Race/ethnicity and socioeconomic status affect the assessment of lipoprotein(a) levels in clinical practice.

Background and Objective: High Lp(a) levels are a risk factor for ASCVD, however Lp(a) ordering in clinical practice is low. This study examines how race/ethnicity and socioeconomic status influence Lp(a) ordering. Methods: This is a single center, retrospective study (2/1/2020-6/30/2023) using electronic medical records of adults with at least one ICD-10 diagnosis of ASCVD or resistant hyperlipidemia (LDL-C >160 mg/dL on statin therapy). We evaluated Lp(a) level differences among racial/ethnic groups and sexes. We also assessed associations between diagnosis type, diagnosis number, age at diagnosis, race, socioeconomic score (based on zip codes), public health coverage and presence of Lp(a) orders. Results: 4% of our cohort (N=56,833) had an Lp(a) order (17.3% Hispanic, 8.7% non-Hispanic Black, 47.5% non-Hispanic White and, 27% Asian/others). Non-Hispanic Black and Hispanic patients had lower rates of Lp(a) orders (0.17%, 0.28%, respectively) when compared to non-Hispanic White patients (2.35%), p<0.001, however, their median Lp(a) levels were higher. Individuals belonging to deprived socioeconomic groups or on Medicaid, were less likely to have an Lp(a) order (RR=0.39, p<0.001 and RR=0.40, p<0.001 respectively). Certain diagnoses (carotid stenosis, family history of ASCVD and FH) and multiple diagnoses (>2) resulted in more Lp(a) orders compared to those with only one diagnosis (p<0.001). Conclusions: Lp(a) ordering is low in patients with ASCVD. Non-Hispanic Black and Hispanic patients at risk are less likely to have an Lp(a) order. Individuals residing in socioeconomically deprived neighborhoods and on Medicaid are also less like have Lp(a) order. Lp(a) orders depend on the type and number of patients' diagnoses.

Small apolipoprotein(a) isoforms may predict primary patency following peripheral arterial revascularization.

Background: High lipoprotein (a) [Lp(a)] is associated with adverse limb events in patients undergoing lower extremity revascularization. Lp(a) levels are genetically pre-determined, with LPA gene encoding for two apolipoprotein (a) [apo(a)] isoforms. Isoform size variations are driven by the number of kringle IV type 2 (KIV-2) repeats. Lp(a) levels are inversely correlated with isoform size. In this study, we examined the role of Lp(a) levels, apo(a) size and inflammatory markers with lower extremity revascularization outcomes. Methods: 25 subjects with chronic peripheral arterial disease (PAD), underwent open or endovascular lower extremity revascularization (mean age of 66.7±9.7 years; F=12, M=13; Black=8, Hispanic=5, and White=12). Pre- and post-operative medical history, self-reported symptoms, ankle brachial indices (ABIs), and lower extremity duplex ultrasounds were obtained. Plasma Lp(a), apoB100, lipid panel, and pro-inflammatory markers (IL-6, IL-18, hs-CRP, TNFα) were assayed preoperatively. Isoform size was estimated using gel electrophoresis and weighted isoform size ( wIS ) calculated based on % isoform expression. Firth logistic regression was used to examine the relationship between Lp(a) levels, and wIS with procedural outcomes: symptoms (better/worse), primary patency at 2-4 weeks, ABIs, and re-intervention within 3-6 months. We controlled for age, sex, history of diabetes, smoking, statin, antiplatelet and anticoagulation use. Results: Median plasma Lp(a) level was 108 (44, 301) nmol/L. The mean apoB100 level was 168.0 ± 65.8 mg/dL. These values were not statistically different among races. We found no association between Lp(a) levels and w IS with measured plasma pro-inflammatory markers. However, smaller apo(a) wIS was associated with occlusion of the treated lesion(s) in the postoperative period [OR=1.97 (95% CI 1.01 - 3.86, p<0.05)]. The relationship of smaller apo(a) wIS with re-intervention was not as strong [OR=1.57 (95% CI 0.96 - 2.56), p=0.07]. We observed no association between wIS with patient reported symptoms or change in ABIs. Conclusions: In this small study, subjects with smaller apo(a) isoform size undergoing peripheral arterial revascularization were more likely to experience occlusion in the perioperative period and/or require re-intervention. Larger cohort studies identifying the mechanism and validating these preliminary data are needed to improve understanding of long-term peripheral vascular outcomes. Key Findings: 25 subjects with symptomatic PAD underwent open or endovascular lower extremity revascularization in a small cohort. Smaller apo(a) isoforms were associated with occlusion of the treated lesion(s) within 2-4 weeks [OR=1.97 (95% CI 1.01 - 3.86, p<0.05)], suggesting apo(a) isoform size as a predictor of primary patency in the early period after lower extremity intervention. Take Home Message: Subjects with high Lp(a) levels, generally have smaller apo(a) isoform sizes. We find that, in this small cohort, patients undergoing peripheral arterial revascularization subjects with small isoforms are at an increased risk of treated vessel occlusion in the perioperative period. Table of Contents Summary: Subjects with symptomatic PAD requiring lower extremity revascularization have high median Lp(a) levels. Individuals with smaller apo(a) weighted isoform size (wIS) have lower primary patency rates and/or require re-intervention.

Supporting evidence for lipoprotein(a) measurements in clinical practice.

High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)'s main protein components are apolipoprotein (apo) (a) and apoB100, the latter being the main component of Low-Density Lipoprotein (LDL) particles. Studies have identified Lp(a) to be associated with inflammatory, coagulation and wound healing pathways. Lack of validated and accepted assays to measure Lp(a), risk cutoff values, guidelines for diagnosis, and targeted therapies have added challenges to the field. Scientific efforts are ongoing to address these, including studies evaluating the cardiovascular benefits of decreasing Lp(a) levels with targeted apo(a) lowering treatments. This review will provide a synopsis of evidence-based effects of high Lp(a) on disease presentation, highlight available guidelines and discuss promising therapies in development. We will conclude with current clinical information and future research needs in the field.

Endovenous microfoam ablation of below knee superficial truncal veins is safe and effective in patients with prior saphenous treatment across a wide range of CEAP classes.

OBJECTIVE: Patients requiring thermal or chemical ablation of below knee (BK) truncal veins often have their proximal saphenous veins treated initially and comprise a study population with multilevel, refractory chronic venous insufficiency. The study objective was to assess the outcomes after microfoam ablation of BK truncal and tributary veins in patients with a history of proximal great saphenous vein (GSV) ablation or stripping. METHODS: A retrospective review of a prospectively maintained database was performed. All the patients who had undergone endovenous chemical ablation with commercially manufactured polidocanol microfoam for symptomatic BK truncal vein reflux after a previous saphenous ablation or stripping were identified. The patients had undergone duplex ultrasound scanning 48 to 72 hours after the procedure; those who had not adhered to the recommended follow-up protocol were excluded. The demographic data, CEAP (clinical, etiologic, anatomic, pathophysiologic) classification, venous clinical severity score (VCSS), procedure details, adverse thrombotic events, and follow-up data were abstracted. RESULTS: Between April 2018 and April 2021, 201 limbs were treated for symptomatic superficial truncal vein reflux with microfoam ablation. Of the 201 limbs, 68 in 49 patients met the inclusion criteria for the present study. The veins treated included the BK GSV (n = 45) and small saphenous vein (n = 23). The median follow-up was 97 days (range, 33-457 days) for the entire cohort. Most patients (63%) had a preoperative CEAP classification of C4 to C6. The median preoperative VCSS was 12.5. All the limbs that had undergone microfoam ablation in this cohort had a previously treated proximal ipsilateral GSV, with either thermal ablation or stripping. The median postoperative VCSS after BK treatment decreased to 10 (P < .001). The closure rate at the last follow-up was 96%. The overall symptomatic relief was 78% at the last follow-up. The absolute ulcer healing rate during the study period was 64% (16 of 25 ulcers had healed). One patient had developed thrombus extension into the popliteal vein, which resolved with anticoagulation therapy. One asymptomatic patient had developed nonocclusive thrombus in a gastrocnemius vein after small saphenous vein ablation. Because she was asymptomatic, anticoagulation therapy was not prescribed. Postoperative pain, phlebitis, and swelling were reported in 12%, 12%, and 2% of patients, respectively, and all had resolved at the last follow-up visit. Three limbs treated with chronic oral anticoagulant agents had had recanalized truncal veins during the study period after initial closure. No pulmonary emboli or neurologic adverse events were reported. No symptoms of saphenous or sural nerve injury had occurred. CONCLUSIONS: Endovenous chemical ablation with commercially manufactured polidocanol microfoam of BK truncal veins is a safe and effective treatment for patients with severe, refractory chronic venous insufficiency and prior saphenous interventions. This technique results in excellent overall closure rates and symptomatic relief with low adverse venous thrombotic events, across a wide range of CEAP classes.

Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects.

Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects.

Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans.

BACKGROUND: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. METHODS: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. RESULTS: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. CONCLUSIONS: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a). CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.