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Rheumatic heart disease: pathophysiology

Rheumatic Heart Disease Pathophysiology PDF

The pathogenesis of rheumatic heart disease (rhd) is not well understood. However, it is known that there are at least three major pathways involved in its development. These include (1) inflammation; (2) remodeling of cardiac myocytes; and (3) apoptosis.

Inflammation is a normal response to injury or infection. Inflammatory responses result from activation of innate immune cells such as neutrophils, monocytes, macrophages and T lymphocytes. This activation occurs by binding of specific pathogen-associated molecular patterns (PAMPs).

A PAMP is a molecule that can be found on a wide range of pathogens. Examples include lipopolysaccharide (LPS) on the outer membrane of gram-negative bacteria, peptidoglycans on the cell wall of gram-positive bacteria and double-stranded RNA viruses. PAMPs are detected by pattern recognition receptors (PRRs), which result in the activation of inflammatory signaling pathways.

Inflammatory signaling pathways can lead to the release of inflammatory mediators such as prostaglandins, bradykinins and cytokines. These inflammatory mediators cause an increase in capillary permeability. This is required for the recruitment of immune cells to the site of infection where they can combat the infection.

In pathologic conditions such as rheumatic fever, there is an excessive inflammatory response. The innate immune response that usually clears up the infection is exaggerated and out of control. The prolonged production of inflammatory mediators can cause damage to the heart and other organs.

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In addition to inflammation, remodeling of the myocardium and apoptosis of cardiomyocytes are other important processes in the development of rheumatic heart disease.

The pathogenesis of these two processes are linked: enhanced inflammation leads to an increase in cardiomyocyte apoptosis which further enhances inflammation. In addition, apoptotic cells generate an array of cytokines (such as TNF-a) that promote inflammation.

Because of the process of apoptosis of cardiomyocytes, the myocardium becomes progressively thinner and less able to pump blood. This results in further damage to the heart and so on. The process continues until the vicious cycle is broken.

It has been suggested that apoptosis of cardiomyocytes is a protective mechanism to limit the extent of damage. For example, if the immune attack is a type-I hypersensitivity reaction against antigens from ingested peanuts, apoptosis of cardiomyocytes will limit the extent of inflammatory damage to the myocardium.

However, with repeated antigen challenge and injury, the apoptotic threshold is passed. The result is irreversible damage to the myocardium that causes rheumatic heart disease (and potentially death).

In a similar manner, excessive activation of inflammatory cells will lead to an increase in cardiomyocyte apoptosis. This results in a vicious cycle of increased inflammation and apoptosis.

Rheumatic fever is a type-I hypersensitivity reaction against antigens from group A streptococci (GAS). Antigens from GAS are endocytosed and transported via macropinocytosis to the late endosome. Here, the antigens bind to MHC-I molecules.

Class I MHC-I molecules then interact with the invariant chain (CD74) and are transported to the cell surface.

MHC-I molecules with the bound antigen are displayed on the surface of heart muscle cells where they can be recognized by T cells. If the T cells recognize the antigen as being foreign (in this case, GAS), they will be activated and produce cytokines.

Activated T cells produce IL-1 which triggers the process of macropinocytosis. This causes large quantities of GAS antigen to be internalized by the cell. This antigen can then bind MHC-I and get transported to the surface of the cell.

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The GAS antigen is recognized by CD4+ T helper cells and CD8+ cytotoxic T cells. The CD4+ cells secrete IL-2 which will activate more T cells. The CD8+ cells recognize the GAS antigen as foreign and kill the infected cell.

This is done by a process called target cell death or apoptosis.

Activated T cells release perforins which form pores in the cell membrane. Cytolytic proteins such as granzymes then enter the cytoplasm and directly induce apoptosis.

Apoptosis results in the cell becoming fragile and fragmenting into apoptotic bodies which are quickly phagocytosed.

The fragments of the cell containing DNA are digested by DNase enzymes. The digested DNA is then presented on class I MHC molecules and recognized as foreign by CD8+ T cytotoxic cells. The CD8+ cells release perforins which form pores in the cell membrane, cytolytic proteins such as granzymes enter the cytoplasm and direct apoptosis is induced.

Apoptosis is an essential part of the immune response. This ensures that infected cells are killed and prevents them from causing disease.

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It is thought that excessive macropinocytosis of GAS antigens causes apoptosis of cardiomyocytes. This, in turn, leads to heart failure which can be fatal.

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