Michelle M. Kittleson, MD, PhD, is an American Heart Association national volunteer expert as well as professor of medicine at Cedars-Sinai and director of education in heart failure and transplantation at the Smidt Heart Institute. The information shared here represents her expertise as a cardiologist who specializes in cardiac amyloidosis.
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare, progressive heart disease caused by the buildup of a protein called transthyretin (TTR). TTR is a protein your body makes naturally, but when you have ATTR-CM, it doesn’t form, or fold, correctly and collects in your heart, nerves, and organs. TTR buildup in your heart muscle makes your heart thicker and stiffer than normal. This prevents your heart from pumping blood efficiently, which leads to symptoms such as fluid backup, leg swelling, and shortness of breath with exertion.
To help you understand more about this condition and what it means to live with and manage it, American Heart Association national volunteer expert Michelle M. Kittleson, MD, PhD, shares her expert insights.
How do doctors differentiate ATTR-CM from other heart diseases?
Because the most common symptoms of ATTR-CM are classic general heart failure symptoms such as shortness of breath with exertion and leg swelling, we look for other important clinical clues as well. For example, if you're above the age of 60 and you've developed bilateral carpal tunnel syndrome, that is a clue that amyloidosis could be the source and in your heart as well. Spinal stenosis, or the narrowing of your spinal column that causes pain, numbness, and weakness, is another warning sign. Sometimes this is just a normal sign of aging, but it can also happen from deposits of TTR in your spinal canal. Neuropathy, like numbness in tingling hands or feet, or lightheadedness and blood pressure drops during changes in position may be a sign as well. A family history of heart failure is another clue. All of these things heighten clinicians’ awareness and should start the diagnosis process.
What does symptom management of ATTR-CM typically involve?
Our ATTR-CM treatment plans have two goals: first, to help you feel better by managing the symptoms of the disease, and second, to prevent hospitalizations and help you live longer by using disease-modifying therapies. To help with immediate symptoms, we use medications that target fluid retention. These include diuretics and sodium-glucose cotransporter-2 (SGLT2) inhibitors — dapagliflozin or empagliflozin — as well as mineralocorticoid antagonists like spironolactone. My typical approach is to put people on a diuretic like furosamide (Lasix) together with an SGLT2 inhibitor and a mineralocorticoid. These treatments work synergistically, meaning they work together to increase the others’ effects, to help immediately relieve fluid congestion and improve your quality of life.
How do disease-modifying therapies for ATTR-CM work?
Alongside symptom-relieving treatments, we initiate disease-modifying therapy, which is therapy unique and dedicated to targeting the problem: the TTR protein. There are three medications that can modify the ATTR-CM disease course:
- Acoramidis (Attruby)
- Tafamidis (Vyndamax, Vyndaqel)
- Vutrisiran (Amvuttra)
These medications work in slightly different ways, but all target the TTL protein. Vutrisiran silences TTR production on the MRNA level. It turns out that your body doesn’t necessarily need TTR, so stopping its production isn’t harmful to health. You get this treatment as an injection under the skin every three months in a clinic. In clinical trials, vutrisiran has shown to be 80%-90% effective at preserving quality of life and reducing hospitalizations.
Acoramidis and tafamidis and approach the problem from another angle. In its normal state, the TTR exists in a stable configuration. For mysterious reasons, in ATTR-CM it decides to unfold and then go into the heart. The second class of medications we call the stabilizers, because they stabilize TTR in its stable, normal structure so it won’t cause any problems. Both treatments have been shown in clinical trials to preserve quality of life, reduce hospitalizations, and increase survival. These medications come as oral tablets you take either once or twice every day.
Which disease-modifying therapy is best for me?
There's no data to suggest one is better than the others. We know they all work, but there is no evidence to promote relative superiority of one medicine versus the other. In addition to that, there is no evidence from clinical trials to show that combination therapy is superior to a single medication. So then how do we choose which medicine to prescribe? This is the way I think about it: Vutrisiran is also FDA approved for those patients who have the variant (genetic) form of ATTR-CM with neuropathy, so if these factors are present, it’s a no-brainer. But if you have wild-type and no neuropathy, we look at practical considerations. To date, there hasn't been an extreme price difference in the treatments, but if that were to happen, I would pick the cheapest option. Because if three medications are medically equivalent, I choose the one that's going to cost the patient the least amount of money. I’d also take into consideration your preferences: Do you want to take pills? Do you want to take an injection every three months? And then let that help us decide.
What are the side effects of disease-modifying therapies for ATTR-CM?
These medications are extraordinary, not only because they are effective in reducing hospitalizations and increasing survival, but because they really only do one thing in the body and therefore don't cause a lot of side effects. We also don't worry about serious interactions with other drugs. We don't worry about kidney function or liver function. None of that needs to be monitored. That said, there are important things to keep in mind. Tefamitus does have an interaction with high-intensity statin therapy that can be used to treat high cholesterol. And so the most important thing to know with that is that you should be on a low dose of rosuvastatin (Crestor), particularly if you're on tafamidis. The second minor thing to note is that one function of TTR in our body is to transport vitamin A around. So you can become vitamin A deficient if you’re taking vutrisiran and have to take a vitamin A supplement. But short of that, there really are no side effects and no required monitoring. These medicines are very easy to prescribe and take.
Are there lifestyle changes I should make to help manage my ATTR-CM?
More activity is always great to help you preserve functional capacity. Some people are very salt sensitive with this condition. They will notice more puffiness and shortness of breath the next day after they eat more salt. So be aware of how salt affects your symptoms and if you notice your body doesn't like it, stay away from it. Some people don't notice that pattern and don't need to worry as much about it. Some people are more vulnerable to the side effects of dehydration when they’re on diuretics. There's a balance between managing your fluid retention and diuretics. You may have to work on a balance between feeling dry and fainting when you stand up (too high a dose of diuretics) and feeling wet, really short of breath, puffy, congested, and swollen (too low a dose). You have to know your own body. The doctor can't tell you the perfect dose. You have to be comfortable making minor adjustments to your diuretic regimen within the parameters your doctor has given you. You can’t take 10 times the dose one day and half of one dose the next. But be flexible based on your symptoms, and that will optimize your quality of life.
How will I know if my disease-modifying therapy is working?
When talking about disease-modifying medications, I’m careful with my words. These medications preserve quality of life, which is different from saying they improve quality of life. The mechanism of action of these medications doesn’t reverse your disease, so they won't fix what's already there. They can only prevent future progression. That’s why early diagnosis is key — you can freeze things at an earlier part of your disease.
The purpose of disease-modifying medications is to prevent you from feeling worse over time. And clinical trials show they work; when compared to people who don’t take them, people on these treatments will preserve quality of life, prevent hospital stays, and live longer. But on an individual basis, we can’t check a blood test or imaging scan to see if you are responding to treatment. And even if we could, we wouldn’t really know what to do with that information. Here’s the good news, though: This condition progresses very slowly. Typically the progression of cardiac amyloidosis is indistinguishable from the progression of old age. And most exciting is that data in the most contemporary era shows us that the survival of people living with cardiac amyloidosis on appropriate disease modifying therapy is essentially comparable to people of the same age without cardiac amyloidosis. This means in the last decade it has been transformed from a condition you will die from to very likely a condition you will die with. The way I frame it is it's a disease of winning the game. You lived long enough to get this condition, and you got it at times that there are effective therapies for it, and it’s slowly progressive. The best thing you can do is take your meds and live your life.
