Understanding the vulnerability of the ageing heart

The ageing demographic predicts a major rise in heart failure (HF) and associated deaths in the next decades. Novel solutions, based on better understanding of the vulnerability of the ageing heart to HF and of the processes that direct healthy heart ageing are therefore required. HF, as a result of injury or increased workload, is associated with remodelling of heart muscle cells and increase of matrix collagen, which combine to affect systolic and diastolic function as well as to increase arrhythmia. Cardiomyocyte hypertrophy and death, fibroblast differentiation and inflammation are equally features of cardiac ageing. However, the mechanisms that establish this phenotype and those underlying the vulnerabity of the aged heart to additional insults are not determined. Based on our preliminary findings and published data, we will test the hypothesis that deleterious cardiac ageing is mediated by increased cell-cell variability, altered cell compositon and cell-cell communication and that DNA methylation changes mediate this process. Further, we will probe whether cardiac cell methylomes are modifiable and can be used as both a biomarker and determinant of cardiac health. Multi-omics and bioinformatic approaches will be employed to test the associations of age, disease and cardiac function with cardiac cell transcriptomes, epigenomes and cell-cell interactions. Preclinical models will be used to mechanistically probe associations and findings will be validated in human samples.

Keywords:Cardiac ageing, Transcriptomics, Cardiac vulnerability, Heart Failure, DNA methylation

Disciplines:Cardiology, Biomarker discovery, Inflammation, Physiological biophysics, Pathophysiology, Molecular physiology, Cell physiology, Epigenetics, Cellular interactions and extracellular matrix