2.1 Study Design and Population

This study was a single-center, retrospective case–control study conducted at our hospital. This study included 323 patients (aged 25–80 years) with STEMI who underwent PCI at our hospital between October 2017 and June 2023.

2.2 Definitions and Medication Therapy

STEMI was defined according to the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guidelines for the Evaluation and Diagnosis of Chest Pain [18]. CKD was defined based on the National Kidney Foundation K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease [19]. Slow flow was defined as blood flow to the distal end of the occluded vessel taking more than one cardiac cycle or failing to reach the distal vessel end. Nonreflow was defined as the complete disappearance of forward coronary flow after mechanical blockage of the coronary artery was relieved, with no residual stenosis, thrombosis, dissection, or spasm [20]. Renal dysfunction was classified based on estimated glomerular filtration rate (eGFR) as follows: mild renal dysfunction: eGFR ≥ 60 mL/min/1.73 m²; moderate renal dysfunction: 30 ≤ eGFR < 60 mL/min/1.73 m²; severe renal dysfunction: eGFR < 30 mL/min/1.73 m². Drinking history was defined as an average daily alcohol intake greater than 40 g for men and 20 g for women, with a drinking duration of at least 5 years. Elevated Lp(a) levels were defined as > 30 mg/dL.

All patients received statin therapy (either 10 mg atorvastatin or 20 mg rosuvastatin). Patients who exhibited elevated Lp(a) levels (> 30 mg/dL) and failed to achieve LDL-C targets (> 1.4 mmol/L) were evaluated for eligibility for PCSK-9 inhibitor therapy on the first postoperative day. PCSK-9 inhibitor therapy was defined as therapy with either 140 mg evolocumab or 75 mg alirocumab, administered every 2 weeks for a minimum duration of least 6 months.

2.3 Grouping

Patients were divided into two groups: CKD (n = 132) and non-CKD (n = 191). Among patients with CKD, subgroups were defined based on Lp(a) levels: the elevated Lp(a) group (> 30 mg/dL, n = 81) and the normal Lp(a) group (≤ 30 mg/dL, n = 51). In the elevated Lp(a) group, 36 patients received PCSK-9 inhibitor therapy, while 45 did not.

2.4 Study Endpoints

In the subgroup elevated Lp(a) group, patients were followed for 1 year. The primary endpoints included bleeding events, worsening renal function, and major adverse cardio-cerebrovascular events (MACCEs), defined as cardiac death, nonfatal myocardial infarction, nonfatal stroke, readmission for angina, and readmission for heart failure.

2.5 Statistical Methods

Statistical analyses were performed using SPSS version 25.0 (IBM SPSS Statistics, Chicago, USA). Continuous data with a normal or approximately normal distribution were expressed as mean ± SD, and comparisons between groups were conducted using the T-test. For continuous data with a skewed distribution, results were expressed as the median (Q1, Q3), and group comparisons were performed using the Mann–Whitney test. One-way Analysis of variance (ANOVA) was used to assess statistically significant differences among the means of three independent groups. Categorical data were presented as frequencies (%), and comparisons between groups were carried out using the χ² test. Univariate logistic regression analysis was conducted to identify potential predictors of slow flow or no reflow after PCI. Variables with p < 0.05 in the univariate analysis were included in the multivariate logistic regression model to determine independent predictors. Multicollinearity among independent variables was assessed using the variance inflation factor (VIF). A VIF threshold of 10 was used to identify severe multicollinearity. Given the high VIF values observed for total cholesterol (TC) in both the overall AMI cohort and the AMI subgroup with CKD, TC was excluded from the final multivariable regression models to ensure model stability. A two-sided test was applied for all analyses, with a significance level set at α = 0.05, and results were considered statistically significant when p < 0.05.

3.1 Baseline Clinical Characteristics of STEMI Patients Underwent PCI

Baseline clinical characteristics are summarized in Table 1. Compared to the non-CKD group, the CKD group exhibited significantly higher levels of triglyceride (TG) (median 1.57 vs. 1.35 mmol/L, p = 0.022), Lp(a) (median 36.75 vs. 15.90 mg/dL, p = 0.0001), blood glucose (7.20 ± 2.81 vs. 6.27 ± 2.90 mmol/L, p = 0.004), and fibrinogen (3.73 ± 0.90 vs. 2.93 ± 0.71 g/L, p = 0.0001). In contrast, high density lipoprotein cholesterol (HDL-C) levels were significantly lower in the CKD group (1.16 ± 0.33 vs. 1.24 ± 0.32 mmol/L, p = 0.033). Low density lipoprotein cholesterol (LDL-C) levels were comparable between the two groups. The prevalence of coronary slow flow or no reflow after PCI was significantly higher in the CKD group compared to the non-CKD group (28.79% vs. 14.66%, p = 0.002).

3.2 Baseline Clinical Characteristics of PCI Patients With CKD Stratified by Lp(a) Levels

A total of 132 PCI patients with CKD were evaluated: 28 (21.21%) with mild, 62 (46.97%) with moderate, and 42 (31.82%) with severe renal dysfunction. Lp(a) levels increased with worsening renal function (median: 24.60 vs. 32.60 vs. 55.45 mg/dL, p = 0.002). Patients with CKD were accordingly divided into two groups: the elevated Lp(a) group (n = 81) and the normal Lp(a) group (n = 51). Baseline clinical characteristics of patients with CKD (n = 132) stratified by Lp(a) levels are presented in Table 2. No significant differences in age, smoking history, drinking history, hypertension, diabetes, or triglycerides were observed between the groups. At the same time, there was no difference between the two groups in the procedural characteristics of PCI surgery (time from onset of chest pain to culprit vessel patency, culprit vessel, stent mean diameter, total stent length, all p > 0.05). However, the elevated Lp(a) group had higher levels of total cholesterol (TC, median: 4.78 vs. 3.89 mmol/L, p = 0.0001), HDL-C (1.23 ± 0.35 vs. 1.04 ± 0.24 mmol/L, p = 0.0001), LDL-C (3.07 ± 1.24 vs. 2.27 ± 0.77 mmol/L, p = 0.0001), fibrinogen (3.93 ± 0.91 vs. 3.43 ± 0.81 g/L, p = 0.002), and prothrombin activity (PT, 102.42 ± 25.57% vs. 93.78 ± 16.41%, p = 0.019), along with shorter clotting time (INR, 1.01 ± 0.13 vs. 1.05 ± 0.11, p = 0.038). Coronary slow flow or no reflow after PCI were more common in the elevated Lp(a) group than in the normal Lp(a) group (38.27% vs. 13.73%, p = 0.002). Post-PCI blood flow grading was as follows: in the elevated Lp(a) group, TIMI3: 61.73%, slow-TIMI3: 27.16%, TIMI2: 7.41%, TIMI1: 2.47%, TIMI0: 1.23%; in the normal Lp(a) group, TIMI3: 86.27%, slow-TIMI3: 7.84%, TIMI2: 3.92%, TIMI1: 1.96%, TIMI0: 0%.

Additionally, when CKD patients were stratified by renal function levels (eGFR), the prevalence of slow flow or no reflow after PCI were comparable across the groups (mild vs. moderate vs. severe renal dysfunction: 14.3% [4/28] vs. 35.5% [22/62] vs. 28.6% [12/42], p = 0.121).

3.3 Predictive Value of CKD and Lp(a) Levels for Coronary Slow Flow or No Reflow After PCI in STEMI Patients

Risk factors associated with coronary slow flow/no reflow after PCI in the whole STEMI cohort were identified by univariate and multivariate logistic regression models (Table 3). Elevated Lp(a) (OR = 1.725, 95% CI: 0.913–3.259, p = 0.040), LDL-C levels (OR = 1.457, 95% CI: 1.102–1.927, p = 0.008) and blood glucose levels (OR = 1.128, 95% CI: 1.001–1.257, p = 0.048) were determined to be independent risk factors for coronary slow flow/no-reflow after PCI in this STEMI cohort.

Although univariate analysis indicated CKD as a significant factor associated with coronary slow flow/no reflow after PCI (OR = 2.353, 95% CI: 1.357–4.08, p = 0.002), this association was no longer significant in the multivariate model after adjustment (p > 0.05).

3.4 Predictive Value of Lp(a) Levels for Coronary Slow Flow or No Reflow After PCI in STEMI Patients With CKD

Elevated Lp(a) level (> 30 mg/dL) was observed as an independent risk factor for coronary slow flow or no reflow after PCI in STEMI patients with CKD (OR = 2.985, 95% CI: 1.134–7.853, p = 0.027; Table 4 and Figures 1 and 2). However, stratification by renal function level in these CKD patients revealed that renal function level was not a risk factor for coronary slow flow/no reflow after PCI (OR = 1.332, 95% CI: 0.782–2.268, p = 0.291).

3.5 PCSK-9 Inhibitor Therapy and Clinical Outcomes of PCI Patients With CKD and Elevated Lp(a)

Baseline clinical features of STEMI patients with CKD and elevated Lp(a) receiving PCSK-9 inhibitor therapy versus conventional therapy are summarized in Table 5. The general characteristics and biochemical parameters were comparable between the two groups. After 6 months of therapy, the reduction in Lp(a) levels was significantly greater in the PCSK-9 inhibitor therapy group compared to the conventional therapy group (median: −31.75% vs. −13.06%, p = 0.0001).

During 1-year follow-up, the prevalence of MACCEs was significantly lower in the PCSK-9 inhibitors therapy group than in the conventional therapy group (22.2% vs. 51.1%, p = 0.008). Readmission due to angina pectoris was also markedly reduced in the PCSK-9 inhibitors therapy group compared to the conventional therapy groups (5.6% vs. 24.4%, p = 0.031).

In addition, adverse events such as worsening renal function occurred in 5.6% (n = 2) of patients and bleeding in 8.3% (n = 3) in the PCSK-9 inhibitor therapy group, compared to 13.3% (n = 6) and 0% (n = 0), respectively, in the conventional therapy group (all p > 0.05).

At the 12-month follow-up, re-angiography was performed in 27 patients with post-PCI slow flow or no reflow (1 patient died of myocardial infarction, and 3 refused re-angiography), revealed that coronary slow flow was improved in patients receiving PCSK-9 inhibitors compared to those on conventional therapy [57.1% (8/14) vs. 15.4% (2/13), p = 0.025].

4.1 Lp(a) With CKD

Lp(a) levels are primarily determined by genetic factors, but kidney function is one of the few nongenetic factors known to influence plasma Lp(a) levels. Elevated Lp(a) is a hallmark of dyslipidemia specific to renal insufficiency [4]. This effect is particularly pronounced with high molecular weight apolipoproteins (a), providing strong evidence for the role of kidney in Lp(a) catabolism [21]. Renal insufficiency in patients with CKD contributes to elevated Lp(a) levels through a dual mechanism of reduced clearance and increased synthesis, independent of genetic factors [22, 23]. Consistent with previous findings, our results demonstrated significantly higher Lp(a) levels in CKD patients compared to non-CKD patients (median 36.75 vs. 15.90 mg/dL, p = 0.0001). Furthermore, Lp(a) levels increased progressively with worsening renal function (median 24.60 vs. 32.60 vs. 55.45 mg/dL, p = 0.002).

On the other hand, previous studies have shown that high Lp(a) levels are not only a consequence but also a contributing factor to CKD [4]. Lp(a) can promote kidney damage through several mechanisms: (1) Lp(a) contains low-density lipoprotein particles that oxidize upon entering the vascular wall, becoming highly immunogenic and pro-inflammatory oxidized LDL, which can damage renal tissue. (2) The apolipoprotein (a) component of Lp(a), can induce microvascular injury, further impairing renal function [21, 24]. (3) Dysregulation of Lp(a) metabolism can damage the glomeruli and tubulointerstitial structures of the kidney [25]. In summary, the interplay between elevated Lp(a) and CKD exacerbates renal dysfunction and amplifies the risk of cardiovascular events [4].

4.2 CKD and Slow Flow/No Reflow After PCI

Previous studies have shown a significant association between reduced renal function and impaired coronary blood flow reserve [12, 15], with CKD identified as an independent risk factor for coronary slow flow/no reflow [26]. This relationship has been confirmed across varying grades of CKD [15, 27, 28]. Adam et al. demonstrated a marked reduction in coronary flow velocity reserve in patients with chronic renal insufficiency compared to those with normal renal function (2.34 ± 0.4 vs. 3.05 ± 0.3, p = 0.003) [27]. Similarly, Akin and colleagues reported that eGFR was significantly correlated with slow coronary blood flow (OR = 0.972, 95% CI: 0.957–0.987, p < 0.001) [15].

Consistent with prior studies, our findings revealed that slow or no reflow after PCI was significantly more common in the CKD group than in the non-CKD group (28.79% vs. 14.66%, p = 0.002). However, multivariate regression analysis indicated that different grades of renal dysfunction were not independent predictors of slow flow/no reflow after PCI in CKD patients (OR = 1.997, 95% CI: 0.865–4.611, p = 0.105). Prior studies have implicated factors such as preoperative blood glucose, total cholesterol, D-Dimer, and fibrinogen levels no reflow after PCI [29]. In our study, multivariate regression analysis confirmed that elevated Lp(a) and blood glucose remained associated with slow flow of no reflow after PCI in our STEMI cohort. Interestingly, despite disrupted lipid metabolism, LDL-C levels were comparable between the two groups (2.76 ± 1.15 vs. 2.68 ± 1.00 mmol/l, p = 0.489). This finding may be attributed to the complex interplay between lipid metabolism disorders and the inflammatory response in patients with CKD.

4.3 Lp(a) and Slow Flow/No Reflow After PCI

The 2022 EAS Consensus Statement proposes that Lp(a) concentrations > 50 mg/dL are associated with clinically significant increase in cardiovascular risk, with a “grey zone” between 30 and 50 mg/dL [30]. While the 2023 Chinese Lipid Management Guidelines identify Lp(a) levels > 30 mg/dL as increasing the risk of arteriosclerotic coronary artery disease [31]. Moreover, elevated Lp(a) levels have been linked not only to the severity of coronary arterial stenosis, but also to worse clinical outcomes after PCI [32]. In our study, elevated Lp(a) was identified as an independent risk factor for slow flow or no reflow after PCI in patients with chronic renal insufficiency (OR = 2.985, CI: 1.134–7.853, p = 0.027). This aligns with previous evidence suggesting that Lp(a) contributes to endothelial injury [33] and thrombosis [34, 35], mechanisms that could underlie slow flow or no reflow.

Our data demonstrated that patients with elevated Lp(a) levels exhibited enhanced clotting function, as evidenced by higher fibrinogen levels (3.93 ± 0.91 vs. 3.43 ± 0.81 g/L, p = 0.002), increased prothrombin activity (102.42 ± 25.57% vs. 93.78 ± 16.41%, p = 0.019), and shorter clotting times (INR: 1.01 ± 0.13 vs. 1.05 ± 0.11, p = 0.038). We hypothesize that, in CKD patients, the interplay between renal dysfunction and lipid metabolism disorders exacerbates Lp(a) elevation, contributing to both inflammatory responses and endothelial damage. These mechanisms likely facilitate coronary slow flow/no reflow. Additionally, Lp(a) may promote coagulation and thrombosis, further compounding the risk of these events in STEMI patients with CKD following PCI.

4.4 PCSK-9 Inhibitors and Outcomes

PCSK-9 inhibitors effectively reduce residual lipid levels, stabilize atherosclerotic plaques, and improve coronary blood flow and myocardial perfusion [36]. These benefits are supported by clinical trials that demonstrated the efficacy of PCSK-9 inhibitors in significantly reducing LDL-C levels an improving cardiovascular outcomes [37-39]. In our study, PCSK-9 inhibitors were associated with a significant reduction in Lp(a) levels in CKD patients with elevated Lp(a) (−31.75% vs. −13.06%, p = 0.0001) and a lower prevalence of MACCEs over 1 year (22.2% vs. 51.1%, p = 0.008), particularly angina pectoris (8.3% vs. 24.4%, p = 0.031). However, it remains unclear whether these benefits are primarily attributable to Lp(a) reduction or the greater LDL-C reduction.

4.5 PCSK-9 Inhibitors and Slow Flow/No Reflow After PCI

A study by Ji and colleagues involving 120 patients with acute coronary syndrome (ACS) demonstrated that PCSK-9 inhibitors combined with statins significantly improved microcirculation function and coronary blood flow after PCI. At 6 months after PCI, the PCSK-9 inhibitor group had a significantly higher proportion of patients achieving grade 3 coronary flow compared to the control group at 6 months after PCI (98.2% vs. 89.1%, p = 0.04) [40]. Similarly, in our study, at the 12-month follow-up, re-angiography was performed in 27 patients with post-PCI slow flow or no reflow, revealing that revealing improved coronary blood flow in the PCSK-9 inhibitor group compared to the conventional therapy group [57.1% (8/14) vs. 15.4% (2/13), p = 0.025]. However, the primary outcome of coronary blood flow improvement was based on a limited sample of patients undergoing repeat angiography, underscoring the need for further studies with larger cohorts.

Although the mechanisms by which PCSK-9 inhibitors improve coronary blood flow are not fully elucidated, potential associations may include: PCSK-9 inhibitors reduce LDL-C and other residual lipids [36, 41]. (2) Reduced platelet reactivity: Cristina Barale and colleagues observed a reduction in platelet reactivity during a 1-year follow-up of PCSK-9 inhibitor therapy [42]. (3) Enhanced microcirculation function: Combined with statins, PCSK-9 inhibitors improve microvascular function in ACS patients post-PCI [40]. (4) Anti-inflammatory effects and improved endothelial function: PCSK-9 inhibitors mitigate inflammation and enhance endothelial cell function, further supporting coronary blood flow [43]. Further studies are warranted to clarify the specific mechanisms by which PCSK-9 inhibitors improve coronary blood flow, particularly in STEMI patients with CKD.

4.6 Study Limitations

This study has several limitations. First, as a retrospective, observational analysis, it is inherently subject to biases due to unmeasured confounding variables that may affect the results. Second, the single-center design and relatively small sample size limit the generalizability of our findings to broader patient populations. Additionally, the primary outcome of coronary blood flow improvement was based on a small subset of patients who underwent repeat angiography, which underscores the need for larger studies to confirm these results. Moreover, it remains unclear whether the observed clinical benefits are primarily due to Lp(a) reduction or the more significant LDL-C reduction achieved with PCSK-9 inhibitors, necessitating further investigation. To address these limitations, future research should include multicenter studies with larger sample sizes and randomized controlled trials to establish causal relationships and evaluate the long-term effects of Lp(a) reduction and PCSK-9 inhibitor therapy in this patient population.