Investigating non-myocyte regulation of mitochondrial function in failing hearts

Cardiac energetic deficit and mitochondrial dysfunction pervade human heart failure, though the underlying mechanisms remain unclear. Recent research, including my pilot data, reveals the crucial role of heart macrophages as custodians of cardiac mitochondrial health. However, in heart failure, these macrophages undergo reprogramming, compromising their ability to support mitochondria. In this proposed BHF Intermediate Clinical Research Fellowship, I will unravel alterations in heart macrophages and their circulating monocyte precursors in human heart failure, and determine their links to cardiac energetics and function. Employing advanced magnetic resonance and single-cell transcriptomics at the whole heart/body level (Workstream 1) coupled with spatial genomics at the cell-cell level (Workstream 2), I will concurrently profile cardiac macrophages and energetics from macro- to micro-scale, exploiting natural clinical and informatic experiments to maximise rigour. Subsequently, I will computationally integrate these datasets to construct a compendium of cardio-mitochondrial-immune interactions in human heart failure. Through a systems biology lens, I aim to pinpoint new targets for rejuvenating mitochondria in the failing heart.