Elevated nuclear and mitochondrial cell-free deoxyribonucleic acid measurements are associated with death after infant cardiac surgery. J Thorac Cardiovasc Surg 2022 Aug;164(2):367-375
Date
02/12/2022Pubmed ID
35144816DOI
10.1016/j.jtcvs.2021.10.066Scopus ID
2-s2.0-85120861361 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
OBJECTIVES: Mortality rates following pediatric cardiac surgery with cardiopulmonary bypass have declined over decades, but have plateaued in recent years. This is in part attributable to persistent issues with postoperative global inflammation and myocardial dysfunction, commonly manifested by systemic inflammatory response syndrome and low cardiac output syndrome, respectively. Quantified cell-free DNA (cfDNA), of nuclear or mitochondrial origin, has emerged as a biomarker for both inflammation and myocardial injury. Recent data suggest that nuclear cfDNA (ncfDNA) may quantify inflammation, whereas mitochondrial cfDNA (mcfDNA) may correlate with the degree of myocardial injury. We hypothesize that threshold levels of ncfDNA and mcfDNA can be established that are sensitive and specific for postoperative mortality mediated through independent pathways, and that association will be enhanced with combined analysis.
METHODS: Prospective observational study of infants younger than age 1 year undergoing planned surgery with cardiopulmonary bypass. The study received institutional review board approval. Samples were drawn before skin incision, immediately after completion of cardiopulmonary bypass, and subsequently at predetermined intervals postoperatively. Association of early postoperative ncfDNA and mcfDNA levels with mortality were assessed by logistic regression with cut-points chosen by receiving operating characteristic curve exploration.
RESULTS: Data were available in 59 patients. Median age and weight were 122 days (interquartile range, 63-154 days) and 4.9 kg (interquartile range, 3.9-6.2 kg). Median STAT category was 3 (interquartile range, 1-4). The primary outcome of death was met in 3 out of 59 (5%). Combined analysis of ncfDNA and mcfDNA levels at 12 hours after the initiation of cardiopulmonary bypass with death at a threshold of 50 ng/mL ncfDNA and 17 copies/μL mcfDNA yielded 100% sensitivity and negative predictive value. The specificity (91%) and positive predictive value (38%) increased through combined analysis compared with univariate analysis. Combined analysis exhibited high specificity (93%) and negative predictive value (78%) for prolonged (>30 postoperative days) hospitalization.
CONCLUSIONS: Combined analysis of early postoperative ncfDNA and mcfDNA can stratify risk of mortality and prolonged hospitalization following infant cardiac surgery. Evaluation of both ncfDNA and mcfDNA to identify states of generalized inflammation and myocardial injury may allow for targeted interventions and improved outcomes.
Author List
Scott JP, Tanem JM, Tomita-Mitchell A, Hoffman GM, Niebler RA, Liang HL, Simpson PM, Stamm KD, North PE, Mitchell MEAuthors
George M. Hoffman MD Chief, Professor in the Anesthesiology department at Medical College of WisconsinAoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin
Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Robert Niebler MD Professor in the Pediatrics department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
John P. Scott MD Professor in the Anesthesiology department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Justinn M. Tanem MD Assistant Professor in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Cardiac Output, LowCardiac Surgical Procedures
Cardiopulmonary Bypass
Cell-Free Nucleic Acids
DNA, Mitochondrial
Humans
Infant
Inflammation
Postoperative Complications
Prospective Studies
