Abstract
Background
The prognostic performance of biomarker-based staging systems in light chain cardiac amyloidosis (AL-CA) remains limited. In addition, the role of echocardiography in risk stratification has not been fully established in the era of contemporary therapies. This study aimed to identify echocardiographic parameters that independently predict adverse outcomes after accounting for treatment status, and to assess their incremental prognostic value beyond established biomarker-based staging systems.
Methods
Clinical data and two-dimensional echocardiography were collected from patients with AL-CA, who were staged according to the 2012 revised Mayo staging system. The primary endpoint was all-cause mortality. Treatment status was defined as a time-dependent covariate and categorized as on-treatment or off-treatment. Receiver operating characteristic (ROC) analyses were performed to determine optimal cutoffs for echocardiographic parameters.
Results
Among 100 patients with AL-CA, the median follow-up was 35 [15, 46] months, during which 36 deaths occurred. Patients who experienced events showed more severe structural and functional cardiac impairment than those who remained event-free. After multivariable adjustment, only left ventricular ejection fraction (LVEF) [hazard ratio (HR): 0.963, 95% confidence interval (CI): 0.930–0.998, P=0.041], mitral s' (HR: 0.737, 95% CI: 0.596–0.911, P=0.005), and mid-cavity circumferential strain (CS) (HR: 1.125, 95% CI: 1.022–1.240, P=0.016) remained independent predictors of mortality. ROC analyses identified optimal cutoff values of 5 cm/s for mitral s' and −15.9% for mid-cavity CS in discriminating between patients with and without events. Kaplan-Meier curves demonstrated progressively worse survival with increasing Mayo stage (P<0.001). Likelihood ratio tests indicated that mitral s' ≤5 cm/s and mid-cavity CS >−15.9% provided significant incremental prognostic value over the revised Mayo staging system. Incorporating mitral s' ≤5 cm/s into the Mayo staging system further improved risk reclassification, with an overall net reclassification improvement (NRI) of 31.8%.
Conclusions
After adjusting for treatment status, mitral s' and mid-cavity CS remained independent prognostic markers in AL-CA, underscoring their potential to enhance current biomarker-based staging systems.
Keywords: Prognosis, light chain cardiac amyloidosis (AL-CA), speckle tracking echocardiography, Doppler tissue imaging
Introduction
Light chain cardiac amyloidosis (AL-CA) is a progressive and fatal infiltrative cardiomyopathy (1,2). In AL-CA, median survival is strongly associated with the extent of cardiac involvement at diagnosis (3). Although survival has improved over recent decades, early mortality—particularly within the first year—remains unacceptably high (4).
Given this poor prognosis, accurate risk stratification is essential for guiding treatment decisions. Circulating biomarkers, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), are well-established predictors of outcomes in AL-CA (5,6). Elevated NT-proBNP level predicts worse outcomes (7), while a significant reduction following plasma cell-directed therapy correlates with improved survival (8). However, current prognostic systems, including the 2012 revised Mayo staging system (based on NT-proBNP, troponin-T, and the difference between involved and uninvolved light chain), rely exclusively on serum biomarkers (9). A key limitation of these prognostic staging systems is that biomarker concentrations can be easily influenced by both cardiac and extracardiac factors. Supporting this concern, Pun et al. reported substantial heterogeneity in echocardiographic features and clinical outcomes among individuals classified within the same Mayo stage (10). These inconsistencies highlight a critical gap in risk assessment and suggest that biomarkers alone may not fully reflect the extent of myocardial damage.
Meanwhile, the therapeutic landscape for AL-CA has evolved rapidly, with contemporary regimens significantly prolonging overall survival, even among patients classified as advanced-stage by biomarker-based staging systems (11-13). However, treatment response has itself become a major source of variation in outcomes (14). Furthermore, treatment interruption due to intolerance or treatment-related complications is common, resulting in divergent clinical outcomes among patients with similar baseline characteristics. This complex interplay between intrinsic disease severity and treatment-related variability underscores the need for prognostic tools that more directly quantify cardiac involvement. Transthoracic echocardiography provides a real-time, comprehensive assessment of cardiac structure and function. We therefore hypothesized that specific echocardiographic parameters, by reflecting the true extent of cardiac infiltration, would retain prognostic power regardless of treatment status or treatment exposure duration. Accordingly, this study aimed (I) to identify echocardiographic predictors of adverse outcomes independent of treatment effects, and (II) to determine their incremental prognostic value beyond established biomarker-based staging system. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1963/rc).
Methods
Study population
This mixed retrospective-prospective cohort study was conducted at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from September 2012 to April 2025. AL-CA was diagnosed by endomyocardial biopsy or extracardiac histological biopsy with typical cardiac imaging findings or abnormal cardiac biomarkers (15). The study protocol was approved by the Medical Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. TJ-IRB20220413) and informed consent was taken from all individual participants. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Clinical information
At enrollment, baseline clinical characteristics were obtained, including blood pressure, heart rate, and New York Heart Association (NYHA) functional class. Medical history and laboratory data were systematically extracted through comprehensive electronic medical record review. Patients with AL-CA underwent prognostic staging using the 2012 revised Mayo staging system (9,16).
Echocardiography
Standard echocardiographic images were acquired by experienced sonographers using the GE Vivid E9 or E95 ultrasound machine (GE Medical System, Horten, Norway). Offline analysis of the images was performed using the EchoPAC v204 workstation (GE Vingmed, Horten, Norway). Q-analysis was employed to quantify the multi-component global and regional deformation characteristics, such as left ventricular longitudinal, circumferential, radial, and torsional deformation characteristics. Myocardial automatic functional imaging technology was utilized to quantify the left atrial and right ventricular deformation. Left ventricular longitudinal strain (LS) was excluded from analysis if more than two segments could not be accurately tracked, and right ventricular strain (RVS) was excluded if more than one segment demonstrated inadequate tracking. Left atrial strain was measured from left atrial focused apical four-chamber and two-chamber views; images demonstrating left atrial foreshortening were excluded from strain quantification.
Left ventricular restrictive filling pattern was characterized by a mitral E/A ratio >2 and an average E/e' ratio >14 (17). The formula for calculating the left ventricular relative apical LS was as follows:
| [1] |
The apical sparing pattern was defined as relative apical LS ≥1 (18).
Follow-up
Patients with AL-CA who underwent transthoracic echocardiography were enrolled in this study. The follow-up endpoint was all-cause mortality. Outcome status was ascertained through review of electronic medical records or telephone contacts with patients or their relatives. Follow-up commenced on the date of echocardiography and continued until the occurrence of the endpoint event (n=36, 36.0%). Data for surviving patients were censored at the date of last contact (n=11, 11.0%) or at the study’s conclusion in July, 2025 (n=53, 53.0%). Follow-up duration was defined as the interval between the echocardiography date and the latest documented follow-up, whereas survival time referred to the time from echocardiography to the occurrence of the endpoint.
For AL-CA, disease-specific treatments consisted of various anti-plasma cell therapies, including chemotherapy, targeted molecular agents, and autologous hematopoietic stem cell transplantation. Treatment status was categorized as on-treatment or off-treatment, with on-treatment defined as an interval of ≤30 days between consecutive treatment administrations; longer intervals were categorized as off-treatment.
Statistical analyses
Statistical analyses were performed using R software version 4.4.2 (R Foundation) and GraphPad Prism 9.0. Continuous variables were expressed as mean ± standard deviation for normally distributed data or median with interquartile range for non-normally distributed data. Categorical variables were presented as number and percentage. Between-group differences were analyzed using the independent-samples t-test for normally distributed continuous variables and the Mann-Whitney U test for non-normally distributed continuous variables. Categorical variables were compared using the Pearson Chi-squared test, continuity-corrected Chi-squared test, or Fisher’s exact test. Cox proportional hazards regression model was conducted to identify prognostic factors in patients with AL-CA. Treatment status was defined as a time-dependent covariate. Prior to multivariate analysis, variables that were significant in the univariate analysis were assessed for multicollinearity using the variance inflation factor. A receiver operating characteristic (ROC) analysis was then performed to identify the optimal cutoff values for echocardiographic predictors of mortality. Kaplan-Meier survival analysis with the log-rank test was used to compare event-free survival across different risk strata. Finally, Likelihood ratio tests were performed to compare the goodness-of-fit between different Cox regression models. All statistical tests were performed using a two-tailed approach, with statistical significance defined as P value <0.05.
Results
Patient characteristics
A total of 100 patients with AL-CA were included, with a median follow-up duration of 35 [15, 46] months. During follow-up, 36 (36.0%) patients experienced all-cause mortality.
Baseline clinical characteristics and laboratory findings for the event and event-free groups are summarized in Table 1. No significant differences were observed between groups with respect to sex distribution or mean age. However, patients in the event group presented with lower systolic blood pressure and a higher prevalence of advanced NYHA functional class (III–IV) compared with those in the event-free group. Significant differences were also noted in prognostic staging and cardiac biomarkers. Advanced-stage disease was markedly more common in the event cohort, whereas early-stage disease predominated among event-free group. Consistent with these findings, serum NT-proBNP and troponin-I levels were substantially higher in the event group. Time-varying treatment exposure analysis further demonstrated that the proportion of patients remaining on-treatment throughout follow-up was significantly greater in the event-free group than in the event group (P<0.001, Figure 1).
Table 1. Basic characteristics in patients with light chain cardiac amyloidosis: event group vs. event-free group.
| Variable | All (n=100) | Event-free (n=64) | Event (n=36) | P value |
|---|---|---|---|---|
| Clinical characteristics | ||||
| Male | 68 (68.0) | 45 (70.3) | 23 (63.9) | 0.509 |
| Age (years) | 58±9 | 57±9 | 60±8 | 0.081 |
| BSA (m2) | 1.7±0.1 | 1.7±0.2 | 1.7±0.1 | 0.494 |
| SBP (mmHg) | 108 [97, 118] | 114 [101, 123] | 99 [92, 109] | 0.001 |
| DBP (mmHg) | 70±11 | 70±10 | 68±12 | 0.268 |
| Heart rate (bpm) | 81±13 | 80±12 | 83±15 | 0.304 |
| NYHA III–IV stage | 50/99 (50.5) | 25/64 (39.1) | 25/35 (71.4) | 0.002 |
| Hypertension | 27 (27.0) | 21 (32.8) | 6 (16.7) | 0.081 |
| Coronary heart disease | 18 (18.0) | 9 (14.1) | 9 (25.0) | 0.172 |
| Diabetes | 6 (6.0) | 4 (6.3) | 2 (5.6) | >0.99 |
| Stroke | 8 (8.0) | 5 (7.8) | 3 (8.3) | >0.99 |
| 2012 revised Mayo stage | <0.001 | |||
| Stage II | 22 (22.0) | 21 (32.8) | 1 (2.8) | |
| Stage III | 28 (28.0) | 21 (32.8) | 7 (19.4) | |
| Stage IV | 50 (50.0) | 22 (34.4) | 28 (77.8) | |
| Cardiac biomarkers | ||||
| NT-proBNP (pg/mL) | 4,334 [1,585, 9,227] | 2,822 [598, 5,819] | 5,737 [3,927, 11,295] | 0.002 |
| Troponin-I (pg/mL) | 78.3 [35.7, 212.4] | 64.5 [23.2, 171.9] | 95.7 [74.2, 291.4] | 0.032 |
Values are n (%), mean ± standard deviation, or median [interquartile range]. BSA, body surface area; DBP, diastolic blood pressure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.
Figure 1.
Time-varying treatment exposure curves (1-month interval) in the event vs. event-free groups. The curves characterize the longitudinal treatment status (on-treatment or off-treatment) in patients with light chain cardiac amyloidosis. At each time point, the proportion of patients remaining on-treatment (blue area) was calculated for both groups. Throughout the follow-up period, the event-free group demonstrated a significantly higher proportion of patients who remained on-treatment compared with the event group (P<0.001).
Conventional and speckle-tracking echocardiography
Table 2 summarizes the conventional and speckle-tracking echocardiographic findings. Regarding cardiac morphology, patients in the event group exhibited markedly increased left ventricular wall thickness relative to the event-free group. However, no significant differences were observed in right ventricular free wall thickness, indexed left atrial volume, or right atrial area between the two groups. With respect to cardiac function, the event group demonstrated more pronounced systolic impairment, characterized by a lower left ventricular ejection fraction (LVEF), reduced mitral annular s' velocity, and decreased tricuspid annular plane systolic excursion. Although the average E/e' ratio was higher in the event group, the prevalence of left ventricular restrictive filling pattern was comparable between groups.
Table 2. Conventional and speckle-tracking echocardiographic characteristics in patients with light chain cardiac amyloidosis: event group vs. event-free group.
| Variable | All (n=100) | Event-free (n=64) | Event (n=36) | P value |
|---|---|---|---|---|
| Conventional echocardiography | ||||
| IVST (mm) | 14 [12, 17] | 14 [12, 16] | 16 [14, 17] | 0.054 |
| LV PWT (mm) | 13 [12, 15] | 13 [11, 15] | 15 [13, 15] | 0.045 |
| LV ejection fraction (%) | 50±10 | 52±9 | 47±11 | 0.027 |
| Mitral E/A ratio | 1.26 [0.81, 2.46] | 1.14 [0.78, 2.38] | 1.39 [0.90, 2.46] | 0.286 |
| Mitral annular e' velocity (cm/s) | 5 [4, 6] | 5 [4, 7] | 4 [4, 5] | 0.020 |
| Mitral annular s' velocity (cm/s) | 6.0 [5.0, 7.5] | 6.5 [5.5, 9.0] | 5.0 [4.0, 7.0] | <0.001 |
| Average E/e' ratio | 18.3 [13.1, 25.6] | 17.0 [11.5, 24.1] | 21.5 [16.9, 31.8] | 0.010 |
| Left ventricular restrictive filling pattern | 33/98 (33.7) | 20/64 (31.3) | 13/34 (38.2) | 0.486 |
| LA ejection fraction (%) | 34 [21, 47] | 36 [24, 49] | 29 [20, 39] | 0.083 |
| Indexed LAV (mL/m2) | 35.5±10.3 | 35.0±10.3 | 36.8±10.5 | 0.439 |
| RV free wall thickness (mm) | 7 [5, 8] | 7 [5, 8] | 7 [6, 8] | 0.396 |
| RV fractional area change (%) | 41.9±11.0 | 42.8±11.2 | 40.0±10.5 | 0.223 |
| TAPSE (mm) | 15±4 | 16±4 | 14±3 | 0.008 |
| Tricuspid annular s' velocity (cm/s) | 12±3 | 12±3 | 11±3 | 0.140 |
| Right atrial area (cm2) | 16.7 [13.9, 19.2] | 16.2 [13.6, 18.5] | 17.5 [14.6, 20.2] | 0.372 |
| Pericardial effusion | 67 (67.0) | 42 (65.6) | 25 (69.4) | 0.697 |
| Speckle tracking echocardiography | ||||
| Left ventricle | ||||
| Basal LS (−%) | 8.1 [5.4, 10.4] | 8.8 [6.1, 11.6] | 6.8 [4.6, 9.7] | 0.021 |
| Mid-cavity LS (−%) | 11.0±4.6 | 11.7±4.8 | 9.8±3.9 | 0.029 |
| Apical LS (−%) | 14.9 [11.7, 20.3] | 15.3 [11.6, 21.9] | 13.9 [11.9, 17.8] | 0.300 |
| Global LS (−%) | 10.7 [8.2, 14.6] | 12.0 [8.5, 16.3] | 10.1 [7.4, 13.1] | 0.070 |
| Apical sparing pattern | 24 (24.0) | 14 (21.9) | 10 (27.8) | 0.507 |
| Basal CS (−%) | 12.8±4.6 | 13.3±4.4 | 12.0±5.0 | 0.192 |
| Mid-cavity CS (−%) | 15.9±4.1 | 16.8±4.1 | 14.2±3.6 | 0.002 |
| Apical CS (−%) | 20.0±5.6 | 20.6±5.5 | 18.9±5.7 | 0.155 |
| Global CS (−%) | 16.2±4.1 | 16.9±4.0 | 15.0±3.9 | 0.031 |
| Basal RS (%) | 18.1 [12.0, 27.1] | 19.7 [13.5, 30.3] | 16.6 [11.0, 24.4] | 0.193 |
| Mid-cavity RS (%) | 25.5 [17.8, 34.1] | 26.8 [20.2, 37.0] | 23.1 [16.2, 31.6] | 0.067 |
| Apical RS (%) | 19.5 [14.3, 27.6] | 19.3 [14.6, 27.7] | 20.4 [12.8, 27.0] | 0.916 |
| Global RS (%) | 21.5 [16.9, 27.9] | 22.4 [18.1, 29.4] | 19.4 [15.6, 25.2] | 0.082 |
| Basal rotation (−°) | 6.70 [3.61, 10.57] | 7.31 [4.34, 10.66] | 5.42 [3.27, 9.93] | 0.459 |
| Apical rotation (°) | 11.60±4.89 | 12.38±4.56 | 10.26±5.19 | 0.046 |
| Twist (°) | 18.73 [14.95, 21.66] | 19.08 [15.68, 21.83] | 17.97 [9.93, 20.28] | 0.061 |
| Left atrium | ||||
| Reservoir strain (%) | 12 [7, 21] | 14 [8, 23] | 8 [6, 16] | 0.014 |
| Conduit strain (−%) | 6 [5, 9] | 7 [5, 10] | 6 [5, 7] | 0.166 |
| Contraction strain (−%) | 5 [2, 12] | 6 [2, 15] | 4 [1, 8] | 0.015 |
| Right ventricle | ||||
| Global strain (−%) | 16.5±5.1 | 17.2±5.3 | 15.1±4.6 | 0.052 |
| Free wall strain (−%) | 21.0±6.3 | 21.7±6.4 | 19.7±5.8 | 0.129 |
Values are n (%), mean ± standard deviation, or median [interquartile range]. CS, circumferential strain; IVST, interventricular septum thickness; LA, left atrial; LAV, left atrial volume; LS, longitudinal strain; LV, left ventricular; PWT, posterior wall thickness; RS, radial strain; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.
Strain analysis further revealed significantly worse LS in the basal and mid-cavity segments among patients with events. Similarly, mid-cavity and global circumferential strain (CS) were significantly reduced in the event group. Left atrial strain analysis also indicated substantially impaired phasic function in the event group. In contrast, RVS analysis did not differ significantly between the two groups.
Prognostic assessment
Kaplan-Meier survival analysis demonstrated significant differences in event-free survival across Mayo stages (log-rank P<0.001, Figure 2). As shown in Table 3, univariate Cox regression analysis further identified systolic blood pressure, 2012 revised Mayo stage, and treatment status as significant prognostic predictors in patients with AL-CA. Notably, with the exception of left ventricular posterior wall thickness, most echocardiographic parameters that differed between the event and event-free groups also demonstrated prognostic relevance in univariate analysis. To further determine the independent prognostic contribution of echocardiographic parameters, a basic Cox model was established containing systolic blood pressure, 2012 revised Mayo stage, and treatment status. A series of upgraded models was then constructed by adding one echocardiographic variable at a time, selected based on significance in the univariate analysis. After adjustment for the basic Cox model, most echocardiographic variables were no longer significant. However, three parameters retained independent prognostic value, namely LVEF, mitral annular s' velocity, and mid-cavity CS.
Figure 2.
Event-free survival in patients with light chain cardiac amyloidosis, staged by 2012 revised Mayo staging system. The revised Mayo staging system showed significant prognostic value, with the log-rank test demonstrating a stepwise increase in all-cause mortality risk across higher Mayo stages (II, III, and IV) (P<0.001).
Table 3. Univariable and multivariable Cox proportional hazards regression analyses.
| Variable | Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | ||
| Systolic blood pressure | 0.966 | 0.946–0.987 | 0.002 | † | |||
| 2012 revised Mayo stage | |||||||
| Stage II | 1.000 | – | – | ||||
| Stage III | 7.188 | 0.881–58.622 | 0.065 | ||||
| Stage IV | 20.363 | 2.763–150.086 | 0.003 | ||||
| Treatment status | |||||||
| Off-treatment | 1.000 | – | – | ||||
| On-treatment | 0.099 | 0.040–0.245 | <0.001 | ||||
| Echocardiographic characteristics | |||||||
| LV PWT | 1.122 | 0.991–1.269 | 0.069 | ||||
| LV ejection fraction | 0.957 | 0.929–0.987 | 0.005 | 0.963 | 0.930–0.998 | 0.041 | |
| Mitral annular e' velocity | 0.738 | 0.594–0.917 | 0.006 | 0.972 | 0.747–1.266 | 0.835 | |
| Mitral annular s' velocity | 0.665 | 0.549–0.805 | <0.001 | 0.737 | 0.596–0.911 | 0.005 | |
| Average E/e' ratio | 1.034 | 1.007–1.062 | 0.013 | 1.014 | 0.981–1.047 | 0.417 | |
| TAPSE | 0.882 | 0.804–0.967 | 0.007 | 1.023 | 0.901–1.161 | 0.724 | |
| Basal LS | 1.128 | 1.036–1.229 | 0.006 | 1.043 | 0.939–1.160 | 0.431 | |
| Mid-cavity LS | 1.099 | 1.021–1.184 | 0.012 | 1.010 | 0.921–1.108 | 0.830 | |
| Mid-cavity CS | 1.133 | 1.049–1.224 | 0.002 | 1.125 | 1.022–1.240 | 0.016 | |
| Global CS | 1.100 | 1.016–1.192 | 0.019 | 1.041 | 0.947–1.143 | 0.407 | |
| Apical rotation | 0.924 | 0.860–0.994 | 0.033 | 1.001 | 0.922–1.086 | 0.987 | |
| LA reservoir strain | 0.951 | 0.912–0.991 | 0.018 | 0.999 | 0.949–1.051 | 0.967 | |
| LA contraction strain | 1.071 | 1.011–1.134 | 0.019 | 1.024 | 0.960–1.093 | 0.467 | |
†, basic Cox model: systolic blood pressure + 2012 revised Mayo stage + treatment status. CI, confidence interval; CS, circumferential strain; HR, hazard ratio; LA, left atrial; LS, longitudinal strain; LV, left ventricular; PWT, posterior wall thickness; TAPSE, tricuspid annular plane systolic excursion.
Figure 3 presents ROC analyses for echocardiographic predictors of clinical events. Mitral annular s' velocity showed the best discriminatory ability [area under the curve (AUC): 0.74, 95% confidence interval (CI): 0.64–0.85, P<0.001; cut-off ≤5 cm/s]. Mid-cavity CS demonstrated moderate performance (AUC: 0.68, 95% CI: 0.57–0.79, P=0.003; cut-off >−15.9%), while LVEF was less predictive (AUC: 0.64, 95% CI: 0.52–0.75, P=0.022; cut-off ≤47%). These cut-off values were applied for subsequent dichotomized analyses. As shown in Figure 4, adding mitral annular s' velocity ≤5 cm/s to the revised Mayo staging system yielded the greatest incremental prognostic value (Δχ2=12.62, P<0.001), followed by mid-cavity CS >−15.9% (Δχ2=4.60, P=0.032), whereas LVEF ≤47% provided no significant improvement (Δχ2=1.42, P=0.235). Net reclassification improvement (NRI) analyses (Table 4) further confirmed the superiority of mitral annular s' velocity, which significantly improved risk reclassification (NRI: 0.318, 95% CI: 0.000–0.487, P=0.038), supported by both event and non-event components (0.144 and 0.542, respectively). Mid-cavity CS resulted in a smaller yet significant overall NRI (0.115, 95% CI: 0.000–0.283, P=0.040), although neither component alone was significant.
Figure 3.
Receiver operating characteristic curve analysis of echocardiographic parameters for predicting clinical events. The optimal cut-off values for identifying events were ≤5 cm/s for mitral annular s' velocity, >−15.9% for mid-cavity CS, and ≤47% for LVEF. AUC, area under the curve; CS, circumferential strain; LVEF, left ventricular ejection fraction.
Figure 4.
Incremental prognostic value of echocardiographic parameters over the 2012 revised Mayo staging system. The likelihood ratio test showed that incorporating mitral annular s' velocity ≤5 cm/s (P<0.001) and mid-cavity CS >−15.9% (P=0.032) significantly improved risk discrimination over the revised Mayo staging system, whereas LVEF did not provide incremental prognostic value. CS, circumferential strain; LVEF, left ventricular ejection fraction.
Table 4. Net reclassification improvement for mortality risk prediction with the 2012 revised mayo stage plus echocardiographic parameters.
| Variable | Event | Event-free | NRI, % |
|---|---|---|---|
| 2012 revised Mayo stage | |||
| Stage II/III | 8 | 42 | |
| Stage IV | 28 | 22 | |
| 2012 revised Mayo stage + mitral annular s' velocity | 31.8 | ||
| Stage II/III + mitral annular s' velocity ≤5 cm/s | 3 | 5 | |
| Stage II/III + mitral annular s' velocity >5 cm/s | 5 | 37 | |
| Stage IV + mitral annular s' velocity ≤5 cm/s | 18 | 6 | |
| Stage IV + mitral annular s' velocity >5 cm/s | 10 | 16 | |
| 2012 revised Mayo stage + mid-cavity CS | 11.5 | ||
| Stage II/III + mid-cavity CS >−15.9% | 5 | 12 | |
| Stage II/III + mid-cavity CS ≤−15.9% | 3 | 30 | |
| Stage IV + mid-cavity CS >−15.9% | 19 | 11 | |
| Stage IV + mid-cavity CS ≤−15.9% | 9 | 11 | |
Values are n, unless noted otherwise. CS, circumferential strain; NRI, net reclassification improvement.
Stratified analysis of patients with revised Mayo stage II/III and stage IV revealed that a mitral annular s' velocity ≤5 cm/s were associated with a significantly poorer prognosis (Mayo stage II/III: P=0.026, Figure 5A; Mayo stage IV: P<0.001, Figure 5B, respectively). However, mid-cavity CS >−15.9% failed to stratify risk in different Mayo stages; the survival curves for patients with mid-cavity CS >−15.9% and those with ≤−15.9% were not significantly different (Mayo stage II/III: P=0.059, Figure 5C; Mayo stage IV: P=0.087, Figure 5D). Figure 6 presented representative cases of AL-CA patients with the same Mayo stage and treatment status but differing echocardiographic features, illustrating their distinct clinical outcomes (Patient A vs. Patient B; Patient C vs. Patient D).
Figure 5.
Event-free survival stratified by echocardiographic features at different Mayo stages in patients with light chain cardiac amyloidosis. Among patients with revised Mayo stage II/III, mitral annular s' velocity ≤5 cm/s (A, P=0.026) was associated with worse prognosis, while mid-cavity CS >−15.9% did not reach statistical significance (C, P=0.059). Similarly, in patients with revised Mayo stage IV, mitral annular s' velocity ≤5 cm/s identified individuals at higher mortality risk compared with those with values >5 cm/s (B, P<0.001). However, no significant difference in outcomes was observed based on mid-cavity CS >−15.9% versus ≤−15.9% (D, P=0.087). CS, circumferential strain.
Figure 6.
Differential clinical outcomes in Mayo stage IV AL-CA patients with distinct echocardiographic features. From left to right, echocardiographic analysis showed wall thickness (first column), septal mitral annular systolic velocity (s', second column), left ventricular 18-segment longitudinal strain bull’s-eye plot (third column), and mid-cavity CS (fourth column). Patient A (NT-proBNP 15,351 pg/mL, troponin I 147.4 pg/mL, dFLC 1,005 mg/dL; Mayo stage IV) received only a single cycle of a bortezomib-based regimen. Patient B (NT-proBNP 5,753 pg/mL, troponin I 79.2 pg/mL, dFLC 3,255 mg/dL; Mayo stage IV) also received only a single cycle of a bortezomib-based regimen. Patient C (NT-proBNP 4,888 pg/mL, troponin I 117.9 pg/mL, dFLC 1,526 mg/dL; Mayo stage IV) remained on continuous bortezomib-based therapy at follow-up. Patient D (NT-proBNP 4,347 pg/mL, troponin I 80.1 pg/mL, dFLC 1,465 mg/dL; Mayo stage IV) experienced the endpoint event while on regular bortezomib-based therapy. Importantly, adverse events were observed in patients with mitral s' ≤5 cm/s and mid-cavity CS >−15.9% (Patient B and Patient D), irrespective of treatment exposure duration. AL-CA, light chain cardiac amyloidosis; CS, circumferential strain; dFLC, difference between involved and uninvolved light chain; GLS, global longitudinal strain; IVSd, interventricular septum thickness at diastole; LVIDd, left ventricular internal dimension at diastole; LVPWd, left ventricular posterior wall at diastole; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
Discussion
This study identifies key echocardiographic parameters as independent predictors of outcomes in AL-CA, supporting the refinement of existing prognostic models. Our primary findings are that LVEF, mitral annular s' velocity, and mid-cavity CS independently predict prognosis even after adjusting for treatment status. Crucially, we demonstrate that incorporating mitral annular s' velocity (≤5 cm/s) adds significant incremental prognostic value over the revised Mayo staging system and markedly improved risk reclassification in both event and event-free AL-CA patients.
The diagnostic and prognostic utility of echocardiography in AL-CA is well established, with numerous studies demonstrating the importance of comprehensive multi-chamber assessment, particularly deformation imaging (19-25). For example, Cohen et al. showed that overall survival in amyloid light-chain (AL) amyloidosis shortens significantly as global longitudinal strain (GLS) worsens (20). Similarly, Ternacle et al. identified left ventricular apical LS as an independent predictor of major adverse cardiac events (21), and the incremental prognostic value of adding GLS to biomarker-based staging systems has also been confirmed (22). In addition, the prognostic relevance of atrial strain and RVS has been validated (23-26). These deformation abnormalities are thought to directly reflect the extent of amyloid fibril deposition in the myocardium. However, a critical factor not consistently accounted for in prior studies is the profound influence of disease-specific therapies on clinical outcomes. Modern targeted treatments are known to significantly improve prognosis in AL-CA. In our study, the proportion of patients who remained on treatment differed significantly between the event and event-free groups throughout follow-up (Figure 1). As reported by Martinez-Naharro et al. (27) and Clerc et al. (28), effective therapy can also lead to improvements in GLS in patients with AL amyloidosis. Due to the variable treatment response, baseline echocardiographic parameters may be improved, stabilized, or even deteriorated. Thus, AL amyloidosis patients with similar baseline echocardiographic profiles may experience distinctly different clinical trajectories depending on their treatment response. In the present analysis, although deformation parameters were associated with outcomes in univariate analyses, their prognostic significance largely disappeared after adjustment for treatment status and the 2012 revised Mayo stage, with the exception of mid-cavity CS.
Furthermore, discrepancies in study populations may also explain differing results. Unlike previous studies by Clerc et al. (28) and Barros-Gomes et al. (29), which included substantial numbers of AL amyloidosis patients without cardiac involvement, our study exclusively enrolled patients with cardiac involvement. Specifically, our cohort included a high proportion (50.0%) of patients with advanced disease (Mayo stage IV). This focused patient selection likely enhanced our ability to identify parameters that retain prognostic value in the context of advanced disease and contemporary therapeutic interventions.
Our study found that mitral annular s' velocity and mid-cavity CS demonstrated consistently significant prognostic value, which may indicate more advanced cardiac involvement. The pathophysiology of AL-CA involves a progressive impairment of strain, typically beginning with longitudinal function and later affecting circumferential function, with a characteristic base-to-apex gradient (30,31). Mid-cavity CS may therefore represent a “sweet spot” that captures advanced myocardial infiltration more reliably than global deformation like GLS, which can be influenced by early therapeutic response. While a small-sample study by Hou et al. (32) hinted at this potential, our larger cohort provides statistically significant evidence for the incremental value of mid-cavity CS. Similarly, a low mitral annular s' velocity (≤5 cm/s), a well-known marker of advanced disease (33), emerged as a powerful and independent predictor in our cohort. Its simplicity and wide availability make it an ideal candidate for integration into routine prognostic assessment. Based on our findings, future staging systems for AL-CA may be enhanced by incorporating echocardiographic indices to better stratify patients in the modern treatment era.
Limitations
This study has several limitations that should be acknowledged. First, the single-center design and relatively small sample size may limit the generalizability of our findings. Furthermore, our institution as a tertiary referral center resulted in a cohort with a high prevalence of advanced disease, introducing a potential selection bias. Second, patients with transthyretin-related cardiac amyloidosis were not included; therefore, we were unable to assess whether mitral annular s' velocity and mid-cavity CS provide incremental prognostic value in that population. Finally, treatment regimens among patients with AL-CA were heterogeneous. Specifically, 97 patients (97.0%) received the currently recommended first-line therapies (cyclophosphamide, bortezomib, and dexamethasone with or without daratumumab), whereas the remaining 3 patients (3.0%) were treated with non-first-line agents such as lenalidomide.
Conclusions
In summary, echocardiography offers additional prognostic information beyond biomarkers for patients with AL-CA. Mitral annular s' velocity ≤5 cm/s and mid-cavity CS >−15.9% may indicate more advanced cardiac involvement and hold potential for enhancing current staging system.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors would like to thank the patients and their families for their participation, and clinical staffs from the Department of Hematopathology and Medical Ultrasound for their supports.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. TJ-IRB20220413), and informed consent was taken from all individual participants.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1963/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1963/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1963/dss
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Data Availability Statement
Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1963/dss