Novel insights into lipoprotein(a): News from Atherosclerosis

Lipoprotein(a) [Lp(a)] has had a varied history. While numerous epidemiologic studies documented an association of elevated Lp(a) levels with increased risk of cardiovascular disease [[1]Kostner K.M. Kostner G.M. Lipoprotein(a): still an enigma?.Curr. Opin. Lipidol. 2002; 13: 391-396Google Scholar], it was not until the advent of genetic studies, especially those using a Mendelian randomization design, that the association with cardiovascular outcomes, including myocardial infarction (MI) and ischaemic stroke, as well as aortic valve stenosis, was demonstrated [2Kamstrup P.R. Lipoprotein(a) and cardiovascular disease.Clin. Chem. 2021; 67: 154-166Google Scholar, 3Kamstrup P.R. Tybjærg-Hansen A. Steffensen R. Nordestgaard B.G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA. 2009; 301 (2009): 2331-2339Google Scholar, 4Kamstrup P.R. Benn M. Tybjaerg-Hansen A. Nordestgaard B.G. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study.Circulation. 2008; 117: 176-184Google Scholar, 5Langsted A. Nordestgaard B.G. Kamstrup P.R. Elevated lipoprotein(a) and risk of ischemic stroke.J. Am. Coll. Cardiol. 2019; 74: 54-66Google Scholar, 6Langsted A. Kamstrup P.R. Nordestgaard B.G. High lipoprotein(a) and high risk of mortality.Eur. Heart J. 2019; 40: 2760-2770Google Scholar, 7Erqou S. Kaptoge S. Perry P.L. et al.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.JAMA. 2009; 302: 412-423Google Scholar, 8Clarke R. Peden J.F. Hopewell J.C. et al.Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Google Scholar, 9Thanassoulis G. Campbell C.Y. Owens D.S. et al.Genetic associations with valvular calcification and aortic stenosis.N. Engl. J. Med. 2013; 368: 503-512Google Scholar, 10Kamstrup P.R. Tybjærg-Hansen A. Nordestgaard B.G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.J. Am. Coll. Cardiol. 2014; 63: 470-477Google Scholar]. Collectively, these findings prompted expert reappraisal and reconsideration of Lp(a) in clinical guidelines [11Nordestgaard B.G. Chapman M.J. Ray K. et al.Lipoprotein(a) as a cardiovascular risk factor: current status.Eur. Heart J. 2010; 31: 2844-2853Google Scholar, 12Mach F. Baigent C. Catapano A.L. et al.ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2019; 41 (2020): 111-188Google Scholar, 13Grundy S.M. Stone N.J. Bailey A.L. et al.AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.Circulation. 2019; 139: e1082-e1143Google Scholar] and catalysed the development of novel therapeutic approaches to managing elevated Lp(a). The final test – whether lowering elevated Lp(a) concentration reduces cardiovascular events – awaits the results of the ongoing Lp(a)HORIZONS trial [[14]Assessing the impact of lipoprotein (A) lowering with TQJ230 on major cardiovascular events in patients with CVD.http://doi.org/10.31525/ct1-nct04023552Google Scholar]. Yet we have still much to learn about this enigmatic lipoprotein. Recent studies in Atherosclerosis extend our knowledge about Lp(a) epidemiology, including its association with peripheral artery disease (PAD) outcomes, and different manifestations of aortic valve disease. Lp(a) concentration is known to vary among different ethnicities, potentially impacting its association with cardiovascular risk. The INTERHEART Study showed that the population-attributable risk for MI was higher in ethnic groups with higher Lp(a) levels, such as South Asian and Latin American individuals [[15]Pare G. Caku A. McQueen M. et al.Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups.Circulation. 2019; 139: 1472-1482Google Scholar]. However, limited information among populations with ethnic diversity, as in South East Asia, may lead to uncertainty about the need for Lp(a) measurement as recommended in clinical guidelines. A recent study from Singapore addressed this gap in evidence, using a cohort from the Singapore Coronary Artery Disease Genetics Study (SCADGENS), an ongoing cross-sectional multi-ethnic study [[16]Loh W.J. Chang X. Aw T.C. et al.Lipoprotein(a) as predictor of coronary artery disease and myocardial infarction in a multi-ethnic Asian population.Atherosclerosis. 2021; https://www.atherosclerosis-journal.com/article/S0021-9150(21)01446-5/fulltextGoogle Scholar]. Specifically, the study investigated whether Lp(a) was a predictor of coronary artery disease (CAD) in different ethnic groups using data from 2,025 individuals (94% men, 62% of Chinese ethnicity) who underwent coronary angiography. Three groups were defined: patients with CAD (≥50% stenosis) and a history of MI, those with CAD alone, and normal (<30% stenosis). The frequency of elevated Lp(a) (≥120 nmol/L) was highest among the group with CAD and MI (11.8%) compared with those with CAD alone or with normal angiography (9.1% and 2.4%, respectively). Across each group, Lp(a) levels were highest among Asian Indians, and lowest among Chinese individuals. Irrespective of ethnic background, however, higher Lp(a) concentration was predictive of increased risk for CAD. Thus, despite the recognised caveats of a cross-sectional study design, these findings should counter potential barriers to measuring Lp(a) in this region, given that elevated concentration is predictive of increased CAD risk in this multi-ethnic cohort. PAD has been in the news following a 2021 Joint Statement from the European Atherosclerosis Society and the European Society of Vascular Medicine, which highlighted the importance of lipid lowering therapy to reduce the very high cardiovascular risk associated with this patient group [[17]Belch J.J.F. Brodmann M. Baumgartner I. et al.Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease: European Atherosclerosis society/European society of vascular medicine Joint statement.Atherosclerosis. 2021; 338: 55-63Google Scholar]. Much of the focus was on low-density lipoprotein cholesterol, the priority lipid target. There is, however, evidence for a likely association between elevated Lp(a) concentration and PAD phenotypes [[18]Laschkolnig A. Kollerits B. Lamina C. et al.Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts.Cardiovasc. Res. 2014; 103: 28-36Google Scholar,[19]Gurdasani D. Sjouke B. Tsimikas S. et al.Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-norfolk prospective population study.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 3058-3065Google Scholar]. Recent insights from Athero-Express also indicate an association of plasma Lp(a) concentration and risk of (recurrent) major adverse limb events in patients with severe PAD undergoing surgical intervention [[20]Verwer M.C. Waissi F. Mekke J.M. et al.High Lipoprotein(a) Is Associated with Major Adverse Limb Events after Femoral Artery Endarterectomy. Atherosclerosis, 2021https://linkinghub.elsevier.com/retrieve/pii/S0021915021014477Google Scholar]. This study evaluated data from 384 patients from the Athero-Express Biobank with severe PAD (73% male, mean age 69 years) who underwent iliofemoral endarterectomy. Overall, 41% had undergone peripheral intervention and 43% had CAD. Lp(a) levels ranged from 7 to 566 nmol/L (median 25.9 nmol/L). Over a median follow-up of 5.6 years, 132 patients experienced 225 major adverse limb events (MALE), a composite of infrainguinal (endo)vascular interventions performed due to a loss of patency or novel stenosis/occlusion. In total, 94 (42%) MALE were recurrent events. Elevated Lp(a) concentration was associated with increased risk of both first (Hazard ratio 1.36, 95% confidence interval 1.02–1.82, p = 0.036) and recurrent MALE (1.36, 1.10–1.67, p = 0.004) [[20]Verwer M.C. Waissi F. Mekke J.M. et al.High Lipoprotein(a) Is Associated with Major Adverse Limb Events after Femoral Artery Endarterectomy. Atherosclerosis, 2021https://linkinghub.elsevier.com/retrieve/pii/S0021915021014477Google Scholar]. Although the patient population was of Western European ancestry, potentially limiting wider generalisability, this consistent association with MALE implies that measuring Lp(a) would identify those patients at high risk of recurrent MALE and allow for targeting therapeutic interventions. Given that the prevalence of PAD is increasing in aging populations [[21]Fowkes F.G. Aboyans V. Fowkes F.J. et al.Peripheral artery disease: epidemiology and global perspectives.Nat. Rev. Cardiol. 2017; 14: 156-170Google Scholar], these findings suggest likely cost and quality of life benefits with inclusion of Lp(a) measurement in standard lipid screening of PAD patients. Elevated Lp(a) is already recognised as a risk factor for aortic valve calcification and stenosis [[9]Thanassoulis G. Campbell C.Y. Owens D.S. et al.Genetic associations with valvular calcification and aortic stenosis.N. Engl. J. Med. 2013; 368: 503-512Google Scholar,[10]Kamstrup P.R. Tybjærg-Hansen A. Nordestgaard B.G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.J. Am. Coll. Cardiol. 2014; 63: 470-477Google Scholar]. It is, however, not known whether it is also associated with mitral valve calcification, a common finding on imaging studies [[22]Massera D. Kizer J.R. Dweck M.R. Mechanisms of mitral annular calcification.Trends Cardiovasc. Med. 2020; 30: 289-295Google Scholar]. This analysis from the Copenhagen General Population Study addressed this question [[23]Kaltoft M. Sigvardsen P.E. Afzal S. et al.Elevated Lipoprotein(a) in Mitral and Aortic Valve Calcification and Disease: the Copenhagen General Population Study. Atherosclerosis, 2021https://www.atherosclerosis-journal.com/article/S0021-9150(21)01468-4/fulltextGoogle Scholar], using data from 12,006 individuals (mean age 59.2 years, 57% female) who underwent computed tomography scanning for mitral and aortic valve calcification and had information on Lp(a) (plasma levels and genetic data). Overall, 1,521 individuals (13%) had mitral valve calcification and 3,018 (25%) had aortic valve calcification. Incidences were higher among older individuals (29% and 56%, respectively, among those aged 70–79 years). Elevated plasma Lp(a) was both observationally and genetically associated with increased risk of mitral and aortic valve calcification. A 10-fold increase in Lp(a) concentration increased risk for mitral and aortic valve calcification by 26% (odds ratio 1.26, 95% confidence interval 1.13–1.41) and 62% (1.62, 1.48–1.77), respectively. Similarly, risk for both conditions was increased among individuals with a lower number of kringle IV type 2 repeats (≤23 versus ≥36), or with LPA single nucleotide polymorphisms (for the rs10455872 variant, risk was increased by 33% and 86%, respectively, when compared with non-carriers). The increased risk of aortic valve calcification was accompanied by an increased risk for aortic valve stenosis, mediated in part by elevated Lp(a) concentration. However, the investigators failed to show a link between mitral valve calcification and clinical manifestations of mitral valve stenosis and regurgitation. This may relate to the limited number of mitral valve events in this report; 0.2% (n = 19) of subjects had mitral valve stenosis versus 1.4% (n = 1,158) with aortic valve stenosis, with a similar low percentage with mitral or aortic valve regurgitation (0.4% and 0.3%, respectively). Taken together, and consistent with other studies [[9]Thanassoulis G. Campbell C.Y. Owens D.S. et al.Genetic associations with valvular calcification and aortic stenosis.N. Engl. J. Med. 2013; 368: 503-512Google Scholar,[10]Kamstrup P.R. Tybjærg-Hansen A. Nordestgaard B.G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.J. Am. Coll. Cardiol. 2014; 63: 470-477Google Scholar,[24]Garg P.K. Guan W. Karger A.B. et al.Lipoprotein (a) and risk for calcification of the coronary arteries, mitral valve, and thoracic aorta: the Multi-Ethnic Study of Atherosclerosis.J. Cardiovasc. Comput. Tomogr. 2021; 15: 154-160Google Scholar],these findings imply that Lp(a) facilitates both aortic and mitral valve calcification, suggesting that it may be a common factor in the pathway of cardiac valve calcification. Given escalating prevalence of cardiac valve calcific disease in aging societies, and the associated burden of morbidity and mortality, further study is clearly indicated. There is now extensive support for elevated Lp(a) concentration as a causal risk factor for ASCVD and aortic valve disease, providing a strong rationale for the development of novel, specific interventions for this lipoprotein. RNA therapeutics that specifically target hepatic synthesis of apolipoprotein(a) are in development. These include the antisense oligonucleotide pelacarsen, currently being tested in the Lp(a)HORIZONS trial [[14]Assessing the impact of lipoprotein (A) lowering with TQJ230 on major cardiovascular events in patients with CVD.http://doi.org/10.31525/ct1-nct04023552Google Scholar], as well as small interfering RNA (siRNA) therapeutics. In a recent phase I dose escalation study [[25]Koren M.J. Moriarty P.M. Baum S.J. et al.Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).Nat. Med. 2022; https://doi.org/10.1038/s41591-021-01634-wGoogle Scholar], olpasiran, a first-in-class N-acetylgalactosamine-conjugated siRNA, substantially reduced Lp(a) concentration with effects persisting for several months. Although at an early stage of development, these findings support for continued investigation with this agent.