Cardiac surgeries are essential for treating a variety of heart diseases, including coronary artery disease and congenital heart defects [1, 2]. However, these procedures are associated with several potential complications, such as cardiovascular death, atrial fibrillation (AF), acute kidney injury (AKI), and spontaneous myocardial infarction (MI). AF represents a common complication, affecting 30% to 50% of patients following cardiovascular interventions [3]. The development of AF is associated with increased morbidity and mortality, including higher risks of stroke, heart failure, and prolonged hospital stays [4]. AKI occurs in a significant portion of patients undergoing cardiovascular interventions, resulting in increased morbidity and mortality [5]. The development of AKI post-surgery necessitates prolonged hospital stays and intensive care, significantly impacting patient quality of life and increasing healthcare costs [6]. Given the significant morbidity and mortality associated with these complications, it is crucial to identify patients who are at high risk to take appropriate measures, including monitoring of renal function, maintaining adequate hydration, and so on [7, 8]. Therefore, early detection and intervention are essential in mitigating potential complications.

Growth differentiation factor-15 (GDF-15), a stress-responsive cytokine, is elevated in response to myocardial stretch, inflammation, and oxidative stress, making it a potential indicator of various complications following cardiac procedures [9]. A study has explored the predictive effect of GDF-15 on adverse outcomes after cardiovascular interventions, highlighting its potential as a significant biomarker for risk stratification and outcome prediction. A prospective, single-center study found that low preoperative plasma levels of GDF-15 are a strong independent predictor of postoperative AF in patients undergoing off-pump and on-pump coronary artery bypass graft (CABG) surgery, adding predictive value to classic risk factors [10]. Kato et al. [11] reported preoperative levels of GDF-15 can help identify short-term operative risks including AKI, as well as 30-day mortality and morbidity in patients undergoing cardiovascular surgery. Preoperative biomarkers reflecting cardiac, inflammatory, renal, and metabolic disorders are strongly associated with cardiac surgery-associated AKI and can enhance the identification of at-risk elderly patients compared to clinical risk factors alone [12]. In revascularized patients with non-ST-elevation acute coronary syndrome, biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and GDF-15 could improve the prognostication of cardiovascular death and spontaneous MI beyond clinical risk factors alone [13]. Wollert et al. [14] reported that elevated GDF-15 levels improve risk stratification in non-ST-elevation acute coronary syndrome, predicting outcomes better with an invasive strategy. Given the diverse findings across multiple studies regarding the predictive value of GDF-15 on adverse outcomes after cardiovascular interventions, conducting a meta-analysis and systematic review is crucial to consolidate this evidence, resolve inconsistencies, and provide robust, comprehensive insights.

The aim of this systematic review and meta-analysis is to evaluate the predictive effect of GDF-15 on adverse outcomes following cardiovascular interventions. The hypothesis of this systematic review and meta-analysis is that elevated preoperative GDF-15 are significant predictors of adverse outcomes in patients undergoing cardiovascular interventions.

In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this systematic review and meta-analysis aimed to evaluate the prognostic value of GDF-15 for adverse outcomes following cardiovascular interventions [15]. We have registered our study on the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42024582279.

This meta-analysis highlights the significant association between elevated GDF-15 levels and various adverse outcomes in patients undergoing cardiac surgery. Elevated GDF-15 levels were significantly linked to increased all-cause mortality, with a more pronounced effect observed in retrospective studies compared to prospective ones. Higher GDF-15 cutoff levels showed a stronger association with increased mortality, indicating that as the cutoff level for GDF-15 increases, the disparity in outcomes between patients with high and low GDF-15 levels becomes more pronounced. Additionally, GDF-15 levels were associated with increased risks of cardiovascular death, acute kidney injury, and spontaneous MI, but not with atrial fibrillation. The analysis of overall adverse outcomes showed no significant difference, but subgroup analyses suggested significant associations primarily in studies with higher GDF-15 cutoff levels. These findings underscore the critical role of GDF-15 as a biomarker for predicting adverse outcomes in cardiovascular interventions patients, emphasizing the need for careful monitoring and management of patients with high GDF-15 levels to improve surgical outcomes.

Postoperative AF was a common complication, and its occurrence ranged from 20% to 45% in those who have undergone CABG surgery [10, 27]. The presence of postoperative AF adversely affected patient outcomes by increasing the duration of hospitalization, escalating healthcare costs, and heightening the risks of stroke, and mortality [28]. Bouchot et al. [10] analyzed the postoperative AF in a total of 100 patients undergoing CABG, and demonstrated that low plasma GDF-15 levels before CABG surgery are a strong independent predictor of postoperative AF. However, El-Harasis et al. [20] suggested that the inclusion of GDF-15 and other biomarkers did not enhance the predictive ability for the occurrence of AF (p = 0.09). This meta-analysis pooled data from these two studies and found that GDF-15 levels were not associated with an increased risk of postoperative AF following cardiovascular interventions. The limited number of studies included in this analysis highlights the need for further research. The current evidence is insufficient to draw definitive conclusions about the predictive value of GDF-15 for postoperative AF. Future studies with larger sample sizes and more rigorous designs are necessary to fully understand the relationship between GDF-15 levels and postoperative AF risk.

AKI represents a common and serious complication following cardiovascular interventions and is linked with adverse outcomes, including prolonged hospital stays, increased healthcare costs, and higher mortality rates [21]. Guenancia et al. [21] demonstrated that pre-operative GDF-15 plasma levels are significantly associated with post-operative AKI in CABG patients. The predictive value of pre-operative GDF-15 for AKI was assessed against other biomarkers using receiver operating characteristic (ROC) curves. GDF-15 achieved an area under the curve (AUC) of 0.83, establishing itself as the most effective pre-operative biomarker for predicting AKI. This performance outperformed both the estimated glomerular filtration rate (eGFR) with an AUC of 0.67 and NT-proBNP with an AUC of 0.62 [21]. This meta-analysis pooled data from four studies, further indicates that elevated pre-operative GDF-15 plasma levels are strongly linked to post-operative AKI. These findings reinforce the potential application of GDF-15 as a reliable biomarker for identifying patients at high risk of developing AKI following cardiovascular interventions. Lindholm et al. [13] demonstrated that in revascularized patients with non–ST-elevation acute coronary syndrome, adding the extent of NT-proBNP and GDF-15 to clinical risk variables significantly improves the prediction of spontaneous MI. GDF-15, in particular, contributes to better risk stratification, highlighting its potential utility in guiding more intensive or prolonged antithrombotic treatment in this patient population [13]. This meta-analysis further indicates that elevated GDF-15 plasma levels are strongly associated with post-operative spontaneous MI and cardiovascular death in patients with cardiovascular interventions. The findings indicate that GDF-15 enhances risk stratification and may be valuable for predicting these adverse outcomes.

Higher GDF-15 cutoff levels were associated with increased mortality, reflecting a greater disparity in outcomes between patients with high and low GDF-15 levels. While the overall analysis of adverse outcomes did not show a significant difference, subgroup analyses suggested significant associations primarily in studies with higher GDF-15 cutoff levels. Higher cutoff values for GDF-15 displayed more pronounced differences between groups, likely due to increased specificity. However, this increase in specificity may come at the cost of reduced sensitivity, potentially missing some high-risk patients. Therefore, further research is necessary to determine the optimal cutoff value through Youden index. This approach will help balance sensitivity and specificity, ensuring that GDF-15 remains an effective predictive biomarker for adverse outcomes after cardiovascular interventions.

This study has several limitations to be addressed. First, significant heterogeneity was observed among the included studies, particularly regarding the patients undergoing different cardiovascular interventions and the cutoff values applied. This variability may affect the consistency of the findings and limits the ability to draw definitive conclusions. Second, although efforts were made to include all relevant studies, there is a possibility of publication bias, and this bias could affect the overall results of the meta-analysis. Third, this meta-analysis did not analyze the sensitivity and specificity of GDF-15 as a predictive biomarker for adverse outcomes after cardiovascular interventions due to limited data. Future research should include Youden index to determine optimal cutoff values, balancing sensitivity and specificity, to enhance the clinical utility of GDF-15 in risk stratification. Fourth, this study analyzed GDF-15 as a predictor of all-cause mortality, cardiovascular death, atrial fibrillation, AKI, and spontaneous MI as adverse outcomes [16]. However, it did not assess bleeding events or other adverse outcomes, indicating a limitation that future research should address by further analyzing these factors. Fifth, this study primarily focused on the predictive value of GDF-15 and did not include comparisons with other established biomarkers, such as NT-proBNP, C-reactive protein (CRP), and albumin. This represents a limitation of our research. Future large-scale randomized controlled trials are needed to analyze the advantages of GDF-15 in relation to other prognostic indicators. Finally, it is important to note that 10 of the 13 studies included in this study were published between 2015 and 2019. Changes in treatment approaches for cardiovascular diseases during this time may influence the relevance and applicability of the findings. This temporal limitation should be considered when interpreting the results of this systematic review.

In conclusion, this systematic review and meta-analysis indicated that GDF-15 is associated with increased risks of all-cause mortality, cardiovascular death, AKI, and spontaneous MI in patients undergoing cardiovascular interventions. Given the heterogeneity observed across the studies, particularly with respect to the diverse surgical techniques employed, it is imperative that the finding be interpreted with caution. Further research is required to elucidate the underlying mechanisms of these associations and to refine the clinical application of GDF-15 as a prognostic biomarker.

All data generated or analyzed during this study are included in this article and supplementary information files.

Concept and design: XTJ, ZYQ, JM; Data acquisition: XTJ, JWG, ZYQ; Data analysis: XTJ, JWG, ZYQ; Data interpretation: All authors; Drafting of the manuscript: XTJ, JWG, ZYQ; Revising of the manuscript: All authors; Supervision: ZYQ, JM. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This study was supported by the National Natural Science Foundation of China (No.82372191).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM28279.