Should Lipoprotein(a) be Measured in Youth?

Abstract

The Journal of Clinical Lipidology published a scientific statement on behalf of the National Lipid Association (NLA) concerning the utility of measuring lipoprotein(a) [Lp(a)] as a biomarker in clinical practice.1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar The scientific statement of the NLA summarizes published data from meta-analyses, large observational studies, Mendelian randomization studies, and genome-wide association studies, all of which support elevated levels of Lp(a) as an independent risk factor in the development of atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD)-related events, including myocardial infarction (MI), ischemic stroke, atherosclerotic stenosis, and valvular aortic stenosis. Recommendations are offered for laboratory testing of Lp(a), risk stratification, and treatment of children and adults with elevated levels. Other organizations and professional societies have published guidelines as well.1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 2Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).Eur Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1514) Google Scholar, 3Nordestgaard B.G. Chapman M.J. Ray K. Borén J. Andreotti F. Watts G.F. et al.Lipoprotein (a) as a cardiovascular risk factor: current status.Eur Heart J. 2010; 31: 2844-2853Crossref PubMed Scopus (1057) Google Scholar, 4Arnett D.K. Blumenthal R.S. Albert M.A. Buroker A.B. Goldberger Z.D. Hahn E.J. et al.2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2019; 74: 1376-1414Crossref PubMed Scopus (309) Google Scholar, 5Jellinger P.S. Handelsman Y. Rosenblit P.D. Bloomgarden Z.T. Fonseca V.A. Garber A.J. et al.American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.Endocrine Pract. 2017; 23: 1-87Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar Although European guidelines have advocated universal Lp(a) screening at least once in an individual's lifetime, those in the US have suggested targeted screening. By comparison, there is limited information to help clinical decision-making in youth (<18 years of age). We review newer data relevant to youth and discuss the role of elevated Lp(a) as an independent risk factor for premature ASCVD. We call attention to the lack of consolidated guidelines regarding the role of Lp(a) in youth and offer suggestions that may prove useful in clinical practice, and encourage further dialog about this import topic. Large prospective population-based studies of Lp(a) levels using fresh samples and isoform-insensitive measurements demonstrate that compared with those in the lowest 20th percentile (7 nmol/L; <5 mg/dL) adults with Lp(a) in the top 5th percentile (258 nmol/L; >120 mg/dL) have a 3- to 4-fold increase in MI and 3-fold increase in stroke.6Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S.C. et al.Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N Engl J Med. 2009; 361: 2518-2528Crossref PubMed Scopus (862) Google Scholar,7Kamstrup P.R. Tybjaerg-Hansen A. Steffensen R. Nordestgaard B.G. Genetically elevated lipoprotein (a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339Crossref PubMed Scopus (720) Google Scholar Genome-wide association studies focusing on the links between genetic variation and risk of disease concluded that of all known genetic variation in the human genome, genetic variation for elevated Lp(a) is associated with the highest risk of ASCVD and valvular aortic stenosis. Individuals with extremely elevated Lp(a) levels >180 mg/dL (>430 nmol/L) appear to have a lifetime risk of premature ASCVD equivalent to individuals with heterozygous familial hypercholesterolemia.2Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).Eur Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1514) Google Scholar Published studies, however, have shown that large absolute changes in Lp(a) may be needed to produce a significantly meaningful reduction in the risk of ASCVD-related events.8Burgess S. Ference B.A. Staley J.R. Freitag D.F. Mason A.M. Nielsen S.F. et al.Association of LPA variants with risk of coronary disease and the implications for lipoprotein (a)-lowering therapies: a Mendelian randomization analysis.JAMA Cardiol. 2018; 3: 619-627Crossref PubMed Scopus (174) Google Scholar These publications represent only a few of the many studies that have convincingly demonstrated the causal role of Lp(a) in atherosclerosis. Unlike acquired risk factors, levels of Lp(a) are 90% genetically determined; this exposure to elevated levels of atherogenic lipoprotein is present from birth and continues throughout the individual's lifetime. Effective treatments to safely lower Lp(a) levels are lacking. Although the cholesterol content of Lp(a) is included in standard laboratory estimates of low-density lipoprotein-cholesterol (LDL-C), lowering of Lp(a) is not accomplished by medications commonly used in clinical practice to lower LDL-C, such as statins and ezetimibe. Paradoxically, mild elevation of Lp(a) and oxidized phospholipids may be observed in response to statin therapy. This effect of statins, however, seems to be primarily in individuals with the low-molecular weight apolipoprotein(a) phenotype.9Yahya R. Berk K. Verhoeven A. Bos S. Van Der Zee L. Touw J. et al.Statin treatment increases lipoprotein (a) levels in subjects with low molecular weight apolipoprotein (a) phenotype.Atherosclerosis. 2019; 289: 201-205Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Unlike statins, PCSK9 inhibitors (PCSK9i) are among the few drugs that have an ability to lower Lp(a). Although PCSK9i have been shown to modestly reduce Lp(a), it is not clear that this reduction contributed independently to the observed treatment benefit.10Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. et al.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (2392) Google Scholar Nonetheless, it has been suggested that in high-risk and very-high-risk adults, use of more intensive therapies, such as PCSK9i, is reasonable to achieve greater ASCVD risk reduction.1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar In women, hormone replacement therapy with estrogen11Shlipak M.G. Simon J.A. Vittinghoff E. Lin F. Barrett-Connor E. Knopp R.H. et al.Estrogen and progestin, lipoprotein (a), and the risk of recurrent coronary heart disease events after menopause.JAMA. 2000; 283: 1845-1852Crossref PubMed Scopus (307) Google Scholar,12Hulley S. Grady D. Bush T. Furberg C. Herrington D. Riggs B. et al.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA. 1998; 280: 605-613Crossref PubMed Scopus (5488) Google Scholar lowers Lp(a) levels, but is not recommended because it potentially increases the risk of stroke and thrombosis. Although lipoprotein apheresis is successful in the lowering of circulating Lp(a) levels by 60% or more, its use is advocated only for individuals with elevated Lp(a) who, despite maximally tolerated lipid-lowering medications, have persistently elevated LDL-C and a history of recurrent ASCVD-related events.13Moriarty P.M. Hemphill L. Lipoprotein apheresis.Cardiol Clin. 2015; 33: 197-208Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Several targeted therapies, such as apo(a) antisense oligonucleotides, are in development.14Viney N.J. Geary R.S. Wang Y. Yu Z. Gunawan R. Conjugated antisense compounds for use in therapy. Google Patents, 2019Google Scholar Although some of these therapies have been shown to reduce Lp(a) by as much as 80%, data supporting safety and efficacy are lacking. There are no data in children. A consensus statement by the European Society of Cardiology and European Atherosclerosis Society suggests that measurement of Lp(a) be considered at least once in each adult's lifetime to identify those with very high inherited levels of Lp(a) >180 mg/dL (>430 nmol/L) and who, therefore, may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous familial hypercholesterolemia. In addition, testing should be considered in selected individuals with a family history of premature cardiovascular disease (CVD), and for reclassification in individuals who are borderline between moderate and high-risk. In contrast, while acknowledging the potential benefits of universal Lp(a) screening, currently the NLA favors only targeted screening of at-risk adults and children. Screening criteria and a comparison of recommendations by the European Society of Cardiology/European Atherosclerosis Society and NLA are shown in Table I.1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar,2Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).Eur Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1514) Google ScholarTable IA comparison of major guidelines on Lp(a) screening recommendationsEuropean Society of Cardiology and European Atherosclerosis Society∗Class IIa, level of evidence C.Lp(a) measurement should be consideredI. Universal Screening:At least once in each adult person's lifetime to identify those with very high inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous FH.II. Targeted screening: a) In select patients with a family history of premature CVD.b) For reclassification in people who are borderline between moderate and high-risk category.NLA†Class IIa.Targeted screening is recommended:I. Adults (age ≥20 y)a. Measurement of Lp(a) is reasonable to refine risk assessment for ASCVD events in:1) Individuals with a family history of first-degree relatives with premature ASCVD.‡Premature ASCVD <55 y of age in men; <65 years of age in women.2) Individuals with premature ASCVD‡Premature ASCVD <55 y of age in men; <65 years of age in women. particularly in the absence of traditional risk factors.3) Individuals with primary severe hypercholesterolemia (LDL-C ≥190 mg/dL) or suspected FH.4) Individuals at very-high-risk of ASCVD to better define those who are more likely to benefit from PCSK9i therapy.b. Measurement of Lp(a) may be reasonable for individuals with:1) Intermediate (7.5%–19.9%) 10-y ASCVD risk when the decision to use a statin is uncertain, to improve risk stratification in primary prevention.2) Borderline (5%-7.4%) 10-y ASCVD risk when the decision to use a statin is uncertain, to improve risk stratification in primary prevention.3) Less-than-anticipated LDL-C lowering, despite good adherence to LDL-C lowering therapy.4) A family history of elevated Lp(a).5) Calcific valvular aortic stenosis.6) Recurrent or progressive ASCVD, despite optimal lipid-lowering therapy.II. Youth (age <20 y)a. Measurement of Lp(a) may be reasonable with:1) Clinically suspected or genetically confirmed FH.2) A family history of first-degree relatives with premature ASCVD‡Premature ASCVD <55 y of age in men; <65 years of age in women.3) An unknown cause of ischemic stroke.4) A parent or sibling found to have an elevated Lp(a).(Wilson 2019; EHJ 2020).∗ Class IIa, level of evidence C.† Class IIa.‡ Premature ASCVD <55 y of age in men; <65 years of age in women. Open table in a new tab (Wilson 2019; EHJ 2020). The rationale for Lp(a) targeted screening within the adult population is based on several studies demonstrating that lowering LDL-C attenuates the CVD risk attributable to Lp(a).15Verbeek R. Hoogeveen R.M. Langsted A. Stiekema L.C. Verweij S.L. Hovingh G.K. et al.Cardiovascular disease risk associated with elevated lipoprotein (a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.Eur Heart J. 2018; 39: 2589-2596Crossref PubMed Scopus (46) Google Scholar Several recent guidelines1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar,2Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).Eur Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1514) Google Scholar,4Arnett D.K. Blumenthal R.S. Albert M.A. Buroker A.B. Goldberger Z.D. Hahn E.J. et al.2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2019; 74: 1376-1414Crossref PubMed Scopus (309) Google Scholar have incorporated Lp(a) levels, when available, into risk-stratification guidelines for initiation and intensity of statin therapy in adults. More stringent adherence to diet, exercise, and avoidance of smoking is recommended in both adults and children commensurate with the level of risk. Given the well-defined role of Lp(a) as a CVD risk factor, it seems reasonable to consider whether Lp(a) should be measured in youth and, if so, under what circumstances should testing be performed? If measured, it important to consider the potential utility of knowing the Lp(a) level (eg, in improving risk assessment and recommendations for intervention). Elevated Lp(a), defined as >50 mg/dL or >100 nmol/L,1Wilson D.P. Jacobson T.A. Jones P.H. Koschinsky M.L. McNeal C.J. Nordestgaard B.G. et al.Use of Lipoprotein (a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.J Clin Lipid. 2019; 13: 374-392Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar is one of the most common genetic dyslipidemias, affecting nearly 1 in 5 individuals in the US. Levels of Lp(a) are determined by an autosomal co-dominant inheritance. Although acute inflammation may cause temporary interference with measurement, levels remain constant throughout the lifespan of the individual. Adult levels of Lp(a) are achieved by 2 years of age16McNeal C.J. Lipoprotein (a): its relevance to the pediatric population.J Clin Lipidol. 2015; 9: S57-S66Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,17Wang X.L. Wilcken D.E. Dudman N.P. Early expression of the apolipoprotein (a) gene: relationships between infants' and their parents' serum apolipoprotein (a) levels.Pediatrics. 1992; 89: 401-406PubMed Google Scholar and thereafter may serve as a reliable biomarker in helping to assess CVD risk. Although data are limited, studies indicate that even extremely high concentrations of Lp(a) are clinically silent in youth, as defined by a lack of symptoms and absence of evidence of subclinical atherosclerosis using surrogate markers of atherogenesis such as cIMT.18Qayum O. Alshami N. Ibezim C.F. Reid K.J. Noel-MacDonnell J.R. Raghuveer G. Lipoprotein (a): examination of cardiovascular risk in a pediatric referral population.Pediatr Cardiol. 2018; 39: 1540-1546Crossref PubMed Scopus (7) Google Scholar It is important to note that elevated Lp(a) levels have been linked to increased risk of ischemic stroke and peripheral venous thrombosis in childhood. Although genetic data, using Mendelian randomization, have provided supportive evidence that these associations are causal in adults, the evidence is less clearly defined in children.7Kamstrup P.R. Tybjaerg-Hansen A. Steffensen R. Nordestgaard B.G. Genetically elevated lipoprotein (a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339Crossref PubMed Scopus (720) Google Scholar,9Yahya R. Berk K. Verhoeven A. Bos S. Van Der Zee L. Touw J. et al.Statin treatment increases lipoprotein (a) levels in subjects with low molecular weight apolipoprotein (a) phenotype.Atherosclerosis. 2019; 289: 201-205Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 10Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. et al.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (2392) Google Scholar, 11Shlipak M.G. Simon J.A. Vittinghoff E. Lin F. Barrett-Connor E. Knopp R.H. et al.Estrogen and progestin, lipoprotein (a), and the risk of recurrent coronary heart disease events after menopause.JAMA. 2000; 283: 1845-1852Crossref PubMed Scopus (307) Google Scholar, 12Hulley S. Grady D. Bush T. Furberg C. Herrington D. Riggs B. et al.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA. 1998; 280: 605-613Crossref PubMed Scopus (5488) Google Scholar, 13Moriarty P.M. Hemphill L. Lipoprotein apheresis.Cardiol Clin. 2015; 33: 197-208Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 14Viney N.J. Geary R.S. Wang Y. Yu Z. Gunawan R. Conjugated antisense compounds for use in therapy. Google Patents, 2019Google Scholar, 15Verbeek R. Hoogeveen R.M. Langsted A. Stiekema L.C. Verweij S.L. Hovingh G.K. et al.Cardiovascular disease risk associated with elevated lipoprotein (a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.Eur Heart J. 2018; 39: 2589-2596Crossref PubMed Scopus (46) Google Scholar, 16McNeal C.J. Lipoprotein (a): its relevance to the pediatric population.J Clin Lipidol. 2015; 9: S57-S66Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 17Wang X.L. Wilcken D.E. Dudman N.P. Early expression of the apolipoprotein (a) gene: relationships between infants' and their parents' serum apolipoprotein (a) levels.Pediatrics. 1992; 89: 401-406PubMed Google Scholar, 18Qayum O. Alshami N. Ibezim C.F. Reid K.J. Noel-MacDonnell J.R. Raghuveer G. Lipoprotein (a): examination of cardiovascular risk in a pediatric referral population.Pediatr Cardiol. 2018; 39: 1540-1546Crossref PubMed Scopus (7) Google Scholar, 19Kenet G. Lütkhoff L.K. Albisetti M. Bernard T. Bonduel M. Brandao L. et al.Clinical perspective.Circulation. 2010; 121: 1838-1847Crossref PubMed Scopus (278) Google Scholar, 20Sultan S.M. Schupf N. Dowling M.M. DeVeber G.A. Kirton A. Elkind M.S. Review of lipid and lipoprotein (a) abnormalities in childhood arterial ischemic stroke.Int J Stroke. 2014; 9: 79-87Crossref PubMed Scopus (24) Google Scholar, 21Thanassoulis G. Campbell C.Y. Owens D.S. Smith J.G. Smith A.V. Peloso G.M. et al.Genetic associations with valvular calcification and aortic stenosis.N Engl J Med. 2013; 368: 503-512Crossref PubMed Scopus (521) Google Scholar Given Lp(a)'s homology with plasminogen, it seems reasonable that it may inhibit fibrinolysis, thus, increasing thrombosis and potentially causing or contributing to MI and ischemic stroke, including acute ischemic stroke occasionally presenting in childhood.22Boffa M.B. Koschinsky M.L. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?.J Lipid Res. 2016; 57: 745-757Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar,23Brown M.S. Goldstein J.L. Teaching old dogmas new tricks.Nature. 1987; 330: 113-114Crossref PubMed Scopus (169) Google Scholar It is also possible that this unique property of Lp(a) may impair resolution of blood clots, irrespective of the underlying cause. Thus, the role of Lp(a) as a proatherogenic, prothrombotic, and proinflammatory biomarker seems to be established and potentially present from an early age. Several populations may be especially vulnerable to the adverse effects of an elevated Lp(a). Patients with familial hypercholesterolemia (FH) may be at particular risk of accelerated ASCVD when substantially elevated LDL-C is accompanied by an elevated Lp(a). Approximately 30% of individuals with FH24Ellis K.L. de Isla L.P. Alonso R. Fuentes F. Watts G.F. Mata P. Value of measuring lipoprotein (a) during cascade testing for familial hypercholesterolemia.J Am Coll Cardiol. 2019; 73: 1029-1039Crossref PubMed Scopus (36) Google Scholar may have elevated Lp(a), further enhancing CVD-related risk. In children with FH, elevated Lp(a) may be more predictive than elevated LDL-C for early onset disease in family members.25Zawacki A.W. Dodge A. Woo K.M. Ralphe J.C. Peterson A.L. In pediatric familial hypercholesterolemia, lipoprotein (a) is more predictive than LDL-C for early onset of cardiovascular disease in family members.J Clin Lipidol. 2018; 12: 1445-1451Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The 2019 American Heart Association scientific statement for cardiovascular risk reduction in high-risk pediatric patients26de Ferranti S.D. Steinberger J. Ameduri R. Baker A. Gooding H. Kelly A.S. et al.Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association.Circulation. 2019; 139: e603-e634Crossref PubMed Scopus (69) Google Scholar recognized the value of screening for Lp(a) levels in children with FH, noting that elevated Lp(a) “could represent a useful marker to identify young FH patients at very high risk of premature CVD,” and concluding that for youth with high Lp(a), the current approach is “to focus on minimizing the impact of other cardiovascular risk factors, including LDL-C:” Although supporting evidence is limited, further risk enhancement may also be present in those with elevated Lp(a) who develop high risk medical conditions, such as diabetes mellitus and diseases associated with chronic inflammation, such as systemic lupus erythematosus. Although the guidelines by the 2011 National Heart, Lung, and Blood Institute Expert Panel highlighted the importance of global risk assessment and early intervention of youth with moderate-to-high risk medical conditions, the Panel only suggested measurement of Lp(a) in children who had experienced either hemorrhagic or ischemic stroke.27For E.P.O.I.G. children R.R.I. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report.Pediatrics. 2011; 128: S213PubMed Google Scholar Several arguments have been raised in opposition to universal Lp(a) screening in youth. The absence of targeted treatment for lowering Lp(a); the potential of creating unwarranted fear and/or over-treatment of young children found to have elevated levels; the uncertainty that results of Lp(a) testing will be carried forward to help assess risk and inform clinical decision-making as children become adults; and an incomplete understanding of population norms and well -defined risk-thresholds, particularly in children. For example, although extremely high Lp(a) levels in all populations are associated with ASCVD, African and Arab populations demonstrate higher concentrations of Lp(a) across all percentile compared with Caucasians and Asians. Based on the 2004 third National Health Nutrition and Examination Survey (NHANES-III) data,28Obisesan T.O. Aliyu M.H. Adediran A.S. Bond V. Maxwell C.J. Rotimi C.N. Correlates of serum lipoprotein (A) in children and adolescents in the United States. The third National Health Nutrition and Examination Survey (NHANES-III).Lipids Health Dis. 2004; 3: 29Crossref PubMed Scopus (23) Google Scholar the median Lp(a) level in non-Hispanic black children ages 4-19 years is 32 mg/dL; with an Lp(a) of 75 mg/dL representing the 90%. In contrast, non-Hispanic whites have a significantly lower median Lp(a) of 10 mg/dL and 50 mg/dL representing the 90%. It is uncertain whether the higher Lp(a) levels in individuals of African or Arab descent confer greater susceptibility to ASCVD or whether a different risk-threshold exists that needs to be defined in these and other genetic populations. Those who advocate expanded or universal Lp(a) screening propose that knowing that a child's Lp(a) level is elevated helps to define risk and impact clinical decision-making by motivating behavior to improve or avoid other risk factors, and by considering the potential benefits of LDL-C lipid-lowering medications. In contrast to those opposed to universal screening, proponents of universal screening of Lp(a) in childhood view universal screening as an opportunity to better define normative data that will positively impact patient care. It is likely that a biorepository, categorized by genetic background and other important variables, as well as long-term observational follow-up, will help to improve our knowledge of Lp(a)'s role in modifying an individual's risk of premature ASCVD. Utilizing a large multiethnic dataset, Paré et al examined the role of Lp(a) across ethnicities using state-of-the-art methods and was able to confirm an association between Lp(a) >50 mg/dL and MI. Importantly, this association was more or less consistent across ethnicities, indicating that Lp(a) is a risk factor regardless of ethnicity.29Paré G. Çaku A. McQueen M. Anand S.S. Enas E. Clarke R. et al.Lipoprotein (a) levels and the risk of myocardial infarction among 7 ethnic groups.Circulation. 2019; 139: 1472-1482Crossref PubMed Scopus (67) Google Scholar Although out-of-pocket costs vary, testing is generally inexpensive with cost ranging between $50 and $100. Lp(a) testing is readily available commercially and does not require fasting. Often available to youth with private insurance, Lp(a) testing is also covered by public insurance in many states. The cost-benefit ratio of Lp(a) testing and potential of lowering the future financial burden of premature ASCVD, warrants further evaluation. Although there is currently no approved targeted therapy for Lp(a) lowering, several agents are in development which appear to be highly effective in lowering plasma Lp(a), most of which appear to have an excellent safety profile in adults. Phase III outcome trials in adults are currently underway with apo (a) antisense oligonucleotides, an agent that decreases synthesis of Lp(a) by binding to the LPA gene that encodes the apoliporotein (a) component of Lp(a). In recent phase II trials, a once weekly injection produced an impressive 80% decrease in Lp(a) levels, with lowering of Lp(a) levels to <50 mg/dL in 90% of patients.30Tsimikas S. Karwatowska-Prokopczuk E. Gouni-Berthold I. Tardif J.-C. Baum S.J. Steinhagen-Thiessen E. et al.Lipoprotein (a) reduction in persons with cardiovascular disease.N Engl J Med. 2020; 382: 244-255Crossref PubMed Scopus (158) Google Scholar,31Lippi G. Favaloro E.J. Sanchis-Gomar F. Antisense lipoprotein [a] therapy: State-of-the-art and future perspectives.Eur J Intern Med. 2020; Abstract Full Text Full Text PDF Scopus (2) Google Scholar Other treatment modalities32Dolgin E. Lp(a)-lowering drugs bolster cardiovascular pipeline.Nat Rev Drug Discov. 2020; 19: 154-155Crossref PubMed Scopus (1) Google Scholar anticipated to begin phase II trials are in the pipeline. Individuals with elevated Lp(a) levels have a higher lifetime burden of atherogenic lipoproteins and are, therefore, at higher risk of ASCVD. Such individuals may benefit from more aggressive lifestyle modifications and early optimization/avoidance of risk factors, especially if implemented at an early age. Some might also benefit from use of lipid-lowering medication, such as statins. In theory, Lp(a) testing could be included in recommendations for universal cholesterol screening of all children, starting at 10 years of age (range 9-11 years). Nonetheless, the low levels of screening by pediatric healthcare providers despite recommendations for universal testing suggests Lp(a) screening would likely meet with a similar fate.33de Ferranti S.D. Rodday A.M. Parsons S.K. Cull W.L. O'Connor K.G. Daniels S.R. et al.Cholesterol screening and treatment practices and preferences: a survey of United States pediatricians.J Pediatr. 2017; 185: 99-105.e2Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The understanding by primary care physicians of Lp(a)'s role as a CVD risk factor is likely limited, and their willingness to accept recommendations for Lp(a) screening, uncertain. These valid concerns and limitations notwithstanding, given the likely causal role of Lp(a) in premature ASCVD, perhaps a good place to start would be to improve targeted screening of moderate-to-high risk youth (Table II). For those in primary care, the threshold for Lp(a) screening would be based upon an accurate family history, and pediatric specialties or subspecialties would target measurement of Lp(a) in youth whose health behaviors and the presence of medical conditions predispose to the development of atherosclerosis, as well as healthy youth identified through universal screening with an elevated LDL-C.Table IIRecommendations for Lp(a) screening in youth (<20 y of age)∗Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011;128:S213-56.I. Primary care providersTargeted Lp(a) screening of all children ≥2 y of age in whom:•One or both biologic parents are known to have hypercholesterolemia or are receiving lipid-lowering medications•A parent or sibling known to have an elevated Lp(a)†Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92.•Who have a family history of premature CVD (men <55 y of age; women <65 y of age•Whose family history is unknown (eg, children who were adopted)II. Specialty/subspecialty providersTargeted Lp(a) screening as above of all children ≥2 y of age + with moderate-high risk factors and risk conditions:Moderate riskRisk factors•Hypertension that does not require drug therapy•BMI at the ≥95th percentile, <97th percentile•HDL-C <40 mg/dLRisk conditions•Kawasaki disease with regressed coronary aneurysms•Chronic inflammatory disease (systemic lupus erythematosus, juvenile rheumatoid arthritis)•HIV infection•Nephrotic syndromeHigh riskRisk Factors•Hypertension that requires drug therapy (blood pressure ≥99th percentile + 5 mm Hg)•Current cigarette smoker•BMI at the ≥97th percentileRisk conditions•T1DM and T2DM•Chronic kidney disease/end-stage renal disease/postrenal transplant•Postorthotopic heart transplant•Kawasaki disease with current aneurysms•FH†Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92.•An unknown cause of ischemic stroke†Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92.BMI, body mass index; HDL-C, high-density lipoprotein-cholesterol; T1DM, type 1 diabetes; T2DM, type 2 diabetes.∗ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011;128:S213-56.† Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92. Open table in a new tab BMI, body mass index; HDL-C, high-density lipoprotein-cholesterol; T1DM, type 1 diabetes; T2DM, type 2 diabetes. Successful implementation of these recommendations will create several additional questions that will need to be addressed. Will Lp(a) testing be acceptable to and/or understood by parents/caregivers? Healthcare providers? Will testing be covered by private and/or public insurance? How will testing impact healthcare costs? How will test results be best explained to the child/parents or caregiver, and made available as the child transitions into adult healthcare? How will the results impact the child and family? Is there risk of emotional harm to the child and family? Other than recommendations for heart-healthy living, what additional treatment(s), if any, will be offered? What should be the targets of our intervention? Evidence supports Lp(a) as an independent risk factor for ASCVD. This evidence and emerging Lp(a) targeted therapies suggest that Lp(a) screening in youth may enhance risk assessment, with the goal of preventing premature ASCVD and related events. Both primary care and specialty/subspecialty heathcare providers have an important role in identifying those children and adolescents who would benefit from early intervention.