Low circulating levels of mitochondrial and high levels of nuclear DNA predict mortality in chronic heart failure
Yangchen Dhondup 1,2,7,9 , Thor Ueland 1,9 , Christen Peder Dahl 1,2,4 , Erik Tandberg Askevold
1,2 , Arnt Fiane 6 , Ingrid Kristine Ohm 1,2,7 , Ivar Sjaastad 2,10 , Alexandra Vanessa Finsen 1,2,7 ,
Anne Wæhre 2,10 , Lars Gullestad 2,4,8,9 , Pål Aukrust 1,3,7,9 , Arne Yndestad 1,2,7,9 * Leif Erik Vinge
1,2,4,5 *
Aim: Inflammation is crucial in the pathogenesis of heart failure (HF). Mitochondrial DNA
(mtDNA) and possibly nuclear DNA (nDNA) are released as danger associated molecular patterns (DAMPs) during cardiac stress/cell death, and may activate several innate immune receptors. The purpose of this study was to investigate the regulation of these DAMPs during human HF.
Methods and Results : Plasma levels of mtDNA and nDNA from HF patients (n=84) were analysed by RT-PCR and compared with healthy controls (n=72). Increased circulating levels of mtDNA were found in NYHA I-II and NYHA III-IV compared with controls (p<0.05). There was clear evidence of increased nDNA in NYHA III-IV compared with controls (p<0.0001) and
NYHA I-II (p<0.05). Kaplan-Meier analysis with log-rank test on dichotomized mtDNA and nDNA levels revealed a higher mortality rate in patients with low mtDNA levels (p=0.05) and high nDNA levels (p=0.043). Cardiac tissue was sampled upon implantation of a Left
Ventricular Assist Device (LVAD, n=18) and at the time of heart transplantation. A reduction in cardiac TLR9 mRNA levels was found upon LVAD treatment (p=0.002). The latter corroborated experimental data.
Conclusion: Plasma levels of mtDNA and nDNA are elevated in human HF. Whereas high levels of nDNA are associated with mortality, elevated levels of mtDNA are associated with increased survival. HF is associated with increased levels of cardiac TLR9, a putative mtDNA receptor, suggesting a salutary effect of cardiac TLR9 signalling in HF. This study suggests a rationale for exploring TLR9 as a new target in treatment of human HF.
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