Calling All Carriers

Corresponding Author

Amyloidogenic transthyretin (ATTR) amyloidosis results from dissociation of the tetrameric ATTR protein into monomers that misfold and aggregate into amyloid fibrils, depositing in multiple organs and tissues. When caused by a pathogenic TTR gene variant, the condition is classified as variant ATTR (ATTRv) amyloidosis. The c.424G>A, p.Val142Ile (V142I) variant is the most prevalent in the United States, affecting approximately 3% to 4% of individuals of African descent, with variable penetrance.¹ Although cardiomyopathy (CM) is the most common clinical manifestation, extracardiac features often precede cardiac involvement and serve as important diagnostic clues. Bilateral carpal tunnel syndrome (CTS), related to amyloid deposition in the transverse carpal ligament and flexor tenosynovium; spinal stenosis (SS), due to infiltration of the ligamentum flavum; and a progressive, length-dependent sensorimotor polyneuropathy are among the most frequent associations.^2,3 With an estimated 1.6 million carriers in the United States, the V142I variant represents a large at-risk population with a well-described pattern of extracardiac and cardiac manifestations, yet recognition frequently occurs only after advanced disease has developed, despite the availability of disease modifying therapies for ATTR amyloidosis.

In this issue of JACC: CardioOncology, Sideris et al⁴ present a retrospective analysis of V142I carriers in the MVP (Million Veteran Program), which collects genetic data from blood samples obtained at enrollment. The investigators identified individuals of African ancestry with at least 1 V142I allele and matched carriers 1:5 to noncarriers by sex, race, and age. The primary outcome was the cumulative incidence of heart failure (HF) or CM, atrial fibrillation or flutter, CTS, SS, and neuropathy; secondary outcomes included HF hospitalization, cardiovascular (CV) mortality, and all-cause mortality. Among 2,658 carriers, V142I status was associated with a significantly higher cumulative incidence of HF or CM, atrial fibrillation or flutter, CTS, SS, and neuropathy compared with noncarriers. There was also a higher incidence of HF or CM among V142I carriers who developed amyloidosis red-flag symptoms, including atrial fibrillation or flutter, CTS, SS, and neuropathy. Importantly, V142I carriers experienced significantly higher risk for all-cause mortality, CV mortality, and HF hospitalization compared with matched control subjects.

One of the most critical findings of the study is how rarely amyloidosis was clinically recognized. During the study period, only 88 V142I carriers (3.3%) and 59 control subjects (0.4%) received a clinical diagnosis of amyloidosis (P < 0.001), even though 83% of carriers and nearly one-half of control subjects already had HF or CM at the time of diagnosis. Importantly, genetic results from the MVP were available solely for research purposes and not disclosed to clinicians, underscoring a critical disconnect between genetic risk and clinical recognition. This gap becomes even more evident when contrasted with the SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study, a prospective, multicenter, cross-sectional cohort of 646 self-identified Black or Caribbean Hispanic patients aged >60 years with HF. SCAN-MP reported a V142I allele prevalence of 5.6%, and among these carriers, 52.8% had ATTRv cardiac amyloidosis, a dramatically higher rate of disease expression than observed in the present study.⁵ How many V142I carriers with evidence of clinical disease are we missing in practice? It is a sobering question, particularly when the present study highlights the heightened CV risk that V142I carriers face, and we know that ATTRv cardiac amyloidosis is associated with a high degree of morbidity and mortality. The present study findings underscore the urgent need to close the gap between genetic prevalence and timely diagnosis, a true call to action for providers.

Two priorities stand out: early identification of carriers and timely clinical recognition of disease. This is a call not for universal screening but for heightened clinical suspicion when features that may signal early disease evolution precede CM. Two complementary strategies could help with early identification of carriers. First, community awareness of the disease should be increased through robust educational initiatives. Community-based education should extend beyond clinicians to include patients and families, ensuring that knowledge reaches those most affected. Partnerships with churches, advocacy organizations, and community leaders can amplify outreach efforts, while mobile health tools, such as those used in the FAITH! (Fostering African American Improvement in Total Health) trial to raise CV awareness in certain communities, may offer scalable models that could be applied for raising awareness of ATTRv amyloidosis symptoms.⁶ Second, genetic counseling and cascade testing for first-degree relatives are equally critical. Genetic counselors provide comprehensive education, guide patients through sponsored testing programs, and address insurance concerns under the Genetic Information Nondiscrimination Act, and this type of support often exceeds what can be accomplished during a busy clinic visit by clinicians, highlighting the need for collaboration with genetic counselors.

Once carriers are identified, how do we ensure timely diagnosis and treatment of disease? First, multidisciplinary collaboration becomes essential. V142I ATTRv amyloidosis often manifests with orthopedic, neuropathic, and arrhythmic features before overt CM, creating opportunities for earlier detection. Consensus statements recommend ongoing evaluation for disease penetrance, and neurologists can help identify extracardiac signs such as CTS and polyneuropathy. The present study emphasizes an increased risk for neuropathy in V142I carriers, a risk likely underestimated in the past.⁷ Early recognition of these systemic clues can enable timely initiation of therapy before HF develops. Multidisciplinary collaboration, particularly with neurologists, could help identify neuropathy earlier, avoiding diagnostic delays that could lead to negative clinical implications in care. Second, increased research focus on prevention could help further improve care for carriers. The ACT-Early (Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young; NCT06563895) trial will test whether TTR stabilizers, such as acoramidis, can delay or prevent disease onset in asymptomatic carriers approaching typical age of clinical manifestation.

Sideris et al⁴ highlight the systemic impact of V142I and its association with HF or CM, arrhythmias, CTS, SS, and neuropathy, while exposing a persistent delay in clinical recognition. This continued and often overlooked delay in disease recognition not only is a missed opportunity but represents a preventable loss of therapeutic benefit given the effectiveness of disease modifying therapy in early stages. Answering this call to action will require a united effort among clinicians, genetic counselors, and community partners working together to close the gap between genetic predisposition and timely diagnosis, and to ensure initiation of therapy for those at greatest risk.

Funding Support and Author Disclosures

Dr Lyle has received research funding from Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.