Age Related Chromatin Remodelling as a Therapeutic Target for Organ Protection in Cardiac Surgery

Overview

People who have multiple long-term conditions (MLTC) like kidney disease or lung disease are at higher risk of developing organ damage and poor quality of life following heart surgery. Decades of research have failed to identify drugs or treatments that prevent this. Our research has shown that people with MLTC have changes in their heart cells before surgery that are referred to by researchers as Biological Ageing. These changes combine to make people with MLTC more susceptible to organ damage after heart surgery, have delayed recovery, and lower quality of life. This research programme will investigate the processes linking MLTC, changes in heart cells, and organ damage. Our previous research suggests that MLTC lead to the infiltration of white cells from the blood into the heart muscle, a process called inflammageing. This alters the DNA in heart cells, reduces their pumping function and leaves them more likely to be damaged by surgery. We have also shown that these changes are affected by obesity. We have also shown that changes in other types of heart cells with ageing are associated with damage to the lining of blood vessels, bleeding and damage to the kidneys. We will use existing clinical data from previous studies and molecular data from heart cells obtained at surgery to better understand the molecular changes underlying our previous observations. This includes data from previous trials of drugs and dietary modification that aimed to modify the cellular DNA changes caused by inflammageing. Using external data, we will check whether similar results are evident in other studies. We will then select the most likely processes underlying our observations and test whether these relationships are causal using genomic analysis and the UK Biobank data. Finally, we will use established analytical methods to identify potential drugs that may target these processes. Positive results will provide a better understanding of the heart damage that is often seen in people with MLTC as well as new treatments for evaluation on further research.

Organ injury is common following cardiac surgery, where it contributes to excess mortality, delayed recovery, progression of LTC, poor quality of life, and increased use of healthcare resources. People with MLTC demonstrate increased susceptibility to organ injury and its complications. Using a multi-omics approach we have shown that MLTC are associated with biological ageing in human myocardium. Using snRNAseq, we have shown that progression of MLTC are associated with acceleration of biological ageing, characterised by T cell exhaustion, dysregulated tissue resident macrophage activation, and increased susceptibility of cardiomyocytes to metabolic stress. Genetic modification of these processes altered susceptibility to 90-day mortality following cardiac surgery in UK Biobank. Reversal of biological ageing mechanisms including mTOR activation, histone modification, disabled autophagy, or cell senescence reduces the susceptibility of myocardium to ischaemia reperfusion injury in mice. These observations lead us to hypothesise that pre-surgery reversal of biological ageing may have organ protective effects. Cellular ageing is characterised by changes in chromatin accessibility that are determined by histone DNA interaction. The interaction between histones and DNA in the nucleosome determine the accessibility of promoters, enhancers, and transcription factors to molecular DNA and subsequently gene expression. Reversal of age-related changes in chromatin prevents cardiac ageing in mice. In preliminary work we have shown that genetic modification underlying biological ageing in human myocardial biopsies is determined in part by changes in chromatin accessibility. We have shown associations between MLTC including obesity, genetic modification, and organ injury affecting the heart, kidney and vascular endothelium (bleeding). We now propose to comprehensively characterise the changes in chromatin accessibility, gene expression, cell secretomes and cell-cell interactions and single cell resolution that underly these observations. This will be the first study to use integrated multi-omics to identify cellular phenotypes associated with different stages of biological ageing. The study will explore the contribution of a central hallmark of biological ageing; chromatin accessibility. Observational data from multi-omics snRNAseq and snATACseq will be validated in external datasets, and the causal effect of chromatin accessibility of susceptibility to organ injury will be explored using secondary analyses of RCTs. This research represents a first in man analysis of the role of chromatin remodelling in myocardial ageing and susceptibility to organ injury.