What is Cardiac Amyloidosis?
Amyloidosis is a disease that happens when insoluble proteins start to build up outside of our cells, in a process called extracellular deposition. The most common form of Amyloidosis is called amyloid light chain (AL) amyloidosis, which affects more than ten out of every million people each year. The proteins involved in AL amyloidosis are called monoclonal light chains. Another form of this disease is called amyloid transthyretin (ATTR) amyloidosis, and it happens when a regular or altered form of proteins known as transthyretin proteins start to deposit.
Both types of amyloidosis can affect the heart, leading to a condition called cardiac amyloidosis. This is the most common type of a heart condition known as restrictive cardiomyopathy. Other types of restrictive cardiomyopathy include cardiac sarcoidosis and cardiac hemochromatosis. These conditions make the heart muscle stiff, decreasing the heart’s ability to fill with blood and pump it through the body. When these diseases occur, the heart is unable to expand (non-dilated), leading to problems particularly when the heart is trying to fill with blood (depressed diastolic function).
Regardless of what causes it, cardiac amyloidosis is the most frequent cause of death in patients with systemic amyloidosis, a disease that affects the whole body.
Relative to systemic amyloidosis, cardiac amyloidosis can either show itself through its symptoms or be discovered by chance when a patient shows signs of systemic amyloidosis. Due to its elusive nature, diagnosis of cardiac amyloidosis is often delayed, which, unfortunately, also postpones the start of treatment. It is crucial to detect cardiac involvement in systemic amyloidosis as it heavily influences the prognosis and is the key element that determines the survival rate of this disease.
What Causes Cardiac Amyloidosis?
Cardiac Amyloidosis happens when a harmful component called amyloid builds up outside the cells in your heart. Amyloid is a mix of unusual proteins, as well as other substances such as proteoglycans, glycosaminoglycans, collagen, and laminin that help structure cells. These unusual proteins come from two sources: amyloid light (AL) chain proteins and amyloid transthyretin (ATTR).
When seen under a microscope, these amyloid fibers are straight structures that are 7-10 nm wide. When these fibers accumulate outside of the cells, it makes the heart muscle stiff and weaker. This buildup mostly affects the heart’s ability to relax and fill with blood in between heartbeats, until the later stages of the disease, where it also impacts the heart’s ability to pump blood effectively.
There are several different types of Cardiac Amyloidosis, each with a different cause:
1. Primary Amyloidosis (also known as Amyloid Light Chain Amyloidosis, or AL Amyloidosis) happens when AL fibers deposit in the heart. These fibers are made by abnormal cells similar to white blood cells, in patients suffering from conditions like multiple myeloma (a type of cancer that forms in a type of white blood cell).
2. Secondary Amyloidosis (also known as AA Amyloidosis) is caused by the accumulation of Serum Amyloid A, an inflammation protein that is produced in conditions with chronic inflammation.
3. Senile Systemic Amyloidosis (also known as Wild Type Transthyretin Amyloidosis, or ATTRw) is caused by an age-related buildup of Amyloid made from normal TTR (a protein that carries thyroid hormone and vitamin A). This is the most common type of Cardiac Amyloidosis.
4. Familial Amyloidosis (also known as Mutant Type Transthyretin Amyloidosis, or ATTRm) is caused by TTR that has changed (or mutated).
Isolated Atrial Amyloidosis is caused by the buildup of Amyloid made from the Atrial Natriuretic Peptide (a hormone that helps to lower blood pressure).
Risk Factors and Frequency for Cardiac Amyloidosis
Cardiac amyloidosis is a rare disease that affects the heart. This disease takes different forms depending on its cause. For instance, around 10% of people with multiple myeloma may also have a variant of this disease known as AL amyloidosis, with a majority of these patients also experiencing cardiac involvement. On an annual basis, the incidence of AL amyloidosis is about one case per 100,000 people.
Familial, or hereditary, amyloidosis is caused by over 100 different TTR genes. However, the exact number of people affected by this version of the disease is not known. In one study that involved 14,333 African American individuals, the occurrence of one specific TTR gene variant (V122I) associated with the disease was found to be 0.0173.
The most common form of cardiac amyloidosis is senile amyloidosis, particularly in patients over 60 years old. It is frequently diagnosed as heart failure with preserved ejection fraction (HFpEF). It’s estimated that at least 10% of patients with aortic stenosis might have a type of the disease called ATTRw amyloidosis. Additionally, between 10 and 15% of patients aged over 65 years old with HFpEF may also have cardiac amyloidosis.
Thanks to better diagnostic techniques and longer survival rates, more cases of cardiac amyloidosis are now identified than in the past. Over a span of 12 years, the estimated rate of occurrence for the disease has gone up, from 8 to 17 cases per 100,000 person-years.
Signs and Symptoms of Cardiac Amyloidosis
Amyloidosis is a medical condition that can show up in different ways for different patients. Sometimes, it causes heart-related symptoms and is identified when a patient is getting a heart checkup. At other times, it’s noticed while doctors are investigating other body disorders.
The symptoms related to the heart include difficulty breathing during activity, chest discomfort, a fluttery feeling in the chest, feeling faint, and occasionally fainting. It may also cause more pronounced symptoms of heart failure such as breathlessness even when resting, trouble breathing when lying down, sudden breathlessness during sleep, swelling in the lower legs, and a bloated belly due to fluid buildup.
Amyloidosis affects other systems in the body as well. Symptoms can include indigestion, feeling nauseous, constipation, feeling full quickly, a swollen tongue, dark circles under the eyes, or signs of nerve damage such as carpal tunnel syndrome or problems with sexual function.
During a physical exam, doctors may find clues to the condition like dark circles under the eyes, swelling in the feet, high pressure in the neck veins, fluid buildup in the abdomen, abnormal lung sounds, an enlarged tongue, nerve damage, low blood pressure when standing, enlarged liver, and bleeding in the digestive system. Specifically, the appearance of dark circles under the eyes and an enlarged tongue can clearly suggest cardiac amyloidosis.
The list of possible symptoms includes:
- Difficulty breathing during physical activity
- Chest discomfort
- Fluttery feeling in the chest
- Feeling faint
- Fainting
- Shortness of breath while at rest
- Difficulty breathing when lying down
- Sudden breathlessness during sleep
- Swollen lower legs
- Abdominal bloating due to fluid buildup
- Indigestion
- Nausea
- Constipation
- Feeling full quickly
- A swollen tongue
- Dark circles under the eyes
- Signs of nerve damage like carpal tunnel syndrome
- Issues with sexual function
- Dark circles under the eyes (exam finding)
- Swelling in the feet (exam finding)
- High pressure in the neck veins (exam finding)
- Fluid buildup in the abdomen (exam finding)
- Abnormal lung sounds (exam finding)
- Enlarged tongue (exam finding)
- Nerve damage (exam finding)
- Low blood pressure when standing up (exam finding)
- Enlarged liver (exam finding)
- Bleeding in the digestive system (exam finding)
Testing for Cardiac Amyloidosis
Cardiac amyloidosis is a type of heart disease that can often go unnoticed due to its wide range of symptoms and effects on the body. Therefore, a number of tests need to be done to make proper diagnosis. Here’s what each of these look like:
The first is a 12-lead EKG (or electrocardiogram), which checks your heart’s electrical activity. With cardiac amyloidosis, the EKG might show certain patterns that make it look like there was a heart attack, or sometimes there can be blockages in the signals from the top to the bottom part of the heart. The EKG results might vary based on the specific type of cardiac amyloidosis a person has.
Next is an echocardiogram, which uses sound waves to create images of your heart. This test commonly shows that the walls of the heart are thicker than usual and gives the first hint towards the presence of cardiac amyloidosis. Often, both chambers on the top of the heart (the atria) are enlarged, the bottom left part of the heart (the left ventricle) stays the same size and its ability to squeeze is kept till late into the disease. The heart’s ability to relax (or diastolic function) is usually affected. The way the heart squeezes in cardiac amyloidosis is often compared to a ‘cherry on top’ look. If a person faints often, has chest pain or heart failure, and has specific changes on the echo and the EKG, these signs might suggest cardiac amyloidosis.
The changes seen on the echocardiogram depend on whether a person has the AL or TTR type of cardiac amyloidosis. In TTR amyloidosis, there’s a chance of having more effects on the heart function and thicker heart and heart chamber walls.
Cardiac magnetic resonance imaging (or CMR) has now become an important test for diagnosing cardiac amyloidosis. This test separates it from heart diseases due to high blood pressure and sarcoidosis (heart inflammation due to immune responses). It also tells us about the tissues of the heart and helps catch the disease early on, but it can’t tell us whether a person has the TTR or AL type.
A nuclear SPECT test looks at the blood flow to your heart. It uses a type of radioactive substance and a special camera to do this. If this test is strongly positive and a person has all the echo changes and lacks signs and symptoms for multiple myeloma (a type of cancer), there’s a pretty good chance of having TTR amyloidosis. For AL amyloidosis, there’s little to no uptake of the radioactive tracer.
An endomyocardial biopsy is the best test to confirm cardiac amyloidosis. It involves taking a small piece of the heart wall to look at under a microscope. This test shows a specific ‘apple-green’ color under polarized light after using a ‘Congo-red’ stain, which is very typical for amyloidosis.
Lastly, genotyping (or genetic testing) is crucial for ATTR amyloidosis. This type can be caused by many gene changes, and these are important to know because they tell us about the likely response to treatment and outlook of the disease. The type of gene changes can vary based on the location of a person and their ethnicity.
Treatment Options for Cardiac Amyloidosis
The aim of treating cardiac amyloidosis (a condition where abnormal proteins called amyloids build up in the heart, making it hard for it to work properly) is to address both the root cause and the symptoms of heart failure.
If you have cardiac amyloidosis, doctors use medications that help your body to remove excess fluid and maintain blood pressure to manage heart failure symptoms. Specifically for AL amyloidosis (a type of cardiac amyloidosis), diuretics—which help you to urinate more and get rid of extra fluid—are a mainstay treatment. Using blood pressure medications called renin-angiotensin-aldosterone inhibitors (RAAS-I) can lead to low blood pressure, especially in patients with AL amyloidosis, so they’re used more cautiously. However, these blood pressure medications are usually better tolerated if you have ATTR amyloidosis, another type of cardiac amyloidosis.
Doctors also consider using other medications like beta-blockers or midodrine to maintain blood pressure but note that these might not be tolerated well by some patients. To help manage heart failure, doctors rely on meds that control the amount of salt your body retains and the medi-ications that promote urine production.
As for treating AL amyloidosis specifically, this involves a team of heart doctors and blood doctors since the treatment approach is similar to treating multiple myeloma, a type of bone marrow cancer. The goal is to remove abnormal proteins from the blood and urine and stabilize bone marrow. Chemotherapy agents used include medications such as melphalan and bortezomib, often used together with dexamethasone and cyclophosphamide, to attain this goal.
Heart transplant, while high risk, could be a chosen course of action to manage AL amyloidosis if your heart is the only affected organ and you’re willing to go through chemotherapy after the transplant. A liver transplant may be necessary if you have mutant ATTR because the liver is the main producer of the amyloid proteins. If you have amyloidosis affecting both the heart and liver, you might require a combined heart and liver transplant. But if you have wild ATTR, another type of ATTR amyloidosis, liver transplantation isn’t normally done.
For people with cardiac amyloidosis who develop irregular heartbeat (atrial arrhythmias), treatment options might include medications, although some are not well tolerated. Some could be used for controlling the heart rate if carefully administered. Some patients might need a procedure called catheter ablation to restore the regular rhythm, especially for a condition called atrial flutter. People with cardiac amyloidosis also have an increased likelihood of blood clotting, so anticoagulation medicines are often necessary to prevent clots from forming.
If there is an atrioventricular block (an obstruction of the electrical signals from the upper chambers of the heart to the lower chambers), biventricular pacing—a technique that helps the heart beat more effectively—could be advantageous. An implantable cardioverter-defibrillator, a device placed under your skin to monitor your heart rate and rhythm, is not usually recommended for prevention but could be necessary in some scenarios. And if you happen to have secondary amyloidosis (when amyloid proteins are formed due to chronic inflammatory diseases), your doctor will focus on treating the underlying cause. If you have a condition called isolated atrial amyloidosis (a buildup of amyloids in the heart’s upper chambers only), it may not need the treatment.
What else can Cardiac Amyloidosis be?
There are various heart conditions that may appear similar to restrictive cardiomyopathy, which makes it challenging to diagnose correctly. Some common characteristics of these conditions include difficulty breathing despite the heart pumping enough blood, problems with the heart filling with blood between beats, and enlargement of the two upper chambers of the heart.
Conditions often confused with restrictive cardiomyopathy include:
- Cardiac sarcoidosis (a disease that causes inflammation and can affect any part of the body, including the heart)
- Glycogen storage diseases (a group of genetic disorders that affect how the body processes glycogen, a form of sugar stored in cells)
- Hemochromatosis (a disorder that causes the body to absorb too much iron from the diet)
Additionally, diseases such as hypertensive heart disease (a condition due to high blood pressure) and hypertrophic cardiomyopathy (a disease where the heart muscle becomes abnormally thick) can also resemble restrictive cardiomyopathy in their heart scanning results.
What to expect with Cardiac Amyloidosis
The outcome for patients suffering from cardiac amyloidosis can differ greatly depending on the type of the disease. On average, patients who don’t receive any treatment can expect to live for the following times: between 9 to 24 months for AL (primary) amyloidosis, 7 to 10 years for ATTR familial amyloidosis, 5 to 7 years for senile amyloidosis, and more than ten years for AA (secondary) amyloidosis.
In general, ATTR amyloidosis has a better outcome than AL amyloidosis as it tends to progress more slowly. It usually appears later in life, around the seventh decade. If AL amyloidosis patients receive a stem-cell transplant, the four-year survival rate is over 90%. Specifically, patients with heart complications who get a stem-cell transplant typically survive more than 10 years. However, the average survival in AL amyloidosis is 10 years, but for those with a late-stage diseases, the survival rate drops to only 50% within the first year.
The mutated form of ATTR amyloidosis has a four-year survival rate of 16%. But this rate can vary depending on the specific mutation. The most common mutation, called Val30Met, has a prognosis of 79%, while another mutation, known as Val122Ile, has a four-year prognosis rate of 40%.
Possible Complications When Diagnosed with Cardiac Amyloidosis
Cardiac amyloidosis can lead to various complications due to abnormalities in the structure of the heart. These irregularities increase the likelihood of heart failure, atrial fibrillation (irregular heartbeats), and ventricular arrhythmias (abnormal heart rhythms).
Here are some potential problems a patient with cardiac amyloidosis might experience:
- Atrial fibrillation: This can increase the risk of blood clots and subsequent heart failure.
- Diastolic dysfunction: This condition can lead to heart failure, a higher possibility of irregular heart rhythms, and an elevated risk of death.
- Heart failure: This can result in repeated hospital visits and an increased mortality rate.
- Ventricular arrhythmias and cardiac conduction abnormalities: These are irregularities in heart rhythms and electrical activity of the heart.
- Autonomic neuropathy: This condition can occur when the disease affects the entire body. It is a nerve disorder that affects involuntary bodily functions such as heart rate, blood pressure, and digestion.
- Tendinopathies: These are disorders relating to the tendons which might appear when the disease has spread throughout the body.
Preventing Cardiac Amyloidosis
Cardiac amyloidosis, a condition where an abnormal protein called amyloid builds up in the heart, can affect people differently. There are various treatments available, and the best approach will depend on the specific type of the disease a person has. For patients, understanding the course of the disease is really important. Be aware that the disease can affect the whole body, not just the heart.
Patients should know that treating cardiac amyloidosis often requires a team of specialists, including a heart doctor (cardiologist), a blood disease doctor (hematologist), a doctor specializing in the digestive system (gastroenterologist), and a doctor specialized in transplant surgery. Treating heart failure caused by cardiac amyloidosis is different from how other types of heart failure are usually managed. This is because patients with this condition can be very sensitive even to very small doses of medication, which means the doctor will need to increase the medication slowly and carefully. As a result, patients may need more frequent medical checkups than with other types of heart failure.
