The acronym ATTR CM stands for Transthyretin Amyloid Cardiomyopathy, a serious, progressive condition of the heart muscle. This disease involves the buildup of abnormal protein deposits, called amyloid fibrils, within the heart tissue. When these deposits accumulate, they physically stiffen and thicken the heart walls, impeding normal function. ATTR CM is a form of heart failure often misdiagnosed because its symptoms resemble those of more common cardiac conditions.
Defining Transthyretin and Amyloidosis
The condition’s name begins with Transthyretin (TTR), a protein naturally produced by the body, primarily in the liver. TTR is a circulating protein that transports thyroid hormones and Vitamin A throughout the bloodstream. Under normal circumstances, four TTR protein units bind together to form a stable structure known as a tetramer.
The issue arises when this stable tetramer structure becomes unstable and dissociates into individual units, or monomers. These unstable monomers then misfold and aggregate into insoluble fibers called amyloid fibrils. This process of protein misfolding and subsequent tissue deposition is defined as amyloidosis.
In ATTR CM, the TTR protein is the specific precursor that forms these pathogenic amyloid fibrils. These fibrils are deposited in the extracellular spaces of various organs and tissues, including the nerves and gastrointestinal tract. When this accumulation is concentrated in the heart muscle, the resulting condition is termed Transthyretin Amyloid Cardiomyopathy.
How ATTR Deposits Damage the Heart
The pathology of Transthyretin Amyloid Cardiomyopathy centers on the physical infiltration of the heart muscle (myocardium) by the misfolded TTR amyloid fibrils. These fibrils occupy the spaces between the heart muscle cells, increasing the thickness and rigidity of the heart walls. This thickening is often observed in the left ventricle, the heart’s main pumping chamber.
The heart’s ability to function depends on its capacity to contract and relax rhythmically, but amyloid deposits impede this process. The stiff, unyielding amyloid mass restricts the heart’s ability to relax between beats, a condition known as restrictive cardiomyopathy. Because the heart cannot relax effectively, it is unable to fill with the normal volume of blood returning from the body and lungs.
This failure to fill efficiently increases pressure inside the heart chambers, especially the left atrium, leading to a backlog of fluid. The resulting symptoms are typical of heart failure, including shortness of breath (particularly during exertion or when lying flat) and fluid retention, manifesting as swelling in the legs and feet. Over time, the sustained strain and physical disruption from the amyloid deposits lead to a progressive decline in the heart’s pumping function. The electrical conduction system can also be affected by the amyloid infiltration, potentially causing irregular heart rhythms, such as atrial fibrillation.
Understanding the Two Forms of ATTR CM
Transthyretin Amyloid Cardiomyopathy is categorized into two primary forms, distinguished by the underlying cause of the TTR protein misfolding: the Wild-Type form and the Hereditary or Variant form. Understanding this difference is important for diagnosis and assessing familial risk.
The Wild-Type ATTR CM (wtATTR-CM) is considered an age-related disease, as it most commonly affects older individuals, particularly males over 60. In this form, the TTR protein has a normal genetic structure, but the aging process renders the protein less stable, making it prone to misfolding and aggregation. The term “wild-type” refers to the fact that no specific genetic mutation is responsible for the protein’s instability.
Conversely, the Hereditary ATTR CM (hATTR-CM) is caused by a specific genetic mutation in the TTR gene. There are over 120 known mutations that can destabilize the protein, causing it to misfold and form amyloid deposits prematurely. Because it is inherited, symptoms can appear earlier in life, often starting in the 50s or 60s, and it affects both men and women.
The hereditary form is often associated with more widespread amyloid deposition, frequently involving the nervous system in a condition called polyneuropathy, in addition to the heart. Genetic testing is necessary to confirm the diagnosis of hATTR-CM and identify the specific mutation, which has implications for family screening and treatment selection. While wtATTR-CM is more common overall, both forms result in the same physical damage to the heart tissue.
Detection and General Management Strategies
The diagnosis of ATTR CM often begins with clinical suspicion, especially when a patient presents with heart failure symptoms alongside other signs, such as carpal tunnel syndrome or unexplained nerve problems. Standard cardiac imaging, such as an echocardiogram or cardiac magnetic resonance imaging (MRI), can reveal the characteristic thickening of the heart walls that suggests an infiltrative disease. Low electrical voltage on an electrocardiogram (ECG) despite a thickened heart wall is a classic, though not universally present, sign.
A definitive diagnosis can often be established non-invasively through a specialized nuclear scintigraphy scan, which uses a radioactive tracer that binds specifically to TTR amyloid in the heart. If imaging suggests ATTR CM, blood and urine tests are performed to rule out the more aggressive AL amyloidosis, which is caused by a different protein. Genetic testing is then performed to determine whether the disease is the Wild-Type or Hereditary form.
Management of ATTR CM centers on two main goals: supportive care for heart failure symptoms and disease-modifying treatments aimed at slowing or stopping amyloid deposition. Supportive care involves using diuretics and other medications to manage fluid retention and control heart rhythm abnormalities. Disease-modifying treatments work by either stabilizing the TTR protein to prevent its dissociation and misfolding or by reducing the protein’s production. These treatments are designed to halt the accumulation of amyloid fibrils, making early and accurate diagnosis a high priority for improving patient outcomes.