The Collagen Challenge: Preventing Myocardial Fibrosis Is the Hype Reflective of the Potential?

Abstract

Mounting evidence has suggested that the cardiac extracellular matrix (ECM) has a nuanced but determinative role in myocardial remodeling in response to pathological insult and subsequent recovery [1-3]. These alterations in the structure and actual composition of ECM may actually reflect many of the welldescribed phenotypic cardiac properties typical of common diseases states including diabetes, hypertension, obesity and ischemia. Current thought is that dysregulatory influences result in a maladaptive remodeling process that begins an inevitable progression to irreversible and often untimely cardiac failure [1,2]. This potentially injurious perturbation in the dysfunctional ECM response is complex involving profibrotic collagen synthesis and post-translational modification including increased crosslinking and reduced degradation [1,4]. The result is a stiffening noncompliant and impaired myocardium that underpins observed clinical changes causing the heart failure syndrome. Sampling changing serum levels of distinct proteins or molecular fragments are now being used to assess collagen turnover. This includes using the N-terminal propeptide of procollagen type III and C-terminal propeptide of procollagen type I considered directly correlative to histologically proven fibrosis [1,5]. Other biomarkers have been proposed to be associated with pathology involving collagen metabolism, (tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase [MMP]-2, MMP-9, galectin-3 [Gal-3], etc) but are not yet validated as directly representative of histologically confirmed fibrosis [1,6].