Â鶹ÊÓƵ

Open to UK applicants only

Supervisors

• Professor Gavin Murphy gjm19@le.ac.uk
• Professor Veryan Codd vc15@le.ac.uk
• Dr Tom Webb tw126@le.ac.uk
• Charles Solomon cs806@le.ac.uk
• Dr Weiqi Liao wl211@le.ac.uk

Organ injury is common following cardiac surgery, where it contributes to excess mortality, delayed recovery, progression of long-term conditions, poor quality of life, and increased use of healthcare resources. People who are overweight or who have mild obesity demonstrate reduced susceptibility to organ injury and its complications after cardiac surgery. (1) In contrast, people with lower (<25) and very high (>35) Body Mass Index (BMI) demonstrate increased levels of organ injury and death after surgery. This is referred to as the obesity paradox.

People with lower (<25) and very high (>35) BMIs also demonstrate increased prevalence of Multiple Long-term Conditions (MLTC) or multimorbidity. It follows that the obesity paradox may simply reflect reverse causation, whereby those at the extremes of BMI are sicker at the outset. However, the mechanisms by which MLTC increase susceptibility to organ injury is unknown. Understanding these mechanisms will provide new insight into organ injury and the obesity paradox, and may identify novel therapeutic targets for organ protection. 

Our previous research suggests that accelerated Biological Ageing associated with Multiple Long-term Conditions (MLTC) at lower (<25) and very high (>35) BMIs may underlie our observations. (2) Biological ageing refers to a cluster of 14 cellular processes (reviewed in (22)) common to many age-related diseases. We have also shown that myocardial biopsies from people with MLTC demonstrate the hallmarks of biological ageing. (3) Next, we demonstrated that accelerated biological ageing in MLTC is characterised by T cell exhaustion, dysregulated tissue resident macrophage activation, dedifferentiated cardiomyocytes and increase susceptibility to acute myocardial and renal injury. (4) Finally, in unpublished work, we demonstrated that accelerated biological ageing in cardiomyocytes was associated with attenuation of the iron restriction response, systemic iron deficiency, and increased chromatin accessibility for the DDIT4L promoter (unpublished, Figure 1), a stress response gene expressed in cardiomyopathy, and a regulator of dedifferentiation.(5). Cardiomyocyte dedifferentiation in the setting of iron deficiency is analogous to hibernating myocardium that shows increased susceptibility to ischaemia reperfusion.(40) This provides a plausible mechanism for the increased susceptibility to myocardial injury we observed in the accelerated ageing/ inflammageing group, (26) and also the obesity paradox.

References

1. Mariscalco G, Wozniak MJ, Dawson AG, Serraino GF, Porter R, Nath M, et al. Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery: A Nationwide Study With a Systematic Review and Meta-Analysis. Circulation. 2017;135(9):850-63.
2. Adebayo AS, Roman M, Zakkar M, Yusoff S, Gulston M, Joel-David L, et al. Gene and metabolite expression dependence on body mass index in human myocardium. Sci Rep. 2022;12(1):1425.
3. Tomkova K, Roman M, Adebayo AS, Sheikh S, Yusoff S, Gulston M, et al. Multimorbidity is associated with myocardial DNA damage, nucleolar stress, dysregulated energy metabolism, and senescence in cardiovascular disease. NPJ Aging. 2024;10(1):58.
4. Lai F, Adebayo, A.S., Sheikh, S., Roman, M., Joel-David, L., Aujla, H., Chad, T., Tomkova, K., Ladak, S., Condorelli, G., Zakkar, M., Solomon, C., Woźniak, M.J.,  Murphy, G.J. Immune system homeostasis in people with multiple long-term conditions determines susceptibility to organ injury and mortality following cardiac surgery. MedRxiv2024.
5. Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D, Brown JW, et al. A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle. Dev Cell. 2020;55(2):178-94 e7.

Additional project information can be found here: MLTC related chromatin remodelling and dysregulated iron homeostasis as the basis for the Obesity Paradox