Prognostic Thresholds of Tricuspid Regurgitation in Transthyretin Amyloid Cardiomyopathy

Importance: In transthyretin amyloid cardiomyopathy (ATTR-CM), tricuspid regurgitation (TR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria derived from nonamyloid populations, given the restrictive, low-flow hemodynamics characteristic of the disease. Objectives: To derive and validate disease-specific prognostic, quantitative TR risk thresholds in ATTR-CM and to compare their prognostic performance with current guideline definitions and the Tricuspid Valve Academic Research Consortium (TVARC) 5-grade extension. Design, setting, and participants: This international, multicenter cohort study was conducted from January 2016 to February 2026 at 8 high-volume tertiary referral centers across Austria, Italy, Germany, and the Netherlands, with data analysis February to May 2026. Patients with newly diagnosed ATTR-CM were enrolled and underwent standardized transthoracic echocardiography with blinded core laboratory quantitative analysis of echocardiography TR severity parameters (vena contracta width [VCW], effective regurgitant orifice area [EROA], and regurgitant volume [RegVol]). Exposures: TR severity defined by VCW, EROA, and RegVol from blinded core laboratory quantitative analysis and TR severity according to 2025 European Society of Cardiology/European Association for Cardio-Thoracic Surgery, 2020 American Heart Association/American College of Cardiology, 2017 American Society of Echocardiography, and 2023 TVARC grading schemes. Main outcomes and measures: Outcomes were all-cause mortality (primary end point) and time to first heart failure hospitalization (HFH; secondary end point). Results: A total of 1124 patients with newly diagnosed ATTR-CM were enrolled (derivation cohort: n = 745; validation cohort: n = 379). Median (IQR) patient age was 80 (75-84) years, and 260 patients (23.1%) were female. Over a median (IQR) follow-up of 25.2 (12.2-43.2) months, 324 patients (28.8%) died and 251 (22.3%) experienced HFH. All TR metrics independently predicted both end points. Spline-derived thresholds delineated intermediate (VCW ≥3 mm; EROA ≥0.15 cm2; RegVol ≥10 mL), high (≥5 mm; ≥0.25 cm2; ≥20 mL), and extreme risk (≥8 mm; ≥0.50 cm2; ≥40 mL), with stepwise Kaplan-Meier separation in both cohorts. Whereas the guideline-based and TVARC schemes each classified 130 patients (11.6%) as having severe TR, the proposed framework classified 334 patients (29.7%) as having at least high or extreme risk (P < .001 for comparison to all other definitions). The framework was independently associated with both end points, with the highest point estimate among the schemes (mortality: hazard ratio [HR], 1.41; 95% CI, 1.23-1.62; HFH: HR, 1.31; 95% CI, 1.12-1.54), and showed superior discrimination over guideline definitions, particularly at later time points. Conclusions and relevance: In this multicenter cohort study among patients with ATTR-CM, a validated, risk-based conceptual framework of echocardiographic parameters to quantify TR improved prediction of mortality and HFH over standard classification of TR severity, better reflecting restrictive low-flow pathophysiology and supporting disease-specific TR grading in ATTR-CM.