Update on lipoprotein(a): the rising star in residual lipid risk

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on Dyslipidaemias starts with a Special Article entitled ‘Familial hypercholesterolaemia in children and adolescents: a European Atherosclerosis Society consensus statement’, by Albert Wiegman from Amsterdam University Medical Center in the Netherlands, and colleagues. The aim of the authors was to address the challenges of familial hypercholesterolaemia (FH), supported by increased knowledge of its pathogenesis and the availability of an increasing range of lipid-lowering therapies (LLTs) that can be used from early ages.1 FH is a common genetic disorder characterized by lifelong elevated LDL cholesterol (LDL-C) concentrations. FH exists in two forms: heterozygous FH (HeFH), which affects ∼1 in 300 people worldwide, and homozygous FH (HoFH), which affects ∼1 in 300 000. Individuals with FH are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD) and death, and those with HoFH are, if untreated, at extreme risk of ASCVD manifestations even before adulthood.2–11 Early diagnosis and treatment in childhood can extend or normalize life expectancy, but limited awareness, underdiagnosis, and undertreatment remain major challenges. To increase the detection rate of FH, all countries are encouraged to establish a paediatric screening programme and, given that current diagnostic criteria often fail to identify children with an FH-causing genetic variant, revised diagnostic criteria are presented. Updated LDL-C treatment goals are proposed, and the importance of starting LLTs before puberty in children with HeFH and, if needed, from 6 years of age, is highlighted. Guidance on how to manage FH is provided, including treatment algorithms for use in children with either HeFH or HoFH and a discussion on how to promote a smooth transition to adult care. Early detection and optimal treatment as advocated in this consensus statement are crucial to improving life expectancy for children and adolescents with FH. Despite significant advances in LLTs, residual lipid risk persists in patients with or at risk of ASCVD, even after optimizing LDL-C. In a State of the Art Review article entitled ‘Residual lipid risk in atherosclerotic cardiovascular disease’, Børge Nordestgaard from Copenhagen University Hospital–Herlev and Gentofte Hospital, Denmark, and colleagues explore the evolving understanding of residual lipid risk in ASCVD, practical guidance for clinicians today, recent advances in therapeutic interventions, and their implications for clinical practice, aiming to optimize lipid management beyond LDL-C reduction today and in the future.12 Emerging evidence highlights the role of non-LDL-C fractions, such as remnant cholesterol, lipoprotein(a) [Lp(a)],13–17 apolipoprotein B (apoB), and non-HDL-C, as key contributors to residual ASCVD risk (Figure 1). Remnant cholesterol, Lp(a), and LDL-C represent three independent lipoprotein species causing ASCVD, while apoB and non-HDL-C integrate the other three variables. Thus, clinically interpreting elevated apoB and non-HDL-C is potentially complicated since remnants, Lp(a), and LDL cause ASCVD by different mechanisms and by varying proportions in different patients. Indeed, recent research into the pathophysiology of lipid-driven atherogenesis and development of ASCVD has revealed novel mechanisms that in turn suggest new therapeutic strategies targeting non-LDL-C lipid components. Elevated remnant cholesterol jointly with elevated LDL-C contributes to arterial wall cholesterol deposition, plaque development, and ASCVD endpoints. Furthermore, the additional triglyceride content in remnant particles may theoretically promote intimal inflammation and possibly plaque rupture and erosion, independently contributing to atherogenesis and ASCVD. The lipid component and proinflammatory properties of Lp(a) could similarly contribute directly to atherosclerotic plaque development and ASCVD. In addition, the homology with plasminogen of the defining apolipoprotein(a) moiety of Lp(a) has long been speculated to confer antifibrinolytic and prothrombotic properties that could produce more severe ASCVD outcomes independent of atherogenesis. Pathophysiology, diagnosis, current therapies for residual lipid risk, and novel therapies for atherosclerotic cardiovascular disease.12 On the basis of seminal genetic discoveries, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were developed as a new class of LDL-C-lowering drug, with a potency on a par with and on top of high-intensity statins and an excellent safety profile. In a State of the Art Review article entitled ‘Proprotein convertase subtilisin/kexin type 9 inhibitors: past, present, and future’, Marc Sabatine from Harvard Medical School in Boston, MA, USA, and colleagues examine the clinical impact and future therapeutic potential of PCSK9 inhibition for LDL-C reduction and cardiovascular risk prevention.18 A series of large cardiovascular outcome trials have now established the ability of monoclonal antibody PCSK9 inhibitors to reduce the risk of major adverse cardiovascular outcomes across a broad range of patients, including those with a prior major ASCVD event, those with atherosclerosis but without a prior major ASCVD event, and those with diabetes. Moreover, these trials have shown the clinical benefit of lowering LDL-C to ∼1 mmol/L (∼40 mg/dL) in such patients. New members of this class are being studied, including oral inhibitors, RNA interference, and gene therapy. Lp(a) is a significant, genetically determined contributor to the risk of ASCVD, which remains the leading cause of mortality worldwide despite successes in the management of LDL-C. In a State of the Art Review article entitled ‘Lipoprotein(a)-lowering therapies: a promising future’, Jingwen Zhang from the University of Texas Southwestern Medical Center in Dallas, TX, USA, and colleagues sum