| 1. |
- Ahmed, M., et al.
(författare)
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Human serum albumin-based probes for molecular targeting of macrophage scavenger receptors
- 2019
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Ingår i: International Journal of Nanomedicine. - 1176-9114 .- 1178-2013. ; 14, s. 3723-3741
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inflammation and accumulation of macrophages are key features of unstable atherosclerotic plaques. The ability of macrophages to take up molecular probes can be exploited in new clinical imaging methods for the detection of unstable atherosclerotic lesions. We investigated whether modifications of human serum albumin (HSA) could be used to target macrophages efficiently in vitro. Materials and methods: Maleylated and aconitylated HSA were compared with unmodified HSA. Fluorescent or radiolabeled (89 Zr) modified HSA was used in in vitro experiments to study cellular uptake by differentiated THP-1 cells and primary human macrophages. The time course of uptake was evaluated by flow cytometry, confocal microscopy, real-time microscopy and radioactivity measurements. The involvement of scavenger receptors (SR-A1, SR-B2, LOX-1) was assessed by knockdown experiments using RNA interference, by blocking experiments and by assays of competition by modified low-density lipoprotein. Results: Modified HSA was readily taken up by different macrophages. Uptake was mediated nonexclusively via the scavenger receptor SR-A1 (encoded by the MSR1 gene). Knockdown of CD36 and ORL1 had no influence on the uptake. Modified HSA was preferentially taken up by human macrophages compared with other vascular cell types such as endothelial cells and smooth muscle cells. Conclusions: Modified89Zr-labeled HSA probes were recognized by different subsets of polarized macrophages, and maleylated HSA may be a promising radiotracer for radio-nuclide imaging of macrophage-rich inflammatory vascular diseases. © 2019 Ahmed et al.
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| 2. |
- Ahmed, M., et al.
(författare)
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Molecular Imaging of a New Multimodal Microbubble for Adhesion Molecule Targeting
- 2019
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Ingår i: Cellular and Molecular Bioengineering. - : Springer Science and Business Media LLC. - 1865-5025 .- 1865-5033. ; 12:1, s. 15-32
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionInflammation is an important risk-associated component of many diseases and can be diagnosed by molecular imaging of specific molecules. The aim of this study was to evaluate the possibility of targeting adhesion molecules on inflammation-activated endothelial cells and macrophages using an innovative multimodal polyvinyl alcohol-based microbubble (MB) contrast agent developed for diagnostic use in ultrasound, magnetic resonance, and nuclear imaging.MethodsWe assessed the binding efficiency of antibody-conjugated multimodal contrast to inflamed murine or human endothelial cells (ECs), and to peritoneal macrophages isolated from rats with peritonitis, utilizing the fluorescence characteristics of the MBs. Single-photon emission tomography (SPECT) was used to illustrate Tc-99m-labeled MB targeting and distribution in an experimental in vivo model of inflammation.ResultsFlow cytometry and confocal microscopy showed that binding of antibody-targeted MBs to the adhesion molecules ICAM-1, VCAM-1, or E-selectin, expressed on cytokine-stimulated ECs, was up to sixfold higher for human and 12-fold higher for mouse ECs, compared with that of non-targeted MBs. Under flow conditions, both VCAM-1- and E-selectin-targeted MBs adhered more firmly to stimulated human ECs than to untreated cells, while VCAM-1-targeted MBs adhered best to stimulated murine ECs. SPECT imaging showed an approximate doubling of signal intensity from the abdomen of rats with peritonitis, compared with healthy controls, after injection of anti-ICAM-1-MBs.ConclusionsThis novel multilayer contrast agent can specifically target adhesion molecules expressed as a result of inflammatory stimuli in vitro, and has potential for use in disease-specific multimodal diagnostics in vivo using antibodies against targets of interest.
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| 3. |
- Asp, Anna M., et al.
(författare)
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Cardiac remodelling and functional alterations in mild-to-moderate renal dysfunction: Comparison with healthy subjects
- 2015
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Ingår i: Clinical Physiology and Functional Imaging. - : Wiley. - 1475-0961 .- 1475-097X. ; 35:3, s. 223-230
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Tidskriftsartikel (refereegranskat)abstract
- © 2014 The Authors. Introduction: Left ventricular (LV) hypertrophy (LVH) and reduced LV function correlate with poor prognosis in patients with chronic kidney disease (CKD). Our aim is to investigate whether mild-to-moderate CKD is associated with cardiac abnormalities. Methods: Echocardiography, including tissue Doppler imaging, was performed in 103 patients with CKD at stages 2-3 and 4-5, and in 53 healthy controls. The systolic (s′) and diastolic myocardial velocity (e′), and the transmitral diastolic flow velocity (E) were measured, and E/e′ was calculated. Results: Patients with chronic kidney disease had higher mean E/e′ than controls (mean E/e′: controls 5·00 ± 1·23 versus CKD 4-5 6·36 ± 1·71, P < 0·001 and versus CKD 2-3 5·69 ± 1·47, P = 0·05), indicating altered diastolic function in the patients. The CKD groups showed lower longitudinal systolic function than controls, as assessed by atrio-ventricular plane displacement and s′ (mean s′: controls 11·5 ± 1·9 cm s < sup > -1 < /sup > versus CKD 4-5 10·4 ± 2·1 cm s < sup > -1 < /sup > , P = 0·03 and versus CKD 2-3 10·4 ± 2·1 cm s < sup > -1 < /sup > , P = 0·02). The prevalence of LVH was higher in patients with CKD than in controls (controls 13% versus CKD 4-5 37%, P = 0·006 and versus CKD 2-3 30%, P = 0·03). Conclusion: Alterations in systolic and diastolic myocardial function can be seen in mild-to-moderate CKD compared with controls, indicating that cardiac involvement starts early in CKD, which may be a precursor of premature cardiac morbidity.
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| 4. |
- Backdahl, J., et al.
(författare)
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Long-Term Improvement in Aortic Pulse Wave Velocity After Weight Loss Can Be Predicted by White Adipose Tissue Factors
- 2018
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Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 31:4, s. 450-457
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Arterial stiffness, measured by pulse wave velocity (PWV), is linked to obesity, cardiovascular disease, and all-cause mortality. Short-term weight loss improves PWV, but the long-term effects are unknown. We investigated the effect of pronounced long-term weight loss on PWV and whether anthropometric/metabolic parameters and/or white adipose tissue (WAT) phenotype could predict this change in PWV. Eighty-two obese subjects were examined before and 2 years after Roux-en-Y gastric bypass. Analyses included anthropometrics, routine clinical chemistry, and hyperinsulinemic-euglycemic clamp. Arterial stiffness was measured as aortic PWV (aPWV) using the Arteriograph device. WAT mass and distribution were assessed by dual-X-ray absorptiometry. Baseline visceral and subcutaneous WAT samples were obtained to measure adipocyte cell size. Transcriptomic profiling of subcutaneous WAT was performed in a subset of subjects (n = 30). At the 2-year follow-up, there were significant decreases in body mass index (39.4 +/- 3.5 kg/m(2) vs. 26.6 +/- 3.4 kg/m(2); P < 0.0001) and aPWV (7.8 +/- 1.5 m/s vs. 7.2 +/- 1.4 m/s; P = 0.006). Multiple regression analyses showed that baseline subcutaneous adipocyte volume was associated with a reduction in aPWV (P = 0.014), after adjusting for confounders. Expression analyses of 52 genes implicated in arterial stiffness showed that only one, COL4A1, independently predicted improvements in aPWV after adjusting for confounders (P = 0.006). Bariatric surgery leads to long-term reduction in aPWV. This improvement can be independently predicted by subcutaneous adipocyte volume and WAT COL4A1 expression, which suggests that subcutaneous WAT has a role in regulating aPWV.
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| 5. |
- Caidahl, Kenneth, 1949, et al.
(författare)
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Homeostatic Chemokines and Prognosisin Patients With Acute Coronary Syndromes.
- 2019
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 1558-3597 .- 0735-1097. ; 74:6, s. 774-782
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Tidskriftsartikel (refereegranskat)abstract
- The chemokines CCL19 and CCL21 are up-regulated in atherosclerotic disease and heart failure, and increased circulating levels are found in unstable versus stable coronary artery disease.The purpose of this study was to evaluate the prognostic value of CCL19 and CCL21 in acute coronary syndrome (ACS).CCL19 and CCL21 levels were analyzed in serum obtained from ACS patients (n=1,146) on the first morning after hospital admission. Adjustments were made for GRACE (Global Registry of Acute Coronary Events) score, left ventricular ejection fraction, pro-B-type natriuretic peptide, troponin I, and C-reactive protein levels.The major findings were: 1) those having fourth quartile levels of CCL21 on admission of ACS had a significantly higher long-term (median 98months) risk of major adverse cardiovascular events (MACE) and myocardial infarction in fully adjusted multivariable models; 2) high CCL21 levels at admission were also independently associated with MACE and cardiovascular mortality during short-time (3months) follow-up; and 3) high CCL19 levels at admission were associated with the development of heart failure.CCL21 levels are independently associated with outcome after ACS and should be further investigated as a promising biomarker in these patients.
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| 6. |
- Chen, X., et al.
(författare)
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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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| 7. |
- Chen, Xiaojing, et al.
(författare)
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Impact of changes in heart rate with age on all-cause death and cardiovascular events in 50-year-old men from the general population
- 2019
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Ingår i: Open Heart. - : BMJ. - 2053-3624. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Resting heart rate (RHR), a known cardiovascular risk factor, changes with age. However, little is known about the association between changes in RHR and the risk of cardiovascular events. The purpose of this study was therefore to assess the impact of RHR at baseline, and the change in RHR over time, on the risk of all-cause death and cardiovascular events. Design A random population sample of men born in 1943 who were living in Gothenburg, Sweden was prospectively followed for a 21-year period. Methods Participants were examined three times: first in 1993 and then re-examined in 2003 and 2014. At each visit, a clinical examination, an ECG and laboratory analyses were performed. Change in RHR between 1993 and 2003 was defined as a decrease if RHR decreased by 5 beats per minute (bpm), an increase if RHR increased by 5 bpm or stable if the RHR change was <4bpm). Results Participants with a baseline RHR of >75 bpm in 1993 had about a twofold higher risk of all-cause death (HR 2.3, CI 1.2 to 4.7, p=0.018), cardiovascular disease (CVD) (HR 1.8, CI 1.1 to 3.0, p=0.014) and coronary heart disease (CHD) (HR 2.2, CI 1.1 to 4.5, p=0.025) compared with those with <55 bpm in 1993. Participants with a stable RHR between 1993 and 2003 had a 44% decreased risk of CVD (HR 0.56, CI 0.35 to 0.87, p=0.011) compared with participants with an increasing RHR. Furthermore, every beat increase in heart rate from 1993 was associated with a 3% higher risk for all-cause death, 1% higher risk for CVD and 2% higher risk for CHD. Conclusion High RHR was associated with an increased risk of death and cardiovascular events in men from the general population. Moreover, individuals with an increase in RHR between 50 and 60 years of age had worse outcome. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 8. |
- Damlin, A., et al.
(författare)
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Associations between echocardiographic manifestations and bacterial species in patients with infective endocarditis: a cohort study
- 2019
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Ingår i: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: The diagnosis of infective endocarditis (IE) is based on microbiological analyses and diagnostic imaging of cardiac manifestations. Echocardiography (ECHO) is preferred for visualization of IE-induced cardiac manifestations. We investigated associations between bacterial infections and IE manifestations diagnosed by ECHO. Methods: In this cohort study, data from patients aged 18 years or above, with definite IE admitted at the Karolinska University Hospital between 2008 and 2017 were obtained from Swedish National Registry of Endocarditis. Bacteria registered as pathogen were primarily selected from positive blood culture and for patients with negative blood culture, bacteria found in culture or PCR from postoperative material was registered as pathogen. Patients with negative results from culture or PCR, and patients who did not undergo ECHO during hospital stay, were excluded. IE manifestations diagnosed by ECHO were obtained from the registry. Chi-squared test and two-sided Fisher's exact test was used for comparisons between categorical variables, and student's t test was used for continuous numerical variables. Multivariable analyses were performed using logistic regression. Secular trend analyses were performed using linear regression. Associations and the strength between the variables were estimated using odds ratios (ORs) with 95% confidence intervals (CIs). P < 0.05 was considered significant. Results: The most common bacteria were Staphylococcus aureus (n = 239, 49%) and viridans group streptococci (n = 102, 21%). The most common manifestations were vegetation in the mitral (n = 195, 40%), aortic (n = 190, 39%), and tricuspid valves (n = 108, 22%). Associations were seen between aortic valve vegetations and Enterococcus faecalis among patients with native aortic valves, between mitral valve vegetations and streptococci of group B or viridans group, between tricuspid valve vegetations and S. aureus among patients with intravenous drug abuse, and between perivalvular abscesses as well as cardiovascular implantable electronic device (CIED)-associated IE and coagulase negative staphylococci (all P < 0.05). Conclusions: Associations were found between certain bacterial species and specific ECHO manifestations. Our study contributes to a better understanding of IE manifestations and their underlying bacterial etiology, which pathogens can cause severe infections and might require close follow-up and surgical treatment.
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| 9. |
- Daniel, M., et al.
(författare)
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Prevalence of Anxiety and Depression Symptoms in Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries
- 2018
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Ingår i: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 131:9, s. 1118-1124
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Myocardial infarction with non-obstructive coronary arteries is a working diagnosis for several heart disorders. Previous studies on anxiety and depression in patients with myocardial infarction with non-obstructive coronary arteries are lacking. Our aim was to investigate the prevalence of anxiety and depression among patients with myocardial infarction with non-obstructive coronary arteries. METHODS: We included 99 patients with myocardial infarction with non-obstructive coronary arteries together with age- and sex-matched control groups who completed the Beck Depression Inventory and the Hospital Anxiety and Depression Scale (HADS) 3 months after the acute event. RESULTS: Using the Beck Depression Inventory, we found that the prevalence of depression in patients with myocardial infarction with non-obstructive coronary arteries (35%) was higher than in healthy controls (9%; P = .006) and similar to that of patients with coronary heart disease (30%; P = .954). Using the HADS anxiety subscale, we found that the prevalence of anxiety in patients with myocardial infarction with non-obstructive coronary arteries (27%) was higher than in healthy controls (9%; P = .002) and similar to that of patients with coronary heart disease (21%; P = .409). Using the HADS depression subscale, we found that the prevalence of depression in patients with myocardial infarction with non-obstructive coronary arteries (17%) was higher than in healthy controls (4%; P = .003) and similar to that of patients with coronary heart disease (13%; P = .466). Patients with myocardial infarction with non-obstructive coronary arteries and takotsubo syndrome scored higher on the HADS anxiety subscale than those without (P = .028). CONCLUSIONS: This is the first study on the mental health of patients with myocardial infarction with non obstructive coronary arteries to show that prevalence rates of anxiety and depression are similar to those in patients with coronary heart disease. (C) 2018 Elsevier Inc. All rights reserved.
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| 10. |
- Di Gennaro, A., et al.
(författare)
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Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:8, s. 1907-1912
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Tidskriftsartikel (refereegranskat)abstract
- Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
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