Key Information
Cardiac amyloidosis used to be considered an ultra-rare disease with no treatment options. No longer. Advances in noninvasive testing have led to greater awareness, earlier diagnosis and improved outcomes for patients. Concurrently, important advancements in the treatment of ATTR amyloidosis have significantly changed the landscape of care for those affected by the disease.
But these important gains come with a caveat. The disease is underdiagnosed. If clinicians don't detect and diagnose the disease early, patients will continue to suffer, except now that suffering may be needless.
"Every provider has probably seen patients with cardiac amyloidosis in their office several times over the years and never recognized it. Now that we have a noninvasive means of diagnosing it and a disease-specific treatment that works, it's time to stop missing the diagnosis," suggests Mathew S. Maurer, MD, FACC, at Columbia University Irving Medical Center in New York City.
Cardiac Amyloidosis 101
Cardiac amyloidosis is an infiltrative heart disease wherein misfolding proteins aggregate amyloid fibrils deposited in the interstitial space between cardiac myocytes. While as many as 40 proteins are known to form insoluble amyloid fibrils, the vast majority of cardiac amyloidosis is caused by just two: light-chain amyloid (AL) and transthyretin amyloid (ATTR).1
AL amyloidosis is a rare disease with a rapidly progressive clinical course in part due to the toxic nature of light chains. The disease arises from overproduction and misfolding of monoclonal immunoglobulin light chains. Left untreated, AL amyloidosis has a median survival of less than six months in patients with cardiac involvement.
ATTR-cardiomyopathy (ATTR-CM) is the form of cardiac amyloidosis currently getting the most attention. There are two subtypes: hereditary or variant ATTR (ATTRv) is caused by TTR mutations (of which there are about >130), while wild-type ATTR amyloidosis (ATTRwt), the most common form of cardiac amyloidosis, occurs without a pathogenic mutation and is a result of as yet undefined age-related changes.
"Ten or 15 years ago, amyloidosis was thought to be an ultra-rare disease and providers were nihilistic because there weren't any treatments. So, not only was it hard to diagnose and protean," says Maurer, there was little impetus to diagnose it because there was no treatment.
"Now, we're not even sure it's still a rare disease, using the accepted definition of a disease affecting <200,000 folks in the U.S. It's certainly much more common than we thought."
This change is a result of two concurrent advances in the field. The first is the advent of a nonbiopsy method using technetium-labeled bone scintigraphy to diagnose the condition in patients for whom lab tests have ruled out the substrate for AL.2 Previously, definitive diagnosis of amyloidosis required an endomyocardial tissue biopsy, but now biopsy is required in a minority of affected patients.
"Once we realized we could use noninvasive testing, we learned important things, like that up to 13% of patients hospitalized with heart failure with preserved ejection fraction [HFpEF] who have a thick-walled heart have amyloidosis,"3 says Maurer.
Indeed, several epidemiological studies now indicate that cardiac amyloidosis is far more common than previously thought. For example, as many as one in seven to eight patients referred for TAVR show cardiac amyloid infiltration on bone scintigraphy.4-6
"We think it's likely that maybe 1% of people over the age of 75 without a clinical syndrome just walking on the street may have cardiac amyloid because it's an age-dependent phenomenon," says Maurer. There is also a male preponderance for reasons that are unclear.
Epidemiological studies have also revealed that certain disease variants almost exclusively affect certain populations, such as Black and Caribbean Hispanics who have West African ancestry. One common variant encountered in the U.S., the Val122Ile variant, is present in 3.4% of individuals (1 in 29) who self-identify as Black. Given its prevalence, there are about 1.5 million allele carriers of the Val122Ile variant in the U.S., although its penetrance is incomplete.