Effects of deep sedation or general anesthesia on cardiac function in mice undergoing cardiovascular magnetic resonance

<p>Abstract</p> <p>Background</p> <p>Genetically engineered mouse models of human cardiovascular disease provide an opportunity to understand critical pathophysiological mechanisms. Cardiovascular magnetic resonance (CMR) provides precise reproducible assessment of cardiac structure and function, but, in contrast to echocardiography, requires that the animal be immobilized during image acquisition. General anesthetic regimens yield satisfactory images, but have the potential to significantly perturb cardiac function. The purpose of this study was to assess the effects of general anesthesia and a new deep sedation regimen, respectively, on cardiac function in mice as determined by CMR, and to compare them to results obtained in mildly sedated conscious mice by echocardiography.</p> <p>Results</p> <p>In 6 mildly sedated normal conscious mice assessed by echo, heart rate was 615 ± 25 min^-1(mean ± SE) and left ventricular ejection fraction (LVEF) was 0.94 ± 0.01. In the CMR studies of normal mice, heart rate was slightly lower during deep sedation with morphine/midazolam (583 ± 30 min^-1), but the difference was not statistically significant. General anesthesia with 1% inhaled isoflurane significantly depressed heart rate (468 ± 7 min^-1, p < 0.05 vs. conscious sedation). In 6 additional mice with ischemic LV failure, trends in heart rate were similar, but not statistically significant. In normal mice, deep sedation depressed LVEF (0.79 ± 0.04, p < 0.05 compared to light sedation), but to a significantly lesser extent than general anesthesia (0.60 ± 0.04, p < 0.05 vs. deep sedation).</p> <p>In mice with ischemic LV failure, ejection fraction measurements were comparable when performed during light sedation, deep sedation, and general anesthesia, respectively. Contrast-to-noise ratios were similar during deep sedation and during general anesthesia, indicating comparable image quality. Left ventricular mass measurements made by CMR during deep sedation were nearly identical to those made during general anesthesia (r²= 0.99, mean absolute difference < 4%), indicating equivalent quantitative accuracy obtained with the two methods. The imaging procedures were well-tolerated in all mice.</p> <p>Conclusion</p> <p>In mice with normal cardiac function, CMR during deep sedation causes significantly less depression of heart rate and ejection fraction than imaging during general anesthesia with isoflurane. In mice with heart failure, the sedation/anesthesia regimen had no clear impact on cardiac function. Deep sedation and general anesthesia produced CMR with comparable image quality and quantitative accuracy.</p

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction

A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation

SummaryCalcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA−/− mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis

HEP Community White Paper on Software trigger and event reconstruction

Realizing the physics programs of the planned and upgraded high-energy physics (HEP) experiments over the next 10 years will require the HEP community to address a number of challenges in the area of software and computing. For this reason, the HEP software community has engaged in a planning process over the past two years, with the objective of identifying and prioritizing the research and development required to enable the next generation of HEP detectors to fulfill their full physics potential. The aim is to produce a Community White Paper which will describe the community strategy and a roadmap for software and computing research and development in HEP for the 2020s. The topics of event reconstruction and software triggers were considered by a joint working group and are summarized together in this document.Comment: Editors Vladimir Vava Gligorov and David Lang

Cytokine Profiles in Asthma Families Depend on Age and Phenotype

Background: Circulating cytokine patterns may be relevant for the diagnosis of asthma, for the discrimination of certain phenotypes, and prognostic factors for exacerbation of disease. Methodology/Principal Findings: In this study we investigated serum samples from 944 individuals of 218 asthma-affected families by a multiplex, microsphere based system detecting at high sensitivity eleven asthma associated mediators: eotaxin (CCL11), granulocyte macrophage stimulating factor (GM-CSF), interferon gamma (IFNγ), interleukin-4 (IL-4), IL-5, IL-8, IL-10, IL-12 (p40), IL-13, IL-17 and tumor necrosis factor alpha (TNFα). Single cytokine levels were largely similar between asthmatic and healthy individuals when analysing asthma as single disease entity. Regulatory differences between parental and pediatric asthma were reflected by six of the eleven mediators analyzed (eotaxin, IL-4, IL-5, IL-10, IL-12, TNFα). IL-12 (p40) and IL-5 were the best predictor for extrinsic asthma in children with an increased odds ratio of 2.85 and 1.96 per log pg/ml increase (IL-12 (p40): 1.2-6.8, p = 0.019, and IL-5: 1.2-2.5, p = 0.025). Frequent asthma attacks in children are associated with elevated IL-5 serum levels (p = 0.013). Cytokine patterns seem to be individually balanced in both, healthy and diseased adults and children, with various cytokines correlating among each other (IL-17 and IFNγ (rs = 0.67), IL-4 and IL-5 (rs = 0.55), IFNγ and GM-CSF (rs = 0.54)). Conclusion/Significance: Our data support mainly an age- but also an asthma phenotype-dependent systemic immune regulation. © 2010 Pukelsheim et al

Study of Gluon versus Quark Fragmentation in Υ→ggγ\Upsilon\to gg\gamma and e+e−→qqˉγe^{+}e^{-}\to q\bar{q}\gamma Events at \sqrt{s}=10 GeV

Using data collected with the CLEO II detector at the Cornell Electron Storage Ring, we determine the ratio R(chrg) for the mean charged multiplicity observed in Upsilon(1S)->gggamma events, to the mean charged multiplicity observed in e+e- -> qqbar gamma events. We find R(chrg)=1.04+/-0.02+/-0.05 for jet-jet masses less than 7 GeV.Comment: 15 pages, postscript file also available through http://w4.lns.cornell.edu/public/CLN

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Acute effects of euglycemic‐hyperinsulinemia on myocardial contractility in male mice

Abstract Type 2 diabetes and obesity are associated with increased risk of cardiovascular disease, including heart failure. A hallmark of these dysmetabolic states is hyperinsulinemia and decreased cardiac reserve. However, the direct effects of hyperinsulinemia on myocardial function are incompletely understood. In this study, using invasive hemodynamics in mice, we studied the effects of short‐term euglycemic hyperinsulinemia on basal myocardial function and subsequent responses of the myocardium to β‐adrenergic stimulation. We found that cardiac function as measured by left ventricular (LV) invasive hemodynamics is not influenced by acute exposure to hyperinsulinemia, induced by an intravenous insulin injection with concurrent inotropic stimulation induced by β‐adrenergic stimulation secondary to isoproterenol administration. When animals were exposed to 120‐min of hyperinsulinemia by euglycemic‐hyperinsulinemic clamps, there was a significant decrease in LV developed pressure, perhaps secondary to the systemic vasodilatory effects of insulin. Despite the baseline reduction, the contractile response to β‐adrenergic stimulation remained intact in animals subject to euglycemic hyperinsulinemic clamps. β‐adrenergic activation of phospholamban phosphorylation was not impaired by hyperinsulinemia. These results suggest that short‐term hyperinsulinemia does not impair cardiac inotropic response to β‐adrenergic stimulation in vivo