Loss of cardiac resident macrophage self-renewal as a trigger for Heart Failure with preserved Ejection Fraction.

Heart Failure with Preserved Ejection Fraction (HFpEF) is a pathology with few current therapeutic options that are further diminished as HFpEF is mostly diagnosed at a late stage. At a cellular level, vascular dysfunction, fibrosis, and an increased inflammatory response are known HFpEF characteristics, but no consensus has been researched concerning underlying mechanisms. The cardioprotective function of resident cardiac macrophages is an emerging perspective in the prevention of systolic HF upon ischemic injury. However, the role of cardiac macrophages in the development of diastolic heart failure remains unclear. I hypothesise that HFpEF progression can be driven by the loss of cardiac macrophages and their cardioprotective effect of inhibiting the direct recruitment of circulating monocytes. In this study, I will characterise the function of cardiac macrophages in HFpEF and test transgenic mouse models with a reduced macrophage self-renewal capacity, or with inhibited monocyte recruitment, during the onset of HFpEF. Moreover, I will identify the most important genes involved in cardiac macrophage self-renewal and validate them as Genes Of Interest in a murine HFpEF model. The long-term aim is to use cardiac macrophage self-renewal as a positive target for novel personalised treatments that could prevent the progression towards HFpEF in patients already suffering from its comorbidities.