
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39256506
72175
10.1038/s41598-024-72175-8
Article
Abnormal left atrial strain and left atrial stiffness index are associated with adverse outcomes in children with cardiomyopathies: a pilot study
Łuczak-Woźniak Katarzyna 1
Niszczota Cezary 2
Obsznajczyk Klaudia 2
Werner Bożena bozena.werner@wum.edu.pl

3
1 https://ror.org/04p2y4s44 grid.13339.3b 0000 0001 1328 7408 Department of Pediatric Cardiology and General Pediatrics, Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
2 Department of Pediatric Cardiology and General Pediatrics, Jozef Polikarp Brudzinski Public Pediatric Hospital, 02-091 Warsaw, Poland
3 https://ror.org/04p2y4s44 grid.13339.3b 0000 0001 1328 7408 Department of Pediatric Cardiology and General Pediatrics, Medical University of Warsaw, 02-091 Warsaw, Poland
10 9 2024
10 9 2024
2024
14 210594 12 2023
4 9 2024
© The Author(s) 2024
2024
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Conventional diastolic dysfunction parameters seem to be imperfect when applied to the pediatric cardiomyopathy population. The aim of this pilot study was to search for novel echocardiographic parameters associated with adverse outcomes in children with the most common cardiomyopathies. Fifty-six patients with pediatric cardiomyopathies (28 with dilated, 21 with hypertrophic, 7 with left ventricular non-compaction cardiomyopathy) and 28 healthy subjects were included in the study. Left atrial reservoir (LASr), conduit (LAScd) and contraction (LASct) strain, left atrial stiffness index (LASI), as well as conventional diastolic dysfunction parameters were measured using echocardiography. Adverse outcomes were defined as heart failure (including heart transplant) and arrhythmic endpoints. Patients with adverse outcomes presented with significantly lower LASr (16.68% ± 8.64% vs. 33.97% ± 9.99%, p-value < 0.001), lower LAScd (− 10.37% ± 5.83% vs. − 25.50% ± 9.24%, p-value < 0.001) and higher values of LASI (0.69 [IQR 0.34; 1.11] vs. 0.21 [IQR 0.16; 0.31], p-value < 0.001). LASr < 20%, LAScd ≥ − 12%, and LASI ≥ 0.26 were all associated with reduced survival. LASr, LAScd and LASI seem to be promising parameters in predicting adverse outcomes in the most common pediatric cardiomyopathies. Left atrial strain parameters and LASI are helpful in differentiating healthy control subjects from children with hypertrophic and dilated cardiomyopathies.

Subject terms

Paediatric research
Risk factors
Warszawski Uniwersytet Medyczny (Medical University of Warsaw)2M6/1/M/MB/N/20 Łuczak-Woźniak Katarzyna issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Conventional echocardiographic ventricular diastolic dysfunction assessment is not perfect in pediatric patients with cardiomyopathies due to variability of the measured parameters with age, difficulty in discriminating cardiomyopathy patients from healthy subjects as well as poor interobserver agreement1. Furthermore, some diastolic function parameters may lengthen or shorten depending on the severity of the ventricular stiffness. For instance, mitral valve deceleration time may lengthen in the early diastolic dysfunction stages but shorten with the progression of the disease. Thus, the search for new, easily obtainable, and more objective parameters is necessary in the pediatric population.

Left atrial strain has recently received attention in adult studies on various cardiomyopathy types2–7. Left atrial strain measurements reflect both the systolic and diastolic function of the ventricle, while being influenced by the ventricle’s contractility, relaxation, compliance, and intra-ventricular pressures. Atrial filling and emptying abnormalities are dependent on the ventricular conditions. Atrial wall deformation measured by strain may be more accurate in describing ventricular diastolic dysfunction in the pediatric population compared to conventionally measured inflow and annular movement velocities, especially when taking into account the variability of the latter with age.

Because left atrial strain is an easily obtainable and reproducible parameter helpful in outlining adult cardiomyopathy patients at greatest cardiovascular risk, it appears to be worthy of attention also in children8,9. There are scarce studies concerning left atrial strain in pediatric cardiomyopathies10–12. To our knowledge, no studies concerning the association between left atrial strain and survival in pediatric cardiomyopathies have been published so far. Thus, the aim of our prospective pilot study was to assess the value of left atrial strain in predicting adverse events in children with the 3 most common types of cardiomyopathies: dilated, hypertrophic and left ventricular non-compaction. Furthermore, we aimed at outlining whether left atrial strain parameters differ between healthy subjects and patients with early stages of cardiomyopathies.

Methods

Patients with dilated, hypertrophic, and left-ventricular non-compaction cardiomyopathies were recruited from the Department of Pediatric Cardiology and General Pediatrics between 2020 and 2023. The diagnosis was based on echocardiography; hypertrophic cardiomyopathy was defined as left ventricular wall thickness z-score > 2 measured in diastole; dilated cardiomyopathy as left ventricular internal end-diastolic dimension (LVIDd) z-score > 2 with concomitant reduced ejection fraction, and left ventricular non-compaction according to the Jenni et al. criteria with non-compaction to compaction (NC:C) ratio in systole > 2:113–15. When borderline cases were present, diagnosis was confirmed using cardiac magnetic resonance (CMR) imaging. Children aged 0–18 years were included in the pilot study.

The exclusion criteria included the following: co-existing co-morbidities including genetic syndromes co-existing with cardiomyopathies (i.e. Noonan syndrome, myopathies, metabolic diseases), ventricular hypertrophy or dilatation due to secondary reasons (i.e. congenital heart defects, hypertension), and lack of consent for participation in the study.

The control group consisted of healthy age- and sex-matched children. They were either recruited from the daily clinic, where they appeared due to a benign heart murmur, or from schools. Two patients from the control group were excluded from the analysis because of newly diagnosed ventricular arrhythmia.

Each patient had an ECG, echocardiography, and ECG Holter monitoring performed at the baseline visit. Moreover, among children with cardiomyopathies serum biomarkers N-Terminal prohormone of Brain Natriuretic Peptide (Nt-proBNP) and high-sensitivity troponin I were additionally analyzed. The medication and family history of each patient was recorded. Previous medical history for malignant arrhythmia (defined as ventricular tachycardia) was evaluated. Heart failure symptoms were assessed using NYHA or Ross scale in younger children16. If available, genetic test results were reported; the majority had a TruSight Cardio Sequencing Panel, while in a few patients with familial genotype Sanger sequencing was performed.

Unfavorable outcome were defined as follows: malignant arrhythmia (non-sustained ventricular arrhythmia (nsVT), sustained ventricular arrhythmia (sVT), ventricular fibrillation (VF)), listing for heart transplant, ICD implantation or appropriate ICD shock, and cardiac death. The arrhythmic endpoint included the presence of malignant arrhythmia, qualification for ICD implantation, or sudden cardiac death. The heart failure endpoint was defined as listing for heart transplant, undergoing heart transplant, or death due to heat failure.

This prospective study was approved by the local University Bioethics Committee. The study was performed in accordance with relevant guidelines and regulations (including Declaration of Helsinki and STROBE guidelines). Prior to participating in the study, all participants’ legal guardians as well as children ≥ 16 years signed a written informed consent form.

Echocardiography

Echocardiography was performed using Phillips EPIQ ultrasound system 9.0.1 with X5-1, S5-2 and S8-3 transducers. In each patient left ventricular ejection fraction (LVEF) was recorded using the Simpson biplane method. The left ventricular measurements such as: left ventricular internal diastolic dimension (LVIDd), left ventricular posterior wall thickness in diastole (LVPWd), and interventricular septum thickness in diastole (IVSd) were acquired using M-mode. Z-scores were used to account for the differences between the patients’ height and weight17.

Diastolic function was assessed using both pulsed-wave Doppler and tissue Doppler velocities (TDI). Mitral inflow peak E-wave, A-wave velocities and mitral E-wave deceleration time (DT) were measured. In TDI medial (septal) and lateral early (e′) and late (a′) mitral annulus velocities as well as isovolumetric relaxation time (IVRT) were assessed18. The left atrial volume was measured using the area-length approximation using the 4-chamber and 2-chamber views and corrected for body surface area (LAVi left atrial volume index)19. Mitral valve regurgitation (MR) was graded from 0 to 420.

Myocardial strains were acquired using speckle tracking echocardiography with Philips software. Left ventricular global longitudinal strain (LV GLS) was obtained from the 4-chamber, 3-chamber, and 2-chamber views. Atrial strain was obtained from the 4-chamber view using ventricular end diastole as the zero reference point in accordance with the current recommendations21. Left atrial strain during the reservoir (LASr), conduit (LAScd) and contraction phases (LASct) were recorded. Non-invasive left atrial stiffness index (LASI) was defined as the ratio between average E/e′ to LASr22. 20% of randomly selected studies of cardiomyopathies patients were reanalyzed by a second observer to look for inter-observer variability in terms of differences in left atrial strain.

Statistical analysis

Statistical analysis was performed using Statistica 13.3 version and R version 4.2.2 GNU General Public License. Continuous data are presented as mean and standard deviation (SD) or median and first and third quartile (IQR), depending on the distribution. Categorical variables were compared using the test for equality of proportions. For continuous variables t-test, Mann–Whitney U test, F test and Kruskal–Wallis test were used depending on the number and distribution of the compared variables. Correlation analysis was performed using Pearson’s or Spearman’s correlations depending on the distribution. Random forest model was used to define the echocardiographic parameters that were most helpful in outlining patients with adverse outcomes in the whole cardiomyopathy group, as well as in dilated and hypertrophic cardiomyopathy subgroups. Kaplan–Meier survival curves were used for survival assessment in the whole cardiomyopathy group. This analysis was not performed on the subgroups due to a limited number of patients. Inter-observer variability was calculated using Lin’s concordance correlation coefficient. A p-value < 0.05 was considered statistically significant.

Conference presentation

Part of the results concerning DCM were presented at the 56th Annual Meeting of the Association for European Paediatric and Congenital Cardiology.

Results

A total of 84 patients was included in the study, 28 with DCM, 21 with HCM, 7 with LVNC, and 28 in the control group. The median age was 8 years (IQR 3; 14). The median observation time of cardiomyopathy patients was 270 days (IQR 158; 525 days). The baseline characteristics of patients with cardiomyopathies and the control group are presented in Table 1. There were no significant differences between the cardiomyopathy groups and the control group in terms of age, sex, BMI, or heart rate (Table 1). Baseline echocardiographic parameters in the 3 cardiomyopathy subgroups are presented in Table S1 (Supplementary Materials). DCM group was characterized by reduced LVEF (40.68% [IQR 30.53; 45.95]) and enlarged left ventricle (LVIDd z-score: + 3.74 ± 1.42). In the HCM group hypertrophy of the ventricular septum and left ventricular wall (IVSd z-score + 5.40 [IQR 3.02; 11.30]; LVPWd z-score + 3.08 [IQR 1.74; 5.30]), as well as increased maximal LVOT pressure gradient (9 mmHg [IQR 6; 17]) were present. In the LVNC group the median LVEF was 56.7% (IQR 55.1; 58.3). The 3 cardiomyopathy groups differed only in terms of only some of the diastolic function parameters (Table S1, Supplementary Materials). There were no significant differences in LASr, LAScd, LASI, or LAVi between the 3 groups; LASct was borderline significant (p-value 0.049).Table 1 Baseline characteristics of patients with cardiomyopathies and the control group.

	DCM
n = 28	HCM
n = 21	LVNC
n = 7	CTRL
n = 28	p-value	
Age (years)	8 (2.08; 14.0)	6.5 (0.5–15)	11.0 (9.0; 15.0)	7 (3.5; 13.5)	0.332	
Sex (F/M)	11/17	8/13	6/1	11/17	0.125	
BMI (kg/m2)	15.96 (13.47; 19.91)	19.61 (15.61; 23.56)	15.42 (13.91; 16.74)	17.13 (15.29; 19.49)	0.065	
Heart rate (bpm)	91.58 (77.43; 109.45)	80 (70.0; 96.62)	83.80 (59.94; 110.0)	85.59 (73.91; 102.13)	0.355	
Observation time (days)	226.50 (148.5; 379)	447 (166; 637)	168 (436; 441)	x	0.316	
Medication (Y/N)	28/0	17/4	5/2	x	0.027	
Data are presented as median and (IQR) or number of patients.

BMI body mass index, bpm beats per minute, CTRL control group, DCM dilated cardiomyopathy, F female, HCM hypertrophic cardiomyopathy, LVNC left ventricular non-compaction, M male, n number of patients, nN no,Y yes. Significant values are in bold.

Altogether, 29% of patients (16/56) experienced adverse outcomes, 7 (25%) in the DCM group, 7 (33%) in the HCM group and 2 (29%) in the LVNC group. Among all cardiomyopathy patients 9 (16%) experienced a heart failure endpoint, whereas 12 (21%) experienced an arrhythmic endpoint. During the observation time 9 children were listed for heart transplant.

Eighteen patients (32%) had a positive family history of cardiomyopathies, 6 of whom experienced an adverse outcome. There was no statistically significant difference in terms of positive family history between patients with and without adverse outcomes (p = 0.59). Genetic testing was performed in 43 patients (78%): in 15 (27%) the panel was positive, in 13 (23%) a variant of uncertain significance was found, in 2 the results were not available yet, and 13 (23%) had a negative panel.

Patients with cardiomyopathies and adverse outcomes had significantly lower LASr (16.68% ± 8.64% vs. 33.97% ± 9.99%), less negative LAScd (− 10.37% ± 5.83% vs. − 25.50% ± 9.24%) and greater LASI (0.69 [IQR 0.34; 1.11] vs. 0.21 [IQR 0.16; 0.31]) when compared to cardiomyopathy patients without adverse outcomes (Table 2). In terms of other echocardiographic parameters, patients with adverse outcomes had significantly greater LAVi, lower LVEF, lower E, A, average e′ wave velocities, and greater E/A ratio and lateral IVRT (Table S2, Supplementary Materials). There were no significant differences in terms of LASct, MR, and some of the diastolic function parameters (DT, a′, medial and lateral e′/a′, medial IVRT, average E/e′).Table 2 Differences in left atrial reservoir strain, left atrial conduit strain and left atrial stiffness index between cardiomyopathy patients with and without adverse outcomes.

	LASr [%]	LAScd [%]	LASI	
End-point	No end-point	p-value	End-point	No end-point	p-value	End-point	No end-point	p-value	
HF endpoint	11.54 ± 6.31	32.38 ± 10.25	< 0.001	− 7.39 ± 4.45	− 23.82 ± 9.62	< 0.001	0.92 (0.57; 2.09)	0.24 (0.18; 0.38)	< 0.001	
Arrhythmia endpoint	18.39 ± 8.56	31.93 ± 11.71	 < 0.001	− 11.20 ± 6.24	− 23.90 ± 10.24	< 0.001	0.60 (0.37; 1.10)	0.23 (0.18; 0.37)	< 0.001	
All endpoint	16.68 ± 8.64	33.97 ± 9.99	< 0.001	− 10.37 ± 5.83	− 25.50 ± 9.24	< 0.001	0.69 (0.34; 1.11)	0.21 (0.16; 0.31)	< 0.001	
Data are presented as mean and ± standard deviation or median and (inter-quartile range) depending on the variables’ distribution.

HF heart failure, LASct left atrial conduit strain, LASI left atrial stiffness index, LASr left atrial reservoir strain. Significant values are in bold.

When applying the random forest model to assess echocardiographic parameters most helpful in predicting adverse outcomes LAScd, LASr and LASI were among the top 3 variables, with the model having a 50% sensitivity, 100% specificity, 100% positive predictive value and 90% negative predictive value (Fig. F1, Supplementary Materials). On Kaplan–Meier survival curves LASr < 20%, LAScd ≥ − 12%, and LASI ≥ 0.26 were all associated with reduced survival in patients with cardiomyopathies (Figs. 1, 2, 3).Fig. 1 Kaplan–Meier survival curves in cardiomyopathy patients with different left atrial reservoir strain (LASr).

Fig. 2 Kaplan–Meier survival curves in cardiomyopathy patients with different left atrial conduit strain (LAScd).

Fig. 3 Kaplan–Meier survival curves in cardiomyopathy patients with different left atrial stiffness index (LASI).

Dilated cardiomyopathy

There were 28 children with dilated cardiomyopathy, 7 of whom (33%) experienced an adverse outcome (4 had an arrhythmic event, 7 heart failure adverse outcome). The differences between DCM patients with and without adverse outcomes are presented in Table 3. Patients with adverse outcomes had significantly greater NT-proBNP serum concentrations than those without, as well as greater NYHA or Ross scale score.Table 3 Differences between patients with dilated cardiomyopathy with and without adverse outcomes.

	Adverse outcome	No adverse outcome	p-value	
Age [years]	14 (4–17)	8.0 (1.17; 11.0)	0.093	
NYHA/Ross scale	4 (3–4)	1 (1–1)	< 0.001	
Positive family history	1 (14%)	5 (24%)	0.595	
NT-proBNP [pg/ml]	3851.0 (2448; 7033)	49 (30; 323)	0.001	
Troponin [ng/ml]	25.9 (1.9; 95.4)	1.8 (0.99; 20.6)	0.134	
LASI	0.93 (0.69; 3.07)	0.22 (0.16; 0.42)	0.001	
LAVi [ml/m2]	49.85 ± 39.03	31.61 ± 12.29	0.084	
LASr [%]	10.70 ± 7.01	31.79 ± 12.17	< 0.001	
LAScd [%]	− 7.43 ± 4.41	− 25.49 ± 10.99	< 0.001	
LASct [%]	− 3.29 ± 5.06	− 6.21 ± 8.91	0.421	
LV GLS [%]	− 5.97 ± 3.00	− 16.69 ± 3.80	< 0.001	
LVEF [%]	24.10 ± 6.57	42.26 ± 7.68	< 0.001	
LVIDd z-score	5.12 ± 0.89	3.27 ± 1.26	0.001	
MR grade	1 (1; 2)	1 (0; 2)	0.656	
E [cm/s]	73.67 ± 20.64	89.51 ± 18.53	0.068	
DT [ms]	124 (74–139)	129.5 (107; 152)	0.361	
A [cm/s]	32.03 ± 11.26	57.47 ± 15.61	0.001	
E/A	2.15 (1.95–2.90)	1.46 (1.31; 1.63)	0.042	
IVRT med [ms]	70.0 ± 29.81	63.86 ± 18.49	0.521	
e′ med [cm/s]	7.15 ± 3.14	9.67 ± 2.56	0.043	
a′ med. [cm/s]	3.69 (3.48; 7.18)	5.77 (5.44; 6.53)	0.232	
e′/a′ med	1.64 ± 0.22	1.71 ± 0.60	0.770	
IVRT lat [ms]	96.83 ± 27.89	56.52 ± 17,09	< 0.001	
e′ lat [cm/s]	8.49 ± 3.75	13.96 ± 4.89	0.018	
a′ lat [cm/s]	3.67 ± 0.71	6.66 ± 2.80	0.017	
e′/a′ lat	2.23 (1.61; 2.67)	1.87 (1.79; 2.88)	0.838	
e′ avg [cm/s]	8.77 ± 2.17	11.81 ± 3.22	0.0398	
E/e′ avg	8.15 (7.42; 10.21)	6.85 (5.96; 8.96)	0.210	
Data are presented as mean and ± standard deviation or median and (inter-quartile range) depending on the variables’ distribution.

A peak atrial (A-wave) mitral velocity, a′ tissue Doppler late mitral annulus velocity, avg average, DT deceleration time, E peak early (E-wave) mitral velocity, e′ tissue Doppler early mitral annulus velocity, IVRT isovolumetric relaxation time, LAScd left atrial conduit strain, LASct left atrial contraction strain, LASI left atrial stiffness index, LASr left atrial reservoir strain, lat lateral, LAVi left atrial volume indexed, LVEF left ventricular ejection fraction, LV GLS left ventricular global longitudinal strain, LVIDd left ventricular internal diastolic dimension, med medial, MR mitral regurgitation. Significant values are in bold.

In terms of echocardiographic parameters, patients with adverse outcomes had significantly lower LASr, less negative LAScd and greater LASI (Table 3). They presented with significantly lower LV GLS, and LVEF, as well as greater LVIDd z-scores. There were significant differences only in some of the diastolic function parameters between the 2 groups (lower A-wave velocity, greater E/A ratio, lower e′, lateral a′, greater IVRT lateral). However, there were no significant differences in terms of LASct, LAVi, MR and some diastolic dysfunction parameters, such as E-wave velocity, DT, medial IVRT, medial a′, medial and lateral e′/a′ and average E/e′.

Both LASr and LAScd had a strong correlation with LASI, and a moderate correlation with some systolic function parameters (LV GLS, LVEF), as well as some diastolic function parameters (average e′ wave velocity, lateral IVRT). There was a moderate correlation between LASr and LASct and NT-proBNP as well as NYHA/or Ross scale score. The detailed correlation analysis is presented in Table 4.Table 4 Correlation analysis of echocardiographic parameters in the dilated and hypertrophic cardiomyopathy groups.

	DCM	HCM	
LASI	LASr	LAScd	LASI	LASr	LAScd	
NYHA/Ross scale	0.81*	− 0.65*	0.66*	0.28*	− 0.32*	0.44*	
Nt-proBNP	0.75*	− 0.66*	0.64*	0.54*	− 0.48*	0.72*	
Troponin	0.39*	− 0.28*	0.34*	0.35*	− 0.44*	0.61*	
LASI	1.00*	− 0.91*	0.72*	1.00*	− 0.81*	0.65*	
LAVI	0.36*	− 0.29*	0.54*	0.63*	− 0.57*	0.66*	
LASr	− 0.69*	1.00	− 0.83	− 0.81*	1.00	− 0.83	
LAScd	0.51*	− 0.83	1.00	0.65*	− 0.83	1.00	
LASct	0.45*	− 0.48	− 0.09	0.19*	− 0.12*	− 0.37*	
LV GLS	0.41*	− 0.64	0.48	0.48*	− 0.32*	0.33*	
LVEF	− 0.53*	0.59	− 0.54	− 0.33*	0.75	− 0.53	
MR grade	0.31*	− 0.23*	0.19*	0.628*	− 0.445*	0.590	
E	− 0.04*	0.31	− 0.50	− 0.15*	0.53	− 0.67	
DT	− 0.31*	0.22*	− 0.33*	− 0.11*	− 0.15	0.10	
A	− 0.47*	0.47	− 0.34	− 0.08*	0.55	− 0.60	
E/A	0.35*	− 0.36*	0.26*	0.02*	− 0.02	− 0.10	
IVRT med	0.11*	0.03	− 0.03	0.51*	− 0.53*	0.55*	
e′ med	− 0.21*	0.29	− 0.26	− 0.75*	0.53	− 0.75	
a′ med	− 0.19*	0.36	− 0.11	− 0.07*	0.05	− 0.36	
e′/a′ med	0.01*	− 0.05*	− 0.08*	− 0.65*	0.56	− 0.59	
E/e′ med	0.39*	− 0.11*	− 0.04*	0.76*	− 0.46*	0.54*	
IVRT lat	0.42*	− 0.53	0.39	0.14*	− 0.29*	0.08*	
e′ lat	− 0.55*	0.58	− 0.49	− 0.69*	0.60	− 0.58	
a′ lat	− 0.61*	0.50*	− 0.34*	0.22*	0.72	− 0.61	
e′/a′ lat	− 0.20*	0.10*	− 0.15*	− 0.72*	0.22	− 0.22	
E/e′ lat	0.71*	− 0.42*	0.23*	0.75*	− 0.35*	0.36*	
e′ avg	− 0.40*	0.54	− 0.43	0.27*	− 0.09	0.16	
E/e′ avg	0.67*	− 0.34*	0.12*	0.27*	− 0.11*	0.18*	
Data are presented as r value, correlations with p-value < 0.05 were bolded, *Spearman’s correlation.

A peak atrial (A-wave) mitral velocity, a′ tissue Doppler late mitral annulus velocity, avg average, DCM dilated cardiomyopathy, DT deceleration time, E peak early (E-wave) mitral velocity, e′ tissue Doppler early mitral annulus velocity, IVRT isovolumetric relaxation time, HCM hypertrophic cardiomyopathy, LAScd left atrial conduit strain, LASct left atrial contraction strain, LASI left atrial stiffness index, LASr left atrial reservoir strain, lat lateral, LAVi left atrial volume indexed, LVEF left ventricular ejection fraction, LV GLS left ventricular global longitudinal strain, med medial, MR mitral regurgitation.

LASI showed a strong correlation with NT-proBNP and NYHA, and a moderate correlation with LVEF. Similarly to LASr and LAScd, LASI correlated with only some of the conventional echocardiographic diastolic dysfunction parameters (Table 4).

When applying the random forest model, the top 3 parameters associated the strongest with adverse outcomes in patients with dilated cardiomyopathy were LASr, LASI and LAScd. The positive predictive value of the model was 66%, negative predictive value 93%, specificity 93%, sensitivity 66%, and ACC 0.88.

Also among patients with DCM and an arrhythmic endpoint, there were significant differences in terms of LASI (0.90 [IQR 0.57; 2.09] vs. 0.23 [IQR 0.16; 0.52] p-value 0.027), LASr (11.03% ± 6.81 vs. 29.10% ± 13.73, p-value 0.017) and LAScd (− 8.08% ± 5.32 vs. − 23.12% ± 12.13, p-value 0.023).

When compared to the control group, patients with DCM without adverse outcomes differed significantly from the control group in terms of: LASI (0.22 [IQR 0.16; 0.42] vs. 0.12 [IQR 0.10; 0.14] p-value < 0.001), LAVi (31.61 ± 12.29 vs. 17.88 ± 5.12 p-value < 0.001), LASr (30.10% [24.20; 41.40] vs. 50.65% [44.90; 56.10] p-value < 0.001), LAScd (− 25.49% ± 10.99% vs. − 38.77% ± 10.34% p-value < 0.001), and LASct (− 6.21% ± 8.91% vs. − 13.77% ± 4.25% p-value < 0.001). The detailed data concerning differences in the echocardiographic parameters between DCM patients without adverse outcomes and the control group are presented in Table S3, Supplementary Materials.

Hypertrophic cardiomyopathy

There were 21 patients with hypertrophic cardiomyopathy, 7 of them (33%) experienced an adverse outcome (all of them had an arrhythmic adverse outcome), and one died due to sudden cardiac death. The differences in HCM children with and without adverse outcomes are presented in Table 5. Patients with adverse outcomes had significantly greater NT-proBNP and troponin levels when compared to patients without adverse outcomes. There were no differences in terms of age or NYHA/Ross scale score.Table 5 Differences between patients with hypertrophic cardiomyopathy with and without adverse outcomes.

	Adverse outcome	No adverse outcome	p-value	
Age [years]	13.0 (8–17)	6.5 (0.5; 15)	0.12	
NYHA/Ross scale	2 (1–2)	1 (1; 2)	0.054	
Positive family history	5 (71%)	6 (43%)	0.216	
Nt-proBNP [pg/ml]	3415.0 (1463.0; 6388.0)	133.0 (42.0; 748.0)	0.003	
Troponin [ng/ml]	59.20 (18.8; 215)	5.1 (1.5; 10.4)	0.007	
LASI	0.72 ± 0.44	0.22 ± 0.11	< 0.001	
LAVi [ml/m2]	47.07 ± 15.97	21.07 ± 6.56	< 0.001	
LASr [%]	20.87 ± 6.58	36.66 ± 5.53	< 0.001	
LAScd [%]	− 11.66 ± 6.01	− 25.44 ± 7.64	< 0.001	
LASct [%]	− 10.10 (− 11; − 4.5)	− 10.5 (− 12.5; − 7.7)	0.74	
LV GLS [%]	− 16.02 (− 20.7; − 3.73)	− 18.53 (− 19.83; − 13.87)	0.74	
LVEF [%]	55.29 ± 12.66	62.50 ± 4.91	0.072	
LVIDd z-score	− 1.95 ± 2.83	− 1.61 ± 2.09	0.76	
IVSd z-score	5.99 (5.54; 21.11)	3.93 (2.43; 6.08)	0.023	
LVPWd z-score	6.17 ± 3.97	2.44 ± 1.79	0.007	
MR grade	1 (1; 1)	0 (0; 1)	0.24	
E [cm/s]	82.07 ± 38.08	87.61 ± 21.69	0.67	
DT [ms]	132.86 ± 65.72	127.29 ± 41.71	0.81	
A [cm/s]	51.58 ± 26.09	61.59 ± 18.75	0.35	
E/A	1.53 (1.52; 1.64)	1.47 (1.29; 1.57)	0.31	
IVRT med [ms]	149.17 ± 82.06	72.92 ± 26.41	0.006	
e′ med [cm/s]	5.33 ± 1.86	9.24 ± 2.85	0.004	
a′ med [cm/s]	6.70 ± 2.49	6.58 ± 1.61	0.91	
e′/a′ med	0.80 ± 0.41	1.46 ± 0.51	0.033	
IVRT lat [ms]	130.86 ± 64.12	79.36 ± 27.28	0.030	
e′ lat [cm/s]	8.08 ± 4.18	11.92 ± 2.86	0.025	
a′ lat [cm/s]	9.27 ± 2.98	7.68 ± 1.25	0.11	
e′/a′ lat	0.87 ± 0.44	1.62 ± 0.59	0.014	
e′ avg [cm/s]	6.71 ± 2.83	10.58 ± 2.68	0.007	
E/e′ avg	13.07 ± 5.42	8.37 ± 2.53	0.015	
LVOT max [mmHg]	17.0 (7.0; 51.0)	7.5 (5.0; 11.0)	0.17	
Data are presented as mean and ± standard deviation or median and (inter-quartile range) depending on the distribution of the variables.

A peak atrial (A-wave) mitral velocity, a′ tissue Doppler late mitral annulus velocity, avg average, DT deceleration time, E peak early (E-wave) mitral velocity, e′ tissue Doppler early mitral annulus velocity, IVRT isovolumetric relaxation time, IVSd interventricular septum dimension, LAScd left atrial conduit strain, LASct left atrial contraction strain, LASI left atrial stiffness index, LASr left atrial reservoir strain, lat lateral, LAVi left atrial volume indexed, LVEF left ventricular ejection fraction, LV GLS left ventricular global longitudinal strain, LVIDd left ventricular, LVOT max maximal left ventricular outflow tract pressure gradient, LVPWd left ventricular posterior wall dimension, internal diastolic dimension, med medial, MR mitral regurgitation. Significant values are in bold.

In terms of echocardiographic parameters there were significant differences in terms of LASI, LAVi, LASr, LAScd, ventricular wall thickness (IVSd and LVPWd z-scores), and some diastolic function parameters (IVRT, e′/a′ medial and lateral, average e′ and E/e′) between patients with and without adverse outcomes (Table 5). However, there were no significant differences in terms of LASct, MR, or LVOT gradient. Furthermore, not all diastolic dysfunction parameters were different between the 2 subgroups (Table 5).

Correlation analysis showed a strong correlation between LASr and LASI, LVEF, and lateral a′ (Table 4). There was a moderate correlation between LASr and LAVI, MR, some diastolic function parameters (medial IVRT, medial E/e′), and NT-proBNP. LAScd showed a strong correlation with NT-proBNP and medial e′, and a moderate correlation with NYHA/Ross scale score, troponin, LASI, LAVi, MR, and some diastolic dysfunction parameters. Detailed correlation analysis is presented in Table 4.

On the random forest model, the top 3 parameters most helpful in predicting patients with adverse outcomes included the following LAScd, LASr, and left ventricular ejection fraction with a 100% positive predictive value, 89% negative predictive value, 50% sensitivity, 100% specificity, and ACC 0.90.

Patients with HCM, who did not reach the endpoint in comparison to the control group, had significantly different LASI (0.20 [IQR 0.18; 0.27] vs. 0.12 [IQR 0.10; 0.14], p-value < 0.001), LASr (37.40% [32.10; 39.70] vs. 50.65% [44.90; 56.10], p-value < 0.001), LAScd (− 23.75% [− 30.20; − 21.20] vs. − 36.90% [− 44.15; − 31.60], p-value < 0.001) and LASct (− 10.05% [− 12.50; − 7.70] vs. − 14.25% [− 17.50; − 10.65], p-value 0.03). Furthermore, there were significant differences between the 2 subgroups in terms of LV GLS and some diastolic function parameters (e′, e′/a′ medial and lateral, average E/e′, lateral IVRT). The detailed data are presented in Table S4 in the Supplementary Materials.

Interobserver variability was analyzed in terms of left atrial strain parameters using Lin’s concordance coefficient. The agreement between the observers was 0.928 (CI 0.774; 0.979) for LASr, 0.948 (CI 0.843; 0.984) for LAScd, and 0.984 (CI 0.947; 0.995) for LASct.

Discussion

Conventional echocardiographic diastolic function parameters outlined in the adult guidelines are characterized by low interobserver agreement in assessing differences between healthy children and pediatric patients with cardiomyopathies1. Furthermore, classification of diastolic dysfunction into grades is often difficult due to various parameters measured, their variability in time, dependence on the loading conditions, as well as problems with classification of borderline cases. Therefore, in the pediatric population the search for new, easily obtainable and reproducible parameters is crucial. Left atrial strain, which reflects loading abnormalities that occur secondarily to impaired left ventricular relaxation and compliance, seems to be a promising parameter in pediatric patients with primary myocardial diseases such as cardiomyopathies. It was proven to be superior to E/e′ measurements in predicting elevated pulmonary pressure in children qualified for heart transplant23. To our knowledge, there are no studies concerning left atrial strain and survival in children with cardiomyopathies. In our pilot study, both LASr and LAScd were associated with adverse outcomes in children with cardiomyopathies, whereas there were no significant differences in terms of LASct. Similarly to what has been reported in adults, pediatric patients with LASr < 20% as well as LAScd ≥ − 12% had worse survival on the Kaplan–Meier curves2,4. Furthermore, on the random forest model both parameters were among the top 3 parameters most helpful in predicting adverse outcomes, but one must keep in mind the models’ moderate sensitivity and excellent specificity. Thus, both left atrial reservoir and conduit strain appear to be noteworthy parameters in the risk assessment of pediatric cardiomyopathy patients.

Left atrial stiffness index, which is the ratio of left atrial reservoir strain to a conventional echocardiographic diastolic parameter (E/e′), has recently received attention in the adult population24–27. In patients with heart failure with preserved ejection fraction (HFpEF), increased left atrial stiffness index (> 0.26) has been associated with substantial risk of death or heart failure hospitalizations and was superior to conventional echocardiographic measurements of elevated left ventricular filling pressures24. It predicted elevated NT-proBNP and was associated with reduced exercise tolerance in adults with HFpEF26,27. In adults with HCM and DCM it was suggested that LASI might be superior to left atrial strain alone in terms of predicting elevated pulmonary artery pressures and thus be more accurate in detecting ventricular diastolic dysfunction25. We did not find any studies on LASI in pediatric cardiomyopathies. In our analysis LASI was significantly greater in patients with adverse outcomes, and, similarly to adults, LASI ≥ 0.26 was associated with significantly reduced survival24. Furthermore, LASI was among the top 3 echocardiographic variables helpful in predicting adverse outcomes in pediatric cardiomyopathy patients. LASI was also significantly greater among patients with cardiomyopathies without adverse outcomes compared to control subjects, which shows its potential in assessing early diastolic dysfunction. Therefore, LASI shines as an easily obtainable parameter that might be helpful in assessing risk stratification among cardiomyopathy patients as well as differentiating patients with myocardial diseases from healthy individuals.

Dilated cardiomyopathy

In our study patients with dilated cardiomyopathy and adverse outcomes had significantly lower LASr and less negative LAScd. To our knowledge, no previous studies concerning left atrial strain and survival in pediatric DCM have been published. Furthermore, adult studies concerning left atrial function in dilated cardiomyopathy are mostly based on CMR rather than echocardiography2,28. Raafs et al. showed that LAScd < 12% was a predictor of freedom of adverse events or rehospitalization due to heart failure in adults and was superior in predicting adverse outcomes to LV GLS, LVEF, as well as LAVi2. In another adult CMR study on patients with heart failure, left atrial reservoir strain was associated with adverse cardiovascular events independently of late gadolinium enhancement28. Our results are in line with previous adult studies, because both LASr and LAScd were associated with adverse outcomes2,29. Furthermore, they were both, together with LASI, among the top parameters helpful in predicting adverse outcomes among children with DCM, although one has to keep in mind the model’s moderate sensitivity and high specificity. In our study, not all diastolic dysfunction parameters differed between patients with and without adverse outcomes. For instance, there were no differences in terms of DT, E-wave velocity, E/e′, medial IVRT, or medial a′ wave velocity between DCM children with and without adverse outcomes. This seems to agree with previous studies, in which the usefulness of conventional diastolic dysfunction parameters in the pediatric cardiomyopathy population has been questioned1. Furthermore, in the random forest model, these parameters were inferior to LASr and LAScd. Thus, conventional echocardiographic diastolic dysfunction parameters seem to be imperfect in outlining patients with and without adverse outcomes.

When compared to the control group, patients with DCM without adverse outcomes differed in terms of all 3 measured left atrial strain parameters, LASI, and only some of the conventional echocardiographic diastolic function parameters. Similarly to Sabatino et al., we observed greater E/e′ ratio and LAVi as well as lower left atrial peak systolic strain10. We also did not observe significant differences in terms of DT or E/A ratio, which again points to the imperfection of the conventional diastolic dysfunction parameters in the pediatric population10. Because all left atrial strain parameters and LASI were different between the control group and DCM patients without adverse outcomes, it points toward their value not only in assessing pediatric diastolic dysfunction but also in discriminating healthy control subjects from early stages of dilated cardiomyopathy.

In adults, A-wave velocity, E/A wave ratio and LV GLS have been associated with malignant ventricular arrhythmias30. Similarly, in our study they were also significantly different between DCM children with and without ventricular arrhythmias. Thus, in our study, we also observed differences in terms of greater LASI, lower LASr, and less negative LAScd, which could be new, additional parameters helpful in predicting arrhythmic events in the pediatric DCM population.

In our study, similarly as reported by Pahl et al., positive family history in children with dilated cardiomyopathy was not associated with adverse outcomes31. The role of genetic testing should be stressed because it has been shown that pathogenic or likely pathogenic variants occur independently of family history among pediatric dilated cardiomyopathy patients32.

Hypertrophic cardiomyopathy

Left atrial strain parameters have been better studied in the HCM adult population; unfavorable outcomes such as heart failure, stroke, or death have been associated with LASr ≤ 23.8% and LAScd ≤ 10.2% on echocardiography3. In children, no such values have been defined so far. In our study, LASr and LAScd were significantly different between HCM patients with and without adverse outcomes, which suggests that the abnormalities in the left atrial function and pressures increase with the disease’s progression.

In an adult CMR study, it has been shown that impaired LASct appears with the disease’s progression and is associated with fibrosis, whereas lower LAScd is abnormal in earlier stages of the disease33. This observation might not be valid in the pediatric population. In our study, patients with HCM and adverse outcomes did not differ significantly from HCM patients without end-point in terms of LASct, however, they had significantly different LASr and LAScd. Thus, abnormalities associated with the most severe disease progression in the pediatric population might not be identical to the adult population. However, further studies regarding survival in pediatric HCM are necessary to assess this finding.

LASr and LAScd were significantly different between the control group and HCM patients without adverse outcomes, whereas the difference in terms of LASct was borderline significant (p-value 0.03). In the study by Jhaveri et al. on children and young adults (up to 25 years old) with HCM, both LASr and LASct were reduced in phenotype-positive patients compared to genotype-positive11. Phenotype-positive patients and the control group differed in terms of LASr in the 2-chamber view; however, no difference was found in terms of LASct11. Thus, both LASr and LAScd seem to be valuable parameters in differentiating healthy individuals from early stages of pediatric hypertrophic cardiomyopathy. The usefulness of LASct in the pediatric population is yet to be determined.

Alis et al. showed that abnormalities in LASr and LAScd on CMR preceded enlargement of the left atrial volumes in children with HCM12. This is in agreement with our results, although we did not observe differences in terms of LAVi on echocardiography between control patients and HCM patients without the end-point of the study; thus, we observed significant differences in terms of LASr and LAScd. It appears, that LASr and LAScd both on CMR and echocardiography are more accurate in depicting left atrial abnormalities than LAVi. For this reason, left atrial strain parameters may be more useful in differentiating healthy controls from early stages of pediatric hypertrophic cardiomyopathy.

In children with HCM, it has been suggested that left ventricular outflow tract obstruction leads to abnormalities in left atrial volume, left atrial total strain and conduit strain34. However, we believe that abnormalities in the left atrial strain are caused not only by the degree of the left ventricular outflow tract obstruction, but also reflect changes in the diastolic dysfunction and increased stiffness of the ventricle itself. On the contrary, in our study HCM patients with and without adverse outcome did not differ significantly in terms of left ventricular outflow tract obstruction; thus, they differed in terms of LASI, left atrial reservoir and conduit strain.

The relationship between family history and sudden cardiac death in the pediatric hypertrophic cardiomyopathy population is disputable. So far, family history has not been included in the HCM-Risk KIDS scale as a risk factor35. Similarly to this finding, in our study positive family history was not associated with increased risk of adverse outcomes.

In adults left atrial volume index (LAVi), left ventricular global longitudinal strain, as well as mechanical dispersion were associated with an adequate ICD therapy, and therefore the occurrence of malignant ventricular arrhythmia36. To our knowledge, no studies concerning the association between ventricular arrhythmia and atrial strain echocardiography in children with hypertrophic cardiomyopathy have been published. In our study, in HCM patients with adverse events (who all had arrhythmic adverse events) LAVi was significantly greater than in those without; thus, they did not differ significantly in terms of LV GLS. This suggests that LV GLS abnormalities might progress with age, and pediatric risk factors for adverse outcomes are not identical to the adult ones.

Left ventricular non-compaction

There is scarce literature concerning left atrial strain in left ventricular non-compaction cardiomyopathy. In adults, reduced LASr was a predictor of exacerbation of heart failure5. Furthermore, LASr and LASct were different between patients with multiple gene variants with LVNC and genotype-negative patients, which suggests a more severe disease in patients with multiple mutations6. In our study, due to a limited number of patients, we could not perform analysis in the LVNC group only. As left ventricular-non compaction is a heterogenous disorder, left atrial strain might be an easily obtainable parameter helpful in outlining those with cardiovascular risk. Thus, the role of genetic testing in left ventricular non-compaction should not be understated, because various cardiomyopathy phenotypes, including hypertrabeculation, may be present among different family members37.

Some limitations to the study should be outlined. Because cardiomyopathies in children are rare diseases and this was a single-center study, the sample size was relatively small. For this reason, multicenter studies on a larger number of patients are crucial to more accurately assess left atrial strain values that would be helpful to identify patients with the greatest cardiovascular risk. Furthermore, due to the limited sample size, we did not assess the grade of the diastolic dysfunction abnormalities. Another limitation is that we only used Phillips software for left atrial strain assessment; therefore, variability of left atrial strain in the pediatric population using different software was not assessed. The observation time of the study was relatively short; thus, while this was a pilot study, we believe it sheds light on new and promising echocardiographic parameters helpful in outlining patients with pediatric cardiomyopathies at greatest cardiovascular risk.

Conclusions

Left atrial reservoir and conduit strain as well as left atrial stiffness index appear to be promising new parameters in predicting adverse outcomes in pediatric patients with cardiomyopathies. Moreover, they appear to help differentiate healthy individuals from those with the early stages of dilated and hypertrophic cardiomyopathies.

Supplementary Information

Supplementary Information.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-72175-8.

Author contributions

KLW, BW conceived the experiment; KLW, CN, KO conducted the experiment; KLW analyzed the results and wrote the original manuscript. BW supervised the work on the manuscript. All authors reviewed the manuscript.

Funding

Part of the research was funded by the Medical University of Warsaw, grant number 2M6/1/M/MB/N/20.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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