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October 13, 2026Circulation
Definition and Prognosis of Mitral Regurgitation in Transthyretin Amyloid Cardiomyopathy: A Multicenter International Cohort Study
Laurenz HauptmannChristina KronbergerStéphanie Kristina SchwartingDaniela TomasoniLara S. SchlenderSophia KoschatkoMaximilian AutherithCharlotte JantschCaglayan DemirelFranz DucaAndreas A. KammerlanderLuca BordignonGabriele Guidi ColombiNora SchwegelMatteo SerenelliAldostefano PorcariSteven A. MullerNicolas VerheyenMarish I.F.J. OerlemansΜαρία ΠαπαθανασίουChristian HengstenbergMarco MerloJörg HausleiterMarianna AdamoPhilipp E. BartkoChristian Nitsche
Key result
Novel amyloid-specific MR grading linked to ~20% higher mortality in ATTR cardiomyopathy.
- HR 1.20
- 95% CI 1.07-1.36
- P<0.05
- n=1,101
Why the study?
Mitral regurgitation severity in transthyretin amyloid cardiomyopathy may be underestimated by conventional echocardiographic criteria due to restrictive low-flow hemodynamics, necessitating disease-specific MR risk thresholds.
Does a disease-specific composite mitral regurgitation grading scheme improve prognostic discrimination for mortality and heart failure hospitalization compared to conventional guideline definitions in patients with transthyretin amyloid cardiomyopathy?
Key Points
- To define and validate disease-specific echocardiographic risk thresholds for mitral regurgitation in transthyretin amyloid cardiomyopathy and compare their prognostic utility with conventional guideline criteria.
- Multicenter investigation across 8 centers in 4 countries evaluating 1101 patients with newly diagnosed transthyretin amyloid cardiomyopathy (derivation n=722, validation n=379; NCT06836011).
- Standardized echocardiograms were assessed by a blinded core laboratory to quantify vena contracta width, effective regurgitant orifice area, regurgitant volume, and regurgitant fraction.
- Spline analysis identified prognostic thresholds for all-cause mortality and first heart failure hospitalization over a median follow-up of 24.9 months (interquartile range, 12.0–42.0).
- During follow-up, 314 patients (28.5%) died and 244 (22.2%) had a heart failure hospitalization, with every quantitative mitral regurgitation metric independently predicting both endpoints (all P<0.05).
- Spline thresholds identified intermediate risk at effective regurgitant orifice area ≥0.10 cm², regurgitant volume ≥15 mL, and regurgitant fraction ≥20%, and high risk at >0.25 cm², >38 mL, and >35%.
- The composite scheme reclassified 21% of patients as having severe mitral regurgitation (versus ≈12%–13% by guidelines) and independently predicted mortality (HR, 1.20 [95% CI, 1.07–1.36]) and heart failure hospitalization (HR, 1.21 [95% CI, 1.05–1.38]).
Study Design
Type
Cohort (n=1,101)
Blinding
Blinded core laboratory analysis
Multicenter
Yes
Structured PICO
Does a disease-specific composite mitral regurgitation grading scheme improve prognostic discrimination for mortality and heart failure hospitalization compared to conventional guideline definitions in patients with transthyretin amyloid cardiomyopathy?
P
Population
1,101 patients with newly diagnosed transthyretin amyloid cardiomyopathy followed for a median of 24.9 months.
E
Exposure
Disease-specific composite mitral regurgitation (MR) grading scheme based on echocardiographic measures (vena contracta width, effective regurgitant orifice area, regurgitant volume, and regurgitant fraction) reflecting restrictive low-flow hemodynamics.
C
Comparator
Conventional guideline-based mitral regurgitation grading definitions (American Heart Association/American College of Cardiology, European Society of Cardiology/European Association for Cardiothoracic Surgery, and American Society of Echocardiography).
O
Outcome
All-cause mortality and time to first heart failure hospitalization (HFH)hard clinical
Main Result
Hazard Ratio: 1.2 (95% CI 1.07–1.36)
p-value: p=<0.05
Quantitative mitral regurgitation thresholds in transthyretin amyloid cardiomyopathy are substantially lower than current guideline cutoffs, and a disease-specific composite grading scheme improves the prediction of mortality and heart failure hospitalization.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The data demonstrate that mitral valve regurgitation in ATTR amyloidosis requires its own, disease-specific criteria. This provides, for the first time, a robust basis for the further development of international guidelines and for the selection of those patients who could benefit from a procedure to treat mitral valve regurgitation.”
“According to the standard criteria, roughly one in eight people is classified as severely affected; according to the disease-specific thresholds, it is one in five. These patients have a measurably increased risk, but had not previously been identified as such.”
Implication
May refine risk stratification in transthyretin amyloid cardiomyopathy; challenges conventional grading thresholds and warrants prospective validation.
Abstract
BACKGROUND: In transthyretin amyloid cardiomyopathy, mitral regurgitation (MR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria due to restrictive low-flow hemodynamics. We sought to define and validate disease-specific MR risk thresholds and compare their prognostic performance with guideline definitions. METHODS: In a multicenter cohort study (8 centers, 4 countries), 1101 patients with newly diagnosed transthyretin amyloid cardiomyopathy (derivation, n=722; validation, n=379) underwent standardized echocardiography with blinded core laboratory analysis, including MR measures (vena contracta width, effective regurgitant orifice area, regurgitant volume, and regurgitant fraction). All-cause mortality and time to first heart failure hospitalization (HFH) served as end points. Prognostic thresholds were derived from spline analysis, validated externally, and compared with American Heart Association/American College of Cardiology, European Society of Cardiology/European Association for Cardiothoracic Surgery, and American Society of Echocardiography definitions. RESULTS: During a median follow-up of 24.9 months (interquartile range, 12.0–42.0), 314 patients (28.5%) died and 244 (22.2%) experienced HFH. All MR metrics independently predicted mortality and HFH (all P <0.05). Spline-derived thresholds identified intermediate risk at vena contracta width ≥3.0 mm, effective regurgitant orifice area ≥0.10 cm 2 , regurgitant volume ≥15 mL, and regurgitant fraction ≥20% and high risk at effective regurgitant orifice area >0.25 cm 2 , regurgitant volume >38 mL, and regurgitant fraction >35%. Compared with guideline grading (≈12%–13%), the composite MR grading scheme classified a significantly higher proportion (21%) as severe MR and provided superior discrimination for clinical outcomes at 12 and 24 months in both the derivation and validation cohort. After multivariable adjustment, only the composite MR grading scheme remained strongly predictive for both mortality (hazard ratio, 1.20 [1.07–1.36]) and HFH (hazard ratio, 1.21 [1.05–1.38]). CONCLUSIONS: Quantitative MR thresholds in transthyretin amyloid cardiomyopathy are substantially lower than current guideline cutoffs. A validated, risk-based composite MR grading scheme improves prediction of both mortality and HFH, better reflecting the restrictive low-flow pathophysiology of transthyretin amyloid cardiomyopathy and supporting disease-specific MR grading. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06836011.
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Cite This Study
Hauptmann et al. (2026) conducted a cohort in Transthyretin amyloid cardiomyopathy (n=1,101). Composite mitral regurgitation grading scheme vs. Current guideline definitions was evaluated on All-cause mortality (HR 1.20, 95% CI 1.07-1.36, p=<0.05). A disease-specific composite mitral regurgitation grading scheme strongly predicted mortality (HR 1.20; 95% CI 1.07-1.36) and heart failure hospitalization in transthyretin amyloid cardiomyopathy.