Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children

Abstract

Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (29 days -<21 years at onset; n=43) and healthy controls (n=127) were recruited for plasma sampling and laboratory determinations. Cases were followed for recurrence in a prospective cohort study. The median lipoprotein (a) concentration did not differ between groups [cases: median 18.0 nmol/L (7.5 mg/dL) and observed range 0.9-259 nmol/L (0.38-108.0 mg/dL), controls: 20.4 nmol/L (8.5 mg/dL) and 0.2-282 nmol/L (0.08-117.5 mg/dL); P=0.62]. While odds of incident stroke were not significantly increased, risks of recurrent arterial ischemic stroke were each more than ten-times increased for lipoprotein(a) >90 th percentile of racespecific reference values and apolipoprotein (a) <10 th percentiles [odds ratio=14.0 (95% confidence interval: 1.0-184), P=0.05 and odds ratio=12.8 (1.61-101), P=0.02]. Statistically significant but weak correlations were observed between euglobulin lysis time and both lipoprotein (a) level (r=0.18, P=0.03) and apolipoprotein (a) size (r= -0.26, P=0.002). In conclusion, elevated lipoprotein (a) and small apolipoprotein (a) potently increase the risk of recurrent arterial ischemic stroke in children, with a mechanism only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to investigate these findings further and, more broadly, to establish key risk factors for incident and recurrent arterial ischemic stroke in children. More recently, in a study in the USA, 17 the prevalence of elevated Lp(a) among 59 children with porencephaly or a history of perinatal or childhood onset-AIS was significantly increased compared to that of historical controls who had consisted of healthy German children (20% versus 5.4%); however, concomitant USAbased controls were lacking. Interestingly, in a French study of mother-infant diads of neonatal AIS, elevated maternal Lp(a) was not only implicated in perinatal AIS but also correlated with low birth weight in these infants, leading to a hypothesis that elevated Lp(a) may mediate placental insufficiency. Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children18 With regard to recurrent AIS in childhood, a prospective multicenter cohort study in Germany 13 demonstrated that Lp(a) >30 mg/dL was an independent risk factor for recurrent AIS (OR: 2.8; 95% CI: 1.1-7.5).In consideration of the lack of well-controlled studies of Lp(a) in childhood-onset AIS outside of Germany, and given also that apo(a) size has received little attention in pediatric AIS, we sought to determine the odds of inci...

Lipoprotein(a) Levels and Recurrent Vascular Events After First Ischemic Stroke

“…16,17 In contrast to the reported HR of 14.0 at 36 months in 1 study, 17 we report a lower HR of 2.6 for adult stroke survivors with elevated Lp(a) levels of >30 mg/dL at 12 months. The difference in relative risk of recurrent events remains unexplained; however, the increased risk of younger versus older patients with stroke might be explained because of the low absolute risk of young individuals and differences in study design.…”

“…Only 2 prospective studies exist that assessed the risk of recurrent ischemic stroke events in children. 16,17 Both studies indicated that elevated Lp(a) levels were associated with a 4-to >10-fold increase in risk of recurrent stroke.…”

Thrombophilia risk is not increased in children after perinatal stroke

“…For example, many studies of Lp(a) used a cutoff of .0.3 mg/dL. 34,35 In contrast, our results found that the normal range in controls extended far above this number, with no differences observed between cases and controls. Finally, another highly powered study of perinatal stroke thrombophilia submitted for publication also describes a similar lack of association between known thrombophilias and perinatal stroke (L. Lehman, personal communication, 11 October 2016).…”

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

“…In other words, elevated Lp(a) may affect the penetrance of procoagulant thrombophilic risk factors. One recent study reported that elevated Lp(a) was associated with risk for recurrent, but not incident, stroke (137). Another study found no relationship between elevated Lp(a) and thromboembolism (of either venous or arterial origin) in Thai children (138).…”