TY - JOUR
T1 - Myocardial Amyloid Burden in Transthyretin Amyloidosis
AU - Sheikh, Awais
AU - Achten, Anouk
AU - Aimo, Alberto
AU - Razvi, Yousuf
AU - Mansell, Josephine
AU - Rauf, Muhammad U.
AU - Porcari, Aldostefano
AU - Patel, Rishi
AU - Venneri, Lucia
AU - Martinez-Naharro, Ana
AU - Whelan, Carol
AU - Quarta, Cristina
AU - Virsinskaite, Ruta
AU - Feffer Barak, Daniel
AU - Wechalekar, Ashutosh
AU - Lachmann, Helen
AU - Knight, Daniel
AU - Kotecha, Tushar
AU - Kellman, Peter
AU - Manisty, Charlotte
AU - Moon, James
AU - Emdin, Michele
AU - Solomon, Scott D.
AU - Hawkins, Philip N.
AU - Gillmore, Julian
AU - Fontana, Marianna
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/1/1
Y1 - 2025/1/1
N2 - Background: Stabilizers/silencers limit new transthyretin amyloid formation, whereas emerging agents aim to clear existing deposits. Cardiovascular magnetic resonance (CMR) extracellular volume (ECV) reflects myocardial amyloid and may provide a quantitative framework for therapeutic planning Objectives: The aim was to define calibrated ECV thresholds, evaluate their diagnostic and prognostic value, and explore how CMR-ECV could provide a quantitative framework for disease staging and therapeutic planning. Methods: We studied 1,541 subjects undergoing CMR for transthyretin amyloidosis (ATTR) classified as TTR-variant carriers (n = 123), extracardiac ATTR (n = 41), early-stage ATTR-CM (n = 70), or overt ATTR-CM (n = 1,308). The endpoint was all-cause mortality. Results: ECV was similar in carriers and extracardiac ATTR but rose from early-stage to ATTR-cardiomyopathy (CM). Associations with biomarkers, National Amyloidosis Centre (NAC) stage, Perugini grade, and echocardiographic measures were modest, with wide overlap. Diagnostic performance was excellent: ECV <30% excluded and =40% confirmed cardiac involvement, whereas 30% to 39% indicated early infiltration. Over a median follow-up of 2.8 years (IQR: 1.4-4.3 years), 612 patients (40%) died. Prognostically, ECV independently predicted mortality (HR: 1.22 per 10% increase; 95% CI: 1.10-1.34 per 10% increase; P < 0.001) after multivariable analysist. Stratifying patients by ECV categories (degree of infiltration: none <30%; mild = 30%-39%; moderate = 40%-49%; moderate-to-severe = 50%-59%; severe =60%) showed monotonic risk increase across categories. ECV retained prognostic value across hs-troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strata, Perugini grades 1 to 3, and left ventricular mass index (LVMI) tertiles, with steeper gradients in low-biomarker/low-LVMI strata. Conclusions: ECV directly quantifies myocardial amyloid load and, for the first time, defines reproducible thresholds that stratify burden and refine risk prediction beyond stage, biomarkers, and imaging, providing a quantitative framework for staging and therapeutic planning in ATTR amyloidosis.
AB - Background: Stabilizers/silencers limit new transthyretin amyloid formation, whereas emerging agents aim to clear existing deposits. Cardiovascular magnetic resonance (CMR) extracellular volume (ECV) reflects myocardial amyloid and may provide a quantitative framework for therapeutic planning Objectives: The aim was to define calibrated ECV thresholds, evaluate their diagnostic and prognostic value, and explore how CMR-ECV could provide a quantitative framework for disease staging and therapeutic planning. Methods: We studied 1,541 subjects undergoing CMR for transthyretin amyloidosis (ATTR) classified as TTR-variant carriers (n = 123), extracardiac ATTR (n = 41), early-stage ATTR-CM (n = 70), or overt ATTR-CM (n = 1,308). The endpoint was all-cause mortality. Results: ECV was similar in carriers and extracardiac ATTR but rose from early-stage to ATTR-cardiomyopathy (CM). Associations with biomarkers, National Amyloidosis Centre (NAC) stage, Perugini grade, and echocardiographic measures were modest, with wide overlap. Diagnostic performance was excellent: ECV <30% excluded and =40% confirmed cardiac involvement, whereas 30% to 39% indicated early infiltration. Over a median follow-up of 2.8 years (IQR: 1.4-4.3 years), 612 patients (40%) died. Prognostically, ECV independently predicted mortality (HR: 1.22 per 10% increase; 95% CI: 1.10-1.34 per 10% increase; P < 0.001) after multivariable analysist. Stratifying patients by ECV categories (degree of infiltration: none <30%; mild = 30%-39%; moderate = 40%-49%; moderate-to-severe = 50%-59%; severe =60%) showed monotonic risk increase across categories. ECV retained prognostic value across hs-troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strata, Perugini grades 1 to 3, and left ventricular mass index (LVMI) tertiles, with steeper gradients in low-biomarker/low-LVMI strata. Conclusions: ECV directly quantifies myocardial amyloid load and, for the first time, defines reproducible thresholds that stratify burden and refine risk prediction beyond stage, biomarkers, and imaging, providing a quantitative framework for staging and therapeutic planning in ATTR amyloidosis.
KW - cardiovascular magnetic resonance
KW - extracellular volume
KW - risk prediction
KW - transthyretin amyloidosis
U2 - 10.1016/j.jacc.2025.10.054
DO - 10.1016/j.jacc.2025.10.054
M3 - Article
SN - 0735-1097
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
ER -