Introduction

Have you ever considered that your heart– the vital organ responsible for pumping blood throughout your body every day—might expand and change in size without you even realising it?

The heart is typically about the size of a clenched fist, but there are some conditions that can cause it to enlarge, such as high blood pressure, congenital heart defects, viral infections of the middle layer of heart wall (myocardium), narrowed or blocked arteries, thyroid disorders and even pregnancy. This medical condition is known as cardiomegaly or heart enlargement. An enlarged heart becomes thickened, stretched and structurally altered. Many individuals show no symptoms until the condition progresses after which signs may include, shortness of breath, fatigue, swelling in the legs and abdomen, irregular heartbeats, and chest pain. 

How is it possible that our heart can change shape silently over time, sometimes influenced by lifestyle choices and eventually become a ticking time bomb? As researchers are developing molecular and genetic novel therapies to understand cardiomegaly’s underlying cause, the emergent question is: Can we reverse the change before it is too late? 

What is cardiomegaly?

Cardiomegaly is the medical term used to describe an enlarged heart. To visualise this, imagine the silhouette of the heart and if it takes up more than half of the chest’s width, this raises concern for enlargement. This measurement is known as the cardiothoracic ratio (CTR). A CTR below 0.5 is generally considered normal, whereas a ratio greater than 0.5 suggests possible cardiomegaly.¹  

The projection is very important. The CTR must be measured on a posterior–anterior (PA) chest X-ray, meaning the X-ray beam enters from the patient’s back and exits through the front. In contrast, on an anterior–posterior (AP) view, the beam enters from the front and exits through the back. Because the heart lies closer to the X-ray detector in the AP view, it appears artificially enlarged, making the CTR unreliable in this case.¹

Cardiomegaly can be caused by heart related problems that cause damage to the heart muscle or it can be due to other diseases that lead to this. It may involve enlargement of the right or left ventricle and can also affect the atria.¹

Underlying causes of heart enlargement

There are many causes that contribute to the development of heart enlargement resulting in an abnormally thickened or stretched heart muscle. These include:

1. Coronary heart disease, including heart attacks and ischaemia, which is the most common cause.
2. High blood pressure (hypertension)
3. Valvular heart diseases
4. Congenital structural heart disorders present from birth
5. Pulmonary diseases
6. Infections of the heart muscle (myocarditis) 
7. Damage caused by toxins such as caffeine, alcohol, cocaine and cardiotoxic effects of certain chemotherapy treatments. 
8. Autoimmune diseases
9. Arrhythmias (abnormal heart rhythms) 
10. Genetic heart disorders
11. Natural or temporary causes such as stress, pregnancy or physiological enlargement seen in athletes
12. Unknown causes¹

Gene- based therapies and RNA- based approaches in cardiomyopathies

Antisense Oligonucleotide (ASO) & RNA‑Based Approaches

Antisense oligonucleotides (ASOs) are short, synthetic nucleic acid sequences designed to silence specific alleles. This allele-specific silencing is particularly useful in autosomal-dominant conditions such as hypertrophic cardiomyopathy (HCM), where a pathogenic allele produces a mutant protein while the wild-type allele remains functional. By suppressing the mutant allele, ASO therapy can prevent the symptoms of the disease.² 

In mouse models carrying a MYBPC3 mutation—a common genetic cause of HCM—ASO-mediated exon-skipping improved the function of the heart and stopped the developing hypertrophy. This therapeutic strategy mediates controlled manipulation of RNA splicing to reduce the production of the mutant protein.²

Mutations in the Myh6 gene have also been linked to many cardiac diseases such as HCM and dilated cardiomyopathy (DCM). In an HCM mouse model with this gene mutation, small interfering RNA (siRNA) suppressed the mutant allele.²

Gene Replacement Therapy

HCM (MYBPC3): AAV9-mediated delivery uses adeno-associated virus serotype 9 (AAV9), a non-pathogenic viral vector capable of infecting a wide range of cell types, to introduce therapeutic genes into target tissues. In mouse models of HCM caused by MYBPC3 mutations, AAV9-mediated gene delivery has been shown to prevent hypertrophy and it has also improved function of the heart.²

Induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) are laboratory-generated cardiac muscle cells used to model disease and test therapeutic strategies. Studies have demonstrated that AAV9- mediated delivery of iPSC-derived cardiomyocytes can restore protein expression levels.²

ARVC (PKP2): Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is commonly caused by mutations in the PKP2 gene which affect the myocardium. They increase the risk for developing arrhythmias and sudden death. The importance is to replace the mutated genes with a  “good” copy of the PKP2 gene. Preclinical models have shown improved cardiac function following delivery of a healthy gene copy, leading to the initiation of phase I clinical trials.² 

A similar gene replacement approach is being investigated for Danon disease, a rare genetic disorder caused by mutations in the LAMP2 gene. AAV9- mediated delivery of a functional LAMP2B gene has demonstrated improved cardiac function.²

Gene Editing Tools (CRISPR/Cas9, Base Editing, Prime Editing)

CRISPR/Cas9 is a genome-editing technology that allows scientists to interfere in an organism's DNA. Cas9 is a molecule that acts like a scissor, generating site-specific double-strand breaks that can be repaired through homology-directed repair (HDR) or the more error-prone non-homologous end joining (NHEJ).²

Base editing is a more targeted gene editing strategy used effectively on mutations in genes like LMNA, RBM20, MYH6, and MYH7 in experimental models.²

Prime editing is an advanced gene editing platform capable of introducing precise DNA modifications, including small insertions, deletions, and point mutations. This approach has been used in hiPSC-derived cardiomyocytes and in select in vivo models.²

Novel pharmacological agents

1. Vutrisiran and Acoramidis

Vutrisiran is a siRNA medication used in the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM), a severe form of cardiac amyloidosis. Cardiac amyloidosis or amyloid cardiomyopathy is a condition where the proteins misfold and are deposited in the heart muscle and the surrounding tissues, impairing cardiac structure and function. In ATTR-CM, the protein called Transthyretin (TTR) misfolds and accumulates in the heart muscle. This makes the heart wall thicken leading to diastolic dysfunction, and ultimately heart failure.³ 

Vutrisiran works by silencing production of TTR protein, thereby reducing circulating TTR levels and preventing further amyloid build-up in the heart. This medication has shown extended survival rate in patients, reduced risk of cardiac complications and enhanced quality of life.³

Acoramidis is a molecule that helps stabilise the TTR protein. This means it won’t misfold and deposit in the heart muscle. In a clinical trial evaluating an 800-mg twice-daily dosing regimen in patients with ATTR-CM, acoramidis significantly improved clinical outcomes compared with placebo. Hospitalisation for heart related problems was significantly lower in the group that was administered acoramidis. There were improvements regarding increased walking distance and better quality of life. Participants who transitioned from placebo to acoramidis had stabilised TTR serum levels. Acoramidis is now approved by the FDA for the treatment of ATTR-CM.³

2. Danicamtiv

Danicamtiv, formerly known as MYK- 491 is a new medication that enhances cardiac actomyosin activity. Preclinical and early clinical studies have shown promising results. Danicamtiv makes the heart muscle contract longer and then relax normally, and importantly, it does so without altering intracellular calcium homeostasis. This medication enhances both ventricular and atrial performance.⁴

3. Mavacamten

Mavacamten, marketed as Camzyos, is an oral small-molecule inhibitor of cardiac myosin and represents a major therapeutic advancement in the management of obstructive hypertrophic cardiomyopathy (oHCM). In oHCM, the heart wall is too thick and contracts strongly, so mavacamten helps reduce excessive contraction so the blood flows easily. Phase II and III clinical trials demonstrated significant improvements in overall quality of life. Long term studies further showed that the heart’s structure improved including improvements in diastolic function..⁵

4. Cenderitide

Cenderitide is a natriuretic peptide made by combining two peptides. This medication works wonders without lowering the blood pressure. It increases the excretion of sodium in urine and increases urination. Through these mechanisms, cenderitide supports improved cardiac function. Clinical evaluations to date indicate that it is well tolerated.⁶

Importance of addressing underlying causes of cardiomegaly

Cardiomegaly is a symptom and it can arise from a wide range of underlying conditions—including chronic hypertension, genetic cardiomyopathies, and infections. So this means, we need to pinpoint the cause because by missing it, treatment may not be effective. Early detection enables targeted interventions that can prevent worsening cardiac dysfunction and reduce the risk of severe outcomes. 

It is also very crucial to address the underlying cause of heart enlargement because there are factors that cause it temporarily such as pregnancy or acute infection. In these cases, appropriate management of the condition can lead to a normalised heart size.

Different causes require different management strategies. For example, patients with hypertension or obesity may benefit from lifestyle changes, while individuals with structural heart defects may require surgical correction.

Addressing risk factors, tailoring precise and effective management can improve quality of life and life expectancy. 

Summary

Cardiomegaly, or heart enlargement, is not a disease, but a symptom that is caused by numerous underlying conditions, including high blood pressure, genetic mutations, and infections. While traditional treatments often focus on managing symptoms, emerging therapeutic approaches aim to address the root causes of cardiac enlargement.

Advances in gene editing—such as CRISPR/Cas9, base editing, and prime editing—offer powerful tools to correct gene mutations that contribute to cardiomyopathies.

Novel pharmacological agents, including vutrisiran, danicamtiv, and mavacamten are groundbreaking medications that improve the quality of life for patients with cardiomegaly.

Ultimately, effective management relies on identifying and treating the underlying causes rather than solely controlling symptoms. Today’s innovations are transforming care by improving heart function, slowing disease progression, and enhancing overall patient quality of life.