Left ventricular deformation in chronic schizophrenia—a detailed analysis from the three-dimensional speckle-tracking echocardiographic MAGYAR-Path Study

Introduction

Schizophrenia (SCH) is a chronic and debilitating mental disorder characterized by acute episodes of positive symptoms such as disorganized thinking and behaviour, inappropriate affect and hallucinations, alternating with partial or total remission stages. These chronic phases are associated with predominantly negative and affective symptoms, as well as cognitive decline, and contribute to SCH being one of the top 10 causes of disability worldwide. Even if the lifetime prevalence of SCH is relatively low (0.3–0.9%), the economic burden is substantial (1). The major drivers of economic costs in the chronic stage of SCH (CS-SCH) are the frequent somatic comorbidities such as metabolic syndrome, obesity, type 2 diabetes mellitus leading to cardiovascular disorders (CVDs). Approximately 50% of premature deaths are related to CVD in SCH, resulting in a 10–20-year reduction in life-expectancy, as patients have a threefold and 1.2–3.6-fold higher risk for sudden cardiac death and coronary artery disease, respectively (2). Recent SCH guidelines, developed jointly by leading psychiatric and cardiological societies worldwide, recommend regular screening for CVD risks and abnormalities in SCH spectrum disorders, however, the exact nature of structural and functional myocardial changes remains to be elucidated (3).

Modern cardiovascular imaging methods can help in identifying high-risk individuals, for instance by assessing left ventricular (LV) function. The novel three-dimensional (3D) speckle-tracking echocardiography (STE) enables detailed volumetric and strain analysis of LV from a single acquired 3D echocardiographic dataset (4-9). The major aim of our cross-sectional, naturalistic observational study was to provide new information, including detailed analysis of LV deformation mechanics using 3DSTE in patients with CS-SCH. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0371/rc).

Methods

Patient population

CS-SCH patients with active psychotic symptoms were excluded to avoid communication and cooperation difficulties. After initial screening of 74 CS-SCH outpatients with a history of more than five psychotic episodes, 36 patients were enrolled in the study due to compliance limitations. The diagnosis of SCH was established (multiple episodes, currently in remission) according to ICD-11 code 6A20.11 by a psychiatrist based on the review of medical history and clinical interview by evaluating the current clinical picture, including actual symptomatology and information obtained from staff and caregivers (10). Mental and somatic health history, pharmacological treatment history, smoking habits and current medications were recorded together with CVD risk factors, however the presence of these was not an exclusion criterion for either patients or controls. Age over 65 years was considered an exclusion criterion. Due to suboptimal image quality, 13 subjects were excluded, therefore the final cohort consisted of 23 patients with CS-SCH [mean: 45.9±9.3 years, 13 males, body mass index (BMI): 30.4±5.1 kg/m²]. CS-SCH patients were compared to age-, gender- and BMI-matched healthy controls. The control group consisted of 59 healthy individuals (mean age: 46.7±9.4 years, 33 men, BMI: 30.1±4.5 kg/m²) without any known conditions theoretically affecting the findings. Study subjects were identified using community-based convenience sampling. The recruited cohort represented a broad professional spectrum, spanning the medical, academic, municipal, and law enforcement sectors. All controls were free of acute or chronic diseases, had no known pathological conditions, and were not receiving any medication. All subjects were non-smokers and did not engage in professional sports. M-mode and two-dimensional (2D) Doppler echocardiographic parameters were normal and were within the normal reference ranges in all healthy controls. Electrocardiographic (ECG) and laboratory results were normal as well. The present cross-sectional case-control prospective study is part of the MAGYAR-Path Study (Motion Analysis of the heart and Great vessels bY three-dimensionAl speckle-tRacking echocardiography in Pathological cases), which aimed to identify disease-specific abnormalities using 3DSTE in certain disorders, including SCH (“MAGYAR” means Hungarian in the Hungarian language). The studies were conducted as a joint project between the Department of Medicine and the Department of Psychiatry at the University of Szeged. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional and Regional Human Biomedical Research Committee of the University of Szeged, Hungary (registration number: 71/2011; latest extension: 17 March 2025) and by the Scientific and Research Ethics Committee with latest extension approval for CS-SCH population (IV/1230-6/2022/EKU). Written informed consent was obtained from all CS-SCH patients and matched controls.

2D Doppler echocardiography

A comprehensive routine 2D Doppler echocardiographic assessment of cardiac chambers was performed in typical parasternal and apical views in all patients and controls by a Toshiba Artida^TM echocardiographic tool (Toshiba Medical Systems, Tokyo, Japan) attached to a PST-30BP (1–5 MHz) phased-array transducer. LV ejection fraction (EF) was assessed by the modified Simpson’s method. The latest guidelines were used for chamber quantifications and assessments of valvular dimensions, and to exclude significant regurgitations and stenosis (11).

3DSTE

During 3DSTE, the same Toshiba Artida^TM cardiac ultrasound system was employed after switching the transducer to a PST-25SX matrix-array transducer with 3D imaging capability. As a first step, 3D echocardiographic data were acquired from the apical window, when subjects were positioned in the left lateral decubitus position. To optimize image quality, all SCH patients and healthy controls were instructed to perform breath-hold, while six echocardiographic subvolumes were acquired during six cardiac cycles. Then the software automatically merged these digitally acquired datasets into a complete full volume 3D dataset. As the second step, offline data analysis was performed using the vendor-provided 3D Wall Motion Tracking software version 2.7 (Ultra Extend, Toshiba Medical Systems, Tokyo, Japan). Following selection of optimal standard apical longitudinal views, as well as basal, midventricular, and apical cross-sectional views, the mitral annular—LV septal and lateral edges and the apical LV endocardial surface were selected, then a virtual 3D LV cast was constructed through sequential analysis (4-9) (Figures 1,2).

Figure 1 3D speckle-tracking echocardiographic measurements of LV strains in a matched healthy individual. Apical four-chamber (A) and two-chamber (B) views, as well as apical (C1), midventricular (C2), and basal (C3) short-axis views, are demonstrated—extracted automatically from the acquired 3D echocardiographic database. (D) A 3D cast of the LV, while (E) represents LV volumes and ejection fraction. Bulls-eye views and time-LV strain curves are presented in longitudinal (F1 and G1), circumferential (F2 and G2), and radial (F3 and G3) directions, as well as for complex area (F4 and G4) and 3D (F5 and G5) strains. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Figure 2 3D speckle-tracking echocardiographic measurements of LV strains in a patient with schizophrenia. Apical four-chamber (A) and two-chamber (B) views, as well as apical (C1), midventricular (C2), and basal (C3) short-axis views, are demonstrated—extracted automatically from the acquired 3D echocardiographic database. (D) A 3D cast of the LV, while (E) represents LV volumes and ejection fraction. Bulls-eye views and time-LV strain curves are presented in longitudinal (F1 and G1), circumferential (F2 and G2), and radial (F3 and G3) directions, as well as for complex area (F4 and G4) and 3D (F5 and G5) strains. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Using the 3D LV cast, LV strains, quantitative features of wall contractility, were measured. The following global (featuring the whole LV) and basal, midventricular and apical regional LV strains were calculated from segmental values (4-9,12):

• LV radial strain (LV-RS), for unidimensional/unidirectional estimation of thinning/thickening of the myocardial tissue.
• LV circumferential strain (LV-CS) for unidimensional/unidirectional estimation of widening/narrowing of the myocardial tissue.
• LV longitudinal strain (LV-LS) for unidimensional/unidirectional estimation of lengthening/shortening of the myocardial tissue.
• LV area strain (LV-AS), combination of circumferential and longitudinal strains (multidimensional/complex strain).
• LV 3D strain (LV-3DS), combination of all unidimensional/unidirectional strains (multidimensional/complex strain).

Statistical analysis

For continuous and categorical variables mean ± standard deviation and n (%) formats were used. In case of P<0.05, statistical significance was considered. For analysis of categorical variables, Fisher’s exact test was applied. Shapiro-Wilks test was performed for normality of distribution assessments. For normally and non-normally distributed data, Student’s t-test and Mann-Whitney-Wilcoxon test were used, respectively. For intraobserver and interobserver comparisons, intraclass correlation coefficients (ICCs) were calculated. SPSS software (version 29.0, IBM Corp., Armonk, NY, USA).

Results

Demographic data

Comparison of demographic, laboratory and medication data of the study groups is presented in Table 1.

2D Doppler echocardiography

From routine 2D echocardiographic parameters, all parameters were similar between CS-SCH patients and controls, except reduced LV systolic volume in the CS-SCH group. None of the CS-SCH patients and controls showed larger than grade 1 regurgitation on any valves (Table 2). 2DSTE-derived global LV-LS was significantly reduced in CS-SCH patients (16.1%±2.3% vs. 22.1%±1.2%, P<0.05).

3DSTE-derived LV volumes and strains

The varying degrees of increased LV volumes were associated with reduced LV-EF in patients with CS-SCH as compared with controls. All global and mean segmental LV strains proved to be impaired in CS-SCH patients. From regional LV strains, only midventricular LV strains were reduced, basal and apical LV strains did not differ between CS-SCH patients and controls (Tables 3,4).

Reproducibility of 3DSTE-derived LV parameters

Intraobserver and interobserver ICCs for 3DSTE-derived parameters were 0.85 and 0.80 for global LV-RS, 0.81 and 0.78 for global LV-CS, 0.81 and 0.78 for global LV-LS, 0.80 and 0.78 for global LV-3DS and 0.82 and 0.80 for global LV-AS, respectively.

Discussion

Theoretically, the majority of diseases and pathologies may carry a genetic abnormality that can lead to deterioration of myocardial function, either alone or under the influence of other external factors. Mental disorders like SCH are not exceptions either. Based on a recently published review, it can be stated, that not only the increased sympathetic activity associated with the disease, the classic risk factors, early fibrosis and inflammation, and the abnormal renin-angiotensin-aldosterone system may be responsible for the abnormalities, but due to the nature of the disease, several environmental factors, the availability and method of health care and the drugs used may also have an effect (3).

Therefore, accurate assessment of myocardial function is essential due to its prognostic value. Today’s modern cardiovascular non-invasive diagnostic procedures, including echocardiography, are suitable for accurate assessment of LV pumping function, the most well-known parameter being LV-EF (13). Objective features of the LV wall contractility include strain parameters, which can be calculated in three spatial directions using STE (11,12). If measurements are made in a predefined plane, the method is referred to as 2DSTE, and derived from an acquired 3D echocardiographic database, then it is termed 3DSTE, with ECG gating to account for timing in the cardiac cycle. The most well-known and widely used strain parameter is the 2DSTE-derived global LV-LS (11,12). Currently, 3DSTE offers the most comprehensive volumetric and strain analysis.

It is important to know that 3DSTE allows for a much broader and more detailed LV analysis compared with both 2D Doppler echocardiography and 2DSTE (4-9). First, it is suitable for accurate measurement of LV volumes respecting the cardiac cycle and the derived LV-EF, as demonstrated in previous studies (14-16). The strain parameters determined in this way are typically lower than those obtained with 2D echocardiography (17). The explanation for this is that 3DSTE underestimates LV volumes and end-diastolic LV volume is more affected than the end-systolic one, thus leading to lower LV-EF (18). Together with accurate LV volumes, several global, regional and segmental LV strains can be measured as demonstrated in this study. During the cardiac cycle, the LV not only shortens in longitudinal direction (represented by global LV-LS), but also narrows circumferentially and thickens in the radial direction during systole, both globally and segmentally/regionally, which characteristics can be quantified by 3DSTE-derived LV strains as well, which can be measured from a single acquired 3D echocardiographic database at the same time (4-9,12). 3DSTE-derived LV strains are validated and their normal reference values are also published (15,16,19).

This cross-sectional case-control study provides new information regarding the structural and functional abnormalities associated with subclinical cardiac damage in CS-SCH patients by means of 3DSTE. The 2D Doppler echocardiographic method was not sufficiently sensitive to detect LV abnormalities in these cases. Based on our detailed 3DSTE-derived analysis of LV strains, it could be concluded that LV-EF, which characterizes the LV pumping function, is reduced in CS-SCH, and is accompanied by impairment of all global and mean segmental LV strains in CS-SCH patients as measured simultaneously by 3DSTE. As regards topography, from regional LV strains, only midventricular LV strains were reduced, basal and apical LV strains were not different between the two groups. These findings suggest the superiority of 3DSTE measurements for the detailed exploration of CS-SCH-related structural and functional abnormalities.

Besides the SCH-related CVD risk factors, the cardiotoxicity of chronic use of antipsychotics could be a potential contributor to our findings. However, it is pertinent to mention, that asymptomatic mild LV impairment, including reduced LV-EF and global LV-LS, was found to be common in patients with SCH receiving long-term clozapine treatment (20). In another study the effect of long-acting injectable olanzapine/risperidone antipsychotic (AP) treatment was correlated with BMIs and mitral inflow velocities. The global LV-LS was significantly lower in patients with prolonged long-acting injectable olanzapine/risperidone treatment, and was not influenced by the duration of this treatment (21). Most of our CS-SCH patients had a long history of first, second and combined treatment of AP medications and other psychopharmacons. Currently the majority of our CS-SCH patients were on oral second-generation AP therapy, but they were also using other 1st and 2nd generation APs, 5–15 different molecules according to their pharmacotherapy history before. Due to the naturalistic, cross-sectional nature of our study we cannot attribute our 3DSTE findings regarding LV strain to the specific effects of certain APs and AP classes on the heart-brain axis function. Further studies are warranted to confirm our findings and to examine the effects of above mentioned factors on LV volumetric and functional properties.

Limitation section

Some important limiting factors affected the present study.

• There are differences between images quality of 3DSTE versus 2D echocardiography with significant advances of the latter one. This is due to lower 3DSTE-associated frame rate (33±2 fps), larger transducer and the fact that for optimal images, 6 subvolumes during 6 cardiac cycles are required to be acquired leading for high chance for stitching and/or motion artifacts limiting usability of images (4-9).
• LV rotational mechanics were not aimed to be assessed in the present study, which could be a topic of future investigations.
• Although control individuals claimed to be healthy and none of examinations raised suspicious of a pathological state, it could not be completely excluded that some cases had subclinical disorders or diseases.
• Due to compliance and measurement quality problems, even if we were willing to include 74 CS-SCH patients, finally only 23 were finally analyzed. Although a significant proportion of the planned SCH patients had to be excluded, the generalizability of our findings is supported by the fact that the excluded patients showed no significant differences in BMI, risk factors, or medications compared to those included in the final analysis. However, larger number of cases would have made the whole study more convincing.
• SCH patients present multiple cardiovascular risk factors and are treated with various cardiovascular and psychotropic medications, all of which may influence LV function and strain parameters. Due to the small sample size, no statistical analysis was performed to evaluate the impact of these confounders on the observed results. Moreover, the small sample size limited the feasibility of performing in-depth statistical analyses, such as subgroup analyses related to medication, as well. However, recognizing the clinical importance of this issue, further studies with larger cohorts are warranted to comprehensively analyze the role of all potential confounding factors.
• Our results should be confirmed with other studies in larger patient population using other imaging techniques.
• 3DSTE-derived LV strains were not validated in the present paper due to their validated nature.
• Only LV volumes and strains were analysed in the present study. Although 3DSTE is enabled to assess other parameters like LV rotational features or volumes/strains for both atria and the right ventricle, this study did not aim such analyses. However, they can be a topic of future investigations.
• Due to the naturalistic, cross-sectional nature of our study design, we were not able perform AP pharmacotherapy related data analysis.

Conclusions

In contrast to our negative findings with 2D Doppler echocardiography, detailed 3DSTE-derived LV deformation analysis revealed significant abnormalities including reduced LV-EF and associated reduction in midventricular LV strains in CS-SCH patients. These results highlight the importance of cardiovascular assessment and management in this severe mental condition.

Acknowledgments

We would like to thank Dr. Gabriella Galsi, Dr. Anna Szőke and Ilona Zsuzsanna Zsótér for their valuable support and patient selection, as well as all participants and their families for their support of this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0371/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0371/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0371/coif). A.N. serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery. The other 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 the Institutional and Regional Human Biomedical Research Committee of the University of Szeged, Hungary (registration number: 71/2011; latest extension: 17 March 2025) and by the Scientific and Research Ethics Committee with latest extension approval for CS-SCH population (IV/1230-6/2022/EKU). Written informed consent was obtained from all CS-SCH patients and matched controls.

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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