Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

Abstract

Cardiac fibrosis is a common pathological consequence of most myocardial diseases. It is associated with the excessive accumulation of extracellular matrix proteins as well as fibroblast differentiation into myofibroblasts in the cardiac interstitium. This structural remodeling often results in myocardial dysfunctions such as arrhythmias and impaired systolic function in patients with heart conditions, ultimately leading to heart failure and death. An understanding of the precise mechanisms of cardiac fibrosis is still limited due to the numerous signaling pathways, cells, and mediators involved in the process. This review article will focus on the pathophysiological processes associated with the development of cardiac fibrosis. In addition, it will summarize the novel strategies for anti-fibrotic therapies such as epigenetic modifications, miRNAs, and CRISPR technologies as well as various medications in cellular and animal models.

Keywords: anti-fibrotic therapies; cardiac fibrosis; cardiovascular diseases; myofibroblasts; scar tissue.

Figure 1

Development of reparative fibrosis in the heart. A healthy heart contains cardiomyocytes that are mainly involved in the contractile function of the heart. An injury to the heart results in myocardial damage. This activates repair mechanisms, leading to the formation of fibrosis. Heart trauma causes the death of cardiomyocytes that express DAMP molecules and by this induce the infiltration of leukocytes and fibroblasts into the damaged area. At the same time, cardiac fibroblasts begin to trans-differentiate into pathological myofibroblasts which, in turn, begin the over-production of ECM proteins. When the wound is cleared from phagocytosing dead cells and matrix debris, resident cells undergo apoptosis and the collagen-based scar is formed.

Figure 1

Development of reparative fibrosis in the heart. A healthy heart contains cardiomyocytes that are mainly involved in the contractile function of the heart. An injury to the heart results in myocardial damage. This activates repair mechanisms, leading to the formation of fibrosis. Heart trauma causes the death of cardiomyocytes that express DAMP molecules and by this induce the infiltration of leukocytes and fibroblasts into the damaged area. At the same time, cardiac fibroblasts begin to trans-differentiate into pathological myofibroblasts which, in turn, begin the over-production of ECM proteins. When the wound is cleared from phagocytosing dead cells and matrix debris, resident cells undergo apoptosis and the collagen-based scar is formed.

Figure 2

An overview of the novel strategies utilized to alleviate fibrotic remodeling after cardiac diseases. Multiple cardiac pathologies tend to terminate in the replacement of contractile myocardium with the fibrous tissue, one of these diseases is myocardium infarction (infarction area is depicted in yellow). Novel anti-fibrotic therapies target various levels of the pathogenesis of cardiac fibrosis: (1) Epigenetics-based therapies such as histone deacetylase (HDAC) and histone methyltransferases (HMT) have been shown to regulate the gene expression of many fibrosis-associated proteins such as TGF-β1, collagen type I, collagen type III, fibronectin, and many others. Consequently, HDAC inhibitors and HMT inhibitors have been applied to suppress the expressions of those proteins and downregulate fibrosis. (2) Clustered regularly interspaced short palindromic repeats (CRISPR) technology has been used to silence pro-fibrotic genes as well as to introduce “useful” genes into stem cells to enhance their therapeutic potential for myocardial fibrosis. (3) Anti-fibrotic microRNAs (miRNAs) can be utilized to repress the gene expression of fibrosis-mediating genes at the level of mRNA whereas miRNA inhibitors interact with pro-fibrotic miRNA and inhibit them. Viral vectors (shown as hexagons) are generally used to deliver miRNAs while miRNA inhibitors can be transferred using liposomes (depicted as circles). (4) Anti-fibrotic medications such as pirfenidone, angiotensin receptor blockers, and NLRP3 inflammasome inhibitors work by inhibiting enzymes and signaling molecules involved in the pathophysiology of cardiac fibrosis.