Transthyretin amyloid cardiomyopathy (ATTR-CM)

Overview

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a serious condition that affects the heart. It happens when a protein made by the liver, called transthyretin (TTR), folds the wrong way and sticks together. This forms deposits called amyloid. When amyloid builds up in the heart, the heart walls get thick and stiff. The condition makes it hard for the heart to fill up with blood and pump it through the body.

ATTR-CM is a disease of the heart muscle, which means it's a form of cardiomyopathy. Symptoms of ATTR-CM may include shortness of breath, tiredness, swelling in the legs, or irregular heartbeats. Because these symptoms occur in many other conditions, ATTR-CM can be hard to recognize. As the amyloid builds up in the heart walls, the condition may lead to heart failure. Amyloid deposits also can affect the nerves and other parts of the body.

Healthcare experts think ATTR-CM may be more common than once thought and is often missed. Letting members of your care team know when you don't feel well may help them find the condition earlier. Treatments have improved in recent years. Newer medicines can slow the disease and help people live longer. However, heart damage that has already happened may not fully go away. Some people with advanced ATTR-CM may need a heart transplant.

Transthyretin amyloidosis is a broad term for when the TTR protein builds up in the body. You may see several different names for this condition. They can be confusing, but they often describe closely related conditions. In general, when transthyretin protein builds up as amyloid in the body, the condition may be called:

• ATTR.
• ATTR amyloidosis.
• TTR amyloidosis.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is the name used when the amyloid buildup affects the heart muscle. Other names for ATTR-CM are:

• ATTR cardiac amyloidosis.
• ATTR cardiomyopathy.
• Transthyretin cardiac amyloidosis.

Some types of ATTR-CM are passed down through families, which means they are inherited. When this happens, the condition is called hereditary ATTR. The form that is not inherited is called wild-type ATTR. Both forms can affect the heart.

Types

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of cardiac amyloidosis.

There are two main types of ATTR-CM:

• Wild-type transthyretin (ATTRwt) cardiac amyloidosis, also called wild-type ATTR. This is the most common type of ATTR amyloidosis. It used to be called senile systemic amyloidosis. The gene related to the TTR protein is not changed. Why the protein folds the wrong way is not clear, but aging may play a role. Wild-type ATTR-CM mostly affects older adults.
• Hereditary transthyretin (ATTRv or hATTR) cardiac amyloidosis, also called hereditary ATTR. This type is caused by a change in the gene that makes the transthyretin protein. This gene change is called a gene variant. It can be passed from a parent to a child. Other names for this type are variant transthyretin amyloidosis and familial transthyretin amyloidosis. It may affect the heart, the nerves, or both.

Symptoms

Symptoms of transthyretin amyloid cardiomyopathy (ATTR-CM) happen as amyloid builds up in the heart and other parts of the body. But the symptoms may look like those of other heart conditions.

ATTR-CM symptoms may include:

• Chest pain.
• Fast, pounding or fluttering heartbeats.
• Fainting or feeling dizzy, especially after standing up.
• Feeling very tired, even after getting rest.
• Feeling weak or not able to do as much physical activity.
• Shortness of breath or trouble breathing with activity or even at rest.
• Swelling in the legs, ankles, feet or belly area.

Hereditary ATTR may affect nerves that control sensation, movement, blood pressure and how the digestive tract works. This nerve damage is called polyneuropathy and may occur with or without heart involvement. When many nerves are affected in hereditary ATTR, the condition is called polyneuropathy of hereditary transthyretin-mediated amyloidosis.

When the nerves are involved, symptoms may include:

• Weakness, numbness, tingling or pain in the feet or hands.
• Nausea, diarrhea or constipation.
• Feeling full quickly after a small meal.

Amyloid also can build up in tissues around nerves and cause pressure on them. This may lead to carpal tunnel syndrome or spinal stenosis, sometimes years before ATTR-CM is diagnosed. These conditions result from nerve compression rather than amyloid directly damaging the nerves.

Nerve damage is more common in ATTR-CM that is passed down through families than in wild-type ATTR-CM. However, the symptoms and organs affected depend on the specific change in the TTR gene.

Tell your healthcare team about all your symptoms. Your care team can do tests to find the cause of your symptoms. Your care team may test for amyloidosis if you have several of these symptoms together.

When to seek care

Make an appointment for a health checkup if you have symptoms of transthyretin amyloid cardiomyopathy (ATTR-CM). Also contact your healthcare professional if:

• You have new symptoms or your symptoms are getting worse.
• You gain 5 pounds (2.3 kilograms) or more within a few days to a week. Fast weight gain may mean that your body is holding fluid. If you have heart failure due to ATTR-CM, fast weight gain may mean your heart failure is getting worse.

When to seek emergency care

Transthyretin amyloid cardiomyopathy (ATTR-CM) can make it hard for the heart to pump blood. Call 911 or your local emergency number if you have:

• Chest pain.
• Sudden, severe shortness of breath.
• A very fast or irregular heartbeat with shortness of breath.
• Fainting or loss of consciousness.

There are many possible causes for these symptoms. A complete checkup from a healthcare professional is needed to learn the cause. Always call 911 or your local emergency number if you think you are having a heart attack.

Causes

The cause of transthyretin amyloid cardiomyopathy (ATTR-CM) is a change in a protein called transthyretin (TTR). The protein becomes less stable and folds the wrong way. The liver makes most of this protein. In ATTR-CM, the protein folds the wrong way and forms deposits called amyloid.

The amyloid deposits build up in the heart, making the heart walls stiff and thick. This makes it harder for the heart to fill with blood and pump it through the body. Amyloid also can build up in the nerves and affect how they work.

The TTR protein is more likely to fold the wrong way when it is less stable. But why the TTR protein becomes less stable can vary.

• In hereditary ATTR, a change in the TTR gene causes the protein to be less stable and fold the wrong way. Many different changes in this gene can cause hereditary ATTR. A person with one of these gene changes can pass it to a child. But not everyone who has a gene change develops ATTR.
• In wild-type ATTR, the TTR gene is not changed. The TTR protein gets less stable with age. The exact cause for this is not known.

Risk factors

Some things may make you more likely to get transthyretin amyloid cardiomyopathy (ATTR-CM). Risk factors include:

• Age. Wild-type ATTR mainly affects people over age 60. Hereditary ATTR can affect people at different ages. It depends on the type of TTR gene change you have.
• Sex. Wild-type ATTR is diagnosed much more often in men, although women also develop the condition.
• Genetics. Hereditary ATTR is passed down through families. That means it's inherited. A parent has a 1 in 2 chance of passing the changed TTR gene to each child. This is called an autosomal dominant inheritance pattern. However, not everyone with the gene change develops ATTR amyloidosis.
• Ancestry. Some TTR gene changes are more common in people whose families come from certain parts of the world. One gene change linked with hereditary ATTR cardiac amyloidosis is more common in people with West African or African Caribbean ancestry. Other TTR gene changes are more common in families from Portugal, Sweden, Japan, Ireland, Italy and Denmark. However, hereditary ATTR can affect people of any ancestry.

Complications

Complications of transthyretin amyloid cardiomyopathy (ATTR-CM) can happen because amyloid buildup changes how the heart beats and pumps blood. The condition can lead to serious medical conditions. Possible complications include:

• Heart failure. In ATTR-CM, the heart gets stiff. So it can't stretch as well as it should to fill with blood. As a result, the heart can't pump enough blood to meet the body's needs. Heart failure can be life-threatening.
• Irregular heartbeats, called arrhythmias. Amyloid buildup and changes in the structure of the heart can affect the heartbeat. The heart may beat too fast or too slow. Or the heartbeat may not follow a steady pattern. Atrial fibrillation (AFib) is one type of irregular heartbeat that can be common in people with ATTR cardiomyopathy. AFib raises the risk of blood clots that lead to stroke.
• Heart block, also called conduction block. Amyloid deposits can damage the heart's electrical pathways that carry signals from the heart's upper chambers to its lower chambers. This can slow or stop the signals that tell the heart to beat. Heart block may cause a slow heartbeat, fainting or dizziness. Some people need a pacemaker to help the heart beat at a safe rate.
• Sudden cardiac arrest. Rarely, a dangerous heartbeat or severe failure in how the heart beats or pumps can cause the heart to suddenly stop pumping blood effectively. Without emergency treatment, sudden cardiac arrest can lead to sudden cardiac death.

Regular health checkups can help your care team watch for these complications. Finding and treating them early can help you feel better and protect your heart.