Tafamidis binds the misfolded transthyretin protein to keep it from breaking apart and going on to form deposits in the myocardium, causing transthyretin amyloid cardiomyopathy (ATTR-CM).
New treatments are available for patients with transthyretin amyloid cardiomyopathy (ATTR-CM), a rare, underdiagnosed condition that causes faulty proteins to build up in the heart. Untreated, the condition leads to heart failure and death.
An oral medication, tafamidis, serves as a stabilizer, binding the misfolded transthyretin (TTR) protein to keep it from breaking apart. When the TTR protein does break apart, it forms deposits in the myocardium, thickening the heart muscles and making it increasingly difficult for the heart to pump.
The abnormal TTR protein is produced by the liver and also can affect the nerves and kidneys.
Tafamidis is designed to halt or stall progression of the disease. We’ve seen how well the drug can work firsthand at Norton Heart & Vascular Institute. We’ve had patients on the medication increase their exercise activity, and we’ve seen improvement in the echocardiographic findings in some patients.
A large clinical trial followed ATTR-CM patients for 2½ years and found tafamidis produced a significant survival benefit compared with the placebo. It also reduced cardiovascular-related hospitalizations and slowed the decline in quality of life.
Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID) developed to treat arthritis, is another TTR stabilizer, though it carries the typical potential side effects of an NSAID: gastrointestinal bleeding, upset stomach and renal insufficiency. The medication is used less frequently since tafamidis was approved in 2019.
There are also two infusion drugs approved by the Food and Drug Administration (FDA) for TTR amyloidosis associated with peripheral neuropathy — patisiran and inotersen — which are “silencers,” targeting the liver synthesis of the transthyretin protein. Patisiran was the first small interfering ribonucleic acid (siRNA) treatment approved by the FDA. Inotersen is an antisense oligonucleotide that binds to specific molecules of RNA.
Since the mechanism of action is different with the TTR stabilizers and silencers, there is some discussion of giving a combination therapy, though there have been no published studies to date on this.
TTR cardiac amyloidosis can be wild type or hereditary. Among patients with heart failure or aortic stenosis, an estimated 10% to 16% have cardiac amyloidosis, though they often go undiagnosed.
A second type of amyloidosis, AL amyloidosis (amyloid light chain or primary amyloidosis) is a bone marrow disorder. The condition results in abnormal light chain proteins accumulating on your organs and tissues, including your heart.
Because it originates in the bone marrow, AL amyloidosis is treated like multiple myeloma, with chemotherapy and, sometimes, bone marrow (stem cell) transplants.
An estimated 4,000 people develop AL amyloidosis each year in the United States. The disease typically is diagnosed between the ages of 50 to 65 but can affect people as young as 20.
Drugs slow ATTR-CM progression, so early diagnosis needed
Because the drugs for cardiac amyloidosis slow, rather than reverse, disease progression, it’s important to diagnose as early as possible.
Diagnosing ATTR-CM begins with an echocardiogram and lab work. An echocardiogram can show increased left ventricle wall thickness, atrial enlargement, increased echogenicity of the myocardium or other abnormalities.
In patients with ATTR-CM, the lab work typically shows elevated troponins. These are proteins released when the heart muscle has been damaged.
Diagnosing AL amyloidosis includes urine and serum immunofixation electrophoresis and serum free light chains to check for the presence of elevated kappa and lambda light chains and the presence of monoclonal protein.
Cardiac MRI and single-photon emission computed tomography (SPECT) pyrophosphate (PYP) scans are both useful diagnostic tools, and positron emission tomography (PET) scan using targeted tracers for amyloid-specific proteins is a potentially promising option in the future.
For a long time, we couldn’t do anything for people with TTR amyloidosis. We now can, and this is an exciting development. If we can treat patients early, before complications, we can significantly decrease a lot of morbidity — and maybe even arrest the disease.
Steven J. Raible, M.D., is a cardiologist with Norton Heart & Vascular Institute.