Investigating Lipoprotein(A) as a Risk Factor for Ischemic Arterial Stroke in U.S. Children. New Understanding from a Case-Control Study with Gold-Standard Laboratory Assessment.
Authors: Goldenberg Neil A. , Knapp-Clevenger R. , Jacobson Linda , Hays Taru , Marcovina Santica M. , Manco-Johnson Marilyn J. 
Published: April 2020

Abstract
Background: Lipoprotein(a) [Lp(a)] is a plasma lipoprotein that has been implicated in both atherogenesis and thrombophilia. A few reports in recent years, principally in European populations, have suggested that elevated plasma Lp(a) level may constitute a risk factor for ischemic arterial stroke (IAS) in children. However, the ELISA assays used in these studies are technically limited by their ability to provide accurate Lp(a) values independently of apo(a) size.
Objective: To determine the prevalence of elevated plasma Lp(a) concentration among children with non-neonatal IAS and healthy children in a U.S. population using the current gold-standard laboratory methodology, toward the evaluation of Lp(a) as a risk factor for pediatric IAS.
Methods: In a case-control study, children from 1 month to 21 years of age with a history of radiologically-confirmed IAS (case group, n=22) and healthy children (contemporaneous control group, n=41) were consecutively recruited from The Children’s Hospital, Denver, and the Mountain States Regional Hemophilia and Thrombosis Center (Aurora, CO). Children with IAS who were receiving drugs that affect Lp(a) level, such as niacin or statins, were excluded. Fasting plasma samples were obtained by peripheral venipuncture into EDTA with susequent centrifugation to yield platelet-poor plasma. Lp(a) assay was performed in the Northwest Lipid Metabolism and Diabetes Research Laboratories at the University of Washington, Seattle, using a double monoclonal antibody-based ELISA validated to be sensitive to apo(a) size heterogeneity. Results were expressed in nmol/L of Lp(a) protein, with corresponding race-appropriate percentiles. In accordance with NHLBI recommendations, values above the 75th percentile were considered to indicate increased risk, and were hence designated as elevated.
Results: Median Lp(a) concentration did not significantly differ between the two groups (cases: 16.9 nmol/L, controls: 24.7 nmol/L; P=0.96). While the prevalence of elevated Lp(a) levels was increased among children with IAS (cases: 36%, controls: 24%), this difference did not reach statistical significance (P=0.32). The odds of having elevated Lp(a) were nearly two times that of healthy controls (OR=1.8, 95% CI=0.50–6.3); however, this also was not statistically significant.
Conclusions: The present study demonstrates a qualitatively increased prevalence of elevated plasma Lp(a) concentration among children with non-neonatal IAS when compared to healthy children, using the gold-standard methodology for Lp(a) assessment. Expansion of the study to a larger population via multicenter collaboration will be necessary to definitively determine whether Lp(a) is a risk factor for IAS in children. Furthermore, given that genetic variation in the apo(a) gene is the major determinant of plasma Lp(a) concentration, apo(a) phenotyping may be useful to better define risk strata. These efforts are an important precursor to interventional studies evaluating Lp(a) management strategies in the secondary prevention of IAS in children.