(Stroke. 1996;27:1231-1235.)
© 1996 American Heart Association, Inc.
Articles |
Lipoprotein(a) in Patients With Acute Cerebral Ischemia
the Departments of Neurology (F. van Kooten, J. van Krimpen, D.W.J.D, P.J.K.) and Internal Medicine III (N.H.), University Hospital Rotterdam Dijkzigt, the Netherlands.
Correspondence to Fop van Kooten, MD, Department of Neurology, University Hospital Rotterdam Dijkzigt, 40 Dr Molewaterplein, 3015 GD Rotterdam, Netherlands. E-mail vanKooten@neuro.fgg.eur.nl.
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Abstract |
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Background and Purpose In several cross-sectional studies, a high serum lipoprotein(a) [Lp(a)] level was found to be an independent risk factor for cerebral infarction. In a recent prospective study, however, no association was found between Lp(a) levels at baseline and future risk of stroke. Whether Lp(a) is a prognostic factor in a high-risk population of patients with acute ischemic stroke remains unclear.
Methods We assessed Lp(a) level on admission to study its relationship with cardiovascular risk profile, stroke severity, and prognosis in 151 consecutive patients with acute cerebral ischemia. The mean follow-up period was 2.5±1.2 years. Lp(a) was measured by means of a solid-phase two-site immunoradiometric assay.
Results Increased Lp(a) levels were found in 53 (35%) of the patients with cerebral ischemia. Median (5th and 95th percentile) values of Lp(a) were 191 (12 and 1539) mg/L and 197 (10 and 1255) mg/L for patients with transient ischemic attack and patients with ischemic stroke, respectively. No relationship was found between Lp(a) levels and stroke severity (P=.68) or the occurrence of vascular events during follow-up (P log rank=0.81).
Conclusions We conclude that Lp(a) is increased in about one third of patients with acute cerebral ischemia, but it does not appear to be associated with the cardiovascular risk profile, stroke characteristics, or the prognosis of such patients.
Key Words: cerebral ischemia • lipoproteins • prognosis
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Introduction |
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Lipoprotein(a) consists of an LDL particle covalently linked by disulfide-bridge formation with a large glycoprotein called apo(a).1 2 Sequencing of apo(a) at both the protein and cDNA levels has revealed a high degree of homology to plasminogen.3 4 This finding was supported by immunochemical studies that showed cross-reactivity of apo(a) and plasminogen.5 6 In addition, it has been shown that Lp(a) competes with plasminogen for the plasminogen binding site and reduces cellular plasminogen binding.7 It thereby may suppress endothelial cell fibrinolysis and produce a procoagulant state. Moreover, accumulation of Lp(a) was found on the endothelium of atherosclerotic coronary arteries but not in normal blood vessels.8 All this evidence has fostered the idea that Lp(a) is a potential risk factor for both atherogenesis and thrombogenesis. Lp(a) levels have been reported to be associated with cerebral ischemia in many cross-sectional studies, both hospital- and community-based.9 10 11 12 13 14 15 16 17 However, in a recent prospective follow-up study, no association was found between plasma concentration of Lp(a) and future risk of stroke.18 Similarly conflicting results were found in patients with ischemic heart disease. An association between Lp(a) and ischemic heart disease was found in several cross-sectional studies19 20 21 22 23 and in one24 but not two other25 26 prospective follow-up studies. The aim of our study was to investigate the prognostic value of Lp(a) in patients with acute cerebral ischemia.
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Subjects and Methods |
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We studied 172 consecutive patients who were admitted to the Dijkzigt University Hospital of Rotterdam and included in the Rotterdam Stroke Data Bank between June 1990 and June 1991. Twenty-one patients (12%) had an intracerebral hemorrhage; these were excluded from the present study. The University Hospital of Rotterdam is an area hospital serving an urban population. This center has no specific selection criteria for the admission of stroke patients; however, young stroke patients are referred more frequently to this center compared with the nonacademic centers in the region. All patients were screened according to a strict protocol consisting of a full neurological examination, standardized blood tests, at least one and usually two CT scans of the brain, duplex scanning of the carotid arteries, and a cardiac analysis that included standard 12-lead ECG and, if indicated, 24-hour ECG monitoring and echocardiography. The nature and time course of the symptoms were recorded by means of a detailed checklist.27 Patients with cerebral ischemia were further subdivided according to a clinical classification: TACI, PACI, LACI, or POCI.28 CT scans were reviewed by at least two neurologists. Cerebral infarcts were classified according to location and vascular territory.29 Subcortical infarctions were further classified as small (
15 mm) or large (>15 mm). Finally, patients were classified into four subgroups of different presumed etiology: (1) cardioembolic stroke: patients with atrial fibrillation, myocardial infarction within the last 6 weeks, valve disease, or other echocardiographic findings of a probable embolic source; (2) large-vessel disease: patients with cortical, large subcortical, or large infratentorial infarctions on CT scan and patients with TACI or PACI and an inconclusive CT scan; (3) small-vessel disease: patients with lacunar infarctions on CT scan and patients with LACI and an inconclusive CT scan; and (4) undetermined cause: patients with POCI and an inconclusive CT scan. Apart from the neurological history, the following vascular risk factors were recorded: smoking habits, hypercholesterolemia (history of hypercholesterolemia and/or fasting total cholesterol level >6.5 mmol/L),30 hypertension (history of hypertension and/or systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg, treated or not), diabetes mellitus (history of diabetes mellitus type I or II and/or a random blood glucose of 
8 mmol/L together with an HbA1c level of 6.30% or more, treated or not),31 atrial fibrillation (history of atrial fibrillation and/or atrial fibrillation on ECG), and a history of intermittent claudication, angina pectoris, prior myocardial infarction, or prior vascular surgery (carotid, coronary, aorta bifurcation, or peripheral vascular). Stroke severity was assessed by means of the modified Rankin Scale32 on admission, and functional outcome was assessed by means of this scale at 3-month follow-up. During the follow-up period, all vascular complications were monitored. Blood samples were taken after overnight fasting, the first day after admission to the hospital. The mean±SD interval between onset of symptoms and admission was 0.6±1.4 days. Routine laboratory investigations included levels of hemoglobin, hematocrit, leukocytes, erythrocyte and platelet counts, erythrocyte sedimentation rate, blood urea, creatinine, fasting cholesterol including HDL and LDL cholesterol subfractions, glucose, HbA1c, liver enzymes, and syphilis serology. LDL cholesterol was calculated using the formula of Friedewald.33 In addition, Lp(a) was measured with a commercial solid-phase two-site immunoradiometric assay, ie, the Pharmacia apo(a) IRMA kit.34 The laboratory where the lipid analyses were performed is a member of the Cholesterol Reference Method Laboratory Network established by the Centers for Disease Control and Prevention.35 The results are expressed in units per liter of apo(a). One unit of apo(a) is equal to approximately 0.7 mg Lp(a). Lp(a) values above 352 mg/L (75th percentile of our laboratory references) were considered increased. Laboratory reference values were from 274 healthy men, 50.2±7.4 years of age. Their median (25th and 75th percentile) value of Lp(a) was 136 (46 and 352) mg/L.
Data were analyzed with the personal computer program Stata and Egret statistical software. Lp(a) values in independent groups were compared with the Mann-Whitney U test. We used Kaplan-Meier survival analysis with log-rank testing to compare the occurrence of vascular events (stroke, myocardial infarction, or vascular death, whichever came first). Values of P<.05 were considered statistically significant.
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Results |
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Thirty-two (19%) of the patients had experienced a transient ischemic attack, 119 (69%) an ischemic stroke, and 21 (12%) a primary intracerebral hemorrhage. Elevated Lp(a) levels were found in 24% of patients with a hemorrhage (median [5th and 95th percentile], 153 [11 and 920]; P<.01, Student's t test, normal approximation after logarithmic transformation) and in 35% of patients with transient or permanent cerebral ischemia (195; 11 and 1165). Only patients with cerebral ischemia were considered in the further analysis.
The mean±SD age of the remaining 151 patients was 66.3±15.4 years; 83 were men and 68 were women. The median (5th and 95th percentile) of Lp(a) was 191 (12 and 1539) mg/L and 197 (10 and 1255) mg/L for patients with transient ischemic attack and ischemic stroke, respectively. The distribution of Lp(a) values is given in Fig 1
. There was a highly significant difference in mean level of Lp(a) between this population and our healthy laboratory control subjects (P<.001, normal approximation after logarithmic transformation). Lp(a) was modestly correlated with cholesterol (r2=.21, P<.01) and with LDL (r2=.24, P<.01) but not with HDL or triglyceride. Because renal insufficiency is associated with increased Lp(a) concentrations, we analyzed the association between Lp(a) and serum creatinine. Although patients with a creatinine level above 110 mmol/L had higher values of Lp(a), the difference was not statistically significant (P=.23).
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The baseline characteristics of the study patients are shown in Table 1. There was no statistically significant difference in demographic characteristics between patients with an increased Lp(a) level (>352 mg/L) and patients with normal levels of Lp(a). Although patients with a history of cardiovascular surgery had significantly higher levels of Lp(a) (P=.02), there was no difference in Lp(a) level between patients with or without a history of stroke, cardiac disease, intermittent claudication, or any of the cardiovascular risk factors.
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Table 2 shows the stroke details in relation to Lp(a) level. Patients with a TACI syndrome had significantly lower levels of Lp(a) (P=.03), but no difference was found between all patients with cortical involvement and patients with a lacunar syndrome. Patients with large-vessel disease as the presumed cause of their stroke had significantly lower levels of Lp(a) (P=.03). When compared with patients with small-vessel disease, the difference was not significant (P=.054). No relationship was found between level of Lp(a) and the CT scan findings, severity of stroke, and functional outcome.
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In Table 3, we listed the outcome events that occurred within the follow-up period of 2.5±1.2 years. Forty-five patients (30%) died, 23 (15%) of a vascular event. No statistically significant difference in Lp(a) was found between all patients who died, or patients who died of a vascular cause, and those who survived. Eight patients had nonfatal vascular events. Thus, a total of 31 patients (21%) had a vascular event during follow-up. No relationship was found between the level of Lp(a) and the risk of future stroke or future cardiac events.
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The Kaplan-Meier survival analysis is given in Fig 2. There was no difference between the occurrence of vascular events in patients with normal Lp(a) levels 352 mg/L and those with Lp(a) levels >352 mg/L (P log rank=0.81). Also, after adjusting for potential confounders (history of intermittent claudication, cardiovascular surgery, stroke, atrial fibrillation, angina pectoris, congestive heart failure, and hypercholesterolemia) by means of a proportional hazards regression analysis, we found no statistically significant relationship between Lp(a) and the occurrence of vascular events.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The aim of our study was to elucidate the relationship between Lp(a) and the prognosis after cerebral ischemia. Our findings suggest that Lp(a) is not a prognostic factor for patients with acute cerebral ischemia. This is in accordance with the results of large nested case-control studies that reported no association between the level of Lp(a) at baseline and the risk of stroke during 7.5 years of follow-up18 or Lp(a) and the risk of myocardial infarction during 5 years of follow-up.25 26 In our high-risk population, no association was found between Lp(a) level at baseline and the occurrence of stroke, myocardial infarction, or vascular death during 3 years of follow-up. Also, after adjustment for potential confounders, no association between level of Lp(a) and outcome emerged.
Although the level of Lp(a) was not related to cardiovascular risk profile, stroke characteristics, and prog-nosis, 35% of the patients with cerebral ischemia had elevated levels of Lp(a). This confirms several other hospital- and population-based cross-sectional studies9 10 11 12 13 14 15 16 17 and may suggest that elevation of Lp(a) after stroke reflects an acute-phase reaction. In support of this view are the results of studies that demonstrate a transient increase in Lp(a) with subsequent decrease of Lp(a) after an acute myocardial infarction and in postsurgery patients36 37 ; under normal conditions, serum concentrations of Lp(a) remain remarkably constant throughout life.38 However, no correlation with acute-phase reactants was found in other studies,39 40 and the level of Lp(a) was found to be increased also in the chronic phase after stroke and myocardial infarction11 13 15 16 17 and in patients with stable carotid atherosclerosis.41
Lp(a) concentrations are genetically determined, with more than 90% of the variation being determined within the gene for apo(a).2 42 Although the mechanisms involved in Lp(a) changes remain largely unclear, modulation of Lp(a) concentration appears to be based on changes in the production and not on catabolism.43 Slunga et al39 suggest that changes of Lp(a) levels in patients with acute myocardial infarction are linked to changes of the other lipoprotein levels. In accordance, we found a correlation between the level of Lp(a) and total cholesterol and LDL levels. This relationship is difficult to explain. In contrast to the LDL cholesterol and total cholesterol concentrations, Lp(a) is not influenced by LDL-receptor activity. Recently, it was shown that in patients without LDL-receptor activity (homozygous familial hypercholesterolemia), the Lp(a) catabolic rate was identical to that of control subjects.44 Therefore, in patients with symptomatic atherosclerosis, a mutual catabolic pathway seems an unlikely explanation for the correlation between the LDL cholesterol concentration and the level of Lp(a).
In our study, we did not find a plausible relationship between Lp(a) and the clinical subtype of stroke, although when compared with patients with small-vessel disease, those with large-vessel disease had lower Lp(a) values. Murai et al9 and Woo et al12 found elevated levels of Lp(a) in patients with a cortical infarction but not in patients with lacunar strokes. Lindgren et al14 reported elevated levels of Lp(a) in patients with stroke of undetermined etiology but not in patients with cardioembolic stroke, carotid or vertebrobasilar artery disease, lacunar infarction, or intracerebral hemorrhage. In contrast, Shintani et al15 found elevated levels of Lp(a) in patients with perforating artery disease, after excluding patients with a probable cardioembolic stroke, but not in patients with cortical infarctions. The latter study is in accordance with our findings. However, the lack of a consistent pattern in all these studies does not support a causal relationship between Lp(a) and specific subtypes of stroke.
Although Lp(a) was increased in one third of our patients with acute cerebral ischemia, no association was found with cardiovascular risk factors, stroke severity and outcome, or the occurrence of vascular events during follow-up. It can be argued that the follow-up period of 2.5 years was too short to find a difference in vascular events between the groups and that, although the proportion of events is in accordance with the literature, the absolute number of events may be too small for firm conclusions. On the other hand, the prognosis of patients with stroke is largely determined by vascular events in the first years after stroke, and the usual risk factors for recurrent vascular events appear to be significant in our study, whereas Lp(a) was not. Therefore, we conclude that Lp(a) does not appear to be a major prognostic factor in patients with stroke.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research project was supported by a program grant from the Netherlands Programme for Research on Ageing-NESTOR (funded by the Ministry of Education and Sciences and the Ministry of Health, Welfare, and Sports) and by the Stichting Neurovasculair Onderzoek Rotterdam. The authors wish to thank Christa Boersma-Cobbaert for her advice on Lp(a) measurements and Lydia Loman and Woutine Visser for carefully collecting the blood samples.
Received January 19, 1996; revision received March 4, 1996; accepted March 21, 1996.
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