Cardiac amyloidosis is a rare disease caused by the accumulation of amyloid proteins in the heart tissues, resulting in the gradual loss of function and eventual heart failure.

One of the most common forms of cardiac amyloidosis is caused by transthyretin, a protein produced in the liver and transported to different parts of the body. Transthyretin is responsible for transporting thyroid hormones and vitamin A, but its abnormal folding can cause amyloid deposits that damage the heart tissues.

What is Transthyretin?

Transthyretin, also known as prealbumin, is a protein that binds and transports thyroid hormones and retinol (vitamin A) in the blood.

It is produced mainly in the liver and choroid plexus of the brain, and its primary function is to deliver these important molecules to different tissues in the body. Transthyretin is also present in cerebrospinal fluid, where it helps maintain the homeostasis of certain molecules.

Transthyretin is a tetrameric protein composed of four identical subunits, each with a molecular weight of approximately 14 kDa.

The protein has a structure known as a beta-sandwich, where two beta-sheets form a sandwich-like structure that encases the hormone-binding site. This structural arrangement provides stability and protection to the protein, preventing it from aggregating or folding into amyloid fibrils.

What is Cardiac Amyloidosis?

Cardiac Amyloidosis is a rare disease caused by the abnormal accumulation of amyloid proteins in the heart tissues, leading to the gradual loss of function and eventual heart failure.

Amyloidosis refers to a group of disorders characterized by the deposition of insoluble fibrillar protein aggregates that disrupt normal tissue structure and function. There are several types of amyloidosis, each caused by a different protein, including transthyretin, immunoglobulin light chains, apolipoprotein A-I, and others.

The symptoms of cardiac amyloidosis can be subtle and non-specific, making diagnosis challenging. The initial symptoms can include shortness of breath, fatigue, and edema, which can mimic other cardiac and pulmonary conditions.

As the disease progresses, patients may develop arrhythmias, orthostatic hypotension, gastrointestinal symptoms, and renal dysfunction.

Causes of Cardiac Amyloidosis

The precise mechanisms that lead to the accumulation of amyloid proteins in the heart tissues are not fully understood. However, several factors have been implicated in the development of cardiac amyloidosis.

Transthyretin-Related Cardiac Amyloidosis

Transthyretin-related cardiac amyloidosis (ATTR) is the most common form of cardiac amyloidosis, accounting for approximately 40 to 50% of all cases.

ATTR is caused by mutations in the transthyretin gene that lead to the formation of abnormal transthyretin proteins that can self-assemble into amyloid fibrils. The mutations can be hereditary, in which case the disease is referred to as familial amyloid cardiomyopathy (FAC), or acquired, when the wild-type transthyretin protein undergoes conformational changes that promote amyloid deposition.

Immunoglobulin Light Chain-Related Cardiac Amyloidosis

Amyloidosis caused by immunoglobulin light chains (AL amyloidosis) is the second most common type of cardiac amyloidosis, accounting for approximately 15 to 20% of cases.

AL amyloidosis is a hematological disorder that results from the clonal expansion of plasma cells that produce abnormal monoclonal immunoglobulin light chains. These light chains can aggregate to form amyloid fibrils that deposit in various tissues, including the heart. AL amyloidosis can occur as part of a systemic disease or as a localized form limited to the heart.

Apolipoprotein A-I-Related Cardiac Amyloidosis

Apolipoprotein A-I-related cardiac amyloidosis is a rare type of cardiac amyloidosis caused by the deposition of amyloid fibrils composed of apolipoprotein A-I peptides.

Apolipoprotein A-I is the major protein component of high-density lipoprotein (HDL) particles, which are responsible for transporting cholesterol from the tissues to the liver. However, mutations in the apolipoprotein A-I gene can cause the protein to adopt a misfolded configuration that promotes amyloid aggregation and deposition in the heart and other organs.

Symptoms of Cardiac Amyloidosis

The symptoms of cardiac amyloidosis can vary depending on the type and extent of amyloid deposition in the heart tissues. Some patients may have no symptoms or mild symptoms for several years, while others may rapidly progress to heart failure.

The most common symptoms of cardiac amyloidosis include:.

Shortness of breath, especially during physical exertion or lying down
Fatigue and weakness
Persistent cough
Edema (swelling) of the legs, ankles, or feet
Arrhythmias (irregular heartbeats)
Chest pain or discomfort
Orthostatic hypotension (low blood pressure when standing up)
Gastrointestinal symptoms, such as nausea, diarrhea, or constipation
Renal dysfunction (kidney damage)

Diagnosis of Cardiac Amyloidosis

Diagnosing cardiac amyloidosis can be challenging because the symptoms can be non-specific and overlap with many other cardiac and pulmonary conditions.

However, there are several tests that can help diagnose and differentiate cardiac amyloidosis from other diseases.

Electrocardiogram (ECG)

An electrocardiogram (ECG) is a non-invasive test that records the electrical activity of the heart and can detect abnormalities in heart rhythm or conduction.

In cardiac amyloidosis, the ECG may show low voltage, intraventricular conduction delay, or arrhythmias such as atrial fibrillation or complete heart block.

Echocardiogram

An echocardiogram is a non-invasive test that uses ultrasound waves to create images of the heart and its structures.

In cardiac amyloidosis, the echocardiogram may show thickening and stiffening of the heart muscle, reduced ventricular function, and increased respiratory variation in mitral and tricuspid inflow velocities.

Cardiac MRI

Cardiac MRI is a non-invasive imaging technique that uses magnetic fields and radio waves to create detailed images of the heart and its structures.

In cardiac amyloidosis, cardiac MRI can identify patterns of myocardial involvement and differentiate between different types of amyloidosis based on their characteristic imaging appearances. Cardiac MRI can also assess the extent of myocardial damage and predict prognosis.

Endomyocardial Biopsy

An endomyocardial biopsy is an invasive procedure in which a small tissue sample is obtained from the heart muscle and examined under a microscope for the presence of amyloid fibrils.

Biopsy is considered the gold standard for diagnosing cardiac amyloidosis, but it is not always necessary or feasible, especially in patients with advanced disease.

Treatment Options for Cardiac Amyloidosis

Cardiac amyloidosis is a progressive disease for which there is no cure. However, several treatments are available that can slow down the progression of the disease, alleviate symptoms, and improve quality of life.

Transthyretin Stabilizers

Transthyretin stabilizers are drugs that bind to transthyretin and prevent its misfolding and aggregation into amyloid fibrils.

These drugs can slow down the progression of cardiac amyloidosis caused by transthyretin mutations (ATTR), but they are not effective for the wild type form of the protein (wtATTR). The two transthyretin stabilizers currently approved by the FDA are tafamidis and diflunisal.

Immunomodulatory Drugs

Immunomodulatory drugs such as lenalidomide and pomalidomide can be used to treat cardiac amyloidosis caused by immunoglobulin light chains (AL amyloidosis).

These drugs target the clonal plasma cells that produce the abnormal immunoglobulin light chains and reduce their production, leading to a decrease in amyloid deposition and improved cardiac function.

Heart Transplantation

Heart transplantation is a viable option for patients with end-stage cardiac amyloidosis who have no other therapeutic options. However, transplantation is not without risks, and the availability of donor organs is limited.

Conclusion

Cardiac amyloidosis caused by transthyretin is a deadly condition that results from the accumulation of amyloid proteins in the heart tissues. The disease can be difficult to diagnose and treat due to its non-specific symptoms and progressive nature.

Transthyretin stabilizers, immunomodulatory drugs, and heart transplantation are among the treatment options available for cardiac amyloidosis, but more research is needed to develop better therapies and improve patient outcomes.