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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.
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2.
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.
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3.
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.
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4.
Current Role of Lipoprotein Apheresis.
Thompson, G, Parhofer, KG
Current atherosclerosis reports. 2019;(7):26
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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.
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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.
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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.
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7.
Role of Lipoprotein Apheresis in Cardiovascular Disease Risk Reduction.
Raina, R, Young, C, Krishnappa, V, Chanchlani, R
Blood purification. 2019;(4):301-316
Abstract
BACKGROUND AND AIM Elevated low-density lipoprotein cholesterol and/or lipoprotein(a) are established risk factors for cardiovascular disease (CVD). Management of hypercholesterolemia consists of drug therapies, including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. In patients with familial hypercholesterolemia (FH), lipoprotein apheresis (LA) is utilized to control lipid levels. However, LA is not currently a standard therapy for non-FH. This review summarizes the literature regarding LA therapy in CVD prevention. METHODS PubMed/MEDLINE databases were searched using the keywords "LA" and "CVD". Citations were individually reviewed for relevance. RESULTS The efficacy of LA was clearly demonstrated, largely based on evidence from observational studies. In patients who are unresponsive to traditional lipid-lowering medications, LA effectively reduced serum lipoprotein levels and adverse cardiovascular events. CONCLUSION It was concluded that LA is a safe and effective technique that could be considered in the management of hypercholesterolemia and future risk. Randomized control trials would further support a role for LA as a therapeutic option.
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Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye?
Boffa, MB, Koschinsky, ML
Current opinion in lipidology. 2019;(6):428-437
Abstract
PURPOSE OF REVIEW Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue. RECENT FINDINGS Although the ability of PCSK9i to lower Lp(a) by 15-30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated. SUMMARY Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.
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Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis.
Schnitzler, JG, Ali, L, Groenen, AG, Kaiser, Y, Kroon, J
Biomolecules. 2019;(12)
Abstract
Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.
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10.
Looking at Lp(a) and Related Cardiovascular Risk: from Scientific Evidence and Clinical Practice.
Stulnig, TM, Morozzi, C, Reindl-Schwaighofer, R, Stefanutti, C
Current atherosclerosis reports. 2019;(10):37
Abstract
PURPOSE OF REVIEW A considerable body of data from genetic and epidemiological studies strongly support a causal relationship between high lipoprotein(a) [Lp(a)] levels, and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, unrelated to Lp(a) threshold, and independent of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Unfortunately, the mechanism(s) through which Lp(a) promotes atherosclerosis are not clarified yet. Suggested hypotheses include: an increased Lp(a)-associated cholesterol entrapment in the arterial intima followed by inflammatory cell recruitment, abnormal upload of proinflammatory oxidized phospholipids, impaired fibrinolysis by inhibition of plasminogen activation, and enhanced coagulation, through inhibition of the tissue factor pathway inhibitor. This review is aimed at summarizing the available evidence on the topic. RECENT FINDINGS There are two clinical forms, isolated hyperlipidemia(a) [HyperLp(a)] with acceptable LDL-C levels (< 70 mg/dL), and combined elevation of Lp(a) and LDL-C in plasma. To date, no drugs that selectively decrease Lp(a) are available. Some novel lipid-lowering drugs can lower Lp(a) levels, but to a limited extent, as their main effect is aimed at decreasing LDL-C levels. Significant Lp(a) lowering effects were obtained with nicotinic acid at high doses. However, adverse effects apart, nicotinic acid is no longer prescribed and available in Europe for clinical use, after European Agency of Medicines (EMA) ban. The only effective therapeutic option for now is Lipoprotein Apheresis (LA), albeit with some limitations. Lastly, it is to be acknowledged that the body of evidence confirming that reducing plasma isolated elevation of Lp(a) brings cardiovascular benefit is still insufficient. However, the growing bulk of clinical, genetic, mechanistic, and epidemiological available evidence strongly suggests that Lp(a) is likely to be the smoking gun.