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

Abstract

Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). 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. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, 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 HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.

Keywords: CMR; HFpEF; fibroblast; fibrosis; heart failure.

Figure 1. Illustation of the multiple interacting pathophysiological mechanisms responsible for development of HFpEF

The development of HFpEF has multiple contributing pathophysiological mechanisms acting on the heart. The relative contribution of each of these factors varies depending on the underlying disease state; however, cardiac fibrosis is a common pathway present in almost all patients with symptomatic HFpEF.

Figure 2. Histological differences between replacement fibrosis and interstitial/perivascular fibrosis

Illustration of replacement vs. interstitial/perivascular fibrosis showing the differential spatial accumulation of ECM in the two forms of cardiac fibrosis along with altered cellular architecture, cardiomyocyte hypertrophy, inflammatory cell infiltration and activation of myofibroblasts.