Cardiac Amyloidosis (Amyloid Cardiomyopathy): Symptoms, Types, Diagnosis, And Treatment

Amyloidosis is a group of diseases characterized by a buildup of abnormal protein structures called amyloids in different parts of the body. It can affect different organs and it usually affects multiple organs at once. If amyloids infiltrate the heart, they can cause cardiomyopathy (heart muscle disease), which can lead to dangerous complications like heart failure, stroke or sudden cardiac death.

What is amyloidosis?

If you were to look at what happens in our bodies on a molecular level, you’d notice that there is one key element in the majority of the processes — proteins. Proteins have various roles as enzymes, structural elements, or signaling molecules. These are usually big molecules that need to be folded into a certain shape to perform their biological function. That shape is called the native structure.

While that’s the only 3D structure that allows the protein to be fully functional, proteins can also have other, more stable, structures. Sometimes certain proteins get misfolded into stable but inactive structures that can bind together and form an aggregate.

How do amyloid fibers affect the heart?

The deposition of amyloids can happen in virtually any organ, most commonly the kidneys, the liver, the lungs, and the heart. Skin, eyes, and parts of the nervous system can also be affected. While there are cases in which the heart is the only organ involved, amyloidosis is usually a systemic disorder that affects multiple organs.

When amyloids infiltrate the heart, they can cause restrictive cardiomyopathy (RCM), or “stiff heart syndrome”. In RCM, the walls of the heart muscle become too rigid, making it harder for the heart to relax and contract the way it’s supposed to. The heart muscle is filled with blood once it’s in its relaxed, expanded state. Since rigid walls don’t allow for full expansion, the heart is restricted from filling with blood. This can often lead to heart failure, a condition in which the heart is unable to meet the demands of the body.

Cardiac amyloidosis is often called a negative prognostic factor. This means that amyloidosis patients whose heart is affected are far less likely to recover and survive than those with amyloid buildup in other organs. That is illustrated by the fact that more than half of amyloidosis death cases are related to the heart, even though the heart is involved in one-third of cases. The heart relies on electrical signaling and conductivity, so the infiltration of any substances that can interrupt this process can be very dangerous.

What are the main types of cardiac amyloidosis?

While many proteins can lead to amyloidosis, two proteins are responsible for the majority of cardiac amyloidosis: light chains of immunoglobulins (Ig) and transthyretin.

Light chain (AL) amyloidosis

Light chain amyloidosis or AL (A-amyloidosis, L-light chain) is the most common type of amyloid disease in developed countries, accounting for more than 70 percent of cases. The name refers to the protein that is being misfolded, the light chains of proteins called immunoglobulins (Ig).

Immunoglobulins or antibodies are special proteins that can recognize pathogens like bacteria or viruses that enter our body, which then facilitates an immune response mediated by the immune cells. They are large, Y-shaped proteins made by plasma cells. Plasma cells produce two types of protein chains — heavy and light chains, which are then assembled to form Ig. However, in certain cases these cells start producing an excess of light chains, which can result in misfolding and aggregation. These aggregates then travel through the bloodstream and can be deposited in any organ. In addition to infiltration in tissue which physically disrupts the organ function, they also have a direct toxic effect on the cells, causing oxidative damage.

The most commonly affected organs are the kidneys and the liver, while the heart is involved in around 50 to 60 percent of the cases. In more than 95 percent of patients, the heart is just one of the organs involved. AL affects men more than women and is most common in patients around the age of 60.

Transthyretin (ATTR) amyloidosis

Transthyretin (prealbumin) is a transport protein secreted by the liver. ATTR is a hereditary condition in which the gene for this protein is mutated. The mutations make it prone to misfolding and the formation of amyloids which are typically deposited in the heart and nerves.

Senile systemic (SSA) amyloidosis

In this type of amyloidosis, the protein that forms the amyloids is also prealbumin. However, it’s not mutated but rather builds up over decades to form the amyloid. It primarily affects the heart muscle and the aorta in older people, typically men around 80 years of age.

What are the symptoms of cardiac amyloidosis?

Diagnosing cardiac amyloidosis at an early stage can be very difficult. This is because the aggregates infiltrate the heart's walls gradually, so the heart problems often manifest when the disease has already progressed.

In the early stages of the disease patients might experience non-specific symptoms such as:

• Fatigue
• Weakness
• Light-headedness
• Weight loss
• Shortness of breath ( at first with exertion and later at rest as well)

Upon examination, your doctor might find one of the following symptoms:

• Hypotension (abnormally low blood pressure-lower than 90/60)
• Heart murmur
• Arrhythmias (irregular heartbeat)
• Swelling of the legs and feet
• Ascites (abnormal buildup of fluids in the abdomen)
• Symptoms indicative of dysfunction of other organs (usually the kidneys)

As the disease progresses it can lead to heart failure and sudden cardiac death due to arrhythmias or dissociation of the heart tissue.

Diagnosis

In many cases, definitive diagnosis requires a heart biopsy. A small piece of heart tissue is taken and examined under a microscope to determine the presence of amyloids. However, the biopsy is only performed when other exams and test indicate its necessity. 

• Blood tests. Certain molecules like troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) are used as markers since they are present in the blood in significant amounts only when the heart cells have been damaged in some way.
• Urine tests. These are especially significant for types like AL because light chains can be identified in the urine.
• Electrocardiogram (ECG or EKG, the test that records the electrical signaling of the heart).
• Echocardiogram (echo, heart ultrasound).
• Cardiac MRI (an imaging technique that uses magnets and radio waves to form detailed images of the heart).
• A technetium pyrophosphate scan (a scan that uses radioactive isotope and a camera for imaging and can differentiate between different types of cardiac amyloidosis).

What is the treatment for cardiac amyloidosis?

The cause of death in cardiac amyloidosis is either congestive heart failure or life-threatening arrhythmias (irregular heartbeat). ​However, medications that are typically used to treat the symptoms of heart failure are ineffective and might lead to worsened symptoms. Because of that, patients need to minimize the strain on their heart by monitoring their weight as well as the amount of fluid and salt they consume during the day. In patients who have problems with arrhythmias, a pacemaker is often needed. 

Treatment meant to slow down the progression of the disease depends on the type of amyloidosis a person has. 

Treatment for AL includes:

• Chemotherapy (against the clonal plasma cells which are producing the excess of light chains).
• Auto-stem-cell transplant (the healthy blood cells are used to replace the clonal plasma cells in the bone marrow) 
• Immunotherapy (use of antibodies that target the amyloid fibers).

Treatment for TTR includes:

• Silencing of the TTR gene using RNA interference approach.
  In 2018 the FDA approved the RNA interference technique after 20 years of the clinical trial, causing a wave of excitement among the scientific and medical community. This is a revolutionary approach in which the medicine called patisiran targets the genes, preventing the TTR from forming.
• Diflunisal (a medication used to stabilize prealbumi, so it doesn't form the amyloids)
• Tafamidis (an agent that is approved in some parts of Europe and Japan, but still a part of clinical trials in the US)
• Immunotherapy (use of antibodies that target the amyloid fibers)