0
selected
-
1.
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.
-
2.
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.
-
3.
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).
-
4.
Lipoprotein(a): is it more, less or equal to LDL as a causal factor for cardiovascular disease and mortality?
Langsted, A, Nordestgaard, BG
Current opinion in lipidology. 2020;(3):125-131
Abstract
PURPOSE OF REVIEW To summarize the recent studies directly comparing LDL and lipoprotein(a) as causal factors for cardiovascular disease and mortality. RECENT FINDINGS In approximately 100,000 individuals from the Copenhagen General Population Study for risk of myocardial infarction, in observational analyses per 39 mg/dl (1 mmol/l) cholesterol increase, the hazard ratio was 1.3 (95% confidence interval: 1.2-1.3) for LDL cholesterol and 1.6 (1.4-1.9) for lipoprotein(a) cholesterol. In corresponding genetic analyses, the causal risk ratio was 2.1 (1.3-3.4) for LDL and 2.0 (1.6-2.6) for lipoprotein(a). Also, a 15 mg/dl (0.39 mmol/l) cholesterol increase was associated with a hazard ratio for cardiovascular mortality of 1.05 (1.04-1.07) for LDL cholesterol and 1.18 (1.12-1.25) for lipoprotein(a) cholesterol. Corresponding values for all-cause mortality were 1.01 (1.00-1.01) for LDL cholesterol and 1.07 (1.04-1.10) for lipoprotein(a) cholesterol. In genetic, causal analyses, the mortality increases for elevated lipoprotein(a) appeared to be through apolipoprotein(a) kringle IV-2 rather than through lipoprotein(a) levels per se. SUMMARY On cholesterol scales, lipoprotein(a) and LDL appeared equal as causal factors for myocardial infarction; however, lipoprotein(a) was most important for mortality. Lipoprotein(a) effects may not only be due to cholesterol content but could also be due to the structure of lipoprotein(a) resembling plasminogen.
-
5.
Lp(a): Addressing a Target for Cardiovascular Disease Prevention.
Vasquez, N, Joshi, PH
Current cardiology reports. 2019;(9):102
Abstract
PURPOSE OF REVIEW To review the current recommendations for lipoprotein(a) (Lp(a)) screening, the evidence behind the thresholds for increased cardiovascular disease (CVD) risk, and the available data supporting Lp(a) lowering. RECENT FINDINGS Lp(a) is almost entirely genetically determined and has an independent causal association with CVD. Measurement of Lp(a) is challenging given the structural heterogeneity of apolipoprotein a (apo(a)), for which isoform-insensitive immunoassays should be used. Current guidelines do not recommend treatment to lower Lp(a) but rather focus on intensified preventive measures including low-density lipoprotein cholesterol (LDL-C) lowering in patients with high Lp(a). Evidence suggests that levels higher than 50 mg/dL (125 nmol/L) identify significantly increased CVD risk. Mendelian randomization studies suggest that in order to have a clinically significant reduction in coronary heart disease, Lp(a) levels should be reduced by at least 60-70 mg/dL to attain a significant benefit. Ongoing studies of targeted therapy with antisense oligonucleotides (ASO) have shown promising reductions in Lp(a) up to 80%, but a cardiovascular outcomes trial is needed. There is unquestionably an increased risk for CVD in patients with elevated Lp(a); however, measurement assay issues and the lack of Lp(a)-targeted therapies with proven outcome reduction limit the clinical utility of this important risk factor. Available evidence suggesting specific thresholds for clinically significant CVD risk are based on European or Caucasian populations, not accounting for important racial differences. Novel Lp(a)-targeted emerging therapies may need to account for an expected reduction of at least 60-70 mg/dL to achieve a clinically significant benefit.
-
6.
Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction.
Enas, EA, Varkey, B, Dharmarajan, TS, Pare, G, Bahl, VK
Indian heart journal. 2019;(2):99-112
Abstract
Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.
-
7.
HEART UK consensus statement on Lipoprotein(a): A call to action.
Cegla, J, Neely, RDG, France, M, Ferns, G, Byrne, CD, Halcox, J, Datta, D, Capps, N, Shoulders, C, Qureshi, N, et al
Atherosclerosis. 2019;:62-70
Abstract
Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis.
-
8.
Current Role of Lipoprotein Apheresis.
Thompson, G, Parhofer, KG
Current atherosclerosis reports. 2019;(7):26
-
-
Free full text
-
Abstract
PURPOSE OF REVIEW Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.
-
9.
Can Lp(a) Lowering Against Background Statin Therapy Really Reduce Cardiovascular Risk?
Reiner, Ž
Current atherosclerosis reports. 2019;(4):14
Abstract
PURPOSE OF REVIEW The association between elevated plasma levels of lipoprotein (a) [Lp(a)] and atherosclerotic cardiovascular disease (ASCVD) has been discussed for many years. Recent genetic findings have confirmed that elevated Lp(a) similar to elevated LDL-cholesterol (LDL-C) might be causally related to premature ASCVD. Lp(a) is relatively refractory to lifestyle interventions. The results of studies with statins and their possible effect on Lp(a) are conflicting. Specific Lp(a) apheresis is used as a treatment against background statin therapy and can decrease Lp(a). The purpose of this review is to discuss whether new drugs which decrease Lp(a) can prevent ASCVD and decrease ASCVD mortality when applied in addition to statins. RECENT FINDINGS Some new LDL-C-lowering drugs such as mipomersen and lomitapide decrease elevated Lp(a) in addition to statins but they have some unpleasant adverse effects. Recently, an antisense oligonucleotide against apo(a), AKCEA-APO(a)Rx, has been shown to selectively decrease Lp(a). The most recent advance in LDL-C lowering are PCSK9 inhibitors. Alirocumab and evolocumab do not only significantly reduce LDL-C on top of maximally tolerated statin therapy and prevent ASCVD events, but also further decrease Lp(a). There is no data to indicate whether mipomersen, lomitapide, or IONIS-APO(a)-LRx decrease ASCVD events and mortality. Conclusive evidence is still lacking as to whether the treatment with PCSK9 inhibitors against background statin therapy actually additionally reduces ASCVD risk due to the lowering of Lp(a) or simply due to lowering LDL-C to levels much lower than high-intensity statin treatment as monotherapy. Ongoing trials will probably provide an answer to these questions.
-
10.
Apheresis for severe hypercholesterolaemia and elevated lipoprotein(a).
Waldmann, E, Parhofer, KG
Pathology. 2019;(2):227-232
Abstract
Low-density lipoprotein (LDL)-cholesterol (LDL-c) and lipoprotein(a) [Lp(a)] are independent cardiovascular risk factors. Reduction of LDL-c leads to reduction in cardiovascular events, regardless of the method of reducing LDL-c levels. Lifestyle modification and drugs are first line treatment options. However, many patients do not reach treatment goals, as defined in guidelines worldwide, through standard medication. So far, drugs are not efficient in lowering Lp(a) levels, or the reduction of plasma levels does not result in clinical benefit. In these two groups of patients lipoprotein apheresis is very efficient in decreasing LDL-c and Lp(a) levels. A single apheresis session can decrease LDL-c and Lp(a) by approximately 65%, and apheresis performed weekly or biweekly results in considerably decreased mean interval concentrations (approximately 30% reduction). Most apheresis systems (HELP, heparin induced extracorporeal LDL precipitation; DALI, direct adsorption of lipoproteins; lipoprotein apheresis with dextran sulfate; lipid filtration; immunoadsorption) decrease LDL-c and Lp(a). Lipopac is a specific form of immunapheresis and only decreases Lp(a). Lipoprotein apheresis is a well-tolerated treatment option but it is expensive and time consuming. The evidence for clinical benefit through regular apheresis comes from observational data. Adequate, randomised, controlled trials are lacking.