A Discussion of the Biochemistry of Cardiac Fibrosis

Fibrosis is a malfunction of tissue maintenance, in which excessive amounts of extracellular matrix structure are created, forming scar-like features that disrupt normal tissue function. Fibrosis is a feature of aging and can rise to the level of life-threatening issue in organs such as the lung, liver, kidneys, and heart. This is particularly the case because there are no truly effective therapies to treat fibrosis; it is an inexorable condition that leads towards organ failure. Progress towards the reversal of fibrosis has been slow, unfortunately, despite the comparatively recent discovery that senescent cells appear to drive fibrosis in many organs, including the heart.

Cardiac fibrosis is a common feature of acute myocardial infarction (MI) and various other chronic diseases, such as hypertension, diabetes mellitus, and chronic kidney disease. Numerous studies emphasized that the severity of cardiac fibrosis correlates with adverse cardiac events and mortality. Cardiac fibrosis is defined as an increase in the myocardial extracellular matrix (ECM) protein deposition, mainly collagen I and collagen III, that impairs cardiac function.

Two types of cardiac fibrotic lesions have been defined depending on their localization and the feature of ECM protein deposition. The first one is a reparative process, also named replacement fibrosis, that is observed as scar tissue. In this ischemic disease, oxygen deprivation of the heart muscle results in the necrosis and apoptosis of cardiomyocytes, leading to a loss of large amounts of cardiac cells that are essential for cardiac function. Cardiomyocyte death initiates a triphasic immune response that aims at clearing cell debris and promoting the replacement of the injured myocardium to maintain cardiac function.

The second type of fibrotic lesion is interstitial fibrosis, characterized by the diffuse deposition of collagen in the endomysium and perimysium. This interstitial fibrosis frequently comes with perivascular fibrosis and is specifically observed as secondary to chronic injuries, such as a pressure overload (aortic stenosis, hypertension), cardiac inflammation (myocarditis), and metabolic disorders (obesity, diabetes mellitus) as well as aging. Diffuse fibrosis is also frequently observed in the surviving infarcted heart, where it develops in remote areas. The myocardial interstitial fibrosis development alters myocardial architecture and physiology, modifying left ventricular compliance, diastolic function, and electrical connectivity, leading to arrythmia and adverse outcomes (hospitalization, mortality).

Whatever the context, interstitial cardiac fibrosis is correlated with cardiac dysfunctions and is known to contribute to HF with or without preserved ejection fraction. Thus, understanding the molecular pathways involved in cardiac fibroblast activation will permit the development of new therapeutic strategies to fight cardiac fibrosis and reverse HF.

Link: https://doi.org/10.3390/ijms24021756