NEW YORK – The arrival of new drugs to treat, and maybe even prevent, transthyretin amyloid cardiomyopathy (ATTR-CM) has put a spotlight on this rare heart condition, raising the question of whether broader genetic screening should be implemented to better identify at-risk patients for earlier intervention.
More than 100,000 people in the US are thought to have ATTR-CM, though the exact prevalence of the severe and progressive disease is difficult to come by since it has historically been misdiagnosed. Some patients have a hereditary form of the disease caused by inherited mutations in the TTR gene that result in misfolded proteins, while others have a wild-type TTR gene but still develop the disease due to TTR proteins that misfold as they age.
For years, there were no available treatments other than symptomatic care and, if needed, a heart or liver transplant. But in 2019, the US Food and Drug Administration approved Pfizer subsidiary FoldRx's Vyndamax (tafamidis), an oral medication for patients with hereditary or wild-type ATTR-CM that aims to slow disease progression by stabilizing TTR proteins and stopping them from misfolding.
The FDA has since approved another oral TTR stabilizer, BridgeBio Pharma's Attruby (acoramidis), and just last week approved Alnylam Pharmaceuticals' Amvuttra (vutrisiran), an RNAi drug that, with quarterly subcutaneous injections, is designed to knock down TTR protein production. Other drugs are in development, particularly for treating earlier stages of the disease, prompting interest in identifying patients with a genetic predisposition to the inherited cardiomyopathy for monitoring and treatment before their condition progresses to an advanced stage.
ATTR-CM treatment is "very different" than for other types of heart failure, with "specific, directed" therapies, noted Shudhanshu Alishetti, an assistant professor and advanced heart failure and transplant cardiologist at Weill Cornell Medicine. "That's why it's important for us to know when someone has TTR amyloid."
The medical field has seen dramatic advances in understanding and treating TTR amyloidosis over the past decade, added Nitasha Sarswat, a cardiologist who leads the cardiac amyloidosis program at University of Chicago Medicine and Endeavor Health. "This is something that's really evolving," she said. "It's become a really important topic and has potential for population screening."
But population genetic screening is difficult to set up, given present uncertainties regarding the prevalence of ATTR-CM and whether patients with TTR mutations will actually develop the condition. These unknowns have raised further questions around who should be tested for pathogenic TTR variants and when to intervene with treatment.
At the heart
In ATTR-CM patients, misfolded TTR proteins accumulate in the heart and form amyloid plaques that cause heart muscles to become thick and stiff, hindering their ability to pump blood. The disease symptoms mirror other cardiovascular conditions, making it difficult for doctors to diagnose patients until the condition has progressed to an advanced stage.
The symptoms of hereditary ATTR-CM tend to manifest earlier, in patients in their 60s, while wild-type ATTR-CM tends to be diagnosed in patients in their 70s and 80s. TTR amyloidosis can also be characterized by polyneuropathy (ATTR-PN), which is always hereditary and may or may not be seen alongside cardiomyopathy. There are more than 120 TTR mutations linked with ATTR-CM or ATTR-PN.
Most ATTR-CM patients have the wild-type form, but the hereditary version likely isn't as rare as once thought. "We're learning more and more over time that it's actually more of an underdiagnosed disease," said Senthil Selvaraj, an assistant professor and heart failure cardiologist at Duke University School of Medicine.
In fact, research has suggested that between 3 percent and 4 percent of Black patients have a TTR variant, V142I, linked with ATTR-CM. This variant isn't only seen in Black patients, as it is estimated to occur in 0.3 percent to 1.6 percent of people worldwide, but it is most common among Black patients. TTR V142I represents the most common variant associated with hereditary ATTR-CM in the US and could be a starting point for population screening.
Selvaraj noted that the V142I variant originated in West Africa and is primarily seen in patients with West African ancestry. However, since many patients may not know the details of their geographic ancestry, much of the research on V142I has been conducted in patients who self-identify as Black. Likewise, large data studies tend to collect race and ethnicity information on participants, which makes this data more accessible than ancestry data. He underscored that investigators and researchers should keep in mind that "race is not a proxy or a substitute for ancestry."
Selvaraj led a study published in JAMA last year, in which investigators found that V142I carriers had an increased risk of heart failure and death, particularly at an earlier age, than non-carriers. It's presently unknown what portion of those with the V142I variant go on to develop ATTR-CM, but Selvaraj continues to investigate why some V142I carriers develop disease, while others don't.
"In the future, I could imagine — after we think about this very thoroughly — a genetics-first approach," he said. "That would entail doing broad genetic testing among an at-risk group," with close monitoring of patients who are carriers.
As it stands, doctors typically offer TTR genetic testing to patients who have disease symptoms or who have family members diagnosed with hereditary ATTR-CM.
In heart failure management guidelines the American College of Cardiology (ACC) and the American Heart Association (AHA) issued in 2022, the societies recommended genetic testing for patients who have been clinically diagnosed with ATTR-CM to differentiate between the hereditary and wild-type forms of the disease. The groups advised doctors to refer TTR mutation carriers for genetic counseling and discuss screening family members. In a 2023 expert consensus statement on ATTR-CM management, an ACC committee noted that cascade testing is most useful for a patient's siblings, rather than offspring, given the expected age of disease onset.
The American College of Medical Genetics and Genomics (ACMG) in 2022 added TTR to the list of genes for which it recommends doctors disclose to patients any actionable variants revealed through whole-genome or exome sequencing, even if testing was ordered for a different condition. The ACMG's secondary findings working group cited the prevalence of the V142I variant among patients of African descent, despite its lower prevalence in the total US population, as one of the reasons for adding the gene to this list. Disclosing secondary TTR mutation findings from genomic testing becomes a particularly important consideration, given high rates of heart failure in Black patients in the US.
The ACMG earlier this year reaffirmed that the secondary findings list comprises incidental findings it recommends reporting when patients are undergoing sequencing for unrelated reasons. But these are not genes that the ACMG recommends for inclusion in population screening, as that would require a separate evaluation of penetrance and cost-effectiveness.
Michael Murray, chief of the genomic medicine division and clinical director of the Institute for Genomic Health at the Icahn School of Medicine at Mount Sinai, said that the ACMG is developing a list of genetic variants it recommends for inclusion in population screening programs and that will likely be finalized later this year. Murray, a co-chair of the working group for that report, recently retired from the ACMG's board of directors.
He was one of the people who nominated TTR to the secondary findings list but wasn't part of the secondary findings working group.
"I think it's got value," he said of testing for pathogenic TTR variants, noting that, historically, patients with ATTR-CM often have been misdiagnosed and managed as if they have standard heart failure, instead of receiving amyloidosis-specific care.
There are drawbacks to population screening, however. For example, many carriers may never develop the disease or won't develop it until much later in life, Murray said. It would be crucial for a screening program to have experts involved who can explain what these variants mean in the context of ATTR-CM and guide patient care.
Genetic counselors, for instance, could play a key role in conveying the complexity of genetic risk in ATTR-CM, said Cara Barnett, a cardiovascular genetic counselor at Genexsure, which offers genetic testing and counseling services. She noted that genetic testing, generally, has been underutilized in cardiovascular care.
Given the prevalence of the V142I variant, its strong link to heart failure, and evidence that early treatment can lead to better outcomes, "all those things suggest [TTR] is a great gene to consider" for broader screening in adults, she said. "But the limitation to consider is that there are people with this variant who never develop severe heart failure."
That the disease tends to arise later in life brings further challenges, Barnett said. There's a need to weigh the benefits of early detection against the reality of needing to manage potentially hundreds of thousands of adults who learn about their genetic predisposition years before the disease might emerge, if at all. After patients become aware they carry a pathogenic TTR variant, healthcare systems would need to set up protocols for how often carriers come in to check for signs of the disease and figure out what evaluations they'd undergo.
"It's a really important balance," she said. "Are we prepared to follow them and manage them?"
Early adopters
Some providers are doing proactive TTR genetic testing. At Geisinger, patients might find out they're a TTR-variant carrier if they're participating in the hospital's MyCode Community Health Initiative, a precision medicine and population genomic screening program. These patients, who might not have any symptoms of disease, are referred to a multidisciplinary amyloidosis clinic to receive genetic counseling, discuss cascade testing, and get screened for signs of cardiomyopathy and neuropathy. They might undergo an echocardiogram to check for thickening of the left ventricular wall in the heart, as one example.
If patients don't have signs of disease, physicians discuss what symptoms to look out for and ask them to return for another screening at least 10 years before the expected age of disease onset, based on their family history or what's known about the variant. Older patients with pathogenic variants are monitored annually.
At Geisinger, the aim in screening for TTR mutations is to try to identify patients who would benefit from early intervention. "There are enough patients with this particular condition in the US and probably a lot more than you would think," said Brendan Carry, an advanced heart failure and transplant cardiologist at Geisinger.
He pointed out that if 3 percent of people with African or Afro-Caribbean ancestry have the V142I variant, that amounts to more than a million people in the US. "That's pretty high," he said "They're not all going to have the disease. [The variant] is not 100 percent penetrant, but it's definitely worth checking."
And ATTR-CM is an underdiagnosed disease, according to Carry's research. In a 2021 paper in JACC: CardioOncology, Carry and colleagues analyzed data on more than 134,000 MyCode participants, most of whom were of European ancestry. They found that 157 people had a pathogenic or likely pathogenic TTR variant and 113 specifically had the V142I variant, 91 of whom had African ancestry.
Only two of the 157 patients had been diagnosed with ATTR-CM, even though others had documented cardiomyopathy and heart failure. After bringing carriers in for evaluations, there were additional patients who were found to have signs of ATTR-CM, Carry said.
"These are diseases that otherwise, unfortunately, could have gone undiagnosed or misdiagnosed for many years," Carry said. "If you just find one mutation out of thousands of patients, that's one whole family tree that you're going to potentially have an amazing effect on."
In this study, researchers focused on identifying variant carriers and didn't collect data on clinical outcomes after patients learned of their carrier status.
There are a growing number of medications to treat ATTR-CM. In addition to Vyndamax, last year the FDA approved BridgeBio's Attruby and most recently expanded the indication for Alnylam's Amvuttra, which had already been approved in ATTR-PN. Further, patients who have signs of neuropathy could be a fit for RNA silencing drugs for ATTR-PN that are injected or infused like Alnylam's Onpattro (patisiran) or AstraZeneca and Ionis Pharmaceuticals' Wainua (eplontersen), which is also being studied in ATTR-CM within a Phase III trial.
There are also gene-editing drugs in clinical development, including an in vivo CRISPR-based therapy designed to inactivate the TTR gene being advanced by Intellia Therapeutics. The firm is testing nexiguran ziclumeran (nex-z) in patients with ATTR-CM and ATTR-PN, regardless of their TTR genotype and aims to seek regulatory approval in those two indications in coming years.
"It's amazing how the field has changed," said Sarswat, who's also an assistant professor at UChicago Medicine.
There's still more to learn, such as the natural history and disease trajectory associated with TTR mutations, their penetrance, and how the disease impacts patients who are heterozygous or homozygous carriers. The availability of treatments may spur more screening and earlier diagnosis of ATTR-CM and allow researchers to fill these knowledge gaps.
Before the advent of these drugs, Lisa Wilsbacher, an associate professor at Northwestern University's Feinberg School of Medicine, hadn't been as supportive of population testing. But "because we now have therapies that are available to alter the course of the condition, I do think that population screening for a gene like TTR makes sense," said Wilsbacher, who sees patients at the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital. "Especially, in particular populations."
Who to test
In a TTR population screening program, the first question is: who should get tested? TTR screening would make most sense for patients with African ancestry, due to the high prevalence, as well as in patients with Latino ancestry, who may also be more likely to carry pathogenic TTR variants than the general population, Wilsbacher suggested. She's not against universal screening, but there may not be widespread support for it since the prevalence of pathogenic TTR mutations in the overall population is estimated at less than 1 percent. Further, hospitals may not have the trained staff, such as genetic counselors and physicians with genetics know-how, necessary to implement genetic testing for everyone.
For Carry at Geisinger, results of the MyCode program have strengthened his belief in the benefits of universal genetic screening for this condition. "We're actually finding that it's not really as rare as we once thought," he said. "That's a really good reason to be doing more testing. ... We're finding so much more of this."
Broader, preemptive testing for TTR variants could take many forms, noted Jessica Regan, a cardiology fellow at Duke University School of Medicine, who studies molecular underpinnings of cardiovascular disease. She recently coauthored a perspective in the Journal of Cardiac Failure on the potential of broader systematic screening for the V142I variant.
Population-wide screening, in which all adults are encouraged to receive genetic testing, could be one option. This would be more expensive than targeted screening efforts, encompassing broad genetic testing, follow-up care, and potential pharmaceutical treatment, but would miss fewer people with pathogenic variants.
Another option could involve testing only high-risk populations, such as patients with West African ancestry or who self-identify as Black and who are over the age of 50. If a screening program focuses on patients who self-identify as Black, it would be important to educate physicians and patients that this variant is tied to geographic ancestry, not race, and to not conflate the two, Regan noted.
Still, genetic screening programs for diseases that are prevalent in certain ethnic groups have been successful, such as testing programs for cystic fibrosis or Tay-Sachs in patients with Ashkenazi Jewish ancestry. Implementing screening first in high-risk populations could offer a "walk before we run" approach, Regan said. "That could then be expanded to the whole population down the road, once we've established the care paths," she added.
However, she emphasized that she's not in favor of implementing testing that the healthcare system isn't ready to handle, as providers will need processes for managing variant carriers. For asymptomatic patients, that could involve genetic counseling, frequent monitoring, and, down the line, perhaps early treatment, all of which require multidisciplinary teams of clinicians knowledgeable in genetics, heart failure, amyloid care, and other specialties.
Without establishing equitable access to genetic testing and related expertise, a broad screening program could unintentionally widen, rather than narrow, health disparities. Pankaj Arora, an associate professor in the division of cardiovascular disease at University of Alabama, Birmingham, and director of the UAB cardiogenomics clinic, pointed out that the uptake of TTR testing in symptomatic patients already is variable. While it's become common in academic medical centers, it likely isn't as routine in smaller hospitals with fewer resources.
Daniel Judge, a professor in the cardiology division at the Medical University of South Carolina and director of the MUSC cardiovascular genetics program, understands why one might focus an ATTR-CM screening program on populations most likely to carry a pathogenic TTR variant, in this case Black patients, but said, if possible, it could be best to screen everyone. "The larger you start to draw your circle, the more likely you are to find people," he said.
Still, the lack of established treatment pathways for asymptomatic TTR pathogenic variant carriers has kept MUSC from adding that gene to its community health study and population genomic screening program, called In Our DNA SC. Patients enrolled in that program can get genetic testing to see if they're at risk for certain inherited cancer predisposition syndromes and familial hypercholesterolemia that the US Centers for Disease Control and Prevention has flagged as poorly diagnosed within the healthcare system. The CDC encourages guidelines-based genetic testing for these conditions because early detection can reduce morbidity and mortality through preventive treatment.
A primary reason TTR isn't yet included in MUSC's program — though it is under consideration — is because there isn't a treatment strategy for how to care for patients who have a pathogenic variant but don't have symptoms. "As that becomes a possibility in the future … then we'll have good rationale for [screening]," he said.
A step toward prevention
Preventive treatment for ATTR-CM could be on the horizon. BridgeBio recently launched the Phase III ACT-EARLY trial to evaluate whether Attruby, through early and sustained stabilization of TTR, can prevent or delay onset of ATTR-CM or ATTR-PN in patients who don't have symptoms but are carriers of pathogenic variants. To enroll, patients must be within the 10-year window for the predicted age of disease onset, based on family history or their TTR variant.
Adam Castano, VP of clinical development at BridgeBio and the study lead for ACT-EARLY, believes that preemptive and population-level genetic screening for TTR variants could be useful for addressing TTR amyloidosis. "But genetic testing is a highly personal decision that requires thorough dialogue between individuals considering it and their [healthcare providers]," he added.
Even though current guidelines recommend genetic testing of patients diagnosed with TTR amyloidosis and their family members, limited awareness of ATTR-CM and the symptoms that are "red flags" for the condition, Castano said, are one of the biggest barriers to patients getting TTR testing, leaving patients undiagnosed until their disease has advanced. Doctors must first suspect that a patient has an ATTR phenotype to pursue genetic testing, he said.
For many ATTR-CM drugs, there's evidence that earlier treatment results in better long-term outcomes, said MUSC's Judge, who's an investigator on the ACT-EARLY trial. He's encouraged by the possibility that starting a treatment like Attruby before patients have symptoms could benefit them. "In my early training, we had nothing that we could offer these patients. It was really quite depressing," Judge said. "There's quite a lot in the field right now in terms of therapies that are FDA-approved or investigational. … There's a lot of hope on the horizon."
That potential for preventive care reinforces the utility of broader genetic screening for Daniel Rader, a professor of molecular medicine at the University of Pennsylvania's Perelman School of Medicine and chair of the genetics department at Penn Medicine. "I'm a proponent, in general, of earlier, broader genetic screening for risk factors that are actionable," Rader said. "This is an underdiagnosed condition that has very effective therapies, and those therapies, while they're currently approved for people who already have symptoms, … are clearly going to be moving into an early phase."
He's not necessarily in favor of universal genetic screening but said there's a "strong case" for targeted screening for the V142I variant in older Black patients. For now, without approved drugs for patients who are asymptomatic, it makes sense to continue focusing on testing patients who have early signs of heart failure, for whom there are approved treatments, he said.
Not all cardiologists are bullish on the ACT-EARLY trial, however. "I don't know that that's going to pan out to be beneficial," said Alishetti at Weill Cornell Medicine. Many patients with a TTR variant won't develop ATTR-CM, and drugs on the market come with costs that are "astronomical," he added.
Vyndamax carries an annual wholesale acquisition cost of $268,000, compared to about $244,000 for Attruby. Meanwhile, an analysis published last year determined that these drugs could be cost-effective if priced at just $13,600 to $39,000 per year.
While Alishetti remains skeptical of this type of preventive pharmaceutical treatment in TTR pathogenic variant carriers without any symptoms, he noted that early treatment in patients with minimal symptoms and signs of amyloid deposits in the heart could be beneficial. As for who to begin monitoring for ATTR-CM symptoms, Alishetti said TTR genetic screening in Black patients over the age of 50 would be "a good place to start" to identify those most at risk.
Physicians also shouldn't overlook the psychological distress patients can experience after learning they have a TTR pathogenic variant and not knowing whether they'll develop ATTR-CM, Alishetti added. He also raised the concern that genetic testing information can be used to assess risk in life insurance and inform premiums or eligibility. "That's something that always hangs over my head," Alishetti said.
While the ACT-EARLY study is currently the only preventive treatment trial for ATTR-CM, others may follow in the future. Intellia, another company developing a treatment for TTR amyloidosis, is testing nex-z in two separate Phase III trials for ATTR-CM and ATTR-PN. As a one-time infusion designed to prevent production of TTR, it may provide an economic advantage over other treatments that patients must take for the rest of their lives.
While Intellia doesn't currently have plans to study nex-z in asymptomatic patients who are carriers of TTR mutations, David Lebwohl, chief medical officer at Intellia, said it's something the company is interested in. "It's where the field should go," Lebwohl said. It would also be valuable, he noted, to identify factors that can pinpoint patients at risk for the more common age-related form of wild-type ATTR-CM.
In the absence of population screening, it's possible that awareness campaigns and community education could improve testing rates among patients, said Regan, the cardiology fellow at Duke.
She pointed to blood pressure programs based out of Black barbershops as a possible blueprint. A similar community-based program, she envisions, could connect with high-risk patients and identify those who would benefit from TTR genetic testing but are being missed. Community-based programs could facilitate testing for someone who doesn't have a family member formally diagnosed with ATTR-CM, but who knows of a relative with congestive heart failure who actually might have had ATTR-CM instead.
"There are ways to bring education about TTR amyloid to the places that our patients spend their time in their community," Regan said.