What causes attr-cm

Overview

Amyloid transthyretin cardiomyopathy (ATTR-CM) is a serious and progressive condition characterized by the buildup of abnormal protein deposits, known as amyloid fibrils, in the heart muscle. These deposits stiffen the heart walls, making it difficult for the heart to pump blood effectively. This leads to a type of heart failure called restrictive cardiomyopathy. While the heart is the primary organ affected, amyloid deposits can also accumulate in other parts of the body, causing a range of other symptoms.

What is Transthyretin?

Transthyretin (TTR) is a protein primarily produced by the liver. Its normal function is to transport thyroxine (a thyroid hormone) and retinol (vitamin A) in the bloodstream. In individuals with ATTR-CM, the TTR protein misfolds and clumps together, forming amyloid fibrils. These fibrils are insoluble and accumulate in tissues, particularly the heart muscle and nerves.

Types of ATTR-CM

There are two main forms of ATTR-CM:

1. Wild-type ATTR-CM (ATTRwt-CM): This is the more common form and occurs in individuals without a known genetic mutation. It is associated with aging, typically affecting men over the age of 60. The exact trigger for the misfolding of TTR in wild-type cases is not fully understood but is believed to be related to the natural aging process.
2. Hereditary ATTR-CM (ATTRv-CM): This form is caused by a genetic mutation in the TTR gene. These mutations are inherited in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. There are over 100 known TTR gene mutations, and the specific mutation can influence the severity and type of symptoms experienced, including whether cardiomyopathy or neuropathy (nerve damage) is more prominent.

Causes and Pathophysiology

The fundamental cause of ATTR-CM is the misfolding and aggregation of the transthyretin protein. Normally, TTR exists as a tetramer (a structure composed of four protein subunits). In ATTR-CM, this tetramer dissociates, and the individual TTR monomers misfold into a beta-pleated sheet conformation. These misfolded proteins then aggregate into stable amyloid fibrils. These fibrils are deposited extracellularly in various organs, including the myocardium (heart muscle), peripheral nerves, gastrointestinal tract, kidneys, and blood vessels. The deposition in the heart muscle is what leads to the characteristic stiffening and thickening of the heart walls, impaired diastolic function (the heart's ability to relax and fill with blood), and eventually, heart failure.

Risk Factors

While the underlying cause is TTR misfolding, several factors can increase the risk of developing ATTR-CM:

• Age: The risk of wild-type ATTR-CM increases significantly with age.
• Genetics: A family history of ATTR-CM or hereditary amyloidosis increases the risk of hereditary ATTR-CM. Certain genetic mutations are more prevalent in specific ethnic groups (e.g., Val122Ile mutation is more common in individuals of African descent).
• Sex: Wild-type ATTR-CM is more common in men.
• Ethnicity: Certain ethnic backgrounds have a higher prevalence of specific TTR gene mutations.

Symptoms

Symptoms of ATTR-CM can vary widely depending on the extent of amyloid deposition and which organs are affected. Cardiac symptoms often include:

• Shortness of breath
• Fatigue
• Swelling in the legs, ankles, and feet (edema)
• Irregular heartbeat (arrhythmias)
• Dizziness or fainting

Non-cardiac symptoms, particularly in hereditary forms, can include:

• Carpal tunnel syndrome (often occurring years before cardiac symptoms)
• Numbness, tingling, or pain in the hands and feet (peripheral neuropathy)
• Digestive problems (e.g., constipation, diarrhea, early satiety)
• Unexplained weight loss
• Back pain

It's important to note that many of these symptoms can be non-specific and may be attributed to other conditions, which can delay diagnosis.

Diagnosis

Diagnosing ATTR-CM involves a combination of clinical evaluation, imaging tests, and specific laboratory tests. This may include:

• Electrocardiogram (ECG) and Echocardiogram: To assess heart function and structure.
• Cardiac MRI: Can help identify characteristic patterns of amyloid deposition.
• Nuclear Imaging Scans (e.g., PYP scan): These are crucial for diagnosing ATTR-CM, especially when distinguishing it from other types of amyloidosis. A positive result on a PYP scan in the absence of light chain amyloidosis is highly suggestive of ATTR-CM.
• Blood Tests: To rule out other causes of heart failure and to assess for specific biomarkers. Genetic testing is essential to identify TTR gene mutations in hereditary cases.
• Biopsy: In some cases, a biopsy of affected tissue (e.g., heart, nerve, fat) may be performed to confirm the presence of amyloid deposits, although non-invasive methods are increasingly preferred.

The diagnostic journey can be long, as ATTR-CM is often underdiagnosed or misdiagnosed.

Treatment and Management

The goals of treatment for ATTR-CM are to manage symptoms, slow disease progression, and improve quality of life. Treatment strategies depend on the type of ATTR-CM:

• Supportive Care: Medications may be used to manage heart failure symptoms (e.g., diuretics for fluid retention, medications to control heart rate and rhythm).
• TTR Stabilization: Medications like tafamidis can stabilize the TTR protein tetramer, preventing it from misfolding.
• TTR Silencing: Newer therapies, such as RNA-based drugs (e.g., patisiran, inotersen, vutrisiran), target the production of TTR protein by the liver, reducing the amount of TTR available to misfold. These are primarily used for hereditary ATTR with polyneuropathy (ATTRv-PN), but their role in ATTR-CM is evolving.
• Liver Transplantation: In select cases of hereditary ATTR-CM with predominantly neurological symptoms, a liver transplant can remove the primary source of the mutated TTR protein. However, this does not remove existing amyloid deposits and may not be suitable for patients with advanced cardiac involvement.

Research into new treatments is ongoing, offering hope for improved outcomes in the future.

Prognosis

ATTR-CM is a serious condition with a guarded prognosis, especially if diagnosed late. Without treatment, the median survival can be relatively short. However, with early diagnosis and the availability of new therapies that can slow disease progression, the outlook is improving for many patients. The specific prognosis varies greatly depending on the type of ATTR-CM, the extent of organ involvement, the presence of specific TTR mutations, and the individual's response to treatment.