Lower TR Thresholds Better Predict Mortality in Cardiac Amyloidosis

Standard echocardiographic criteria for grading tricuspid regurgitation (TR) may substantially underestimate the condition's prognostic severity in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), according to a multicenter cohort study published in JAMA Cardiology.¹

Using disease-specific thresholds derived from spline analyses of TR measurements and mortality data, researchers classified nearly 3 times as many patients as having high-risk TR compared with conventional guideline criteria (29.7% vs 11.6%; P < .001). The new framework was also more strongly associated with both death and heart failure hospitalization (HFH) than 4 established grading schemes.

“Collectively, these findings provide the first systematic evaluation of quantitative TR parameters in ATTR-CM to our knowledge and support prognostication based on disease-specific TR grading to account for its distinctive restrictive, low-flow hemodynamics,” wrote the researchers of the study.

Guideline Cutoffs Miss High-Risk Patients

The study enrolled 1124 patients with newly diagnosed ATTR-CM across 8 tertiary centers in Austria, Italy, Germany, and the Netherlands between January 2016 and February 2026. All patients underwent standardized echocardiography with blinded core laboratory analysis of 3 echocardiographic TR parameters: vena contracta width (VCW), effective regurgitant orifice area (EROA), and regurgitant volume (RegVol).

Over a median follow-up of 25.2 months, 324 patients (28.8%) died and 251 (22.3%) experienced at least 1 HFH. All 3 TR metrics independently predicted both outcomes. Using restricted cubic spline models, the investigators derived intermediate-, high-, and extreme-risk thresholds for each parameter that were markedly lower than existing cutoffs from the 2025 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines, the 2020 American Heart Association/American College of Cardiology guidelines, the American Society of Echocardiography, and the Tricuspid Valve Academic Research Consortium (TVARC) 5-grade system.

The resulting 4-tier framework stratified patients into low-risk (36.7%), intermediate-risk (33.5%), high-risk (20.8%), and extreme-risk (8.9%) groups, with a stepwise increase in mortality across categories (extreme risk: hazard ratio [HR], 5.97; 95% CI, 4.19-8.49, relative to low risk). After adjustment for clinical and echocardiographic confounders, the framework remained independently associated with mortality (HR, 1.41; 95% CI, 1.23-1.62) and HFH (HR, 1.31; 95% CI, 1.12-1.54), guideline-based schemes at all time points, with a more consistent advantage over ASE and TVARC criteria emerging later in follow-up.

Restrictive Physiology Changes the Math

The authors attributed the gap between conventional and disease-specific thresholds to the restrictive, low-flow hemodynamics of ATTR-CM, in which even modest regurgitant volumes can represent a clinically meaningful share of a patient's already-diminished forward flow. TR in this population arises from a combination of amyloid infiltration of the valve apparatus, right ventricular dysfunction, annular dilation, and elevated filling pressures, often compounded by atrial fibrillation, which was present in nearly half the cohort.

The findings echo earlier, smaller studies linking TR to worse survival in cardiac amyloidosis, including a 2021 single-center study of 283 patients from the Toulouse Amyloidosis Research Network that found moderate-to-severe TR nearly doubled mortality risk in wild-type ATTR (HR, 1.89; 95% CI, 1.01-3.51).² The new study is the first to systematically validate quantitative, disease-specific TR thresholds in a large ATTR-CM cohort.¹

The authors cautioned that the thresholds are intended for prognostic risk stratification, not as criteria for tricuspid valve intervention, and that dedicated trials are needed to determine whether management guided by the new framework improves outcomes.

Managed Care Implications

The findings add weight to a broader shift in cardiac amyloidosis care: TR in ATTR-CM behaves differently than TR in the general heart failure population, and grading it with the same yardstick likely leaves a meaningful share of high-risk patients under the radar. By showing that a disease-specific framework reclassifies nearly 3 times more patients as high-risk and outperforms 4 established grading systems in predicting mortality and hospitalization, the study gives clinicians a more sensitive tool for identifying patients with ATTR-CM who may need closer surveillance at diagnosis.

The authors caution, however, that the thresholds are not yet grounds for tricuspid valve intervention: because they identify patients with smaller regurgitant volumes than those studied in existing transcatheter tricuspid repair trials, any absolute benefit of intervening earlier is unproven, and such procedures have so far improved symptoms without demonstrating a survival benefit.

“A pragmatic, multiparametric conceptual framework identified nearly 3-fold more high-risk patients and provides superior prognostic discrimination compared with established TR grading schemes,” wrote the researchers. “These findings support disease-specific TR grading for prognostic assessment in ATTR-CM and provide a foundation for future studies testing whether targeted TR interventions can improve outcomes in this population.”

References

1. Hauptmann L, Schwarting SK, Tomasoni D, et al. Prognostic thresholds of tricuspid regurgitation in transthyretin amyloid cardiomyopathy. JAMA Cardiol. Published online August 31, 2026. doi:10.1001/jamacardio.2026.3803
2. Fagot J, Lavie-Badie Y, Blanchard V, et al. Impact of tricuspid regurgitation on survival in patients with cardiac amyloidosis. ESC Heart Fail. 2021;8(1):438-446. doi:10.1002/ehf2.13093