What Is Transthyretin Amyloid Cardiomyopathy (ATTR-CM)?

There are many different reasons a person can develop heart failure. Sometimes, heart failure is caused by a specific condition. One of these conditions is transthyretin amyloid cardiomyopathy (ATTR-CM).¹

What is ATTR-CM?

ATTR-CM is a serious and progressive disease of the heart. It makes the heart muscle stiff. This can lead to symptoms of heart failure. ATTR-CM is often misdiagnosed for other conditions. However, more awareness and research have allowed doctors to understand the condition much better in recent years. There are new tests to diagnose it and new treatments to manage it.¹

What causes ATTR-CM?

ATTR-CM is caused by a protein in the body that does not work properly. This protein is called transthyretin (TTR). The liver makes most of the TTR protein. Its normal job is to carry vitamin A and a thyroid hormone through the blood.¹

In ATTR-CM, however, this TTR protein becomes unstable. It breaks apart and folds in the wrong way. These misfolded proteins stick together and form clumps called amyloid fibrils. These amyloid fibers build up in different parts of the body, including the heart.¹

This buildup of amyloid is called amyloidosis. When the amyloid builds up in the heart muscle, it is called amyloid cardiomyopathy. Another name for it is cardiac amyloidosis.¹

There are 2 main types of ATTR-CM:¹

• Hereditary (hATTR) – This type is caused by a change, or mutation, in the gene that tells the body how to make TTR. This changed gene is passed down from a parent. This type is more common in certain races, such as Black people, and is more common in men.
• Wild-type (ATTRwt) – This type is not passed down in families. In this type, the TTR protein becomes unstable as a person gets older. It is not caused by a changed gene. Wild-type ATTR-CM usually affects adults over the age of 60 and is more common among men.

How does ATTR-CM relate to heart failure?

For the heart to work right, its chambers must relax to fill with blood. Then they must squeeze to pump the blood out. When amyloid fibers build up in the heart, the heart walls become thick and stiff. This stiffness makes it hard for the heart chambers to relax and fill properly. This problem is called restrictive cardiomyopathy. ^1,2

Even if the heart can still squeeze well, it cannot fill with enough blood. This causes pressure to build up in the heart. The pressure can back up into the lungs. This leads to common heart failure symptoms like shortness of breath and swelling.^1,2

Doctors often call this heart failure with preserved ejection fraction (HFpEF). ATTR-CM is an important and treatable cause of HFpEF.²

What are the signs and symptoms of ATTR-CM?

The symptoms of ATTR-CM often look like symptoms of general heart failure. This is one reason the diagnosis can be missed.¹

Heart-related symptoms may include:¹

• Shortness of breath, especially when lying down or with activity
• Extreme tiredness, or fatigue
• Swelling in the legs, ankles, or feet (edema)
• An irregular heartbeat, such as atrial fibrillation (AFib)
• Feeling dizzy or fainting

ATTR-CM is a disease that affects the whole body, not just the heart. Sometimes, other symptoms appear years before the heart problems. These "red flag" symptoms are important clues for doctors.^1,2

Non-heart symptoms may include:^1,2

• Carpal tunnel syndrome – This causes numbness, tingling, and pain in the hands and wrists. It is very common in people with ATTR-CM and often occurs 5 to 10 years before heart failure.
• Spinal stenosis – This is a narrowing of the canal in the spine. It can cause pain in the lower back and legs, especially when walking.
• Numbness or tingling – This can happen in the feet. It is caused by nerve damage (called peripheral neuropathy).
• Stomach problems – These can include diarrhea, constipation, or feeling full quickly.
• Biceps tendon rupture – This is when the tendon in the upper arm tears, sometimes with little or no injury.

How is ATTR-CM diagnosed?

If a doctor suspects ATTR-CM, they will use several tests. In the past, diagnosing ATTR-CM required a heart biopsy. A biopsy is when a doctor takes a tiny piece of the heart muscle to look at under a microscope.^1-3

Today, doctors can often diagnose ATTR-CM without a biopsy. The process may include:^1-3

• Echocardiogram (Echo) – This is an ultrasound of the heart. It lets the doctor see if the heart walls are thick and stiff.
• Cardiac MRI – This scan takes detailed pictures of the heart. It can show patterns that suggest amyloid buildup.
• Scintigraphy – This is a key test for diagnosis. A small amount of a radioactive tracer is injected into a vein. This tracer sticks to the ATTR amyloid in the heart. A special camera takes pictures. If the heart "lights up" on the scan, it is a very strong sign of ATTR-CM.
• Genetic testing – A simple blood test can check for a mutation in the TTR gene. This test finds out if a person has the hereditary (hATTR) type.

What are the treatment options for ATTR-CM?

Treatment for ATTR-CM has 2 main goals. The first goal is to manage the symptoms of heart failure. The second goal is to slow down or stop the body from making more amyloid.^3-5

Managing heart failure symptoms

This often involves eating a low-sodium diet and taking diuretics, or water pills. These drugs help remove extra fluid and salt from the body. This reduces swelling and makes it easier to breathe. Some other common heart failure drugs, like beta-blockers, may not work well for ATTR-CM. Sometimes they can make people feel worse.^2-5

Treating the cause of ATTR-CM

Newer drugs are available that treat the disease itself. These include: ^1,3-5

• TTR stabilizers – These drugs attach to the TTR protein in the blood. They help keep the protein stable. This stops it from breaking apart and forming amyloid. Examples of TTR stabilizers are tafamidis and acoramidis. Both drugs are approved by the US Food and Drug Administration (FDA) to treat ATTR-CM.
• RNA silencers – These drugs are for people with hereditary ATTR-CM. They work by "silencing" the TTR gene. They tell the liver to make much less TTR protein. This means there is less protein to form amyloid. Examples include patisiran and inotersen.

A hopeful outlook

ATTR-CM is a complex disease. But doctors now have better tools to find and treat it. New treatments can slow down the disease and help manage symptoms. This gives new hope to people living with ATTR-CM.⁵

If you have heart failure, talk to your doctor about all your symptoms. This includes non-heart symptoms like carpal tunnel syndrome or back pain. Working with your doctor is the best way to get a correct diagnosis and find the right treatment plan for you.