Cardiomegaly, or heart enlargement, often goes undiagnosed until symptoms emerge, making timely treatment essential. Stem cells have become a prominent area of research in regenerative medicine due to their robust self-renewal capabilities and ease of extraction. 

What is cardiomegaly?  

The term cardiomegaly refers to the enlargement of the heart. It is an umbrella term for various conditions leading to heart enlargement, which usually remains undiagnosed until the symptoms ensue. It has become increasingly prevalent and carries a high mortality. The scientific diagnosis of cardiomegaly is decided when the heart appears larger than 50% of the width of the chest in a computed tomography (CT) scan or X-ray.¹

History and Physical  

Many people with cardiomegaly are asymptomatic, and the diagnosis is based on imaging. A detailed history should help understand the presence or absence of symptoms such as:

• Shortness of breath on exertion or rest, orthopnea, and paroxysmal nocturnal dyspnea
• Peripheral oedema and abdominal distension
• Fatigue and poor exercise tolerance
• Palpitations, lightheadedness, or syncope
• Angina
• Anorexia, nausea, and early satiety
• Family history of cardiomyopathy
• Recent pregnancy or childbirth in a person assigned female at birth (AFAB)
• Comorbid illnesses, such as hypertension and diabetes mellitus

The heart generally functions well at rest but may become less efficient during physical activity, which is why some people with cardiomegaly remain asymptomatic until they exert themselves. The New York Heart Association classifies the severity of heart disease based on symptoms, with class I indicating no symptoms during normal physical activity and class IV indicating symptoms even at rest.

A key clinical sign of cardiomegaly is a displaced point of maximal impulse (PMI), which is typically found lower and farther out on the chest than normal. A strong, sustained PMI can suggest severe thickening of the left side of the heart, known as left ventricular hypertrophy. A visible movement in the chest wall, called a parasternal heave, may indicate enlargement of the right side of the heart.

Other signs of heart failure may appear during a physical exam, including:

• Rapid heart rate due to increased sympathetic activity
• Reduced pulse pressure, reflecting decreased blood output from the heart
• Varying levels of breathing difficulty, depending on disease severity
• Cool, bluish limbs, caused by reduced blood flow to the limbs
• Swelling in the neck veins, abdomen, or legs, due to elevated pressure in the heart and veins
• Fluid accumulation in the lungs, producing crackling sounds during breathing
• Additional heart sounds, such as an S3 gallop (indicating volume overload and systolic dysfunction) or an S4 gallop (related to diastolic dysfunction)

Diagnosis

The diagnosis of cardiomegaly relies mainly on imaging techniques to assess the heart's size and function. The following tests are commonly used:

• Chest X-ray: Often the first step in detecting cardiomegaly. An enlarged heart silhouette on the X-ray, with a heart-to-chest width ratio (cardiothoracic ratio) of more than 50%, suggests an enlarged heart. Specific chamber enlargements can also be seen
• Echocardiogram (transthoracic): This ultrasound provides detailed information about the size and function of the heart chambers and assesses how well the heart valves are working
• Cardiac MRI: An imaging technique that offers highly accurate measurements of heart size and function. It is useful for identifying the cause of heart enlargement, such as inflammation (myocarditis) or lack of blood supply (ischaemia)
• Electrocardiogram (ECG): Records the electrical activity of the heart and may reveal signs of heart muscle thickening, abnormal heart rhythms, or signs of previous heart attacks
• Blood tests: Includes measuring levels of brain natriuretic peptide (pro-BNP) and troponin, can help assess heart function. Tests for kidney and liver function may also be necessary
• Stress test or coronary angiogram: Used to check for coronary artery disease, a common cause of cardiomegaly

Even after these tests, the underlying cause of cardiomegaly may not always be clear. In such cases, further testing may be needed to better understand the cause and guide treatment. This process can be overwhelming, but it’s important to remember that each test brings us closer to understanding the condition and finding the best way to manage it.

Stem Cell Therapy for Cardiomegaly  

Coronary artery disease, the most common cause of cardiomegaly, affects millions of people. In the U.S. alone, it impacts about 18 million adults over the age of 20 and is the leading cause of death.² When a heart attack occurs, significant damage to the heart muscle often remains, and current treatments can’t fully solve this. Over the last decade, stem cell therapy has emerged as a hopeful new way to help restore heart function. Several clinical trials have been conducted which begin to show potential for safe implementation of this treatment. Stem cell therapy offers several benefits including improving how well the heart pumps, increasing the amount of blood pushed out of the heart, and reducing the size of damaged areas. 

Currently, heart transplants are the only treatment that fully addresses heart muscle loss due to damage. Stem cell therapy, however, is being explored as a way to regenerate cardiac cells and repair damaged cardiac tissue. Early research showed that stem cells from other parts of the body could specialise into cardiac cells and help fix damaged heart tissue.³

What are Stem Cells?  

Stem cells are special cells in the body that can differentiate (turn into) different types of cells and help repair tissue. Different types of stem cells have been studied for heart disease:⁴

• Bone marrow stem cells (BMC): These have been the most widely studied for heart repair. They are derived from the bone marrow (which is found in the centre of most bones). There are two types of bone marrow: red and yellow. Red bone marrow contains blood stem cells which can become red blood cells, white blood cells, or platelets. Yellow bone marrow on the other hand is mostly made of fat and contains stem cells that can become cartilage, fat, or bone cells.
• Adipose-derived stem cells (ASC): These come from adipose (fat) tissue and are easy to collect.
• Cardiac stem cells (CSC): In response to injury, such as a heart attack (myocardial infarction), these stem cells activate to produce myocytes (muscle cells), aiding in tissue repair and restoring cardiac function. However, unlike satellite cells in skeletal muscle, CSCs provide only a partial regenerative response and their numbers decrease with age, limiting their use.
• Human umbilical cord stem cells: Previous studies have shown that mesenchymal stem cells taken from umbilical cords after birth, can be used in the treatment of cardiovascular diseases. They tend to be more readily available and less immunogenic.
• Induced pluripotent stem cells (iPSC): Are adult cells reprogrammed to act like embryonic stem cells, making it possible to produce unlimited numbers of patient-specific cardiac cells required for treatment.

How Does Stem Cell Therapy Work? 

Various clinical trials have evaluated the use of different stem cell types for cardiac therapy. Studies indicate that stem cell therapy can enhance heart function and improve blood flow in patients with heart failure or after a heart attack. While further research is needed, this therapy holds promise for treating cardiac diseases, with the potential to regenerate heart muscle and significantly improve patients' quality of life. Some pre-clinical studies involving stem cell-derived cardiac cells have shown encouraging results in promoting heart repair. However, the underlying mechanisms are not yet fully understood, and outcomes can be variable. Benefits may be transient and often lack a clear mechanistic explanation. Several critical challenges must be addressed to optimise stem cell therapy. First, the derived cardiac cells must closely resemble original cardiomyocyte (heart muscle cell) types and integrate seamlessly into damaged heart tissue. Successful integration requires precise timing for cell administration and appropriate delivery methods.

After transplantation, these cells need adequate vascularisation and electrophysiological coupling with the surrounding heart tissue, along with effective strategies to prevent immunological rejection. Additionally, any stem cell therapy must prioritise safety, reproducibility, and affordability to facilitate broad clinical application.⁵

Stem Cell Delivery Methods for Heart Disease  

Scientists are in the process of determining the best way to deliver stem cells to the heart, although this is very case dependent. Several methods have been tested:

1. Intravenous (IV) Infusion: Simple and non-invasive, offers numerous potential benefits, including regenerating damaged tissues and organs, alleviating pain, and improving the quality of life for patients but has shown low efficiency in targeting cardiac tissue.
2. Direct Injection into the Heart Muscle (Intramyocardial Injection): This was a more targeted approach, but research found that only a small number of cells survive after injection due to inflammation and poor blood flow.
3. Catheter-Based Injection (Transendocardial Injection): This technique delivers stem cells directly to the damaged heart area, but is associated with procedural risks, including myocardial injury or arrhythmia.
4. Intracoronary Infusion: This is where stem cells are injected directly into the artery that supplies blood to the heart, but may be less effective in patients with clogged arteries.
5. Adventitial Delivery: This involves injecting stem cells into the outer layer of the artery that supplies blood to the heart, however this approach is still under testing.

Researchers are also exploring when to deliver stem cells after a heart attack. Early delivery may help reduce damage, but if done too soon, the body’s inflammatory response might hinder cell survival. Regardless of the delivery method, keeping stem cells alive long enough to heal the heart remains a challenge. The damaged area has low blood flow and is full of inflammation. To address these issues, scientists are working on ways to "precondition" the stem cells to make them more resistant to stress before injection.

Summary 

Cardiomegaly is a serious condition often undiagnosed until symptoms manifest. With the heart's limited regenerative capacity, the loss of functional cardiomyocytes due to conditions like ischaemic heart disease and cardiomyopathy poses significant challenges. However, stem cell therapy offers a promising approach to cardiac regeneration, showing potential for restoring heart function and improving patient quality of life. While clinical trials have demonstrated encouraging results, further research is essential to understand the mechanisms at play, address existing challenges, and optimise delivery methods for effective treatment. By prioritising safety and patient outcomes, stem cell therapy may become a transformative treatment in managing cardiomegaly and improving heart health.