Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

What is Transthyretin Amyloid Cardiomyopathy (ATTR-CM)?

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a type of disease where a misshapen or improperly folded protein, called transthyretin (TTR), builds up in the heart muscle. A similar but slightly different condition, called cardiac amyloidosis, happens when another kind of protein, called immunoglobulin light-chain (AL), forms clumps and gets stuck in the heart. These are just two types of a group of diseases called systemic amyloidosis, where various kinds of misfolded proteins get stuck in different organs and tissues in the body. The heart is usually spared, but not always.

Transthyretin amyloidosis (ATTR) can affect the whole body (systemic). Because the misfolded proteins can end up in different parts of the body apart from the heart, people with this condition might also have signs and symptoms in other body parts. However, there are cases where only the heart is affected. Diagnosing ATTR-CM can be challenging because the signs and symptoms can be minimal at first, and because of this, the disease can be quite advanced when it is finally detected. This can lead to a poor outlook for the patient.

Thankfully, with advancements in diagnostic technology like bone avid radiotracer scintigraphy, which helps doctors to see and measure the levels of these misfolded proteins, the diagnosis and treatment of ATTR-CM have become possible. These improvements have also led to discovering that ATTR-CM is more common in people with heart failure where the heart is still able to pump a normal amount of blood (preserved ejection fraction) than previously thought.

What Causes Transthyretin Amyloid Cardiomyopathy (ATTR-CM)?

Transthyretin, or prealbumin, is a protein that typically circulates in your body. Its main job is to carry vitamin A and thyroxine, which is a hormone produced by the thyroid gland. This protein is mostly made by your liver, with smaller amounts coming from the tissues in the brain and the back of your eyes.

Normally, this protein consists of four linked parts, a structure we refer to as tetrameric. However, sometimes the protein can change shape, a process called misfolding. When this happens, it loses its four-part structure. Misfolded proteins can then bunch together and deposit in different parts of your body. The tissues of your heart and the nerves outside your brain and spinal cord are particularly prone to these protein deposits.

The structure of Transthyretin is dictated by your genes, particularly a specific gene that’s on chromosome 18. When there’s a mutation in this gene, it causes the transthyretin protein to change shape and misfold. This condition is called hereditary transthyretin amyloid, or hATTR. But not all misfolded proteins are from gene mutations – sometimes, normal aging can cause Transthyretin proteins to misfold, even if the genes are healthy. This is known as wild-type transthyretin amyloid, or wATTR.

In both versions of this condition (hATTR and wATTR), misshaped proteins can damage your heart, leading to a condition called transthyretin amyloid cardiomyopathy or ATTR-CM. Recent studies have found that ATTR-CM is more common with wATTR than with hATTR.

Risk Factors and Frequency for Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

The calculation of how widespread ATTR-CM (a type of heart disease) is, is not straightforward because it’s often easily missed, or diagnoses are delayed. This is due to the fact that its symptoms can vary from person to person and until recently, the technology needed to diagnose it accurately was lacking. However, advancements in heart imaging technology have made it easier to diagnose ATTR-CM without the need for a heart biopsy. This has led to an increase in the number of patients being diagnosed, which has in turn increased its prevalence. This is reflected in the fact that there are between 5,000 to 7,000 new cases reported each year in the US. Additionally, studies have shown that roughly 20% of people with heart failure and increased myocardial wall thickening of more than 14mm suffer from ATTR-CM. The increase in survival rates has also contributed to its growing reach.

The majority of ATTR-CM cases are of the type known as wATTR-CM. This is typically seen in elderly patients, particularly males. As people age, the likelihood of developing wATTR-CM increases and it often accompanies other heart conditions often associated with growing old, like aortic stenosis (thickening of the heart’s main exit door), irregular heartbeats, and HFpEF (a type of heart failure). Studies have found that there’s a considerable prevalence of ATTR-CM amongst older males with HFpEF and excessive thickening of the heart’s left chamber. It’s worth noting that women have a lower likelihood of developing wATTR-CM, and this may be due, in part, to the hypothesized protection offered by estrogen and potential underdiagnosis resulting from women’s generally smaller heart sizes not meeting the screening criteria for ATTR-CM. Compared to wATTR-CM, hATTR-CM is more evenly observed in both males and females, although it is still more commonly diagnosed in males. A review of 69 studies involving 4,669 patients with ATTR-CM found that 17% were female and 83% were male. Of these, wATTR-CM had the lowest share of female patients (9%) versus hATTR-CM, which had the highest (29%).

The TTR gene linked with ATTR-CM is located on chromosome 18 and hATTR-CM follows a pattern of inheritance known as ‘autosomal dominant’. However, whether the disease will manifest in someone who carries this gene is more complex and not very well understood. The age at which symptoms of hATTR-CM start to show can vary significantly and will depend on the specific type of mutation a person has. To date, more than 100 different TTR mutations have been identified each with a host of geographical distributions. In the US, the most common mutation is Val122lle, found in roughly 3-4% of African Americans which translates to around 1.5 million carriers. Outside of the US, the most common mutation is Val30Met.

Signs and Symptoms of Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

ATTR-CM is a medical condition that often gives signs of an increasingly worse heart failure. In some cases, people who have it suffer from various issues with their heart rhythm and conduction system. These problems might appear years prior to heart failure. This condition can manifest in a variety of ways. It could show up primarily as heart disease or at first as autonomic or peripheral neuropathy – a type of nerve damage. Some people might experience a mix of heart disease and neuropathy. The age when symptoms start to appear varies as it depends on the type of mutation. In some cases, nerve disease is more common in hATTR compared to wATTR. However, both conduction system disease and arrhythmias (abnormal heartbeats) are more commonly seen in wATTR than in hATTR.

Here are the common symptoms for each associated conditions:

Heart Failure:

Older adults frequently facing heart failure complications and showing any of the following symptoms, irrespective of their ejection fraction status, could have ATTR-CM:

• Fatigue
• Poor tolerance to exercise
• Shortness of breath (classified as NYHA functional class II to IV)
• Peripheral symptoms like high jugular venous pressure, swelling in the lower extremities, hepatic congestion, and ascites due to significant right ventricle involvement

In its advanced stages, a complication known as cardiorenal syndrome is likely to occur. Interestingly, patients suffering from ATTR-CM often find it tough to tolerate beta-blockers and angiotensin convertase enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB).

Cardiac Arrhythmias:

Atrial fibrillation (an irregular and often rapid heart rate) is the most common cardiac arrhythmia seen in ATTR-CM patients. It tends to present in 40-60% of patients at the time of diagnosis and eventually, all patients develop it during the course of the disease. On top of this, patients might experience significant shortness of breath, palpitation, and low blood pressure, even with a slower heart rate. It is also likely that patients often present with heart failure exacerbation and they may also show signs of stroke or systemic embolization due to undiagnosed atrial fibrillation. Additionally, all patients suffering from ATTR-CM are more susceptible to forming intracardiac thrombus regardless of their rhythm status.

Conduction System Disease:

Patients may present different levels of heart block due to the involvement of atrioventricular (AV) nodal and infra AV nodal conduction. If a patient has atrial fibrillation, it usually presents with a slow or controlled ventricular response. Symptoms include lightheadedness, presyncope, and unexplained falls. One out of every three patients with wATTR-CM eventually requires a permanent pacemaker.

Extracardiac Manifestations:

Problems outside of the heart occur due to TTR amyloid deposition which can cause nerve entrapment in close spaces. Some common issues include:

• Bilateral carpal tunnel syndrome (CTS)
• Lumbar spinal stenosis
• Tendinopathies
• Spontaneous tendon ruptures

Autonomic neuropathy may show as orthostatic hypotension, erectile dysfunction, dyshidrosis, or gastrointestinal motility issues. Both autonomic and peripheral neuropathies are more common in hATTR than wATT.

Clinicians should be alert for ATTR-CM, especially when both cardiac and extracardiac indications are present simultaneously.

Testing for Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

The electrocardiogram (ECG) can provide doctors with clues about a condition called ATTR-CM. It can present with low voltage readings and poor R wave progression. In plain English, these indicators resemble an old heart attack (without there being one), thus they can point to ATTR-CM. However, these ECG clues should not be the only basis for diagnosis since many patients with ATTR-CM might not show these patterns.

The use of an ECG machine involves attaching small sensors to your chest to record the electrical activity of your heart. Despite its utility, it can’t definitively identify ATTR-CM from other conditions like hypertensive heart disease and hypertrophic cardiomyopathies, which also make your heart’s muscle thicker than usual.

An echocardiogram, which is like an ultrasound for your heart, can depict changes caused by ATTR infiltrating your heart, making it thicker and affecting how the heart pumps blood. Signs to look out for include a sparkling appearance of the heart muscle, small left ventricle (the chamber that pumps oxygen-rich blood to the body), enlarged atria (the chambers where blood enters the heart), thickened valves, and a different flow pattern of blood.

Strain echocardiography is another form of echocardiogram that can detect early signs of cardiac amyloidosis, the disease process involved in ATTR-CM. It often presents a specific “bulls-eye pattern” or “cherry-on-top” look in the strain imaging. Although beneficial, these echocardiographic parameters alone cannot differentiate between different types of ATTR-CM.

Cardiac Magnetic Resonance Imaging (CMR), a type of heart scan, has proven useful in diagnosing ATTR-CM and tracking the response to treatment. It gives detailed identifiable markers for the disease by picking up abnormal deposits in the heart caused by ATTR. However, like an echocardiogram, it also cannot reliably differentiate between the different types of ATTR-CM.

Nuclear imaging is another diagnostic tool. This technique involves a radiation-tracing substance, like Technetium pyrophosphate (TC-PYP), being injected into the patient’s bloodstream. The tracer binds to ATTR fibrils in the heart showing up in scans, which can help diagnose ATTR-CM. Grades based on the intensity of uptake can diagnose ATTR-CM with high accuracy. However, the test’s ability to tell ATTR apart from a similar condition, AL amyloidosis, can decrease when other unrelated proteins are present.

Finally, genetic testing can help determine whether the diagnosed ATTR-CM is a hereditary type (hATTR-CM) or a wild type (wATTR-CM), as treatment options might differ between the two types.

Treatment Options for Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), which is a heart condition, managing fluid levels in the body can be challenging due to problems with the smaller left ventricle (LV) and problems with nerve function. The use of certain drugs, such as high-absorption diuretics, can help with this. These medications, combined with limiting intake of sodium in your diet, can help keep your body’s fluid levels stable. Certain heart medications, such as beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, may not be suitable for patients due to the possibility of reduced blood pressure. As the disease progresses, the size of the LV may reduce, resulting in less blood being pumped out to the body and a drop in kidney function. In such cases, other treatments may be used to increase blood pressure or decrease swelling.

Patients with ATTR-CM have a narrow range of tolerance for fast or slow heart rates due to the smaller LV, severe diastolic dysfunction, and low stroke volume, which refers to the amount of blood that the heart pumps out with each beat. Maintaining a steady heartbeat is crucial because coordinating the squeezing and relaxing of your heart muscles, often referred to as ‘atrial kick’, is key to filling the ventricles with blood. Therefore, steady heart rhythm is necessary, which can be achieved through medications or procedures that manage irregular heart rhythms, like catheter ablation. The decision to use a specific antiarrhythmic drug depends on its safety profile and the presence of other conditions. However, it’s important to note that these patients are still at risk of forming blood clots within the heart, even when they are already on blood thinners. Therefore, those with an irregular heartbeat, also known as atrial fibrillation, should be on lifelong anticoagulation, regardless of any calculated risks.

Patients with ATTR-CM often develop a disease of the heart’s electrical system, which may require support from a permanent pacemaker. If patients experience symptoms like heart fluttering, lightheadedness or blackout, continuous heart monitoring may be recommended to look for possible rhythm problems. If people are dependent on their pacemaker and experience worsening heart failure or reduced blood pressure, their pacemaker might be adjusted. If the electrical pacing leads to the two lower chambers of the heart not being coordinated, biventricular pacing might be considered as an alternative. In addition, an implantable cardioverter-defibrillator, which is a device that can correct dangerous arrythmias, should only be considered after careful evaluation.

There are currently three main methods being tested to specifically target ATTR-CM. The first involves silencing mutated TTR protein through mRNA, the process where cells replicate protein. The second strategy aims to stabilize TTR to prevent additional tissues from being deposited. Currently, two agents under this category have been approved for clinical use by the US Food and Drug Administration (FDA). Lastly, the removal of deposited amyloid fibrils is still being evaluated in clinical trials.

One of those approved drugs is Tafamidis, which works by binding to and stabilizing TTR, avoiding further tissue deposits and slowing down the progression of ATTR-CM. However, it’s important to start the treatment early to see clinical benefits, and it is not designed to reverse the condition. Tafamidis has been shown to reduce death and cardiovascular hospitalization and slow the decline in functional capacity and quality of life.

A more drastic treatment option could be an organ transplant. A liver transplant can eliminate the mutant TTR from circulation. This has proven to be a successful hATTR treatment in the past, but it cannot be used for wATTR. Since the development of TTR-specific therapies, the need for liver transplants has dramatically reduced. Although in theory, combined liver and heart transplants can be done in selected patients with both wATTR-CM and hATTR-CM, it’s rarely seen in clinical practice as these patients are often of advanced age with poor long-term survival.

What else can Transthyretin Amyloid Cardiomyopathy (ATTR-CM) be?

Light chain amyloid (AL) cardiomyopathy is a type of heart condition. There are also other conditions that can cause similar effects on the heart, which are known as infiltrative cardiomyopathies. These include:

• Cardiac sarcoidosis
• Cardiac hemochromatosis
• Fabry disease
• Mucopolysaccharidoses

Another related heart condition is called hypertrophic cardiomyopathy.

What to expect with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

Research shows that hATTR-CM, a specific type of heart condition, has a lower survival rate compared to wATTR-CM, another variant of the same condition. The typical survival period for the hATTR-CM condition is about 2.5 years. However, patients with hATTR who only have a neurological condition with no heart problems have a better outlook, with an average survival time of 8 to 10 years.

When it comes to wATTR-CM, the middle range of survival time is around 3.5 years, but it can be divided further based on the Mayo Clinic’s wATTR-CM staging system. This system includes stage I, with an average survival time of 66 months, stage II, with 42 months, and stage III, watch has a survival time of just 20 months.

A study from the UK National Amyloidosis Center looked at both hATTR and wATTR cohorts, and took into account the levels of Nt-proBNP, a kind of protein that indicates heart failure (>3000 pg/dl), and estimated glomerular filtration rate, which measures kidney function (<45 ml/min/1.73 m2). They concluded that the average survival time was 29 months for hATTR-CM and 49 months for wATTR. Interestingly, heart scan findings, such as heart muscle size, wall thickness, and level of diastolic dysfunction, were not separate predictors of survival. Technitium pyrophosphate scan, a type of imaging test, can also be used to predict the outlook for ATTR-CM. A heart to chest uptake ratio (a measure comparing how much a certain molecule is absorbed by the heart compared to the chest area) of 1.6 or higher predicted worse outcomes over a 5-year period.

Possible Complications When Diagnosed with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

If ATTR-CM isn’t treated, it can cause the heart to gradually get worse, lead to irregular heartbeats, and interfere with the electrical system in the heart. This can potentially lead to a sudden heart failure or a complete stoppage of the heart. Plus, every time the heart failure intensifies and a hospital stay is needed, a person’s ability to function and their quality of life go down significantly.

On a positive note, tafamidis, a medicine used to treat ATTR-CM, is generally well-tolerated. But it’s important to note that during medical trials, the occurrence of negative side effects was about the same in groups who took tafamidis and those who took a placebo.

• Gradually worsening heart failure
• Irregular heartbeats
• Interfering with the electrical system in the heart
• Potential for sudden heart failure
• Complete stoppage of the heart
• Deteriorating ability to function
• Decreased quality of life
• Adverse effects from medication similar to placebo group

Preventing Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

Transthyretin amyloid cardiomyopathy, also known as ATTR-CM, is a condition caused by the build-up of an abnormally shaped protein called transthyretin. This protein, which normally helps carry thyroid hormone in the bloodstream, can become deformed and accumulate in different parts of the body like nerves, the heart, kidneys, and the gastrointestinal tract. Trouble arises when this differently shaped protein accumulates in the heart and stiffens the muscle, which may lead to heart failure over time.

There are two main forms of ATTR-CM: inherited (hATTR-CM) and nonhereditary (wATTR-CM). The inherited version is caused by a genetic mutation and can affect younger people, typically in their 50s to 60s. The nonhereditary type usually affects older individuals, often in their late 70s to 80s, where the normally shaped transthyretin protein becomes unstable and collects in the heart.

Common symptoms of ATTR-CM generally center on issues with the heart. This can include heart failure, leading to difficulties in exercising, shortness of breath, and swelling in the legs. Recurring bouts of breathlessness may even require frequent hospital visits. There might be instances of abnormal heart rhythms with dizziness, lightheadedness, and even loss of consciousness from a slow heart rate or momentary pauses in heartbeat. Additionally, patients may not respond well (experiencing reduced blood pressure, and dizziness when standing) to traditional heart medications such as beta-blockers and ACE inhibitors.

There are some treatment options available for ATTR-CM. Various new medicines and treatment strategies are continuously being developed and tested. In 2019, the US Food and Drug Administration approved a daily oral medication named tafamidis for use in ATTR-CM. Although it can’t reverse the disease, tafamidis can prevent it from worsening. Therefore, early detection and treatment of ATTR-CM is strongly recommended.