What Is Transthyretin Cardiac Amyloidosis (ATTR-CM)?

Transthyretin cardiac amyloidosis (ATTR-CM), also known as transthyretin amyloid cardiomyopathy, is a rare and serious heart condition that occurs when your liver produces misshapen transthyretin proteins that accumulate in the heart muscle. These abnormal protein deposits, called amyloids, cause the walls of heart muscle to stiffen, reducing its ability to pump blood. The initial symptoms are similar to those of heart failure . ATTR-CM is a progressive, incurable, and life-threatening condition that can strike at random or run in families. In the United States, it is most common among Black men. Fortunately, new diagnostic tools and promising treatments are improving outcomes and extending lifespans.e60dc2a1-f33c-4a05-9b50-8e3e8e59762922b39bee-7da0-4c55-bd00-88b2a89e3f54
Types of ATTR-CM Types There are two distinct forms of ATTR-CM. One is caused by a genetic component, and the other is associated with aging. Hereditary ATTR-CM runs in families and is caused by inherited mutations in the transthyretin (TTR) gene. More than 130 genetic variants have been identified, but not all people with a genetic mutation will develop the condition. Hereditary ATTR-CM causes amyloid deposits in the heart, nerves, and sometimes other organs like the kidneys.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e0325e4e-57e8-405b-b114-6aab7ff43ce4e60dc2a1-f33c-4a05-9b50-8e3e8e597629f1cd563c-9738-4354-b5b1-64ea47e1abef Wild-type ATTR-CM occurs without a genetic mutation, meaning it doesn’t run in families, and it typically impacts older men. The average age of diagnosis is 75, and it’s related to TTR protein accumulation. Wild-type ATTR-CM mostly affects the heart, though it can also cause musculoskeletal issues like carpal tunnel syndrome and spinal problems.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bb53cb0d-13af-4cdc-95e3-c334516292dee60dc2a1-f33c-4a05-9b50-8e3e8e5976295bc8ee68-0287-4213-b87f-539e99527867
Signs and Symptoms of ATTR-CM Symptoms Initially, ATTR-CM symptoms mimic those of heart failure, the most common being shortness of breath while resting or with little activity. Additional heart-related symptoms include:e60dc2a1-f33c-4a05-9b50-8e3e8e5976292c5f9f0e-9cec-4589-a247-de29c3ad01e2 Fatigue Swelling in the legs or abdomen Chest congestion Coughing or wheezing, especially when lying down Confusion Heart palpitations and abnormal heart rhythms (arrhythmia) Atrial fibrillation (rapid, irregular heartbeat), which nearly all people with ATTR-CM eventually develope60dc2a1-f33c-4a05-9b50-8e3e8e5976293e60da29-48ba-4d5b-841b-9a0f5e3fcc34 Dizzinesse60dc2a1-f33c-4a05-9b50-8e3e8e5976299c05aebd-f411-4d63-94ae-6b019ad34958 The condition can also cause a variety of symptoms outside the heart, some of which may be more common in one type or another, and some of which appear before any cardiac symptoms. They include:e60dc2a1-f33c-4a05-9b50-8e3e8e597629e35070dc-81a3-4568-91c4-23001d5770f6 Gastrointestinal issues like diarrhea, constipation , nausea, bloating, and feeling full quicklye60dc2a1-f33c-4a05-9b50-8e3e8e59762938017ee6-c66b-415c-ae15-697b272c9060 Carpal tunnel syndrome (wild-type ATTR-CM) Spinal stenosis , causing pain or numbness in the lower backs and legs (hereditary ATTR-CM) Tendon ruptures in the biceps (wild-type ATTR-CM)e60dc2a1-f33c-4a05-9b50-8e3e8e597629408169a5-9f75-410d-9038-c810cc38b3dd Ocular issues like glaucoma , dry eye, and dark floaters (hereditary ATTR-CM) Kidney impairment Peripheral neuropathy , causing tingling or numbness in the hands and feet (hereditary ATTR-CM) Erectile dysfunction e60dc2a1-f33c-4a05-9b50-8e3e8e597629e35070dc-81a3-4568-91c4-23001d5770f6
Causes and Risk Factors of ATTR-CM Causes ATTR-CM is ultimately the result of destabilized transthyretin (TTR) proteins. Produced by the liver, TRR circulates in the bloodstream to transport vitamin A and thyroid hormones throughout the body. Structural changes in the protein can cause it to misfold and lose its normal shape, forming amyloids, which are fibrous deposits in the heart and other organs that disrupt normal function.e60dc2a1-f33c-4a05-9b50-8e3e8e597629658fca5c-9761-46d0-825d-7fd7e5fd2c6e With hereditary ATTR-CM, inherited genetic mutations in the TRR gene cause structural changes in transthyretin protein to develop. In the United States, the condition is usually associated with a few different genetic variants — the most common is V122I, which primarily affects African Americans. The second most common variant in the country (and the most common in the United Kingdom) is T60A, which primarily affects people of Irish descent.e60dc2a1-f33c-4a05-9b50-8e3e8e59762992080169-7d77-448f-ade0-0e2811abc7e0e60dc2a1-f33c-4a05-9b50-8e3e8e59762928022cfc-8a02-490f-88b0-2e54c9bfde67 For wild-type ATTR-CM, age-related protein misfolding is responsible for the condition, rather than genetics. But why this occurs is not completely understood. Risk factors for ATTR-CM include: Older age Male sex Black race (hereditary form)e60dc2a1-f33c-4a05-9b50-8e3e8e59762910779577-25ce-4bce-98f9-c031822a8886
How Is ATTR-CM Diagnosed? Diagnosis Because it mimics other heart conditions and not everyone will experience symptoms, ATTR-CM is often misdiagnosed or only caught after it’s reached an advanced stage.e60dc2a1-f33c-4a05-9b50-8e3e8e59762963e9f75d-12b6-4155-a1bd-ccd8ba826dfe Diagnosis starts with your healthcare provider discussing your symptoms and family history. They will then use various diagnostic tools to determine if you have ATTR-CM:e60dc2a1-f33c-4a05-9b50-8e3e8e5976295cfe4d44-f52a-46c1-8f4f-33aaee565af2 Blood tests, used to detect cardiac biomarkers in your blood that suggest heart disease Echocardiogram, also known as an echo, is an ultrasound to look for amyloid deposits in the heart and increased wall thickness of the left ventriclee60dc2a1-f33c-4a05-9b50-8e3e8e59762926c8a7ad-3d84-41e2-8637-86cdb9bffbcd Magnetic resonance imaging (MRI ), which is useful for creating images of heart changes when EEG results are inconclusive. But echo and MRI cannot differentiate thickening caused by ATTR-CM from other forms of heart disease.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298b99a9c6-ee93-4ed9-aa7a-bda12c27f042 Biopsy , the removal and examination of small heart tissue samples, which remains the gold standard for diagnosing ATTR-CM.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291c0e05a5-45a9-4d22-a188-7eb5a105f61e Nuclear scintigraphy , a noninvasive imaging technique that uses tiny amounts of radioactive substances like technetium pyrophosphate that bind to amyloid in the heart. This is the only imaging technique that can diagnose ATTR-CM without a biopsy.e60dc2a1-f33c-4a05-9b50-8e3e8e59762963e9f75d-12b6-4155-a1bd-ccd8ba826dfe Once diagnosed, genetic testing can differentiate if you have hereditary or wild-type ATTR-CM.
Treatment and Medication Options for ATTR-CM Treatment There is no cure for ATTR-CM, and in the past, treatment focused on supportive care to help improve quality of life and control symptoms. But newer, targeted therapies can help slow or halt the progression of the disease. Targeted Therapies A class of drugs called TTR stabilizers can help slow ATTR-CM progression by binding to the TTR protein to help maintain its stability and shape, reducing new amyloid deposits. There are two TRR stabilizers approved by the U.S. Food and Drug Administration (FDA) for ATTR-CM:e60dc2a1-f33c-4a05-9b50-8e3e8e59762976b617f1-8720-4a8c-8bf2-63a97115d7d2 Tafamidis (Vyndaqel/Vyndamax) Acoramidis (Attruby) Both tafamidis and acoramidis stabilize 96 percent of TTR proteins, and have been proven to significantly reduce the risk of early death of users.e60dc2a1-f33c-4a05-9b50-8e3e8e597629aa2a5f3c-28a0-4c1a-85d2-4befb3f45ed7 A second class of drugs called TTR silencers are similarly effective.e60dc2a1-f33c-4a05-9b50-8e3e8e597629ecd4cd5c-399e-476d-9741-0806818a3272 These drugs slow ATTR-CM by suppressing the production of new TTR proteins. Vutrisiran (Amvuttra) is currently the only TTR silencer to receive FDA approval for ATTR-CM, though other silencers like patisiran and inotersen are approved to treat ATTR-polyneuropathy, which occurs when amyloid accumulates in the peripheral nervous system.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293dce6473-8595-4644-9548-beca43f7eb35 If you are treated with a TTR silencer, you will need to take daily vitamin A supplementation to avoid deficiency.e60dc2a1-f33c-4a05-9b50-8e3e8e5976290f6ab949-2348-4ad5-a781-381019c2f9dc Diflunisal, a type of nonsteroidal anti-inflammatory drug (NSAID), has also shown promising TRR stabilizing properties, but it is not yet FDA approved for ATTR-CM. Some doctors may prescribe this drug off-label for certain patients.e60dc2a1-f33c-4a05-9b50-8e3e8e5976294c267c0e-cd73-4fee-a91e-1be784afb0fd Supportive Therapies Supportive care seeks to help manage ATTR-CM symptoms and complications, such as heart failure and arrhythmias , using medications such as: Diuretics and dietary sodium restrictions to treat heart failuree60dc2a1-f33c-4a05-9b50-8e3e8e5976291ecd6f00-d7b5-4af6-8336-ce7d47fa2464 Anti-arrhythmic medications like amiodarone to regulate abnormal heart ratese60dc2a1-f33c-4a05-9b50-8e3e8e5976291978f5dc-562d-463c-835a-aba4c2c9b80d Anticoagulants for blood clots in the heart Catheter ablation, a minimally invasive procedure to treat atrial fibrillation Liver transplants were once used to treat tATTR-CM, but they’re rarely performed now that TRR-specific therapies are available. Heart transplants are rarely performed given the advanced age of most ATTR-CM patients.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297790a357-a362-4e1d-b8ac-45302b260f3a
Prevention of ATTR-CM Prevention ATTR-CM currently cannot be prevented, given that it’s caused by age- or genetics-related changes. If you have hereditary ATTR-CM, it’s important to encourage your family to pursue genetic testing. Hereditary ATTR-CM is autosomal dominant, meaning that first-degree relatives of someone with the condition have a 50 percent chance of inheriting the gene variant and passing it on to their children. Genetic counseling can help you and your family members understand the testing, results, and risks of having ATTR-CM. If you want to have children, genetic counselors can also discuss options to lower the chances of passing the impacted gene to your child.e60dc2a1-f33c-4a05-9b50-8e3e8e5976299c3cb7da-2e2f-45e4-9563-84e6d80e864de60dc2a1-f33c-4a05-9b50-8e3e8e5976296c43d9e0-7bdf-4d8c-9c5d-d54e79315b9d If genetic testing shows you carry a TTR mutation, regular cardiac monitoring can help you catch and treat ATTR-CM early, before it does significant damage.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293afc1129-016a-4ada-a4f8-75a095e56e80 Researchers are investigating whether treatment with acoramidis in asymptomatic people with a TTR variant can delay or prevent hereditary ATTR-CM.e60dc2a1-f33c-4a05-9b50-8e3e8e5976292fa6f981-c6c9-4fde-9972-b8a36b677109
Lifestyle Changes for ATTR-CM Lifestyle Changes Behaviors that support heart health can also improve the quality of life for those who have ATTR-CM. Reduce or limit dietary sodium, especially if you experience swelling. Maintain a heart-healthy diet that limits fats, sugar, and processed foods. Stay hydrated, but monitor your fluids if you experience leg swelling.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291f33b5c9-7fbf-4acc-88a6-655c5bfda3ef Raise your legs on pillows or an ottoman if they swell. Maintain physical fitness with gentle movements like walking and swimming.
ATTR-CM Prognosis Prognosis and Outlook ATTR-CM is incurable and it can be fatal. The median survival rate for hereditary and wild-type ATTR after diagnosis is 2.5 years and 3.6 years, respectively.e60dc2a1-f33c-4a05-9b50-8e3e8e597629729cfe05-0f3f-4816-af19-a229f1c86f13 That statistic, however, doesn’t take into account the newest treatment advancements: TTR stabilizers and silencers can significantly improve longevity. Research suggests, for instance, that vutrisiran treatment reduces the risk of death within 42 months by 36 percent.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297933c298-edc7-478a-ba04-4440c122305e It’s important to recognize that every case is different, and statistics can’t predict how long you’ll live.
Complications of ATTR-CM Complications When left undiagnosed or untreated, ATTR-CM can result in these serious illnesses: Progressive, worsening heart failure and arrhythmias, which may cause sudden cardiac deathe60dc2a1-f33c-4a05-9b50-8e3e8e5976299883e765-8fcd-4d18-914b-21b4b65bc666 Atrial fibrillation Stroke Neuropathy (nerve damage)e60dc2a1-f33c-4a05-9b50-8e3e8e5976292aa33adb-63be-44fc-80f8-d0c2f7889efd
How Many People Have ATTR-CM? Research and Statistics Roughly 5,000 to 7,000 people are diagnosed with ATTR-CM in the United States each year.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296387ffcc-56a4-458b-8b6d-eec1aa2a469d But experts believe ATTR-CM is significantly underdiagnosed, with possibly only less than 2 percent of cases being identified.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291f00118a-c48f-463e-9c89-7336819708db Roughly 3 to 4 percent of Black Americans carry the V122I mutation, making them more prone to ATTR-CM.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296d661c71-ac2b-43c6-b450-b4894f931bc9
Black Americans and ATTR-CM Black Americans ATTR-CM is more likely to be diagnosed in Black Americans, particularly those of West African descent. The genetic mutation responsible — V122I — is the most common cause of late-onset ATTR-CM in the country.e60dc2a1-f33c-4a05-9b50-8e3e8e59762999022add-74ba-4add-907c-00256acdcf5d Research also suggests that Black Americans with ATTR-CM experience worse outcomes, such as heart failure–related hospitalization and death, than other populations. This is partly because V122I causes a more aggressive form of hereditary ATTR-CM. Additionally, Black patients diagnosed with ATTR-CM are more likely than white patients to experience lower socioeconomic status, a factor linked to delayed diagnosis and reduced access to quality medical care.e60dc2a1-f33c-4a05-9b50-8e3e8e597629cf2243f2-7bf9-4a91-9935-e4a77074d9b6
Related Conditions Related Conditions There are dozens of different types of amyloidosis, and they can be localized to another organ rather than the heart.e60dc2a1-f33c-4a05-9b50-8e3e8e597629c418ede1-b6bc-4464-89d5-119c7e3365cb Light-chain (AL) amyloidosis makes up nearly 80 percent of all new amyloidosis cases. The condition stems from a bone marrow disorder, and about two-thirds of the patients are male.e60dc2a1-f33c-4a05-9b50-8e3e8e597629b942ddbe-5d46-4638-8b61-d48a387d9a45 AA amyloidosis happens as a reaction to another illness, such as inflammation or an untreated infection. It is linked to rheumatologic diseases like rheumatoid arthritis and ulcerative colitis .e60dc2a1-f33c-4a05-9b50-8e3e8e59762931b5d257-c0bb-4280-ab8c-b37a64d788af LECT-2 amyloidosis is associated with kidney failure e60dc2a1-f33c-4a05-9b50-8e3e8e597629a88f36e8-6994-497d-b1ab-b0893901e013
Support for People With ATTR-CM Support Amyloidosis Support Groups This site is a resource center for all things amyloidosis, including regional support groups, a treatment center location finder, a patient registry, and information about clinical trials. It also has a list of amyloidosis-related blogs written by people who’ve been impacted by the disease. Amyloidosis Research Consortium With a mission to raise awareness for scientific research and treatment of amyloid disease, this nonprofit offers resources for those who are newly diagnosed, a one-to-one peer support program for patients and caregivers, and other patient resources.
The Takeaway ATTR-CM is a rare, progressive disease that’s caused by protein deposits in the muscles of the heart. This leads to stiffer heart walls that don’t pump blood as efficiently, and the outcome can be critical or fatal. There are two main types: hereditary ATTR-CM, which is caused by genetic mutations, and wild-type ATTR-CM, which mostly occurs in older men. There is currently no cure, but recent advances in treatment, including medications such as TRR stabilizers and TRR silencers, are improving patient outcomes, slowing disease progression, and extending life expectancy.
Resources We Trust Cleveland Clinic: Transthyretin Amyloidosis (ATTR-CM)Mayo Clinic: Genetic TestingAmyloidosis Foundation: Patient ResourcesAmerican Heart Association: What Is Heart Failure?Mass General Brigham: Genetic Heart Conditions