Genetic engineering is a branch of science that harnesses laboratory technologies to manipulate an organism's DNA. Gene therapy, a powerful tool in modern medicine, has the potential to prevent diseases like cardiomegaly by repairing or replacing the faulty genes that cause the disease. Cardiomegaly describes conditions that cause abnormal enlargement of the heart.¹ With advancements in modern medicine and science, gene therapy presents a promising therapeutic tool that can potentially be used to hinder the onset of cardiomegaly. 

Understanding cardiomegaly

What is cardiomegaly?

Cardiomegaly is a term that describes abnormal enlargement of the heart, either the entire heart or sections of the heart. There are genetic and non-genetic causes of cardiomegaly, meaning it may develop due to inherited genetic mutations or other underlying conditions or factors, like those described below:¹

Congenital conditions—these conditions are present at birth due to inheriting genetic mutations that affect the heart's structure and functionality.

Heart diseases/conditions are genetic heart conditions that make the heart beat harder than usual, such as coronary artery disease, hypertensive heart disease, or cardiomyopathy—disorders of the heart muscles, namely hypertrophic cardiomyopathy and dilated cardiomyopathy.

Other risk factors for cardiomegaly include: 

• Lung diseases
• Hypertension
• Pregnancy (preeclampsia)
• Substance abuse
• Rheumatoid arthritis
• Thyroid disease
• Kidney diseases- renal failures
• Infectious myocarditis secondary to viral infection (an inflamed heart caused by infection
• Diabetes 
• Amyloidosis (the build-up of an unwanted group of amyloid proteins in the tissue)
• Family history of cardiomegaly

Symptoms

Cardiomegaly typically presents without any symptoms. Those who are symptomatic may experience: 

• Fatigue
• Heart Palpitations
• Fainting spells
• Shortness of breath on physical activity
• Light-headedness
• Chest pain
• Oedema (swelling) 

How is cardiomegaly diagnosed?

Cardiomegaly can be diagnosed through imaging with diagnostic tools such as chest x-rays that assess the heart's size, alongside the individual's medical history and physical examination. Cardiomegaly is identified on a chest x-ray when the heart is greater than 50% of the inner diameter of the ribcage. 2 Additional tests, such as electrocardiograms, MRIs, and blood tests, are done to confirm the presence of the disorder.

What is genetic engineering? 

Genetic engineering uses specialised techniques to make changes in an organism's DNA. DNA is made up of pairs of the following building blocks called nucleotides: adenosine, thiamine, guanine, and cytosine, denoted as A, T, G and C. These pairs code for proteins that eventually determine your large-scale characteristics, and when it comes to health and disease, may influence your risk of developing a disease such as cardiomegaly. For example, if your genes that influence heart structure are faulty, they may code for structurally abnormal proteins, which may mean that your heart has to become enlarged to be able to pump as it should. In genetic engineering, a single pair of nucleotides is changed, so that an entire section of DNA can be added or removed.³ 

What is gene therapy?

Gene therapy is a targeted gene manipulation treatment that allows scientists to edit a faulty gene to achieve a desirable therapeutic outcome.⁴

Gene editing has become a promising strategy for targeting genetic diseases. When a mutated gene produces a defective protein that causes disease, the gene can be corrected by either deleting, inserting, or repairing segments of DNA to offset diseased outcomes. Several techniques are used in gene therapy, and a range of gene editing tools, such as CRISPR-Cas9, TALENs, and ZFNs, have revolutionised modern medicine in recent years.⁵ 

In vivo vs ex vivo gene therapies

Genetic editing can be achieved in vivo or ex vivo in gene therapy. 

In vivo means “within the living”, so when gene editing takes place within the body. In the process, the gene editing tool is delivered into the body with a viral vector—a modified virus that acts as a delivery system—that targets specific cells to replace or repair the defective gene.

Ex vivo means “out of the living”, so when gene editing occurs outside the body. In this approach, cells are either harvested or healthy donor cells are genetically modified in the lab. Once the necessary changes are made, the corrected cells are introduced into the patient as a form of therapy. 

Applications in medicine

Genetic engineering has numerous applications in treating genetic diseases like sickle cell disorder and cancers such as leukemia.⁶ Several studies and clinical trials demonstrate the effectiveness of gene engineering in targeting these genetic diseases. These advancements in research and medicine aim to correct the gene mutations that cause these conditions and offer promising treatment options for those affected.

What genetic mutations are linked to cardiomegaly?

Cardiomegaly is linked to genetic mutations in some people, for example, those who have the genetic mutations that cause cardiomyopathies. For further explanation, muscle fibers are made of protein units called sarcomeres, which are proteins responsible for muscle contraction.⁶ Mutations in the genes that code for sarcomere proteins can directly affect the heart muscle structure and function, causing the heart muscles to become weak, thick, or stiff. These changes are called cardiomyopathies, and can affect the heart's blood pumping abilities and lead to cardiac arrest.¹

Types of cardiomyopathies

Familial hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle thickens, obstructing blood flow. It affects about 1 in 500 people and is an autosomal dominant disorder. This means there is a 50% chance of an offspring inheriting HCM if a parent has the condition. HCM is caused by gene mutations that encode sarcomere proteins, Myosin heavy chain 7 (MYH7), and Myosin binding protein chain 3 (MYBPC3).⁶ 

Familial dilated cardiomyopathy (DCM) is a condition in which the chambers of the heart are enlarged and weakened. It affects 1 in 2500- 3000 people, and the most common form of DCM also has an autosomal dominant inheritance pattern. The most common mutations in DCM are found in the Titin (TNN) gene.⁷

Research and trials

Recent research has studied gene therapy for these heart diseases, and its potential as a treatment option in cardiomegaly and cardiomyopathies. A recent study utilising gene editing with CRISPR-Cas9 technology has shown potential as a promising therapy targeting cardiovascular conditions.⁸ CRISPR-Cas9 is a powerful gene editing tool initially derived from the immune system of single-celled organisms called prokaryotes. This technique allows scientists to make precise modifications to DNA, targeting specific regions of DNA to correct or alter genetic DNA sequences. In these studies, the mutations associated with cardiomyopathies that cause cardiomegaly are targeted using CRISPR and base-editing techniques. 

Another study revealed recent developments in the enhancement of the strategies used to correct complex genetic mutations using viral vectors to deliver gene-editing tools. This also seems to have promising outcomes for treating the underlying genetic causes of cardiomegaly.⁹

Summary

With emerging gene therapies, preventing cardiomegaly has the potential to be life-changing in the lives of many individuals and families. Although there is still a long way to go, advancements in research are paving the way for developing more precise, accurate, safe and accessible gene therapies targeting genetic cardiovascular diseases. By leveraging genetic engineering techniques, scientists have made significant milestones in gene therapy to address several genetic disorders. Ongoing clinical trials and in-depth studies are crucial for translating these developments into standard clinical practice. Overall, this is an exciting time in genetic engineering as these techniques have revolutionized modern medicine and can provide alternative, cutting-edge, and effective treatment options.