Research Summary

Updated Criteria for Monitoring Disease Progression in Transthyretin Amyloid Cardiomyopathy

Edited by:
Anthony Calabro, MA

Key Highlights:

  • International experts updated proposed disease monitoring criteria for transthyretin amyloid cardiomyopathy to reflect newer evidence on prognostic markers and real-world feasibility of assessments.
  • The proposed framework includes 6 parameters, each with defined thresholds and a 12-month monitoring cadence.
  • The panel proposed that progression in at least 2 parameters over 12 months could be considered disease progression, to reduce the risk of overestimating progression based on a single measure.

International experts have proposed updated criteria to monitor disease progression in transthyretin amyloid cardiomyopathy (ATTR-CM), aiming to fill a persistent gap in practical, evidence-informed follow-up recommendations as the diagnostic window shifts toward earlier-stage disease. In a report published in JACC: Heart Failure, the panel emphasized that the proposed framework is designed to measure clinical disease progression in patients with ATTR-CM, such as worsening heart failure (HF) status, functional decline, or deteriorating quality of life, rather than to define progression of myocardial amyloid deposition.

A key premise of the update is that evidence supporting the prognostic value of candidate monitoring parameters has expanded since a prior 2021 proposal. The authors also stressed an important clinical distinction: patients may worsen due to factors that are not synonymous with increased amyloid deposition, including worsening HF, arrhythmia, or aging. Accordingly, the panel cautioned that meeting progression criteria should not be interpreted as treatment “failure” or an automatic signal to stop, switch, or combine ATTR-CM disease-modifying therapies, noting that it remains unknown whether observed disease progression should prompt treatment modification.

Proposed Criteria

The updated proposed criteria include 6 parameters selected for feasibility in routine practice and for evidence supporting prognostic value in ATTR-CM:

  1. HF-related hospitalization
  2. Outpatient diuretic intensification (ODI)
  3. N-terminal pro–B-type natriuretic peptide (NT-proBNP)
  4. Estimated glomerular filtration rate (eGFR)
  5. 6-minute walk test (6MWT)
  6. Quality of life (QoL) assessed preferably by the Kansas City Cardiomyopathy Questionnaire (KCCQ) or by the New York Heart Association (NYHA) functional class when KCCQ is unavailable

For each parameter, the experts proposed a threshold and a monitoring cadence of every 12 months, with results compared against the prior 12 months rather than against baseline values.

Thresholds included:

  • At least 1 HF-related hospitalization in 12 months
  • ODI defined as initiation of a new oral loop diuretic among patients not taking loop diuretics or a sustained dose increase lasting at least 30 days among those already treated
  • NT-proBNP progression defined as an absolute increase of more than 700 pg/mL with a relative increase of more than 30%
  • eGFR decline defined as a relative decrease of more than 20%
  • A decrease in 6MWT distance of more than 35 meters
  • QoL worsening defined as a KCCQ decline of more than 5 points (or an increase in NYHA class if KCCQ is not available)

For NT-proBNP and eGFR, the panel recommended measurement during clinical stability and noted that 2 measurements approximately 4 weeks apart could help avoid misclassifying transient fluctuations as progression.

To reduce the risk of overestimating progression, the experts proposed that disease progression be considered when at least 2 of the defined parameters meet progression thresholds over the prior year. They cited evidence that combining progression markers may better stratify risk than relying on a single variable. For example, one analysis reported higher mortality risk with 2 markers of progression compared with 1 (HR, 1.50; 95% CI, 1.21-1.85; P < .001). The authors encouraged future validation of the “≥2 parameters” approach and further study to determine whether changing disease-modifying therapy improves outcomes among patients who demonstrate progression.

Clinical Implications

The authors cautioned that the proposed prognostic thresholds are primarily derived from cohort-based analyses and may not be uniformly applicable to all patients with ATTR-CM. Since patient characteristics, treatment exposure, genotype, and rates of disease progression vary widely, the criteria should be interpreted within the context of individual patient factors. Based on this information, the panel emphasized the continued importance of clinical judgment when applying the monitoring framework in routine practice.

Additionally, the panel excluded imaging parameters from the criteria, citing interobserver variability, challenges in interpreting serial changes over time in individual patients, and mixed or limited prognostic signals for several imaging-derived measures in available studies. Arrhythmia-related parameters, troponin (given assay heterogeneity and incomplete validation across troponin types), staging systems that duplicate included markers, and frailty were also omitted, largely due to evidentiary and feasibility considerations described by the authors.

Expert Commentary

“These updated proposed criteria for the monitoring of disease progression in patients with ATTR-CM incorporate recently published data analyzing disease parameters, while also considering their ease of implementation,” the panel concluded. “These data include validated prognostic parameters and provide useful thresholds that can be used to define disease progression in this challenging and heterogeneous disease.”

Reference

García-Pavía P, Witteles RM, Damy T, et al. Monitoring disease progression in patients with transthyretin amyloid cardiomyopathy. JACC Heart Fail. 2026;14(1):102766. doi:10.1016/j.jchf.2025.102766