The role of myocardial membrane proteins and myocardial oedema in postoperative myocardial dysfunction

The vast majority of children undergoing surgical repair of cardiac lesions do spectacularly well. However a significant proportion, ~ 25%, struggle to progress in the early postoperative period and require additional pharmacological and occasionally mechanical circulatory support. All children typically have some degree of postoperative myocardial dysfunction, with the severe spectrum termed the low cardiac output state (LCOS). LCOS is clinically defined as the requirement for new or escalated inotrope therapy, a widened arteriovenous oxygen difference, cardiac arrest or the need for reinstitution of mechanical circulatory support. LCOS is largely responsible for the morbidity and mortality involved in paediatric cardiac surgery. Despite the predictability of LCOS in the initial postoperative hours, the underlying pathophysiology remains unclear. The period of decline in cardiac function that typifies LCOS is temporally associated with the development of oedema in the tissues of the body, including the heart. This relationship between oedema and dysfunction has increasingly become blurred, with a tendency to elevate the temporal association to a causal link. We sought to explore the causes and contributions to myocardial dysfunction in this setting, including the roles of oedema and ischaemia within the heart. In focusing on oedema and ischaemia we also examined the effects of these insults on relevant myocardial membrane proteins, including those that permit rapid water transport – aquaporins (AQPs), and those involved in membrane mechanics – dystrophin, and membrane repair – dysferlin. Experimental settings which enabled the in vitro dissection of these insults and proteins of interest were combined with a clinically accurate in vivo model. This thesis describes a series of thematically linked experiments that examined LCOS, myocardial oedema and the role of various membrane proteins. We performed isolated cardiomyocyte studies, isolated heart studies as well as a clinically relevant large animal (lamb) cardiopulmonary bypass (CPB) model. Across these models we also explored the role of therapeutically protecting myocardial membranes with Poloxamer 188 (P188) and assessed any influence on myocardial function, oedema and membrane proteins. vi The results from these three models suggest that the clinically accepted dogma of a causative link between myocardial oedema and dysfunction overstates the contribution of myocardial oedema to LCOS. We found that ischaemia/reperfusion was of primary importance in causing myocardial dysfunction. Myocardial oedema without ischaemia had a mild and reversible contribution to myocardial dysfunction, but this was minor in comparison to the gross dysfunction attributable to ischaemia. Isolated cardiomyocytes, with induced oedema, functioned well. Whilst ischaemic cardiomyocytes, with less swelling still had severe contractile dysfunction. Isolated hearts, perfused with an oedema inducing crystalloid perfusate developed myocardial oedema and had minimal reversible systolic and diastolic dysfunction. Isolated hearts which experienced global ischaemia had comparable degrees of myocardial oedema, and significantly greater degrees of myocardial dysfunction that increased in severity with increasing duration of ischaemia. In the lamb CPB model, only those lambs which underwent aortic cross clamping and had a period of ischaemia had poor myocardial function. These lambs also had swollen hearts, raised myocardial AQP1 mRNA and reduced membrane dysferlin protein expression. Membrane dystrophin protein expression was not altered, somewhat unexpectedly with CPB with or without ischaemia. Lambs placed on CPB without ischaemia had good myocardial function, minimal oedema and unchanged membrane protein expression during the survival period. In a blinded lamb CPB trial of P188 there were improved haemodynamics and indicies of myocardial function associated with its use. This was also associated with preservation of dysferlin expression and reduced membrane injury. In parallel isolated heart trials of this therapy, there was a reduction in myocardial oedema associated with its use in non-ischaemic experiments. There was also a suggestion of improved diastolic function in ischaemic experiments, but no change in myocardial water content. In conclusion, we have highlighted the primacy of ischaemia/reperfusion over oedema in contributing to LCOS. We have refuted the accepted dogma that myocardial oedema causes significant dysfunction in itself, with important oedema likely to result from ischaemia. We have shown that AQP1 may be involved in the pathogenesis of the capillary leak syndrome. Finally we have hinted at a role for prophylactic P188 in the vii setting of LCOS, possibly highlighting the role of membrane repair in recovery after surgery. Isolated heart trials of P188 further support a non-rheological mechanism of action and also lend support to the causal separation of myocardial oedema and dysfunction. The integral membrane protein dysferlin, rather than dystrophin, is relevant in the setting of LCOS in the current era

The Milky Way bar and bulge revealed by APOGEE and Gaia EDR3

We investigate the inner regions of the Milky Way using data from APOGEE and Gaia EDR3. Our inner Galactic sample has more than 26 500 stars within |XGal| < 5 kpc, |YGal| < 3.5 kpc, |ZGal| < 1 kpc, and we also carry out the analysis for a foreground-cleaned subsample of 8000 stars that is more representative of the bulge–bar populations. These samples allow us to build chemo-dynamical maps of the stellar populations with vastly improved detail. The inner Galaxy shows an apparent chemical bimodality in key abundance ratios [α/Fe], [C/N], and [Mn/O], which probe different enrichment timescales, suggesting a star formation gap (quenching) between the high- and low-α populations. Using a joint analysis of the distributions of kinematics, metallicities, mean orbital radius, and chemical abundances, we can characterize the different populations coexisting in the innermost regions of the Galaxy for the first time. The chemo-kinematic data dissected on an eccentricity–|Z|max plane reveal the chemical and kinematic signatures of the bar, the thin inner disc, and an inner thick disc, and a broad metallicity population with large velocity dispersion indicative of a pressure-supported component. The interplay between these different populations is mapped onto the different metallicity distributions seen in the eccentricity–|Z|max diagram consistently with the mean orbital radius and Vφ distributions. A clear metallicity gradient as a function of |Z|max is also found, which is consistent with the spatial overlapping of different populations. Additionally, we find and chemically and kinematically characterize a group of counter-rotating stars that could be the result of a gas-rich merger event or just the result of clumpy star formation during the earliest phases of the early disc that migrated into the bulge. Finally, based on 6D information, we assign stars a probability value of being on a bar orbit and find that most of the stars with large bar orbit probabilities come from the innermost 3 kpc, with a broad dispersion of metallicity. Even stars with a high probability of belonging to the bar show chemical bimodality in the [α/Fe] versus [Fe/H] diagram. This suggests bar trapping to be an efficient mechanism, explaining why stars on bar orbits do not show a significant, distinct chemical abundance ratio signature

APOGEE Kinematics I: Overview of the Kinematics of the Galactic Bulge as Mapped by APOGEE

We present the stellar kinematics across the Galactic bulge and into the disk at positive longitudes from the SDSS-III APOGEE spectroscopic survey of the Milky Way. APOGEE includes extensive coverage of the stellar populations of the bulge along the mid-plane and near-plane regions. From these data, we have produced kinematic maps of 10,000 stars across longitudes 0 deg < l < 65 deg, and primarily across latitudes of |b| < 5 deg in the bulge region. The APOGEE data reveal that the bulge is cylindrically rotating across all latitudes and is kinematically hottest at the very centre of the bulge, with the smallest gradients in both kinematic and chemical space inside the inner-most region (l,|b|) < (5,5) deg. The results from APOGEE show good agreement with data from other surveys at higher latitudes and a remarkable similarity to the rotation and dispersion maps of barred galaxies viewed edge on. The thin bar that is reported to be present in the inner disk within a narrow latitude range of |b| < 2 deg appears to have a corresponding signature in [Fe/H] and [alpha/Fe]. Stars with [Fe/H] > -0.5 have dispersion and rotation profiles that are similar to that of N-body models of boxy/peanut bulges. There is a smooth kinematic transition from the thin bar and boxy bulge (l,|b|) < (15,12) deg out into the disk for stars with [Fe/H] > -1.0, and the chemodynamics across (l,b) suggests the stars in the inner Galaxy with [Fe/H] > -1.0 have an origin in the disk.Comment: Accepted by ApJ 15 December 201

Mapping The Interstellar Medium With Near-Infrared Diffuse Interstellar Bands

We map the distribution and properties of the Milky Way's interstellar medium as traced by diffuse interstellar bands (DIBs) detected in near-infrared stellar spectra from the SDSS-III/APOGEE survey. Focusing exclusively on the strongest DIB in the H band, at lambda similar to 1.527 mu m, we present a projected map of the DIB absorption field in the Galactic plane, using a set of about 60,000 sightlines that reach up to 15 kpc from the Sun and probe up to 30 mag of visual extinction. The strength of this DIB is linearly correlated with dust reddening over three orders of magnitude in both DIB equivalent width (Wpm) and extinction, with a power law index of 1.01 +/- 0.01, a mean relationship of W-DIB/A(v) = 0.1 angstrom mag(-1) and a dispersion of similar to 0.05 angstrom mag(-1) at extinctions characteristic of the Galactic midplane. These properties establish this DIB as a powerful, independent probe of dust extinction over a wide range of Av values. The subset of about 14,000 robustly detected DIB features have a W-DIB distribution that follows an exponential trend. We empirically determine the intrinsic rest wavelength of this transition to be lambda(0) = 15 272.42 angstrom and use it to calculate absolute radial velocities of the carrier, which display the kinematical signature of the rotating Galactic disk. We probe the DIB carrier distribution in three dimensions and show that it can be characterized by an exponential disk model with a scale height of about 100 pc and a scale length of about 5 kpc. Finally, we show that the DIB distribution also traces large-scale Galactic structures, including the Galactic long bar and the warp of the outer disk.NSF Astronomy & Astrophysics Postdoctoral Fellowship AST-1203017NSF AST-1109665Alfred P. Sloan FoundationNational Science FoundationU.S. Department of Energy Office of ScienceUniversity of ArizonaBrazilian Participation GroupBrookhaven National LaboratoryUniversity of CambridgeCarnegie Mellon UniversityUniversity of FloridaFrench Participation GroupGerman Participation GroupHarvard UniversityInstituto de Astrofisica de CanariasMichigan State/Notre Dame/JINA Participation GroupJohns Hopkins UniversityLawrence Berkeley National LaboratoryMax Planck Institute for AstrophysicsMax Planck Institute for Extraterrestrial PhysicsNew Mexico State UniversityNew York UniversityOhio State UniversityPennsylvania State UniversityUniversity of PortsmouthPrinceton UniversitySpanish Participation GroupUniversity of TokyoUniversity of UtahVanderbilt UniversityUniversity of VirginiaUniversity of WashingtonYale UniversitySpanish Ministry of Economy and Competitiveness AYA-2011-27754McDonald Observator

the SDSS-III APOGEE Spectral Line List for H-Band Spectroscopy

We present the H-band spectral line lists adopted by the Apache Point Observatory Galactic Evolution Experiment (APOGEE). The APOGEE line lists comprise astrophysical, theoretical, and laboratory sources from the literature, as well as newly evaluated astrophysical oscillator strengths and damping parameters. We discuss the construction of the APOGEE line list, which is one of the critical inputs for the APOGEE Stellar Parameters and Chemical Abundances Pipeline, and present three different versions that have been used at various stages of the project. The methodology for the newly calculated astrophysical line lists is reviewed. The largest of these three line lists contains 134,457 molecular and atomic transitions. In addition to the format adopted to store the data, the line lists are available in MOOG, Synspec, and Turbospectrum formats. The limitations of the line lists along with guidance for its use on different spectral types are discussed. We also present a list of H-band spectral features that are either poorly represented or completely missing in our line list. This list is based on the average of a large number of spectral fit residuals for APOGEE observations spanning a wide range of stellar parameters.Alfred P. Sloan FoundationNational Science FoundationU.S. Department of Energy Office of ScienceJanos Bolyai Research Scholarship of the Hungarian Academy of SciencesSpanish Ministry of Economy and Competitiveness AYA-2011-27754, AYA-2014-58082-PRSF 14-50-00043McDonald Observator

Extinction Maps Toward The Milky Way Bulge: Two-Dimensional And Three-Dimensional Tests With APOGEE

Galactic interstellar extinction maps are powerful and necessary tools for Milky Way structure and stellar population analyses, particularly toward the heavily reddened bulge and in the midplane. However, due to the difficulty of obtaining reliable extinction measures and distances for a large number of stars that are independent of these maps, tests of their accuracy and systematics have been limited. Our goal is to assess a variety of photometric stellar extinction estimates, including both two-dimensional and three-dimensional extinction maps, using independent extinction measures based on a large spectroscopic sample of stars toward the Milky Way bulge. We employ stellar atmospheric parameters derived from high-resolution H-band Apache Point Observatory Galactic Evolution Experiment (APOGEE) spectra, combined with theoretical stellar isochrones, to calculate line-of-sight extinction and distances for a sample of more than 2400 giants toward the Milky Way bulge. We compare these extinction values to those predicted by individual near-IR and near+mid-IR stellar colors, two-dimensional bulge extinction maps, and three-dimensional extinction maps. The long baseline, near+mid-IR stellar colors are, on average, the most accurate predictors of the APOGEE extinction estimates, and the two-dimensional and three-dimensional extinction maps derived from different stellar populations along different sightlines show varying degrees of reliability. We present the results of all of the comparisons and discuss reasons for the observed discrepancies. We also demonstrate how the particular stellar atmospheric models adopted can have a strong impact on this type of analysis, and discuss related caveats.NSF Astronomy & Astrophysics Postdoctoral Fellowship AST-1203017Physics Frontier Center/Joint Institute for Nuclear Astrophysics (JINA) PHY 08-22648U.S. National Science FoundationAlfred P. Sloan FoundationParticipating InstitutionsU.S. Department of Energy Office of Science ANR-12-BS05-0015-01Astronom

Chemical abundances and ages of the bulge stars in APOGEE high-velocity peaks

A cold high-velocity (HV, $\sim$ 200 km/s) peak was first reported in several Galactic bulge fields based on the APOGEE commissioning observations. Both the existence and the nature of the high-velocity peak are still under debate. Here we revisit this feature with the latest APOGEE DR13 data. We find that most of the low latitude bulge fields display a skewed Gaussian distribution with a HV shoulder. However, only 3 out of 53 fields show distinct high-velocity peaks around 200 km/s. The velocity distribution can be well described by Gauss-Hermite polynomials, except the three fields showing clear HV peaks. We find that the correlation between the skewness parameter ($h_{3}$) and the mean velocity ($\bar{v}$), instead of a distinctive HV peak, is a strong indicator of the bar. It was recently suggested that the HV peak is composed of preferentially young stars. We choose three fields showing clear HV peaks to test this hypothesis using the metallicity, [$\alpha$/M] and [C/N] as age proxies. We find that both young and old stars show HV features. The similarity between the chemical abundances of stars in the HV peaks and the main component indicates that they are not systematically different in terms of chemical abundance or age. In contrast, there are clear differences in chemical space between stars in the Sagittarius dwarf and the bulge stars. The strong HV peaks off-plane are still to be explained properly, and could be different in nature.Comment: 13 pages, 10 figures, published in ApJ. Updated to match the final ApJ published version. Minor revisions to the text and Figure