Fatigue, shortness of breath, and leg swelling are symptoms you should always pay attention to, as they may be signs of a heart issue, such as heart failure. These symptoms can also be caused by cardiac amyloidosis, a disease caused by the buildup of clumps of abnormally folded protein in the heart muscle.

While a diagnosis of cardiac amyloidosis may sound worrisome, various effective treatments are available.

"Cardiac amyloidosis has become a treatable condition thanks to rapid advances in our understanding of the disease mechanisms and novel therapies,” says Edward Miller, MD, PhD, vice chief of Cardiovascular Medicine at Yale Medicine. “Here at Yale, we are committed to offering state-of-the-art therapies for patients with cardiac amyloidosis."

Cardiac amyloidosis is caused by the buildup of clumps of abnormally folded protein (known as amyloid fibrils) in the heart muscle. This impairs its ability to function normally. Cardiac amyloidosis can cause heart failure symptoms, such as shortness of breath and leg swelling, and irregular heartbeat (arrhythmia)—and it can lead to reduced life expectancy.

Because the amyloid fibrils that build up in the heart muscle can also accumulate in other organs and tissues in the body, such as the gastrointestinal tract and nerve tissue, people with cardiac amyloidosis may also have symptoms related to other organs.

Proteins are found throughout the body, where they perform a range of critical functions. Proper functioning requires that the proteins retain their specific shape. If the protein “misfolds” or changes from its normal shape, it does not function properly. In amyloidosis, certain proteins misfold, binding together to form amyloid clumps or fibrils.

The body usually breaks down and recycles misfolded proteins, but this doesn’t happen with amyloid fibrils. Instead, they get deposited in organs and tissues, where they accumulate and impair the functioning of those organs and tissues.

When amyloid fibrils accumulate in the heart, they cause a disease known as cardiac amyloidosis. This causes the heart muscle to thicken and become stiff, which diminishes its ability to pump blood effectively and efficiently through the body, leading to cardiac complications.

Several types of proteins can cause amyloidosis; however, two proteins, in particular, are responsible for over 95% of cardiac amyloidosis cases.

Transthyretin amyloidosis (ATTR amyloidosis). In this form of amyloidosis, transthyretin, a protein produced in the liver, misfolds and forms amyloid fibrils that build up in the heart or other sites, such as tissues in the wrist, neck, or the nerves. This means that people with cardiac ATTR amyloidosis may have heart problems, as well as carpal tunnel syndrome, cervical stenosis, and/or neuropathy.

There are two types of ATTR amyloidosis.

• Wild-type ATTR amyloidosis (wtATTR) is the most common type of ATTR amyloidosis. It is not inherited and is associated with aging. It usually occurs in people over the age of 70 and affects more men than women.
• Hereditary ATTR amyloidosis (hATTR), sometimes known as mutant ATTR amyloidosis, is caused by an inherited genetic mutation in the TTR gene that predisposes the transthyretin protein to misfold. This form of cardiac amyloidosis can affect people as young as 30 years old and can affect the nervous system as well.

Amyloid light-chain amyloidosis (AL amyloidosis) is caused by “light chain” proteins produced by plasma cells in the bone marrow. The amyloid fibrils associated with light-chain proteins can build up in organs and tissues throughout the body. However, they tend to deposit in the heart, kidney, liver, tongue, gastrointestinal tract, and peripheral nerves. AL amyloidosis generally occurs in people over age 40; most people diagnosed with the condition are over 65.

Cardiac amyloidosis can cause a range of symptoms including:

• Fatigue
• Shortness of breath during exercise or other physical activities
• Shortness of breath while lying down
• Feeling faint or light-headed
• Swelling in the legs
• Abdominal distension or "swelling"

To diagnose cardiac amyloidosis, doctors evaluate the patient’s medical history, conduct a physical exam, and run diagnostic tests.

Your doctor will ask about symptoms and your family history of heart problems. He or she will also do a physical exam to check for signs and symptoms of cardiac amyloidosis.

Pinning down the diagnosis requires several tests based on your symptoms. If your doctor suspects cardiac issues, an ultrasound of your heart or echocardiogram and an electrocardiogram (ECG) might be required. If these tests suggest cardiac amyloidosis, your doctor will need to determine whether it’s AL or ATTR amyloidosis because treatment for these forms of the disease differs. Initial tests include bloodwork and a urine test. A nuclear scan, cardiac magnetic resonance, or MRI might also be necessary.

Depending on the results of the initial diagnostic tests, the doctor may perform a biopsy, a procedure involving the removal of a small piece of tissue from abdominal fat, the heart, and/or other organs affected by the disease. A pathologist will then examine the biopsied tissue to determine which protein is involved in the disease.

If the hereditary form of ATTR amyloidosis is suspected, genetic testing (via a blood or saliva test) may be required to confirm the diagnosis.

Treatment of cardiac amyloidosis depends on the type: ATTR or AL. It also requires a two-pronged approach. Some therapies aim to treat the underlying condition or protein (ATTR or AL); others are focused on alleviating cardiac symptoms and complications.

Treatments for the underlying condition. Therapies that treat the underlying amyloid disorder aim to reduce the number of amyloid fibrils, resulting in less amyloid buildup in the heart tissue. The treatment for the two most frequent types of cardiac amyloidosis differ because different abnormal proteins cause them.

• Treatment for ATTR Cardiac Amyloidosis. In this case, treatment aims to stabilize the protein once it is produced to prevent misfolding or reduce its production. These treatments include:
  • TTR stabilizers (e.g., Vyndamax® (tafamidis) and Vyndaqel® (tafamidis meglumine). This medication stabilizes the transthyretin protein and keeps it from misfolding, reducing the levels of the amyloid fibrils that build up in the heart.
  • TTR silencers (e.g., Amvuttra® (vutrisiran), Onpattro® (patisiran), Wainua™ (eplontersen)). These medications alter the liver’s production of the transthyretin protein, thereby reducing the amount of transthyretin that can misfold and accumulate in organs.
  • Organ transplantation. For people with hereditary ATTR cardiac amyloidosis, cardiac transplantation may be an option. Some patients may also receive a liver transplant in certain situations.
• Treatment for AL Cardiac Amyloidosis. Treatment for this form of amyloidosis targets the plasma cells. The goal is to reduce or prevent the production of abnormal light-chain proteins.
  
  
  • Chemotherapy/Stem Cell Transplant. Chemotherapy medications work by reducing the number of plasma cells, which in turn reduces the number of light-chain proteins produced. These medications are often combined with steroids and other drugs. Patients may also be candidates for stem cell transplantation.

Treatments for cardiac symptoms and complications.

• Diuretics. Also known as water pills, these medications increase the amount of urine to help remove excess fluid from the body. If someone has substantial swelling in their legs, abdomen, or elsewhere, intravenous diuretics (in a hospital) may be required.
• Blood thinners. People with cardiac amyloidosis are at increased risk for blood clots, particularly if they have abnormal rhythms like atrial fibrillation. They may be treated with blood thinners or anticoagulants, a type of medication that reduces blood clot formation.
• Heart transplantation. Some patients with cardiac amyloidosis may require heart transplantation.

The life expectancy and degree of heart impairment depends on the type of amyloidosis. Because AL cardiac amyloidosis has a more serious impact on the body, early diagnosis and treatment are important and are associated with better outcomes. For those with ATTR cardiac amyloidosis, drugs that reduce the level of the proteins responsible for the condition have recently been developed and have helped people with the disease live longer, healthier lives.

Yale Medicine offers multidisciplinary expert care for cardiac amyloidosis and other heart muscle diseases. Doctors from the Yale Cardiac Amyloidosis Program work alongside other subspecialties, such as advanced heart failure and transplant, electrophysiology, hematology/oncology, and neurology, to provide early diagnosis and treatment. Yale also provides state-of-the-art cardiac imaging, which is critical for diagnosis. Patients are also offered access to important clinical trials, and the Yale Specialty Pharmacy offers expertise in ensuring access to state-of-the art amyloid medications.

“At Yale, our cardiac amyloidosis team involves multidisciplinary practitioners committed to providing access to care for all of our patients,” says Cesia Gallegos Kattan, MD, MHS, a Yale cardiologist. “With our pharmacy team, social services support staff, and specialized medical professionals, we are committed to personalizing the treatment plans for all of our patients with cardiac amyloidosis."