Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Cooney SJ

PROVIDER: S-EPMC8457331 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery. CPB is however associated with a strong induction of systemic inflammatory response syndrome (SIRS) which in conjunction with ischemia and reperfusion may lead to multiple organ failure. The aim of the study was to establish and characterize a CPB rat model incorporating deep hypothermic circulatory arrest with a specific focus on the extent of the inflammatory reactions and organ damage as a groundwork for novel therapeutics against SIRS and I/R induced organ injury.Materials and methodsMale Wistar rats (n?=?6) were cannulated for CPB, connected to a heart-lung-machine (HLM) and cooled to a temperature of 16°C before they underwent 45 minutes of deep hypothermic circulatory arrest with global ischaemia. Arrest was followed by rewarming and 60 minutes of reperfusion. Haemodynamic and vital parameters were recorded throughout the CPB procedure. Only animals displaying sinus rhythm throughout reperfusion were utilized for analysis. Rats were euthanized and tissue samples were harvested. Blood gas analysis was performed and blood samples were taken. Induction of organ damage was examined by analysis of protein levels and phosphorylation status of kinases and stress proteins. Results were compared to animals (n?=?6) which did not undergo CPB.ResultsCPB induced leucocytosis and an increase of interleukin-6 and TNF-? plasma values indicating an inflammatory response. Markers of tissue damage and dysfunction, such as troponin T, creatinine and AST were elevated. Phosphorylation of STAT3 was induced in all examined organs. Activation of MAPK and induction of heat shock proteins occurred in an organ-specific manner with most pronounced effects in heart, lungs and kidneys.ConclusionsThe presented CPB rat model shows the induction of SIRS and activation of specific signalling cascades. SIRS seems not to be provoked during DHCA and is elicited mainly during reperfusion. This model might be suitable to test the efficacy of therapeutics applied in major heart surgery with and without DHCA.

Project description:Identification of microRNAs (miRNA) associated with cardiopulmonary bypass, cardiac arrest and subsequent myocardial ischemia/reperfusion may unravel novel therapeutic targets and biomarkers. The primary aim of the present study was to investigate the effects of cardiopulmonary bypass and temperature of cardioplegic arrest on myocardial miRNA profile in pigs' left ventricular tissue. We employed next-generation sequencing to analyse miRNA profiles in the following groups: (1) hearts were arrested with antegrade warm St Thomas Hospital No. 2 (STH2) cardioplegia (n = 5; STH2-warm, 37 °C) and (2) cold STH2 (n = 6; STH2-cold, 4 °C) cardioplegia. Sixty min of ischemia was followed by 60 min of on-pump reperfusion with an additional 90 min of off-pump reperfusion. In addition, two groups without cardiac arrest (off-pump and on-pump group; n = 3, respectively) served as additional controls. STH2-warm and STH2-cold cardioplegia revealed no hemodynamic differences. In contrast, coronary venous creatine kinase-myocardial band (CK-MB) levels were significantly lower in pigs receiving STH2-warm cardioplegia (p < 0.05). Principal component analysis revealed that cardiopulmonary bypass and cardioplegic arrest markedly affected miRNAs in left ventricular tissue. Accordingly, ssc-miR-122, ssc-miR-10a-5p, ssc-miR-193a-3p, ssc-miR-499-3p, ssc-miR-374a-5p, ssc-miR-345-5p, ssc-miR-142-3p, ssc-miR-424-5p, ssc-miR-545-3p, ssc-miR-30b-5p, ssc-miR-145-5p, ssc-miR-374b-5p and ssc-miR-139-3p were differently regulated by cardiopulmonary bypass (false discovery rate (FDR) < 0.05 versus off-pump group). However, only ssc-miR-451 was differently expressed between STH2-warm and STH2-cold (FDR < 0.05). These data demonstrate for the first time that cardiopulmonary bypass and temperature of cardioplegic solution affected the expression of miRNAs in left ventricular tissue. In conclusion, specific miRNAs are potential therapeutic targets for limiting ischemia-reperfusion injury in patients undergoing cardiac surgery.

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Project description:Cardiopulmonary bypass triggers systemic inflammation, resulting in lung injury, and frequently leads to prolonged mechanical ventilation. Biomarkers of systemic inflammation are required to predict the risk of such complications. We hypothesize that specific serum proteins can be used as biomarkers to predict the severity of lung injury following cardiac surgery.DesignRetrospective chart review study.SettingClinical variables were collected and used in conjuncture with unbiased proteomic analysis using mass spectrometry that was performed on frozen plasma samples from a study group (patients with mechanical ventilation > 48 hr post surgery) and a control group (patients with mechanical ventilation < 48 hr post surgery).SubjectsSubjects included were infants who underwent cardiac surgery with similar complexity (Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery 3 or 4) using cardiopulmonary bypass. Patients in both groups were matched for their weight, age, and duration of cardiopulmonary bypass.InterventionNone.Measurements and main resultsFour-hundred eighty-three proteins were identified (99% minimum confidence and two peptides minimum, protein false discovery rate 0.1%) on proteomic analysis of four control and four study patients at precardiopulmonary bypass, 0, and 48 hours postcardiopulmonary bypass samples. Thirty-six of 178 proteins were significantly different (≥ 1.5-fold; p < 0.05) at precardiopulmonary bypass (top increased: tenascin; top decreased: tetranectin), 18 of 140 proteins at 0 hour (top increased: hemoglobin beta; top decreased: C8 beta), and 25 of 166 proteins at 48 hours post surgery (top increased: proteoglycan 4; top decreased: galectin-3-binding protein). The top pathway involved cytoskeleton remodeling. Other pathways involved immune response and blood coagulation. Proteoglycan 4 was validated by enzyme-linked immunosorbent assay in a different set of samples (n = 20/group; mean ± sd: 128 ± 67 vs 195 ± 160 ng/mL) (p = 0.037).ConclusionsMultiple proteomic biomarkers were associated with worse respiratory outcomes. Precardiopulmonary bypass biomarkers might indicate risk factors (e.g., abnormalities of coagulation), whereas those identified at 0 hour and post cardiopulmonary bypass may reflect mechanisms of ongoing pathobiology.