Right Atrial Stiffness: An Emerging Prognostic Marker in Cardiac Amyloidosis?

Strain-based myocardial and atrial imaging has transformed the evaluation of cardiac involvement in immunoglobulin light-chain (AL) amyloidosis. Among these tools, left ventricular global longitudinal strain (LVGLS)—notably the “apical sparing” pattern—has become central to diagnostic discrimination and early detection of systolic dysfunction, outperforming traditional metrics of wall thickness or ejection fraction [1, 2]. Beyond diagnosis, LVGLS is a powerful prognostic marker: worsening deformation predicts mortality and complements Mayo staging in risk stratification [3]. Given that amyloid infiltration is diffuse and involves all cardiac chambers, deformation analysis has expanded toward the right ventricle (RV), left atrium (LA), and, more recently, the right atrium (RA). Modern comprehensive imaging studies confirm that strain abnormalities of all four chambers—LV, RV, LA, and RA—track disease severity and predict outcomes, with atrial strain, in particular, offering incremental value beyond ventricular deformation alone [4-6]. Furthermore, RA stiffness, commonly expressed as the ratio of tricuspid E/e′ to RA reservoir strain (RASr), is a composite index that reflects the inverse of RA compliance: higher E/e′ indicates elevated right-sided filling pressures, while reduced RASr reflects impaired atrial distensibility and reservoir function, so a higher RA stiffness index signals a stiffer, pressure-loaded RA. This concept has been tested in several cardiovascular conditions: in systemic sclerosis without pulmonary arterial hypertension, RA stiffness independently predicted all-cause mortality beyond RV longitudinal function, supporting its role as an integrated marker of right-sided loading and intrinsic atrial damage [7]. In dilated cardiomyopathy, a combined LA and RA stiffness index improved prediction of heart-failure rehospitalization compared with conventional parameters, underscoring the broader prognostic value of atrial stiffness phenotyping [8]. In cardiac amyloid (CA) —where amyloid infiltration produces a diffuse “atrial cardiomyopathy” [9] and LA stiffness (E/e′/LASr) is already prognostically validated [10]—extending the same framework to the RA is pathophysiologically compelling: it has the potential to capture the combined burden of increased right-sided filling pressures and intrinsic RA stiffening and identify AL patients with advanced hemodynamic compromise at an earlier stage. In this issue of Echocardiography, Chunxiao Su et al. provide important new evidence by focusing on RA stiffness. In a single-center cohort of 78 biopsy-proven AL cardiac amyloidosis (AL-CA) patients, the investigators report a linear relationship between RA stiffness and mortality, with a clear inflection point at approximately 0.90, above which outcomes worsen substantially. Patients with RA stiffness < 0.90 had markedly better survival, whereas those ≥ 0.90 demonstrated a nearly 4-fold higher adjusted hazard of death (HR 3.89; 95% CI 1.12–13.57; p = 0.032) (Figure 1). Notably, RA stiffness also stratified risk within key clinical subgroups—those with NYHA functional class ≥ III and those in higher Mayo 2012 stages—where conventional markers often lack sensitivity. These observations highlight RA stiffness as an easily derived, clinically interpretable index with promising incremental value in AL-CA [11]. The findings of Su et al. resonate with the growing body of literature underscoring RA involvement in AL-CA. RASr and RA conduit strain are frequently and profoundly reduced in CA, reflecting a combination of amyloid infiltration, chronic elevation of right-sided pressures, and impaired atrial compliance—an “atrial myopathy” that may precede overt RV failure. In a 3D speckle-tracking study, Nemes et al. demonstrated that RA deformation is significantly depressed even when volumetric indices remain only modestly abnormal, supporting its sensitivity to early right-sided involvement [12]. Contemporary evidence, exemplified by the study of Singulane et al., demonstrates that RA strain correlates with NT-proBNP, NYHA class, and all-cause mortality in both AL and transthyretin amyloidosis [5]. Usuku et al. developed a new staging model integrating RASr and BNP that significantly stratified all-cause mortality risk in AL-CA, whereas the prior BNP/hs-troponin staging failed to separate early stages [6]. Together, these studies establish RA deformation as a robust prognostic biomarker with diagnostic and staging applications. Several important gaps in evidence, however, call for a cautious interpretation of these findings. First, the study by Su et al. is a single-center, retrospective analysis with a relatively small sample size (78 patients) and a predominantly high-risk population, in whom NYHA class and Mayo stage were already advanced, limiting generalizability to earlier disease stages [13]. Patients with atrial fibrillation or suboptimal image quality were excluded, yet these are common and clinically relevant subgroups in AL-CA. Second, RA stiffness was assessed at a single time point; whether this index is dynamic—that is, whether it improves with effective hematologic response or disease-modifying therapy—and whether changes over time track with prognosis remains entirely unknown. Third, both components of RA stiffness are load- and context-dependent: tricuspid E/e′ is influenced by pulmonary hypertension, RV remodeling and respiratory mechanics, while RA strain is affected by blood pressure, rhythm, and technical factors (vendor, image quality, frame rate). Comorbid conditions such as chronic lung disease, systemic sclerosis, or pulmonary vascular disease may therefore modulate RA stiffness independently of amyloid burden. Likewise, potential differences according to age or sex were not explored, and the modest number of events precludes robust subgroup analyses. All these factors argue against adopting a universal “0.90 threshold” without external validation in larger, multiethnic, multicenter cohorts. Finally, vendor-specific algorithms and the lack of dedicated RA-strain software mean that cut-offs may not be directly transferable across platforms, and careful standardization will be essential before RA stiffness can be routinely implemented. In this context, the work of Su et al. nonetheless provides an important proof-of-concept that RA stiffness independently predicts all-cause mortality in AL-CA and offers meaningful incremental prognostic stratification beyond established scores [13]. Incorporating this metric into conventional risk models could enhance their predictive performance and highlight the contribution of right-sided impairment in a disease traditionally viewed through a left-sided lens, while recognizing that the complex anatomy of the RV–RA unit and the above-mentioned confounders mandate cautious, context-aware interpretation. In conclusion, RA stiffness, in contrast with conventional prognostic tools (NYHA class and Mayo 2012 staging, which are largely driven by clinical status and circulating biomarkers), offers additional insight into myocardial mechanics by evaluating structural atrial damage and its hemodynamic consequences. The study by Su et al. adds more objective evidence linking RA stiffness with adverse outcomes in AL-CA and suggests that, after rigorous external validation and methodological standardization, this parameter could be incorporated into clinical practice as an adjunct for risk stratification and potentially for tailoring treatment intensity and follow-up strategies aimed at improving patient outcomes and quality of life.