Lipoprotein(a) (Lp[a]) can enhance the accuracy of evaluation of atherosclerotic heart problems and the danger of aortic valve stenosis. At present, there is no such thing as a particular remedy to decrease its circulating focus. Raised Lp(a) is a function of familial hypercholesterolaemia. Administration of excessive ranges encourages rigorous consideration to correction of different threat elements, comparable to blood strain, smoking and low-density lipoprotein (LDL).
Introduction
Lipoprotein(a) (Lp[a]) was found in 1963 as an antigen inflicting uncommon blood transfusion reactions.1 The antigen was discovered to be current within the lipoprotein fraction of plasma, therefore the identify lipoprotein(antigen). As strategies for its measurement improved, researchers realised that Lp(a) had a steady inhabitants frequency distribution, which in folks of European descent, was markedly positively skewed.2,3 It was additionally reported that in these with greater concentrations, the prevalence of coronary coronary heart illness was elevated. Moreover, greater ranges have been inherited; the focus of Lp(a) was twice as a lot in males who had skilled acute myocardial infarction (AMI) earlier than the age of 60 years in contrast with a management inhabitants of manufacturing facility staff with no earlier historical past of cardiac ischaemia.4 Lp(a) accounted for a lot of the danger related to a parental historical past of early-onset ischaemic coronary heart illness on this and bigger later investigations.5,6 It has been repeatedly confirmed in epidemiological and Mendelian randomisation research that Lp(a) is a threat issue for atherosclerotic heart problems (ASCVD) and aortic stenosis.2–8
Regardless of being studied for the previous 60 years and being measured in lots of international locations as a part of ASCVD threat evaluation, Lp(a) has aroused little scientific curiosity in Britain.9
Lipoprotein(a) construction
A breakthrough in our understanding of Lp(a) occurred in 1987 when a genetics group from San Francisco collaborated with researchers in Chicago who had situated Lp(a) within the lipoproteins with a hydrated density on the denser finish of the low-density lipoprotein (LDL) spectrum and the least dense a part of high-density lipoprotein (HDL).10 Lp(a) was discovered to have a composition much like LDL however along with containing one molecule of apolipoprotein B (apoB) per particle, there was one other giant protein termed apolipoprotein (a) (apo[a]). Research of a human hepatic cDNA library allowed the amino acid sequence and predicted construction of apo(a) to be determined11; this and subsequent work2,3 revealed that apo(a) was a member of the plasminogen household of molecules with a protease area and an extended chain of coiled, pretzel-like buildings known as kringles (determine 1). It’s situated on the skin of an LDL-like particle, disulphide-linked to its apoB, which winds out and in of the lipid micelle. The hydrolytic website of its protease area is blocked – the apparent hypothesis is that it interferes with the exercise of plasminogen, selling thrombogenesis. The size of the kringle chain is very variable in line with the frequency with which kringle IV-2 has been repeated, which might vary from 1 to greater than 40 instances. This provides apo(a) a molecular mass which might vary from 200–700 kDa. The decrease molecular mass isoforms are synthesised extra quickly by the liver and provides rise to greater plasma concentrations of Lp(a). Not like LDL, Lp(a) has no very low-density lipoprotein (VLDL) precursor. The mass of the entire Lp(a) particle when apo(a) has a molecular mass round 300–400 kDa is roughly 4000 kDa however is variable in line with the lipid burden and the apo(a) isoform current. A lot of the lipid current is phospholipid and this ceaselessly undergoes peroxidation.12
Key: ApoB = apolipoprotein B; KIV = kringle IV; KV = kringle V
Lipoprotein(a) measurement
There was a lot controversy concerning assay strategies and items of measurement in Lp(a) evaluation. Assays measure immunoreactivity, which might solely be translated instantly into focus when molecules share the same immunoreactivity; this isn’t the case for apo(a). Probably the most antigenic website for polygenic antibodies raised in opposition to apo(a), which don’t cross-react with different proteins like plasminogen, is the kringle sequence, significantly the kringle IV-2 repeats. Which means that low molecular mass isoforms will likely be much less immunoreactive than greater molecular mass ones. Thus, an assay standardised in opposition to typical apo(a) with a molecular mass of ~300–400 kDa will are likely to underestimate excessive Lp(a) concentrations and overestimate decrease values. One answer is to develop assays that are insensitive to Lp(a) isoforms; up to now, this has solely been doable in a analysis laboratory utilizing a kringle 9-specific monoclonal antibody.13 One other potential answer is to calibrate the assay in opposition to apo(a) isoforms more likely to be current on the focus of Lp(a) related to a scientific choice.14 Thus, if the assay is for use to display screen for elevated ASCVD threat, then ranges of 30–40 mg/dL have ceaselessly been used (across the seventy fifth percentile). However, a distinct commonplace curve in opposition to decrease molecular mass apo(a) isoforms could be higher for figuring out significantly excessive ranges, say, 90 mg/dL.
Relating to the items during which Lp(a) needs to be measured, most experiences at present use mg/dL, the place mg refers back to the mass of the entire Lp(a) particle, not simply its apo(a) part. It has been advocated that nmol/L needs to be the items of alternative.13 Nonetheless, as has been defined, antibody/Lp(a) advanced formation will differ not merely with the Lp(a) focus but in addition with the apo(a) molecular isoform current. Till an isoform-insensitive assay is usually out there, nmol/L is illusory. Moreover, there could be no common conversion issue for mg/dL to nmol/L. A conversion issue of two.4 is usually used,15 based mostly on a mean molecular mass just a little over 4,000 kDa. Nonetheless, if a excessive stage is to be transformed, the molecular mass is more likely to be decrease and the conversion issue thus decrease than 2.4. One method to overcome that is to make use of inhabitants percentiles, reasonably than absolute ranges, to tell scientific selections and decide the general value of remedy within the goal inhabitants.
Atherogenicity of lipoprotein(a)
Desk 1. Potential mechanisms by which lipoprotein(a) might promote atherosclerotic cardiovascular disease2,3,12,16
LDL-like protein wealthy in ldl cholesterol
Not cleared by physiological LDL receptor, prolonging its time in circulation
Retention inside arterial sub-intima higher than that of LDL because of presence of apo(a)
Circulating repository of oxidised phospholipids, which might trigger fragmentation of its different protein moiety (apoB) and uptake by arterial wall macrophage receptors
Affiliation with inflammatory markers
Professional-thrombotic (homology with plasminogen however no proteolytic exercise)
Key: apoB = apolipoprotein B; LDL = low-density lipoprotein
Many of the variation in Lp(a) is accounted for by variations in its manufacturing charge with greater plasma concentrations occurring in folks inheriting the decrease molecular mass apo(a) variants. This has made it troublesome to resolve whether or not the atherogenicity of Lp(a) is decided by its focus or by decrease molecular mass isoforms. Present pondering tendencies are that Lp(a) focus is pre-eminent. Focus is simpler to measure than the scale of the apo(a) alleles current. Desk 1 summarises the doable the explanation why Lp(a) might trigger atherothrombosis.
Components contributing to variation in circulating lipoprotein(a) concentrations
Though the speed of manufacturing decided by the molecular mass polymorphism is the principle determinant of Lp(a) concentrations within the inhabitants as an entire, different elements can play out in opposition to this background (desk 2).2,3,16–18
Desk 2. Components which affect the circulating lipoprotein(a) concentrations2,3,16–18
Major
Secondary
1. Molecular mass polymorphism; plasma focus inversely proportional to size of KIV2 sequence. Inherited co-dominantly explaining the affect of parental historical past of ASCVD
1. Elevated in continual renal illness; reversible in profitable renal transplantation and upon decision of minimal change nephropathy
2. Ethnicity (greater in folks of African and Asian descent)
3. Decrease in sort 2 diabetes and metabolic syndrome
4. Will increase with bariatric surgical procedure
5. Slight improve with statins (contentious)
6. Decreases with PCSK9 inhibitors, nicotinic acid and oestrogen alternative
7. Decreases in liver illness
8. Elevated in familial hypercholesterolaemia
9. Influenced by APOE genotype (APOE4>APOE3>APOE4)
Key: APOE = apolipoprotein E; ASCVD = atherosclerotic heart problems; KIV2 = kringle IV sort 2; PCSK9 = proprotein convertase subtilisin/kexin sort 9
Lipoprotein(a) in familial hypercholesterolaemia
Familial hypercholesterolaemia (FH) in its heterozygous kind impacts 1 in 250 to 500 folks. Sometimes in adults, it results in LDL ldl cholesterol >5 mmol/L and the event of tendon xanthomata on the dorsum of the fingers and the Achilles tendons, typically preceded by Achilles tenosynovitis.19 If left untreated, ASCVD happens within the majority of affected males and at the very least 1 / 4 of ladies earlier than the age of 60 years, on account of faulty LDL catabolism. That is most ceaselessly because of both a lack of perform mutations of the LDL receptor, however often to mutation of apolipoproteinB (apoB), which decreases LDL receptor binding; or to a acquire of perform mutations of proprotein convertase subtilisin/kexin sort 9 (PCSK9), which improve hepatic LDL receptor degradation.
A consortium from Innsbruck and London was the primary to report that Lp(a) was elevated in heterozygous FH (HeFH),20 which we confirmed, and by finding out unaffected first-degree relations of individuals with HeFH, discovered that the inheritance of FH roughly doubled the Lp(a) stage.21 We additionally discovered that the extra frequent polygenic hypercholesterolaemia didn’t itself improve Lp(a) concentrations. Lp(a), like LDL ldl cholesterol, is raised in childhood FH.22 Disagreement reverberates to this present day about whether or not the rise in FH was just because it was extra more likely to current clinically with ASCVD when Lp(a) was raised because of the coincidental inheritance of decrease molecular mass apo(a), or whether or not it’s a consequence of the inherited LDL catabolic defect.23 The previous opinion is supported by proof that Lp(a) catabolism, which isn’t mediated by LDL receptors, is unimpaired by inheritance of FH and the raised Lp(a) is because of elevated manufacturing.24 Nonetheless, that FH-causing mutations instantly improve Lp(a) was powerfully strengthened when the Innsbruck group collaborated with a bunch in Johannesburg (FH is frequent in South Africa because of founder gene results) and confirmed that the upper Lp(a) in HeFH and homozygous FH was elevated impartial of the apo(a) molecular polymorphism.25
From a scientific standpoint, raised Lp(a) needs to be thought to be a part of the FH syndrome.26 A very excessive Lp(a), even within the absence of identification of an FH-causing mutation, can characterize a considerably elevated ASCVD threat.27 From a analysis perspective, there seems to be a hyperlink between hepatic LDL receptor-mediated catabolism and Lp(a) manufacturing.28 This hyperlink might contain PCSK9.29 Moreover in FH, a proportion of LDL is launched from the liver, like Lp(a), and not using a VLDL precursor.30
Many individuals have written concerning the excellent storm for ASCVD threat of getting each a raised LDL and Lp(a) in FH.28 It seems apparent, however does Lp(a) actually improve the already significantly raised chance of ASCVD occasions in FH? Early experiences that this was the case might have been because of the admixture of polygenic hypercholesterolaemia with its decrease ASCVD threat and decrease Lp(a) ranges within the inhabitants thought-about by the investigators to have HeFH.30 Utilizing strict scientific standards for the prognosis of HeFH, we weren’t capable of finding any improve within the prevalence of ASCVD in these whose Lp(a) >30 mg/dL.31 In HeFH outlined by DNA evaluation, it was, nonetheless, reported from Norway that there was an elevated prevalence of ASCVD when Lp(a) >90 mg/dL.32
Scientific administration of excessive lipoprotein(a) concentrations
Earlier than discussing the scientific administration of elevated Lp(a) concentrations, one should think about how folks with excessive ranges are recognized. Some authorities advocate that everybody ought to have Lp(a) measured at the very least as soon as.9,14,33 At current, few, if any, healthcare suppliers fund this proposal. It may, for instance, be argued that funding could be higher supplied for detecting and treating metabolic syndrome and kind 2 diabetes, which look like the key trigger for the resurgence of ASCVD in lots of populations. Nonetheless, it appears affordable to argue for Lp(a) measurement within the following situations:
Somebody suspected of getting HeFH. A excessive stage of each LDL ldl cholesterol and Lp(a) drastically improve the chance that the affected person has FH and genetic testing and cascade household screening could also be applicable
When a very excessive Lp(a) is coincidentally inherited with raised LDL ldl cholesterol from any trigger. Assiduous administration of mutable ASCVD threat elements needs to be instituted
In households the place precocious ASCVD is clear, however with no apparent threat elements, neglecting Lp(a) may lead to a marked underestimation of threat (threat calculator, from the European Atherosclerosis Society, could be discovered at http://www.lpaclinicalguidance.com). With co-dominant transmission of genetic variants inflicting excessive Lp(a) focus, household screening might help to detect different first-degree relations at excessive threat
In circumstances of calcific aortic valve stenosis34
When ASCVD threat is deemed borderline for the introduction of cholesterol-lowering treatment.
Of those, the final is probably the most contentious, significantly if value is borne not individually, however by a socialised healthcare system. Though logical, it may contain giant numbers. This isn’t to say that testing shouldn’t be accomplished in these circumstances: what is probably going extra essential could be the affected person’s angle to medicalisation and recognition that any choice just isn’t absolute and threat estimation could be repeated with advancing age.
The remedy path will likely be influenced by the Lp(a) stage. For a few years, values in extra of 30–40 mg/dL have been thought-about a particular threat issue. That is across the seventy fifth percentile for populations of European descent. It has been prompt that related values needs to be thought to be clinically related, no matter ethnicity. Lp(a) concentrations >90 mg/dL (across the ninety fifth percentile) have been thought to be conferring ASCVD threat broadly equal to inheritance of HeFH, even when that prognosis has not been confirmed by genetic testing.27 Such excessive ranges demand much more assiduous consideration to optimising different threat elements. The place else can the clinician flip? Numerous medicines have been explored for Lp(a) discount, however are both unlicensed for this function or not really helpful by present NICE steerage. Nicotinic acid lowers Lp(a),35 however is poorly tolerated and lacks scientific trial proof of efficacy.36 Oestrogen alternative decreases Lp(a) and could also be related to a lower in ASCVD occasions in girls with greater Lp(a) unselected for top ASCVD threat,37 however then few would advocate oestrogen for these at greater ASCVD threat. Aspirin might decrease Lp(a) and reduce its thrombogenicity, however proof just isn’t but convincing in main prevention38 and presumably, aspirin is prescribed in secondary prevention anyway. Renal transplantation will decrease Lp(a) and it decreases on decision of minimal change glomerulopathy.17,18 Conversely, bariatric surgical procedure might increase Lp(a) slightly39 however because it improves insulin resistance, and lipoprotein and inflammatory markers of atherosclerosis, that is more likely to be of little significance.16
Statins don’t decrease Lp(a) and should even increase it barely.40 Nonetheless, statins are the simplest medical remedy for prevention of recent or recurrent ASCVD occasions: for each 1 mmol/L lower in LDL ldl cholesterol, there’s a 22% lower in ASCVD incidence. For instance, lowering LDL ldl cholesterol by 3 mmol/L in somebody whose ASCVD threat is 30 per 100 over the following 10 years will usually lower threat to 30 x 0.783 = 14 occasions.41 But, there’s nonetheless a residual threat; on this case, 16 ASCVD occasions per 100 over the following 10 years. Adjunctive lipid-lowering medicine supposed to cut back this residual threat when given in opposition to a background of efficient statin remedy fall into two classes: those who have failed or had restricted success, like CETP (cholesterylester switch protein) inhibitors, which increase HDL,42 and fibrates which lower VLDL and chylomicron remnants43; and people that are profitable, like ezetimibe44 and PCSK9 inhibitors.45 PCSK9 inhibitors should not licensed for Lp(a) discount; nonetheless, within the FOURIER trial, a big secondary prevention trial of evolocumab versus placebo in contributors receiving statin and statin/ezetimibe mixed lasting 2.2 years, there was a median 26.9% lower in Lp(a) focus within the remedy group in comparison with placebo.45 In contributors with Lp(a) concentrations above the median worth of 37 nmol/L (15 mg/dL), ASCVD occasions have been decreased by 23% (quantity wanted to deal with [NNT]=40) while in these with decrease ranges, the lower was solely 7% (NNT=105). Thus, excessive Lp(a) might help a scientific choice to provoke PCSK9 inhibitors in sufferers who’re thought-about borderline for his or her introduction, regardless of not being licensed particularly for this function. The identical is also true for LDL apheresis. Lp(a) is decreased by LDL apheresis and there are apheresis methods particularly designed to decrease Lp(a); these are nonetheless not but broadly out there exterior of specialist tertiary centres.46
Outcomes of scientific trials of particular therapies to cut back Lp(a) are in progress. These will report not solely on profit but in addition on potential in poor health results. Low Lp(a) concentrations improve the chance of creating sort 2 diabetes.9,33,47 There may be additionally the likelihood that decreasing Lp(a) ranges may impede blood clotting. While research have proven no vital affect of Lp(a) stage on outcomes following remedy of acute coronary insufficiency utilizing streptokinase,48 there could also be a better incidence of cerebral haemorrhage when Lp(a) concentrations are low.49
Case examine
The referral letter to the lipid clinic reads as follows:
‘Please see this 35-year-old man who has been advised by his sister residing in Germany that he ought to have lipoprotein(a) measured. She additionally assumes he may have had his ldl cholesterol measured, however in line with native pointers, he isn’t because of have his ldl cholesterol measured till he reaches 40 and we suspended this anyway throughout COVID. Moreover, Lp(a) just isn’t listed amongst the NHS assessments we are able to order and our native heart specialist says that, though it may be accomplished privately, he wouldn’t know what needs to be accomplished a couple of raised stage.’
On the clinic, the affected person described himself as a wholesome, non-smoker who runs 5 miles as soon as per week. He had a BMI of 28.4 kg/m2 and a blood strain of 134/76 mmHg. He has had issue discovering trainers that don’t give him painful ankles. His 45-year-old sister has lately undergone coronary angioplasty. His father died instantly on the age of 43 years.
Examination revealed early corneal arcus (prime and backside, not but concentric) and a few nodularity of the Achilles tendons. Urinalysis revealed no abnormalities and a resting electrocardiogram (ECG) was regular. Laboratory findings (together with creatinine, thyroid and liver features, and HbA1C) have been unremarkable, apart from his levels of cholesterol, which have been as follows:
whole ldl cholesterol: 10.7 mmol/L
triglyceride: 1.6 mmol/L
HDL ldl cholesterol: 1.4 mmol/L
LDL ldl cholesterol: 8.6 mmol/L
non-HDL ldl cholesterol: 9.3 mmol/L.
Lp(a) testing was out there within the lipid clinic, and the outcome was 79 mg/dL (198 nmol/L). The affected person was prescribed rosuvastatin 40 mg each day and ezetimibe 10 mg each day. On follow-up two months later, the LDL ldl cholesterol had decreased to three.6 mmol/L however Lp(a) was 83 mg/dL.
An train ECG was requested, together with genotype research to evaluate for FH. The outcomes of those are at present awaited. Ought to the genotype examine affirm the presence of FH, cascade screening will likely be organised for the affected person’s relations. At present, NICE recommends PCSK9 inhibitor remedy in FH with out proof of ASCVD when LDL ldl cholesterol is >5 mmol/L, or if >3.5 mmol/L with proof of ASCVD.50,51
If FH just isn’t confirmed, we might nonetheless advocate to the affected person that his first-degree relations attend our clinic for measurement of their ldl cholesterol and Lp(a) ranges.
Conclusion
Lp(a) is now properly established as a threat issue for ASCVD. Nonetheless, questions stay concerning how identification, measurement and administration of elevated Lp(a) can finest be carried out in scientific observe.
Key messages
Lipoprotein(a) (Lp[a]) is a threat issue for atherosclerotic heart problems and calcific aortic valve stenosis
Lp(a) is elevated by inheritance of familial hypercholesterolaemia
At present, there are not any medicine particularly indicated for discount of elevated Lp(a), and thus the discovering of a excessive stage calls for assiduous consideration to different threat elements
Conflicts of curiosity
None declared.
Funding
PD has obtained an honorarium for writing this text.
Paul DurringtonProfessor of MedicineUniversity of Manchester([email protected])
Articles on this complement
IntroductionLipoprotein(a) measurement – how, why and in whom?Scientific utility of lipoprotein(a): an interventionist’s perspectiveRaised lipoprotein(a): real-world examples of communication and scientific administration
References
1. Berg Ok. A brand new serum sort system in man – the Lp system. Acta Pathol Microbiol Scand 1963;59:369–82. https://doi.org/10.1111/j.1699-0463.1963.tb01808.x
2. Schmidt Ok, Noureen A, Kronenberg F, Utermann G. Construction, perform, and genetics of lipoprotein (a). J Lipid Res 2016;57:1339–59. https://doi.org/10.1194/jlr.R067314 [Epub online ahead of print]
3. Kostner KM, Kostner GM. Lipoprotein (a): a historic appraisal. J Lipid Res 2017;58:1–14. https://doi.org/10.1194/jlr.R071571 [Epub online ahead of print]
4. Durrington PN, Ishola M, Hunt L, Arrol S, Bhatnagar D. Apolipoproteins (a), AI, and B and parental historical past in males with early onset ischaemic coronary heart illness. Lancet 1988;1:1070–3. https://doi.org/10.1016/s0140-6736(88)91895-8
5. Durrington PN. Household historical past and lipoprotein(a) contribute independently to threat evaluation and scientific administration. J Am Coll Cardiol 2020;76:794–6. https://doi.org/10.1016/j.jacc.2020.07.003
6. Mehta A, Virani SS, Ayers CR et al. Lipoprotein(a) and household historical past predict heart problems threat. J Am Coll Cardiol 2020;76:781–93. https://doi.org/10.1016/j.jacc.2020.06.040
7. Burgess S, Ference BA, Staley JR et al; European Potential Investigation Into Most cancers and Diet–Cardiovascular Illness (EPIC-CVD) Consortium. Affiliation of LPA variants with threat of coronary illness and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization evaluation. JAMA Cardiol 2018;3:619–27. https://doi.org/10.1001/jamacardio.2018.1470
8. Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG. Lipoprotein(a)-lowering by 50 mg/dL (105 nmol/L) could also be wanted to cut back heart problems 20% in secondary prevention: a population-based examine. Arterioscler Thromb Vasc Biol 2020;40:255–66. https://doi.org/10.1161/ATVBAHA.119.312951 [Epub online ahead of print]
9. Kronenberg F, Mora S, Stroes ESG et al. Lipoprotein(a) in atherosclerotic heart problems and aortic stenosis: a European Atherosclerosis Society consensus assertion. Eur Coronary heart J 2022;43:3925–46. https://doi.org/10.1093/eurheartj/ehac361
10. Fless GM, ZumMallen ME, Scanu AM. Physicochemical properties of apolipoprotein(a) and lipoprotein(a-) derived from the dissociation of human plasma lipoprotein (a). J Biol Chem 1986;261:8712–8.
11. McLean JW, Tomlinson JE, Kuang WJ et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987;330:132–7.
12. Tsimikas S, Witztum JL. The function of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol 2008;19:369–77. https://doi.org//10.1097/MOL.0b013e328308b622
13. Behera S, Belyeu JR, Chen X et al. Identification of allele-specific KIV-2 repeats and affect on Lp(a) measurements for heart problems threat. bioRxiv [Preprint] 2023:2023.04.24.538128. https://doi.org/10.1101/2023.04.24.538128
14. Cegla J, France M, Marcovina SM, Neely RDG. Lp(a): When and the way to measure it. Ann Clin Biochem 2021;58:16–21. https://doi.org/10.1177/0004563220968473 [Epub online ahead of print]
15. Virgil Brown W, Ballantyne CM, Jones PH, Marcovina S. Administration of Lp(a). J Clin Lipidol 2010;4:240–247. https://doi.org/10.1016/j.jacl.2010.07.002
16. Durrington PN, Schofield JD, Siahmansur T, Soran H. Lipoprotein (a): gene genie. Curr Opin Lipidol 2014;25:289–96. https://doi.org/10.1097/MOL.0000000000000096
17. Kerschdorfer L, König P, Neyer U et al. Lipoprotein(a) plasma concentrations after renal transplantation: a potential analysis after 4 years of follow-up. Atherosclerosis 1999;144:381–91. https://doi.org/10.1016/s0021-9150(99)00014-3
18. Brief CD, Durrington PN, Mallick NP, Bhatnagar D, Hunt LP, MBewu A. Serum lipoprotein (a) in males with proteinuria because of idiopathic membranous nephropathy. Nephrol Dial Transplant 1992;7(suppl 1):S109–13.
19. Sniderman A, Durrington P. Quick Info: Hyperlipidemia. sixth version. Oxford: Karger, 2021:166.
20. Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boerwinkle E. Defects within the low-density lipoprotein receptor gene have an effect on lipoprotein (a) ranges: multiplicative interplay of two gene loci related to untimely atherosclerosis. Proc Natl Acad Sci USA 1989;86:4171–4.
21. Mbewu AD, Bhatnagar D, Durrington PN et al. Serum lipoprotein(a) in sufferers heterozygous for familial hypercholesterolemia, their relations, and unrelated management populations. Arterioscler Thromb 1991;11:940–6. https://doi.org/10.1161/01.atv.11.4.940
22. de Boer LM, Wiegman A, Kroon J et al. Lipoprotein(a) and carotid intima-media thickness in kids with familial hypercholesterolaemia within the Netherlands: a 20-year follow-up examine. Lancet Diabetes Endocrinol 2023;11:667–74. https://doi.org/10.1016/S2213-8587(23)00156-0 [Epub online ahead of print]
23. Trinder M, DeCastro ML, Azizi H et al. Ascertainment bias within the affiliation between elevated lipoprotein(a) and familial hypercholesterolemia. J Am Coll Cardiol 2020;75:2682–93. https://doi.org/10.1016/j.jacc.2020.03.065
24. Rader DJ, Mann WA, Cain W et al. The low density lipoprotein receptor just isn’t required for regular catabolism of Lp(a) in people. J Clin Make investments 1995;95:1403–8. https://doi.org/10.1172/JCI117794
25. Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G. Lipoprotein(a) in homozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20:522–8. https://doi.org/10.1161/01.atv.20.2.522
26. Chan DC, Pang J, Hooper AJ, Bell DA, Burnett JR, Watts GF. Impact of lipoprotein(a) on the prognosis of familial hypercholesterolemia: does it make a distinction within the clinic? Clin Chem 2019;65:1258–66. https://doi.org/10.1373/clinchem.2019.306738 [Epub online ahead of print] Erratum in: Clin Chem 2020;66:737–8.
27. Hedegaard BS, Bork CS, Kaltoft M et al. Equal Impression of elevated lipoprotein(a) and familial hypercholesterolemia in sufferers with atherosclerotic heart problems. J Am Coll Cardiol 2022;80:1998–2010. https://doi.org/10.1016/j.jacc.2022.09.021
28. Durrington PN, Bashir B, Bhatnagar D, Soran H. Lipoprotein (a) in familial hypercholesterolaemia. Curr Opin Lipidol 2022;33:257–63. https://doi.org/10.1097/MOL.0000000000000839
29. Tavori H, Christian D, Minnier J et al. PCSK9 affiliation with lipoprotein(a). Circ Res 2016;119:29–35. https://doi.org/10.1161/CIRCRESAHA.116.308811 [Epub online ahead of print]
30. Janus ED, Nicoll AM, Turner PR, Magill P, Lewis B. Kinetic bases of the first hyperlipidaemias: research of apolipoprotein B turnover in genetically outlined topics. Eur J Clin Make investments 1980;10:161–72. https://doi.org/10.1111/j.1365-2362.1980.tb02076.x
31. Neil HA, Seagroatt V, Betteridge DJ et al. Established and rising coronary threat elements in sufferers with heterozygous familial hypercholesterolaemia. Coronary heart 2004;90:1431–7. https://doi.org/10.1136/hrt.2003.022764
32. Bogsrud MP, Græsdal A, Johansen D et al. LDL-cholesterol objective achievement, heart problems, and attributed threat of Lp(a) in a big cohort of predominantly genetically verified familial hypercholesterolemia. J Clin Lipidol 2019;13:279–86. https://doi.org/10.1016/j.jacl.2019.01.010 [Epub online ahead of print]
33. Kronenberg F, Mora S, Stroes ESG et al. Frequent questions and responses on the 2022 lipoprotein(a) consensus assertion of the European Atherosclerosis Society. Atherosclerosis 2023;374:107–20. https://doi.org/10.1016/j.atherosclerosis.2023.04.012 [Epub online ahead of print]
34. Moncla LM, Briend M, Bossé Y, Mathieu P. Calcific aortic valve illness: mechanisms, prevention and remedy. Nat Rev Cardiol 2023;20:546–59. https://doi.org/10.1038/s41569-023-00845-7 [Epub online ahead of print]
35. Carlson LA, Hamsten A, Asplund A. Pronounced decreasing of serum ranges of lipoprotein Lp(a) in hyperlipidaemic topics handled with nicotinic acid. J Intern Med 1989;226:271–6. https://doi.org/10.1111/j.1365-2796.1989.tb01393.x
36. Haynes R, Valdes-Marquez E, Hopewell JC et al; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members. Severe hostile results of extended-release niacin/laropiprant: outcomes from the guts safety examine 2-treatment of HDL to cut back the incidence of vascular occasions (HPS2-THRIVE) trial. Clin Ther 2019;41:1767–77. https://doi.org/10.1016/j.clinthera.2019.06.012 [Epub online ahead of print]
37. Honigberg MC, Trinder M, Natarajan P. Lipoprotein(a), menopausal hormone remedy, and threat of coronary coronary heart illness in postmenopausal people. JAMA Cardiol 2022;7:565–8. https://doi.org/10.1001/jamacardio.2022.0716
38. Bhatia HS. Aspirin and lipoprotein(a) in main prevention. Curr Opin Lipidol 2023;34:214–20. https://doi.org/10.1097/MOL.0000000000000891 [Epub online ahead of print]
39. Ho JH, Adam S, Liu Y et al. Impact of bariatric surgical procedure on plasma ranges of oxidised phospholipids, biomarkers of oxidised LDL and lipoprotein(a). J Clin Lipidol 2021;15:320–31. https://doi.org/10.1016/j.jacl.2020.12.002 [Epub online ahead of print]
40. de Boer LM, Oorthuys AOJ, Wiegman A et al. Statin remedy and lipoprotein (a) ranges: a scientific evaluation and meta-analysis. Eur J Prev Cardiol 2022;29:779–92. https://doi.org/10.1093/eurjpc/zwab171
41. Soran H, France M, Adam S, Iqbal Z, Ho JH, Durrington PN. Quantitative analysis of statin effectiveness versus intolerance and techniques for administration of intolerance. Atherosclerosis 2020;306:33–40. https://doi.org/10.1016/j.atherosclerosis.2020.06.023 [Epub online ahead of print]
42. Sammons E, Hopewell JC, Chen F et al; REVEAL Collaborative Group. Lengthy-term security and efficacy of anacetrapib in sufferers with atherosclerotic vascular illness. Eur Coronary heart J 2022;43:1416–24. https://doi.org/10.1093/eurheartj/ehab863
43. Das Pradhan A, Glynn RJ, Fruchart JC et al; PROMINENT Investigators. Triglyceride decreasing with pemafibrate to cut back cardiovascular threat. N Engl J Med 2022;24;387:1923–34. https://doi.org/10.1056/NEJMoa2210645 [Epub online ahead of print]
44. Baigent C, Landray MJ, Reith C et al; SHARP Investigators. The results of decreasing LDL ldl cholesterol with simvastatin plus ezetimibe in sufferers with continual kidney illness (Research of Coronary heart and Renal Safety): a randomised placebo-controlled trial. Lancet 2011;377:2181–92. https://doi.org/10.1016/S0140-6736(11)60739-3 [Epub online ahead of print]
45. O’Donoghue ML, Fazio S, Giugliano RP et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular threat. Circulation 2019;139:1483–92. https://doi.org/10.1161/CIRCULATIONAHA.118.037184
46. Parhofer KG. Apheresis: what ought to a clinician know? Curr Atheroscler Rep 2023;25:77–83. https://doi.org/10.1007/s11883-023-01081-7 [Epub online ahead of print]
47. Gudbjartsson DF, Thorgeirsson G, Sulem P et al. Lipoprotein(a) focus and dangers of heart problems and diabetes. J Am Coll Cardiol 2019;74:2982–94. https://doi.org/10.1016/j.jacc.2019.10.019 [Epub online ahead of print]
48. MBewu AD, Durrington PN, Mackness MI, Hunt L, Turkie WH, Creamer JE. Serum Lp(a) lipoprotein focus and consequence of thrombolytic remedy for myocardial infarction. Br Coronary heart J 1994;71:316–21. https://doi.org/10.1136/hrt.71.4.316
49. Langsted A, Kamstrup PR, Nordestgaard BG. Excessive Lipoprotein(a) and low threat of main bleeding in mind and airways within the basic inhabitants: a Mendelian randomization examine. Clin Chem 2017;63:1714–23. https://doi.org/10.1373/clinchem.2017.276931 [Epub online ahead of print]
50. Nationwide Institute for Well being and Care Excellence. Alirocumab for treating main hypercholesterolaemia and combined dyslipidaemia [TA393]. 2016. London: NICE. Obtainable at: https://www.good.org.uk/steerage/ta393 (accessed March 2024)
51. Nationwide Institute for Well being and Care Excellence. Evolocumab for treating main hypercholesterolaemia and combined dyslipidaemia [TA394]. 2016. London: NICE. Obtainable at: https://www.good.org.uk/steerage/ta394 (accessed March 2024)