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

How Uncertain Are Solar Neutrino Predictions?

Solar neutrino fluxes and sound speeds are calculated using a systematic reevaluation of nuclear fusion rates. The largest uncertainties are identified and their effects on the solar neutrino fluxes are estimated.Comment: LaTeX file, 12 pages including three postscript figures. To be published in Phys. Lett. B. One reference correcte

BBN and the Primordial Abundances

The relic abundances of the light elements synthesized during the first few minutes of the evolution of the Universe provide unique probes of cosmology and the building blocks for stellar and galactic chemical evolution, while also enabling constraints on the baryon (nucleon) density and on models of particle physics beyond the standard model. Recent WMAP analyses of the CBR temperature fluctuation spectrum, combined with other, relevant, observational data, has yielded very tight constraints on the baryon density, permitting a detailed, quantitative confrontation of the predictions of Big Bang Nucleosynthesis with the post-BBN abundances inferred from observational data. The current status of this comparison is presented, with an emphasis on the challenges to astronomy, astrophysics, particle physics, and cosmology it identifies.Comment: To appear in the Proceedings of the ESO/Arcetri Workshop on "Chemical Abundances and Mixing in Stars in the Milky Way and its Satellites", eds., L. Pasquini and S. Randich (Springer-Verlag Series, "ESO Astrophysics Symposia"

Solar Neutrino Constraints on the BBN Production of Li

Using the recent WMAP determination of the baryon-to-photon ratio, 10^{10} \eta = 6.14 to within a few percent, big bang nucleosynthesis (BBN) calculations can make relatively accurate predictions of the abundances of the light element isotopes which can be tested against observational abundance determinations. At this value of \eta, the Li7 abundance is predicted to be significantly higher than that observed in low metallicity halo dwarf stars. Among the possible resolutions to this discrepancy are 1) Li7 depletion in the atmosphere of stars; 2) systematic errors originating from the choice of stellar parameters - most notably the surface temperature; and 3) systematic errors in the nuclear cross sections used in the nucleosynthesis calculations. Here, we explore the last possibility, and focus on possible systematic errors in the He3(\alpha,\gamma)Be7 reaction, which is the only important Li7 production channel in BBN. The absolute value of the cross section for this key reaction is known relatively poorly both experimentally and theoretically. The agreement between the standard solar model and solar neutrino data thus provides additional constraints on variations in the cross section (S_{34}). Using the standard solar model of Bahcall, and recent solar neutrino data, we can exclude systematic S_{34} variations of the magnitude needed to resolve the BBN Li7 problem at > 95% CL. Additional laboratory data on He3(\alpha,\gamma)Be7 will sharpen our understanding of both BBN and solar neutrinos, particularly if care is taken in determining the absolute cross section and its uncertainties. Nevertheless, it already seems that this ``nuclear fix'' to the Li7 BBN problem is unlikely; other possible solutions are briefly discussed.Comment: 21 pages, 3 ps figure

Nucleosynthesis Constraints on a Massive Gravitino in Neutralino Dark Matter Scenarios

The decays of massive gravitinos into neutralino dark matter particles and Standard Model secondaries during or after Big-Bang nucleosynthesis (BBN) may alter the primordial light-element abundances. We present here details of a new suite of codes for evaluating such effects, including a new treatment based on PYTHIA of the evolution of showers induced by hadronic decays of massive, unstable particles such as a gravitino. We also develop an analytical treatment of non-thermal hadron propagation in the early universe, and use this to derive analytical estimates for light-element production and in turn on decaying particle lifetimes and abundances. We then consider specifically the case of an unstable massive gravitino within the constrained minimal supersymmetric extension of the Standard Model (CMSSM). We present upper limits on its possible primordial abundance before decay for different possible gravitino masses, with CMSSM parameters along strips where the lightest neutralino provides all the astrophysical cold dark matter density. We do not find any CMSSM solution to the cosmological Li7 problem for small m_{3/2}. Discounting this, for m_{1/2} ~ 500 GeV and tan beta = 10 the other light-element abundances impose an upper limit m_{3/2} n_{3/2}/n_\gamma < 3 \times 10^{-12} GeV to < 2 \times 10^{-13} GeV for m_{3/2} = 250 GeV to 1 TeV, which is similar in both the coannihilation and focus-point strips and somewhat weaker for tan beta = 50, particularly for larger m_{1/2}. The constraints also weaken in general for larger m_{3/2}, and for m_{3/2} > 3 TeV we find a narrow range of m_{3/2} n_{3/2}/n_\gamma, at values which increase with m_{3/2}, where the Li7 abundance is marginally compatible with the other light-element abundances.Comment: 74 pages, 40 Figure

Inhomogeneous Big Bang Nucleosynthesis and Mutual Ion Diffusion

We present a study of inhomogeneous big bang nucleosynthesis with emphasis on transport phenomena. We combine a hydrodynamic treatment to a nuclear reaction network and compute the light element abundances for a range of inhomogeneity parameters. We find that shortly after annihilation of electron-positron pairs, Thomson scattering on background photons prevents the diffusion of the remaining electrons. Protons and multiply charged ions then tend to diffuse into opposite directions so that no net charge is carried. Ions with Z>1 get enriched in the overdense regions, while protons diffuse out into regions of lower density. This leads to a second burst of nucleosynthesis in the overdense regions at T<20 keV, leading to enhanched destruction of deuterium and lithium. We find a region in the parameter space at 2.1E-10<eta<5.2E-10 where constraints 7Li/H<10^{-9.7} and D/H<10^{-4.4} are satisfied simultaneously.Comment: 9 pages, minor changes to match the PRD versio

SuperWIMP Dark Matter Signals from the Early Universe

Cold dark matter may be made of superweakly-interacting massive particles, superWIMPs, that naturally inherit the desired relic density from late decays of metastable WIMPs. Well-motivated examples are weak-scale gravitinos in supergravity and Kaluza-Klein gravitons from extra dimensions. These particles are impossible to detect in all dark matter experiments. We find, however, that superWIMP dark matter may be discovered through cosmological signatures from the early universe. In particular, superWIMP dark matter has observable consequences for Big Bang nucleosynthesis and the cosmic microwave background (CMB), and may explain the observed underabundance of 7Li without upsetting the concordance between deuterium and CMB baryometers. We discuss implications for future probes of CMB black body distortions and collider searches for new particles. In the course of this study, we also present a model-independent analysis of entropy production from late-decaying particles in light of WMAP data.Comment: 19 pages, 5 figures, typos correcte

Pre-main-sequence Lithium Depletion

In this review I briefly discuss the theory of pre-main-sequence (PMS) Li depletion in low-mass (0.075<M<1.2 Msun) stars and highlight those uncertain parameters which lead to substantial differences in model predictions. I then summarise observations of PMS stars in very young open clusters, clusters that have just reached the ZAMS and briefly highlight recent developments in the observation of Li in very low-mass PMS stars.Comment: 8 pages, invited review at "Chemical abundances and mixing in stars in the Milky Way and its satellites", eds. L. Pasquini, S. Randich. ESO Astrophysics Symposium (Springer-Verlag

Primordial nucleosynthesis with a varying fine structure constant: An improved estimate

We compute primordial light-element abundances for cases with fine structure constant alpha different from the present value, including many sources of alpha dependence neglected in previous calculations. Specifically, we consider contributions arising from Coulomb barrier penetration, photon coupling to nuclear currents, and the electromagnetic components of nuclear masses. We find the primordial abundances to depend more weakly on alpha than previously estimated, by up to a factor of 2 in the case of ^7Li. We discuss the constraints on variations in alpha from the individual abundance measurements and the uncertainties affecting these constraints. While the present best measurements of primordial D/H, ^4He/H, and ^7Li/H may be reconciled pairwise by adjusting alpha and the universal baryon density, no value of alpha allows all three to be accommodated simultaneously without consideration of systematic error. The combination of measured abundances with observations of acoustic peaks in the cosmic microwave background favors no change in alpha within the uncertainties.Comment: Phys. Rev. D accepted version; minor changes in response to refere

Physics of rotation in stellar models

In these lecture notes, we present the equations presently used in stellar interior models in order to compute the effects of axial rotation. We discuss the hypotheses made. We suggest that the effects of rotation might play a key role at low metallicity.Comment: 32 pages, 7 figures, lectures, CNRS school, will be published by Springe