Critically ill patients with low vitamin D were 13X more likely to have a lot of mitrocondrial DNA in blood – Sept 2014

Circulating mitochondrial dna and vitamin d in critical illness

ORAL PRESENTATION: 0474.ESICM LIVES 2014 Barcelona, Spain. 27 September - 1 October 2014
Intensive Care Medicine Experimental
AA Litonjua1, LE Fredenburgh1, RM Baron1, L Gazourian1, AF Massaro1, K Nakahira2, AMK Choi2, KB Christopher
1Brigham and Women's Hospital, Pulmonary and Critical Care Division, Boston, MA, USA. 2Weill Cornell Medical Center, Department of Medicine, New York, NY, USA. 3Brigham and Women's Hospital, Renal Division, Boston, MA, USA.

Introduction
Mitochondrial dysfunction and an impaired autophagic response is associated with mortality in experimental sepsis. Vitamin D is shown to upregulate NOD2 which is linked to autophagy. Autophagy regulates innate immunity via inhibition of mitochondrial DNA (mtDNA) release via by the inflammasome. Circulating plasma mt- DNA is a robust predictor of mortality in ICU patients.

Objectives:We hypothesized that critically ill patients with low plasma 25(OH)D would have high levels of circulating plasma mt-DNA.

Methods
We performed a prospective observational cohort of MICU patients at the Brigham and Women’s Hospital from 2008-2010 [n=49]. The exposure of interest was 25(OH)D categorized a priori as deficiency (25(OH)D < 15 ng/mL) and measured via competitive chemiluminescence immunoassay. Circulating plasma mitochondrial DNA (mt-DNA) were assessed by measuring copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Plasma 25(OH)D was measured from the same plasma sample as mtDNA. Adjusted associations were estimated through fitting of multivariable logistic regression models including covariate terms for potential confounders of interest. Time-to-event analysis was performed using Cox proportional hazard regression.

Results
Of the cohort patients studied, 37% were women and 84% were white.
The mean age at critical care initiation was years (SD 14.2).
The mean APACHE II score was (SD 8.3), while

• 100% of the cohort had SIRS,
• 71% had a source of infection identified and
• 18% had ARDS.

The mean plasma 25(OH)D was 20.6 (SD 11.4) and 28.6% of the study cohort had plasma 25(OH)D < 15 ng/mL.
Gross unadjusted 30-day mortality was 26.5%.
The mean (SD) plasma 25(OH)D was significantly higher in patients with mtDNA < 4000 copies/ml [25(OH)D 22.0 (11.2) ng/ml] relative to those with mtDNA > 4000 copies/ml [25(OH)D 14.9 (10.9) ng/mL]; P < 0.001. When the cohort was analyzed with the exposure as plasma 25(OH)D and the outcome as plasma mtDNA > 4000 copies/ml, we find that patients with plasma 25(OH)D < 15 ng/mL have a significantly higher odds of having plasma mtDNA > 4000 copies/ml (unadjusted OR= 7.50, 95% CI 1.53-36.79; P=0.013). 25(OH)D in the cohort remains a significant predictor of plasma mtDNA > 4000 copies/ml following adjustment for age, gender, race and APACHE II (adjusted OR= 13.19, 95% CI 1.69-103.34; P=0.014). Cox proportional hazard multivariable regression modeling, adjusting for a priori defined covariates comprising APACHE II score, age, sex, race, and plasma 25(OH)D, showed that mtDNA was predictive of all cause mortality following critical care (HR, 4.02; 95% CI, 1.14-14.20 ng/ml).

Conclusions
25(OH)D levels are associated with circulating mtDNA levels. This study cannot determine a relationship between 25(OH)D and mtDNA beyond association but raises the question as to whether vitamin D-mediated pathways might play a role in linking autophagic and inflammasome processes.

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Abbreviations

• ARDS = Acute respiratory distress syndrome: occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in your lungs.
• SIRS = Systemic Inflammatory Response Syndrome: is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so. It is related to sepsis, a condition in which individuals meet criteria for SIRS and have a known infection.