Transthyretin amyloid cardiomyopathy (ATTR-CM)

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 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.

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.

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 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.

Transthyretin amyloid cardiomyopathy (ATTR-CM) can be challenging to diagnose. Its early symptoms can be a lot like those of other more common heart conditions. Talk about all your symptoms with your healthcare professional. Doing so may help with the diagnosis. For example, a history of carpal tunnel syndrome, especially in both hands, spinal stenosis, tendon rupture or nerve symptoms that are not explained can help your care team recognize ATTR-CM.

To diagnose ATTR-CM, a healthcare professional asks about your symptoms, your health history and your family health history. Next, your healthcare professional examines you and listens to your heart.

You also may need tests to check your heart and look for causes of your symptoms.

Electrocardiogram (ECG/EKG)

Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause changes in the electrical signals that make the heart beat.

An ECG shows how the heartbeat signals move through your heart. The test is quick and painless. An ECG can often be done when you first see your healthcare professional. The test can find irregular heartbeats, heart block and other changes that may give clues to ATTR-CM.

To do the test, sticky patches with sensors on them go on your chest and sometimes your arms and legs. Wires connect the sensors to a computer, which prints or shows the results.

There's no single treatment that cures transthyretin amyloid cardiomyopathy (ATTR-CM) or reverses all the damage in the heart. But newer treatments can help slow or stop more amyloid from forming. Treatments also can help prevent further damage.

Your healthcare team works with you to create an ATTR-CM treatment plan that fits your condition and symptoms. The goals of treatment are to:

• Manage symptoms.
• Keep the condition from getting worse.
• Lower the risk of complications.

Treatment includes medicines that target the cause of amyloidosis. It also includes medicines that help the heart work better. The type of medicine you need may change over time.

Your healthcare team may change your treatment based on:

• How much your heart is affected.
• Whether other organs are affected.
• Your overall health.

Medicines for ATTR-CM

There are two main types of medicines used to treat transthyretin amyloid cardiomyopathy (ATTR-CM).

• TTR stabilizers. These medicines help stop the transthyretin (TTR) protein from breaking apart. This slows amyloid from forming. But they do not remove amyloid already in the body. TTR stabilizers used to treat transthyretin amyloid cardiomyopathy include tafamidis (Vyndamax) and acoramidis (Attruby). By slowing the disease, these medicines can help people stay active longer. The medicines may help protect quality of life. They also can lower the risk of death and hospital stays for heart concerns. TTR stabilizers may affect some thyroid hormone blood tests, usually without causing thyroid disease. Side effects vary by medicine. Acoramidis may cause diarrhea and stomach pain. Tafamidis is generally well tolerated.

• TTR silencers. These medicines lower the amount of transthyretin protein made by the liver. Vutrisiran (Amvuttra) is one example. Research shows that vutrisiran helps people with wild-type or hereditary ATTR-CM live longer. It also lowers the chance of hospital stays for heart-related reasons. The medicine also treats nerve damage due to polyneuropathy of hereditary transthyretin-mediated amyloidosis.

  Vutrisiran is given as a shot under the skin. Side effects may include pain in the arms or legs, joint pain, shortness of breath, and low vitamin A. People taking vutrisiran need vitamin A supplements. Follow the advice of your healthcare team.

If a medicine is not a good fit or the condition continues to get worse, your care team may consider other treatment options. A clinical trial also may be an option.

Medicines to treat symptoms and prevent complications

Your healthcare professional also may give you medicines to treat your symptoms and to prevent complications. Medicines can help:

• Control irregular heartbeats.
• Remove extra fluid from the body.
• Prevent blood clots.

Some medicines commonly used for heart failure or high blood pressure may not work well for people with transthyretin amyloid cardiomyopathy (ATTR-CM). They also may cause blood pressure to drop too low. Your healthcare team chooses these medicines carefully.

Heart transplant

If amyloid deposits cause a lot of damage to your heart, you might need a heart transplant. During a heart transplant, a surgeon removes your heart and replaces it with a donor heart. A heart transplant may be a treatment option for some people with advanced ATTR-related heart failure.

Cardiac ablation

If ATTR-CM causes an irregular heartbeat called AFib, some people may need a treatment called atrial fibrillation cardiac ablation. Most often, a doctor places one or more thin, flexible tubes called catheters into a blood vessel and guides them to the heart. The doctor then uses heat or cold energy to create small scars in the heart. The scars block the faulty heart signals that cause AFib.

AFib can come back after ablation, particularly in people with more advanced ATTR-CM. You and your healthcare team can decide whether ablation is right for you.

Heart devices

Some people with transthyretin amyloid cardiomyopathy (ATTR-CM) have a very slow heartbeat or other dangerous heartbeat changes. They may need a heart device to control the heartbeat or help the heart pump more effectively. The device is placed under the skin of the chest during minor surgery. Heart devices may include:

• Pacemaker. If ATTR-CM makes your heart beat too slowly, you may need this device. It helps keep the heart beating regularly.
• Implantable cardioverter-defibrillator (ICD). This device is a treatment for certain dangerous heartbeats. It delivers an electric shock when needed to restore a regular heartbeat. ICDs are not routinely used for everyone with ATTR-CM.
• Cardiac resynchronization device. This is a treatment for some people with moderate to severe heart failure. It helps the heart chambers squeeze in a better and more organized way.

After treatment for ATTR-CM, you need regular health checkups. This may include tests to check your heart and to see how well treatment is working.

Prognosis

Prognosis means what may happen with the condition over time. It also means how well you may do after treatment. It also may be called your outlook.

The prognosis for transthyretin amyloid cardiomyopathy (ATTR-CM) differs for each person. No single life-expectancy estimate applies to everyone treated today. The condition can be life-threatening. But newer treatments can slow the condition and help people live longer.

The prognosis depends on:

• The type of ATTR.
• The stage of ATTR-CM when it is diagnosed.
• How well your heart and kidneys work.
• Your age.
• Overall health and whether you have other medical conditions.

People who have milder symptoms and start treatment before severe heart damage happens tend to have a better prognosis.

For hereditary ATTR amyloidosis, the specific change in the TTR gene may affect when your symptoms start. It also may affect which organs are involved and how your condition changes over time. Your healthcare professional may suggest genetic counseling. A genetic counselor can explain what your gene change may mean for you and your family.

To understand your prognosis, your healthcare team uses results from blood tests and imaging tests, such as echocardiograms and cardiac MRI. No single test can predict exactly what will happen to one person.

Transthyretin amyloid cardiomyopathy (ATTR-CM) can make everyday activities harder because you may feel tired, weak or short of breath. These steps may help you manage symptoms and stay as active as you can.

• Take your medicines as directed.
• Go to your regular health checkups.
• Do not smoke.
• Follow your healthcare team's advice about salt and fluids.
• Talk to your care team before you make major changes to your diet or activities.
• Stay active in ways your healthcare team says are safe.
• Rest when you feel tired.

It also is important to manage emotional stress. Learning that you have ATTR-CM may be hard. Some people find that talking about their concerns with others in similar situations can help. You might connect with friends or family or join a support group.

If you have symptoms of transthyretin amyloid cardiomyopathy (ATTR-CM) or are worried about your risk of the condition, make an appointment with your healthcare professional. You may be sent to a doctor trained in heart disease, called a cardiologist.

Appointments can be brief. Because there's often a lot to talk about, it's a good idea to be prepared for your appointment. Here's some information to help you get ready.

What you can do

When you make your appointment, ask if you need to do anything in advance. For example, you may be told not to eat or drink for a while before some tests.

Other things you can do to prepare:

• Write down any symptoms. Include those that may not seem related to transthyretin amyloid cardiomyopathy (ATTR-CM).
• Write down important personal information. Tell your healthcare team if you have a family history of ATTR amyloidosis. Knowing as much as you can about your family history can help your care team make a diagnosis.
• Make a list of all the medicines, vitamins and supplements that you take. Include the doses.
• If possible, ask someone to go with you to help you remember what your care team says.

Also write down questions to ask your healthcare team. For ATTR-CM, some basic questions include:

• What organs are affected?
• What tests do I need?
• What treatments do I need?
• What types of side effects can I expect from treatment?
• What are the possible complications?
• Do I need to change my diet or activities?
• Should I consider genetic testing or genetic counseling?

Don't hesitate to ask other questions during your appointment.

What to expect from your doctor

Your healthcare team usually asks many questions, such as:

• When did your symptoms start?
• How bad are they?
• Do the symptoms come and go, or do you have them all the time?
• Does anything make your symptoms better or worse?
• How is your appetite?
• Have you recently lost weight without trying?
• Have you had any swelling in your legs, feet or ankles?
• Have you felt short of breath?
• Are you able to work and do your usual daily tasks?
• Has anyone in your family ever been diagnosed with amyloidosis?