Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients

Abstract

Background: Mitochondrial dysfunction may be causally related to the pathogenesis of organ failure in critically ill patients. Decreased mitochondrial DNA (mtDNA) levels have been associated with mitochondrial dysfunction and were investigated here in relation to short-term (31-day) survival.

Methods: This was a prospective longitudinal cohort study of 28 mechanically ventilated critically ill adults admitted to a single center tertiary care intensive care unit (ICU) with hypotension secondary to cardiogenic (N = 13), septic (N = 14) or hypovolemic (N = 1) disease processes. Clinical data and blood were collected at baseline and patients were followed until they expired or left the ICU. Blood was collected every Monday, Wednesday and Friday, and the buffycoat relative mtDNA/nuclear DNA (nDNA) ratio was determined. An archived pool of healthy controls was also studied.

Results: At baseline, the patients' mtDNA/nDNA ratio was 30% lower than a pool of 24 healthy controls (0.76 versus 1.09) and was not different between short-term survivors and non-survivors (0.74 +/- 0.05 (N = 16) versus 0.79 +/- 0.06 (N = 12), p = 0.49). By day 4, the percent mtDNA/nDNA change from baseline in survivors was significantly different from that in non-survivors (+29.5% versus -5.7%, p = 0.03). It also tended to be higher in survivors at last measurement (+38.4% versus +7.1%, p = 0.06). There was a weak correlation between within patient mtDNA/nDNA and platelet count (r = 0.20, p = 0.03) but not with Sequential Organ Failure Assessment (SOFA) scores (r = 0.12, p = 0.23). The mtDNA associations remained after adjustment for platelet.

Conclusion: Blood mtDNA levels appeared initially low, increased over time in patients who ultimately survived, and remained low in those who did not. This is consistent with mitochondrial recovery being associated with survival and warrants further investigation as a marker of mitochondrial alterations and outcome in critical illness.

Figure 1

Longitudinal relative blood mitochondrial DNA (mtDNA)/nuclear DNA (nDNA) ratio. Of the 28 critically ill subjects, survivors are presented in (a) and non-survivors in (b). Patients admitted with septic shock are represented by circles, those with cardiogenic shock by squares, and the hypovolemic patient by a triangle. Patients belonging to the four antioxidant treatment groups are distinguished by the color of their symbol (white, light grey, dark grey and black). Males are represented by a solid line and females by a dashed line. The thick lines represent the linear modeling of the mean mtDNA/nDNA slopes for the short-term survivors (N = 16, solid line) and the non-survivors (N = 12, dashed line) over the first 14 days after enrollment. Though the entire duration of data collected is shown on the graph, only data collected up to the first 14 days are used in the linear model shown here. ICU, intensive care unit.

Figure 2

Change in mitochondrial DNA (mtDNA)/nuclear DNA (nDNA) ratio between baseline and day 4 (± 1) in the intensive care unit. Of the 28 critically ill subjects, survivors are presented in (a) and non-survivors in (b). Patients admitted with septic shock are represented by circles, those with cardiogenic shock by squares, and the hypovolemic patient by a triangle. Patients belonging to the four antioxidant treatment groups are distinguished by the color of their symbol (white, light grey, dark grey and black).