1,394 research outputs found
DĂ©veloppement dâun modĂšle de suivi en imagerie TEP de la cardiotoxicitĂ© induite par chimiothĂ©rapie chez la souris
Le cancer est la premiĂšre cause de dĂ©cĂšs au Canada et le cancer du sein est la forme la plus courante de cancer chez la femme. Le traitement privilĂ©giĂ© lors dâun diagnostic de cancer du sein est lâutilisation de la doxorubicine, un agent de chimiothĂ©rapie de la famille des anthracyclines. Cet agent grandement utilisĂ© en clinique permet de traiter diffĂ©rents types de cancer et possĂšde un large spectre dâaction. Cependant, son utilisation est limitĂ©e par lâapparition dâeffets secondaires, lesquels peuvent se manifester longtemps aprĂšs lâarrĂȘt des traitements. Lâun de ces effets particuliĂšrement nocifs est le dĂ©veloppement dâune cardiotoxicitĂ©, qui est dĂ©pendante de la dose et conduit Ă une insuffisance cardiaque congestive et irrĂ©versible. Les techniques utilisĂ©es en clinique pour dĂ©terminer le dĂ©veloppement dâune cardiotoxicitĂ© reposent principalement sur lâĂ©valuation de la fraction dâĂ©jection du ventricule gauche (FEVG).
Le projet comprend deux objectifs; 1) dĂ©velopper un modĂšle de cardiotoxicitĂ©, induite par lâadministration de doxorubicine, chez la souris; 2) effectuer un suivi longitudinal par tomographie dâĂ©mission par positrons (TEP) afin de vĂ©rifier si certains paramĂštres mĂ©taboliques ou physiologiques permettraient de prĂ©dire le dĂ©veloppement de la cardiotoxicitĂ©. Le suivi est effectuĂ© avec deux traceurs, le [indice supĂ©rieur 11]C-acĂ©toacĂ©tate ([indice supĂ©rieur 11]C-AcAc), permettant dâĂ©valuer Ă la fois la captation et la clairance du traceur par le coeur, mais semble avoir lâavantage de mettre en Ă©vidence lâinsuffisance cardiaque sans avoir recours Ă un test Ă lâeffort, comme le [indice supĂ©rieur 11]C-acĂ©tate. Le deuxiĂšme traceur est le [indice supĂ©rieur 18]F-FDG, couramment utilisĂ© pour les examens cliniques, il permet de mesurer la consommation de glucose par le tissu cardiaque ainsi que la FEVG. Les deux traceurs ont Ă©tĂ© analysĂ©s Ă lâaide de modĂšles pharmacocinĂ©tiques afin de vĂ©rifier si les changements observĂ©s permettent de prĂ©dire hĂątivement le dĂ©veloppement de la cardiotoxicitĂ©, avant dâatteindre un Ă©tat de non-retour.
Les travaux rĂ©alisĂ©s ont permis de mettre au point un modĂšle de cardiotoxicitĂ© chez la souris suite Ă lâadministration de chimiothĂ©rapie. Les rĂ©sultats obtenus dĂ©montrent que des changements rĂ©vĂ©lant le dĂ©veloppement dâinsuffisance cardiaque peuvent ĂȘtre observĂ©s hĂątivement par une diminution de la captation myocardique et de la clairance du [indice supĂ©rieur 11]C-AcAc, indice de la perfusion et du mĂ©tabolisme oxydatif myocardique, suivi dâune augmentation du taux de transfert du glucose vers le coeur qui arrive au mĂȘme moment que la diminution de la FEVG
Metformin reduces left ventricular eccentric remodeling in experimental volume overload in the rat
Left ventricular hypertrophy (LVH) is often associated with a change in myocardial energy substrate preference
from fatty acids to glucose. A possible anti hypertrophic treatment strategy could aim at stimulating or restoring
normal myocardial energy metabolism. Metformin, an adenosine monophosphate-activated protein kinase (AMPK)
activator used in the management of glucose metabolism in diabetes, is also a fatty acid oxidation stimulator. The
effect of metformin on the development of eccentric LVH and ventricular function in chronic left ventricular (LV)
volume overload (VO) is unknown. This study was designed to study this question in a VO rat model caused by
severe aortic valve regurgitation (AR). Male Wistar rats were divided in four groups (13-15 animals / group): Shams
(S) treated or not (C) with metformin (M; 100 mg/kg/d PO) and severe ARreceiving or not metformin. Treatment was
started one week before surgery and the animals were sacrificed 9 weeks later. As expected AR rats developed
severe eccentric LVH during the course of the protocol. Metformin treatment did not influence the total heart weight.
However, LV remodeling associated with the severe VO was severe in ARM than in ARC. Fractional shortening, a
marker of systolic function, was significantly higher in ARM compared to ARC group. Metformin also increased the
activity of enzymes associated with fatty acid oxidation while inhibiting phosphofructokinase, a glycolytic enzyme. A
2 month treatment with metformin reduced LV eccentric remodeling associated with severe VO and helped maintain
a better systolic function
Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload.
BACKGROUND:
Patients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR.
METHODS:
LV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (nâ=â10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months.
RESULTS:
MicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them.
CONCLUSION:
This study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats
Angiotensin II converting enzyme inhibition improves survival, ventricular remodeling and myocardial energetics in experimental aortic regurgitation.
Backgroundâ Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation.
Methods and ResultsâForty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by ” positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use.
ConclusionsâIn a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial
Transcriptional changes associated with long-term left ventricle volume overload in rats : impact on enzymes related to myocardial energy metabolism.
Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA ÎČ-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling
Erratum: Characterization and Mathematical Modeling of Alginate/Chitosan-Based Nanoparticles Releasing the Chemokine CXCL12 to Attract Glioblastoma Cells
Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires
The production of tt⟠, W+bb⟠and W+cc⟠is studied in the forward region of protonâproton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fbâ1 . The W bosons are reconstructed in the decays WââÎœ , where â denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of , and is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 0.02 \mbox{fb}^{-1}. The bosons are reconstructed in the decays , where denotes muon or electron, while the and quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions
Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era
The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2Ă1034
cmâ2sâ1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b â sl+lâand b â dl+lâ transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 â ÎŒ+ÎŒâ)/B(Bs â ÎŒ+ÎŒâ). Probing charm CP violation at the 10â5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier
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