First-phase ejection fraction as a potential early indicator for left ventricular function in cardiac amyloidosis

Introduction

Light-chain amyloidosis is a rare disease. From 2007 to 2015, its annual incidence in the United States was 9.7–14.0/million (1), but detailed data for its incidence in China are lacking. Secondary light-chain amyloidosis occurs in 10–15% of multiple patients with myeloma, and it is more common in older adults (median age ~60 years) and slightly more common in men. Severe cardiac amyloidosis (CA) involves a median survival <1 year (2), and its pathogenesis involves clonal plasma cell proliferation, misfolding of monoclonal light chains, formation of amyloid deposits in tissues/organs, and subsequent organ dysfunction (3,4), with the heart and kidney often being affected. Diagnosis requires clinical, biopsy, and immunoglobulin/light-chain evidence (5,6). Treatment primarily involves reducing light-chain levels, preventing amyloid deposition, and reversing organ dysfunction (7).

Echocardiography is vital for diagnosing CA, monitoring progression, predicting prognosis, and facilitating treatment adjustment. Despite advances in this technology, it has certain drawbacks (8). Gu et al. introduced left ventricular first-phase ejection fraction (LVEF1), the percentage of left ventricular volume at aortic valve flow peak to end-diastolic volume (9). Unlike left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (LVGLS), it represents the most active ejection from the aortic valve opening to peak flow, reflecting the rapid shortening inactivation of the myocardium and the reduction of myocardial wall stress. Studies from Gu et al. suggest that LVEF1 is comparable to LVGLS and more sensitive than LVEF in left ventricular function assessment (9,10). It predicts heart failure in patients with hypertension, increased risk in patients with asymptomatic aortic stenosis with preserved ejection fraction, and is associated with coronavirus disease 2019 (COVID-19) mortality. However, only a few studies have examined its role in myocardial amyloidosis (10,11). We conducted a study to examine the ability of LVEF1 to evaluate left ventricular function in patients with light-chain amyloidosis. Specifically, we investigated the impact of treatment response in patients with light-chain CA on left ventricular function and echocardiographic index LVEF1 and the prognostic significance of LVEF1. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1085/rc).

Methods

Study population

From August 2020 to August 2023, 156 patients diagnosed with light-chain amyloidosis and suspected of CA on echocardiography at the Hematology Department of The First Affiliated Hospital of Guangxi Medical University were selected as research participants. Patients suspected of CA on echocardiography consistently demonstrate unexplained left ventricular wall thickness ≥12 mm with apical sparing pattern on longitudinal strain imaging. A total of 37 patients were excluded, including those with LVEF <50%, those with previous diseases that could seriously affect cardiac afterload (e.g., including patients with chronic kidney disease not caused by amyloidosis and those with hypertension lasting more than 5 years), those with severe heart disease (e.g., coronary heart disease, valvular disease including moderate-to-severe stenosis and prolapse from various causes, persistent atrial fibrillation, and third-degree atrioventricular block), those unable to comply with standard treatment protocols, and those with poor echocardiogram image quality. Finally, 119 patients with light-chain amyloidosis with suspected CA diagnosed on echocardiography were enrolled, with a median age of 61 years. Among them, the control group included patients not diagnosed with CA (n=47) by clinicians considering other test results, while the case group comprised those with CA (n=72).

The diagnosis of light-chain amyloidosis largely followed the guidelines jointly released by the International Society of Amyloidosis (ISA) and the American Society of Hematology (ASH), among others. These guidelines include evidence of multi-organ involvement, amyloid deposition, abnormal plasma cell hyperplasia, and genetic testing. Multiple methods were combined to achieve accurate diagnosis and rule out other diseases (5,6).

The diagnosis of CA was evaluated by a team consisting of hematologists and cardiologists in the hospital using multidimensional evidence including symptoms, hematological tests, echocardiography, electrocardiograms (ECGs), cardiac magnetic resonance (CMR), and tissue biopsy. Clinical symptoms included fatigue, weight loss, and organ-specific manifestations. Hematological test evidence was the same as the diagnostic criteria for light-chain amyloidosis mentioned above. Low voltage on ECG and echocardiographic findings of ventricular hypertrophy, diastolic dysfunction, and “apical sparing” on strain imaging were key diagnostic indicators for CA. Elevated cardiac biomarkers such as troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were also included to assist in diagnosis, as were diffuse subendocardial delayed enhancement on CMR and amyloid deposition in tissue biopsy. According to the diagnostic process recommended by the European Society of Cardiology, in this study, patients suspected of having CA were those with positive results in symptoms, hematological tests, echocardiography, and ECG. However, to confirm the diagnosis of CA, positive results of CMR and tissue biopsy were also required to diagnose patients with CA; otherwise, they were classified into the non-CA group. Due to the difficulty of endomyocardial biopsy, all patients in this study underwent subcutaneous abdominal fat biopsy (12).

As shown in Figure 1, Baseline data, including demographic, cardiac ultrasound, and blood biochemical tests, were collected at the time of the patient’s first hospitalization. After 1 year of treatment, the examination results of patients with CA were obtained again. According to the relevant standards, hematologic complete response (hemCR) at the 1-year mark was defined as follows: (I) negative serum and urine immunofixation and (II) either a free light-chain (FLC) ratio within the reference range or an abnormal FLC ratio as long as the uninvolved FLC concentration was greater than the involved FLC concentration. Patients who do not meet these criteria were classified as having a nonhematologic complete response (non-hemCR) (13). The survival status of all patients with CA was followed up via telephone or outpatient visits until September 30, 2024. When calculating the survival rate, we considered the time from the first echocardiogram examination to death. The primary endpoint was all-cause mortality. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (Approval No. 2024-E785-01). Informed consent was obtained from all individual participants.

Figure 1 Flowchart of the study. CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; hemCR, hematologic complete response; LVEF, left ventricular ejection fraction.

Clinical data and echocardiography

For each patient visit, a comprehensive clinical assessment was conducted, and the medical history (including vital signs, past medical history, family history, symptoms, etc.) was collected. Blood and urine samples were collected for laboratory tests, including myocardial injury markers, free light chain, serum immunofixation, etc. Experienced cardiac ultrasound clinicians used the EPIQ 7C/iE33 ultrasound diagnostic instrument (s5-1 cardiac probe, frequency 1–5 MHz; Philips Healthcare, Amsterdam, The Netherlands) for examination. After the three-lead ECG was connected, the heart sections were routinely scanned for at least three cardiac cycles and saved in Digital Imaging and Communications in Medicine (DICOM) format for further data processing. The collected parameters included interventricular septal (IVS) thickness, left ventricular posterior wall (LVPW), early diastolic mitral flow velocity (E), late diastolic mitral flow velocity (A), early diastolic lateral and septal mitral annular velocity (e’), LVGLS, LVEF, and LVEF1, among others. The mean left ventricular wall thickness (LVWT), E/e’, and E/A ratio were calculated. Doppler sample volume positioned at the aortic valve orifice was used to record the aortic flow spectrum. Time of peak aortic valve flow (TPAVF) was defined as the timepoint of peak velocity on the aortic flow waveform. Left ventricular volume at end-diastole (LVEDV) and TPAVF were measured with the Simpson biplane method from apical two- and four-chamber views (Figure 2). The formula for LVEF1 was as follows:

LVEF1=(LVEDV−TPAVFvolume)/LVEDV×100%[1]

Figure 2 LVEF1 in CA vs. non-CA. Case 1: CA patient. Case 2: non-CA patient. Left: TPAVF measurement. Middle: LVEDV. Right: left ventricular volume at TPAVF. The LVEF1 of patients with CA (28%) was lower than that of patients without CA (35%). CA, cardiac amyloidosis; LVEDV, end-diastolic left ventricular volume; LVEF1, left ventricular first-phase ejection fraction; TPAVF, flow spectrum for time of peak aortic valve flow.

Measurements for all parameters were conducted three times, and the average value was recorded.

Statistical analysis

Data with normal distribution were presented as the mean ± standard deviation (SD) and were compared between the two groups via the t-test. Data with a skewed distribution were presented as median (with quartiles) and were compared via the Mann-Whitney rank-sum test. Count data were reported as the number of cases and percentages, and the Chi-squared test or the continuity-corrected Chi-squared test was used to assess differences between groups. The correlation between LVEF1 and parameters such as LVGLS and NT-proBNP was analyzed via Pearson correlation analysis. Kaplan Meier curves and uni- and multivariate Cox regression were applied for survival analysis. Hematological status, assessable for patients with survival ≥1 year, was modeled as a time-dependent covariate in Cox regression with baseline variables. Its hazard ratio (HR) was considered to reflect the effect of achieving hemCR on subsequent survival. The receiver operating characteristic (ROC) curve was generated, and the Youden index was calculated to determine the optimal cutoff value of LVEF1 for predicting survival probability. The continuous relationship between LVEF1 and prognosis was evaluated via restricted cubic splines (RCSs). The significance level was set at α=0.05, with P<0.05 being considered statistically significant. All statistical analyses were performed with R software version 4.2.2 (The R Foundation for Statistical Computing, Vienna, Austria) in conjunction with MSTATA software (https://www.mstata.com/).

Results

A total of 119 patients with light-chain amyloidosis suspected of having CA on echocardiography were included in the study. According to the relevant clinical examinations, there were 72 (61%) patients with CA and 47 (29%) with non-CA (Table 1). During the 1-year treatment process, 8 patients died. The patients with CA who survived after 1 year of treatment (n=64) were stratified according to hematological response. The characteristics of patients with hemCR (n=26) and non-hemCR (n=38) are presented in Table 2.

CA vs. non-CA

As shown in Table 1, there were no statistically significant differences in basic characteristics, including age, gender, height, weight, and blood pressure, between the CA and non-CA groups. When compared to the non-CA group, the CA group exhibited higher levels of NT-proBNP (median NT-proBNP: 3,795 vs. 2,633 pg/mL; P=0.015) and cardiac troponin I (cTnI) (median cTnI: 0.18 vs. 0.03 ng/mL; P=0.006). However, there were no statistically significant differences in symptoms [New York Heart Association (NYHA) classification] between the two groups. Regarding echocardiography parameters, both the CA and non-CA groups displayed normal LVEF (62.64%±7.31% vs. 63.64%±11.23%; P=0.180). Although the ventricular wall thickness significantly differed between the CA and non-CA groups, the difference magnitude was minimal (LVWT: 13.82±1.53 vs. 13.07±1.9 mm; P=0.013). In comparison to the non-CA group, the CA group had worse diastolic function (E/A: 1.63±0.83 vs. 1.04±0.54, P<0.001; e’: 5.77±2.65 vs. 7.43±2.65 cm/s, P<0.001; E/e’: 18.62±8.29 vs. 12.72±5.77, P<0.001). Both LVEF1 and LVGLS were significantly reduced in the CA group as compared to the non-CA group (LVEF1: 31.35%±7.78% vs. 36.25%±8.74%, P=0.004; LVGLS: 14.93%±4.84% vs. 20.17%±5.76%, P<0.001), with LVEF1 showing a certain correlation with NT-proBNP (r=0.484; P<0.001). On the other hand, the correlation between LVEF1 and LVGLS was not significant (r=–0.245; P=0.186).

hemCR vs. non-hemCR

The average age of hemCR patients was 58 years, and that of non-hemCR patients was 64 years. Among the hemCR patients, 42% had Mayo stage III amyloidosis, while 66% of non-hemCR patients were Mayo stage III. Among the hemCR patients, 81% were NYHA class III–IV, while 76% of non-hemCR patients were NYHA class III–IV. As shown in Table 2, after 1-year follow-up, there were no significant differences in basic characteristics such as height, weight, or blood pressure among all patients, and both NT-proBNP and serum cardiac troponin showed a downward trend. For echocardiographic parameters, there was a significant difference in ventricular wall thickness pre- and posttreatment between the hemCR and non-hemCR groups, yet the average difference between the two was minimal (mean LVWT in hemCR group: 14.12±0.9 to 13.67±1.06 mm; P=0.011; mean LVWT in non-hemCR group: 14.30±1.74 to 14.52±1.86 mm; P=0.034). Regardless of hematological response, the 1-year treatment-induced change in LVEF was statistically nonsignificant (hemCR group: 62.35%±7.29% to 61.15%±4.64%, P=0.292; non-hemCR group: 60.84%±6.87% to 60.6%±4.55%, P=0.247). We observed that the common diastolic function evaluation indices of hemCR patients showed an improvement after 1 year of treatment (E/A: 1.52±0.8 to 1.42±0.57, P=0.039; e’: 4.98±1.94 to 5.45±1.83 cm/s, P=0.040; E/e’: 20.34±5.22 to 17.35±5.25, P=0.012), and LVEF1 increased significantly (32.62%±8.13% to 39.24%±7.36%; P<0.01). However, in non-hemCR patients, no statistically significant differences were observed for these indices. Before and after 1 year of treatment, the difference in LVEF1 (ΔLVEF1) of patients with CA was correlated with the difference in NT-proBNP (ΔNT-proBNP) (r=–0.761; P<0.001).

Survival analysis

Survival analysis was performed on all patients with CA (n=72). By the end of follow-up, 30 patients had died (8 during 1 year of treatment). The remaining 64 patients had a median 18-month posttreatment follow-up, with 22 deaths. The prognostic value of parameters was evaluated with Kaplan-Meier curves and Cox regression. As shown in Table 3, in the univariate Cox regression analysis, the factors associated with adverse events included hematological response status, Mayo stage, NT-proBNP, ΔNT-proBNP, LVEF1 (HR =0.92, 95% CI: 0.88–0.97; P=0.003), and ΔLVEF1. After adjustments were made for key variables including age, Mayo stage, NYHA classification, hematological response status (model 1), LVEF, LVGLS (model 2), and ΔLVEF1 (model 3), baseline LVEF1 remained significantly associated with all-cause death. Excluding patients surviving <1 year might have introduced survivor bias and skewed the early-stage survival risk assessment. Multivariable analyses of models 1 and 2 were conducted in all patients with CA. In model 1, hematological response status was handled as a time-dependent covariate since its assessment required patients to survive ≥1 year. Multivariable Cox regression (with time-dependent covariates) demonstrated that patients assessed as hemCR after surviving 1 year had reduced subsequent mortality risk (HR =0.31, 95% CI: 0.10–0.98; P=0.017). For model 3, since both ΔLVEF1 and hematological response status were obtained after 1 year of treatment, multivariate Cox analysis excluding patients with less than 1 year of survival indicated that ΔLVEF1 was not a significant independent predictor of all-cause death (HR =0.90, 95% CI: 0.81–1.00; P=0.051). ROC curve analysis was performed for three echocardiographic parameters of left heart function: LVEF, LVEF1, and LVGLS. As shown in Figure 3A, their respective areas under the curve (AUCs) for predicting all-cause death were 0.648 (95% CI: 0.508–0.788), 0716 (95% CI: 0.591–0.841), and 0.743 (95% CI: 0.628–0.858). Both LVEF1 and LVGLS demonstrated good predictive potential, and their predictive abilities were comparable (DeLong test P=0.444). According to the Youden index, the optimal cutoff for LVEF1 was 30% (sensitivity =80%; specificity =69%), with LVEF1 >30% related to a better prognosis (P<0.001; Figure 3B). Given the current lack of an established clinical cutoff for LVEF1, we evaluated its continuous relationship with prognosis using RCSs. The results demonstrated a monotonic gradient of prognostic value (P for nonlinearity=0.177), supporting its utility as a continuous risk marker. Specifically, across the entire analytical range, every 1% decrease in LVEF1 was associated with increased risk.

Figure 3 Survival analysis of LVEF1, LVEF, and LVGLS in patients with cardiac amyloidosis. (A) ROC curve of LVEF1, LVEF, and LVGLS. (B) Kaplan-Meier curves of baseline LVEF1 ≥30% vs. LVEF1 <30%. The primary outcome of interest was severe events, including readmission for heart failure and all-cause mortality. AUC, area under the curve; CI, confidence interval; LVEF, left ventricular ejection fraction; LVEF1, left ventricular first-phase ejection fraction; LVGLS, left ventricular global longitudinal strain; ROC, receiver operating characteristic.

LVEF1 ≥30% vs. LVEF1 <30%

As shown in Table 4, when patients with CA were stratified by LVEF1 <30% or ≥30%, those with LVEF1 <30% demonstrated a higher prevalence of Mayo stage III, elevated NT-proBNP and cardiac troponin T level, and greater impairment in LVGLS (10.47%±2.00% vs. 15.52%±2.82%; P<0.001) and E/e′, indicating greater severity of cardiac dysfunction; this group also exhibited significantly higher mortality (35.1% vs. 17.1%; P<0.001) and shorter median survival (15 vs. 24 months; P=0.001). After adjustments for age, Mayo stage, NYHA class, and NT-proBNP level, patients with CA with LVEF1 <30% had a 3.76-fold increased mortality risk than did those with LVEF1 ≥30% (HR =3.76, 95% CI: 2.24–7.92; P=0.001).

Reproducibility assessment

All measured parameters demonstrated excellent intraobserver and interobserver reproducibility. Among these, the LVEF1, the primary focus of this study, yielded an intraobserver intraclass correlation coefficient (ICC) of 0.974 (95% CI: 0.944–0.988) and an interobserver ICC of 0.943 (95% CI: 0.882–0.973).

Discussion

This study primarily examined the clinical value of the echocardiographic parameter LVEF1 for CA. The findings indicate that patients with CA have lower LVEF1 values than do those suspected of having CA but who are not diagnosed with it. Further analysis revealed that among patients achieving hemCR 1 year after treatment, LVEF1 showed significant improvement as compared to levels recorded 1 year prior. Additionally, there was a correlation between ΔLVEF1 and ΔNT-proBNP level. Furthermore, baseline LVEF1 demonstrated a strong discriminative performance for identifying patients at risk of poor prognosis. Notably, patients with LVEF1 >30% exhibited significantly improved survival during the follow-up period.

Amyloidosis directly harms the myocardium. It impairs diastolic function as amyloid deposits change the extracellular matrix, thicken and stiffen the myocardium, and delay calcium clearance, hindering ventricular filling (3). It also damages myocardial cells, reducing contractility (14), and disrupts electrical conduction, inducing arrhythmias and affecting contraction coordination (15). Previous studies have reported significant differences between patients with CA and those without it. In patients with CA with preserved LVEF, two-dimensional speckle-tracking strain imaging can detect subclinical myocardial injury, as reflected by alterations in strain parameters (16,17). These strain values are more reduced as compared to those in other cardiomyopathies with thickened myocardium (18), which is in line with the finding our study in which patients with CA and preserved EF had worse cardiac function than did non-CA patients with preserved EF. Patients with CA and preserved LVEF have worse myocardial injury markers, diastolic function, and LVGLS than do non-CA patients. The lower LVEF1 in patients with CA suggested that this could be an early subclinical left ventricular dysfunction indicator.

In our study, LVEF1 and LVGLS showed no linear correlation, likely due to different evaluation dimensions (19). LVGLS indicates myocardial longitudinal deformation. The heart’s systolic and diastolic functions are interlinked; systole primes for diastole and vice versa (20). LVEF1 reflects early left ventricular systole, related to both systolic and diastolic functions (21). Diastolic dysfunction may affect LVEF1 through various mechanisms. For example, the increase in myocardial stiffness caused by amyloid deposition and the decrease in myocardial relaxation ability due to alerted calcium handling and other causes hinder the normal reduction of myocardial wall stress in patients with CA. Subsequently, this affects the shortening speed and degree of myocardial cells, which destroys the systolic–diastolic coordination and the sequence of myocardial activities, thus leading to a decrease in LVEF1. The systolic-diastolic interplay reflects the heart’s integrity. As an early systolic indicator, LVEF1’s change may signal an overall shift in heart function (22).

In CA, NT-proBNP and cardiac troponin serve as key biomarkers that are characteristically elevated. Incorporated into the Mayo staging system, their concentrations correlate with myocardial injury severity and independently predict mortality. Longitudinal assessment provides critical insights into disease trajectory and therapeutic efficacy (23,24). In hemCR patients, cardiac function indices change notably, with improvements in NT-proBNP level, diastolic indices—and most prominently—LVEF1. LVEF1 correlates with NT-proBNP level, reflecting myocardial function better than LVEF and indicating the link between cardiac mechanics and biomarkers. For patients with renal failure (a complication of CA affecting NT-proBNP level), echocardiography aids treatment evaluation. These indices can be secondary endpoints in antifibrillary trials. Their improvement supports the positive effect of hematological response on cardiac function and survival, perhaps due to reduced myocardial toxicity from decreased circulating light-chain levels (25). In the survival analysis in our study, hematological response and LVEF1 were good predictors of survival. hemCR benefits survival, and baseline LVEF1 is related to adverse outcomes. Greater improvement in pretreatment LVEF1 implies a lower risk of all-cause mortality and may aid clinicians in preventing adverse outcomes and managing the disease course; however, the value of LVEF1 in prognostic stratification needs to be studied further.

LVEF1 lacks a universally accepted cutoff due to limited research in the area. Disease-specific thresholds exist [e.g., 25% in asymptomatic aortic stenosis with preserved ejection fraction (9) and 30% in stable coronary artery disease (26)]. RCS analysis confirmed a monotonic relationship: each 1% decrease in LVEF1 increased risk of death. Future applications of LVEF1 in clinic should report specific values and avoid binary classification. The proposed cutoff suggests a preliminary safety threshold for patients with CA but requires larger multicenter validation.

Limitations

This study involved certain limitations which should be addressed. First, the small sample size, single-center design, lack of external validation, limit the generalizability of the results. Second, we only assessed the baseline LVGLS. Due to physician turnover during follow-up, complete cardiac ultrasound images for some patients were not archived, preventing the evaluation of LVGLS changes before and after 1 year of treatment. Moreover, the lack of serial LVGLS data limit comparison. Third, the small sample size not only restricted the inclusion of important variables in the multivariate analysis but also potentially weakens the statistical power. Given that important variables such as age, gender, hematological response status, NYHA, and Mayo grade were incorporated, only one of LVEF1, LVEF, and LVGLS could be included separately. Simultaneously adding LVEF1 and LVGLS would undermine the analysis’s statistical power. Thus, we were unable to compare whether LVEF1 has incremental prognostic value relative to LVGLS. Otherwise, the nonsignificant association of ΔLVEF1 with outcomes in model 3 likely reflects survival bias, as early deaths were excluded, thus limiting the assessment of ΔLVEF1 in high-risk patients. Larger-scale studies are expected to explore if LVEF1 offers more incremental value in predicting the survival of patients with CA and integrate these meaningful indicators to construct a more comprehensive efficacy and survival prediction model, providing more assistance for the clinical treatment of CA. Furthermore, lacking cardiac function data from CMR, we could not compare LVEF1 (an echocardiogram-based index) with CMR-related cardiac function indicators. Whether LVEF1 outperforms other imaging methods (positron emission tomography-computed tomography, CMR, etc.) in assessing CA remains unknown, and further relevant research is anticipated.

Conclusions

For patients with CA and preserved LVEF, LVEF1 can capture subtle changes in left ventricular function in the early stage of the disease. Baseline LVEF1 is related to the prognosis of patients with CA. A decrease in LVEF1 indicates an increased risk of poor prognosis. This shows that LVEF1 is not only an observational indicator but also has predictive value and can provide a basis for the clinical evaluation of disease progression and risk prediction. Due to the low event count and thus low statistical power in this exploratory study, the results need to be evaluated in larger cohorts.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1085/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1085/dss

Funding: This study was funded by the Key Program of Guangxi Natural Science Foundation (No. 2022JJD140147).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1085/coif). The authors have no conflicts of interest to declare.

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 trial was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (No. 2024-E785-01) and informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Quock TP, Yan T, Chang E, Guthrie S, Broder MS. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv 2018;2:1046-53. [Crossref] [PubMed]
2. Nienhuis HL, Bijzet J, Hazenberg BP. The Prevalence and Management of Systemic Amyloidosis in Western Countries. Kidney Dis (Basel) 2016;2:10-9. [Crossref] [PubMed]
3. Mishra S, Guan J, Plovie E, Seldin DC, Connors LH, Merlini G, Falk RH, MacRae CA, Liao R. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol 2013;305:H95-103. [Crossref] [PubMed]
4. Merlini G, Dispenzieri A, Sanchorawala V, Schönland SO, Palladini G, Hawkins PN, Gertz MA. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers 2018;4:38. [Crossref] [PubMed]
5. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging. J Card Fail 2019;25:e1-e39. [Crossref] [PubMed]
6. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization. J Card Fail 2019;25:854-65. [Crossref] [PubMed]
7. Kittleson MM, Ruberg FL, Ambardekar AV, Brannagan TH, Cheng RK, Clarke JO, Dember LM, Frantz JG, Hershberger RE, Maurer MS, Nativi-Nicolau J, Sanchorawala V, Sheikh FH. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2023;81:1076-126. [Crossref] [PubMed]
8. Huang PN, Liu YN, Cheng XQ, Liu HY, Zhang J, Li L, Sun J, Gao YP, Lu RR, Gao YP, Deng YB. Relative apical sparing obtained with speckle tracking echocardiography is not a sensitive parameter for diagnosing light-chain cardiac amyloidosis. Quant Imaging Med Surg 2024;14:2357-69.
9. Gu H, Saeed S, Boguslavskyi A, Carr-White G, Chambers JB, Chowienczyk P. First-Phase Ejection Fraction Is a Powerful Predictor of Adverse Events in Asymptomatic Patients With Aortic Stenosis and Preserved Total Ejection Fraction. JACC Cardiovasc Imaging 2019;12:52-63.
10. Gu H, Sidhu BS, Fang L, Webb J, Jackson T, Claridge S, Einarsen E, Razavi R, Papageorgiou N, Chow A, Bhattacharyya S, Chowienczyk P, Rinaldi CA. First-Phase Ejection Fraction Predicts Response to Cardiac Resynchronization Therapy and Adverse Outcomes. JACC Cardiovasc Imaging 2021;14:2275-85.
11. Leyva F. First-Phase Left Ventricular Ejection Fraction: A Predictor of CRT Response? JACC Cardiovasc Imaging 2021;14:2286-7.
12. Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2021;42:1554-68.
13. Sanchorawala V. Systemic Light Chain Amyloidosis. N Engl J Med 2024;390:2295-307.
14. Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 2004;94:1008-10.
15. Giancaterino S, Urey MA, Darden D, Hsu JC. Management of Arrhythmias in Cardiac Amyloidosis. JACC Clin Electrophysiol 2020;6:351-61.
16. Barros-Gomes S, Williams B, Nhola LF, Grogan M, Maalouf JF, Dispenzieri A, Pellikka PA, Villarraga HR. Prognosis of Light Chain Amyloidosis With Preserved LVEF: Added Value of 2D Speckle-Tracking Echocardiography to the Current Prognostic Staging System. JACC Cardiovasc Imaging 2017;10:398-407.
17. Shi J, Wu Y, Wu B, Yu D, Chu Y, Yu F, Han D, Ye T, Tao X, Yang J, Wang X. Left ventricular myocardial work index and short-term prognosis in patients with light-chain cardiac amyloidosis: a retrospective cohort study. Quant Imaging Med Surg 2023;13:133-44.
18. Risum N, Ali S, Olsen NT, Jons C, Khouri MG, Lauridsen TK, Samad Z, Velazquez EJ, Sogaard P, Kisslo J. Variability of global left ventricular deformation analysis using vendor dependent and independent two-dimensional speckle-tracking software in adults. J Am Soc Echocardiogr 2012;25:1195-203.
19. Cotella J, Randazzo M, Maurer MS, Helmke S, Scherrer-Crosbie M, Soltani M, et al. Limitations of apical sparing pattern in cardiac amyloidosis: a multicentre echocardiographic study. Eur Heart J Cardiovasc Imaging 2024;25:754-61.
20. Briasoulis A, Bampatsias D, Petropoulos I, Rempakos A, Patras R, Theodorakakou F, Makris N, Dimopoulos MA, Stamatelopoulos K, Kastritis E. Left ventricular myocardial work improves in response to treatment and is associated with survival among patients with light chain cardiac amyloidosis. Eur Heart J Cardiovasc Imaging 2024;25:698-707.
21. Chirinos JA, Segers P, Rietzschel ER, De Buyzere ML, Raja MW, Claessens T, De Bacquer D, St John Sutton M, Gillebert TC. Early and late systolic wall stress differentially relate to myocardial contraction and relaxation in middle-aged adults: the Asklepios study. Hypertension 2013;61:296-303. [Crossref] [PubMed]
22. Gu H, Li Y, Fok H, Simpson J, Kentish JC, Shah AM, Chowienczyk PJ. Reduced First-Phase Ejection Fraction and Sustained Myocardial Wall Stress in Hypertensive Patients With Diastolic Dysfunction: A Manifestation of Impaired Shortening Deactivation That Links Systolic to Diastolic Dysfunction and Preserves Systolic Ejection Fraction. Hypertension 2017;69:633-40. [Crossref] [PubMed]
23. Gu H, Cirillo C, Nabeebaccus AA, Sun Z, Fang L, Xie Y, et al. First-Phase Ejection Fraction, a Measure of Preclinical Heart Failure, Is Strongly Associated With Increased Mortality in Patients With COVID-19. Hypertension 2021;77:2014-22. [Crossref] [PubMed]
24. Hu K, Liu D, Salinger T, Oder D, Knop S, Ertl G, Weidemann F, Frantz S, Störk S, Nordbeck P. Value of cardiac biomarker measurement in the differential diagnosis of infiltrative cardiomyopathy patients with preserved left ventricular systolic function. J Thorac Dis 2018;10:4966-75. [Crossref] [PubMed]
25. Pregenzer-Wenzler A, Abraham J, Barrell K, Kovacsovics T, Nativi-Nicolau J. Utility of Biomarkers in Cardiac Amyloidosis. JACC Heart Fail 2020;8:701-11. [Crossref] [PubMed]
26. Minczykowski A, Zwanzig M, Dziarmaga M, Rutkowska A, Baliński M, Krauze T, Guzik P, Wykrętowicz A. First-Phase Left Ventricular Ejection Fraction as an Early Sign of Left Ventricular Dysfunction in Patients with Stable Coronary Artery Disease. J Clin Med 2023;12:868. [Crossref] [PubMed]