-
1.
Replacing Saturated Fats with Unsaturated Fats from Walnuts or Vegetable Oils Lowers Atherogenic Lipoprotein Classes Without Increasing Lipoprotein(a).
Tindall, AM, Kris-Etherton, PM, Petersen, KS
The Journal of nutrition. 2020;(4):818-825
-
-
Free full text
-
Abstract
BACKGROUND Walnuts have established lipid-/lipoprotein-lowering properties; however, their effect on lipoprotein subclasses has not been investigated. Furthermore, the mechanisms by which walnuts improve lipid/lipoprotein concentrations are incompletely understood. OBJECTIVES We aimed to examine, as exploratory outcomes of this trial, the effect of replacing SFAs with unsaturated fats from walnuts or vegetable oils on lipoprotein subclasses, cholesterol efflux, and proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS A randomized, crossover, controlled-feeding study was conducted in individuals at risk of cardiovascular disease (CVD) (n = 34; 62% men; mean ± SD age 44 ± 10 y; BMI: 30.1 ± 4.9 kg/m2). After a 2-wk run-in diet (12% SFAs, 7% PUFAs, 12% MUFAs), subjects consumed the following diets, in randomized order, for 6 wk: 1) walnut diet (WD) [57-99 g/d walnuts, 7% SFAs, 16% PUFAs [2.7% α-linolenic acid (ALA)], 9% MUFAs]; 2) walnut fatty acid-matched diet [7% SFAs, 16% PUFAs (2.6% ALA), 9% MUFAs]; and 3) oleic acid replaces ALA diet (ORAD) [7% SFAs, 14% PUFAs (0.4% ALA); 12% MUFAs] (all percentages listed are of total kilocalories ). Serum collected after the run-in (baseline) and each diet period was analyzed for lipoprotein classes and subclasses (vertical auto profile), cholesterol efflux, and PCSK9. Linear mixed models were used for data analysis. RESULTS Compared with the ORAD, total cholesterol (mean ± SEM -8.9± 2.3 mg/dL; -5.1%; P < 0.001), non-HDL cholesterol (-7.4 ± 2.0 mg/dL; -5.4%; P = 0.001), and LDL cholesterol (-6.9 ± 1.9 mg/dL; -6.5%; P = 0.001) were lower after the WD; no other pairwise differences existed. There were no between-diet differences for HDL-cholesterol or LDL-cholesterol subclasses. Lipoprotein(a) [Lp(a)], cholesterol efflux, and PCSK9 were unchanged after the diets. CONCLUSIONS In individuals at risk of CVD, replacement of SFAs with unsaturated fats from walnuts or vegetable oils improved lipid/lipoprotein classes, including LDL-cholesterol, non-HDL cholesterol, and total cholesterol, without an increase in Lp(a). These improvements were not explained by changes in cholesterol efflux capacity or PCSK9. This trial was registered at clinicaltrials.gov as NCT01235832.
-
2.
Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities.
Vuorio, A, Watts, GF, Schneider, WJ, Tsimikas, S, Kovanen, PT
Journal of internal medicine. 2020;(1):2-18
-
-
Free full text
-
Abstract
There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.
-
3.
Effect of Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies.
Toth, PP, Jones, SR, Monsalvo, ML, Elliott-Davey, M, López, JAG, Banach, M
Journal of the American Heart Association. 2020;(5):e014129
Abstract
Background Dyslipidemia guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time. Methods and Results Data from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies. The effects of evolocumab on percent change from baseline for non-HDL-C, ApoB, and lipoprotein(a) and achievement of treatment goals for non-HDL-C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non-HDL-C (Q2W dose: -49% to -56%, monthly dose: -48% to -52%), mean ApoB (Q2W dose: -46% to -52%, monthly dose: -40% to -48%), and median lipoprotein(a) (Q2W dose: -22% to -38%, monthly dose: -20% to -33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid-lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus). Conclusions In this pooled analysis, evolocumab substantially reduced non-HDL-C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.
-
4.
Impact of lipoprotein(a) on long-term outcomes after percutaneous coronary intervention in patients with reduced low-density lipoprotein cholesterol.
Liu, Y, Zeng, Z, Yu, X, Li, T, Yao, Y, Chen, R, Zheng, J
Reviews in cardiovascular medicine. 2020;(1):147-153
Abstract
The purpose of this study is to investigate the effect of lipoprotein(a) level on long-range prognosis after Percutaneous Coronary Intervention (PCI) in patients with low-density lipoprotein cholesterol (LDL-C) goal attainment. In this retrospective study, 350 patients in Coronary artery disease (CAD) with LDL-C less than 1.8 mmol/L were enrolled in the Guangdong Institute of Cardiovascular Diseases from January 2011 to December 2013. Follow-up was 1 year after PCI. According to the median value of the study population based on Lp(a), the patients were assigned to the high-level group and low-level group. The clinical data of the 2 groups were collected. We compared the baseline data between the 2 groups and the incidence rate of major cardiovascular events. After statistical analysis, the gender composition, hypertension, diabetes, and age of the patients between the 2 groups were similar, and the distinction was not significant. There was no significant distinction in cardio-vascular death, ischemic stroke, and recurrent myocardial infarction between the 2 groups, but the incidence of revascularization was higher in the high-level group (P < 0.05). High Lp(a) level predicts an increased incidence of revascularization of patients in CAD with LDL-C less than 1.8 mmol/L after PCI.
-
5.
Plasma kinetics of mature PCSK9, furin-cleaved PCSK9, and Lp(a) with or without administration of PCSK9 inhibitors in acute myocardial infarction.
Nakamura, A, Kanazawa, M, Kagaya, Y, Kondo, M, Sato, K, Endo, H, Nozaki, E
Journal of cardiology. 2020;(4):395-401
Abstract
BACKGROUND There are two types of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), mature and furin-cleaved. Most types of lipoprotein(a) [Lp(a)], an independent risk factor of cardiovascular events, bind to mature PCSK9. OBJECTIVE This study examined the effects of monoclonal anti-PCSK9 antibody on plasma PCSK9 and Lp(a) levels in acute myocardial infarction (MI). METHODS Acute MI patients (n=36) were randomly divided into evolocumab (140mg; n=17) and non-evolocumab (n=19) groups. Changes in plasma PCSK9 and Lp(a) levels were monitored before and 1, 3, 5, 10, and 20 days after evolocumab administration. RESULTS In the non-evolocumab group, plasma levels of mature PCSK9, furin-cleaved PCSK9, and Lp(a) (236.4±57.3ng/mL, 22.4±5.8ng/mL, and 19.2.±16.5mg/dL, respectively) significantly increased by day 3 (408.8±77.1ng/mL, p<0.001; 47.2±15.7ng/mL, p<0.001; and 39.7±21.3mg/dL, p<0.005, respectively) and returned to the baseline by day 10 or 20. In the evolocumab group, mature PCSK9 significantly increased by >1000ng/mL with a simultaneous decline of furin-cleaved PCSK9 below the measurement sensitivity level after day 3. The incremental area under the curve for plasma Lp(a) levels was significantly smaller in the evolocumab group compared with the non-evolocumab group (p=0.038). CONCLUSION Mature and furin-cleaved PCSK9 are transiently upregulated after MI onset. Evolocumab significantly increases mature PCSK9 and decreases furin-cleaved PCSK9 and might inhibit transient increase of plasma Lp(a) in acute MI.
-
6.
Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.
Tsimikas, S, Karwatowska-Prokopczuk, E, Gouni-Berthold, I, Tardif, JC, Baum, SJ, Steinhagen-Thiessen, E, Shapiro, MD, Stroes, ES, Moriarty, PM, Nordestgaard, BG, et al
The New England journal of medicine. 2020;(3):244-255
Abstract
BACKGROUND Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).
-
7.
Monozygotic twins with familial hypercholesterolemia and high lipoprotein(a) levels leading to identical cardiovascular outcomes: Case report and review of the literature.
Kayıkçıoğlu, M, Uzun, HG, Tetik Vardarlı, A, Tokgözoğlu, L
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2020;(5):531-538
Abstract
Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant disease that leads to premature cardiovascular disease (CVD). Since monozygotic twins share the intrauterine environment and have the same age and gene profile, they could represent a very special resource for the investigation of the causes and the natural course of FH. This report is a description of 36-year-old monozygotic twin brothers with almost identical early coronary artery involvement due to FH concomitant with high lipoprotein(a) (Lpa) levels and a review of the literature. Sequence analysis revealed that the twins were homozygous for the LDLR c.1060+10G>A (rs12710260) mutation and heterozygous for the LDLR c.542C>T (rs557344672) mutations. Both were also homozygous for the c.1060+7T>C (rs2738442) and c.1586+53A>G (rs1569372) mutations in the LDLR gene as well as c.4265A>T (rs568413) mutations in the APOB gene. In the literature, there are 7 twin cases with reported FH, but none with high Lpa levels. The HoFH twins in this case report had lower low-density lipoprotein (LDL) cholesterol levels than expected (before treatment 204 and 223 mg/dL), with almost identical coronary involvement. Both had an extremely high Lpa level (308 and 272 nmol/L) with a very low coronary calcium score (16 AU) and a good response to statins (>60%). There was a history of the first CVD event occurring at nearly the same age (32-34 years) in the family. This could be an important aspect of FH families as a result of the similar timing of cumulative LDL exposure exceeding the threshold of CVD events. In conclusion, this first report of monozygotic HoFH twins with elevated Lpa levels and almost identical early coronary artery involvement at the same age provides evidence to substantiate the hypothesis of lifetime cholesterol burden/exposure.
-
8.
Effects of soy isoflavones on serum lipids and lipoprotein (a) in peritoneal dialysis patients.
Yari, Z, Tabibi, H, Najafi, I, Hedayati, M, Movahedian, M
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(8):1382-1388
Abstract
BACKGROUND AND AIM Lipid abnormalities are common in peritoneal dialysis (PD) patients and no effective treatment to decrease serum lipoprotein (a) [Lp(a)] in dialysis patients is known so far. Therefore, this research was designed to investigate the effects of soy isoflavone supplement on serum lipids and Lp(a) in PD patients. METHODS & RESULTS In this randomized, double-blind, placebo-controlled trial, 40 PD patients were randomly assigned to either the isoflavone or the placebo group. The patients in the isoflavone group received 100 mg soy isoflavone daily for 8 weeks, whereas the placebo group received corresponding placebos. At baseline and the end of the 8th week, 7 mL of blood was obtained from each patient and serum triglycerides, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and Lp(a) were measured. Serum Lp(a) reduced significantly up to 10% in the isoflavone group at the end of week 8 compared to baseline (P < 0.05), and the reduction was significant in comparison with the placebo group (P < 0.05). Serum HDL-C increased significantly up to 11.5% in the isoflavone group at the end of week 8 compared to baseline (P = 0.05), and the increment was significant in comparison with the placebo group (P < 0.05). There were no significant differences between the two groups in mean changes of serum triglycerides, total cholesterol, and LDL-C. CONCLUSIONS This study indicates that daily administration of 100 mg soy isoflavones reduces serum Lp(a) and increases HDL-C concentration which are two determinants of cardiovascular disease in PD patients. CLINICALTRIALS.GOV: NCT03773029. REGISTRATION NUMBER AND DATE NCT03773029 - 2018.
-
9.
The interconnection between lipoprotein(a), lipoprotein(a) cholesterol and true LDL-cholesterol in the diagnosis of familial hypercholesterolemia.
Yeang, C, Willeit, P, Tsimikas, S
Current opinion in lipidology. 2020;(6):305-312
Abstract
PURPOSE OF REVIEW Elevated levels of lipoprotein(a) [Lp(a)] are present in 30-50% of patients with familial hypercholesterolemia. The contribution of Lp(a) towards risk stratification of patients with familial hypercholesterolemia has been recently recognized, with studies showing a significantly worse prognosis if Lp(a) is elevated. However, the role of elevated Lp(a) in diagnosis of familial hypercholesterolemia is less well defined or accepted. RECENT FINDINGS An important confounder in the diagnosis of familial hypercholesterolemia is the significant contribution of the cholesterol content on Lp(a) (Lp(a)-C) in individuals with elevated Lp(a). Because Lp(a)-C is incorporated into all clinical LDL-C measurements, it can contribute significantly to the cholesterol threshold diagnostic criteria for familial hypercholesterolemia used in most clinical algorithms. SUMMARY In this review, we discuss the interrelationship of Lp(a), Lp(a)-C and correct LDL-C in the diagnosis and prognosis of familial hypercholesterolemia. Future studies of accurately measuring correct LDL-C or in using apoB-100 and Lp(a) criteria may overcome the limitations of using estimated LDL-C in the diagnosis of familial hypercholesterolemia in individuals with concomitant elevation of Lp(a).
-
10.
Coronary artery disease with normal lipids and low coronary artery calcium in two women with high lipoprotein(a).
Haxhi, J, Pershwitz, G, Thompson, PD
Journal of clinical lipidology. 2020;(2):186-188
Abstract
We present 2 patients with elevated levels of lipoprotein (a) and significant coronary artery disease despite having little coronary artery calcification. Clinicians should be aware that patients with elevated lipoprotein (a) may have important coronary artery disease with low coronary artery calcification scores.