Definition and prognosis of tricuspid regurgitation in transthyretin amyloid cardiomyopathy: a multicentre international cohort study
L Hauptmann, S K Schwarting, D Tomasoni, F Duca, M Serenelli, A Porcari, N Verheyen, M I F J Oerlemans, M Papathanasiou, C Hengstenberg, M Merlo, J Hausleiter, M Adamo, P E Bartko, C NitscheAbstract
Background and Aims
In transthyretin amyloid cardiomyopathy (ATTR-CM), tricuspid regurgitation (TR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria derived from non-amyloid populations, given restrictive low-flow hemodynamics. We sought to define and validate disease-specific TR risk thresholds and compare their prognostic performance with guideline definitions and the tricuspid valve academic research consortium (TVARC) 5-grade extension.
Methods
In this international multicenter cohort study (8 centres, 4 countries), 1,124 patients with newly diagnosed ATTR-CM (derivation: n=745, validation: n=379) underwent standardised echocardiography with blinded core-laboratory analysis including TR parameters [vena contracta width (VCW), effective regurgitant orifice area (EROA), and regurgitant volume (RegVol)]. All-cause mortality and time to first heart failure hospitalisation (HFH) served as endpoints. Prognostic thresholds were derived from restricted cubic spline analysis, externally validated, and integrated into a multiparametric 4-grade conceptual framework (grade defined by the worst-risk category across VCW/EROA/RegVol). Prognostic performance was compared with 2025 ESC/EACTS, 2020 AHA/ACC, 2017 ASE, and TVARC definitions using multivariable Cox regression and time-dependent discrimination analyses.
Results
During a median follow-up of 25.2 months (IQR 12.2–43.2), 324 (28.8%) patients died, and 251 (22.3%) experienced HFH. Spline-derived thresholds identified stepwise risk strata at VCW 3/5/8 mm, EROA 0.15/0.25/0.50 cm², and RegVol 10/20/40 mL, delineating intermediate-, high-, and extreme-risk ranges (Figure 1). Integration into the conceptual framework yielded 411 (36.6%) patients classified as low risk, 379 (33.7%) as intermediate risk, 234 (20.8%) as high risk, and 100 (8.9%) as extreme risk, with clear separation of Kaplan–Meier curves in the overall cohort and consistent stepwise separation in both derivation and validation cohorts. Compared with guideline-based and TVARC grading (each 11.6%), the framework classified a significantly higher proportion (29.7%) as ≥severe TR (all comparisons: p<0.001) and demonstrated the strongest independent association with outcomes after multivariable adjustment for disease stage and ATTR-specific therapy (mortality: HR 1.45, 95% CI 1.29–1.64; HFH: HR 1.32, 95% CI 1.14–1.52). Time-dependent analyses confirmed superior discrimination of the framework for mortality from 12–60 months in the derivation and validation cohorts (Figure 2).
Conclusions
Quantitative TR thresholds in ATTR-CM are substantially lower than current guideline cut-offs. A validated, risk-based conceptual framework improves prediction of both mortality and HFH, better reflecting restrictive low-flow pathophysiology and supporting disease-specific TR grading in ATTR-CM.Figure 1.Spline CurvesFigure 2.Central Illustration