Toll-like receptor 9 activity influences mortality in heart failure

To her surprise, PhD student Yangchen Dhondup discovered that higher levels of mitochondrial DNA in blood were associated with reduced mortality in patients with heart failure.


MAIN RESULTS:

  1. Patients with chronic heart failure have increased levels of circulating mitochondrial and nuclear DNA.
  2. Higher levels of circulating nuclear DNA are linked to increased mortality risk in chronic heart failure. However, higher levels of mitochondrial DNA are linked to increased survival.
  3. Both overactivation and no activation of toll-like receptor 9 worsen prognosis in mice with HFpEF.

THESIS DEFENCE:

Thesis: Toll-like receptor 9 signalling in heart failure
Candidate: Yangchen Dhondup
Time: February 8, 2018 at 13:15
Place: Oslo University Hospital, Rikshospitalet: Green Auditorium
Link to university website (in Norwegian)


SUMMARY:

Toll-like receptor 9 (TLR9) is part of the innate immune system, and TLR9 activity is linked to progression of heart failure. Yangchen Dhondup and co-workers are the first to look at how TLR9 influences heart failure with preserved ejection fraction, HFpEF.

(1) For four weeks, mice with HFpEF were injected with either saline or CpG B, which activates TLR9. After four weeks, the reduced diastolic heart function was more pronounced in the group who received CpG B. These mice died or were euthanized due to severe heart failure after a mean of 59 days, far earlier than the control group.

Toll-like receptor 9 can be activated by mitochondrial DNA released from damaged or dead cells or tissue. This activation causes inflammation. The study shows that CpG B stimulation increases the expression of several inflammatory markers, and there were also signs of increased cell death, cell stress and cardiac fibrosis. Thus, increased inflammation and potentially fibrosis might be the reason why persistent stimulation of TLR9 worsens diastolic function in mice with HFpEF.

(2) Levels of both mitochondrial and nuclear DNA in the bloodstream were increased in 84 patients with chronic heart failure, compared to 72 age- and sex-matched healthy individuals. Furthermore, the levels of nuclear DNA increased with increased severity of heart failure, and were closely associated with the risk of dying within the next few years.

However, the researchers were surprised to find the opposite for mitochondrial DNA; 11 of the 15 patients who died during follow-up were among those with the lowest circulating levels of mitochondrial DNA. They speculate that moderate activation of TLR9 by mitochondrial DNA can actually be protective in heart failure patients, and that the stimulation in the previous study on mice was artificially high.

(3) Mice with HFpEF without the ability to activate TLR9 had increased mortality compared to mice with HFpEF and intact TLR9 activation. These results support a protective effect of TLR9 in heart failure. However, the mechanisms remain unclear, as there were no between-group differences in known characteristics of diastolic heart failure.


REFERENCES:

(1) Dhondup, Y., Sjaastad, I., Scott, H., Sandanger, Ø., Zhang, L., Haugstad, S. B., Aronsen, J. M., Ranheim, T., Holmen, S. D., Alfsnes, K., Ahmed, M. S., Attramadal, H., Gullestad, L., Aukrust, P., Christensen, G., Yndestad, A., & Vinge, L. E. (2015). Sustained toll-like receptor 9 activation promotes systemic and cardiac inflammation, and aggravates diastolic heart failure in SERCA2a KO micePloS one10(10), e0139715.

(2) Dhondup, Y., Ueland, T., Dahl, C. P., Askevold, E. T., Sandanger, Ø., Fiane, A., Ohm, I. K., Sjaastad, I., Finsen, A. V., Wæhre, A., Gullestad, L., Aukrust, P., Yndestad, A., Vinge, L. E. (2016). Low circulating levels of mitochondrial and high levels of nuclear DNA predict mortality in chronic heart failureJournal of cardiac failure22(10), 823-828.

(3) Dhondup, Y., Sjaastad, I., Sandanger, Ø., Aronsen, J. M., Ahmed, M. S., Attramadal, H., Finsen, A. V., Zhang, L., Ranheim, T., Alfsnes, K., Aukrust, P., Christensen, G., Yndestad, A., & Vinge, L. E. (2017). Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure MiceMediators of inflammation2017.