Introduction

Tropical endomyocardial fibrosis (TEF) is a rare heart disease mainly characterised by the stiffening of the heart muscle caused by fibrosis (scarring of tissue).¹ TEF is usually more prevalent in populations that live in tropical or subtropical areas, hence its name. Unfortunately, fibrotic diseases like TEF can be responsible for approximately 800,000 deaths worldwide.² As a result, understanding the causes, and more specifically, the genetic predispositions to TEF is important to determine high-risk individuals and develop therapies to either slow down disease progression or treat the fibrotic heart tissue and restore normal heart function. 

Overview of tropical endomyocardial fibrosis

Epidemiology and affected regions

As indicated by the name of this condition, TEF predominantly affects individuals in tropical regions such as Uganda, coastal regions of India, Mozambique, and parts of West Africa and South America, predominantly Columbia and Brazil.¹ Whilst this increased prevalence may be linked to tropical climates, there have also been associations made to socioeconomic status, due to an increased risk of developing parasitic infections and pre-existing nutrient deficiencies. There may also be an indicated increased risk in people assigned female at birth between approximately the ages of 15-45, but researchers are yet to fully understand why this is. 

Clinical features

TEF develops following the chronic inflammation of the heart walls’ muscle layers known as the endocardium and myocardium.¹ This inflammation can be triggered by a parasite known as schistosomiasis, which is notably endemic in tropical regions such as sub-saharan Africa, Southeast Asia, the Caribbean and South America.³ Overtime, the inflammatory components cause the formation of scar tissue (fibrosis), ultimately changing the structure of the heart through a ‘remodelling’ of the heart muscle, which leads to progressive stiffening of the heart muscle walls and impaired contraction.¹

As a result of this stiffening, the heart muscle is unable to expand, reducing the amount of blood that can fill the heart, and therefore reducing the volume of blood (cardiac output) that can be pumped out of the heart. This may lead to the development of heart failure. 

Impaired contraction of the heart can manifest as shortness of breath, swelling of the lower limbs (oedema), fatigue, an increased risk of arrhythmias and blood clot formation (thrombosis) and its associated risks such as strokes and pulmonary embolisms. 

Genetic underpinnings of endomyocardial fibrosis

Hereditary evidence

TEF is not generally referred to as a genetic condition due to it not being linked to a single specific gene that causes the disease.¹ However, there have been a few population studies that have found links between higher incidences (presence of disease) within certain families and clustering populations.⁴ This pointed towards an indication that there may be genetic risk factors in the form of certain gene clusters which increase the likelihood of TEF development.

Suspected genetic mutations and variants

Human leukocyte antigen (HLA)

As mentioned, the development of fibrotic scar tissue is usually preceded by an inflammatory response.¹ How the immune system differentiates between the body’s cells and the cell of the pathogen it wants to attack is by recognising human leukocyte antigen (HLA) complexes that are present on the surface of every cell in the body like a cellular signature.⁵ These are coded by a group of genes located on chromosome 6 and the overall complex can vary from person to person. One study found a correlation in individuals with TEF from Uganda and Mozambique with certain specific subtypes of HLA complexes. These variants in HLA complexes may therefore have a role in susceptibility to TEF development. However, clear evidence underpinning the mechanism on how exactly this happens is yet to be found. 

One possible explanation is that following infection from a parasite that has a similar surface ‘signature’ to the patient's own cells, the inflammatory response triggered by the body then also targets the host’s cells. If the cells of the heart muscle wall are targeted, this will lead to damage and the subsequent formation of fibrotic scar tissue.

Type 1 Collagen

When fibrosis or scarring of the heart tissue occurs, a type of cell called fibroblasts are activated following inflammation.¹ Generally, fibroblasts are tasked with building up the connective tissue between cells, creating a linking between various proteins and holding the cells of a tissue together, giving it its structure.⁶ One such protein is collagen, of which there are various types. In the case of TEF, there is an increased prevalence of type 1 collagen in the fibrotic tissue of the heart, which may indicate a genetic predisposition to increased type 1 synthesis.⁷ T However, studies on this association are limited, therefore the link between genetics and collagen type 1 synthesis needs to be further researched in these patients.

Epigenetics

Epigenetics describes changes in gene expression without any associated altering of the ‘base sequence’ of the genetic code - deoxyribose nucleic acid (DNA).⁸ The environment can greatly impact which genes are switched “on” or “off” (their ‘expression’) by making the DNA sequences for certain genes more accessible. In cardiac fibrotic diseases like TEF, links have been identified between epigenetic modulation of certain genes and the formation of fibrotic heart tissue.⁹ Switching on certain genes, especially those associated with the fibrosis pathway, can increase the likelihood of scarring and ultimately, the restriction of the heart and its function.

Investigating genetic susceptibility

Genetic studies can be done in a number of ways both in clinic and during research, some of the most common methods are as follows:

• Whole genome sequencing (WGS) - sequencing of the entire DNA genetic sequence of TEF patients in order to identify specific gene variants that may be associated with disease susceptibility¹⁰
• Family Studies and Genetic Linkage Analysis - can be used to identify patterns of inheritance between certain affected families in endemic regions. Twin studies can also be useful to discern between genetic and environmental factors¹¹
• Animal Models - animals can be genetically engineered to carry certain mutations. When a target gene is mutated, researchers can observe how that gene functions and gives rise to certain diseases based on its change in expression¹²

Summary

• TEF is a restrictive heart disease caused by the formation of fibrotic scar tissue in the endocardium and myocardium 
• It typically affects populations living in tropical regions and eventually leads to heart failure and other serious cardiovascular complications 
• Genetic susceptibility is important to determine in such individuals to develop appropriate therapies and initiate early intervention 
• While there is still much research to be done, some genetic links have been made regarding type 1 collagen production, epigenetics and HLA subtypes 
• Further genetic research must be conducted to fully understand these risks and mechanisms