Investigational drugs targeting cardiac fibrosis

Abstract

Fibrosis is an accumulation of proteins including collagen in the extracellular space, which has previously been considered as irreversible damage in various cardiovascular diseases including heart failure and hypertension. The pathophysiology of fibrosis is currently better understood and can be evaluated by non-invasive methods. Here, the authors present briefly the impact and molecular mechanisms of fibrosis in the myocardium and the promising therapeutic candidates including anti-hypertensive therapies, heart-rate lowering drugs, anti-inflammatory agents, as well as other innovative approaches such as inhibitors of growth factors, miRNA or cell therapy. Surrogate end points allow for larger clinical trials than previously possible with endomyocardial biopsies, and magnetic resonance and molecular imaging should open new fields of research on cardiac fibrosis. Several pre-clinical findings are very promising, and some clinical data support the proofs of concept, mainly those with inhibitors of the renin-angiotensin system. These approaches open the field for regression of fibrosis and include the following: first, some of these drugs are widely used like renin-angiotensin system inhibitors; second, inflammation modulators; third, in near future entirely new approaches targeting the TGF-β pathways, or others like cell therapies or genetic interventions.

Keywords::

• cardiac fibrosis
• collagen
• extracellular matrix
• heart failure
• hypertrophy
• myocardium
• myofibroblast
• remodeling
• TGF-β

Acknowledgement

We are grateful to Dr. Matthias Friedrich for reviewing the sections pertinent to MRI.

Financial & competing interests disclosure

F Roubille has received grants and honoraria from Servier – Abbot – Roche. JC Tardif has received grants from Servier – Roche and honoraria from Servier – Abbot – Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Fibrosis is an important player in various pathways in cardiovascular pathogeny.

• Assessment of cardiac fibrosis is currently possible, through MRI, developing molecular imaging and validated biomarkers.

• First trials evaluating cardiac fibrosis and its regression have been completed, validating both the concept and the feasibility.

• Promising results have been reported as regards to the renin-angiotensin-aldosterone system antagonists, especially with the mineraloreceptor inhibitors.

• Other profibrotic processes will be of interest, such as the pro-inflammatory cytokines or bradycardic therapies. If confirmed, their antifibrotic properties could be of interest in clinical settings.

• New pathways, more specifically involved in fibrosis, are to be tested including the TGF-β modulation.

Notes