Highlights
Cardiovascular magnetic resonance (CMR) utilizing extracellular volume (ECV) mapping has emerged as a robust tool for the longitudinal assessment of transthyretin amyloid cardiomyopathy (ATTR-CM).
Untreated ATTR-CM patients exhibit a significant and progressive increase in amyloid burden, with 62% showing disease progression by two years.
Treatment with the TTR-silencer patisiran effectively stabilizes cardiac amyloid load, with 100% of treated patients maintaining stable ECV levels at the two-year mark.
A 5% or greater increase in ECV at one year is an independent predictor of mortality, offering a critical surrogate endpoint for clinical monitoring and trial design.
Background: The Challenge of Quantifying Amyloid Burden
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure and mortality, particularly among older adults. The disease is characterized by the misfolding of transthyretin proteins, which deposit as amyloid fibrils within the myocardial extracellular space. Historically, monitoring the progression of ATTR-CM relied on non-specific markers such as echocardiographic wall thickness or N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels. However, these markers often lack the sensitivity to detect subtle changes in the actual amyloid load.
The advent of cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping has revolutionized the field. By quantifying the proportion of the myocardium not occupied by myocytes, ECV mapping provides a direct, non-invasive surrogate measure of the amyloid burden. Despite its potential, the natural history of ECV changes over time and the specific impact of modern TTR-silencing therapies on these metrics required rigorous clinical validation. The study by Patel et al. (2025) provides the necessary evidence to integrate ECV mapping into the standard of care for ATTR-CM management.
Study Design and Patient Cohort
This prospective observational study enrolled 189 patients diagnosed with ATTR-CM. The cohort was divided into two primary groups: those who were untreated (n=119) and those receiving patisiran (n=70), an RNA interference therapeutic that inhibits the production of transthyretin. The primary objective was to assess the natural history of amyloid deposition and the treatment response using CMR-ECV mapping.
Patients underwent baseline CMR assessments, with follow-up scans performed at one year (n=160) and two years (n=75). The researchers defined CMR response based on the absolute change in ECV: progression was categorized as an increase of 5% or more, stable disease as a change of less than 5%, and regression as a decrease of 5% or more. This standardized grading allowed for a clear comparison between the therapeutic and natural history arms.
Key Findings: The Natural History of Untreated ATTR-CM
The data for the untreated cohort painted a stark picture of the progressive nature of ATTR-CM. At the one-year follow-up, 36% of untreated patients met the criteria for ECV progression. By the two-year mark, this figure rose significantly to 62%. The mean increase in ECV was 4.1% after one year and 6.8% after two years. These quantitative increases in amyloid burden were closely mirrored by a deterioration in other clinical parameters, including worsening biomarkers (NT-proBNP) and structural changes such as increased left ventricular mass and reduced ejection fraction.
These findings underscore that ATTR-CM is not a static condition. Without targeted intervention, the myocardial interstitium continues to expand with amyloid fibrils, leading to progressive cardiac dysfunction. The study provides a clear timeline for this progression, suggesting that annual monitoring may be necessary to identify rapid progressors.
Key Findings: Impact of Patisiran on Amyloid Load
In contrast to the untreated group, patients receiving patisiran demonstrated remarkable stability in their amyloid burden. There was no significant difference in the mean ECV at either the one-year or two-year follow-up compared to baseline. Specifically, stable ECV was observed in 88% of patients at one year and 100% of patients at two years.
Beyond ECV, structural parameters and cardiac biomarkers also remained stable in the patisiran group. This suggests that TTR-silencing therapy effectively halts the deposition of new amyloid fibrils, allowing the heart to maintain its current state of function. While the study did not observe widespread “regression” (significant decrease in ECV), the prevention of progression represents a major therapeutic success in a disease that was once considered universally terminal.
Prognostic Significance: ECV as a Surrogate Marker
Perhaps the most clinically impactful finding of the study was the association between ECV changes and survival. After adjusting for known predictors of mortality—such as age, baseline ECV, and NT-proBNP—the researchers found that ECV progression (a 5% or greater increase) at one year was independently associated with a higher risk of death. The hazard ratio (HR) was 2.021 (95% confidence interval 1.081–3.781; P = .028).
This finding validates ECV as a powerful prognostic tool. It suggests that clinicians can use the one-year CMR scan to risk-stratify patients. If a patient shows ECV progression despite therapy, it may indicate the need for a change in management or a more aggressive treatment approach. Conversely, stable ECV provides reassurance that the current therapeutic strategy is effectively mitigating the risk of mortality.
Expert Commentary: Clinical Implications and Limitations
The integration of ECV mapping into clinical practice offers a more nuanced understanding of ATTR-CM than traditional imaging. While echocardiography remains the first-line screening tool, CMR provides the precision required for longitudinal tracking. Expert opinion suggests that ECV mapping should now be considered the gold standard for monitoring treatment response in ATTR-CM, especially as new therapies like TTR silencers and stabilizers become more widely available.
However, some limitations must be considered. The study was observational, and while the groups were well-characterized, the lack of randomization means that some selection bias could exist. Additionally, the definition of “progression” as a 5% absolute increase in ECV is a specific threshold that may require further validation across different CMR platforms and centers. Future research should also investigate whether even smaller changes in ECV carry clinical significance over longer periods.
Another area of interest is the potential for amyloid regression. While this study primarily showed stabilization with patisiran, longer-term follow-up or combination therapies might eventually reveal whether the body is capable of clearing existing amyloid deposits once the production of the precursor protein is halted.
Conclusion
The study by Patel et al. confirms that CMR with ECV mapping is an essential tool for the modern management of ATTR-CM. It provides a clear window into the natural history of the disease—revealing a relentless progression in untreated patients—and demonstrates the profound stabilizing effect of patisiran. By linking ECV progression to mortality, the research provides clinicians with a quantifiable metric to guide prognosis and treatment decisions. As the therapeutic landscape for amyloidosis continues to evolve, CMR-ECV mapping will undoubtedly play a central role in optimizing patient outcomes.
References
Patel RK, Ioannou A, Sheikh A, Razvi Y, Mansell J, Martinez-Naharro A, Knight D, Kotecha T, Porcari A, Chacko L, Brown J, Manisty C, Moon JC, Lachmann HJ, Wechalekar A, Whelan C, Venneri L, Kellman P, Hawkins PN, Gillmore JD, Fontana M. Transthyretin amyloid cardiomyopathy: natural history and treatment response assessed by cardiovascular magnetic resonance. Eur Heart J. 2025 Dec 8;46(46):5049-5058. doi: 10.1093/eurheartj/ehaf412. PMID: 40643267.
