Mapping the phenotypic spectrum of transthyretin amyloid cardiomyopathy using a multidomain red flag scoring system
F E Kourti, A Antonopoulos, V Kytinos, V Gardikioti, T Tsampras, M E Koilakou, A Kouroutzoglou, A Xintarakou, D Kyriakopoulos, A Kasiakogias, D Terentes-Printzios, C Chrysochoou, G Lazaros, K Tsioufis, C VlachopoulosAbstract
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) demonstrates marked phenotypic heterogeneity that is not fully captured by left ventricular hypertrophy (LVH). Disease expression spans clinical, electrocardiographic, imaging, and extracardiac domains. A structured phenotypic quantification model may better reflect this multidimensional spectrum.
Purpose
To develop and apply a multidomain scoring system (a “phenomap”) to characterize the phenotypic continuum of ATTR-CM and to explore the relationship between red flag burden and disease severity.
Methods
Eighty-two consecutive patients (87% male, median age of 84 [77- 89]) with confirmed ATTR-CM were retrospectively analyzed. Four domains were assessed: clinical profile, features of extracardiac disease, electrocardiographic and laboratory/echocardiographic parameters. Within each domain, predefined ATTR-related features were arranged in concentric layers reflecting their strength of association with ATTR-CM (Figure 1A) (1). Also, patient clinical phenotypes were categorized as typical or atypical, e.g., based on presence of LVH or typical ECG and laboratory features. Disease severity was assessed according to the NAC staging system.
Results
Increasing total phenotypic score correlated with greater MWT (β = 0.21, 95% CI 0.08–0.34; p = 0.003), explaining 11% of the variance in MWT (R² = 0.11) (Figure 1C). Differences in total and individual scores were observed among NAC groups, except for clinical profile and extracardiac disease score (Figure 2 A-C). Total phenotypic score was significantly higher in patients with NAC III compared to NAC I (Figure 2A). Patients with advanced disease also demonstrated higher ECG and laboratory/echocardiographic subscores (p = 0.03 and p = 0.04, Figure 2D-E). In contrast, no significant difference in total score was observed between typical and atypical presentations (p = NS, Figure 2F).
Conclusion
The multidomain phenomap score captures the ATTR-CM phenotype spectrum and is indicative of the severity burden of the disease. Even patients with atypical disease features have a high ATTR-CM phenomap score, highlighting the importance of a multiparametric approach to raise suspicion and aid in the diagnosis of ATTR-CM.Figure 1Figure 2