What causes it?

Wild-type ATTR is also referred to as wtATTR. It is not caused by any known genetic mutations, such as in the case of hereditary forms of the disease (hATTR). Deposits of TTR amyloid can be found throughout the body, so it is a systemic amyloidosis disease. The most common place it is found is in the heart.

As with hATTR, wild-type ATTR causes problems due to the breaking apart, misfolding and deposition of amyloid protein fibrils in healthy tissue. “Wild-type” refers to this form of the disease because it is the natural form of this protein, without genetic mutation. These deposits can interfere with the heart’s normal function, by causing stiffness of the heart tissue, making it more difficult for the heart to fill, leading to heart rhythm problems and heart failure. This is a disease that has traditionally been found mostly in men, originally reported in those aged 80 and over. As awareness of the disease increases, wild-type ATTR average age at diagnosis is 75. It is often overlooked as an amyloidosis disease because so many people experience heart problems in their later years.

What are the signs and symptoms?

Wild-type ATTR is also known to cause some cases of carpal tunnel syndrome, which can be the first (early) symptom. Recent data suggests that lumbar spine involvement as well as a rupture of the biceps tendon in the forearm can precede cardiac involvement by many years. Other symptoms include:

• • Fatigue
  • Shortness of breath
  • Dizziness
  • Pain in the back of the leg
  • Irregular heartbeat
  • Swelling in the legs

How is it diagnosed?

ATTR can cause very similar symptoms to other forms of Congestive Heart Failure, but those other forms of Congestive Heart Failure are treated with medications that can be harmful to people with ATTR. Therefore, the correct and full diagnosis of ATTR is necessary and critical.

In the past, it was difficult to get a positive diagnosis of wild-type ATTR. If wtATTR was suspected, a biopsy of the heart tissue was needed to get an accurate diagnosis. However, studies using nuclear scintigraphy with agents used to evaluate bones have shown that they can diagnose wild-type and hereditary TTR cardiac amyloidosis without the need for a biopsy.

These scans need to be coupled with blood tests to evaluate for the substrate for AL amyloid (e.g., light chains) and in the absence of any evidence of light chains and a positive scan, can diagnose ATTR cardiac amyloidosis. However, if there is evidence of light chains on blood testing, then a biopsy is still needed to establish the diagnosis and type of amyloidosis.

If a biopsy of the heart tissue is obtained, then this biopsy tissue is sent to a lab for Congo-red staining. The lab will stain the biopsy and, if it turns an apple green color under a ‘polarizing’ microscope, then amyloidosis is confirmed. The lab will also take the biopsy tissue and run a protein sequence analysis test to see which type of protein is affected. If this test shows that the transthyretin (TTR) protein is involved, then a simple blood sample is sent to a lab and experts do a genetic sequencing test to examine the DNA chains.

If this TTR genetic sequencing test produces no identifiable mutations, then wild-type ATTR is the resulting diagnosis. So, you can see that it takes several steps, and a doctor must continue testing until an accurate diagnosis is achieved.

How is wtATTR managed and treated?

In ATTR amyloidosis there are several different therapeutic approaches, which aim to stabilize the TTR protein.

In ATTR-CM, a protein called transthyretin (TTR) breaks up and may form fibrils called amyloid. Amyloid can build up between cells in your heart preventing your heart from working normally. This can cause heart-related symptoms and problems. TTR stabilizing agents help to prevent the TTR protein from breaking up and forming amyloid in the heart.

Tafamidis Meglumine (Vyndaqel™) approved following priority review by Health Canada in January 2020
is used in adults (18 years of age and above) to treat a heart disease called transthyretin amyloidosis
cardiomyopathy (also known as ATTR-CM). Tafamidis Meglumine helps to reduce death and
hospitalization related to heart symptoms and problems from ATTR-CM.

Tafamidis (Vyndamax™) approved by Health Canada in July 2021 is used in adults (18 years of age and
above) to treat a heart disease called transthyretin amyloidosis cardiomyopathy (also known as ATTR-CM). Tafamidis Meglumine helps to reduce death and hospitalization related to heart problems from ATTR-CM.

Stopping the production of TTR protein: The approach in stopping production of TTR proteins is through ‘gene silencing’. These drugs prevent TTR production by blocking the TTR gene. Several drugs using this approach have been approved for the treatment of hereditary transthyretin amyloidosis.

Removing amyloid deposits: The approach in removing amyloid deposits aims to make amyloid fibrils easier for the body to identify and remove from organs. There are currently no approved drugs aimed at removing amyloid deposits in wild-type ATTR.

Typically, for congestive heart failure problems, diuretics are prescribed to increase urination, which helps to decrease fluid retention in the body. The same is true for ATTR. They help reduce swelling and shortness of breath. As with any other condition, the use of diuretics for an amyloid heart condition must be carefully controlled by your doctor. All diuretic dosing can be helped by limiting the amount of sodium that you consume.

Supportive Care

Supportive care options are aimed at managing symptoms. Due to the progressive nature of ATTR amyloidosis, managing symptoms is an ongoing process. Examples that a physician may recommend include:

• Diuretic medicine to remove extra water from the body
• Thickeners to add to fluids to prevent choking if a person has trouble swallowing
• Compression stockings to relieve swelling in the legs or feet
• Dietary changes, especially for people who have gastrointestinal amyloidosis