Key Points
Question
What is the prevalence of transthyretin cardiac amyloidosis (ATTR-CA) and the proportion of ATTR-CA attributable to the common hereditary TTR gene variant V142I among Black and Caribbean Hispanic patients with heart failure (HF) aged 60 years and older?
Findings
In this cross-sectional study, among 646 participants with median (IQR) age 73 (66-80) years, ATTR-CA was the cause of HF in 7.8% of Black participants overall and 17.2% of Black participants older than 75 years, but only 2.2% of Hispanic participants. Wild-type ATTR-CA was more common (55.8%) than abnormal hereditary V142I ATTR-CA (ATTRv-CA, 44.2%); among V142I genotype carriers with HF, the phenotype of ATTRv-CA was present in 52.8%.
Meaning
Older men were more likely to have ATTR-CA and penetrant V142I disease, and the presence of V142I alone was insufficient to identify ATTR-CA in this at-risk population.
Abstract
Importance
Transthyretin cardiac amyloidosis (ATTR-CA) is an underdiagnosed but treatable cause of heart failure (HF) in older individuals that occurs in the context of normal wild-type (ATTRwt-CA) or an abnormal inherited (ATTRv-CA) TTR gene variant. While the most common inherited TTR variant, V142I, occurs in 3% to 4% of self-identified Black Americans and is associated with excess morbidity and mortality, the prevalence of ATTR-CA in this at-risk population is unknown.
Objective
To define the prevalence of ATTR-CA and proportions attributable to ATTRwt-CA or ATTRv-CA among older Black and Caribbean Hispanic individuals with HF.
Design, Setting, and Participants
This prospective, multicenter, cross-sectional study was conducted in several major US cities (Boston, Massachusetts; New York, New York; and New Haven, Connecticut) among individuals who self-identified as Black or Caribbean Hispanic older than 60 years with HF. Participants were enrolled between May 2019 and June 2024, and data analysis was conducted from June 2024 to May 2025.
Main Outcomes and Measures
ATTR-CA was determined by radionuclide imaging, with blood testing to exclude light-chain amyloidosis and genotyping to determine TTR gene variant. Echocardiographic, biochemical, physical performance, and quality-of-life data were collected.
Results
Among 646 participants, median (IQR) participant age was 73 (66-80) years, 329 (50.6%) were women, 550 (85.1%) identified as Black, and 186 (28.8%) identified as Caribbean Hispanic. Median (IQR) left ventricular wall thickness was 13 (12-14) mm, and median (IQR) left ventricular ejection fraction was 61% (55%-66%). Overall prevalence of ATTR-CA was 6.66% (95% CI, 4.73%-8.58%), of whom 24 (55.8%) had ATTRwt-CA and 19 (44.2%) had ATTRv-CA owing to V142I. Overall prevalence of V142I allele was 5.6%, and of those, 19 (52.8%) had ATTRv-CA. Prevalence of ATTR-CA was 8.15% (95% CI, 5.15%-11.15%) in men and 5.20% (95% CI, 2.79%-7.61%) in women (P = .13). Prevalence of ATTR-CA was 7.82% (95% CI, 5.57%-10.06%) in Black participants and 2.15% (95% CI, 0.07%-4.24%) in Hispanic participants (P = .004). Among Black participants aged 75 years or younger, ATTR-CA was observed in 3.42% of participants (95% CI, 1.43%-5.40%) compared to 14.04% (95% CI, 9.53%-18.54%) of those older than 75 years (P < .001). Among Black male participants older than 75 years, prevalence of ATTR-CA was 17.17% (95% CI, 9.74%-24.60%).
Conclusions and Relevance
In this cross-sectional study, ATTR-CA was an important cause of HF in older Black individuals with HF, particularly in men older than 75 years. Approximately half of V142I carriers with HF had ATTR-CA, while 55.8% of all ATTR-CA cases had normal TTR genotype.
Trial Registration
ClinicalTrials.gov Identifier: NCT03812172
This multicenter cross-sectional study defines the prevalence of transthyretin cardiac amyloidosis and proportions attributable to normal wild type or an abnormal inherited TTR gene variant among older Black and Caribbean Hispanic individuals with heart failure.
Introduction
Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) morbidity and mortality in individuals older than 60 years.1 ATTR-CA results from misfolding of circulating TTR protein, followed by aggregation and myocardial deposition of TTR amyloid fibrils.2 TTR (eg, prealbumin) is a homotetramer coded by a 4-exon gene on chromosome 18 that transports thyroxine and retinol (vitamin A). While inherited pathological variants in TTR facilitate tetramer dissociation and misfolding (ATTRv), misfolding can also occur sporadically in the context of normal TTR genetic sequence (ATTRwt) through incompletely understood mechanisms. ATTR-CA is a disease of aging, with typical onset over age 60 years and male predilection.1 The most common variant, V142I (legacy nomenclature V122I or Val122Ile), has been identified in 3% to 4% of self-identified Black individuals in the US, rendering it present in 1.5 million Black US individuals.3,4 As most V142I carriers have ancestry that originated in western Africa, the allele also occurs at increased frequency in Afro-Caribbean and Caribbean Hispanic individuals. Recent evidence suggests that carriage of this allele increases the risk for HF hospitalization at age 50 years and death at age 65 years, conferring substantial public health implications.5 Despite strong evidence that V142I allele carriers experience increased risk,6,7 to our knowledge, no studies have established the actual presence of ATTR-CA among carriers, such that phenotypic penetrance remains poorly defined.8
Increased awareness and improvements in diagnostic imaging testing have identified ATTR-CA in different disease cohorts, including those hospitalized or community dwelling with heart failure with a preserved ejection fraction (HFpEF),9,10 with severe aortic stenosis referred for valve replacement,11,12 and with assumed hypertrophic cardiomyopathy.13,14 Importantly, these studies enrolled very few (if any) Black individuals, such that the true prevalence of ATTR-CA in the at-risk population of older Black patients with HF more likely to inherit V142I remains unknown. Finally, ATTR-CA is now a treatable disease, with multiple US Food and Drug Administration (FDA)–approved therapies that reduce the risk for HF progression and improve survival.15,16,17 These therapies are most effective when instituted early in the course of disease.16 Thus, it is imperative to define the proportion of older Black patients with HF that is caused by ATTR-CA.
The SCAN-MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study was designed to address these critical uncertainties. SCAN-MP was funded by the US National Heart, Lung, and Blood Institute (NHLBI) as a multicenter, prospective, observational study to enroll self-identified individuals who are Black or Caribbean Hispanic with HF and older than 60 years. Participants were tested for TTR gene variants, as well the presence of ATTR-CA, using cardiac amyloid nuclear imaging. The principal objectives of SCAN-MP were to identify the prevalence of ATTR-CA as stratified by sex, age, and race or ethnicity, as well as to define the proportion of ATTR-CA attributable to the V142I allele.
Methods
Study Participants
The SCAN-MP study was a prospective, multicenter, cross-sectional cohort study, funded by the US National Institutes of Health (NIH)/NHLBI, that commenced in 2019 and ended in 2024. Study sites included Columbia University Irving Medical Center and Harlem Hospital in New York, New York; Boston Medical Center in Boston, Massachusetts; and, as of April 2022, Yale New Haven Hospital (New Haven, Connecticut). Study design details have been reported elsewhere.18 Primary inclusion criteria included age 60 years or older, self-identified Black race or Hispanic ethnicity of Caribbean origin, a diagnosis of HF validated by record review using prespecified criteria (see eMethods in Supplement 1), as well as echocardiographic left ventricular wall thickness of 1.2 cm or higher and left ventricular ejection fraction (LVEF) greater than 30% (as reported on clinical echocardiograms). Primary exclusion criteria included known systemic amyloidosis, HF primarily caused by left-sided valvular heart disease or ischemic heart disease (in the opinion of the study team), end-stage kidney disease (defined as an estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2), dementia or prior stroke precluding participation in study procedures, or active malignancy with expected survival less than 1 year. The final enrollment was 650 participants. eFigure 1 in Supplement 1 demonstrates screened, excluded, eligible, and enrolled participants. There were 4 dropouts, conferring a final study population of 646 participants.
SCAN-MP was an observational, noninterventional study wherein enrolled participants were tested for ATTR-CA by cardiac amyloidosis nuclear imaging and 4-exon TTR genotyping to determine the presence or absence of ATTR-CA and underlying genotype. Participants diagnosed with ATTR-CA or a pathogenic genotype (all V142I) were referred to the amyloidosis treatment centers at respective institutions for subsequent testing to exclude light-chain amyloidosis and for clinical care. The study protocol was approved by the Western Institutional Review Board through a single-IRB mechanism. All participants provided written informed consent before inclusion. All data collected will be deposited into an NHLBI-supported data repository. Biological samples, imaging, and associated metadata were contributed to the NHLBI HeartShare initiative via the BioData Catalyst cloud-based interface and Trans-omics for Precision Medicine (TOPmed) biorepository. Additional details regarding study design can be found in the eMethods and eTables 1 and 2 in Supplement 1. Data presentation follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Diagnostic Testing
Echocardiography, Electrocardiography, and Nuclear Imaging
Study protocols and case report forms were developed for the diagnostic testing modalities. Echocardiography was performed at the study sites per protocol, with images transferred to the core reading laboratory at Boston Medical Center. Electrocardiograms were performed at all study sites, with measurements and interpretations by study staff at those sites. Tc99m-pyrophosphate (PYP) or Tc99m–hydroxymethylene diphosphonate imaging (the latter performed in 2 participants only in the instance of PYP shortage owing to nationwide supply chain disruptions) was performed, with images transferred to a core laboratory at Columbia University and analyzed by 3 expert independent readers. Additional details regarding imaging are in the eMethods in Supplement 1.
Biomarker Analyses and Genotyping
Cardiac-specific biomarker analyses were performed through an in-kind research contract with Abbott Laboratories. Creatinine was measured locally by the clinical chemistry laboratories at sites, while prealbumin was measured exclusively at the Boston Medical Center site. eGFR was calculated using the CKD-Epi equation. The UK National Amyloidosis Centre (NAC) and Columbia stages for ATTR-CA were calculated accordingly. Genotyping of TTR was performed by 4-exon polymerase chain reaction at the Clinical Laboratory Improvement Amendments–certified core laboratory at Boston University. The variant p.V142I is commonly referred to as V142I, and this abbreviation was used in this study.
Questionnaires, Functional Testing, and Socioeconomic Assessment
Participants completed questionnaires assessing symptom burden, including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Short Form Survey-12. The area deprivation index (ADI) was calculated for each participant to assess the degree of socioeconomic disadvantage experienced. ADI is a multidimensional evaluation of socioeconomic conditions and was reported in state and national deciles, with higher values associated with greater socioeconomic disadvantage. Functional testing included 6-minute walk distance and the Short Physical Performance Battery, which includes chair stand, tandem walk, and gait speed components.
Statistical Analysis
Comparison of demographics and baseline clinical and laboratory parameters was performed between positive and negative ATTR-CA participants and between participants with ATTRwt-CA and ATTRv-CA. Continuous variables were described as mean and interquartile range, with differences assessed with t tests for normally distributed data or the Mann-Whitney U test for data that were not normally distributed. Normality was assessed with the Shapiro-Wilk test for sample sizes less than 50 or the Kolmogorov-Smirnov test for larger sample sizes. Categorical variables were described as numbers and percentages and compared using the χ2 test or Fisher exact test (where appropriate). ATTR-CA prevalence within predefined categories (ie, overall, men, women, Black, Hispanic, age ≤75 years, and age >75 years) was compared between the following 4 different groups: entire cohort, Black race, wall thickness 1.2 cm or greater, and Black race and wall thickness 1.2 cm or greater. Any differences in the predefined categories between the 4 groups were evaluated using 95% confidence intervals. Statistical tests were 2-sided; P < .05 was deemed significant. Statistical analyses were performed using SAS software, version 9.4 (SAS Institute).
Results
Participant Demographics and Characteristics
Table 1 illustrates the demographics and characteristics of the SCAN-MP cohort, stratified by the presence or absence of ATTR-CA. A total of 646 participants were enrolled, of whom 43 (6.7%) had testing diagnostic consistent with ATTR-CA, and 2 participants were diagnosed with light-chain cardiac amyloidosis. Median (IQR) age was 73 (66-80) years, 329 participants (50.6%) were women, 550 (85.1%) identified as Black race, and 186 (28.8%) identified as having Caribbean Hispanic ethnicity. Compared to ATTR-CA–negative participants, those with ATTR-CA were older (median age, 80 vs 72 years; P < .001) and less commonly of Hispanic ethnicity (9.3% vs 30.2%; P = .004). Participants with ATTR-CA also had lower median body mass index (BMI, calculated as weight in kilograms divided by height in meters squared; 28.6 vs 31.6; P < .001) and less hypertension (58.1% vs 77.9%; P = .003) and diabetes (23.3% vs 53.2%; P < .001). There was no difference in sex, history of atrial fibrillation, or evidence of increased social disability by the ADI between the 2 groups. Medication use in the community screening cohort is shown in eTable 2 in Supplement 1.
Table 1. Participant Demographics and Characteristics.
| Characteristic | No. (%)a | P value | ||
|---|---|---|---|---|
| Overall (N = 646) | ATTR-CA | |||
| Negative (n = 603) | Positive (n = 43) | |||
| Age, median (IQR), y | 73 (66-80) | 72 (65-79) | 80 (75-86) | <.001 |
| Sex | ||||
| Female | 327 (50.6) | 310 (51.4) | 17 (39.5) | .13 |
| Male | 319 (49.4) | 293 (48.6) | 26 (60.5) | |
| Raceb | ||||
| Black | 550 (85.1) | 507 (84.1) | 43 (100) | .02 |
| Non-Black | 13 (2) | 13 (2.2) | 0 | |
| Unknown or not reported | 83 (12.9) | 83 (13.8) | 0 | |
| Hispanic ethnicityb | 186 (28.8) | 182 (30.2) | 4 (9.3) | .004 |
| BMI, median (IQR)c | 31.5 (27.5-36.5) | 31.6 (27.8-36.8) | 28.6 (25.4-32.6) | <.001 |
| Hypertensiond | 495 (76.6) | 470 (77.9) | 25 (58.1) | .003 |
| Diabetes | 331 (51.2) | 321 (53.2) | 10 (23.3) | <.001 |
| History of AF | 184 (28.5) | 172 (28.5) | 12 (27.9) | .93 |
| ADI state decile, median (IQR) | 5 (2-6) | 5 (2-6) | 4 (2-6) | .09 |
| ADI national percentile, median (IQR) | 18 (8-26) | 18 (8-26) | 16 (4-28) | .26 |
Abbreviations: ADI, area deprivation index; AF, atrial fibrillation; ATTR-CA, transthyretin cardiac amyloidosis; BMI, body mass index.
Continuous variables were compared using Mann-Whitney U test; categorical variables were compared using χ2 test or Fisher exact test, as appropriate.
Race and ethnicity were self-reported.
Calculated as weight in kilograms divided by height in meters squared.
Hypertension defined as blood pressure ≥130/80 mm Hg at baseline visit.
Biomarker, Echocardiographic, and Functional Parameters
Compared to those without ATTR-CA, participants with ATTR-CA had substantially higher median plasma cardiac biomarkers, including B-type natriuretic peptide (BNP, 294.0 vs 75.4 pg/mL [to convert to nanograms per liter, multiply by 1]; P < .001), N-terminal pro-BNP (NT-proBNP, 1616.9 vs 352.1 pg/mL; P < .001), high-sensitivity troponin I (Hs-TnI, 55.7 vs 9.9 ng/L; P < .001), and high-sensitivity troponin T (Hs-TnT, 45.7 vs 17.0 pg/mL [to convert to micrograms per liter, multiply by 0.001]; P < .001) (Table 2). ATTR-CA–positive participants also had lower median prealbumin (20 vs 25 mg/dL [to convert to milligrams per liter, multiply by 10]; P < .001) and lower mean eGFR (57.4 vs 63.3 mL/min/1.73 m2; P = .05). Cardiac structural and functional differences by echocardiography were evident among participants with ATTR-CA, including higher median maximal wall thickness (1.5 vs 1.2 cm; P < .001). While overall LVEF for the entire cohort was normal (median [IQR] LVEF, 61% [55%-66%]), and 549 participants (86.2%) in the entire cohort had LVEF greater than 50% (ie, consistent with HFpEF), a smaller proportion of participants with ATTR-CA had LVEF greater than 50% (29 [74.4%] vs 520 [86.2%]; P = .03). Participants with ATTR-CA also had evidence of more pronounced diastolic dysfunction by mean e’ (4.3 vs 5.7 cm/s; P < .001) and evidence of increased left atrial pressure by median E/e’ (18.9 vs 13.3; P < .001). Electrocardiography (ECG) demonstrated a low voltage pattern more commonly among participants with ATTR-CA (12 [27.9%] vs 50 [8.3%]; P < .001) and a lower ECG voltage to LV mass ratio (12 vs 19 µV/g/m2; P < .001). There was no difference in the presence of an LV hypertrophy pattern or atrial fibrillation. Finally, participants with ATTR-CA had evidence of more impaired functional capacity by median 6-minute walk distance (245 vs 273 m; P < .001), while self-reported health status by median KCCQ overall score (67.5 vs 65.3; P = .86) and New York Heart Association (NYHA) classification did not significantly differ between those with and without ATTR-CA.
Table 2. Biomarker, Echocardiographic, and Functional Parameters.
| Parameter | Median (IQR)a | P value | ||
|---|---|---|---|---|
| Overall (N = 646) | ATTR-CA | |||
| Negative (n = 603) | Positive (n = 43) | |||
| Laboratory | ||||
| BNP, pg/mL | 82.0 (33.9-209.4) | 75.4 (31.9-192.8) | 294.0 (118.4-589.3) | <.001 |
| NT-proBNP, pg/mL | 393.6 (147.8-1042.8) | 352.1 (139.3-919.9) | 1616.9 (691.2-3007.8) | <.001 |
| Ln BNP, pg/mL | 4.4 (3.5-5.3) | 4.3 (3.5-5.3) | 5.7 (4.8-6.4) | <.001 |
| Ln NT-proBNP, pg/mL | 6.0 (5-6.9) | 5.9 (4.9-6.8) | 7.4 (6.5-8) | <.001 |
| Hs-TnI, ng/L | 10.4 (5.3-21.8) | 9.9 (5.1-18.2) | 55.7 (31.9-97.8) | <.001 |
| Hs-TnT, ng/L | 18.0 (11.7-30.8) | 17.0 (11.3-27.5) | 45.7 (29.9-75.1) | <.001 |
| eGFR, mean (SD), mL/min/1.73 m2 | 62.9 (23.9) | 63.3 (24.2) | 57.4 (18.1) | .05 |
| Prealbumin, median (IQR), mg/dL | 25 (21-29) | 25 (22-29) | 20 (15-24) | <.001 |
| Echocardiography | ||||
| Maximal wall thickness, cm | 1.3 (1.2-1.4) | 1.2 (1.2-1.4) | 1.5 (1.3-1.7) | <.001 |
| LVEF, % | 61 (55-66) | 61 (55-67) | 60 (50-65) | .10 |
| HFpEF (LVEF >50%), No. (%) | 549 (86.2) | 520 (86.2) | 29 (74.4) | .03 |
| LA volume, mL | 74 (60-94) | 73.4 (60-93) | 79 (69-98) | .07 |
| Mean e’, cm/s | 5.6 (4.5-7) | 5.7 (4.5-7) | 4.3 (3.6-5.4) | <.001 |
| E/e’ | 13.5 (10.3-17.5) | 13.3 (10.3-17.1) | 18.9 (14.5-23.4) | <.001 |
| Electrocardiography | ||||
| Low voltage, No. (%) | 62 (9.6) | 50 (8.3) | 12 (27.9) | <.001 |
| LVH pattern, No. (%) | 46 (7.3) | 45 (7.6) | 1 (2.3) | .35 |
| AF on ECG, No. (%) | 86 (13.4) | 81 (13.5) | 5 (11.6) | .73 |
| Voltage to LV mass ratio, µV/g/m2 | 18.5 (12.3-25.7) | 19 (13.3-26.1) | 12 (7.8-16.1) | <.001 |
| Functional testing | ||||
| 6MWT, m | 273 (160-360) | 273 (163-360) | 245 (120-330) | <.001 |
| SPPB total score | 8 (5-9) | 8 (5-9) | 7 (5-9) | .05 |
| NYHA class, No. (%) | ||||
| I | 155 (24.1) | 146 (24.3) | 9 (21.4) | .39 |
| II | 329 (51.2) | 309 (51.4) | 20 (47.6) | |
| III | 154 (24) | 142 (23.6) | 12 (28.6) | |
| IV | 5 (0.8) | 4 (0.7) | 1 (2.4) | |
| Patient-reported outcomes | ||||
| KCCQ-OS | 65.4 (46.6-84.9) | 65.3 (46.6-85.4) | 67.5 (51.1-83.4) | .86 |
| SF-12v2 | ||||
| PCS | 38.4 (31-45.7) | 38.4 (30.7-45.7) | 38.7 (34.4-44.6) | .44 |
| MCS | 51.3 (42.4-59.4) | 51.3 (42.1-59.6) | 51.1 (46.3-58) | .56 |
Abbreviations: 6MWT, 6-minute walk test; AF, atrial fibrillation; ATTR-CA, transthyretin cardiac amyloidosis; BNP, B-type natriuretic peptide; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; Hs-TnI, high-sensitivity troponin I; Hs-TnT, high-sensitivity troponin T; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire overall summary; LA, left atrial; Ln, natural logarithm; LV, left ventricular; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; MCS, Mental Component Summary; NT-proBNP, N-terminal pro-BNP; NYHA, New York Heart Association; PCS, Physical Component Summary; SF-12v2, 12-item Short-Form Health Survey, version 2; SPPB, short physical performance battery.
SI conversion factors: To convert BNP from pg/mL to ng/L, multiply by 1; Hs-TnI and Hs-TnT, from ng/L to µg/L, multiply by 0.001; prealbumin, from mg/dL to mg/L, multiply by 10.
Continuous variables were compared using Mann-Whitney U test for all variables except eGFR, which was analyzed using the independent samples t test; categorical variables were compared using χ2 test or Fisher exact test, as appropriate.
Prevalence of ATTR-CA
The prevalence of ATTR-CA in the entire cohort and among prespecified subgroups is illustrated in the Figure. The overall prevalence of ATTR-CA among the entire cohort (Figure A) was 6.66% (95% CI, 4.73%-8.58%), of whom 24 (55.8%) were ATTRwt-CA and 19 (44.2%) were ATTRv-CA owing to V142I. While numerically greater, there was no statistically significant difference in the prevalence of ATTR-CA among men (8.15%; 95% CI, 5.15%-11.15%) and women (5.20%; 95% CI, 2.79%-7.61%; P = .13). Conversely, the ATTR-CA prevalence was greater among participants who identified as Black (7.82%; 95% CI, 5.57%-10.06%) vs those who identified as Hispanic (2.15%; 95% CI, 0.07%-4.24%; P = .004). The prevalence of ATTR-CA was higher among participants in the older age group: ATTR-CA prevalence among those older than 75 years was 11.72% (95% CI, 7.91%-15.54%), while it was 2.95% (95% CI, 1.23%-4.67%) among those aged 75 years or younger (P < .001). Figure B illustrates the prevalences of ATTR-CA stratified by age and sex among participants who identified as Black (n = 550). Similar to the overall cohort, the prevalence of ATTR-CA among Black participants was similar among men (9.70%; 95% CI, 6.16%-13.25%) and women (6.03%; 95% CI, 3.25%-8.81%; P = .11), while the prevalence was higher in older (>75 years) participants (14.04%; 95% CI, 9.53%-18.54%) vs younger participants (≤75 years; 3.42%; 95% CI, 1.43%-5.40%; P < .001). The prevalence of ATTR-CA was highest among Black men over age 75 years at 17.17% (95% CI, 9.74%-24.60%). Protocol-acquired echocardiograms analyzed in a core laboratory determined that 444 participants (78.2%) met the wall thickness inclusion threshold of 1.2 cm or greater. There were no differences in ATTR-CA prevalences among the prespecified subgroups for the entire cohort and those with wall thickness of 1.2 cm or greater (Table 3; eFigure 2 in Supplement 1).
Figure. Prevalence of Transthyretin Cardiac Amyloidosis (ATTR-CA) Among All SCAN-MP Participants and Among Self-Identified Black SCAN-MP Participants.
Prevalence of ATTR-CA is demonstrated, with points indicative of means and error bars reflective of 95% confidence intervals for all participants (n = 646) (A) and self-identified Black participants (n = 550) (B). Prevalence data are further demonstrated by prespecified subgroups, including further characterization by sex, Black race, Hispanic ethnicity, and age ≤75 or >75 years.
Table 3. Transthyretin Cardiac Amyloidosis (ATTR-CA) Prevalence in the Entire Cohort and Among Subgroups.
| Prevalence (95% CI), % | ||||
|---|---|---|---|---|
| Entire cohort (N = 646) | Black race (n = 550) | Wall thickness ≥1.2 cm (n = 444) | Black race and wall thickness ≥1.2 cm (n = 384) | |
| Overall | 6.66 (4.73-8.58) | 7.82 (5.57-10.06) | 8.11 (5.57-10.65) | 9.38 (6.46-12.29) |
| Men | 8.15 (5.15-11.15) | 9.70 (6.16-13.25) | 10.43 (6.48-14.39) | 11.94 (7.46-16.42) |
| Women | 5.20 (2.79-7.61) | 6.03 (3.25-8.81) | 5.61 (2.52-8.69) | 6.56 (2.97-10.14) |
| Black race | 7.82 (5.57-10.06) | 7.82 (5.57-10.06) | 9.38 (6.46-12.29) | 9.38 (6.46-12.29) |
| Hispanic ethnicity | 2.15 (0.07-4.24) | 4.44 (0.19-8.70) | 3.08 (0.11-6.05) | 5.71 (0.28-11.15) |
| Age ≤75 y | 2.95 (1.23-4.67) | 3.42 (1.43-5.40) | 3.91 (1.53-6.28) | 4.44 (1.75-7.14) |
| Age >75 y | 11.72 (7.91-15.54) | 14.04 (9.53-18.54) | 13.83 (8.90-18.76) | 16.35 (10.60-22.10) |
Features of Hereditary V142I and Wild-Type ATTR-CA
Genotyping identified 36 participants (5.6%) with V142I. Among those with V142I, 19 (52.8%) had testing consistent with ATTR-CA and therefore had clinically penetrant disease, while 17 (47.2%) did not have testing consistent with ATTR-CA and therefore were categorized as allele carriers. V142I carriers with and without penetrant ATTRv-CA were older (median [IQR] age, 78 [73-83] years vs 70 [65-83] years; P = .18) but similar by sex (52.6 vs 52.9%; P = .99). Genotype classification of the 43 ATTR-CA cases demonstrated that 19 (44.2%) were V142I ATTRv-CA, while 24 (55.8%) were ATTRwt-CA. Table 4 illustrates the demographic, imaging, and biomarker characterization of all ATTR-CA cases stratified by genotype. V142I ATTRv-CA cases trended younger (mean [SD] age, 77.6 [7.3] vs 82.5 [8.6] years; P = .06) and had lower prealbumin (mean [SD] 14.1 [4.2] vs 23.8 [4.0] mg/dL; P < .001) and lower LVEF (51.7% vs. 60.9%; P = .01; P = .03). Notably, there were no significant differences in cardiac-specific biomarkers, eGFR, NAC or Columbia stage, NYHA class, physical performance, or reported quality of life.
Table 4. Features of Wild-Type Transthyretin Cardiac Amyloidosis (ATTRwt-CA) and Hereditary V142I ATTR-CA.
| Characteristic | No. (%)a | P valuea | ||
|---|---|---|---|---|
| Overall (n = 43) | ATTRwt-CA (n = 24) | V142I ATTRv-CA (n = 19) | ||
| Age, mean (SD), y | 80.3 (8.3) | 82.5 (8.6) | 77.6 (7.3) | .06 |
| Sex | ||||
| Female | 17 (39.5) | 8 (33.3) | 9 (47.4) | .35 |
| Male | 26 (60.5) | 16 (66.7) | 10 (52.6) | |
| BMI, mean (SD)b | 28.9 (5.9) | 28.5 (5.3) | 29.4 (6.7) | .62 |
| Laboratory | ||||
| BNP, median (IQR), pg/mL | 294.0 (118.4-589.3) | 269.7 (118.4-589.3) | 328.2 (109.1-675.3) | .82 |
| NT-proBNP, median (IQR), pg/mL | 1616.9 (691.2-3007.8) | 1208.8 (742.4-4215.6) | 1949.3 (637.3-2721) | .97 |
| Ln BNP, mean (SD), pg/mL | 5.6 (1.0) | 5.6 (0.9) | 5.6 (1.1) | .82 |
| Ln proBNP, mean (SD), pg/mL | 7.4 (1.2) | 7.4 (1.2) | 7.4 (1.3) | .89 |
| Hs-TnI, median (IQR), ng/L | 55.7 (31.9-97.8) | 51.0 (30.2-104.9) | 56.2 (39.4-91.2) | .60 |
| Hs-TnT, mean (SD), ng/L | 54.0 (32.3) | 49.3 (27.1) | 59.6 (37.6) | .31 |
| eGFR, mean (SD), mL/min/1.73 m2 | 57.4 (18.1) | 53.2 (16.4) | 62.6 (19.3) | .09 |
| Prealbumin, mean (SD), mg/dL | 19.5 (6.4) | 23.8 (4.0) | 14.1 (4.2) | <.001 |
| NAC biomarker stage | ||||
| I | 26 (63.4) | 13 (56.5) | 13 (72.2) | .59 |
| II | 9 (22.0) | 6 (26.1) | 3 (16.7) | |
| III | 6 (14.6) | 4 (17.4) | 2 (11.1) | |
| Columbia biomarker stage | ||||
| I | 16 (41.0) | 7 (31.8) | 9 (52.9) | .39 |
| II | 21 (53.9) | 14 (63.6) | 7 (41.2) | |
| III | 2 (5.1) | 1 (4.6) | 1 (5.9) | |
| Echocardiography | ||||
| Maximal wall thickness, mean (SD), cm | 1.5 (0.2) | 1.5 (0.3) | 1.6 (0.2) | .42 |
| LVEF, mean (SD), % | 56.9 (11.7) | 60.9 (9.1) | 51.7 (12.9) | .01 |
| HFpEF (LVEF >50%) | 29 (74.4) | 18 (81.8) | 11 (64.7) | .28 |
| LA volume, mean (SD), mL | 84.4 (23.0) | 89.4 (26.8) | 78.2 (15.9) | .12 |
| Mean e’, median (IQR), cm/s | 4.3 (3.6-5.4) | 4.1 (3.7-5.2) | 4.5 (3.6-5.6) | .79 |
| E/e’, median (IQR) | 18.9 (14.5-23.4) | 19.5 (17.3-24.9) | 16.9 (13.7-23.4) | .71 |
| Electrocardiography | ||||
| Low voltage | 12 (27.9) | 4 (16.7) | 8 (42.1) | .06 |
| LVH pattern | 1 (2.3) | 1 (4.2) | 0 | >.99 |
| AF on ECG | 5 (11.6) | 3 (12.5) | 2 (10.5) | >.99 |
| Voltage to LV mass ratio, mean (SD), µV/g/m2 | 12.6 (8.7) | 14.2 (9.8) | 10.5 (6.5) | .24 |
| Functional testing, mean (SD) | ||||
| 6MWT, m | 235.9 (124.6) | 240.3 (141.8) | 230.1 (101.8) | .31 |
| SPPB total score | 6.9 (3.2) | 6.9 (3.5) | 7.0 (2.8) | .09 |
| NYHA class | ||||
| I | 9 (21.4) | 4 (16.7) | 5 (27.8) | .52 |
| II | 20 (47.6) | 13 (54.2) | 7 (38.9) | |
| III | 12 (28.6) | 7 (29.2) | 5 (27.8) | |
| IV | 1 (2.4) | 0 | 1 (5.6) | |
| Patient-reported outcomes, mean (SD) | ||||
| KCCQ-OS score | 64.9 (22.5) | 66.6 (24.1) | 62.5 (20.5) | .56 |
| SF-12v2 | ||||
| PCS | 39.6 (8.6) | 40.3 (8.3) | 38.7 (9.0) | .54 |
| MCS | 51.7 (8.9) | 51.6 (9.8) | 51.7 (7.6) | .98 |
Abbreviations: 6MWT, 6-minute walk test; AF, atrial fibrillation; ATTRv-CA, variant transthyretin cardiac amyloidosis; BMI, body mass index; BNP, B-type natriuretic peptide; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; Hs-TnI, high-sensitivity troponin I; Hs-TnT, high-sensitivity troponin T; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire overall summary; LA, left atrial; Ln, natural logarithm; LV, left ventricular; LVEF, LV ejection fraction; LVH, left ventricular hypertrophy; MCS, Mental Component Summary; NAC, National Amyloidosis Centre; NT-proBNP, N-terminal pro-BNP; NYHA, New York Heart Association; PCS, Physical Component Summary; SF-12v2, 12-item Short-Form Health Survey, version 2; SPPB, short physical performance battery.
SI conversion factors: To convert BNP from pg/mL to ng/L, multiply by 1; Hs-TnI and Hs-TnT, from ng/L to µg/L, multiply by 0.001; prealbumin, from mg/dL to mg/L, multiply by 10.
Categorical variables were compared using χ2 test or Fisher exact test, as appropriate. P values calculated using independent samples t test or Mann-Whitney U test.
Calculated as weight in kilograms divided by height in meters squared.
Discussion
The SCAN-MP study was designed to address critical knowledge gaps in the burden of disease conferred by ATTR-CA in older Black and Hispanic patients with HF who, by virtue of the common TTR V142I variant, are at the highest risk for adverse outcomes. SCAN-MP was distinct from prior studies owing to its prospective design, rigorous genotyping and phenotyping methodology, and inclusion limited to older Black or Hispanic patients with HF. The principal findings of this study included the fact that ATTR-CA was the cause of HF in 7.8% of Black participants overall and 17.2% of Black participants older than 75 years of age, but in only 2.2% of Hispanic participants. Second, the prevalence of ATTR-CA was statistically similar among men (8.2%) and women (5.2%) in this active ascertainment (ie, screening) cohort. Third, among cases of ATTR-CA identified, there were more cases of ATTRwt-CA (55.8%) than V142I ATTRv-CA, indicating that genotyping alone is insufficient to conclude the presence of ATTR-CA in this at-risk population. Fourth, among the V142I genotype carriers with HF, ATTRv-CA was observed in 52.8%, with older male participants more likely to have evident disease. Our findings have important clinical implications. Given the high prevalence of ATTR-CA observed, particularly among individuals older than 75 years, our findings in SCAN-MP suggest that screening for ATTR-CA should be considered for all self-identifying Black individuals with HF and an increased wall thickness.
The observed ATTR-CA prevalence estimates in this cohort of Black or Hispanic patients with HF and an increased wall thickness are similar to previous epidemiologic studies, most of which were not prospective, with estimates from 6% to 18%.9,10,19,20 Notably, one prior study that screened patients with HF but without an increased wall thickness criterion identified a prevalence of 5%.21 In our study, when considering only Black participants with a core laboratory–verified wall thickness of 12 mm or higher, the overall prevalence of ATTR-CA was higher. As interest has grown in identifying patients with ATTR-CA earlier in the course of the disease, when disease-modifying therapy has the greatest benefit, techniques have emerged that leverage scoring systems as well as machine learning and artificial intelligence of electronic health records, electrocardiograms, and echocardiograms.22,23,24,25,26 Such techniques hold great promise for early identification of affected individuals but will require carefully performed prospective investigations of multicenter cohorts in diverse populations to determine clinical utility.
In SCAN-MP, we observed numerically higher prevalence of ATTR-CA in men than in women, but this difference was not statistically significant. In fact, among the new cases of ATTR-CA identified, women comprised nearly 40%, likely owing to study design, which mandated enrollment of equal numbers of women and men. Our findings are discordant from retrospective cohort studies enrolled at large academic referral centers, in which less than 20% of the population with ATTR-CA were women.27,28 While we believe based on clinical experience and the totality of evidence reported that ATTR-CA is indeed more common in men, our data suggest that ATTR-CA is underdiagnosed in women. This may be potentially attributable to the different reference ranges for wall thickness and left ventricular mass index by sex, which are not accounted for in current guidelines that advise a singular wall thickness threshold irrespective of sex (>12 mm) to trigger suspicion of cardiac amyloidosis. Indeed, other screening or active ascertainment studies for ATTR-CA have found increased prevalence among women, with a 50:50 sex distribution among those with ATTR-CA, but not in an older Black or Hispanic patient population.9,29
We found a higher prevalence of ATTR-CA in Black participants (7.82%; 95% CI, 5.57%-10.06%) than in Hispanic participants (2.15%; 95% CI, 0.07%-4.24%). This was in part owing to a lower observed prevalence of V142I in Hispanic participants (2.2%) than among Black participants (6.4%). Data from 2 large biobanks have demonstrated that inheritance of V142I was significantly associated with the risk of HF.6 Similarly, data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study showed that the V142I variant was significantly associated with an increased risk of HF and death.7 In the biobank study,6 only 11% of TTR V142I carriers with HF were diagnosed as having ATTRv-CA, and among those that were diagnosed, there was a significant delay (median time from onset of symptoms to clinical diagnosis of 3 years). A more recent analysis of 754 V142I carriers from 4 pooled epidemiologic studies demonstrated that among Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization and death, with a steep age-dependent penetrance.5 Longevity was reduced by 1.9 years (95% CI, 0.6-3.1) as early as age 50 years in these cohorts, with a cumulative estimate of nearly 1 million years of lost life in this population due to V142I, suggesting that more widespread genomic testing in at-risk individuals and family cascade testing could save lives.30 Importantly, none of these studies were designed to perform testing to associate the inheritance of V142I with ATTR-CA.
A majority of participants identified with ATTR-CA in SCAN-MP had ATTRwt-CA. This differs from the prevalence of ATTRwt reported in large cohort studies from referral centers in which more than 75% of the Black patients with ATTR-CA had ATTRv disease owing to V142I.31,32 Accordingly, genomic screening alone for TTR variants will fail to identify most Black and Caribbean Hispanic patients who have ATTRwt-CA.33 Among those identified in SCAN-MP with ATTR-CA, participants with ATTRv-CA compared to ATTRwt-CA had evidence of a more advanced phenotype, with a lower LVEF and more abnormal global longitudinal strain, despite an earlier age at diagnosis. This is consistent with prior observations that ATTRv-CA from the V142I variant has a more rapidly progressive phenotype than ATTRwt-CA.34 We identified that 47.2% of V142I variant carriers did not have PYP imaging suggestive of ATTR-CA, despite evidence of HF. While it is possible that another mechanism, such as hypertensive remodeling, contributed to the development of HF in these variant carriers, it is also possible that amyloid deposition was indeed present but beneath the detection threshold of the PYP technique. A recent report detailing the capacity of I124-evuzamitide to identify ATTR amyloidosis among V142I variant carriers without diagnostic PYP uptake supports this hypothesis.35 Finally, the lower serum prealbumin levels in ATTRv-CA compared to ATTRwt-CA are consistent with our prior biochemical analyses from SCAN-MP36 demonstrating that TTR is more unstable in ATTRv-CA as measured by a valid physiological assay.37
Limitations
There are several limitations that should be acknowledged. First, SCAN-MP did not enroll the originally intended number of participants (targeted n = 800), in large part owing to enrollment challenges posed by the COVID-19 pandemic, which served to marginally increase the confidence widths around our estimated prevalences (eTable 1 in Supplement 1). Second, while we required a left ventricular wall thickness by clinically performed echocardiograms of 12 mm or higher, 21.8% of enrolled participants did not meet this criterion on echocardiograms when evaluated in the SCAN-MP core laboratory (although overall wall thickness IQR was 12-14 mm). The prevalence estimates for ATTR-CA did not differ significantly among those with a wall thickness greater or less than 12 mm as determined by the SCAN-MP core laboratory. Third, a significant percentage of participants had NYHA class I symptoms, thus our cohort in aggregate was less symptomatic than in other hospitalized ATTR-CA populations that have been reported. That stated, the average KCCQ–overall summary score was 65, which is similar to values reported in an ambulatory outpatient cohort with heart failure with reduced ejection fraction.38 Thus, SCAN-MP enrolled participants across the spectrum of HF severity, and the nonhospitalized and less restrictive wall thickness criteria used here differ from other studies of hospitalized patients.14 Fourth, the prevalence estimate of ATTR-CA may have been impacted by the existence of established amyloidosis treatment programs at the participating institutions through which patients with ATTR-CA may have been identified prior to consideration of study enrollment. Finally, we used the current standard-of-care imaging for ATTR-CA identification, validated in clinically suspected disease, rendering the possibility that there was insufficient sensitivity to detect cases of early ATTR-CA, particularly among V142I allele carriers who tested negative.35
Conclusions
In conclusion, the SCAN-MP cross-sectional study demonstrated that ATTR-CA is a commonly encountered cause of HF in older Black individuals with HF and is particularly common in men older than 75 years. More than half of all cases had genetically normal TTR, indicating that a genotype-first approach would miss a large portion of affected individuals.
eMethods. Modifications to the Protocol and Supplemental Methods
eTable 1. Effect of Sample Size and Observed Prevalence on Precision of the Prevalence Estimates
eTable 2. Medication Use in the Community Screening Cohort
eFigure 1. CONSORT Diagram of Participant Enrollment
eFigure 2. Prevalence of ATTR-CA SCAN-MP Participants With Wall Thickness ≥1.2 cm
eReferences.
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Modifications to the Protocol and Supplemental Methods
eTable 1. Effect of Sample Size and Observed Prevalence on Precision of the Prevalence Estimates
eTable 2. Medication Use in the Community Screening Cohort
eFigure 1. CONSORT Diagram of Participant Enrollment
eFigure 2. Prevalence of ATTR-CA SCAN-MP Participants With Wall Thickness ≥1.2 cm
eReferences.
Data Sharing Statement
