Left atrioventricular coupling index by 2D and 3D echocardiography: association with exercise capacity in chronic kidney disease

Introduction

Exercise capacity is a well-recognized prognostic determinant of adverse cardiovascular events and all-cause mortality, and its predictive value exceeds that of many established cardiovascular risk factors (1-3). Exercise intolerance is frequently observed in patients with chronic kidney disease (CKD) and is independently associated with an increased risk of cardiovascular morbidity and mortality (4-6). The mechanisms underlying exercise intolerance in CKD are multifactorial and include, in part, sedentary behavior, renal osteodystrophy and chronic inflammation accompanying the progression of renal impairment (7,8). Furthermore, diastolic dysfunction is driven by uremic toxins, left ventricular hypertrophy (LVH) and fibrosis, aggravated vascular wall stiffness and pressure overload, which is another contributor to poor exercise capacity in patients with CKD (9).

Previous studies have demonstrated that left atrial reservoir strain (LASr) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity following exercise (exercise E/e’) are independent indicators associated with exercise capacity in patients with CKD (10,11). However, the close physiological interplay between the left atrium (LA) and left ventricle (LV) suggests that the assessment of left atrioventricular coupling may more accurately reflect left atrioventricular dysfunction and potentially serve as a superior predictor of impaired exercise capacity (12,13). This concept has led to the development of a novel and readily accessible imaging parameter that integrates LA and LV, the left atrioventricular coupling index (LACI), which is defined as the ratio of the LA volume to the LV volume at the end-diastolic phase (14,15). At the end of diastole, the LA and LV are directly connected, and in the absence of significant valvular heart disease, their mechanical function and filling pressures are closely related (16).

The severity of diastolic dysfunction has been shown to be closely associated with LACI assessed by two-dimensional echocardiography (2DE), which independently predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF) (17). In addition, LACI derived from 2DE has demonstrated independent prognostic value in patients after acute myocardial infarction and in those with hypertrophic cardiomyopathy (18,19). With advances in cardiac imaging technology, LACI measured by three-dimensional echocardiography (3DE) offers several important advantages over 2DE. Unlike 2DE, 3DE does not rely on geometric assumptions and enables direct and more accurate volumetric assessment. Emerging evidence suggests that LACI measured by 3DE provides significant prognostic information in patients with CKD and HFpEF (20). However, few studies have ever explored the relationship between LACI and exercise capacity.

Based on these considerations, the present study aimed to evaluate the association between LACI and exercise capacity and determine whether 3D-LACI provides a more accurate prediction of exercise intolerance compared with 2D-LACI. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2238/rc).

Methods

Study population and protocol

From May 2024 to March 2025, patients with CKD undergoing echocardiography were consecutively recruited from the outpatient and inpatient departments of Gansu Provincial Hospital, Lanzhou, China. CKD was defined as either damage to the kidneys (including albuminuria, renal cysts, or other structural abnormalities) or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² for a duration exceeding 3 months (21).

Recruited patients were required to be ≥18 years, be in sinus rhythm, have no prior cardiac history, have stable renal function which defined as less than 5% change in baseline eGFR for 3 months before enrollment and be able to provide informed consent and undergo an exercise stress test. We excluded patients with end-stage renal disease requiring maintenance hemodialysis or those who had undergone renal transplantation. Additional exclusion criteria included preexisting cardiac disease, including coronary artery disease, heart failure or arrhythmias, as well as active malignancy or a history of cerebrovascular accident. Individuals with moderate to severe valvular disease and those with reduced left ventricular ejection fraction (LVEF) were also not included. Furthermore, patients with elevated resting blood pressure and those with positive exercise test results were exclude. All enrolled patients underwent a comprehensive clinical assessment, including assessment of coexisting cardiovascular risk factors and medication treatment, Non-invasive blood pressure assessment and ECG were recorded at rest. All patients underwent a comprehensive resting transthoracic echocardiography and treadmill training.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethics Committee of Gansu Provincial Hospital (No. 2025-582) and informed consent was obtained from all individual participants.

Echocardiography

Comprehensive transthoracic echocardiography was performed using a GE vivid E9 ultrasound machine (GE Healthcare, Horton, Norway) in accordance with the recommendations of the American Society of Echocardiography (22). Relative wall thickness (RWT) was calculated as the ratio of twice LV diastolic posterior wall thickness to left ventricular end-diastolic dimension (23). The Devereux formula was used to calculate LV mass (LVM) as follows: 0.8 [1.04 ([(LV end diastolic diameter + interventricular septal diameter + posterior wall diameter)³ − LV end diastolic diameter³])] + 0.6 − at end diastole and indexed to body surface area to derive the LV mass index (LVMI). The definition of normal LVMI included a mass index under 95 g/m² for women and under 114 g/m² for men (23). Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and LVEF were calculated by the Simpson’s biplane method from apical imaging planes. Decreased LVEF was defined as <54% for women and <52% for men (23). LV diastolic function was evaluated from mitral valve E/A ratio, average of the septal and lateral annular e’ velocity and E/e’ ratio (24). Using the biplane Simpson’s method, maximal and minimal LA volumes were determined from the apical 2- and 4-chamber views at end-systole and end-diastole, respectively, and were indexed to body surface area to obtain the indexed LA volume (LAVI) (24).

Speckle-tracking and real-time 3DE

2DE images were obtained for the subjects using the apical 4- and 2-chamber views at a frame rate of 50 to 70 frames/s. All images were stored digitally and analysis was performed offline software (echoPAC v204, GE Vingmed Ultrasound). The endocardial boundary of the LA at end-systole was manually outlined, with automatic tracking applied throughout the cardiac cycle using R to R gating. LASr was the average of the peak systolic strain from 12 segments, LA contractile strain (LASct) was the peak positive strain following p wave (atrial contraction), and LA conduit strain (LAScd) was the difference between peak reservoir and contractile strain (25).

3DE imaging was performed using a matrix-array transducer (4Vc-D) at the cardiac apex view. Four consecutive cardiac cycles for full-volume 3DE imaging at a frame rate of 20 to 25 frames/s were acquired and included all LV and LA segments. All 3DE images were stored for offline analysis using echoPAC 204 software.

We defined LACI as the ratio of the left atrial minimum volume (LAVmin) to the LVEDV. Figure 1 shows the measurement of 2D-LACI and 3D-LACI. LACI was expressed as a percentage, and higher LACI values indicated disproportionate LA-LV volumetric coupling, reflecting progressively impaired left atrioventricular coupling (15).

Figure 1 LACI. (A,B) The measurement of LA and LV volume by 2D echocardiography in 4-chamber. (C,D) The measurement of LA and LV volume by 2D echocardiography in 2-chamber. (E,F) The measurement of LA and LV volume by 3D echocardiography. 2D, two-dimensional; 3D, three-dimensional; LA, left atrial; LACI, left atrioventricular coupling index; LV, left ventricular.

Treadmill training

All participants underwent a symptom-limited, treadmill exercise stress test with continuous electrocardiogram (ECG). According to the Bruce protocol, starting at 25 watts (W) for 5 min, with 25 W increments in 3 min to participant-reported exhaustion. The maximum predicted heart rate was calculated according to age [100% × (220 − age)] with a maximal heart rate of ≥85% considered to be the target heart rate. All patients were encouraged to exert their maximal effort to exercise and exercise capacity was assessed in metabolic equivalents (METs) on the basis of the peak exercise intensity from speed and grade. According to prior research, reduced exercise capacity was estimated METs of ≤7 (26). This cutoff was applied uniformly across the study population without adjustment for age, sex, or body mass index (BMI). In addition to the dichotomous definition, participants were also categorized into tertiles of METs for secondary analyses. In addition, the measured of oxygen saturation at the phase of peak exercise was performed using a fingertip pulse oximeter.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics 27 (SPSS, Inc., Chicago, IL, USA), GraphPad Prism version 10.0.0 software, and R version 4.5.0. Continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as percentages. To enhance clinical interpretation, the baseline clinical and echocardiographic data were summarized both overall and stratified by tertiles of METs. Chi-squared tests were used to evaluate the association between tertiles of METs and ordered categorical variables. Continuous variables were analyzed using one-way analysis of variance (ANOVA) with Bonferroni correction, the nonparametric Kruskal-Wallis test was used for non-normally distributed data. To quantify the strength of the linear association between continuous variables, Pearson correlation coefficients (for normally distributed data) or Spearman correlation coefficients (for non-normally distributed data) were utilized.

Univariate linear regression analyses were performed to identify the relative contribution of the clinical, rest echocardiographic and exercise variables to exercise capacity. Variables meeting the significance threshold of P<0.05 were entered into multivariate linear regression models for subsequent analysis. Partial r quantified the association between each independent variable and the achieved METs levels after controlling for confounding factors. The standardized coefficient was the change in METs achieved associated with a 1 SD change in the variables.

To quantify the performance of 2D-LACI and 3D-LACI in classifying those with reduced exercise capacity, receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used. DeLong test was used for pairwise comparisons of the AUC. Intraclass correlation coefficients (ICCs) and the Bland-Altman plots were estimated to evaluate the interobserver and intraobserver variability of 2D-LACI and 3D-LACI.

Results

Characteristics of the study population

The final sample comprised 122 patients diagnosed with CKD who were enrolled in the study (Figure 2). The mean age was 46.0±12.7 years, and the mean resting systolic and diastolic blood pressure of the cohort was 131.8±20.2 and 85.1±12.7 mmHg. Of these, 64.8% of participants were male, 40.8% had diabetes mellitus, 77.5% had hypertension and 38.5% had anemia (defined as a hemoglobin level of <120 g/dL for women and <130 g/dL for men), and the mean BMI was 24.3±5.6 kg/m². In addition, 60.7% of patients received ACE inhibitor/ARB, 33.6% received CCB therapy, 44.3% of participants received SGLT-2 inhibitors (SGLT-2i) and 13.1% received insulin therapy for diabetes mellitus. Moreover, 17.2% patients were on lipid-lowering therapy by statin medications.

Figure 2 Flow chart of participants. CKD, chronic kidney disease; ECG, electrocardiography; LVEF, left ventricular ejection fraction; NIBP, noninvasive blood pressure; TTE, transthoracic echocardiogram.

Resting echocardiography

All participants exhibited preserved LVEF. 51.2% of the cohort had increased RWT (defined as RWT >0.42 mm) and 43.3% had increased LVMI (defined as >95 g/m² for women and >115 g/m² for men). For diastolic function, 33.1% had an elevated resting E/e’ ratio of >14. Of the atrial indices, the mean LAVI was 28.9±10.9 mL/m² and 23.4% had LA enlargement with LAVI ≥34 mL/m². The mean LASr, LAScd, and LASct were 29.4%±6.2%, 16.3%±4.7%, and 12.1%±3.8%.

Reduced exercise capacity

The baseline clinical and echocardiographic data are summarized in Table 1 according to tertiles of achieved METs. Patients with the lowest exercise capacity (Tertile 1: METs ≤5.10) were more often women with lower eGFR (P<0.001 for all). There were no significant differences in vascular risk factors (hypertension and diabetes mellitus; P>0.05 for all) among these patients. However, the higher rates of anemia were noted among these patients (P<0.001). No significant differences in blood pressure were observed either at rest or at peak exercise.

Among the echocardiographic parameters evaluated, patients with CKD exhibiting reduced exercise capacity demonstrated significantly lower average e’ values (P<0.001), elevated resting mitral E/e’ ratio (P<0.001) and increased LVMI (P=0.031). With regard to atrial indices, patients with reduced exercise capacity exhibited lower LASr, LAScd and LASct (P<0.001 for all). There was also a trend toward larger LAVI (P=0.033) in patients with CKD with reduced exercise capacity. In addition, 2D-LACI and 3D-LACI both demonstrated significant differences across three groups (P<0.001 for all) (Figure 3).

Figure 3 Comparisons of diastolic function in three groups. (A) E/e’; (B) LASr; (C) LAScd; (D) LASct; (E) 2D-LACI; (F) 3D-LACI. Tertile 1: METs ≤5.10; Tertile 2: 5.10< METs ≤7.20; Tertile 3: METs >7.20. ns, not significant; *, P<0.05. 2D, two-dimensional; 3D, three-dimensional; LA, left atrial; LACI, left atrioventricular coupling index; LAScd, LA conduit; LASct, LA contractile; LASr, LA reservoir; METs, metabolic equivalents.

Table S1 shows the values of 2D-LACI and 3D-LACI according to eGFR groups. A significant trend of higher 2D-LACI and 3D-LACI was observed across the groups. By extension, with the progression of renal function deterioration, the LACI exhibited a progressive increase and reflected greater impairment of left atrioventricular coupling in patients with CKD.

Independent associations of exercise capacity

METs achieved with exercise had a modest positive correlation with BMI (r=0.187, P=0.04) and a moderate positive correlation with eGFR (r=0.584, P<0.001). Of the echocardiographic variables, RWT (r=−0.223, P=0.015) and LVMI (r=−0.259, P=0.004) both showed a mild inverse correlation with METs. 2D-LACI (r=−0.605, P<0.001) and 3D-LACI (r=−0.669, P<0.001) showed a strong negative correlation to METs achieved. Other echocardiographic parameters include mitral E/e’ ratio (r=−0.445, P<0.001), LASr (r=0.574, P<0.001), LAScd (r=0.474, P<0.001), LASct (r=0.354, P<0.001) and LAVI (r=−0.250, P=0.005), all of which showed only modest to moderate correlations (Table S2, Figure 4 and Figure S1).

Figure 4 Scatter plot of the correlation analysis between the LACI, conventional echocardiography, clinical parameters and METs. (A) The relationship between the E/e’ value and METs value, r=−0.455, P<0.001. (B) The relationship between the LASr value and METs value, r=0.574, P<0.001. (C) The relationship between the LAScd value and METs value, r=0.474, P<0.001. (D) The relationship between the LASct value and METs value, r=0.354, P<0.001. (E) The relationship between the 2D-LACI value and METs value, r=−0.605, P<0.001. (F) The relationship between the 3D-LACI value and METs value, r=−0.669, P<0.001. 2D, two-dimensional; 3D, three-dimensional; LA, left atrial; LACI, left atrioventricular coupling index; LAScd, LA conduit; LASct, LA contractile; LASr, LA reservoir; METs, metabolic equivalents.

Table 2 presents univariate and multivariate linear regression analyses. To determine the independent associations of exercise capacity, clinical data, conventional echocardiographic parameters and 2D-LACI, 3D-LACI were analyzed in the univariate linear regression models. The clinical variables including sex, BMI, CCB medication treatment, eGFR, anemia, Peak HR, and the echocardiographic variables including RWT, LVMI, Mitral e’, Mitral E/e’ ratio, LASr, LAScd, 2D-LACI and 3D-LACI were all significantly associated with METs. The multivariate linear regression models were based on candidate variables that had been demonstrated to be significant univariate associations with the METs. To avoid overfitting, we used nested models: Model 1, comprising clinically significant variables; Model 2 and Model 3, comprising echocardiographic variables with 2D-LACI and 3D-LACI; Model 4, consisting of integrated independent clinical and echocardiographic variables from Model 1, Model 2, and Model 3. In the multivariable Model 1, sex, eGFR, and peak HR were identified as independent clinical predictors of METs attained. Of the echocardiographic parameters, LVMI LASr, LAScd, 2D-LACI and 3D-LACI were associated with exercise capacity in the echocardiographic models. However, both 2D-LACI and 3D-LACI continued to serve as independent predictors of achieved METs achieved within the integrated clinical and echocardiographic models (Table 2 and Table S3).

To evaluate the performance of the independent echocardiographic variables, we compared the AUC of ROC curves of 2D-LACI and 3D-LACI. The DeLong test was used to assess the statistical significance of differences in diagnostic accuracy between the two indicators. The performance of 3D-LACI (AUC, 0.8105; 95% CI: 0.7237–0.8972, P<0.001) was superior to 2D-LACI (AUC, 0.7718; 95% CI: 0.6757–0.8679, P<0.001; P=0.014 on DeLong test) to predict reduced exercise capacity (Figure 5 and Table S4). The optimal cutoff value of 3D-LACI for identifying reduced exercise capacity was 0.2850, with a sensitivity of 77.2% and a specificity of 81.0%. The optimal cutoff value of 2D-LACI for identifying reduced exercise capacity was 0.2097, with a sensitivity of 76.2% and a specificity of 81.0%.

Figure 5 Comparison of ROC curves of 2D-LACI and 3D-LACI. 2D, two-dimensional; 3D, three-dimensional; AUC, area under the curve; CI, confidence interval; LACI, left atrioventricular coupling index; ROC, receiver operating characteristic.

Inter- and intraobserver variability

2D-LACI and 3D-LACI measurements were independently assessed by two separate observers, as well as by the same observer on different occasions, in order to evaluate both inter-observer and intra-observer variability. There were good overall agreement and reproducibility of 2D-LACI and 3D-LACI. The inter- and intra-observer ICC for 2D-LACI was 0.984 (0.977–0.989) and 0.968 (0.955–0.978), for 3D-LACI was 0.990 (0.985–0.993) and 0.979 (0.970–0.985) (Table S5). The Bland-Altman plots of 2D-LACI and 3D-LACI are shown in Figure 6.

Figure 6 The Bland-Altman plots of 2D-LACI and 3D-LACI. (A) Intra- and inter-Bland-Altman plots of 2D-LACI. (B) Intra- and inter-Bland-Altman plots of 3D-LACI. 2D, two-dimensional; 3D, three-dimensional; LACI, left atrioventricular coupling index.

Discussion

To the best of our knowledge, the study is the first to comprehensively compare LACI by 2DE and 3DE, and to further investigate the association between resting LACI and exercise capacity in patients with CKD. The principal findings of our study are summarized as follows: (I) both 2D-LACI and 3D-LACI progressively increased with declining eGFR in patients with CKD; (II) 2D-LACI and 3D-LACI exhibited strong negative correlations with achieved METs, whereas MV E/e’ ratio, LASr, LAScd, LASct and LAVI showed only modest to moderate correlations; (III) both 2D-LACI and 3D-LACI were independently and robustly associated with METs after adjustment for other clinical and echocardiographic parameters; (IV) importantly, 3D-LACI demonstrated superior predictive performance compared with 2D-LACI for identifying exercise capacity intolerance in patients with CKD. Therefore, a comprehensive assessment of atrioventricular interaction using 3DE may be important for risk stratification in patients with CKD.

It is believed that exercise intolerance is a major determinant of poor quality of life. It is evident even in the early stages of CKD, with its severity increasing progressively as renal function declines and advances toward end-stage kidney disease (ESKD) (27,28). During physical activity, an increase in oxygen consumption is required to meet the metabolic demands of working skeletal muscle, however, impairments in oxygen delivery and extraction mechanisms may limit this response, ultimately leading to premature exercise termination (29). With the deterioration of renal function, inflammation contributes to protein energy-wasting syndrome and muscle wasting in CKD, and underlying hypoxia exacerbate inflammation and oxidative stress (30,31). Anemia is consistently linked to decreased physical function and exercise capacity throughout the continuum of CKD, contributing to exercise intolerance by reducing the oxygen-carrying capacity of the blood (32). Furthermore, oxidative stress, inflammation, and uremia have been identified as critical contributors to mitochondrial dysfunction, which is closely associated with impaired skeletal muscle function (33). Collectively, these interrelated mechanisms culminate in a marked reduction in exercise capacity in patients with CKD.

The LA plays a pivotal role in the pathophysiology of patients with CKD, and LA dysfunction contributes substantially to cardiorespiratory symptoms and reduced exercise tolerance (34). Kusunose et al. showed a strong association between reduced LA function and impaired exercise capacity in patients with HFpEF (26). Similarly, among consecutive patients with stage 3 and 4 CKD referred for exercise stress echocardiogram, Gan et al. reported a significant association between reduced LASr and reduced exercise capacity (10). Our study also confirmed that LASr was positively correlated with exercise tolerance. Impaired LA function imposes an increased hemodynamic burden on the pulmonary vasculature and has been robustly correlated with increased pulmonary vascular resistance as well as diminished peak oxygen consumption. Moreover, persistent pulmonary venous congestion, frequently attributable to abnormal LA mechanics, contributes to decreased pulmonary artery compliance, thereby, compromising oxygen transport and gas exchange efficiency (35). LA dysfunction is characterized by reduced active LA emptying and loss of the LA’s contribution to LV filling (36). Therefore, assessment of LA function should take LV function into consideration. It is well established that LAVmin is measured at the end of LV diastole, a phase during which the LA is directly exposed to LV filling pressures (37). Accordingly, LAVmin has been shown to correlate more closely with invasively measured LV filling pressure than left atrial maximal volume (LAVmax) (14,36). Considering the significant interplay between the LA and the LV, assessing the ratio of the LAVmin to the LVEDV within a single cardiac cycle may facilitate the evaluation of the association between the LACI and exercise capacity (38).

In recent years, the concept of LACI had received increasing attention. In a large cohort of 4,124 patients without cardiovascular disease, LACI had shown better prognostic value than individual LA and LV parameters, including strain tracking parameters (15). More recently, Fortuni et al. demonstrated in a retrospective cohort study involving 1,158 HF patients with both reduced and preserved ejection fractions that the LACI was associated with the severity of LV diastolic dysfunction, and also proved that LACI was an independent predictor of all-cause mortality in HF patients (17). With advancements in echocardiographic images, LACI assessed with 3DE had been reported to be an independent predictor of adverse events in dilated cardiomyopathy and associated with all-cause mortality in light-chain cardiac amyloidosis (39). Importantly, a recent review by Zornitzki demonstrated that LACI provides incremental prognostic value beyond conventional echocardiographic indices across diverse cardiovascular conditions, supporting its role as an integrative marker of LA-LV interaction (40).

To the best of our knowledge, this study is the first to demonstrate that LACI is inversely associated with exercise capacity and serves as an independent predictor of exercise capacity in patients with CKD across a patient cohort covering the entire CKD spectrum. In our cohort, the optimal cutoff values of LACI were 0.29 for 3D-LACI (sensitivity 77.2%, specificity 81.0%) and 0.21 for 2D-LACI (sensitivity 76.2%, specificity 81.0%) for identifying reduced exercise capacity. These values are consistent with those reported in previous studies. Fortuni et al. identified a LACI cutoff of ≥0.26 for predicting moderate-to-severe diastolic dysfunction in heart failure patients, while in CKD populations, a LACI cutoff of ≥0.24 has been reported for predicting adverse prognosis. Together, these findings support the robustness of LACI-derived thresholds across different disease states and reinforce the value of LACI as an integrative marker of left atrioventricular coupling impairment. Moreover, our study shows that 3D-LACI provides superior prediction performance compared to 2D-LACI, potentially enhancing the early detection of reduced exercise capacity. An increased LACI may reflect LA pressure and hemodynamic pressure in the pulmonary vasculature, and this association extends beyond traditional diastolic function indices, including the E/e’ ratio and LA volume (17). Furthermore, in the presence of abnormal LACI, long-term pulmonary venous congestion may lead to changes in pulmonary arterial compliance, thereby impeding oxygen delivery and gas exchange. Our study demonstrates that LACI is negatively correlated with the reduction in eGFR. This indicates that the pathophysiological mechanisms specific to CKD may also be cumulative and deteriorate as renal dysfunction progresses. In addition to left-sided cardiac dysfunction, right ventricular (RV) dysfunction and tricuspid regurgitation (TR) are well-established contributors to renal function deterioration, particularly in patients with CKD. Impaired RV systolic function and significant TR result in elevated right atrial pressure and systemic venous congestion, leading to increased renal venous pressure, reduced renal perfusion gradient, and progressive decline in glomerular filtration rate. Previous studies have demonstrated that echocardiographic indices of RV dysfunction and significant TR are independently associated with adverse renal outcomes and poor prognosis through mechanisms involving venous congestion, neurohormonal activation, and chronic inflammation (41,42). Moreover, the mortality-associated thresholds for tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (S’) are higher than those derived from healthy adults and these cutoffs are lower in patients with significant TR compared to those with lesser TR (43).

This may be because 3D-LACI provides a more accurate assessment of cardiac chamber volumes due to its ability to capture the entire heart without relying on geometric assumptions. Although 2D-LACI was an indicator for exercise capacity intolerance in our study, the AUC of 3D-LACI was greater than 2D-LACI for detecting reduced exercise capacity. This suggests that the volumetric differences between 2D and 3D imaging are clinically meaningful and should not be overlooked. The incremental value of 3DE over 2DE lies in its higher accuracy and lower measurement variability. By avoiding geometric assumptions, 3DE enables more precise volumetric quantification, which may be especially advantageous in cardiovascular diseases with structural remodeling. Importantly, the implementation of LACI in clinical route is possible based on conventional parameters. It does not require complex post-processing analysis and represent a practical advantage over LA speckle tracking parameters and may become a valuable parameter to investigate LA-LV coupling and diagnostic and prognostic implications.

Limitations

Our study has several limitations. First, this was a single-center study with a relatively small sample size, which may limit the generalizability of the findings and introduce potential selection bias. Second, patients with poor-quality ECG images and those with arrhythmias during the examination were included, which may have further increased the risk of selection bias. Third, exercise capacity was assessed using calculated METs derived from a symptom-limited treadmill exercise test rather than directly measured oxygen consumption. Although this approach is widely used in clinical practice, it represents an indirect measure of exercise tolerance and does not provide direct physiological parameters such as peak oxygen consumption obtained from cardiopulmonary exercise testing (CPET), which remains the gold standard. In addition, a uniform cutoff value of 7 METs was applied to define reduced exercise capacity without adjustment for individual factors such as age, sex, and BMI. Although secondary analyses using tertiles of METs were performed to partially account for interindividual variability in exercise capacity, the lack of adjustment for these factors remains an important limitation. Fourth, CKD etiology was not stratified in the primary analysis owing to the small number of patients with anatomical abnormalities. This may limit the assessment of etiology-specific effects on cardiac structure and function.

Finally, cardiovascular outcomes and all-cause mortality were not evaluated, Therefore, the prognostic value of LACI beyond exercise capacity remains unclear. Future studies with larger, well-characterized cohorts and longitudinal follow-up are needed to further define the clinical and prognostic significance of LACI across different CKD etiologies.

Conclusions

Among patients with all stages of CKD without prior cardiac disease, the LACI demonstrates the strongest association with exercise intolerance, outperforming other echocardiographic parameters. More importantly, 3D-LACI emerges as the most robust predictor of reduced exercise capacity and provides incremental predictive value beyond that of 2D-LACI. The LACI, especially 3D-LACI, may serve as a valuable biomarker for exercise capacity in this population and has potential utility for monitoring therapeutic response.

Acknowledgments

We express our sincere gratitude to all participating patients and medical staff for their support, as well as to the generous funding from the various grants.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2238/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2238/dss

Funding: This work was supported by the Central Guidance Fund for Local Science and Technology Development Reserve Project (grant No. 24ZYQA029); the Lanzhou Municipal Science and Technology Plan Project (grant No. 2025-2-102); the Key Research and Development Program – International Cooperation Project of the Gansu Provincial Department of Science and Technology (grant No. 25YFWA027); and The Key Specialty Construction Project of Shanghai Pudong New Area Health Commission (grant No. PWZzk2022-07).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2238/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 study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethics Committee of Gansu Provincial Hospital (No. 2025-582) and informed consent was obtained 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/.

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