What is heart enlargement?

Heart enlargement, also known as cardiomegaly, is the structural change of the heart resulting from underlying cardiovascular conditions. A common underlying cause of heart enlargement is cardiomyopathy, which is a collection of conditions in which the heart muscles develop structural and functional abnormalities.

In some cases, this can be acquired with causes ranging from viral infections, toxins, and autoimmune diseases, although genetic factors are recognised as major contributors to this disease. Advances in molecular genetics have identified a range of mutations that lead to dilated, hypertrophic, and arrhythmogenic cardiomyopathies, respectively known as DCM, HCM, and ACM.¹ 

HCM is when the heart muscles, specifically the wall of the left ventricle, become thick, making it harder for the heart to fill with blood in order to pump blood around the body efficiently. 

DCM is when the left ventricle stretches and becomes enlarged. As a result, the walls become thinner and weaker, reducing the power the heart can pump blood, leading to fatigue and heart failure. 

ACM is when healthy heart muscle is slowly replaced with scar tissue or fat, usually beginning with the right ventricle. This can disrupt the heart’s electrical signals, increasing dangerous arrhythmias. 

This article outlines the key genetic mutations associated with cardiomyopathy and heart enlargement.

Different genetic mutations

TTN (titin) truncating variants 

These are genetic changes in the TTN gene, which makes titin. Titin is a large protein that aids the heart muscles with its structure and ability to stretch. When a truncating mutation occurs, the protein is unable to form properly, leading to a weaker heart that is unable to pump blood adequately around the body. Over time, the left ventricle will increase in size. This mutation has been reported to be seen in 20-25% of inherited cases of DCM, with 15% of cases having a family history. Those with TTN truncation variants will develop heart failure, abnormal heart rhythms, and hence a higher risk of sudden cardiac death.³

LMNA (Lamin) mutations

The LMNA gene makes the lamin A and C proteins, which help form the nuclear envelope that surrounds and protects the cell’s DNA, but also play a role in regulating which genes are active. When LMNA is mutated, the nuclear structure becomes unstable, causing the heart muscles (cardiomyocytes) to malfunction or die. This can affect the conduction of the heart, leading to slow heart rhythms or heart block, before the heart ultimately becomes enlarged. Patients with LMNA mutation are at high risk of arrhythmias and sudden cardiac death. As a result of this, doctors recommend implantation of an ICD(implantable cardioverter-defibrillator) to protect against harmful rhythm disturbances.⁴

MYH7 mutations

MYH7 genes provide the instructions for making the β- myosin heavy chain protein, which is a crucial component of muscle contraction, particularly in the cardiac muscles. This mutation causes both HCM and DCM. When muscles contract, the sliding filament model is unable to perform well due to different kinds of mutations. Some mutations make the heart muscle contract too forcefully or relax, which over time causes the walls of the heart to thicken (HCM) while maintaining normal pumping ability. Other mutations weaken the muscle’s contractile power, leading to stretching and enlargement of the heart chambers (DCM). These changes can cause symptoms such as shortness of breath, fatigue, chest pain, or irregular heartbeats, and the specific effects often depend on the exact mutation a person carries.⁵

TNNT2 mutations

TNNT2 is a gene that makes cardiac troponin, which is a key protein in the heart's muscle fibers that helps to control contraction in response to calcium signals. Mutations in this gene alter how sensitive the heart muscles become to calcium; this interferes with their ability to generate enough force when pumping. Over time, the heart muscles can be adapted in harmful ways, leading to DCM or HCM. The severity varies widely, where some patients may experience early-onset heart failure and others will carry a higher risk of sudden cardiac death. Therefore, it is essential for doctors to carefully monitor and plan early treatment.⁶

DSP and PKP2 mutations

DSP (desmoplakin) and PKP2 (plakophilin-2) are genes that make desmosomal proteins. These form adhesive junctions called desosomes, holding the heart muscle cells together, for when the heart beats. These mutations cause the connections between cells to weaken, causing the heart muscles to become more vulnerable to failure. Over time, the muscle tissue will break down and fatty tissue will form, which disrupts the electrical signal that controls the heartbeat, causing ACM. This mainly affects the right ventricle but can be spread to the left ventricle. Patients with this mutation will experience intense arrhythmia, fainting, and sudden cardiac arrest. DSP will also cause the heart chambers to dilate, decreasing pumping ability, leading to DCM as well.¹

SCN5A mutations

Mutations in the SCN5A gene, which produces the Nav1.5 sodium channel (the main sodium channel in the heart), can lead to DCM, accompanied by conduction abnormalities. The Nav1.5 channel is essential for generating and transmitting the electrical impulses that coordinate each heartbeat. When this mutation occurs, the heart’s electrical signaling becomes slow or irregular, disrupting the timing of contractions. Over time, this electrical disruption leads to structural changes, such as stretching and weakening of the heart’s main pumping chambers, resulting in dilation. People with SCN5A mutations may show overlap syndromes, for example, DCM can occur alongside other electrical heart diseases such as Brugada syndrome, and they often face a higher risk of serious arrhythmias, which can cause fainting or sudden cardiac death.^7,8

PLN mutations

The PLN gene makes a protein called phospholamban, which also plays a key role in controlling how the heart muscle handles calcium. Calcium movement inside heart cells is crucial because it controls how the heart contracts to pump blood. Normally, phospholamban controls a pump called SERCA2a by moving calcium back into storage inside the cell (the sarcoplasmic reticulum) after each heartbeat. This stored calcium is then released again for the next contraction, allowing the heart to beat effectively. When mutations occur in the PLN gene, the calcium is not pumped back into storage properly. As a result, the heart muscle doesn’t relax well after each beat (diastolic dysfunction) and also becomes weaker at pumping blood (systolic dysfunction). Over time, these problems cause the heart chambers to stretch and enlarge, leading to DCM and ACM. PLN mutations often cause an aggressive form of heart disease. Many people develop symptoms of heart failure at a young age, and dangerous heart rhythm problems are common. In some families, these mutations can a; so cause sudden cardiac death, sometimes even before significant heart enlargement is detected.⁹

Summary

Genetic mutations are key in causing cardiomyopathy and heart enlargement. Changes in genes that control heart muscles and cells, electrical channels, and even nuclear structure can disrupt normal heart function, leading to the weakening of the heart.  

With genetic testing becoming more accessible, at-risk individuals can be identified early, allowing for timely treatment, tailored therapies, and preventive care even before symptoms appear. Ongoing research into how specific gene mutations affect the heart will help improve patient management and long-term outcomes.

FAQs

Are these genetic mutations inherited?

Yes. Many mutations are autosomal dominant, meaning only one copy of the mutated gene is enough to increase risk, while others are autosomal recessive, requiring two copies. Some can also occur spontaneously, although it's rarer. 

Which genetic mutations are the most common causes of cardiomyopathy?

Some of the most frequently implicated genes include TTN, LMNA, MYH7, TNNT2, DSP, PKP2, SCN5A, and PLN. Each affects heart muscle function differently, leading to types like dilated, hypertrophic, or arrhythmogenic cardiomyopathy as stated above. 

Can a person have a mutation but not develop cardiomyopathy?

Yes. Some people with these mutations never develop symptoms due to factors like environment, lifestyle, and other genes that influence disease expression.

What symptoms can be a sign for this?

Symptoms may include shortness of breath, fatigue, palpitations, fainting, or unexplained heart failure, especially if there is a family history of cardiomyopathy or sudden cardiac death.

Are there preventive measures for people with a mutation but no symptoms?

Lifestyle modifications such as avoiding excessive alcohol, managing blood pressure, staying active. Regular cardiac imaging, and preventive medications or device implantation are considered based on risk.

Can these mutations affect other family members?

Yes. Family members may carry the same mutation. Genetic counseling can help determine who should be tested and guide family planning decisions.