2023 年 30 巻 11 号 p. 1612-1621
Aim: Adverse limb events after endovascular therapy (EVT) are a major concern. This study aimed to investigate the relationship between serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a potentially potent indicator of atherosclerosis, and clinical outcomes after EVT in patients with lower extremity arterial disease (LEAD).
Methods: A total of 208 LEAD patients who underwent EVT and MDA-LDL measurements were retrospectively analyzed. Those with chronic limb-threatening ischemia (CLTI) were included in the CLTI subgroup (n=106). Patients were further categorized into the High or Low MDA-LDL groups according to the cut-off value calculated by receiver operating characteristic analysis. Major adverse limb events (MALE), a composite of cardiovascular death, limb-related death, major amputation, and target-limb revascularization, were evaluated.
Results: MALE occurred in 73 (35%) patients. The median follow-up interval was 17.4 months. The MDA-LDL cut-off values were 100.5 U/L (area under the curve [AUC] 0.651) in the overall population and 98.0 U/L (AUC 0.724) in the CLTI subgroup. Overall, the High MDA-LDL group showed significantly higher total cholesterol (189.7±37.5 mg/dL vs. 159.3±32.0 mg/dL, p＜0.01), low-density lipoprotein cholesterol (114.3±29.7 mg/dL vs. 87.3±25.3 mg/dL, p＜0.01), and triglyceride (166.9±91.1 mg/dL vs. 115.8±52.3 mg/dL, p＜0.01) than the Low MDA-LDL group. Multivariate Cox regression analyses revealed that MDA-LDL and C-reactive protein were independent predictors of MALE. In the CLTI subgroup, MDA-LDL was an independent predictor of MALE. The High MDA-LDL group showed worse MALE-free survival rates than the Low MDA-LDL group in overall (p＜0.01) and in the CLTI subgroup (p=0.01).
Conclusions: Serum MDA-LDL level was associated with MALE after EVT.
Endovascular therapy (EVT) has been established as a standard treatment for lower extremity arterial disease (LEAD) following the development of procedural techniques, devices, and perioperative medications1). Recent clinical studies have shown favorable long-term clinical outcomes after EVT2, 3). However, some patients experience post-EVT limb events such as target limb revascularization at various rates, depending on existing comorbidities and clinical settings4-6). Notably, patients with chronic limb-threatening ischemia (CLTI) have high amputation and mortality rates after revascularization6). Therefore, it is important to stratify at-risk patients and optimize treatment after EVT.
The oxidative modification of low-density lipoprotein (LDL) plays a key role in the formation and acceleration of atherosclerosis7). Malondialdehyde-modified low-density lipoprotein (MDA-LDL), an epitope of oxidized LDL, has been reported to be a predictive marker of coronary artery disease (CAD) severity8), progression9), and adverse cardiac events after percutaneous coronary intervention10). However, the effect of serum MDA-LDL level on clinical outcomes after EVT in patients with LEAD has not yet been clarified.
This study aimed to investigate the relationship between serum MDA-LDL level and major adverse limb events (MALE) after EVT.
This retrospective observational single-center study was conducted in Japan. Between January 2011 and August 2021, a total of 337 patients with LEAD underwent elective EVT at our institute. Of these, 216 patients with suspected CAD underwent serum MDA-LDL measurement before EVT. After excluding patients lacking follow-up data (n=8), 208 patients were included in the study. Among them, patients who underwent EVT for CLTI, defined as LEAD complicated by ischemic rest pain, gangrene, or ulceration for ＞2 weeks, were included in the CLTI subgroup (n=106). The research protocol was approved by the Nagoya City University Graduate School of Medical Sciences and Nagoya City University Hospital Institutional Review Board (reference number:60-22-0037). The requirement for written informed consent was waived due to the retrospective nature of the study design. All procedures involving human participants were performed in accordance with the ethical standards of the Institutional Research Committee and the Declaration of Helsinki.
3.2. Patient Characteristics, Blood Sampling, and MDA-LDL MeasurementHypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medication. Dyslipidemia was defined as serum LDL cholesterol (LDL-C) ≥ 140 mg/dL, high-density lipoprotein cholesterol (HDL-C) ＜40 mg/dL, triglyceride (TG) ≥ 150 mg/dL, or current use of lipid-lowering medication. Diabetes mellitus (DM) was defined as fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c (HbA1c) level ≥ 6.5%, or current use of diabetic medication. Chronic kidney disease (CKD) was defined as proteinuria or an estimated glomerular filtration rate ＜60 mL/min/1.73 m2.
Venous blood samples were drawn immediately before EVT and after patients had fasted overnight. Serum MDA-LDL level was measured using an enzyme-linked immunosorbent assay kit (Sekisui Medical Co., Tokyo, Japan) as previously reported11). Briefly, a sample was diluted 2,000-fold in a buffer containing 3.5mM sodium dodecyl sulfate. Duplicate 100 µL aliquots of samples were added to the wells of plates coated with a monoclonal antibody against MDA-LDL (ML25). Next, β-galactosidase-conjugated monoclonal antibody targeting apoB (AB16) was added. After incubation for 1 h at room temperature, o-nitrophenyl galactopyranoside was added. After 2 h, the reaction was interrupted by adding 100 µL of a 0.2 mol/L sodium carbonate (pH 12) solution. Absorbance was mesasured at 415 nm using a microplate reader. We tentatively defined 1 U/L MDA-LDL as the absorbance at a primary standard concentration of 1 mg/L. A calibration curve was generated by diluting the reference serum as a secondary standard from 300-to 9,600-fold with buffer and calculating the amount of MDA-LDL in the samples. Serum LDL-C levels were determined using a direct homogenous assay (Kyowa Medex Co., Tokyo, Japan)12). Other parameters, including total cholesterol (TC), HDL-C, TG, C-reactive protein (CRP), and HbA1c, were measured using standard laboratory procedures.
3.3. EVT ProcedureAll the patients were pretreated with aspirin and/or clopidogrel. EVT was performed using standard techniques with an initial bolus of 5,000 units of unfractionated heparin. The procedural strategy and the use of intravascular ultrasound were left to the discretion of the operator. Nitinol stent implantation was used as first-line treatment for the iliac artery and as a bail-out strategy for the femoral artery.
3.4. Clinical Follow-up and Definition of Major Adverse Limb EventsWe established multidisciplinary vascular teams to make decisions regarding patient management before EVT. The team provided exercise therapy, wound care, adapted footwear, pain control, and treatment for concomitant infections. The vascular team discussed and determined the indications for revascularization and amputation. The attending physicians decided on the type and duration of antiplatelet therapy according to the patient’s clinical background. Lipid-lowering therapy, mainly with statins, was used to prevent LEAD progression according to the Japan Atherosclerosis Society Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in 2012 and 2017 13, 14). Antihypertensive and antidiabetic agents were prescribed at the discretion of the attending physician according to age and other comorbidities of the patients. Smoking cessation, a healthy diet, maintenance of a healthy weight, and physical activity according to the patient’s exercise capacity were recommended for each patient.
The patients were followed up for clinical outcomes by reviewing their medical records or telephone interviews. MALE was defined as a composite of cardiovascular death, limb-related death, major amputation, and target limb revascularization (TLR). Cardiovascular death was defined as death due to myocardial or cerebral infarction, other vascular causes, heart failure, or documented sudden cardiac death. Limb-related death was defined as death due to a medical complication related to the target limb. Major amputation was defined as any amputation above the ankle. TLR was defined as surgical or endovascular revascularization of the EVT target limb.
3.5. Statistical AnalysisContinuous variables were compared using Student’s t-test or the Mann-Whitney U test, as appropriate. Chi-squared and Fisher’s exact tests were used to compare categorical variables. Receiver operating characteristic (ROC) curve analysis was used to assess the potential of MDA-LDL in predicting MALE and to calculate the MDA-LDL cut-off value that categorized patients into High or Low MDA-LDL groups. Cox regression analysis was performed to identify potential predictors of MALE. The covariates in the univariate analysis for the overall population were age, male sex, hypertension, dyslipidemia, DM, CKD, hemodialysis, prior EVT history of the target lesion, MDA-LDL, TC, LDL-C, HDL-C, TG, HbA1c, CRP, below-the-knee (BK) lesion, CLTI, Rutherford classification 5/6 (R-5/6)15), TASC II classification C/D (TASC II C/D)16), and ankle-brachial index (ABI) after EVT. The variables included in the multivariate analysis for the overall population were as follows: DM, hemodialysis, MDA-LDL, CRP, CLTI, TASC II C/D, and prior EVT history of the target lesion (model 1); CKD, BK lesion, MDA-LDL, LDL-C, CRP, HbA1c, and R-5/6 (model 2); age, male sex, MDA-LDL, HDL-C, TG, CRP, and ABI after EVT (model 3). The covariates in the univariate analysis for the CLTI subgroup were age, male sex, hypertension, dyslipidemia, DM, CKD, hemodialysis, prior EVT history of the target lesion, MDA-LDL, TC, LDL-C, HDL-C, TG, HbA1c, CRP, BK lesion, R-5/6, TASC II C/D, and ABI after EVT. The variables included in the multivariate analysis for the CLTI subgroup were as follows: DM, hemodialysis, MDA-LDL, CRP, TASC II C/D, and prior EVT history of the target lesion (model 1); CKD, BK lesion, MDA-LDL, LDL-C, HbA1c, and R-5/6 (model 2); age, male sex, MDA-LDL, HDL-C, TG, and ABI after EVT (model 3). The MALE-free survival curves were generated using Kaplan–Meier estimates, and the log-rank test was used to evaluate the difference between the MALE-free survival curves of each group. Statistical significance was set at p＜0.05. All statistical analyses were performed using IBM SPSS Statistics v26 (IBM Corp., Armonk, NY, USA).
MALE was detected in 73 (35%) patients during the median follow-up interval of 17.4 (interquartile range 5.6–49.1) months. In the CLTI subgroup, MALE occurred in 60 (57%) patients. In the analysis of the ROC curve, MDA-LDL showed an area under the curve of 0.651 in the overall population and 0.724 in the CLTI subgroup (Fig.1). The MDA-LDL cut-off values for predicting MALE were 100.5 U/L (sensitivity 0.67, specificity 0.61) in the overall population and 98.0 U/L (sensitivity 0.70, specificity 0.67) in the CLTI subgroup. According to these cut-off values, patients were further categorized into High or Low MDA-LDL groups for each population (overall and CLTI). The clinical, biochemical, and procedural data of patients according to the MDA-LDL categories in the overall population are summarized in Table 1. Regarding the clinical parameters, no significant differences were observed between the two groups. In the biochemical data, the High MDA-LDL group had significantly higher TC, LDL-C, and TG levels, and although not statistically significant, higher HbA1c and lower HDL-C levels than the Low MDA-LDL group. Limb, target lesion, and procedure characteristics were similar between the two groups.
AUC: area under the curve
| Variables | Overall | High MDA-LDL (≥ 100.5 U/L) | Low MDA-LDL (＜100.5 U/L) | p value |
|---|---|---|---|---|
| Number of patients | 208 | 102 | 106 | |
| Age (years) | 73.5±9.3 | 73.5±8.5 | 73.6±9.9 | 0.96 |
| Male sex | 148 (71%) | 70 (69%) | 78 (74%) | 0.43 |
| BMI (kg/m2) | 22.4±3.6 | 22.8±3.8 | 22.1±3.4 | 0.15 |
| Hypertension | 174 (84%) | 86 (84%) | 88 (83%) | 0.80 |
| Dyslipidemia | 145 (70%) | 73 (72%) | 72 (68%) | 0.57 |
| Diabetes mellitus | 135 (65%) | 68 (67%) | 67 (63%) | 0.60 |
| CKD | 123 (59%) | 60 (59%) | 63 (59%) | 0.93 |
| Hemodialysis | 54 (26%) | 24 (24%) | 30 (28%) | 0.43 |
| Current smoker | 39 (19%) | 20 (20%) | 19 (18%) | 0.76 |
| Statin on admission | 114 (55%) | 53 (52%) | 61 (58%) | 0.42 |
| Biochemical data | ||||
| MDA-LDL (U/L) | 108.5±41.7 | 139.5±34.8 | 78.6±16.1 | ＜0.01 |
| TC (mg/dL) | 174.2±39.1 | 189.7±37.5 | 159.3±32.0 | ＜0.01 |
| LDL-C (mg/dL) | 100.5±32.0 | 114.3±29.7 | 87.3±25.3 | ＜0.01 |
| HDL-C (mg/dL) | 49.6±15.4 | 48.0±14.3 | 51.3±16.2 | 0.12 |
| TG (mg/dL) | 140.8±78.1 | 166.9±91.1 | 115.8±52.3 | ＜0.01 |
| CRP (mg/dL) | 0.29 (0.08-0.73) | 0.32 (0.09-0.61) | 0.26 (0.07-0.83) | 0.48 |
| HbA1c (%) | 6.5±1.1 | 6.6±1.2 | 6.4±1.0 | 0.09 |
| ABI | ||||
| ABI before EVT | 0.56±0.28 | 0.59±0.29 | 0.53±0.29 | 0.13 |
| ABI after EVT | 0.90±0.20 | 0.92±0.19 | 0.89±0.20 | 0.35 |
| ⊿ABI | 0.34±0.24 | 0.33±0.25 | 0.37±0.23 | 0.28 |
| Indication of EVT | ||||
| Claudication | 102 (49%) | 47 (48%) | 55 (50%) | |
| CLTI | 106 (51%) | 55 (52%) | 51 (50%) | 0.40 |
| Rutherford classification | ||||
| R-0 | 3 (1%) | 2 (2%) | 1 (1%) | |
| R-1 | 10 (5%) | 4 (4%) | 6 (6%) | |
| R-2 | 46 (22%) | 26 (25%) | 20 (19%) | |
| R-3 | 43 (21%) | 15 (15%) | 28 (26%) | |
| R-4 | 20 (10%) | 12 (12%) | 8 (8%) | |
| R-5 | 82 (39%) | 40 (39%) | 42 (40%) | |
| R-6 | 4 (2%) | 3 (3%) | 1 (1%) | 0.30 |
| Prior EVT history of the target lesion | 15 (7%) | 7 (7%) | 8 (8%) | 0.85 |
| Lesion location | ||||
| Above knee | 168 (81%) | 79 (77%) | 89 (84%) | |
| Below knee | 40 (19%) | 23 (23%) | 17 (16%) | 0.23 |
| TASC II classification | ||||
| A | 56 (27%) | 27 (26%) | 28 (26%) | |
| B | 81 (39%) | 36 (35%) | 44 (42%) | |
| C | 53 (25%) | 28 (27%) | 27 (25%) | |
| D | 18 (9%) | 11 (11%) | 7 (7%) | 0.65 |
| Stent implantation | 104 (50%) | 50 (49%) | 54 (51%) | 0.78 |
Data are expressed as n (%), mean±standard deviation, or median (interquartile range).
BMI, body mass index; CKD, chronic kidney disease; MDA-LDL, malondialdehyde-modified low-density lipoprotein; TC, total cholesterol; LDL- C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; CRP, C-reactive protein; HbA1c, hemoglobin A1c; ABI, ankle brachial index; EVT, endovascular therapy; CLTI, chronic limb-threatening ischemia
The predictors of MALE in the overall population are summarized in Table 2. Univariate Cox regression analysis revealed that MDA-LDL, CRP, CLTI, R-5/6, BK lesion, DM, hemodialysis, CKD, and TASC II C/D were significantly associated with MALE. In the multivariate models, the independent predictors were as follows: MDA-LDL, CRP, CLTI, and DM (model 1); MDA-LDL, CRP, R-5/6, and BK lesion (model 2); MDA-LDL and CRP (model 3). The predictors of MALE in the CLTI subgroup are summarized in Table 3. Univariate Cox regression analysis revealed that MDA-LDL was significantly associated with MALE, while in the multivariate analysis, MDA-LDL was the only independent predictor of MALE regardless of the model. Table 4 shows a summary of all clinical events during the follow-up period and their relationships with the MDA-LDL categories. In both the overall population and the CLTI subgroup, the MALE and TLR rates were significantly higher in the High MDA-LDL group than in the Low MDA-LDL group. Although the difference was not statistically significant, the High MDA-LDL group had higher rates of cardiovascular death, limb-related death, and major amputation. During follow-up, the High MDA-LDL group showed a significantly lower MALE-free survival rate than the Low MDA-LDL group in both the overall population and the CLTI subgroup (Fig.2).
| Variables | Univariate analysis | Multivariate analysis | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | ||||||||||
| HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | |
| MDA-LDL, per 10 U/L | 1.07 | 1.02-1.13 | ＜0.01 | 1.08 | 1.02-1.14 | ＜0.01 | 1.11 | 1.03-1.20 | ＜0.01 | 1.12 | 1.05-1.19 | ＜0.01 |
| CRP, per 1 mg/dL | 1.36 | 1.20-1.53 | ＜0.01 | 1.16 | 1.01-1.33 | 0.03 | 1.21 | 1.05-1.39 | ＜0.01 | 1.42 | 1.22-1.66 | ＜0.01 |
| CLTI | 8.48 | 4.62-15.58 | ＜0.01 | 5.90 | 3.01-11.54 | ＜0.01 | - | - | - | - | - | - |
| Rutherford classification 5/6 | 5.40 | 3.27-8.92 | ＜0.01 | - | - | - | 3.69 | 2.02-6.74 | ＜0.01 | - | - | - |
| BK lesion | 3.95 | 2.37-6.57 | ＜0.01 | - | - | - | 1.88 | 1.05-3.35 | 0.03 | - | - | - |
| Diabetes mellitus | 3.57 | 1.88-6.79 | ＜0.01 | 2.01 | 1.03-3.96 | 0.04 | - | - | - | - | - | - |
| Hemodialysis | 3.56 | 2.21-5.74 | ＜0.01 | 1.34 | 0.80-2.25 | 0.27 | - | - | - | - | - | - |
| CKD | 1.77 | 1.08-2.90 | 0.02 | - | - | - | 1.09 | 0.62-1.91 | 0.77 | - | - | - |
| TASC II classification C/D | 1.67 | 1.04-2.69 | 0.04 | 1.47 | 0.90-2.42 | 0.12 | - | - | - | - | - | - |
| HbA1c, per 1 % | 1.21 | 1.00-1.47 | 0.06 | - | - | - | 1.10 | 0.90-1.34 | 0.38 | - | - | - |
| HDL-C, per 10 mg/dL | 0.89 | 0.76-1.05 | 0.16 | - | - | - | - | - | - | 0.89 | 0.73-1.07 | 0.21 |
| TG, per 10 mg/dL | 0.98 | 0.95-1.01 | 0.23 | - | - | - | - | - | - | 0.94 | 0.90-1.01 | 0.07 |
| LDL-C, per 10 mg/dL | 1.03 | 0.96-1.12 | 0.41 | - | - | - | 0.94 | 0.84-1.05 | 0.26 | - | - | - |
| Prior EVT history of the target lesion | 1.36 | 0.59-3.14 | 0.47 | 0.93 | 0.40-2.20 | 0.87 | - | - | - | - | - | - |
| Age, per 1 year | 1.01 | 0.98-1.03 | 0.56 | - | - | - | - | - | - | 1.01 | 0.98-1.04 | 0.60 |
| Hypertension | 1.17 | 0.60-2.28 | 0.65 | - | - | - | - | - | - | - | - | - |
| ABI after EVT, per 0.10 | 1.03 | 0.90-1.17 | 0.68 | - | - | - | - | - | - | 1.13 | 0.99-1.30 | 0.08 |
| Male sex | 0.92 | 0.55-1.55 | 0.76 | - | - | - | - | - | - | 0.90 | 0.51-1.59 | 0.71 |
| TC, per 10 mg/dL | 1.00 | 0.93-1.06 | 0.88 | - | - | - | - | - | - | - | - | - |
| Dyslipidemia | 0.98 | 0.59-1.63 | 0.95 | - | - | - | - | - | - | - | - | - |
MDA-LDL, malondialdehyde-modified low-density lipoprotein; CRP, C-reactive protein; CLTI, chronic limb-threatening ischemia; BK, below knee; CKD, chronic kidney disease; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; EVT, endovascular therapy; ABI, ankle brachial index; TC, total cholesterol; HR, hazard ratio; CI, confidence interval
| Variables | Univariate analysis | Multivariate analysis | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | ||||||||||
| HR | 95%CI | p value | HR | 95%CI | P value | HR | 95%CI | p value | HR | 95%CI | p value | |
| MDA-LDL, per 10 U/L | 1.07 | 1.00-1.13 | 0.03 | 1.07 | 1.00-1.14 | 0.03 | 1.10 | 1.01-1.21 | 0.03 | 1.08 | 1.00-1.17 | 0.04 |
| CRP, per 1 mg/dL | 1.14 | 0.99-1.32 | 0.07 | 1.14 | 0.99-1.31 | 0.08 | - | - | - | - | - | - |
| BK lesion | 1.55 | 0.91-2.64 | 0.11 | - | - | - | 1.6 | 0.91-2.82 | 0.10 | - | - | - |
| Hemodialysis | 1.52 | 0.91-2.53 | 0.11 | 1.36 | 0.80-2.32 | 0.26 | - | - | - | - | - | - |
| Diabetes mellitus | 1.75 | 0.86-3.56 | 0.12 | 1.56 | 0.74-3.28 | 0.24 | - | - | - | - | - | - |
| HbA1c, per 1 % | 1.19 | 0.96-1.50 | 0.12 | - | - | - | 1.12 | 0.89-1.41 | 0.31 | - | - | - |
| TASC II classification C/D | 1.38 | 0.81-2.35 | 0.24 | 1.48 | 0.86-2.55 | 0.16 | - | - | - | - | - | - |
| ABI after EVT | 1.07 | 0.95-1.22 | 0.27 | - | - | - | - | - | - | 1.09 | 0.95-1.24 | 0.21 |
| TC, per 10 mg/dL | 1.04 | 0.97-1.12 | 0.30 | - | - | - | - | - | - | - | - | - |
| Age, per 1 year | 1.01 | 0.99-1.04 | 0.34 | - | - | - | - | - | - | 1.02 | 0.99-1.05 | 0.28 |
| LDL-C, per 10 mg/dL | 1.04 | 0.96-1.13 | 0.36 | - | - | - | 0.95 | 0.84-1.08 | 0.43 | - | - | - |
| Dyslipidemia | 1.28 | 0.75-2.20 | 0.37 | - | - | - | - | - | - | - | - | - |
| CKD | 1.23 | 0.68-2.20 | 0.50 | - | - | - | 0.95 | 0.50-1.83 | 0.88 | - | - | - |
| Rutherford classification 5/6 | 1.25 | 0.64-2.47 | 0.52 | - | - | - | 1.11 | 0.54-2.26 | 0.78 | - | - | - |
| TG, per 10 mg/dL | 1.01 | 0.98-1.04 | 0.55 | - | - | - | - | - | - | 0.99 | 0.95-1.04 | 0.77 |
| Hypertension | 1.23 | 0.58-2.60 | 0.59 | - | - | - | - | - | - | - | - | - |
| Male sex | 0.92 | 0.52-1.62 | 0.77 | - | - | - | - | - | - | 0.93 | 0.50-1.73 | 0.83 |
| Prior EVT history of the target lesion | 1.02 | 0.41-2.55 | 0.97 | 0.89 | 0.35-2.29 | 0.81 | - | - | - | - | - | - |
| HDL-C, per 10 mg/dL | 1.00 | 0.84-1.20 | 0.99 | - | - | - | - | - | - | 1.00 | 0.81-1.22 | 0.97 |
MDA-LDL, malondialdehyde-modified low-density lipoprotein; CRP, C-reactive protein; BK, below knee; HbA1c, hemoglobin A1c; ABI, ankle brachial index; EVT, endovascular therapy; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; CKD, chronic kidney disease; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; CI, confidence interval
| Outcome | Overall | CLTI | ||||
|---|---|---|---|---|---|---|
| High MDA-LDL (≥ 100.5 U/L) | Low MDA-LDL (＜100.5 U/L) | p value | High MDA-LDL (≥ 98 U/L) | Low MDA-LDL (＜98 U/L) | p value | |
| Number of patients | 102 | 106 | 57 | 49 | ||
| MALE | 49 (48%) | 24 (23%) | ＜0.01 | 42 (74%) | 18 (37%) | ＜0.01 |
| Cardiovascular death | 9 (9%) | 6 (6%) | 0.38 | 8 (14%) | 5 (10%) | 0.55 |
| Limb-related death | 7 (7%) | 2 (2%) | 0.08 | 7 (12%) | 2 (4%) | 0.13 |
| Major amputation | 9 (9%) | 4 (4%) | 0.13 | 10 (18%) | 3 (6%) | 0.07 |
| TLR | 33 (32%) | 16 (15%) | ＜0.01 | 26 (46%) | 12 (24%) | 0.02 |
Data are expressed as n (%). MALE, major adverse limb events; TLR, target limb revascularization; CLTI, chronic limb-threatening ischemia; MDA-LDL, malondialdehyde-modified low-density lipoprotein
Major adverse limb events (MALE)-free survival curves after endovascular therapy according to malondialdehyde-modified low-density lipoprotein (MDA-LDL) categories in the overall population (A) and in the chronic limb-threatening ischemia subgroup (B)
This study aimed to investigate the prognostic impact of MDA-LDL after EVT in patients with LEAD. Our main finding was that serum MDA-LDL level before the procedure was significantly associated with MALE after EVT, as was CRP, an established marker of inflammation. Furthermore, among patients with CLTI, MDA-LDL remained an independent predictor of MALE.
5.1. Adverse Limb Events after EVT in Daily Clinical PracticeDespite the development of EVT and medical therapy, adverse limb events can occur and remain a significant problem in patients with LEAD1). Refractory intermittent claudication, unhealing wounds, and repeated EVT may reduce the quality of life of these patients. Furthermore, major limb amputation causes social disability, psychological disorders, and high mortality1, 17). A recent large clinical study showed over 10% risk of MALE hospitalization within 1 year after EVT18). In our study, despite multidisciplinary therapy, the incidence of MALE continuously increased to 35% over 7 years. Patients who experience MALE after EVT are at risk of limb amputation, stroke, myocardial infarction, and cardiovascular death19). Therefore, preventing MALE by identifying high-risk patients and optimizing multidisciplinary care are clinically important. Previous studies have reported the association of CRP, DM, and CKD with post-procedural adverse limb events5, 18). However, useful clinical markers for predicting MALE after EVT have not yet been established.
5.2. MDA-LDL as a Predictor of MALE after EVT and the Potential PathophysiologyAlthough the impact of MDA-LDL on CAD has been recognized, its association with LEAD has not been highlighted. Considering its proatherogenic effect, we hypothesized that serum MDA-LDL level could exacerbate LEAD. Although a previous report focused on the association between the pre- and post-procedure MDA-LDL ratio and the prognosis of EVT20), the impact of MDA-LDL on clinical outcomes after EVT, especially in the CLTI subset, remains unclear. Our study showed that serum MDA-LDL level was significantly associated with MALE. During the follow-up period, the High MDA-LDL group experienced MALE more frequently than did the Low MDA-LDL group, and this difference was more prominent in the CLTI subgroup. These results indicate the potential of MDA-LDL as a novel marker to predict limb events after EVT.
We speculated that there could be two underlying mechanisms associating high serum MDA-LDL level with post-EVT limb events. First, atherosclerotic progression can lead to limb ischemia. Oxidized LDL, which induces cholesterol deposition, form cell formation, and various inflammatory activities7, 21), is associated with the initiation and acceleration of multi-arterial atherosclerosis9, 22). In our study, considering the high TLR rate in the High MDA-LDL group, MALE could have been caused by recurrent limb ischemia due to high MDA-LDL-induced atherosclerotic development in the lower extremity arteries. Another plausible mechanism is microvascular dysfunction (MVD). Oxidized LDL can lead to cutaneous MVD23) and aggravate CLTI by deteriorating endothelial function and reducing endothelium-derived vasodilators24). In fact, the major amputation rate tended to be higher in the High MDA-LDL group in our study.
The interaction between oxidative stress and inflammation can influence atherosclerosis progression, endothelial dysfunction, increased oxygen demand, and tissue necrosis24, 25). Although it is difficult to quantify in vivo oxidative stress in clinical practice, we focused on MDA-LDL as a potential alternative marker of oxidative stress. We showed that increased levels of MDA-LDL and CRP were independent predictors of MALE, supporting the hypothesis that exposure to oxidative stress and inflammation is a key step in exacerbating LEAD.
5.3. Clinical ImplicationThe clinical implication of this study is that MDA-LDL may be a useful marker for risk stratification after EVT. High-risk patients can be identified in advance by evaluating MDA-LDL before EVT, and postoperative multidisciplinary treatment can be intensified. Although our findings are hypothesis-generating and larger prospective studies are required to confirm the effectiveness of MDA-LDL-lowering therapy and MDA-LDL-guided pharmacotherapy, high MDA-LDL may be a target for treatment in patients after EVT.
5.4. LimitationThis study has several limitations. First, it was a retrospective observational study with a relatively small number of patients recruited from a single center in Japan. Furthermore, only patients with suspected CAD underwent MDA-LDL measurement at the discretion of the attending physicians. Therefore, the study population was biased. Further prospective multicenter studies with larger sample sizes are required. Second, the follow-up period after EVT differed greatly between individual patients due to the retrospective design. Third, owing to the insufficient sample size, we could not perform a subgroup analysis of patients without CLTI. Fourth, we did not incorporate detailed analyses of skin perfusion, lesion characteristics, or intravascular imaging findings. Finally, no serial measurements of MDA-LDL levels were obtained, and the relationship between changes in MDA-LDL level and clinical events remains unclear.
Increased serum MDA-LDL level was associated with MALE following EVT in patients with LEAD.
We would like to thank Editage (www.editage.com) for English language editing.
The authors declare no conflicts of interest.
This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors.
Masashi Yokoi and Tsuyoshi Ito designed the study, the main conceptual ideas, and a proof outline. Masashi Yokoi, Tsuyoshi Ito, Yu Kawada, Tatsuya Mizoguchi, and Junki Yamamoto collected the data. Kento Mori, Kosuke Nakasuka, Shohei Kikuchi, Hiroshi Fujita, Shuichi Kitada, and Toshihiko Goto helped interpret the results. Yoshihiro Seo supervised this project. Masashi Yokoi wrote the manuscript with the support of Tsuyoshi Ito. All the authors critically reviewed and revised the manuscript draft and approved the final version for submission.
