Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure.

Abstract

Therapeutic strategies for heart failure (HF) should increasingly consider measures directly targeting the myocardium itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. In this regard, a new view is emerging that proposes the direct intervention on the pathological structural remodeling of the myocardium as part of HF therapy. One hallmark myocardial lesion in HF is the diffuse accumulation of collagen fibers (namely, collagen type I) within the interstitium and around the microvasculature of the myocardium (ie, myocardial fibrosis [MF]). MF is the result of the predominance of collagen synthesis over its degradation as a result of the actions of a population of persistent metabolically active cells: the myofibroblasts. MF impairs cardiac function and contributes to the development and worsening of HF, in addition to facilitating arrhythmias and ischemia, and thus adversely influences the evolution and outcome of nearly all cardiac diseases.1 Therefore, MF regression is an unmet medical need, and the search for new drugs aiming its reversal is active. However, the efficacy and safety of novel antifibrotic strategies currently under investigation seem questionable.2 We thus propose a therapeutic approach based on targeting the cardiac myofibroblast secretome with already available drugs, which have proven to be both efficient in reducing MF and safe in protecting cardiac function. In addition, we will discuss how to identify those HF patients in whom these therapies can be more beneficial and thus should be personalized. Cardiac myofibroblasts are cells expressing α-smooth muscle actin microfilaments that originate from the differentiation of several cell types (including resident cardiac fibroblasts) under the influence of many local and systemic factors (Figure 1). Myofibroblasts exhibit a synthetic phenotype that includes a secretome consisting of molecules requisite to modify the quantity and quality of the myocardial collagen network and facilitate MF …