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Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation
Kiichi Nakahira1, Sun-Young Kyung2, Angela J Rogers3
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Background:
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods And Findings:
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions:
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Insights
Elevated mitochondrial DNA (mtDNA) levels in plasma are linked to increased mortality risk in intensive care unit (ICU) patients. This biomarker significantly improves mortality prediction in medical ICU settings.
Area of Science:
- Biochemistry
- Immunology
- Critical Care Medicine
Background:
- Mitochondrial DNA (mtDNA) activates inflammation and the innate immune system.
- The role of mtDNA levels as a biomarker in intensive care units (ICUs) remains largely unexplored.
- Circulating cell-free mtDNA levels are hypothesized to correlate with ICU patient mortality and enhance risk prediction.
Purpose of the Study:
- To investigate the association between circulating cell-free mtDNA levels and mortality in ICU patients.
- To determine if mtDNA levels can improve the risk prediction of mortality in ICU settings.
- To explore the potential of mtDNA as a plasma biomarker in medical ICUs.
Main Methods:
- Analysis of plasma mtDNA levels using quantitative real-time PCR to measure NADH dehydrogenase 1 gene copy number.
- Inclusion of data from two prospective observational cohort studies of ICU patients (BWH RoCI and ME ARDS).
- Assessment of the association between elevated mtDNA levels (≥3,200 copies/µl) and 28-day mortality, and evaluation of the net reclassification index (NRI) for mortality prediction.
Main Results:
- Elevated mtDNA levels (≥3,200 copies/µl) were significantly associated with increased odds of 28-day mortality in medical ICU patients in both cohorts (OR 7.5-8.4, p < 1×10(-7)).
- No association was found in non-medical ICU patients.
- Inclusion of mtDNA levels improved 28-day mortality risk prediction in medical ICU patients, with significant NRI improvements (79% in BWH RoCI, 55% in ME ARDS).
- Elevated mtDNA levels indicated increased mortality risk even in patients with sepsis or acute respiratory distress syndrome.
Conclusions:
- Increased plasma mtDNA levels are significantly associated with higher mortality rates in medical ICU patients.
- mtDNA levels serve as a valuable biomarker for improving mortality risk prediction in medical ICUs.
- mtDNA shows potential as a viable plasma biomarker for critical care settings.
