Regional lung metabolic profile in a piglet model of cardiopulmonary bypass with circulatory arrest.

INTRODUCTION: Acute lung injury is common following cardiopulmonary bypass and deep hypothermic circulatory arrest for congenital heart surgery with the most severe injury in the dorsocaudal lung. Metabolomics offers promise in deducing mechanisms of disease states, providing risk stratification, and understanding therapeutic responses in regards to CPB/DHCA related organ injury. OBJECTIVES: Using an infant porcine model, we sought to determine the individual and additive effects of CPB/DHCA and lung region on the metabolic fingerprint, metabolic pathways, and individual metabolites in lung tissue. METHODS: Twenty-seven infant piglets were divided into two groups: mechanical ventilation + CPB/DHCA (n = 20) and mechanical ventilation only (n = 7). Lung tissue was obtained from dorsocaudal and ventral regions. Targeted analysis of 235 metabolites was performed using HPLC/MS-MS. Data was analyzed using Principal Component Analysis (PCA), Partial Least Square Discriminant Analysis (PLS-DA), ANOVA, and pathway analysis. RESULTS: Profound metabolic differences were found in dorsocaudal compared to ventral lung zones by PCA and PLS-DA (R2 = 0.7; Q2 = 0.59; p < 0.0005). While overshadowed by the regional differences, some differences by exposure to CPB/DHCA were seen as well. Seventy-four metabolites differed among groups and pathway analysis revealed 20 differential metabolic pathways. CONCLUSION: Our results demonstrate significant metabolic disturbances between dorsocaudal and ventral lung regions during supine mechanical ventilation with or without CPB/DHCA. CPB/DHCA also leads to metabolic differences and may have additive effects to the regional disturbances. Most pathways driving this pathology are involved in energy metabolism and the metabolism of amino acids, carbohydrates, and reduction-oxidation pathways.

Is Neurodevelopment Related to Exercise Capacity in Single Ventricle Patients Who Have Undergone Fontan Palliation?

Survivors of palliative surgery for single ventricle heart disease (SVHD) are at risk of poor neurodevelopmental outcomes and reduced exercise capacity. In healthy populations, reduced exercise capacity is related to decreased cognition suggesting a possible relationship between exercise capacity and neurodevelopment. Using cardiopulmonary exercise testing (CPET) and neuropsychological testing (NPT) as indicators of exercise capacity and neurodevelopment, respectively, we hypothesized that in SVHD, higher CPET measures are related to better NPT performance. Patients were retrospectively identified. CPET variables included VO2max, anaerobic threshold, peak heart rate, ventilatory efficiency, and respiratory exchange ratio. NPT instruments were divided into domains measuring attention, executive functioning, adaptive functioning, and emotional functioning. Linear regression was used to test for associations between CPET and NPT. 23 subjects with SVHD met inclusion criteria. On both CPET and NPT, the cohort scored worse than healthy, age-matched subjects. Higher VO2max and anaerobic threshold were associated with better parent-rated overall adaptive functioning (p = 0.01 and p = 0.02, respectively). Higher peak heart rate was related to better sustained visual attention (p = 0.01). In SVHD, CPET measures indicating better exercise capacity were positively associated with a subset of scores on NPT. Larger, multisite studies implementing cardiorespiratory fitness intervention and incorporating cognitive outcome measures will be needed to better characterize the relationship between neurodevelopment and functional capacity in this population. Results may assist in providing anticipatory guidance and optimizing post-Fontan developmental trajectories.

808 nm wavelength light induces a dose-dependent alteration in microglial polarization and resultant microglial induced neurite growth.

BACKGROUND AND OBJECTIVE: Despite the success of using photobiomodulation (PBM), also known as low level light therapy, in promoting recovery after central nervous system (CNS) injury, the effect of PBM on microglia, the primary mediators of immune and inflammatory response in the CNS, remains unclear. Microglia exhibit a spectrum of responses to injury, with partial or full polarization into pro- and anti-inflammatory phenotypes. Pro-inflammatory (M1 or classically activated) microglia contribute to chronic inflammation and neuronal toxicity, while anti-inflammatory (M2 or alternatively activated) microglia play a role in wound healing and tissue repair; microglia can fall anywhere along this spectrum in response to stimulation. MATERIALS AND METHODS: The effect of PBM on microglial polarization therefore was investigated using colorimetric assays, immunocytochemistry, proteomic profiling and RT-PCR in vitro after exposure of primary microglia or BV2 microglial cell line to PBM of differing energy densities (0.2, 4, 10, and 30 J/cm(2) , 808 nm wavelength, 50 mW output power). RESULTS: PBM has a dose-dependent effect on the spectrum of microglial M1 and M2 polarization. Specifically, PBM with energy densities between 4 and 30 J/cm(2) induced expression of M1 markers in microglia. Markers of the M2 phenotype, including CD206 and TIMP1, were observed at lower energy densities of 0.2-10 J/cm(2) . In addition, co-culture of PBM or control-treated microglia with primary neuronal cultures demonstrated a dose-dependent effect of PBM on microglial-induced neuronal growth and neurite extension. CONCLUSION: These data suggest that the Arndt-Schulz law as applied to PBM for a specific bioassay does not hold true in cells with a spectrum of responses, and that PBM can alter microglial phenotype across this spectrum in a dose-dependent manner. These data are therefore of important relevance to not only therapies in the CNS but also to understanding of PBM effects and mechanisms.