Elevated nuclear and mitochondrial cell-free deoxyribonucleic acid measurements are associated with death after
John P Scott1, Justinn M Tanem1, Aoy Tomita-Mitchell2
1Division of Pediatric Anesthesiology, Department of Anesthesiology, Herma Heart Institute, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wis; Division of Pediatric Critical Medicine, Department of Pediatrics, Herma Heart Institute, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wis.
Insights
Cell-free DNA (cfDNA) levels can predict mortality after infant heart surgery. Combined analysis of nuclear cfDNA (ncfDNA) and mitochondrial cfDNA (mcfDNA) shows high accuracy in identifying patients at risk for death or prolonged hospitalization.
Area of Science:
- Biomarkers in pediatric cardiac surgery
- Molecular diagnostics for critical care
- Inflammation and myocardial injury assessment
Background:
- Pediatric cardiac surgery outcomes have plateaued due to postoperative inflammation and myocardial dysfunction.
- Cell-free DNA (cfDNA), including nuclear (ncfDNA) and mitochondrial (mcfDNA) forms, shows potential as a biomarker.
- ncfDNA may indicate inflammation, while mcfDNA may reflect myocardial injury.
Purpose of the Study:
- To establish threshold levels of ncfDNA and mcfDNA for predicting postoperative mortality.
- To determine if combined analysis of ncfDNA and mcfDNA improves risk stratification.
- To assess the utility of cfDNA in predicting prolonged hospitalization.
Main Methods:
- Prospective observational study of infants under 1 year undergoing cardiopulmonary bypass.
- Serial blood sampling pre- and post-cardiac surgery.
- Logistic regression and ROC curve analysis to assess cfDNA levels and mortality association.
Main Results:
- Combined analysis of ncfDNA (50 ng/mL) and mcfDNA (17 copies/μL) at 12 hours post-CPB achieved 100% sensitivity and NPV for mortality.
- Combined analysis improved specificity (91%) and PPV (38%) for mortality compared to univariate analysis.
- High specificity (93%) and NPV (78%) for prolonged hospitalization were observed with combined cfDNA analysis.
Conclusions:
- Combined analysis of early postoperative ncfDNA and mcfDNA effectively stratifies risk for mortality and prolonged hospitalization in infant cardiac surgery.
- Evaluating both ncfDNA and mcfDNA aids in identifying generalized inflammation and myocardial injury.
- This approach may enable targeted interventions to improve patient outcomes.
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.
