2022, Volume 29, Supplement 1: Lipoprotein(a) – a perspective on its role in cardiovascular and calcific aortic valve disease

Lipoprotein(a): a historical perspective

March 2022 Br J Cardiol 2022;29(suppl 1):S3–S6

Lipoprotein(a): a historical perspective

R Dermot G Neely

Abstract

Nearly 60 years after it was first described by the Norwegian physician and geneticist Kare Berg in 1963, lipoprotein(a) (Lp[a]) has finally become accepted as an inherited, causal cardiovascular disease risk factor, and a potential target for new therapeutic interventions. Why has it taken so long? A major reason has been the technical challenge of Lp(a) measurement, which has long confounded attempts to prove a causal role for Lp(a) in long-term prospective atherosclerotic cardiovascular disease (ASCVD) outcome studies. Due to its unique macromolecular structure, with a highly variable number of kringle IV type 2 domains in the covalently bound apolipoprotein(a) moiety, serum concentrations spanning a range of 1000-fold between individuals, and instability on long-term storage, it is extraordinarily difficult to quantify Lp(a) reliably. Only with more recent advances in understanding of the genetic determinants of Lp(a) concentrations, the advent of genome-wide association studies, and large-scale epidemiological investigations using the Mendelian-randomisation approach, has conclusive evidence finally been assembled to show that elevated Lp(a) concentrations are causally associated with increased risk of ASCVD....

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Lipoprotein(a): mechanisms of pathogenicity

March 2022 Br J Cardiol 2022;29(suppl 1):S7–S10

Lipoprotein(a): mechanisms of pathogenicity

Tina Z Khan

Abstract

Lipoprotein(a) (Lp[a]) promotes the progression of atherosclerosis and cardiovascular disease through numerous pleiotropic effects including Lp(a) deposition in the intima, inflammatory cell recruitment and binding of pro-inflammatory-oxidised phospholipids, such as oxidised low-density lipoprotein (LDL). In addition, elevated Lp(a) has prothrombotic properties via the inhibition of fibrinolysis and enhanced coagulation. The cardiovascular manifestations associated with raised Lp(a), which is co-dominantly inherited, are also mediated by its genotypic profile; suggesting that, in future, genetic profiling of patients with raised Lp(a) may help in terms of cardiovascular risk stratification. Whether the multi-factorial pathogenic effects of Lp(a) can be reversed by lowering raised Lp(a) remains an interesting and clinically important question. So far, only a handful of small randomised studies have attempted to address this question, and have mainly been limited to assessing the impact of lipoprotein apheresis, which is a non-selective therapy for Lp(a). Nevertheless they have shown promising findings, such as demonstrating improvements in atherosclerotic plaque burden, myocardial perfusion, microvascular function, thrombogenic parameters and oxidised LDL. In future, mechanistic studies involving specific Lp(a)-lowering therapies are needed to establish the specific role that Lp(a) plays in the progression of cardiovascular disease....

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Lipoprotein(a): marker and target in calcific aortic valve disease

March 2022 Br J Cardiol 2022;29(suppl 1):S11–S14

Lipoprotein(a): marker and target in calcific aortic valve disease

Kang H Zheng, Marc R Dweck

Abstract

Calcific aortic valve disease (CAVD) is the most common valvular disorder and is set to become a major healthcare burden with an ageing population. Currently, there are no approved medical therapies known to halt or slow down progression of CAVD. Novel insights in the valvular pathophysiology of aortic stenosis could result in the identification of modifiable risk factors and disease pathways to prevent or slow down CAVD. Elevated plasma levels of lipoprotein(a) (Lp[a]), a low-density lipoprotein (LDL)-like particle, have been recognised to be a strong, genetic and highly likely causal risk factor for CAVD. This review will address the present state of knowledge with regards to the role of Lp(a) in the pathophysiology of CAVD....

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How to measure lipoprotein(a) and in whom

March 2022 Br J Cardiol 2022;29(suppl 1):S15–S19

How to measure lipoprotein(a) and in whom

Christopher S Boot

Abstract

Historically, progress in establishing the contribution of lipoprotein(a) (Lp[a]) in cardiovascular disease (CVD) pathogenesis has been compromised by a lack of standardised methods for measuring serum levels of this atherogenic lipoprotein. It is important to identify who should be tested, and what ‘normal’ levels and treatment targets might be. Serum Lp(a) concentrations should be measured using a method where the effect of isoform size has been minimised using appropriate antibodies and calibrators certified for traceability of Lp(a) values to the WHO/IFCC reference material to achieve optimal standardisation and consistency in testing....

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Current management of the patient with high lipoprotein(a)

March 2022 Br J Cardiol 2022;29(suppl 1):S20–S23

Current management of the patient with high lipoprotein(a)

Wei Yang, Jaimini Cegla

Abstract

Lipoprotein(a) (Lp[a]), a low-density lipoprotein (LDL)-like particle with strong genetically predetermined concentration, is an independent risk factor for cardiovascular disease. Although evidence from previous clinical studies suggests that lowering Lp(a) level may reduce cardiovascular risk, there is no selective therapeutic management approved so far. Non-selective lipoprotein apheresis has limited use, only applying to extreme cases. Promising selective interventions in development, such as antisense oligonucleotides and siRNA therapies, need proper randomised-controlled trials for further assessment. The current management of raised Lp(a) is focused on optimising other risk factors, such as smoking, diet, hypertension, diabetes and high LDL-cholesterol level to reduce the overall cardiovascular risk....

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