| 1. |
- Chen, Yun, 1966, et al.
(author)
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Characterization of VCAM-1-Binding Peptide-Functionalized Quantum Dots for Molecular Imaging of Inflamed Endothelium
- 2013
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
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Journal article (peer-reviewed)abstract
- Inflammation-induced activation of endothelium constitutes one of the earliest changes during atherogenesis. New imaging techniques that allow detecting activated endothelial cells can improve the identification of persons at high cardiovascular risk in early stages. Quantum dots (QDs) have attractive optical properties such as bright fluorescence and high photostability, and have been increasingly studied and developed for bio-imaging and bio-targeting applications. We report here the development of vascular cell adhesion molecule-1 binding peptide (VCAM-1 binding peptide) functionalized QDs (VQDs) from amino QDs. It was found that the QD fluorescence signal in tumor necrosis factor alpha (TNF-alpha) treated endothelial cells in vitro was significantly higher when these cells were labeled with VQDs than amino QDs. The VQD labeling of TNF-alpha-treated endothelial cells was VCAM-1 specific since pre-incubation with recombinant VCAM-1 blocked cells' uptake of VQDs. Our ex vivo and in vivo experiments showed that in the inflamed endothelium, QD fluorescence signal from VQDs was also much stronger than that of amino QDs. Moreover, we observed that the QD fluorescence peak was significantly blue-shifted after VQDs interacted with aortic endothelial cells in vivo and in vitro. A similar blue-shift was observed after VQDs were incubated with recombinant VCAM-1 in tube. We anticipate that the specific interaction between VQDs and VCAM-1 and the blue-shift of the QD fluorescence peak can be very useful for VCAM-1 detection in vivo.
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| 2. |
- Li, Li, et al.
(author)
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Reversible Modification of CdSe-CdS/ZnS Quantum Dot Fluorescence by Surrounding Ca2+ Ions
- 2014
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In: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 118:19, s. 10424-10433
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Journal article (peer-reviewed)abstract
- It has been known for a long time that the fluorescence intensity of colloidal quantum dots (QDs) becomes modified when free ions are added to the QD solution. The consequences of removing free ions from the QD solution, however, have not been closely investigated. In this work we studied fluorescence from 3-mercaptopropionic acid (3-MPA) coated CdSe-CdS/ZnS core-multishell QDs when free Ca2+ ions were added to and subsequently removed from the QD solution. It was found that QD fluorescence intensity was reduced when Ca2+ ions were added to the QD solution, while the wavelength of the QD fluorescence peak remained unchanged. QD fluorescence recovered when the concentration of free Ca2+ ions in the QD solution was reduced by adding Ca2+ chelator (ethylene glycol tetraacetic acid, EGTA). It was further observed that the time of single QD fluorescence at on-state and QD fluorescence lifetimes were also reduced after adding Ca2+ and then recovered when EGTA was added. Theoretical study shows that a free Ca2+ ion can attach stably to the system of [QD + surface ligand], attract the photoexcited electron, and repel the photoexcited hole inside the QD core, leading to the reduction of the radiative recombination between the electron and hole, thereafter decreasing the QD fluorescence intensity, on-state time, and fluorescence lifetimes, as observed experimentally. To the best of our knowledge, this is a first study to show that the changes of QD optical properties are reversible under the influence of Ca2+ ions. We further estimated the equilibrium association constant pK(a) of our QDs with Ca2+, which is much larger than QDs with Mg2+, Na+, and K+, indicating the feasibility of developing a QD-based Ca2+ sensor.
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| 3. |
- Andersson, Irene, 1978, et al.
(author)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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In: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Journal article (peer-reviewed)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 4. |
- Anttila, V., et al.
(author)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Journal article (peer-reviewed)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
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| 5. |
- Drevinge, Christina, 1983, et al.
(author)
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Perilipin 5 is protective in the ischemic heart
- 2016
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
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Journal article (peer-reviewed)abstract
- Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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| 6. |
- Erhardsson, M., et al.
(author)
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Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction
- 2023
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In: ESC Heart Failure. - 2055-5822. ; 10:6, s. 3729-3734
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Journal article (peer-reviewed)abstract
- Aims In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF.Methods and results We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction >= 40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis).Conclusions Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.
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| 7. |
- Faxen, U. L., et al.
(author)
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Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF
- 2021
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In: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 27:7, s. 756-765
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Journal article (peer-reviewed)abstract
- Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers. Methods and Results: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of >= 50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P<.001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P<.001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis. Conclusions: Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.
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| 8. |
- Gan, Li-Ming, 1969, et al.
(author)
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Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.
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| 9. |
- Hage, C., et al.
(author)
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Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction: A Follow-up in the PROMIS-HFpEF Study
- 2020
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In: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 26:11, s. 1016-1021
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Journal article (peer-reviewed)abstract
- Background: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF. Methods and Results: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of <2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test. Of 263 patients enrolled, 257 were evaluable at 1 year. Where the coronary flow reserve was interpretable (n = 201), CMD was present in 150 (75%). The median follow-up was 388 days (Q1, Q3 365, 418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96 per 1000 person-years, 95% confidence interval 54-159, vs non-CMD 0 per1000 person-years, 95% confidence interval 0-68, P = .023, and remained significant after accounting for selected clinical variables. In patients with CMD, the incidence rates were significantly higher also for CV death/ recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization. Conclusions: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CVand HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF.
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| 10. |
- Hage, Camilla, et al.
(author)
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Metabolomic Profile in HFpEF vs HFrEF Patients
- 2020
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In: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 26:12, s. 1050-1059
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Journal article (peer-reviewed)abstract
- Background: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications.Methods and Results: In new-onset HFpEF (EF of >= 50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, L-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (P-interaction = .020).Conclusions: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF.
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