The theatrics of collagens in the myocardium: the supreme architect of the fibrotic heart

Abstract

Heart failure (HF) mediated by cardiac fibrosis (CF) is characterized by an excessive accumulation of collagen-based extracellular matrix (ECM) in the myocardium. CF is a common pathophysiological condition in many heart diseases and can be distinctly categorized into two types: replacement and interstitial. In ischemic heart diseases, sudden loss of cardiomyocytes leads to the replacement of CF to prevent ventricular rupture. In contrast, excessive collagen deposition in the interstitial space between cardiomyocytes (often in response to pressure overload, chronic cardiac stress, hypertension, etc.) is termed interstitial CF. The progression of HF due to cardiac fibrosis is mainly driven by compromised diastolic function, resulting from increased stiffness of the heart wall muscle due to collagen-based scar formation. Increased myocardial stiffness is primarily catalyzed by the differential cross linking of deposited collagens forming the scar in the fibrotic heart. Although collagen deposition remained a hallmark of fibrosis, the pathophysiological progression due to biochemical alterations and mechanistic discrepancy of collagens across cardiac fibrosis subtypes remains elusive. With the advent of next-generation RNA sequencing and high-resolution mass spectrometry, mechanistic insights into collagen-mediated scar maturation have gained impetus. A deeper understanding of the spatiocellular transcriptional heterogeneity and site-specific collagen posttranslational modifications (PTMs) in maneuvering ECM remodeling is gaining attention. The unexplored mechanisms of posttranslational modifications and subsequent collagen cross linking in various cardiac fibrosis may provide the prime target for therapeutic interventions. This review comprehensively summarizes the detailed pattern, role, signaling, and mechanical contributions of different collagens and their PTMs, including cross-linking patterns as newer therapeutic regimens during cardiac fibrosis.

Keywords: collagen cross linking; collagen posttranslational modifications; extracellular matrix; heart failure; replacement and interstitial cardiac fibrosis.