Impact of High Lipoprotein(a) Levels on Delayed Wound Healing in Patients With Chronic Limb-Threatening Ischemia After Peripheral Endovascular Therapy

Abstract

Background: Elevated lipoprotein(a) [Lp(a)] levels are a causal risk factor for peripheral artery disease. However, data on their effect on delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) are limited. The present study assessed the association between elevated Lp(a) levels and delayed wound healing in patients with CLTI.

Methods and Results: This study included 280 patients who successfully received endovascular therapy for CLTI between September 2016 and August 2021. High Lp(a) levels were defined as those >30 mg/dL. The primary outcome was wound healing. During a median follow-up of 20.4 months (interquartile range 6.8–38.6 months), 146 patients achieved wound healing. The wound healing rate at 24 months was significantly lower in the high Lp(a) than low Lp(a) group (41.1% vs. 86.3%, respectively; P<0.001). The adjusted risk ratio was 0.19 (95% confidence interval 0.13–0.29, P<0.001). Lp(a) levels of 31–50 and >50 mg/dL, but not 16–30 mg/dL, were significantly associated with delayed wound healing relative to Lp(a) levels of ≤15 mg/dL.

Conclusions: Elevated Lp(a) levels were independently associated with delayed wound healing in patients with CLTI treated with endovascular therapy.

Chronic limb-threatening ischemia (CLTI) represents the end stage of peripheral artery disease (PAD). Further, it is associated with a poor prognosis in terms of both survival and limb salvage. The 1-year amputation-free survival rate is as low as 50%, and patients commonly require urgent revascularization therapy (surgical or endovascular therapy [EVT]).^1,2 The treatment goal is to relieve pain, heal wounds, preserve functional limb, and improve quality of life. Despite recent advances in revascularization procedures, approximately 20–30% of patients present with unhealed wounds and require subsequent major amputations after successful revascularization in real-world settings.^3–5 Furthermore, the prognosis of patients with limb amputation is extremely poor.¹

Elevated lipoprotein(a) [Lp(a)] levels are a well-known contributor to incident atherosclerotic cardiovascular disease, including PAD.^6,7 A large-scale study showed that high Lp(a) levels were associated with major adverse limb events (MALE) in individuals with PAD.⁸ In addition, a previous report revealed that patients with high Lp(a) levels after EVT for PAD have a significantly higher cumulative incidence of MALE.⁹ However, MALE were typically associated with reinterventions in these studies. Data about the association between Lp(a) levels and wound healing in patients with CLTI are minimal. Thus, the present study investigated the association between Lp(a) levels and wound healing in patients with CLTI receiving EVT.

Methods

Study Population

This was a prospective single-center observational study that registered adult patients (aged ≥18 years) with CLTI who presented with tissue loss (Rutherford categories 5–6) between September 2016 and August 2021. Registration was performed before EVT. Patients originally scheduled for bypass surgery and/or major amputation after EVT were excluded from the study. In all, 304 patients who successfully received EVT for patients with CLTI were registered. After registration, patients with missing data on low-density lipoprotein cholesterol (LDL-C) levels were excluded from the analysis. Thus, 280 patients were analyzed in the present study.

The study protocol was approved by the Institutional Review Board of Kokura Memorial Hospital (Reference no. 16111602) and the study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants or their families. For patients undergoing bilateral EVT, the first limb treated was considered as the representative limb.

Blood samples were collected the day before EVT to measure lipid profiles, including total cholesterol, triglycerides (TGs), LDL-C, high-density lipoprotein cholesterol, and Lp(a). The time interval between the last meal and the time the blood sample was drawn was >12 h in all patients. The LDL-C level was calculated using the Friedewald formula in patients with TG levels were <400 mg/dL. If TG levels were ≥400 mg/dL, LDL-C levels were determined using a direct assay. Lp(a) levels were measured using a latex agglutination immunoassay (Special Reference Laboratories). High Lp(a) levels were defined as those >30 mg/dL based on previous studies.⁶ It has been reported that Lp(a) levels >30 mg/dL are associated with an increased cardiovascular risk.⁶ Moreover, Lp(a) levels were subdivided into 4 categories (≤15, 16–30, 31–50, and >50 mg/dL) based on a previous study.¹⁰

Procedures and Follow-up

EVT procedures were performed using the standard technique according to treatment guidelines.^2,11 Dual antiplatelet therapy (DAPT) started ≥2 days before the EVT procedure. After the procedure, the duration of DAPT was as recommended according to each device package insert. An atherectomy device was not commercially available in Japan during study the period, so it was not used in this study.

Clinical follow-up was performed 1, 3, and 6 months after revascularization and thereafter at least every 6 months.¹² The ankle-brachial index and skin perfusion pressure were routinely checked at follow-up. If a patient did not return to the hospital for follow-up, limb status and the patient’s general health were checked via a telephone interview.

During follow-up, wound care specialists evaluated wound status and managed wound care using the tissue, infection, moisture, edge (TIME) concept.¹³ All wounds were evaluated using the Rutherford classification and the Wound, Ischemia, and Foot Infection (WIfI) classification system.¹⁴ In cases of wound infection, surgical debridement, antibiotic therapy, and the timing of amputation were carefully assessed by wound care specialists. Data on ulcer status and time to complete healing were recorded.

Outcome Measures and Definitions

The primary outcome was wound healing. Secondary outcomes were all-cause mortality and freedom from clinically driven target lesion revascularization. Wound healing was defined as the achievement of complete epithelialization of all wounds without major amputation. Major amputation was defined as above-ankle amputation. Wound healing time was defined as the time from the initial EVT to complete epithelialization, which is the removal of all skin sutures after a minor amputation. In patients who died before complete wound healing, the date of death was considered as the cut-off date. In addition, in patients who underwent major amputation, the healing time was considered infinite. The definition of pedal artery diseases was based on the Kawarada classification.¹⁵ A Type 3 pedal lesion was defined as severe inframalleolar disease involving occlusion of the dorsalis pedis and lateral plantar arteries.

Statistical Analysis

Continuous variables are presented as the mean±SD or median with interquartile range (IQR), whereas discrete variables are presented as frequencies and percentages. Two-tailed P<0.05 was considered statistically significant, and 95% confidence intervals (CIs) are reported as appropriate. The significance of differences in baseline characteristics between the low and high Lp(a) groups was determined using the t-test for continuous variables and the Chi-squared test for discrete variables. The cumulative incidence rate of wound healing and the overall survival rate were estimated using the Kaplan-Meier method. Between-group differences were assessed using the long-rank test. Associations between high Lp(a) levels and clinical outcomes were investigated using the Poisson regression model and are presented as an incidence risk ratio. In regression analysis, a univariate model with only high Lp(a) levels included as the explanatory variable was initially developed. A following 4 multivariate models were subsequently established. Model 1 was further adjusted for age and sex. Model 2 was adjusted for LDL-C levels and statin use in addition to the variables used in Model 1. Model 3 was adjusted for current smoking status and comorbidities (e.g., diabetes and renal failure requiring dialysis) in addition to all variables included in Model 2. Model 4 was adjusted for limb characteristics (WIfI clinical stage, infrapopliteal revascularization, and Type 3 pedal lesion) in addition to all variables included in Model 3. Associations between Lp(a) levels (16–30, 31–50, and >50 mg/dL relative to ≤15 mg/dL) and clinical outcomes were explored using the Poisson regression model. Furthermore, a restricted cubic spline at the quartiles was fitted for Lp(a) levels. All statistical analyses were performed using R version 4.1.1 (R Development Core Team, Vienna, Austria).

Results

Baseline Clinical Characteristics

Table 1 presents the baseline characteristics of the study population. The mean age of patients was 75±10 years, and the median serum Lp(a) concentration was 24 mg/dL (IQR 13–41 mg/dL). In this study, 62.1% of patients had diabetes and 56.4% were receiving regular hemodialysis. Further, 76.4% of patients received infrapopliteal EVT, and 25.7% presented with a Type 3 pedal lesion. The high Lp(a) group had a more severe WIfI clinical stage than the low Lp(a) group. Details about Lp(a) levels and WIfI grade are provided in Supplementary Table 1. The ischemic grade was significantly higher in the high than low Lp(a) group, whereas the wound grade and the foot infection grade did not differ between the 2 groups. Details about Lp(a) levels and wound management are provided in Supplementary Table 2. There were no significant differences in the rates of debridement or minor amputation between the high and low Lp(a) groups. LDL-C levels and the frequency of statin administration also did not differ significantly between the 2 groups. Lp(a) levels and skin perfusion pressure before and after EVT are presented in Supplementary Table 3.

Table 1.

Baseline Characteristics of Participants

	All patients (n=280)	Low Lp(a) group (n=169)	High Lp(a) group (n=111)	P value
Age (years)	75±10	75±11	75±10	0.66
Male sex	178 (63.6)	108 (63.9)	70 (63.1)	0.99
LDL-C (mg/dL)	92±34	90±32	95±38	0.31
Statin use	130 (46.4)	79 (46.7)	51 (45.9)	0.99
Current smoking status	35 (12.5)	20 (11.8)	15 (13.5)	0.82
Diabetes	174 (62.1)	107 (63.3)	67 (60.4)	0.71
Renal failure during dialysis	158 (56.4)	95 (56.2)	63 (56.8)	>0.99
WIfI clinical stage				0.022
Stage I	45 (16.1)	37 (21.9)	8 (7.2)
Stage II	36 (12.9)	21 (12.4)	15 (13.5)
Stage III	99 (35.4)	55 (32.5)	44 (39.6)
Stage IV	100 (35.7)	56 (33.1)	44 (39.6)
Infrapopliteal EVT	214 (76.4)	129 (76.3)	85 (76.6)	>0.99
Type 3 pedal lesionA	72 (25.7)	42 (24.9)	30 (27.0)	0.79

Unless indicated otherwise, data are presented as the mean±SD or n (%). The high lipoprotein(a) [Lp(a)] group consisted of patients with Lp(a) levels >30 mg/dL. ^AThe definition of pedal artery disease was based on the Kawarada classification system.¹⁵ Type 3 pedal lesions were defined as severe inframalleolar disease involving occlusion of the dorsalis pedis and lateral plantar arteries. EVT, endovascular therapy; LDL-C, low-density lipoprotein cholesterol; WIfI, Wound, Ischemia, and Foot Infection.

Clinical Outcomes

During a median follow-up of 20.4 months (IQR 6.8–38.6 months), 146 patients achieved wound healing and 137 died. The high Lp(a) group had a lower wound healing rate than the low Lp(a) group (P<0.001; Figure 1A). The 24-month wound healing rates of the high and low Lp(a) groups were approximately 41.1% (95% CI 27.3–52.4%) and 86.3% (95% CI 77.6–91.6%), respectively. The high Lp(a) group had a lower overall 24-month survival rate than the low Lp(a) group (49.2% [95% CI 40.1–60.3%] vs 71.2% [95% CI 64.0–79.1%]; P=0.002; Figure 1B). The rate of cardiovascular deaths was significantly higher in the high than low Lp(a) group (69.6% [64.7–74.5%] vs. 85.5% [82.4–88.6%]; P=0.002;), but there was no significant difference between the 2 groups in the rate of non-cardiovascular deaths (70.7% [65.3–76.1%] vs. 83.3% [80.0–86.6%]; P=0.24; Supplementary Figures 1,2). In addition, the rate of freedom from clinically driven target lesion revascularization at 24 months was significantly lower the high Lp(a) group than in the low Lp(a) group (47.3% [40.6–54.0%] vs. 77.5% [73.8–81.2%]; P<0.001; Supplementary Figure 3).

Figure 1.

Kaplan-Meier estimates of (A) wound healing and (B) overall survival rates according to lipoprotein(a) [Lp(a)] levels at presentation. The high Lp(a) group consisted of patients with Lp(a) levels >30 mg/dL. EVT, endovascular therapy.

High Lp(a) levels were inversely associated with wound healing and positively associated with all-cause mortality (Table 2). The adjusted incidence risk ratios were 0.19 (95% CI 0.13–0.29; P<0.001) for wound healing and 1.82 (95% CI 1.29–2.55; P=0.001) for all-cause mortality. After dividing Lp(a) levels into 4 categories, Lp(a) levels of 31–50 and >50 mg/dL, but not 16–30 mg/dL, were significantly associated with a reduced incidence of wound healing and an elevated incidence of all-cause mortality relative to Lp(a) levels of ≤15 mg/dL (Figure 2). Restricted cubic spline curves are shown in Figure 3.

Table 2.

Associations Between High Lp(a) Levels and Clinical Outcomes

Outcomes	Crude estimate (univariate model)		Adjusted estimates (multivariate models)
			Model 1		Model 2		Model 3		Model 4
	IRR (95% CI)	P value	IRR (95% CI)	P value	IRR (95% CI)	P value	IRR (95% CI)	P value	IRR (95% CI)	P value
Wound healing	0.21 (0.14–0.31)	<0.001	0.21 (0.14–0.31)	<0.001	0.20 (0.14–0.30)	<0.001	0.20 (0.14–0.30)	<0.001	0.19 (0.13–0.29)	<0.001
All-cause mortality	1.66 (1.19–2.33)	0.003	1.64 (1.18–2.30)	0.004	1.74 (1.24–2.44)	0.001	1.79 (1.28–2.51)	0.001	1.82 (1.29–2.55)	0.001

Model 1 was adjusted for age and sex. Model 2 was adjusted for all covariates in Model 1 plus LDL-C levels and statin use. Model 3 was adjusted for all covariates in Model 2 plus comorbidities (current smoking status, diabetes, and renal failure on dialysis). Model 4 was adjusted for all covariates in Model 3 plus limb characteristics (WIfI clinical stage, infrapopliteal revascularization, and Type 3 pedal lesion^A). ^AThe definition of pedal artery disease was based on the Kawarada classification system¹⁵ and Type 3 pedal lesions were defined as severe inframalleolar disease involving occlusion of the dorsalis pedis and lateral plantar arteries. CI, confidence interval; IRR, incidence risk ratio. Other abbreviations as in Table 1.

Figure 2.

Associations between lipoprotein(a) [Lp(a)] categories and (A,B) wound healing and (C,D) all-cause mortality. Data show crude (A,C) and adjusted (B,D) incidence risk ratios (symbols) and their 95% confidence intervals (whiskers). The adjusted incidence risk ratios were obtained from the multivariate Poisson regression model in which all variables in Model 4 (Table 2) were entered.

Figure 3.

Restricted cubic spline curve of lipoprotein(a) [Lp(a)] levels for (A) wound healing and (B) all-cause mortality. Data show adjusted incidence risk ratios (solid lines) and 95% confidence intervals (dashed lines) obtained using the multivariate Poisson regression model in which all variables in Model 4 (Table 2) were entered.

Discussion

This study revealed that the wound healing rate and overall survival rate were lower in the high Lp(a) group than in the low Lp(a) group.

The treatment goal for patients with CLTI is to relieve pain, heal wounds, preserve a functional limb, and improve quality of life. To achieve this goal, wound healing is an important clinical issue in managing patients with CLTI receiving EVT. In experienced centers, the rate of successful EVT is extremely high; however, the wound healing rate is not, with 1-year wound healing rates remaining at approximately 70%.^3,16 Therefore, the next transformative breakthrough would be improved wound healing for patients with CLTI. To date, there is limited information on the association between high Lp(a) levels and the clinical outcome of patients with CLTI receiving EVT. To the best of our knowledge, this is the first study to report an association between high Lp(a) levels and wound healing in patients with CLTI receiving EVT.

In the present study, wound healing rates were significantly lower in the high Lp(a) group than in the low Lp(a) group at both 1 year (30.7% vs. 75.6%) and 2 years (41.1% vs. 86.3%). In the European Prospective Investigation of Cancer (EPIC)-Norfolk prospective population study, patients within the highest Lp(a) quartiles had an increased risk of developing PAD.¹⁷ Another study reported that individuals with symptomatic artery disease who presented with Lp(a) levels >30 and >50 mg/dL had an approximately 3- and 23-fold higher risk of limb amputation, respectively.¹⁸ Considering that unhealed wounds are an independent risk factor for limb amputation after EVT,¹⁹ this finding is consistent with ours. Furthermore, in our study, higher Lp(a) levels were associated with a significantly lower risk of wound healing, and this association almost plateaued at Lp(a) levels >30 mg/dL. To improve the wound healing rate, Lp(a) levels ≤30 mg/dL could be ideal. Notably, high Lp(a) levels were independently negatively associated with wound healing rates even after adjusting for confounding factors. High Lp(a) levels should be considered an inhibitory factor for wound healing in clinical practice. Early intensive risk factor management can be important, and a more cautious clinical approach should be used by the multidisciplinary team for patients with high Lp(a) levels. In addition, previous studies have identified several predictors of wound healing, including diabetes, renal failure requiring dialysis, severe WIfI clinical stage, infrapopliteal revascularization, and Type 3 pedal lesions.^15,20,21 With the exception of diabetes, which can be managed with glycemic control, it is challenging to provide appropriate interventions for these factors.²² However, lowering Lp(a) levels is a potential therapeutic target in clinical practice. To date, no specific Lp(a)-lowering therapies are available. However, lipoprotein apheresis is an option for patients presenting with extremely high Lp(a) levels with progressive cardiovascular disease, as recommended in a consensus statement.²³ In addition, lipoprotein apheresis (Rheocarna^®; Kaneka Corporation, Osaka, Japan), a novel treatment method, improves peripheral vascular fluidity and contributes to wound healing in patients with CLTI.²⁴ CLTI is an extremely progressive cardiovascular disease. Therefore, lipoprotein apheresis may be a treatment option for patients with CLTI who have high Lp(a) levels.

In this study, high Lp(a) levels were independently associated with all-cause mortality, and the association almost plateaued at Lp(a) levels >30 mg/dL. High Lp(a) levels could be a negative biomarker of overall survival in patients with CLTI. Life expectancy is the most important information in selecting the revascularization strategy (EVT or bypass surgery). Even now, an expected life expectancy of ≥2 years is a key factor in selecting bypass surgery as the first-line revascularization method.^2,11 In the present study, the overall 24-month survival rate of the high Lp(a) group was only 49.2%. Although the present study only included patients receiving EVT, Lp(a) levels ≤30 mg/dL may be a useful marker for assessing 2-year life expectancy.

The 1-year mortality rate of patients with CLTI is approximately 25%, with a 5-year all-cause mortality rate exceeding 50%. The prognosis of CLTI is worse than that of most malignancies.^1,25 Cardioprotective medical treatments have been recommended for the management of CLTI. Nevertheless, such recommendations are based on clinical trials that excluded patients with CLTI.^26,27 There are no randomized trials on medical therapies in patients with CLTI. Elevated Lp(a) levels could be a promising therapeutic target for patients with CLTI. Recently, novel technologies, such as antisense oligonucleotides and small interfering RNA, have been developed; these technologies can significantly reduce Lp(a) levels.^28,29 Future studies should be performed to determine whether Lp(a)-lowering therapy can promote wound healing and reduce mortality risk in patients with CLTI who present with high Lp(a) levels.

Study Limitations

This study has several limitations. First, this was a single-center study with a relatively small sample size. Second, the clinical events were not independently adjudicated by a blinded clinical event committee, which may have resulted in potential reporting bias. In addition, clinicians assessing clinical outcomes could have knowledgeable of patients’ Lp(a) levels. Third, this study did not include patients undergoing bypass surgery. Fourth, medication adherence was not monitored. Fifth, inflammation is associated with Lp(a) levels.³⁰ Therefore, severe inflammation in the lower limbs of patients with CLTI may have affected their Lp(a) levels. Sixth, patients who successfully underwent EVT for CLTI were registered in the study, and it unclear what effect including patients with unsuccessful EVT may have had on the results. Finally, the Lp(a) levels vary with ethnicity.^6,23 Whether similar findings are observed in other ethnic groups is yet to be determined.

Conclusions

High Lp(a) levels were independently associated with delayed wound healing and overall survival in Japanese patients with CLTI treated with EVT.

Acknowledgments

The authors extend special thanks to the catheterization laboratory medical staff.

Sources of Funding / Financial Support

None.

Disclosures

The authors have no conflicts of interest to declare.

IRB Information

The study protocol was approved by the Institutional Review Board of Kokura Memorial Hospital (Reference no. 16111602).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0383

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