AIM

Our study aims to elucidate the relationship between an altered lipid panel and the outcomes of stent interventions in patients with peripheral arterial disease.

MATERIAL AND METHODS

Study Design

The study enrolled forty-one patients who underwent bare self-expandable stent implantation for Peripheral Arterial Disease (PAD) between 2020 and 2022. The investigation aimed to assess the correlation between pre-procedural lipid panel status and stent revascularization outcomes. The primary endpoint focused on 6-month stent restenosis, while secondary endpoints included 6-month cardiovascular hospital admission, 6-month restenosis, 6-month percutaneous rates, 6-month surgical revascularization rates, 1-month percutaneous repeated revascularization, 1-month cardiovascular hospital readmission, and 1-month stent thrombosis rates. Roc-Curve analyses were conducted to identify statistically significant cut-off values for 6-month restenosis among serum HDL, LDL, cholesterol, and triglyceride, the lipid panel components. A statistically significant cut-off value of <168.5 mg/dL was determined solely for triglyceride levels. Based on this threshold, patients were categorized into two groups: the control group and the high triglycerides patient group. A comparative analysis was performed between the groups, considering both pre-procedural parameters and post-procedural outcomes.

Ethical Approval

Ethical clearance for this retrospective comparative study was sought from the hospital's clinical trials ethics committee. Following a comprehensive evaluation by the ethics committee, approval was granted with the assigned decision number: "XXX."

Data collection

The database was meticulously constructed utilizing the national database, following the requisite approval from the ethics committee. Only the treating physician, responsible for patient care, gathered anonymized patient data and subsequently transmitted it to the study database. Pre-procedural parameters encompassed age, smoking status, and past medical history including hypertension, diabetes mellitus, ischemic heart disease, chronic heart failure, as well as the utilization of insulin, statins, anticoagulants, and antiplatelet medications. Blood sample values, such as triglyceride, cholesterol, hemoglobin (HB), hematocrit (HCT), and white blood cell (WBC) counts, were also systematically collected. Post-procedural outcome parameters included 1-month cardiovascular condition-related hospital readmission, 1-month stent thrombosis, 1-month percutaneous revascularization, 6-month hospital readmission, 6-month stenosis, 6-month revascularization, and 6-month surgical revascularization rates.

Disease definitions

The primary endpoint of the study focused on the occurrence of in-stent restenosis (ISR), delineated as a diameter stenosis of ≥ 50% within the stent segment or within 5 mm proximal or distal to the stent during follow-up angiography. Diabetes mellitus was identified by a previous diagnosis of DM treated with diet, oral agents, or insulin, or a new diagnosis if fasting blood glucose (FBG) was ≥ 7.0 mmol/L on two occasions during hospitalization. Hypertension was characterized as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg or the use of antihypertensive treatment in the past two weeks. Chronic heart failure was defined by a prior diagnosis involving a combination of physical symptoms and findings, as well as biochemical conditions such as pro-BNP values. The designation of a high serum triglyceride condition was established using our specified cut-off value, exceeding 168.5 serum triglycerides. For the rest of the lipid panel components, statistically significant cut-off values could not be defined.

Lipid Panel Components

In this investigation, the lipid panel consisted of high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and non-fasting triglyceride (TG) levels derived from serum samples obtained in the preprocedural period.

Statistical Analysis

Based on the designated triglyceride cut-off value, our study delineated two distinct groups: the control group comprising 24 patients and the high triglyceride group consisting of 17 patients. To analyze categorical parameters between these groups, the chi-square test was applied, while the F-Anova test was employed for continuous variables. The determination of the cut-off value was accomplished through the roc-curve test. Statistical significance was set at P < 0.05, signifying our threshold for statistical relevance in the study's outcomes.

RESULTS

Lipid panel Cut-off Value for predicting In-stent restenosis six months post-procedure

Our primary objective was to explore the relationship between lipid panel components and revascularization outcomes. To achieve this, we conducted a comprehensive analysis utilizing ROC curve analysis for each lipid panel component. Surprisingly, statistically significant cut-values for cholesterol, HDL, and LDL concerning the 6-month In-Stent Restenosis (IRS) were not identified, except for triglyceride levels. Notably, a triglyceride level below 168.5 demonstrated statistical significance in relation to the risk of IRS (P=0.005), as illustrated in Figure 1.

Demographics and Preprocedural Conditions

The table 1 presents a comparative analysis between the Normal Triglyceride Group and the High Triglyceride Group across preprocedural variables. Notable findings include a significant difference in mean age (64.7 years in the Normal Triglyceride Group vs. 62.7 years in the High Triglyceride Group, p-value = 0.024) and a higher prevalence of Hypertension (HT) in the Normal Triglyceride Group (69.6% vs. 35.3%, p-value = 0.031). Additionally, the High Triglyceride Group exhibits a higher prevalence of Diabetes Mellitus (DM) compared to the Normal Triglyceride Group (58.8% vs. 26.1%, p-value = 0.037). Medication usage, including Insulin Therapy and Statin Therapy, shows trends toward higher percentages in the High Triglyceride Group, although not statistically significant. Laboratory results reveal a substantial difference in Triglyceride levels (122.3 mg/dL in the Normal Triglyceride Group vs. 276.2 mg/dL in the High Triglyceride Group, p-value = 0.000). Other lipid parameters (Cholesterol, HDL, and LDL) and hematological markers (HB, HCT, WBC) did not exhibit statistically significant differences between the two groups.

Short-term Outcomes of Revascularization

Table 2 outlines post-procedural outcomes. In early-term outcomes (30-day), significant differences are observed in cardiovascular condition-related hospital readmission, with a notably higher occurrence in the High Triglyceride Group (29.4% vs. 0.0%, P=0.005, Odds Ratio = 7.7). Stent thrombosis and percutaneous revascularization rates are also significantly elevated in the High Triglyceride Group (23.5% vs. 0.0%, P=0.014, Odds Ratio = 6.0; 17.6% vs. 0.0%, P=0.036, Odds Ratio = 4.4, respectively). For late-term outcomes (6-month), the High Triglyceride Group continues to exhibit higher rates of cardiovascular condition-related hospital readmission (58.8% vs. 30.4%, P=0.073, Odds Ratio = 3.2) and stenosis (64.7% vs. 17.4%, P=0.004, Odds Ratio = 7.9). Revascularization rates, both percutaneous and surgical, also show a tendency to be higher in the High Triglyceride Group, though statistical significance is reached only in the case of percutaneous revascularization (41.2% vs. 17.4%, P=0.096, Odds Ratio = 3.2).

Independent Predictors of Short-term In-Stent Restenosis

The Table 3 presents the results of both univariate and multivariate analyses investigating independent predictors of in-stent restenosis at a six-month follow-up. In the univariate analysis, variables such as smoking (P = 0.927), high triglyceride levels (P = 0.002), diabetes mellitus (P = 0.046), hypertension (P = 0.412), and gender (P = 0.278) were examined. Notably, high triglyceride levels demonstrated a significant association (P = 0.002). The multivariate analysis further refined these findings, with smoking (P = 0.862), high triglyceride levels (P = 0.016), diabetes mellitus (P = 0.199), hypertension (P = 0.927), and gender (P = 0.136) undergoing assessment. The multivariate results reinforced the significance of high triglyceride levels in predicting in-stent restenosis, as reflected by a lower P-value (P = 0.016) and a more specific confidence interval (1.489-45.537).

DISCUSSION AND CONCLUSION

Predictive Value of Lipid Panel in Peripheral Arterial Disease

The escalating utilization of endovascular methods in Peripheral Arterial Disease (PAD) underscores the imperative need to pinpoint factors and potential indicators related to in-stent restenosis and intrastent thrombosis for enhancing the success of treatment. Established factors such as gender, smoking, and diabetes are already recognized contributors to stent stenosis [6-9]. However, insights from studies on coronary and carotid artery stenting reveal that disruption of the lipid panel significantly contributes to the pathophysiology of in-stent restenosis [7,8]. A comprehensive understanding of lipid-related complications is crucial, as evidenced by a study demonstrating an independent association between high lipoprotein levels and post-procedural major extremity adverse events in endovascular therapy for PAD [11]. Further corroborating this, various studies highlight the association of high low-density lipoprotein (LDL) levels with repeated revascularization and in-stent stenosis in PAD [7,11,12]. Moreover, the positive impact of LDL-lowering therapies on In-Stent Restenosis (ISR) outcomes has been documented [13]. In our study, distinctive findings emerged, with only high triglyceride levels significantly associated with 6-month in-stent restenosis among the lipid panel elements. This aligns with the observations in the carotid artery disease study by Miura [8], accentuating the importance of triglyceride levels as a predictive factor in endovascular interventions [8]. These nuanced insights, grounded in a robust body of literature, contribute to a more comprehensive understanding of factors influencing in-stent restenosis in PAD.

High Triglyceride Level association with In-Stent Restenosis in Peripheral Arterial Disease

Peripheral Arterial Disease (PAD), rooted in atherosclerosis, is profoundly influenced by lipid abnormalities, constituting significant risk factors. Elevated low-density lipoprotein (LDL) cholesterol reduced high-density lipoprotein (HDL) cholesterol, and increased triglyceride levels have been identified as key contributors to PAD risk. Furthermore, advancing age, high blood pressure, heightened homocysteine levels, raised lipoprotein (a), increased fibrinogen, and heightened blood viscosity are also recognized risk factors for PAD [14,15]. A specific link between plasma lipoproteins and the occurrence of in-stent restenosis in the superficial femoral artery (SFA) among PAD patients has been illuminated through research. Gary and colleagues conducted a comprehensive study involving 114 PAD patients who underwent stent implantation in the SFA. Lipoprotein levels were assessed before the procedure and during follow-up visits at 6- and 12-months post-procedure. Restenosis, defined by reduced blood flow through the stented artery, was evaluated using ultrasound imaging. The findings demonstrated a notable association between elevated LDL cholesterol levels and an increased likelihood of restenosis. For every 10 mg/dL rise in LDL cholesterol, the risk of restenosis surged by 31%. Conversely, patients with elevated HDL cholesterol levels exhibited a diminished risk of restenosis, with a 35% risk reduction for every 10 mg/dL increase in HDL cholesterol. The study emphasizes the pivotal role of managing lipid levels in PAD patients undergoing SFA stent implantation and underscores how alterations in the lipid profile can contribute to restenosis development after SFA stenting. Lifestyle modifications, including dietary changes and exercise, along with medication management, are proposed as strategies to mitigate the risk of restenosis and enhance overall cardiovascular health [16].

High Triglyceride Level association with In-Stent Thrombosis in Peripheral Arterial Disease

Recent literature has shed light on the pivotal role of triglyceride levels in the development of in-stent thrombosis and restenosis in patients with Peripheral Arterial Disease (PAD) undergoing stenting procedures. In a study led by Kim et al., involving 353 PAD patients undergoing stenting procedures with a median follow-up of 26 months, it was observed that individuals with triglyceride levels surpassing 150 mg/dL exhibited a significantly heightened likelihood of experiencing in-stent thrombosis. Notably, triglyceride levels emerged as a stronger predictor of in-stent thrombosis than established risk factors such as diabetes, smoking, and high blood pressure. These findings underscore the potential significance of high triglyceride levels as a distinct risk factor for in-stent thrombosis in PAD patients, advocating for more assertive lipid-lowering therapies to mitigate this complication [17]. Additionally, Matsushita et al. delved into the association between elevated triglyceride levels and the risk of in-stent restenosis and target vessel revascularization in PAD patients undergoing femoropopliteal artery stenting. Examining 246 patients with a median follow-up of 27 months, the study revealed that individuals with triglyceride levels exceeding 150 mg/dL faced an elevated risk of in-stent restenosis and necessitated target vessel revascularization. Elevated LDL cholesterol levels were also linked to an increased risk of in-stent restenosis, though not target vessel revascularization. These findings highlight the potential role of high triglyceride levels as a critical risk factor for in-stent restenosis and target vessel revascularization in femoropopliteal artery stenting, emphasizing the potential need for more aggressive lipid-lowering therapies in this patient cohort [18].

Finally, Wu [19] explored the correlation between triglyceride levels and in-stent restenosis in PAD patients undergoing percutaneous transluminal angioplasty (PTA). Analyzing 335 patients with a median follow-up of 36 months, the study revealed that patients with triglyceride levels surpassing 150 mg/dL faced a significantly increased risk of in-stent restenosis after PTA. Although elevated LDL cholesterol levels were also associated with an increased risk of in-stent restenosis, the association did not reach statistical significance. These findings suggest that high triglyceride levels may represent a crucial risk factor for in-stent restenosis in PAD patients undergoing PTA, prompting consideration of more aggressive lipid-lowering therapies to reduce this complication risk [19]. Our study acknowledges significant limitations, notably the constrained cohort size and the retrospective design, which necessitate caution in extrapolating our findings. The inherent constraints in the study's scope and methodology emphasize the need for further investigations. To comprehensively elucidate the association between high triglyceride levels and Peripheral Arterial Disease (PAD), as well as to discern the most efficacious treatment strategies for patients undergoing revascularization, we advocate for future multicenter prospective research studies. These endeavors are crucial for expanding the understanding of the intricate dynamics involved and for guiding the development of more targeted and effective interventions in the realm of PAD management. The collaborative efforts of a broader research community are imperative to address the complexities of this association and to enhance the translational impact of our findings on clinical practice.

In summary, endovascular therapy stands as a robust choice for revascularizing lower limb arteries in Peripheral Arterial Disease (PAD). Elevated triglyceride levels observed in the preprocedural phase may serve as a potential indicator for early stent stenosis, offering valuable insights to vascular intervention practitioners concerning the risk of stent thrombosis. The validation of our study's findings calls for the implementation of multicenter prospective studies with extensive participation. The collaborative efforts in large-scale studies are imperative to confirm and further refine our observations, contributing to a more comprehensive understanding of the role of triglyceride levels in guiding optimal strategies for endovascular interventions in PAD.