News from the 90th EAS Congress, Milan Italy: Tuesday 24th May, 2022
Lipoprotein(a) was in the spotlight in two key presentations in this session.
Is lipoprotein(a) prothrombotic?This question is highly pertinent given that the apo(a) component of Lp(a) is structurally similar to plasminogen, and also is a competitor in vitro for binding sites resulting in reduced fibrinolysis and the formation of thrombi.1 Dr Elena Olmastroni (University of Milan) addressed this by evaluating whether Lp(a) had a genetically and clinically meaningful venous or arterial prothrombotic effect using data from the UK Biobank.2 This is a large prospective UK cohort study including ~500,000 subjects (median Lp(a) 18.7 nmol/L), aged 40-70 years who were recruited between 2006 and 2010 and followed for at least 10 years thereafter. Subjects had both plasma Lp(a) levels measured using a single assay (isoform insensitive), and also data relating to their polygenic disposition to elevated Lp(a), determined using a genetic score based on carriage of two variants in the LPA gene (rs3798220 and rs10455872). The two key endpoints were Major Coronary Events (MCE), defined as a fatal or non-fatal myocardial infarction, or coronary revascularisation, and Venous Thromboembolic Events (VTE), a composite of deep vein thrombosis and pulmonary embolism.
Using adjusted logistic regression analysis, there was no association between Lp(a) and risk for a VTE, based on either measured Lp(a) plasma concentration or the LPA genetic score. However, both higher plasma Lp(a) levels and higher LPA genetic score were associated with an increased risk for MCE. To investigate whether this risk was mediated via a prothrombotic mechanism, the researchers constructed an antiplatelet genetic instrument based on the presence of variants in the gene encoding guanylate cyclase soluble subunit alpha-3 (GUCY1A3), which is involved in regulating vascular tone and platelet activation, as well as an antithrombotic genetic instrument taking into account variants in the Factor II and Factor V genes to mimic the effect of an antithrombin therapy.
Using adjusted Cox proportional hazards modelling, it was demonstrated that the increased risk of MCE caused by elevated Lp(a) concentration was not mediated via an arterial prothrombotic effect, and was therefore unlikely to be impacted by either antiplatelet or antithrombin therapy.
How do clinicians manage the increased cardiovascular risk associated with elevated Lp(a) concentration? In the absence of specific Lp(a)-lowering therapies, guidelines recommend intensification of risk factor modification in individuals with increased cardiovascular risk due to elevated Lp(a) concentration.3 Professor Brian Ference (University of Cambridge, UK) highlighted the need for practical guidance for clinicians regarding the magnitude of intensification that is required, which is not provided in the guidelines.
Using the UK Biobank cohort (N= 445,765 subjects without a history of cardiovascular events, diabetes, or any cancer before the age of 30 years), the researchers determined the trajectories of increased absolute lifetime risk of MCE due to elevated Lp(a) levels. They also determined the absolute risk of atherosclerotic cardiovascular disease (ASCVD) due to BOTH higher Lp(a) and lower low-density lipoprotein cholesterol (LDL-C) levels.
The magnitude of intensification of LDL-C lowering needed to overcome risk caused by elevated Lp(a) concentration depends on the age that LDL-C lowering is initiated. Therefore, if people with elevated Lp(a) concentration are identified early they require less intensive LDL-C lowering than those identified later in life.4 This underlines the need to measure Lp(a) early in life, as recommended by guidelines,3 so as to identify individuals at higher risk due to elevated Lp(a) levels who would benefit from early modest risk factor intensification. This strategy personalises ASCVD prevention specifically in relation to the risk associated with elevated Lp(a) concentration.
References
1. Koschinsky ML, Kronenberg F. Atherosclerosis 2022;349:1-6.
2. Olmastroni E, Galimberti F, Laufs U, et al. Lipoprotein(a) does not have a clinically significant arterial or venous prothrombotic effect. Late Breaker 2. Tuesday 24th May.
3. Mach F, Baigent C, Catapano AL, et al. Eur Heart J 2020;41:111-188.
4. Galimberti F, Olmastroni E, Catapano AL, Ference BA. Estimating the magnitude of LDL-C reduction needed to overcome the increased risk of atherosclerotic cardiovascular events caused by Lp(a) to guide clinical management. Late Breaker 2. Tuesday 24th May.
