Abstract
The development of Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) cardioplegia solution represented a major advancement in cardiac surgery, offering significant myocardial protection. However, metabolic changes induced by this additive in the whole body have not been systematically investigated. Using an untargeted mass spectrometry-based method to deeply explore the urine metabolome, we sought to provide a holistic and systematic view of metabolic perturbations occurred in patients receiving HTK. Prospective urine samples were collected from 100 patients who had undergone cardiac surgery, and metabolomic changes were profiled using a high-performance chemical isotope labeling liquid chromatography-mass spectrometry (LC-MS) method. A total of 14,642 peak pairs or metabolites were quantified using differential 13C-/12C-dansyl labeling LC-MS, which targets the amine/phenol submetabolome from urine specimens. We identified 223 metabolites that showed significant concentration change (fold change > 5) and assembled several potential metabolic pathway maps derived from these dysregulated metabolites. Our data indicated upregulated histidine metabolism with subsequently increased glutamine/glutamate metabolism, altered purine and pyrimidine metabolism, and enhanced vitamin B6 metabolism in patients receiving HTK. Our findings provide solid evidence that HTK solution causes significant perturbations in several metabolic pathways and establish a basis for further study of key mechanisms underlying its organ-protective or potential harmful effects.
Highlights
More than one million patients worldwide undergo cardiac surgery annually[1]
One of the challenges of metabolomic profiling analysis is the diverse hydrophilicity of chemical structures and poor ionization efficiency of metabolites during ionization by reversed-phase (RP) liquid chromatography-mass spectrometry (LC-mass spectrometry (MS)), the most common liquid chromatography (LC) system for MS
We labeled metabolites with dansyl chloride, which increases the hydrophobicity to an extent that the labeled metabolites can be efficiently retained and separated in RPLC and enhances ionization efficiency by 1–3 orders of magnitude[18], enabling us to systematically investigate hydrophilic metabolites as well as hydrophobic metabolites
Summary
More than one million patients worldwide undergo cardiac surgery annually[1]. The development of cardiopulmonary bypass (CPB) in the 1950s and subsequent introduction of cardioplegia solutions were two tremendous leaps in the progression of cardiac surgery that allowed surgeons to repair intra-cardiac lesions with a bloodless field[2]. Acute kidney injury is another common complication following cardiac surgery, reported in up to 30–50% of patients in different studies[5,6] Possible mechanisms for these organ injuries after cardiac surgery include organ ischemia, subsequent reperfusion injury, and a systemic inflammatory response related to exposure to CPB per se or surgical trauma[7]. We report the study of a deep and quantitative analysis of the untargeted urinary metabolite profiles of adult patients undergoing cardiac surgery using differential 12C-/13C-isotope dansylation labeling liquid chromatography (LC)-MS. The purpose of this investigation was to explore the metabolic shifts that occur with cardiac surgery, with a specific focus on the influence of HTK solution
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