Association of endothelial glycocalyx degradation with post-PCI slow flow phenomenon in STEMI patients: a prospective observational study

Introduction

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality globally (1,2). Despite significant advancements in reperfusion strategies, particularly percutaneous coronary intervention (PCI), a substantial subset of patients continues to experience suboptimal myocardial perfusion following the successful recanalization of the infarct-related artery (IRA). This condition manifests clinically as the “slow flow” or “no-reflow” phenomenon (1,3). These phenomena are strongly associated with adverse clinical outcomes, including expanded infarct size, impaired ventricular functional recovery, and elevated rates of short- and long-term mortality (4). Current understanding attributes the pathogenesis of slow flow primarily to distal microembolization, ischemic spasm, and ischemia-reperfusion (I/R) injury (5). However, the precise structural underpinnings of these processes at the microvascular level remain incompletely elucidated. Consequently, shifting the research focus to microvascular endothelial structural integrity is critical. Investigating its role in the development of slow flow is of significant clinical value for identifying early diagnostic biomarkers and novel therapeutic targets.

The endothelial glycocalyx (EG) is a gel-like reticular structure rich in proteoglycans and glycoproteins that coats the luminal surface of vascular endothelial cells (6). It plays a pivotal role in maintaining vascular barrier integrity, regulating microvascular permeability, mechanotransducing shear stress, and inhibiting leukocyte adhesion and thrombosis (7). In pathological contexts such as AMI and I/R injury, systemic and local inflammatory responses, oxidative stress, and mechanical trauma (e.g., balloon dilation and stent implantation) precipitate structural and functional impairment, leading to the degradation and shedding of the EG (8). This degradation exposes the “naked” microvascular wall, inducing endothelial edema and neutrophil entrapment within the microcirculation (5,9). These processes may represent a critical pathological mechanism underlying the coronary slow flow (CSF) phenomenon. Among EG degradation products, syndecan-1 (SDC-1) reflects shedding of membrane-bound proteoglycan components, whereas hyaluronic acid (HA) reflects changes in glycosaminoglycan-related components (10,11). Measuring both biomarkers may therefore capture complementary aspects of EG shedding.

Most prior studies on EG injury in ACS/AMI relied on single time-point measurements, providing limited peri-procedural dynamic information. Consequently, the relationship between pre-procedural glycocalyx shedding signals and post-reperfusion outcomes remains unclear (12-14).
Accordingly, we conducted a prospective observational study with serial measurements of serum SDC-1 and HA at three key time points: pre-PCI, immediately post-PCI, and 24 hours post-PCI. We evaluated the associations of pre-PCI biomarker levels with post-PCI reperfusion outcomes, including CSF [corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) >27 frames] and no-reflow (TIMI flow grade <3), and characterized peri-procedural biomarker trajectories to inform risk stratification and mechanistic understanding. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-642/rc).

Methods

Study design and patient selection

This prospective observational study consecutively enrolled patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PPCI) at the Department of Cardiology, First Hospital of Shanxi Medical University, between August and November 2025. A total of 114 patients were screened initially, and 82 were ultimately enrolled after applying the predefined inclusion and exclusion criteria.

Inclusion criteria were: (I) STEMI as the first clinical presentation of coronary artery disease (CAD) and (II) treatment within 12 hours of symptom onset. Exclusion criteria were: acute or chronic infection; malignancy; cerebrovascular disease; autoimmune disease; recent trauma or surgery; severe valvular heart disease or primary cardiomyopathy; PCI after thrombolysis or rescue PCI; presentation >12 hours after symptom onset; emergency angiography without PCI or elective PCI; previously diagnosed CAD; and refusal to participate or inadequate sample quality.

All patients without contraindications received a loading dose of dual antiplatelet therapy (DAPT) and an injection of tirofiban preoperatively. Postoperatively, routine anticoagulation with low-molecular-weight heparin (LMWH) and standard secondary prevention therapies were administered. The study was registered in the Chinese Clinical Trial Registry (Identifier: ChiCTR2500107421). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the First Hospital of Shanxi Medical University (No. KYLL-2025-115). Written informed consent was obtained from all participants.

Angiographic evaluation and definition of outcomes

Coronary angiography and PPCI procedures were performed by experienced interventional cardiologists. Angiographic images were analyzed independently by two interventional cardiologists who were blinded to the clinical data. Discrepancies were resolved through consensus. Post-procedural myocardial perfusion was quantitatively assessed using the CTFC, following the methodology described by Gibson et al. (15). Images were acquired at a rate of 30 frames/second. Raw TIMI frame counts were used for the right coronary artery (RCA) and left circumflex artery (LCX). For the left anterior descending artery (LAD), due to its longer anatomical course, the raw frame count was corrected by dividing by 1.7.

In this study, CSF was defined as a CTFC >27 frames in the culprit vessel after primary PCI (PPCI). Patients were classified into the CSF and Normal flow groups accordingly, and CSF served as the primary outcome (16). Post-procedural TIMI flow grade was recorded concurrently. No-reflow was defined as a post-procedural TIMI flow grade <3 and was treated as a secondary outcome.

Serum biomarker analysis

For laboratory measurements, 5 mL of antecubital venous blood was collected into serum separator tubes at three time points: before emergent intervention, immediately after the procedure, and 24 hours post-procedure. Samples were allowed to clot at room temperature for 30 minutes and were then centrifuged at 2,000 ×g for 15 minutes at 4 ℃ to separate serum. After centrifugation, samples underwent visual quality control; specimens with visible hemolysis, marked lipemia, clots, or contamination were excluded. Serum aliquots were stored at −80 ℃ until analysis. Aliquoting was used to minimize repeated freeze-thaw cycles, with a maximum of two freeze-thaw cycles allowed per sample. Serum concentrations of SDC-1 and HA were quantified using enzyme-linked immunosorbent assays (ELISAs) (MEIMIAN, China). All assays were performed according to the manufacturer’s instructions. The intra-assay and inter-assay coefficients of variation were both <10%, and laboratory personnel were blinded to group assignment.

Statistical analysis

Statistical analyses were performed using the R programming environment (Version 4.5.0). For variables with <20% missingness (e.g., admission glucose and NT-proBNP), missing values were imputed using multiple imputation by chained equations (MICE), generating five imputed datasets with predictive mean matching (PMM). One imputed dataset was selected at random for descriptive presentation. All regression models were fitted separately in each of the five datasets, and estimates were combined using Rubin’s rules. Continuous variables with a normal distribution were presented as mean ± standard deviation (SD) and compared using the independent Student’s t-test. Non-normally distributed variables were expressed as median [interquartile range (IQR)] and analyzed using the Mann-Whitney U test. Categorical data were reported as frequencies (percentages) and compared using Pearson’s χ² test or Fisher’s exact test, as appropriate. Temporal changes in biomarkers were evaluated using the Wilcoxon signed-rank test for intra-group comparisons and the Mann-Whitney U test for inter-group comparisons. CSF (CTFC >27 frames) was the primary outcome. Multivariable logistic regression was used to evaluate the associations of pre-procedural SDC-1 and HA with CSF. Continuous predictors were standardized as z-scores prior to modeling, and results were reported as odds ratios (ORs) with 95% confidence intervals (CIs) per 1-SD increase. The primary model was prespecified and parsimonious, adjusting for key confounders selected a priori based on a pathophysiological framework: age, symptom-to-treatment time, admission diastolic blood pressure (DBP), and total stent length. To avoid redundancy within blood pressure measures, systolic blood pressure (SBP) was not included in the primary model. Sensitivity analyses were conducted by extending the primary model as follows: (S1) additional adjustment for pre-procedural TIMI flow grade (0–1 vs. 2–3); (S2) additional adjustment for log-transformed NT-proBNP; and (S3) additional adjustment for both pre-procedural TIMI flow grade and log-transformed NT-proBNP. CTFC was also analyzed as a continuous outcome using linear regression. Effects were reported as β coefficients with 95% CIs per 1-SD increase in the exposure, to assess the robustness of the findings. No-reflow (post-procedural TIMI flow grade <3) was treated as a secondary outcome. Given the limited number of events, Firth’s penalized logistic regression was used, with a reduced covariate set (age and symptom-to-treatment time) to mitigate overfitting. Results were reported as ORs with 95% CIs. Receiver operating characteristic (ROC) curve analysis was utilized to calculate the area under the curve (AUC) to assess the discriminative ability of serum markers for CSF risk. The DeLong test was employed to compare the AUCs of SDC-1 and HA to determine superior risk discrimination performance. A two-sided P<0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 82 patients with STEMI were included. Based on post-PCI CTFC, 39 patients (47.6%) were classified as having CSF, and 43 (52.4%) as having normal flow. The mean age was 58.4±10.4 years, and 74 of 82 patients (90.2%) were men. Baseline clinical characteristics are summarized in Table 1, and angiographic/periprocedural and reperfusion indices are presented in Table 2. The two groups were generally well balanced with respect to age, sex, body mass index, and the prevalence of hypertension, diabetes, smoking, alcohol use, and dyslipidemia. No significant between-group differences were observed [age: 58.0 (49.0, 65.0) vs. 60.0 (54.0, 66.0) years, P=0.42; male sex: 90.7% vs. 89.7%, P>0.99]. Common comorbidities/cardiovascular risk factors were comparable between groups, including hypertension (46.5% vs. 43.6%), dyslipidemia (41.9% vs. 33.3%), and diabetes (25.6% vs. 33.3%). Admission systolic and DBP were significantly lower in the CSF group (SBP: 117.5±19.5 vs. 129.2±18.2 mmHg, P=0.007; DBP: 77.1±11.7 vs. 85.7±12.7 mmHg, P=0.002), whereas heart rate and left ventricular ejection fraction did not differ significantly. On admission, the CSF group had a higher neutrophil percentage [75.8% (64.0%, 82.9%) vs. 65.6% (55.0%, 76.8%), P=0.006]. NT-proBNP was numerically higher in the CSF group, but the difference was not statistically significant [555.6 (141.0, 1,300.0) vs. 206.0 (71.0, 897.0) pg/mL, P=0.20]. Regarding angiographic and reperfusion indices, the culprit-vessel distribution and pre-procedural TIMI flow grade were similar between groups. In contrast, post-procedural TIMI flow grade was worse in the CSF group, with a higher incidence of no-reflow (TIMI flow grade <3; 38.5% vs. 0.0%; both P<0.001) and higher CTFC values [35.3 (29.4, 36.0) vs. 20.0 (18.8, 23.5), P<0.001]. Periprocedural interventions—including thrombus aspiration, intracoronary thrombolysis, the number of additional balloon inflations, stent diameter, and total stent length—did not differ significantly between groups; however, the number of stents showed a borderline increase in the CSF group (P=0.051). With respect to serum glycocalyx degradation biomarkers, pre-procedural HA and SDC-1 levels were significantly higher in the CSF group than in the Normal flow group (both P<0.001), and HA and SDC-1 remained elevated at 24 hours post-PCI.

Temporal changes in serum glycocalyx degradation markers

Temporal monitoring of serum glycocalyx degradation products revealed distinct dynamic trajectories between the two groups (Figure 1). For HA, the CSF group exhibited sustained elevation throughout the perioperative period. HA concentrations in the CSF group were significantly higher than those in the Normal Flow group at all three time points: pre-procedure, immediately post-procedure, and 24 hours post-procedure (all P<0.001). Following a sharp surge immediately post-procedure, HA levels in the CSF group remained elevated at 24 hours without significant decline. Regarding SDC-1, baseline levels were significantly higher in the CSF group compared to the NF group (P<0.001). However, immediately post-procedure, the levels in both groups briefly converged, and no statistically significant difference was observed (P>0.05). By 24 hours post-procedure, the trajectories diverged once again: while SDC-1 levels in the NF group returned towards baseline, the CSF group maintained a high plateau, restoring a statistically significant difference between the groups (P<0.001).

Figure 1 Comparison of serum endothelial glycocalyx shedding biomarkers between normal flow and slow flow groups at different time points. (A) Serum syndecan-1 levels (pg/mL) at pre-PCI, post-PCI, and 24 h post-PCI. (B) Hyaluronic acid levels (ng/L) at the corresponding time points. The blue boxes represent the normal flow group, and the orange boxes represent the slow flow group. Data are presented as median and interquartile ranges. ***, P<0.001 vs. normal flow group. PCI, percutaneous coronary intervention.

Independent associations of serum glycocalyx markers with CSF

In multivariable logistic regression analyses, higher pre-procedural SDC-1 and HA (standardized as z-scores, per 1-SD increase) were significantly associated with post-PCI CSF. After adjustment for age, symptom-to-treatment time, total stent length, and admission DBP, pre-procedural SDC-1 was independently associated with CSF (OR =5.03; 95% CI: 2.39–10.60; P<0.001), as was pre-procedural HA (OR =3.56; 95% CI: 1.92–6.60; P<0.001) (Table 3). In sensitivity analyses, additional adjustment for pre-procedural TIMI flow grade (S1), log-transformed NT-proBNP (S2), or both (S3) yielded minimal changes in effect estimates, and both biomarkers remained statistically significant (SDC-1: OR ~5.05–5.15; HA: OR ~3.55–3.65; all P<0.001), supporting the robustness of the findings. When CTFC was modeled as a continuous outcome, higher pre-procedural SDC-1 was associated with higher CTFC (primary model: β=5.64; 95% CI: 3.64–7.65; P<0.001), and pre-procedural HA showed a similar association (primary model: β=5.17; 95% CI: 3.10–7.23; P<0.001) (Table 4). These associations remained consistent across sensitivity analyses (S1–S3), with only modest variation in β estimates (all P<0.001). No-reflow (post-procedural TIMI flow grade <3) was analyzed as a secondary outcome (n=15) using Firth’s penalized logistic regression. Pre-procedural SDC-1 was significantly associated with no-reflow (OR =4.66; 95% CI: 1.86–11.65; P=0.001), and pre-procedural HA was also associated with no-reflow (OR =3.84; 95% CI: 1.69–8.72; P=0.002) (Table 5).

Evaluation of risk discriminatory ability of serum glycocalyx markers

ROC curve analysis (Figure 2) demonstrated that the baseline model, incorporating only clinical variables (age, symptom-to-treatment time, DBP, stent length), exhibited moderate discriminatory ability with an AUC of 0.720. The addition of HA to the baseline model significantly improved its ability to distinguish between slow flow and normal flow, increasing the AUC to 0.843 (P=0.016 vs. baseline). The inclusion of SDC-1 yielded the most robust discriminatory performance, further elevating the AUC to 0.880 (P=0.002 vs. baseline). A combined model incorporating both HA and SDC-1 achieved an AUC of 0.873 (P=0.003 vs. baseline). Although the combined model showed significant improvement over the baseline, its AUC did not numerically exceed that of the SDC-1 model (0.873 vs. 0.880). This suggests that the addition of HA offered no incremental discriminatory value beyond that provided by SDC-1 alone.

Figure 2 ROC curves for the discriminatory of slow flow. ROC analysis showing the sensitivity and specificity of the Baseline Clinical Model (blue) compared to models combining Baseline with HA (green), SDC-1 (orange), and both markers (pink). The Baseline Clinical Model was adjusted for age, diastolic blood pressure, stent length, and symptom-to-treatment time. The inclusion of endothelial glycocalyx shedding markers significantly increased the AUC compared to the baseline clinical variables alone. The respective AUC values and P values for comparison with the Baseline Model are displayed in the key. AUC, area under the curve; HA, hyaluronic acid; ROC, receiver operating characteristic; SDC-1, syndecan-1.

Discussion

In patients with STEMI undergoing emergent PPCI, we serially measured serum markers of EG shedding (SDC-1 and HA) and examined their associations with post-procedural reperfusion outcomes. Key findings were as follows. First, patients with CSF had higher pre-procedural SDC-1 and HA levels than those with normal flow. Second, HA showed a more pronounced immediate post-PCI increase in the CSF group and remained elevated at 24 hours, whereas the between-group difference in SDC-1 became more apparent at 24 hours. After adjustment for key clinical confounders, higher pre-procedural SDC-1 and HA remained independently associated with CSF (CTFC >27 frames). These associations were consistent when CTFC was analyzed as a continuous outcome and extended to worse angiographic reperfusion, including lower post-procedural TIMI flow grade and no-reflow. Collectively, these findings suggest a robust statistical association between glycocalyx injury-related signals and impaired reperfusion after PPCI.

Our findings are consistent with prior evidence. Liu et al. (17) reported that, among patients with suspected CAD, higher SDC-1 levels were independently associated with coronary microvascular dysfunction (CMD) and impaired microvascular vasodilatory capacity (IMVC). Mechanistically, the EG is a key determinant of the microvascular barrier and an anti-adhesive interface. Glycocalyx shedding may promote leukocyte adhesion/aggregation, increase microthrombotic propensity, and enhance vascular permeability, thereby exacerbating microvascular dysfunction (8,18). In addition, the glycocalyx serves as a mechanosensing platform for shear stress; its disruption may impair nitric oxide (NO)-mediated vasoreactivity and may interact bidirectionally with impaired microvascular perfusion (19,20). Ischemia-reperfusion is thought to trigger shedding of glycocalyx components (e.g., SDC-1) (21), and HA fragments may contribute to amplification of inflammatory signaling (22). Accordingly, elevated pre-procedural levels and sustained peri-procedural elevation are biologically plausible in the setting of acute ischemia and reperfusion, consistent with heightened systemic endothelial stress.

Importantly, elevations in circulating SDC-1 and HA are not necessarily confined to the myocardial vascular bed (23,24) and may reflect systemic endothelial and glycocalyx stress. For example, in sepsis, glycocalyx injury-related biomarkers (including SDC-1 and HA) can be markedly increased and have been associated with adverse outcomes (25). To further explore this possibility, we performed an exploratory analysis and found no significant correlation between pre-procedural SDC-1/HA and peak troponin I. However, this finding does not rule out ischemia-reperfusion-related glycocalyx injury. First, peak troponin I is highly sensitive to the sampling window and measurement frequency. Second, under impaired reperfusion (e.g., CSF or no-reflow), the release and “washout” kinetics of necrosis biomarkers may be altered, such that peak levels are not necessarily higher. Prior studies have also shown that glycocalyx shedding biomarkers can increase during acute coronary events; however, these levels may not correlate linearly with infarct size (26) and may instead reflect microvascular endothelial stress and inflammatory burden rather than infarct extent alone. More importantly, our study focused on the association between serum glycocalyx shedding biomarkers and adverse post-PCI reperfusion outcomes. Consistently, when CTFC was analyzed as a continuous outcome, pre-procedural biomarkers remained significantly associated with higher CTFC values, providing convergent evidence for the robustness of the association with impaired reperfusion.

In our baseline comparisons, blood pressure was lower in the CSF group. Given that hemodynamic instability is closely linked to CSF and EG shedding—and because coronary perfusion occurs predominantly during diastole (27)—we selected admission DBP as the primary hemodynamic adjustment variable in the main model. A relatively low-perfusion state at presentation could be associated with both worse reperfusion outcomes and higher glycocalyx biomarkers, thereby acting as a potential confounder. Although we adjusted for DBP and used a parsimonious model to reduce overfitting, residual confounding cannot be fully excluded in this observational study, particularly from unmeasured hemodynamic factors (e.g., shock index or exposure to vasoactive agents). In addition, cardiac function and ischemic severity should be considered within the interpretive framework. NT-proBNP reflects ventricular stress and filling-pressure burden and has been associated with impaired reperfusion in prior studies (28,29). Pre-procedural TIMI flow grade, which captures ischemic and thrombotic burden as well as the risk of distal microvascular injury, could represent a shared driver of both higher biomarker levels and worse reperfusion outcomes (30). In sensitivity analyses, additional adjustment for log-transformed NT-proBNP and pre-procedural TIMI flow grade resulted in minimal changes in effect estimates, supporting the robustness of the primary findings.

In addition, procedure-related factors may influence post-procedural biomarker kinetics and reperfusion outcomes. Although the study was conducted at a single center with experienced operators and a relatively standardized workflow, and we reported key periprocedural procedural characteristics, granular procedural details and structured documentation of rescue vasodilator use were incomplete. This limitation may affect interpretation of immediate post-PCI biomarker changes. Finally, because our primary analyses used pre-procedural biomarkers to predict post-PCI reperfusion outcomes, reverse causation (i.e., impaired reperfusion leading to higher pre-procedural biomarkers) is unlikely. However, post-procedural biomarker trajectories may better reflect a bidirectional vicious cycle between impaired reperfusion and ongoing endothelial injury (5,31); therefore, causal inferences regarding these dynamics should be made cautiously.

This study has several limitations. First, the single-center design and small sample size increase estimation uncertainty and limit subgroup analyses. Second, as an observational study, residual confounding cannot be fully excluded and causality cannot be inferred. Third, some hemodynamic variables as well as intraprocedural medications and procedural details were incompletely captured. Nevertheless, the serial measurements from pre-PCI to immediately post-PCI and 24 hours, together with consistent directions of association across multiple reperfusion endpoints (CSF by CTFC threshold, CTFC as a continuous measure, and TIMI/no-reflow), provide a relatively comprehensive clinical dataset supporting an association between glycocalyx injury and impaired reperfusion.

Conclusions

Peri-procedural elevation of serum SDC-1 and HA is significantly associated with the post-PCI CSF phenomenon in patients with STEMI. Severe glycocalyx degradation spans the entire perioperative period and is critically linked to the pathogenesis of CSF. Higher pre-procedural SDC-1 and HA were independently associated with CSF and may indicate more pronounced baseline glycocalyx injury. The discriminative performance of pre-procedural SDC-1 for CSF was higher than that of HA. Consequently, therapeutic strategies aiming to protect or restore the glycocalyx may represent novel avenues for the prevention and management of post-PCI CSF.

Acknowledgments

We express our heartfelt gratitude to the students and instructors whose guidance was instrumental in preparing this work. We are also indebted to the foundation for its support. In addition, we would like to thank Jinjiang Li for his assistance with language editing and manuscript polishing. We gratefully acknowledge the reviewers for their insightful critiques that improved this manuscript.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-642/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-642/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-642/prf

Funding: This work was supported by Shanxi Provincial Clinical Research Center for Interventional Medicine (No. 202204010501004).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-642/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the First Hospital of Shanxi Medical University (No. KYLL-2025-115). Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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