Cardiac Fibrosis and Remodeling - Prevention and Remodeling

Introduction

Presently, ischemic heart disease (reduced blood supply in the heart and the great vessels of the body) is the number one cause of death in males and females in the United States of America and other western countries. In most industrialized countries, death due the ischaemic heart disease has increased many folds. Chronic heart failure is a syndrome of various cardiovascular diseases. It results in poor life quality and places an economic burden on the health care system worldwide. Many types of cardiac diseases and conditions are associated with abnormal thickening and scarring of the heart tissue, knowns as cardiac fibrosis. Cardiac fibrosis is associated with the progression of heart failure and poor progression. Heart failure progression is mainly caused by left ventricle remodeling. Once cardiac fibrosis is progressed into advanced stages, it is irreversible, with limited options for treatment focussed on managing symptoms and prolonging life. Irrespective of the initial cause, injury to the heart evokes a sustained fibrotic response that results in distorted heart structure and cardiac dysfunction.

What Is Ischemia?

A group of clinicopathological syndromes occurs due to an imbalance between oxygen supply and demand to the heart muscles. There are two types of ischemia- ischemia and isolated hypoxemia. Heart failure is caused by myocardial infarction. Following myocardial infarction, the cardiac cells die in response to ischemia. Ischaemic cell death after a myocardial infarction leads to repair in the affected area. Fibrotic scars replace dead cells because the heart cannot regenerate after an injury. The pathologic changes in heart failure occur in two steps. One is cardiomyocyte hypertrophy (increase in the size of the heart muscle), necrosis (premature death of the cells), and apoptosis (programmed cell death), and the other is cardiac fibroblast hyperplasia and cardiac fibrosis. Cardiac fibrosis is an important feature in the mechanism of heart failure. So most of the studies focus on preventing structurally abnormal cardiomyocyte that causes tissue death.

What Is Cardiac Fibrosis?

Cardiac fibrosis is defined as follows:

• Fibrosis is a physiological process that repairs replace and reinforces severely injured tissue when tissue regeneration and homeostatic mechanisms fail.

• Cardiac fibrosis is a progressive accumulation of fibrillar extracellular matrix in the heart. The regulation of extracellular matrix remodeling is primarily mediated by cardiac fibroblasts (CF). Various T- lymphocytes differentially affect organ fibrosis by modifying the collagen.

• Pathological fibrotic remodeling mediated by activated cardiac myofibroblasts. Pathological fibrotic remodeling involves changes in the myocardial (heart muscle) tissue caused by the proliferation and activation of cardiac fibroblasts and the alteration of extracellular matrix composition.

• Structural collagen is essential for maintaining physiological cardiac function; fibrosis represents pathologic changes corresponding to worsened clinical outcomes.

• The progression of fibrosis from physiologic to pathological is exemplified by myocardial ischaemic and infarction resulting from reduced myocardial tissue perfusion. When cardiomyocytes are deprived of proper blood supply and tissue perfusion, they are deprived of critical sources of energy production, resulting in cell death through necrosis or apoptosis.

• Myocardial death leads initially to an inflammatory response where granulocytes, macrophages, and fibroblasts are recruited to the region of injury. This area is ultimately replaced by secreted ECM proteins such as collagen to form scar tissue. Reparative scar formation is beneficial in replacing dead cardiomyocytes, preventing myocardial rupture, and maintaining myocardial continuity.

• Cardiac fibrosis is a progressive fibrillar extracellular matrix (ECM) accumulation in the myocardium. The regulation of ECM remodeling is primarily mediated by cardiac fibroblast (CF) cells, the primary non-muscle cells in the heart. CFS modulate matrix turnover in nonpathological conditions, and their activity is greatly enhanced after an acute cardiac event or during chronic cardiovascular disease.

• Myocardial fibrosis is the expansion of the cardiac interstitium by depositing extracellular matrix proteins. Fibrosis occurs due to the repair of the cardiac muscle cells. Activated fibroblasts and myofibroblasts are the main factors in cardiac fibrosis. They serve as matrix proteins. The cardiac cells, known as cardiomyocytes, and the immune cells and vascular cells acquire a change because of stress that activates the fibroblasts.

• Fibrogenic growth factors such as cytokines, tumor necrosis factor, and interleukin trigger the fibrogenic signaling cascades by binding through the surface receptors of the myocardium. The matrix metalloproteins are deposited in the myocardium and regulate matrix assembly.

• Fibrosis results in the accumulation of extracellular matrix (ECM) at the injury site and the scar's production. During cardiac damage and stress, various fibroblasts differentiate into myofibroblasts. Myocardial remodeling is associated with myocardial stiffness and contributes to heart failure.

• Cardiac fibrosis represents a common terminal pathway in diverse cardiac pathogenesis. The cardiac fibroblast is an essential myocardial cell responsible for extracellular homeostasis. Stress and pathological stimulation invoke differentiation to a myofibroblast characterized by increased deposition of extracellular matrix proteins leading to cardiac fibrosis and dysfunction.

What Is the Role of Fibroblasts in the Repair of Heart Tissue?

The role of fibroblasts in the repair of the heart tissue are:

• Collagen I in the heart makes 80 percent of the collagen in the heart, which makes it stiffer and increases myocardial fibrosis. Fibrosis reduces the supply of oxygen and nourishment to cardiac muscles. Cross-linking increases collagen stiffness and is different from breaking down with proteinases.

• The fibroblasts produce fibrotic scar fibroblasts and myofibroblasts. The increased mechanical stress after the myocardial infarction triggers the expansion of the connective tissue in some areas. The myocardial ischemic injury causes cardiomyocyte necrosis (death of the tissue). During tissue repair, the molecule signals damage and consequent activation of intense inflammatory response for tissue repair. Myocardial fibrosis is an important part of cardiac remodeling, leading to heart failure and death. The mechanism of cardiac fibrosis includes myofibroblast activity and excessive extracellular matrix deposition.

• Cardiac remodeling is heart failure's key mechanism, including heart cell injury and myocardial fibrosis. Cardiomyocyte injury presents as cardiomyocyte hypertrophy, necrosis, and apoptosis.

• The cardiac myofibroblast is activated through numerous cell signaling pathways following a cardiac injury.

• Cardiac fibroblasts are the primary cells responsible for depositing extracellular matrix in the heart and supporting the heart muscle. Excessive fibroblast proliferation and activation leads to pathological remodeling.

• T lymphocytes control the fibrogenic process of cardiac fibrosis by interacting with myofibroblasts or fibroblasts and secreting cytokines that participate in wound healing. T lymphocyte infiltration after myocardial infarction coincided with increased cardiac fibroblast proliferation and enhanced fibrotic function.

• Cytokines and growth factors produce a fibrotic environment that leads to the development of the profibrotic population of fibroblasts. Alterations in fibroblasts such as type-I and -III collagens, elastin, and fibronectin result in remodeling. Collagen degradation is under the subtle control of matrix metalloproteinases (MMPs).

Conclusion

While much is known about cardiac myocytes, relatively less is known about non-myocytes, which comprise approximately half of the cardiac cells. These non-myocytes are involved in the heart's response to injury, which often takes the form of tissue fibrosis, which can cause damage to the heart, including heart failure and deadly arrhythmias. Non-myocytes are activated in many common cardiac disorders, including acquired remodeling secondary to hypertension, ischemic heart failure, and valve disease.