a pro-inflammatory state
- 2023
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:5, s. 1146-1160
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Journal article (peer-reviewed)abstract
- Aims CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Method and Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/− , respect-Results ively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac−/− compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac−/− atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b− macrophages in the atherosclerotic aorta of CD40mac−/− compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac−/− mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). Conclusions We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
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| 21. |
- Brauner, S, et al.
(author)
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Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content
- 2018
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 114:1, s. 158-167
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Journal article (peer-reviewed)abstract
- AimsPatients with hyperlipidemia are at risk of atherosclerosis, but not all develop cardiovascular disease, highlighting the importance of other risk factors such as inflammation. Both the innate and adaptive arms of the immune system have been suggested in the initiation and propagation of plaque formation. Tri-partite motif (TRIM) 21 is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in chronic inflammatory disease. Here, we investigate a potential role for TRIM21 in coronary artery disease.Methods and resultsTrim21-deficient or wild-type bone marrow was transplanted into Ldlr-/- mice fed a hypercholesterolemic diet. The Trim21-/-->Ldlr-/- mice developed larger atherosclerotic plaques, with significantly higher collagen content compared to mice transplanted with wild-type cells. High collagen content of the atheroma is stabilizing, and has recently been linked to IL-17. Interestingly, Trim21-/-->Ldlr-/- mice had elevated CD4 and IL-17 mRNA expression in plaques, and increased numbers of activated CD4+ T cells in the periphery. An increased differentiation of naïve T cells lacking Trim21 into Th17 cells was confirmed in vitro, with transcriptomic analysis revealing upregulation of genes of a non-pathogenic Th17 phenotype. Also, decreased expression of matrix metalloproteinases (MMPs) was noted in aortic plaques. Analysis of human carotid plaques confirmed that TRIM21 expression negatively correlates with the expression of key Th17 genes and collagen, but positively to MMPs also in patients, linking our findings to a clinical setting.ConclusionIn this study, we demonstrate that TRIM21 influences atherosclerosis via regulation of Th17 responses, with TRIM21 deficiency promoting IL-17 expression and a more fibrous, stable, phenotype of the plaques.
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| 22. |
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| 23. |
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| 25. |
- Bäck, Magnus, et al.
(author)
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Biomechanical factors in the biology of aortic wall and aortic valve diseases
- 2013
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 99:2, s. 232-241
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Research review (peer-reviewed)abstract
- The biomechanical factors that result from the haemodynamic load on the cardiovascular system are a common denominator of several vascular pathologies. Thickening and calcification of the aortic valve will lead to reduced opening and the development of left ventricular outflow obstruction, referred to as aortic valve stenosis. The most common pathology of the aorta is the formation of an aneurysm, morphologically defined as a progressive dilatation of a vessel segment by more than 50% of its normal diameter. The aortic valve is exposed to both haemodynamic forces and structural leaflet deformation as it opens and closes with each heartbeat to assure unidirectional flow from the left ventricle to the aorta. The arterial pressure is translated into tension-dominated mechanical wall stress in the aorta. In addition, stress and strain are related through the aortic stiffness. Furthermore, blood flow over the valvular and vascular endothelial layer induces wall shear stress. Several pathophysiological processes of aortic valve stenosis and aortic aneurysms, such as macromolecule transport, gene expression alterations, cell death pathways, calcification, inflammation, and neoangiogenesis directly depend on biomechanical factors.
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| 26. |
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| 27. |
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| 28. |
- Carlström, Mattias, 1941-, et al.
(author)
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Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension
- 2011
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 89:3, s. 574-585
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Journal article (peer-reviewed)abstract
- Aims Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease. Methods and results Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg(-1) day(-1)), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation. Conclusion Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.
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| 29. |
- Chang, Ya-Ting, et al.
(author)
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Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension
- 2015
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:1, s. 20-31
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Journal article (peer-reviewed)abstract
- Aims Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH. Methods and results In normoxia, Hspg2(Delta 3/Delta 3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Delta 3/Delta 3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Delta 3/Delta 3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Delta 3/Delta 3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Delta 3/Delta 3) compared with wild type. Conclusions Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.
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| 30. |
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| 31. |
- Chen, Qiao Sen, et al.
(author)
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A machine learning based approach to identify carotid subclinical atherosclerosis endotypes
- 2023
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In: Cardiovascular Research. - : OXFORD UNIV PRESS. - 0008-6363 .- 1755-3245. ; 119:16, s. 2594-2606
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Journal article (peer-reviewed)abstract
- Aims To define endotypes of carotid subclinical atherosclerosis. Methods and results We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (& beta;, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (& beta;, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations. Conclusions We report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.
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| 32. |
- Chester, Adrian H, et al.
(author)
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5-Hydroxytryptamine receptor profile in healthy and diseased human epicardial coronary arteries
- 1990
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 24:11, s. 932-937
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Journal article (peer-reviewed)abstract
- STUDY OBJECTIVE--The aim of the study was to investigate the receptor events that mediate the vascular effects of 5-hydroxytryptamine (5-HT) on human coronary arteries, since 5-HT has long been thought to play a role in coronary artery vasospasm. DESIGN--Recently available selective receptor agonists and antagonists were used to examine the 5-HT receptor subtypes present in human epicardial coronary arteries using in vitro organ baths. EXPERIMENTAL MATERIAL--138 segments of coronary arteries were obtained from 21 patients aged 2-66 years undergoing heart transplantation. MEASUREMENTS AND MAIN RESULTS--5-HT produced only concentration dependent contractions of coronary artery segments. No evidence was obtained for 5-HT receptors mediating either endothelium dependent or endothelium independent vasorelaxation. In tissue from patients without ischaemic heart disease, 5-HT effects were mimicked by (+/-)-alpha-methyl-5-HT (alpha-me-5-HT), a selective agonist at 5-HT2 receptors. In addition, the selective 5-HT1-like receptor agonist GR43175 produced contractions which achieved 30% of the maximum response to 5-HT. Responses to alpha-me-5-HT were surmountably antagonised by the non-selective antagonist methiothepin (0.1 mumol.litre-1) as well as the 5-HT2 receptor antagonist ketanserin (0.1 mumol.litre-1). In contrast GR43175 effects were resistant to blockade by ketanserin, but remained sensitive to methiothepin. Responses to the two agonists were not antagonised by the 5-HT3 receptor antagonist MDL72222 (1.0 mumol.litre-1). Vessel segments from ischaemic heart disease patients also contracted to alpha-me-5-HT and GR43175. Diseased arteries contracted with a decrease in the maximal response induced by both alpha-me-5-HT and by 90 mM K+ depolarisation compared to "normal" vessels, but the effect of GR43175 was preserved in the diseased arteries. Vascular rings adjacent to an atheromatous lesion were more reactive to GR43175 than serial segments taken distal to the lesion. CONCLUSIONS--These results show that both 5-HT1-like and 5-HT2 receptors mediate contraction of human epicardial coronary arteries and indicate that effects mediated by 5-HT1-like receptors but not 5-HT2 receptors are preserved in patients with ischaemic heart disease.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Dahm, Peter L., et al.
(author)
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Binding of [3H]-5-hydroxytryptamine to human coronary artery and bypass graft vessels
- 1996
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In: Cardiovascular Research. - 1755-3245. ; 31:5, s. 800-806
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Journal article (peer-reviewed)abstract
- OBJECTIVES: 5-Hydroxytryptamine (5-HT) has a wide range of vascular effects mediated via specific receptors and it has been suggested to be a mediator in ischemic heart disease. The aim of the present study was to localise the 5-HT receptors within the vessel wall. METHODS: Epicardial coronary arteries obtained from patients undergoing cardiac transplantation, internal mammary arteries from heart donors and saphenous veins from patients undergoing coronary bypass surgery, were sectioned and incubated with [3H]-5-HT for in vitro receptor autoradiography. RESULTS: Microscopic analysis of high resolution autoradiographic images revealed a similar pattern of [3H]-5-HT binding in epicardial coronary and internal mammary artery, where it predominated in the lamina muscularis. In the saphenous vein, binding increased towards the adventitia which showed dense, displaceable binding to the vasa vasorum as well as to nerve-like structures, from which binding was only partially displaced. Computer-assisted densitometric analysis of low resolution autoradiographs revealed a high degree of specific binding to all vessels examined. CONCLUSIONS: The distribution of the [3H]-5-HT binding is different in the saphenous vein compared to epicardial coronary and internal mammary artery. The dense binding to vasa vasorum in the saphenous vein suggests a role for 5-HT in closure of these nutrient vessels, which could contribute to the formation of atherosclerotic changes in saphenous vein grafts.
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| 37. |
- Dalin, Martin, 1982, et al.
(author)
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Myocardial KRASG12D expression does not cause cardiomyopathy in mice
- 2014
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 101:2, s. 229-235
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Journal article (peer-reviewed)abstract
- AimsGerm-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRASG12D expression in the heart.Methods and resultsTo generate mice with endogenous cardiomyocyte-specific KRASG12D expression (cKRASG12D mice), we bred mice with a Cre-inducible allele expressing KRASG12D from its endogenous promoter (Kras2LSL) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRASG12D mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRASG12D mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart.ConclusionMice with cardiomyocyte-specific KRAS G12D expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013.
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| 38. |
- Danielsson, Christian, et al.
(author)
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Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism
- 2013
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In: Cardiovascular Research. - : Oxford University Press (OUP): Policy B. - 0008-6363 .- 1755-3245. ; 97:1, s. 23-32
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Journal article (peer-reviewed)abstract
- Several drugs blocking the rapidly activating potassium (K-r) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species. less thanbrgreater than less thanbrgreater thanPatch-clamp and quantitative-mRNA measurements of K-r and slowly activating K (K-s) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K-r channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K-r-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K-r-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K-s channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit. less thanbrgreater than less thanbrgreater thanThis first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K-r-channel blocker in human, rat, and rabbit embryos provides evidence of K-r-channel inhibition as a common mechanism for embryonic malformations and death.
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| 39. |
- Dantuma, NP, et al.
(author)
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Stressing the ubiquitin-proteasome system
- 2010
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 85:2, s. 263-271
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Journal article (peer-reviewed)
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| 40. |
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| 41. |
- Davidsson, Pia, et al.
(author)
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Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease
- 2023
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 119:7, s. 1596-1605
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Journal article (peer-reviewed)abstract
- Aims The vascular endothelial growth factor (VEGF) family is involved in pathophysiological mechanisms underlying cardiovascular (CV) diseases. The aim of this study was to investigate the associations between circulating VEGF ligands and/or soluble receptors and CV outcome in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS).Methods and results Levels of VEGF biomarkers, including bFGF, Flt-1, KDR (VEGFR2), PlGF, Tie-2, VEGF-A, VEGF-C, and VEGF-D, were measured in the PLATO ACS cohort (n = 2091, discovery cohort). Subsequently, VEGF-D was also measured in the STABILITY CCS cohort (n = 4015, confirmation cohort) to verify associations with CV outcomes. Associations between plasma VEGF-D and outcomes were analysed by multiple Cox regression models with hazard ratios (HR [95% CI]) comparing the upper vs. the lower quartile of VEGF-D. Genome-wide association study (GWAS) of VEGF-D in PLATO identified SNPs that were used as genetic instruments in Mendelian randomization (MR) meta-analyses vs. clinical endpoints. GWAS and MR were performed in patients with ACS from PLATO (n = 10 013) and FRISC-II (n = 2952), and with CCS from the STABILITY trial (n = 10 786). VEGF-D, KDR, Flt-1, and PlGF showed significant association with CV outcomes. VEGF-D was most strongly associated with CV death (P = 3.73e-05, HR 1.892 [1.419, 2.522]). Genome-wide significant associations with VEGF-D levels were identified at the VEGFD locus on chromosome Xp22. MR analyses of the combined top ranked SNPs (GWAS P-values; rs192812042, P = 5.82e-20; rs234500, P = 1.97e-14) demonstrated a significant effect on CV mortality [P = 0.0257, HR 1.81 (1.07, 3.04) per increase of one unit in log VEGF-D].Conclusion This is the first large-scale cohort study to demonstrate that both VEGF-D plasma levels and VEGFD genetic variants are independently associated with CV outcomes in patients with ACS and CCS. Measurements of VEGF-D levels and/or VEGFD genetic variants may provide incremental prognostic information in patients with ACS and CCS.
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| 42. |
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| 43. |
- Dunér, Pontus, et al.
(author)
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Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis.
- 2011
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 91, s. 528-536
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Journal article (peer-reviewed)abstract
- Aims. Oxidation of LDL in the extracellular matrix of the arterial wall results in formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin. Methods and Results. Immunization of apoE-deficient mice with MDA-modified fibronectin resulted in a 70% decrease in plaque area and a less inflammatory phenotype of remaining plaques. Immunization shifted a weak naturally occurring Th1 antibody response against MDA-fibronectin into a Th2 antibody response. Cytokine expression and flow cytometry analyses of spleen cells from immunized mice showed an activation of regulatory T cells. Immunization with MDA-fibronectin was also found to reduce plasma fibronectin levels. Conclusions. Immunization with MDA-fibronectin significantly reduces the development of atherosclerosis in apoE-deficient mice suggesting that the immune response observed in humans may have a protective effect. MDA-fibronectin represents a possible novel target for immunomodulatory therapy in atherosclerosis.
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| 44. |
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| 45. |
- Edsfeldt, Andreas, et al.
(author)
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Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events
- 2023
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 119:11, s. 2061-2073
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Journal article (peer-reviewed)abstract
- Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events. TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. Conclusions: TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.
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| 46. |
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| 47. |
- Elliott, Perry, et al.
(author)
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Development, validation and implementation of biomarker testing in cardiovascular medicine state-of-the-art : Proceedings of the European Society of Cardiology - Cardiovascular Round Table
- 2021
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 117:5, s. 1248-1256
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Journal article (peer-reviewed)abstract
- Many biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance characteristics or fail to meet regulatory standards for approval. Despite their potential, new technologies have added to the complexities of successful translation into clinical practice. Biomarker discovery and implementation requires a standardised approach that includes: identification of a clinical need; identification of a valid surrogate biomarker; stepwise assay refinement, demonstration of superiority over current standard-of-care; development and understanding of a clinical pathway; and demonstration of real-world performance. Successful biomarkers should improve efficacy or safety of treatment, while being practical at a realistic cost. Everyone involved in cardiovascular healthcare, including researchers, clinicians, and industry partners, are important stakeholders in facilitating the development and implementation of biomarkers. This paper provides suggestions for a development pathway for new biomarkers, discusses regulatory issues and challenges, and suggestions for accelerating the pathway to improve patient outcomes. Real life examples of successful biomarkers-high sensitivity cardiac troponin (hs-cTn), T2* cardiovascular magnetic resonance (CMR) imaging, and echocardiography-are used to illustrate the value of a standardised development pathway in the translation of concepts into routine clinical practice.
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| 48. |
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| 49. |
- Engelbertsen, Daniel, et al.
(author)
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IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis
- 2018
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 114:1, s. 180-187
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Journal article (peer-reviewed)abstract
- The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. Methods and results We transferred apoe-/-myd88\+/\+ or apoe-/-myd88-/- CD4+ T cells to T-A nd B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88\+/\+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-c. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. Conclusion We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.
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| 50. |
- Engelbertsen, Daniel, et al.
(author)
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Induction of T helper 2 responses against human Apolipoprotein B100 does not affect atherosclerosis in ApoE-/- mice.
- 2014
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363.
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Journal article (peer-reviewed)abstract
- Immune responses against LDL antigens have been found to play an important modulatory role in atherosclerosis. Immunization with homologous oxidized LDL, as well as human apolipoprotein B100 (ApoB)-derived peptides, inhibit atherosclerosis in hypercholesterolemic animal models of atherosclerosis. However, the role of antigen-specific Th2 responses in atherosclerosis remains to be fully clarified.
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