Abstract
Objective
Systemic lupus erythematosus is associated with increased cardiovascular morbidity, even in the absence of overt clinical disease. Sestrin-1 is a stress-responsive antioxidant protein implicated in oxidative homeostasis and cardiovascular protection. This study aimed to evaluate serum Sestrin-1 levels in patients with systemic lupus erythematosus and examine their relationship with subclinical cardiovascular findings.
Methods
In this controlled cross-sectional study, 60 patients with systemic lupus erythematosus and 60 age-matched healthy controls underwent clinical assessment, laboratory testing, 12-lead electrocardiography, transthoracic echocardiography, and carotid intima-media thickness measurement. Serum Sestrin-1 was measured by enzyme-linked immunosorbent assay (ELISA). Between-group comparisons used parametric or nonparametric tests according to data distribution. Within the systemic lupus erythematosus cohort, correlations between Sestrin-1 and disease activity (Systemic Lupus Erythematosus Disease Activity Index), as well as cardiovascular parameters, were assessed. An exploratory multivariable logistic regression model including Sestrin-1, left atrial diameter, corrected QT interval, age, and sex was constructed to identify variables associated with case status.
Results
Serum Sestrin-1 levels were significantly lower in patients with systemic lupus erythematosus than in controls (9.99 ± 2.01 vs. 17.79 ± 5.11 ng/mL; p < 0.001). Patients with systemic lupus erythematosus had a significantly longer corrected QT interval (429.65 ± 32.42 vs. 376.26 ± 33.41 ms; p < 0.001). In the exploratory multivariable logistic regression analysis, lower Sestrin-1 (per 1ng/mL increase, odds ratio 0.63; 95% confidence interval: 0.54–0.75; p < 0.001), larger left atrial diameter (per 1 mm increase, odds ratio 1.13; 95% confidence interval: 1.06–1.22; p < 0.001)), and longer corrected QT interval (per 1ms increase, odds ratio 1.03; 95% confidence interval: 1.02–1.05; p < 0.001) were independently associated with systemic lupus erythematosus status.
Conclusion
Patients with systemic lupus erythematosus exhibit markedly reduced serum Sestrin-1 levels together with subclinical cardiovascular abnormalities. The inverse relationship between Sestrin-1 and left atrial diameter suggests a possible link between reduced antioxidant defense and early atrial remodeling in systemic lupus erythematosus. Sestrin-1 may represent a promising candidate biomarker for subclinical cardiovascular involvement in patients with systemic lupus erythematosus; however, prospective studies are needed to confirm its clinical utility.
Keywords
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation, autoantibody production, and multisystem inflammation. Although renal, hematologic, mucocutaneous, and musculoskeletal manifestations are well recognized, cardiovascular (CV) involvement remains one of the leading contributors to long-term morbidity and mortality in this population. Persistent systemic inflammation, endothelial dysfunction, immune-mediated vascular injury, and accelerated atherosclerosis all contribute to increased CV risk in patients with SLE, even in those without clinically overt heart disease. Early identification of subclinical CV involvement is therefore of considerable clinical importance.1–4
The sestrin family consists of stress-inducible proteins involved in cellular defense against oxidative stress, metabolic dysregulation, and impaired autophagy. Sestrin-1, in particular, has been implicated in antioxidant protection, mitochondrial stability, and the regulation of cardiac remodeling through pathways involving AMP-activated protein kinase (AMPK) and mTOR signaling.5,6 Experimental and clinical studies have suggested that reduced Sestrin-1 expression may be associated with vascular dysfunction and adverse myocardial remodeling. In rheumatic diseases such as axial spondyloarthritis and rheumatoid arthritis, altered Sestrin-1 levels have been linked to subclinical atherosclerosis and cardiovascular abnormalities.7,8 However, evidence regarding Sestrin-1 in patients with SLE remains scarce.
Given the elevated CV burden in patients with SLE and the biological relevance of oxidative stress in both lupus pathogenesis and cardiovascular injury, Sestrin-1 may have potential as a biomarker of subclinical CV involvement in this population. Accordingly, the present study aimed to compare serum Sestrin-1 levels between patients with SLE and healthy controls and to investigate the relationship between Sestrin-1 and laboratory, electrocardiographic, echocardiographic, and vascular imaging parameters. We hypothesized that lower circulating Sestrin-1 levels would be associated with subclinical cardiovascular alterations, particularly indices suggestive of early cardiac remodeling.
Methods
Study design and population
This controlled cross-sectional study was conducted at the Necmettin Erbakan University Faculty of Medicine between 1 October 2024 and 1 October 2025. A total of 60 patients with SLE and 60 healthy controls were enrolled. SLE was diagnosed according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria. 9 Patients were recruited from rheumatology outpatient clinics, whereas controls were age-matched asymptomatic volunteers without known systemic or cardiovascular disease.
Eligible participants were between 18 and 65 years of age. To minimize the effect of traditional cardiovascular risk factors and overt organ dysfunction, the following exclusion criteria were applied to both groups: hypertension, diabetes mellitus, dyslipidemia, chronic renal insufficiency, chronic liver disease, pulmonary disease, previous cardiovascular events, known arrhythmias, use of cardiotoxic agents, pregnancy, active smoking, and concomitant autoimmune or inflammatory disease.
This study was approved by the Necmettin Erbakan University Institutional Review Board (Approval No: 6051; Date: 10 October 2025). For this retrospective study, the Institutional Review Board granted exemption/waiver of written informed consent. All participant data were de-identified prior to analysis. The study was conducted in accordance with the Declaration of Helsinki (1975), as revised in 2024. Sestrin-1 measurements were performed retrospectively using archived serum samples. No additional blood sampling or intervention was performed for research purposes. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 10
Clinical and laboratory assessments
Demographic and clinical data were recorded for all participants. Disease duration and disease activity were assessed in the SLE group, and disease activity was quantified using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Venous blood samples were collected after an overnight fast. Routine laboratory measurements, including complete blood count, blood urea nitrogen, creatinine, and standard biochemical analyses, were performed using automated analyzers. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation.
Medication
All patients with SLE were receiving hydroxychloroquine. A subset of patients was also receiving additional immunosuppressive therapy and/or low-to-moderate-dose corticosteroids. Medication details for the preceding 3 months are summarized in Table 1.
Distribution of data according to SLE and control groups.
Data are presented as mean ± SD or n (%). Bold values indicate statistical significance (p < 0.05).CIMT: carotid intima-media thickness; CS: corticosteroid; EF: ejection fraction; HCQ: hydroxychloroquine; IS: immunosuppressive therapy; LA: left atrial; LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end-systolic diameter; PAP: pulmonary artery pressure; QTc: corrected QT interval; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; TAPSE: tricuspid annular plane systolic excursion.
Measurement of Sestrin-1
Venous blood samples were collected after 10–12 h of fasting, centrifuged at 4000 r/min for 5 min, and serum was aliquoted and stored at −80°C. All Sestrin-1 measurements were performed on thawed serum samples processed on the day of the assay. The study procedures, including sample collection and biochemical and hematological testing, were completed within 3 months.
Serum Sestrin-1 concentrations were measured using a commercially available enzyme-linked immunosorbent assay kit specific for human Sestrin-1 (Human Sestrin-1 ELISA Kit, Bioassay Technology Laboratory, Shanghai, China; Catalog No: E3653Hu), according to the manufacturer's instructions. All samples were thawed once and assayed in duplicate; laboratory personnel were blinded to clinical status. The kit's reported sensitivity (limit of detection) was 0.1 ng/mL, with an analytical range of 0.5–100 ng/mL. The intra-assay and inter-assay coefficients of variation (CV) were <8% and <10%, respectively, ensuring high precision and reproducibility. All measurements were completed within a single analytical run to minimize inter-assay variability. The mean duration of serum storage at −80°C before assay was 6 months, and samples underwent only a single freeze-thaw cycle.
Electrocardiographic evaluation
A standard 12-lead electrocardiogram was recorded at a paper speed of 25 mm/s and a calibration of 10 mm/mV. PR interval, QRS duration, and corrected QT (QTc) interval were measured manually by a single blinded cardiologist.
Echocardiographic evaluation
Transthoracic echocardiography was performed using a Siemens Acuson S3000 ultrasound system with a 2.5 MHz transducer in accordance with the recommendations of the American Society of Echocardiography. The assessed parameters included left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left atrial (LA) diameter, mitral E-wave velocity, mitral A-wave velocity, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), and estimated pulmonary artery pressure (PAP). LVEF was calculated using the modified biplane Simpson method. TAPSE was measured in M-mode at the lateral tricuspid annulus, and values below 1.7 cm were considered indicative of impaired right ventricular systolic function.
Carotid intima-media thickness (CIMT)
CIMT was measured bilaterally at the common carotid artery approximately 3 cm proximal to the carotid bifurcation using high-resolution B-mode ultrasonography (Siemens Acuson S3000, 9L4 linear transducer). For each side, the mean of three consecutive measurements was used for analysis.
Sample size and power
Sample size estimation was performed using G*Power (version 3.1.9.2). The target effect size (Cohen's d = 0.90) was based on previously reported differences in circulating Sestrin-1 between patients with inflammatory rheumatic diseases and controls.7,8 With α = 0.05 and 80% power, the required total sample size was 64 participants. To allow for attrition, a minimum of 70 participants was planned. Ultimately, 120 participants (60 patients with SLE and 60 controls) were enrolled because of the availability of eligible cases and archived samples, increasing the study's power beyond the prespecified minimum.
Statistical analysis
Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation, and categorical variables as number and percentage. Data distribution was evaluated using the Kolmogorov–Smirnov test. Between-group comparisons were performed using the independent-samples Student t test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher exact test, as appropriate.
Correlations between Sestrin-1 levels and clinical, laboratory, electrocardiographic, and echocardiographic variables within the SLE group were assessed using Pearson correlation analysis. In addition, an exploratory multivariable logistic regression model was constructed to evaluate variables independently associated with SLE status. Serum Sestrin-1, LA diameter, QTc interval, age, and sex were entered into the model based on clinical relevance. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A two-tailed p-value <0.05 was considered statistically significant.
Multiple comparisons were performed across numerous ECG, echocardiographic, and laboratory parameters; no formal adjustment for multiple testing was applied, and the analyses should be interpreted as exploratory. The multivariable logistic regression was conducted as an exploratory analysis to identify variables associated with case status (SLE vs. control) rather than to develop or validate a predictive model. The events-per-variable ratio for the regression (60 cases/5 predictors) was approximately 12:1.
Results
Baseline clinical and laboratory findings
A total of 60 patients with SLE and 60 healthy controls were included. The two groups were similar in age (mean ± SD: 54.51 ± 12.81 years in patients with SLE vs. 57.86 ± 10.31 years in controls; p = 0.157), with no statistically significant difference. Baseline demographic, clinical, electrocardiographic, laboratory, and echocardiographic characteristics are presented in Table 1. The two groups were similar in age. Female sex was more frequent in the SLE group, although the difference did not reach statistical significance. Compared with controls, patients with SLE had significantly lower lymphocyte counts, hemoglobin levels, and platelet counts. Serum creatinine was slightly but significantly higher in patients with SLE group. Mean serum Sestrin-1 concentration was markedly lower in patients with SLE group than in the control group (9.99 ± 2.01 vs. 17.79 ± 5.11 ng/mL; p < 0.001).
Electrocardiographic findings
Electrocardiographic analysis showed no significant differences between groups with respect to the PR interval or QRS duration. However, the QTc interval was significantly longer in patients with SLE than in controls (429.65 ± 32.42 vs. 376.26 ± 33.41 ms; p < 0.001).
Echocardiographic and vascular findings
Echocardiographic assessment demonstrated significant differences in several cardiovascular parameters. Patients with SLE had a greater LA diameter, higher mitral E-wave and A-wave velocities, lower TAPSE, mildly lower LVEF, and higher PAP than controls. LVEDD and LVESD did not differ significantly between groups. In addition, both right and left CIMT values were significantly higher in patients with SLE group than in controls.
Correlation of Sestrin-1 With clinical and cardiovascular variables
Within the SLE group, serum Sestrin-1 level showed a moderate inverse correlation with the SLEDAI score (r = −0.511, p < 0.001), indicating that lower Sestrin-1 levels were associated with higher disease activity. Sestrin-1 was also inversely correlated with LA diameter (r = −0.288, p = 0.026). No significant correlations were identified between Sestrin-1 and the PR interval, QRS duration, QTc interval, LVEDD, LVESD, mitral E-wave velocity, mitral A-wave velocity, TAPSE, PAP, EF, CIMT, or eGFR (Table 2).
Correlation between serum Sestrin-1 and clinical/cardiovascular parameters in patients with SLE.
Bold values indicate statistical significance (p < 0.05).
CIMT: carotid intima-media thickness; EF: ejection fraction; LA: left atrium; LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end-systolic diameter; PAP: pulmonary artery pressure; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; TAPSE: tricuspid annular plane systolic excursion.
Exploratory multivariable analysis
In the exploratory multivariable logistic regression analysis, lower Sestrin-1 levels, larger LA diameter, and longer QTc interval were independently associated with SLE status. Each 1 ng/mL increase in Sestrin-1 was associated with lower odds of SLE (OR = 0.63, 95% CI: 0.54–0.75; p < 0.001). Each 1 mm increase in LA diameter (OR = 1.13, 95% CI: 1.06–1.22; p < 0.001) and each 1 ms increase in the QTc interval (OR = 1.03, 95% CI: 1.02–1.05, p < 0.001) were associated with higher odds of SLE. Age and sex were not significantly associated with SLE status (Table 3).
Exploratory multivariable logistic regression analysis for variables associated with SLE status.
CI: confidence interval; LA: left atrial; OR: odds ratio; QTc: corrected QT.
Discussion
In this controlled cross-sectional study, patients with SLE had substantially lower serum Sestrin-1 levels than healthy controls and demonstrated multiple indicators of subclinical cardiovascular involvement. In addition to a significantly prolonged QTc interval and increased CIMT, patients with SLE showed a larger LA diameter, altered mitral inflow velocities, lower TAPSE, mildly reduced ejection fraction, and higher PAP. Most importantly, within the SLE group, lower Sestrin-1 levels were associated with both higher disease activity and a larger LA diameter.
All patients received hydroxychloroquine, and six patients (10%) received additional immunosuppressive therapy and/or low-to-moderate-dose corticosteroids. Because this subgroup was small, formal subgroup analysis would have been underpowered, and medication exposure was not modeled as a primary covariate. Future studies with larger samples should evaluate cumulative corticosteroid dose, duration, and type of immunosuppression, and their potential effects on Sestrin-1 and subclinical cardiovascular measures.
These findings support the concept that oxidative stress-related pathways may contribute to early cardiovascular involvement in SLE. Sestrin-1 is known to regulate cellular responses to oxidative injury, mitochondrial dysfunction, and impaired autophagy. 5,6 A reduction in circulating Sestrin-1 may therefore reflect diminished endogenous defense against inflammation- and oxidative stress-mediated tissue injury. In SLE, where chronic immune activation and vascular dysfunction are central features, decreased Sestrin-1 may be linked to both systemic disease burden and subclinical cardiovascular remodeling.
The finding of increased CIMT in patients with SLE group is consistent with previous literature demonstrating accelerated subclinical atherosclerosis in lupus.2,3,11 Although Sestrin-1 did not correlate with CIMT in our cross-sectional cohort, one possible explanation is that circulating Sestrin-1 reflects a more dynamic measure of current inflammatory or oxidative stress, whereas CIMT captures cumulative arterial wall remodeling over longer periods. Prospective longitudinal studies that measure Sestrin-1 and CIMT repeatedly are needed to determine whether baseline or temporal changes in Sestrin-1 predict CIMT progression. CIMT reflects a chronic structural process that may be influenced by cumulative inflammation, disease duration, age, treatment exposure, and unmeasured vascular risk factors. By contrast, circulating Sestrin-1 may be more closely related to current inflammatory or oxidative stress status than to long-term arterial wall remodeling. This may explain the absence of a direct association between Sestrin-1 and CIMT in the present study.12,13
Among the echocardiographic findings, the inverse association between Sestrin-1 and LA diameter deserves particular attention. LA enlargement is an established marker of chronic diastolic burden and early myocardial remodeling, and it has prognostic relevance across a range of cardiovascular conditions. 14 The observed relationship between lower Sestrin-1 levels and a larger LA diameter may suggest that reduced antioxidant and autophagy-related protective signaling contributes to early atrial structural changes in SLE. These subclinical alterations are clinically relevant, as cardiac involvement in SLE can, in some cases, progress to severe structural pathology. For instance, the literature describes life-threatening complications such as left ventricular pseudoaneurysms requiring surgical repair, underscoring the importance of early detection of subclinical changes. 15 Experimental evidence supports a cardioprotective role for Sestrin-1 in attenuating pathological remodeling and hypertrophic signaling. 16 Although we did not observe significant correlations between Sestrin-1 and TAPSE, EF, or PAP, the association with LA diameter may indicate that atrial remodeling is among the earliest detectable cardiac abnormalities linked to reduced Sestrin-1 in SLE.
Another notable finding was the marked prolongation of the QTc interval in patients with SLE. QTc prolongation has been described in autoimmune disease and may reflect autonomic dysfunction, inflammatory myocardial involvement, electrolyte imbalance, or medication-related effects. 17 In our study, QTc did not correlate significantly with Sestrin-1, suggesting that electrical instability and oxidative stress-related structural remodeling may represent partially distinct pathophysiological domains. This distinction is clinically relevant, as different mechanisms may underlie arrhythmic risk and structural cardiovascular involvement in SLE.
The inverse correlation between Sestrin-1 and SLEDAI further strengthens the biological plausibility of our findings. Higher disease activity likely reflects a greater inflammatory and oxidative stress burden, which may contribute to the downregulation or increased consumption of protective stress-response proteins such as Sestrin-1. This observation suggests that Sestrin-1 may be relevant not only to cardiovascular involvement but also to the broader inflammatory milieu of active lupus.
The exploratory multivariable regression analysis showed that lower Sestrin-1 levels, a larger LA diameter, and a longer QTc interval were independently associated with SLE status. However, this model should be interpreted with caution. Because the dependent variable was disease status rather than a cardiovascular outcome, the regression should not be viewed as evidence of predictive utility for subclinical cardiovascular disease. Rather, it supports the notion that these variables are strongly associated with the SLE phenotype in this cohort. Future studies should preferentially examine whether Sestrin-1 independently predicts specific cardiovascular outcomes or imaging abnormalities within SLE populations.
This study has some limitations. First, its cross-sectional design precludes causal inference and does not allow assessment of whether low Sestrin-1 precedes or follows cardiovascular alterations. Second, the study was conducted at a single center with a relatively modest sample size, which may limit generalizability. Third, detailed medication exposure, including cumulative corticosteroid dose and duration of immunosuppressive therapy, was not fully modeled and may have influenced both Sestrin-1 levels and cardiovascular parameters. Fourth, some potentially important lupus-related variables, including complement levels, anti-dsDNA status, and antiphospholipid antibody profile, were not consistently available for all participants. Fifth, interobserver and intraobserver variability for ECG and echocardiographic measurements was not assessed. Finally, LA diameter was used instead of indexed LA volume, which would provide a more sensitive, guideline-based assessment of atrial remodeling. Despite these limitations, the study has important strengths. The control group was selected to minimize traditional cardiovascular confounding, all participants underwent multimodal cardiovascular evaluation, and Sestrin-1 was examined in relation to both disease activity and subclinical structural cardiovascular findings. To our knowledge, this study is among the first to explore the relationship between Sestrin-1 and cardiovascular involvement in SLE.
In clinical terms, our findings suggest that Sestrin-1 may represent a promising candidate biomarker for identifying patients with SLE who are at higher risk of subclinical cardiovascular involvement, particularly early atrial remodeling. However, the current results should be considered hypothesis-generating. Larger prospective studies incorporating longitudinal follow-up, comprehensive immunologic profiling, and more advanced cardiac imaging are needed before Sestrin-1 can be integrated into routine cardiovascular risk assessment in SLE.
Conclusion
Patients with SLE have significantly lower serum Sestrin-1 levels than healthy controls and exhibit multiple subclinical cardiovascular abnormalities. Lower Sestrin-1 levels correlate with higher disease activity and a larger LA diameter, suggesting a possible link between impaired oxidative stress defense and early cardiac remodeling in SLE. Sestrin-1 may be a promising candidate biomarker for subclinical cardiovascular involvement in SLE, but prospective validation is required before its clinical application.
Footnotes
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki (1975), as revised in 2024. The protocol was approved by the Necmettin Erbakan University Faculty of Medicine Ethics Committee (Approval No: 6051; Date: 10 October 2025). For this retrospective study, the Institutional Review Board granted an exemption/waiver of written informed consent. All participant data were de-identified prior to analysis.
Author contributions
Concept: C.U. and M.T.Y. Design: C.U. and M.C. Analysis and/or interpretation: M.T.Y., M.H.G., and B.I. Writing: M.T.Y., C.U., A.K., M.H.G., and B.I. Critical review: C.U., M.T.Y., A.K., M.C., and B.I.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.