Learn The BasicsTransthyretin amyloid cardiomyopathy (ATTR-CM) is a rare heart disorder characterized by the build-up of amyloid fibrils or misfolded protein fragments in the heart and other organs causing damage.
What causes ATTR-CM?
There are 2 types of ATTR-CM: familial or hereditary ATTR-CM and wild-type ATTR-CM.
Hereditary ATTR-CM is caused by a mutation in the TTR gene, which leads to structural changes in the protein it encodes. The TTR protein normally circulates in a tetrameric form, or an entity of four units. The structural changes caused by the mutation lead to the dissociation of the tetramer and the TTR protein units sticking to each other, forming so-called amyloid fibrils that accumulate in the heart muscle, causing damage.
Wild-type ATTR-CM is not associated with a genetic mutation and is thought to be the result of the TTR tetramer dissociating due to the normal aging process and forming aggregates. In this case, the sequence of the gene is “normal,” hence the term “wild-type,” but the result is the same: aggregated misfolded proteins accumulate in the heart tissue and cause damage.
Risk factors associated with ATTR-CM
There are several risk factors associated with the development of ATTR-CM. These include genetics, age, sex and ethnicity.
Genetics
A family history of ATTR-CM is a risk factor for developing the disease.
Three mutations in the TTR gene are most commonly associated with ATTR-CM. In addition, the Val30Met mutation has been shown to be associated with ATTR-CM.
Age
It is known that increased age is a risk factor for ATTR-CM, with most people usually being diagnosed with the disease after age 60.
This could be because the TTR tetramers are prone to misfolding as part of the normal aging process.
Sex
ATTR-CM is generally diagnosed in men, and the male gender is thought to be a risk factor for the disease.
Women are typically diagnosed at an older age than men. However, research has shown that overall there are no differences in the prognosis or likely course of ATTR-CM between men and women.
The differences in diagnosis rates between men and women may be explained by genetic variations, environmental factors and hormonal changes between the two sexes.
Ethnicity
Ethnicity may also be associated with an increased risk of ATTR-CM, with Blacks being more at risk. Research has shown that the Val122Ile mutation is seen in 4% of African Americans.
Other mutations in the TTR gene that are more common among certain ethnic groups include:
- the Thr80Ala mutation, which most commonly occurs in people of Irish descent
- the Leu131Met mutation, which mainly occurs among Danish people
- the Ile88Leu mutation, which is commonly found in people in Italy.
It is important to note that there is significant geographical variation in the identification of ATTR-CM both worldwide and in the US. Despite the increased risk among Blacks, most clinical data about the disease comes from North America and Europe.
Reviewed by Harshi Dhingra, M.D., on Nov. 7, 2024.