Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction ( HF p EF ). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix‐secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGF β, IL 11, Ang II ), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HF p EF , a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGF β, the master‐regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HF p EF . We provide an overview of trials targeting fibrosis in HF p EF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.