Phenotyping by structural and biomarker remodeling in transthyretin amyloid cardiomyopathy: an international multicenter cohort study

Introduction

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative cardiomyopathy characterized by progressive left ventricular thickening and cardiac biomarker elevation. While structural and biomarker remodeling often progress in parallel, some patients may exhibit a discordance in remodeling patterns. However, the clinical implications of this biomarker-imaging discordance remain unclear.

Methods

This multi-center multi-modal international cohort study recruited consecutive patients with ATTR-CM who underwent cardiac magnetic resonance imaging (CMR) and cardiac biomarker assessment at six tertiary referral centers. Receiver operating characteristic curve analysis with Youden index identified optimal mortality thresholds for left ventricular mass index (LVMi; >75 g/m²) and NT-proBNP (>2000 pg/mL) in the derivation cohort. Patients were stratified according to respective thresholds (low [-] vs. high [+]) yielding four groups: [BNP-, LVMi-], [BNP-, LVMi+], [BNP+, LVMi-], [BNP+, LVMi+]. Groups were compared regarding clinical, echo, CMR structural/functional/tissue characteristics, and all-cause mortality.

Results

We included 630 patients (derivation: n=332, validation: n=298) with ATTR-CM (median age 78 years, 86% male, 92% wild-type ATTR). The discordant phenotype of [BNP-, LVMi+] was characterised by lower symptomatic burden, better kidney function, higher left atrial ejection fraction and peak strain, and less pulmonary hypertension and triscuspid regurgitation compared to [BNP+, LVMi-] and [BNP+, LVMi+] (all p<0.05) despite high extracellular volume fraction (ECV, 51% [43-60]). Conversely, the discordant phenotype of [BNP+, LVMi-] had worse functional parameters including severely impaired left atrial ejection fraction and peak strain similar to [BNP+, LVMi+] despite lower ECV than [BNP-, LVMi+] of 49% (41-56, p<0.05).

After a median of 2.6 years (1.2-4.2) 159 patients (25%) died. By multivariate Cox regression with adjustment for known outcome predictors in ATTR-CM (age, sex, TTR mutation status, eGFR, ECV), [BNP-, LVMi+] had similarly favourable outcome to [BNP-, LVMi-] (adjHR 1.24; 95% CI 0.62 to 2.47) and [BNP+, LVMi-] had similarly poor outcome to [BNP+, LVMi+] (adjHR 1.29; 95% CI 0.80 to 2.07) with consistent results in the derivation and validation cohorts. Worse left atrial ejection fraction and peak strain both independently predicted mortality with consistent effects across tertiles of LVMi and ECV (all p<0.05).

Conclusion

In ATTR-CM, bimodal risk stratification by LVMi and NT-proBNP identifies discordant phenotypes regarding structural and biomarker remodelling with distinct functional and prognostic signatures. Left atrial function emerges as a gatekeeper mechanism which determines decompensation into sequential backward failure irrespective of LV amyloid load. Discordant phenotypes may require tailored treatment strategies based on their distinct pathophysiology and prognostic implications.For image description, please refer to the figure legend and surrounding text.