Transthyretin Amyloid Cardiomyopathy (ATTR-cm) Diagnosis: Genetics, Misdiagnosis, Next Steps, and More
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      / Updated October 17th, 2022

      Transthyretin Amyloid Cardiomyopathy (ATTR-cm) Diagnosis: Genetics, Misdiagnosis, Next Steps, and More

      Diagnosis of ATTR-cm

      • ATTR-cm is a rare and incurable heart disease that is underdiagnosed or misunderstood. The symptoms of ATTR-cm mimic a lot of the same symptoms as other heart diseases.
      • Early diagnosis of ATTR-cm is essential in improving the patient's outcomes and quality of life.
      • To diagnose ATTR-cm, your doctor will look for signs that something is wrong and will order tests that assess how well your heart functions.
      • It is also important to tell your doctor if you have any symptoms that may help assist if a diagnosis. Symptoms can help determine if you need routine tests and imaging techniques.
      Transthyretin amyloid cardiomyopathy (ATTR-cm) is a rare and fatal disease, in fact, it's considered one of the main causes of heart failure. However, it's frequently misdiagnosed, but why is that?

      Misdiagnosis of ATTR-cm

      ATTR-cm is typically underdiagnosed and misdiagnosed due to the following reasons:

      • Lack of awareness about the disease
      • It mimics a lot of the same symptoms of other conditions
      • Rarity of the disease
      • Misconceptions around diagnosis
      • Using insufficient sensitive tests
      • Phenotypic heterogeneity of the disease (different mutations in the same gene that may give rise to very different phenotypes)

      Early Diagnosis for ATTR-cm Why It's Important?

      Read More
      Early diagnosis is pivotal in improved patient outcomes and better quality of life for patients with transthyretin amyloid cardiomyopathy (ATTR-cm), so, researchers have put continuous efforts into discovering better diagnostic techniques and effective treatments. 

      A study published in the Journal of Cardiology and Therapy in 2020, concluded that ATTR-cm is no longer considered an incurable and life-threatening disease thanks to new noninvasive diagnostic tests and raising awareness among clinical practitioners to recognize the symptoms before irreversible damage happens. 

      The authors say, "Clinical cardiologists now have noninvasive tools to screen and diagnose patients with ATTR-CM long before deleterious clinical cardiac disease manifestation." They also add "ATTR-CM can be confidently diagnosed noninvasively by clinical cardiologists."

      What Causes Transthyretin Amyloid Cardiomyopathy (ATTR-CM)?

      Transthyretin amyloid cardiomyopathy (ATTR-cm) is caused as a result of the continuous deposition of the abnormally folded transthyretin protein on the heart muscle. 

      Normally, transthyretin protein transports retinol (vitamin A) and a type of thyroid gland hormone called thyroxine to the liver, but sometimes this protein misfolds and forms clumps that are insoluble and accumulate. These clumps of misfolded proteins are called amyloid fibrils. 

      The prognosis of ATTR-cm patients worsens with the continued amyloid deposition making early diagnosis and management key to improved patient outcomes.

      Transthyretin Amyloid Cardiomyopathy (ATTR-CM) Genetics At A Glance

      There are two types of transthyretin amyloid cardiomyopathy (ATTR-cm) and they differ in the cause or etiology of their disease, these are:

      1. Hereditary Transthyretin Amyloid Cardiomyopathy (hATTR-cm)

      Hereditary ATTR-cm stems from a genetic factor mutation in the gene responsible for producing transthyretin protein where a faulty variant of the gene is inherited from generation to generation.

      Those who have any of the following characteristics are more susceptible to developing hereditary ATTR-cm: 

      • Family history of ATTR-cm or heart failure
      • TTR gene mutation (mutation in the gene responsible for producing transthyretin protein leading to its deposition in the heart as well as other organs)
      • Sex Males are more prone to developing hATTR-cm than females
      • Race African Americans 
      • Older age > 50 years old (although it's possible to have symptoms anywhere between the ages of 20-80 years old)

      Thus, those who have a family history of hATTR-cm are advised to have their genes tested early on to stay ahead of any risks associated with the abnormal gene. Additionally, if they're planning to create a family and have children, they should seek the consultation of a genetic counselor beforehand to be able to prevent this gene from passing on.

      2. Wild-type Transthyretin Amyloid Cardiomyopathy (wATTR-cm)

      Wild-type ATTR-cm stems from an environmental factor the abnormal protein start to randomly misfold and deposit usually associated with old age. 

      Those who have any of the following characteristics are more susceptible to developing wild-type ATTR-cm:

      • Age > 65 years old
      • Sex Males are more prone to developing wATTR-cm than females

      Studies have shown that the wild-type ATTR-cm has a progressively worse prognosis than hereditary ATTR-cm. Presumably, the survival rate for wild-type ATTR-cm is approximately 3.5 years while for hereditary ATTR-cm is between 2-5.5 years. 

      How Is ATTR-cm Diagnosed?

      To diagnose ATTR-cm, your doctor may first order these tests to assess the function of your heart and look for signs that something is wrong, these include the following:

      • Clinical examination and blood tests
      • Ultrasound on the heart
      • Imaging studies cardiac magnetic resonance imaging (MRI)
      • Genetic testing (if it's hereditary transthyretin amyloid cardiomyopathy)
      • Cardiac pyrophosphate scan (PYP) a doctor injects radioactive pyrophosphate into your arm and connects it to a screen, when there's accumulated amyloid the screen lights up
      • Electrocardiogram or ECG a test to check your heart's electrical activity and rhythm
      • Echocardiogram a type of ultrasound scan to check the heart and neighboring blood vessels, their thickness, and how it pumps blood
      • Taking a biopsy from the affected organ (biopsy from the heart muscle) but this is rarely used nowadays because it's invasive (a lot of side effects) and not as conclusive as the other tests

      It's also important to share with your doctor any symptoms that you may be experiencing because this may assist in a diagnosis along with routine tests and imaging techniques, these symptoms may include the following:

      • Shortness of breath
      • Chest pains
      • Irregular heartbeats (arrhythmias especially atrial fibrillation)
      • Edema (swelling in the legs due to fluid retention)
      • Tiredness and extreme fatigue
      • Dizziness
      • Fainting
      • Bloated stomach
      • Coughing and wheezing
      • Confusion
      • Disorientation

      Next Steps for ATTR-cm

      "Number one would be to see your doctor regularly," Dr. Aeshita Dwivedi, a cardiologist at Lenox Hill Hopsital says. "It is important to seek medical care for this condition, because we have good options and can change lives. Second would be talk to your doctor if any of your symptoms change. You would rather know sooner rather than later, before things get worse and when you may need hospitalization."

      After getting a conclusive diagnosis, your doctor will evaluate the following:

      • Type of ATTR-cm that you have
      • Stage of your disease
      • Symptoms you're experiencing
      • Age and overall health
      • Any underlying medical conditions
      • Extent of damage done to the affected organs

      Then they can decide on the best treatment plan suitable for you. Although there is no cure for ATTR-cm yet, there are multiple treatment options available to alleviate the symptoms, improve your quality of life, manage the condition and prevent further organ damage.

      Below is a list of the treatment options available for ATTR-cm patients: 

      • Medications that stop disease progression by preventing further protein build-up
      • Medications to relieve symptoms caused by other comorbidities like heart failure or carpal tunnel syndrome
      • Tafamidis or Vyndamax Drugs that specifically target the TTR gene to stop proteins from misfolding 
      • Inotersen or Tegsedi Drugs to slow the production of amyloid protein by the liver 
      • Organ transplantation surgery (Liver, kidney, or heart transplant) depending on the affected organ 

      The life expectancy for patients with ATTR-cm ranges between 2-6 years from the moment of diagnosis. On the other hand, there are considerable efforts put into discovering promising new treatments through clinical trials that can improve these odds.

      Dr. Dwivedi adds, "ATTR cardiomyopathy is an evolving condition, and until a few years ago, we did not really have anything to treat the disease in and of itself." Dr. Dwivedi explains further, "All we could do was really treat the symptoms of heart failure. More recently, we have been fortunate to have newer drugs that can impact the disease process."

      The Bottom Line

      Transthyretin amyloid cardiomyopathy is an underrecognized and progressive disease that may lead to other irreversible complications like organ damage and heart failure.

      The path to an ATTR-cm diagnosis can be drawn out and frustrating for some. If you think you might have transthyretin amyloid cardiomyopathy (ATTR-cm), keep a detailed log of your symptoms to show your doctor.

      Newer diagnostic techniques are now available which enable clinicians to determine whether a patient in fact has ATTR-cm or not with the help of these tests, early treatment can take place and patients may experience better outcomes.

      Dr. Philip Weintraub, a cardiologist at NYU Langone Health, says "a doctor will likely  go back into your diagnostic work, taking a full history, doing a complete physical examination using the aforementioned objective measures, the electrocardiogram and the echocardiogram." 

      "And frequently, one when there is amyloid infiltration in the heart muscle, it gives off a certain glow. It is called extremely echogenic and when you see that your index of suspicion should go up, unfortunately though, the diagnosis frequently is only made when one has an endomyocardial biopsy. And so therefore that particular glow is not enough to just, to, to make a formal diagnosis of amyloid doses," Dr. Weintraub added. 

      Questions to Ask Your Doctor

      • Which type of transthyretin amyloid cardiomyopathy (ATTR-cm) do I have?
      • What are the symptoms associated with this disease?
      • Should I be monitored for heart failure?
      • What's the difference between invasive and noninvasive diagnostic techniques?
      • How can ATTR-cm be treated?
      • What are the disease complications and how can I avoid them?
      • Will I need organ transplantation at any point during my disease?
      • How can I improve my life expectancy?
      • What are the side effects associated with each treatment?
      • Are there any clinical trials suitable for me?
      • Where can I contact other patients with ATTR-cm that are going through the same thing I'm going through?

      Learn more about SurvivorNet's rigorous medical review process.

      Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

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