Lipoprotein(a) and Ischemic Stroke Risk: Who is At Risk?
Abstract & Commentary
By Dara G. Jamieson, MD, Associate Professor of Clinical Neurology, Weill Medical College. Dr. Jamieson reports no financial relationship relevant to this field of study.
Synopsis: Lipoprotein(a) is a low density lipoprotein that is implicated in atherosclerotic cerebrovascular disease. Elevated levels of Lp(a) appear to confer an increased risk of ischemic stroke. However, its variability in different populations leads to uncertainty about the utility of routine screening.
Sources: Ohira T, et al. Lipoprotein(a) and Incident Ischemic Stroke: The Atherosclerosis Risk in Communities (ARIC) Study. Stroke. 2006;37:1407-1412. Rigal M, et al. Lipoprotein (a) and Risk of Ischemic Stroke in Young Adults. J Neurol Sci. 2007;252:39-44.
Lp(a) is a low density lipoprotein, found in human plasma, which consists of apolipoprotein(a) covalently linked to apolipoprotein B-100. It differs from low density lipoprotein cholesterol (LDL-C) by the apo(a) component, which has a marked size heterogeneity. Its role in the promotion of vascular disease, including ischemic stroke, has been investigated based on several putative mechanisms. Gene expression of the unique glycoprotein apo(a) has been found in atherosclerotic intracerebral and carotid vessels and may presage the development of atherosclerotic plaque in cerebral vessels. The structural homology between apo(a) and plasminogen indicates a role for Lp(a) in the inhibition of tissue plasminogen and thus it may interfere with intrinsic fibrinolysis. Lp(a) is involved in endothelial dysfunction and in the induction of inflammation.
Despite pathophysiological explanations, study of the correlation between elevated levels of Lp(a) and ischemic stroke in specific populations has yielded variable results. The clinical relevance of elevated levels of Lp(a) may be gender, race, and age specific. For example, Lp(a) levels are higher in African-Americans than in whites, and in women than in men. The effect of elevated levels of Lp(a) may depend on the vascular bed with greater cardiovascular, than cerebrovascular, relevance. Specific assays and serum sample storage issues may also factor into the results of clinical investigation. Relevance has varied according to clinical trial design with correlation more likely in case-control and cross-sectional studies, than in prospective population studies. Trials have variably distinguished between ischemic and hemorrhagic stroke end-points.
Two large prospective studies found somewhat disparate risk results based on gender differences. A study by Ariyo et al, published in 2003, found that among older adults in the United States, an elevated level of Lp(a) was an independent predictor of stroke and vascular death in men, but not in women.1 They were not able to explain the absence of an association between Lp(a) and risk of vascular events in women, despite higher levels of Lp(a) in women in their population. In an analysis of the Women's Health Study data, published by Suk Danik et al in 2006, very high levels of Lp(a) in initially healthy women, aged 45 years and older, were predictive of future cardiovascular events, especially in association with elevated levels of LDL-C.2
In the paper by Ohira et al 221 men an d women, aged 45 to 64 years at initiation, participated in the ARIC Study from 1987 and 1989. They were followed for an average of 13.5 years to determine the incidence of stroke through 2002. The Lp(a) level was a single determination at initiation into the study. Qualifying strokes, extracted from hospital records, were classified as to hemorrhagic or ischemic, and type of ischemic stroke was determined when possible. Adjusted geometric mean values of Lp(a) were higher in blacks than whites (P < 0.001), and women than men (P < 0.001). LDL-C levels were greater with increasing Lp(a) levels. Kaplan-Meier plots of ischemic stroke according to Lp(a) levels, stratified by race and gender, showed a significant difference by Lp(a) level in black women (log-rank test, P = 0.03) and white women (P = 0.0005), but not in black men (P = 0.69) and white men (P = 0.90). There was no dose-response relationship between Lp(a) levels and ischemic stroke incidence, indicating a threshold response. Exclusion of cardioem-bolic strokes increased the association between Lp(a) levels and ischemic stroke incidence in men, reaching statistical significance in black men. The study concluded that a high level of Lp(a) is associated with an increased incidence of ischemic stroke in blacks and white women, but not in white men. The authors pointed out that in prior prospective studies assessing stroke incidence, stroke type and race have not been factored into the interpretation of results. Timing of the measurement of the sample as well as the assay of the specific apo(a) isoform also impacts trial results.
The large prospective population studies have examined the risk associated with Lp(a) in an older population, but less is known about younger stroke patients. Rigal, et al studied the impact of Lp(a) on the risk of ischemic stroke in young adults. They collected data on 100 patients (42 women; 58 men) with acute ischemic stroke, aged 18 to 55 years, who were evaluated as neurological inpatients in Toulouse, France, between 2003 and 2005. One hundred controls, free of vascular disease, were matched for gender and age. Vascular risk factors, but not race/ethnicity, were recorded. Smoking, significantly more common in male patients, was associated with a higher ischemic stroke risk. Multivariate logistic regression analysis, adjusting for risk factors, found that higher levels of Lp(a) were significantly associated with ischemic stroke in men, but not in women. The Lp(a) levels did not correlate with the ischemic stroke type by TOAST criteria. The risk of ischemic stroke was significantly elevated with slightly elevated concentrations of Lp(a) and was not further increased with higher levels of Lp(a), indicating a threshold effect.
Commentary
The known involvement of Lp(a) in multiple mechanisms of atherosclerotic cerebrovascular disease should point toward its designation as a significant risk factor for ischemic stroke. However, the studies of its clinical relevance continue to show variable results. Elevated levels seen in African-Americans and women do not necessarily correlate with reproducibly increased risk in these populations. There seems to be a threshold effect with increasing elevations not necessarily increasing risk, except maybe in women. At this point, with the uncertainty about its relevance and the difficulty with its assay, routine screening for elevated Lp(a) levels does not appear practical. Intervention to decrease elevated levels of Lp(a) is not more specific than management of elevated LDL-C levels, with which Lp(a) appears to be correlated. Further studies are needed to show how elevated Lp(a) levels should explicitly dictate patient management.
References:
1. Ariyo AA, et al. for the Cardiovascular Health Study Investigators. Lp(a) Lipoprotein, Vascular Disease, and Mortality in the Elderly. New Engl J Med. 2003;349:2108-2115
2. Suk Danik J, et al. Lipoprotein(a), Measured With an Assay Independent of Apolipoprotein(a) Isoform Size, and Risk of Future Cardiovascular Events Among Initially Healthy Women. JAMA. 2006;296:1363-1370.
Lipoprotein(a) is a low density lipoprotein that is implicated in atherosclerotic cerebrovascular disease. Elevated levels of Lp(a) appear to confer an increased risk of ischemic stroke.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content