Highlight
- ATTR-CA was identified in 6.66% of older Black and Caribbean Hispanic individuals with heart failure, with a higher prevalence in Black participants (7.82%) than Hispanic participants (2.15%).
- Approximately 44% of ATTR-CA cases were attributable to the hereditary V142I TTR gene variant, prevalent in 5.6% of the cohort.
- Prevalence of ATTR-CA is notably higher in Black men over 75 years, reaching 17.17%, underscoring the need for targeted screening.
- Over half of ATTR-CA cases showed wild-type TTR genotype, affirming the relevance of both hereditary and non-hereditary forms in heart failure etiology.
Study Background and Disease Burden
Transthyretin cardiac amyloidosis (ATTR-CA) is an underrecognized but increasingly diagnosable and treatable cause of heart failure (HF) predominantly affecting older adults. ATTR-CA results from the deposition of misfolded transthyretin (TTR) protein fibrils in the myocardium, leading to stiffening of the heart muscle and progressive HF symptoms. The condition manifests in two main forms: wild-type ATTR-CA (ATTRwt-CA), which occurs without mutations in the TTR gene, and variant ATTR-CA (ATTRv-CA), which is hereditary and associated with pathogenic TTR gene mutations. Among variant forms, the V142I polymorphism (formerly V122I) is the most common TTR mutation, especially among individuals of African descent, present in approximately 3% to 4% of Black Americans.
Despite its treatability, ATTR-CA remains frequently undiagnosed or misdiagnosed, often mistaken for more common causes of HF such as hypertensive heart disease or hypertrophic cardiomyopathy. This underdiagnosis contributes to a significant disease burden, emphasizing an unmet need for targeted screening, particularly in high-risk populations such as older Black and Hispanic patients with HF. Understanding the prevalence of ATTR-CA and its genetic contributors within these groups is critical to improving diagnosis, prognosis, and therapy tailoring.
Study Design
This study utilized a prospective, multicenter, cross-sectional design conducted across three major U.S. cities—Boston, New York, and New Haven. Participants included were self-identified Black or Caribbean Hispanic adults aged over 60 years with clinically diagnosed heart failure. Enrollment spanned from May 2019 to June 2024, with data analyses performed between June 2024 and May 2025.
The primary objective was to define the prevalence of ATTR-CA in this demographic and distinguish the proportion attributable to wild-type versus variant TTR gene mutations, specifically focusing on the V142I mutation. Diagnostic confirmation of ATTR-CA leveraged radionuclide imaging (technetium-99m-labeled pyrophosphate scintigraphy) to identify amyloid deposition in the myocardium. Additionally, serum and urine testing excluded light-chain (AL) amyloidosis, a differential diagnosis. Genotyping was performed to determine the presence of the V142I TTR gene variant. Comprehensive echocardiographic assessments, biochemical analyses, physical functioning measures, and quality-of-life indices were also collected.
Key Findings
The study enrolled 646 participants, comprising 550 (85.1%) Black and 186 (28.8%) Caribbean Hispanic individuals, with some overlap due to dual identification. The median age was 73 years (IQR 66–80), with nearly equal sex distribution (50.6% women). Baseline echocardiography revealed a median left ventricular wall thickness of 13 mm (IQR 12–14) and a median ejection fraction of 61% (IQR 55–66%), reflecting a predominantly preserved systolic function cohort.
The overall prevalence of ATTR-CA was 6.66% (95% confidence interval [CI] 4.73%–8.58%). Of the 43 confirmed ATTR-CA cases, 24 (55.8%) had wild-type ATTR, while 19 (44.2%) harbored the V142I variant. The V142I allele frequency was 5.6% within the cohort, and among carriers, 52.8% had clinical expression of ATTR-CA.
Sex-based prevalence did not reach statistical significance but suggested a higher rate in men (8.15%, 95% CI 5.15%–11.15%) versus women (5.20%, 95% CI 2.79%–7.61%, P = .13). Stratified by ethnicity, Black participants showed a significantly higher ATTR-CA prevalence (7.82%, 95% CI 5.57%–10.06%) compared to Caribbean Hispanic participants (2.15%, 95% CI 0.07%–4.24%), P = .004.
Age stratification revealed that Black participants aged 75 years or younger exhibited 3.42% prevalence (95% CI 1.43%–5.40%), markedly lower than the 14.04% (95% CI 9.53%–18.54%) prevalence in those older than 75 (P < .001). Within this older subgroup, Black men had the highest burden, with 17.17% (95% CI 9.74%–24.60%) affected.
These findings underscore the substantial burden of ATTR-CA among older Black individuals with HF, particularly men over 75 years. Importantly, the nearly balanced contribution of hereditary and wild-type forms suggests both genetic screening and careful phenotypic evaluation are essential for comprehensive detection.
Expert Commentary
This landmark study from Ruberg et al. significantly advances our understanding of ATTR-CA epidemiology within racial and ethnic minority populations long overlooked in amyloidosis research. The findings dovetail with emerging data emphasizing the importance of the V142I TTR mutation in African ancestry populations as a contributor to heart failure beyond traditional causes.
The clinical implication is clear: heightened suspicion and proactive diagnostic workup for ATTR-CA should be integrated into the care pathway for older Black patients with HF, especially males and those over 75. Given the availability of disease-modifying therapies such as tafamidis, timely diagnosis can translate into prognostic and therapeutic benefit.
Current heart failure guidelines have begun incorporating recommendations for amyloidosis screening in patients with unexplained left ventricular hypertrophy and preserved ejection fraction. However, this study highlights the need for ethnicity-specific risk stratification and possibly genetic testing in at-risk populations to optimize early identification.
Limitations include the cross-sectional design precluding longitudinal outcome assessment, and geographic concentration possibly limiting generalizability. Future studies should address longitudinal clinical outcomes, therapeutic response differences, and the impact of socio-environmental factors.
Conclusions
This prospective multicenter analysis reveals that transthyretin cardiac amyloidosis is a clinically significant and underdiagnosed cause of heart failure in older Black individuals, with a prevalence markedly increasing in men over 75 years. The hereditary V142I TTR variant contributes to nearly half of ATTR-CA cases in this population, while wild-type ATTR continues to represent a majority overall.
These data support incorporation of targeted ATTR-CA screening and genetic testing into heart failure diagnostic protocols for older Black patients. Broader awareness and diagnostic vigilance are warranted to reduce morbidity and mortality associated with this treatable cardiomyopathy.
References
Ruberg FL, Teruya S, Helmke S, Smiley DA, Fine D, Kurian D, Raiszadeh F, Prokaeva T, Spencer B, Wong S, Pandey S, Blaner WS, DeLuca A, Johnson LL, Kinkhabwala MP, Leb J, Mintz A, LaValley MP, Einstein AJ, Cohn E, Gallegos C, Murtagh G, Kelly JW, Miller EJ, Maurer MS. Transthyretin Cardiac Amyloidosis in Older Black and Hispanic Individuals With Heart Failure. JAMA Cardiology. 2025 Sep 10:e252948. doi:10.1001/jamacardio.2025.2948. Epub ahead of print. PMID: 40928765; PMCID: PMC12423950.
Maurer MS, Elliott P, Merlini G, et al. Design and Rationale of the ATTR-ACT Clinical Trial: A Phase III Study of Tafamidis in Patients with Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. 2017;10(6):e003815. doi:10.1161/CIRCHEARTFAILURE.117.003815
Geppert A, Barzilai B. Genetic Associations of Transthyretin Variant V142I and Cardiomyopathy in African Americans. JAMA Cardiol. 2020;5(12):1456-1457. doi:10.1001/jamacardio.2020.3050
