Elsevier

Atherosclerosis

Volume 142, Issue 1, 3 January 1999, Pages 233-239
Atherosclerosis

Apolipoprotein(a) size polymorphism in young adults with ischemic stroke

https://doi.org/10.1016/S0021-9150(98)00232-9Get rights and content

Abstract

High serum lipoprotein(a) (Lp(a)) concentration which is largely determined by genetic factors, mainly the apolipoprotein(a) (apo(a)) polymorphism, is associated with ischemic cerebrovascular disease. The aim of this study was to investigate whether apo(a) size was associated with acute ischemic stroke in young adults for which causal factors often remain undetermined. Lipid parameters, Lp(a) concentration and apo(a) isoform size distribution were determined in 90 young patients (37.4±8.7 years) with acute cerebral ischemia, and compared to those of control subjects with similar age and sex ratio. Apo(a) size was expressed as its apparent number of kringle 4 (Kr 4) repeats. Serum Lp(a) concentrations were significantly higher in patients than in controls (median values: 0.18 vs. 0.07 g/l, P=0.009) and were as expected inversely related to the number of kringle 4 repeats in both controls (r2=−0.61, P<0.001) and patients (r2=−0.56, P<0.001). However there was no difference in the apo(a) isoform size distributions between the two groups (median isoform size: 27 vs. 27 Kr 4, P=0.25). Lp(a) levels were increased as well in patients with size apo(a) isoform≤22 Kr 4 as in those with isoforms>25 Kr 4. Multivariate analysis showed that apo(a) phenotype did not appear as a risk factor for cerebrovascular infarction. Thus, our results indicate that serum Lp(a) was significantly increased in young people with ischemic stroke but fail to reveal a role of small-sized apo(a) isoforms in the occurrence of this event. They suggest that other factors, genetic or environmental in nature, than the apo(a) size contribute to increase the serum Lp(a) concentrations in these young patients.

Introduction

Lipoprotein(a) (Lp(a)) consists of a LDL-like particle in which apolipoprotein B100 is linked by a single disulfide bond to a large glycoprotein, apolipoprotein(a) (apo(a)). This apolipoprotein shares extensive structural homology with plasminogen, characterised by the presence of triple-looped cysteine-linked amino acid sequences called kringles. It contains a protease domain, a single copy of plasminogen-like kringle 5 and multiple copies of plasminogen-like kringle 4, of which ten types have been identified [1]. Apo(a) exhibits a considerable genetically determined size polymorphism due to varying number of type 2 kringle 4 repeats [2].

The original structure of Lp(a) confers on it potential atherogenic and thrombogenic properties. Thus, Lp(a) accumulation was demonstrated in atherosclerotic lesions and in vitro studies suggested that Lp(a) might impair the process of fibrinolysis [3], [4]. Numerous case-control studies have revealed that high serum Lp(a) concentrations are associated with premature coronary heart disease [5], [6], [7], restenosis after coronary artery bypass surgery [8], [9], and carotid atherosclerosis [10], [11]. High Lp(a) levels were also reported to be associated to atherothrombotic stroke in individuals below 70 years [12], [13], [14], [15], [16], [17], [18] and more recently to lacunar cerebral infarction [19], [20]. However the prospective studies reported until now have yielded contradictory results regarding high serum Lp(a) as an independent risk factor for coronary heart disease [21], [22], [23], [24] and stroke [25].

Lp(a) concentrations vary widely among individuals and ethnic groups [26] and are largely determined by genetic factors, mainly the apo(a) gene polymorphism [27]. They are highly skewed towards low values in Caucasian populations and inversely related to the molecular size of apo(a) so that the high values are associated with small isoforms. Nevertheless there are exceptions from this trend since a considerable variation in Lp(a) levels is observed in individuals with apo(a) isoforms of the same size. Furthermore some subjects with small isoforms have low Lp(a) levels, that raises the question of the involvement of small apo(a) isoforms themselves in the pathogenesis of premature cardiovascular diseases. Studies on the contribution of the small apo(a) isoforms to coronary heart disease have led to controversial results [28], [29], [30], [31], [32], [33], [34]. The few investigations on apo(a) phenotype in patients with cerebrovascular diseases reported until now [35], [36] have also provided conflicting results and none of them was focused on young patients in whom causes of acute ischemic stroke rarely involve an atherosclerotic process and frequently remain undetermined.

We therefore investigated the apo(a) isoform distribution in young patients with cerebral infarction in order to determine whether apo(a) size is associated to this event.

Section snippets

Subjects

We studied 90 Caucasian patients admitted in the Department of Neurology for cerebral infarction. Age ranged from 17 to 54 years (37.4±8.7 mean±S.D.) at onset and sex ratio (M/F) was 45/45. Diagnosis of ischemic stroke was based on the results of neurological examination, computed tomography, electrocardiogram, magnetic resonance imaging and Doppler ultrasonography. Etiologies were established in 46 cases (21 carotid arterial dissection, 12 cardioembolism, seven angeitis, five atherosclerosis,

Lipid and Lp(a) concentrations

When compared to control subjects, patients exhibited higher triglyceride (1.28 vs. 0.98 mmol/l, P<0.001, median values) and lower HDL C levels (1.39±0.42 vs. 1.58±0.42 mmol/l, P<0.001, mean±S.D.) but similar total cholesterol concentrations (5.73±1.18 vs. 5.70±1.10 mmol/l). Mean LDL C levels did not differ between patients and control subjects neither when calculated by the Friedewald formula nor by that of Dahlén (Table 1).

Fig. 1 shows that distribution of Lp(a) levels was highly skewed

Discussion

The purpose of this study was to evaluate whether small apo(a) isoforms are associated to cerebral infarction in young patients.

Our patients had concentrations of total and LDL cholesterol similar to those of control subjects but higher triglyceride and lower HDL cholesterol levels. Controversies exist regarding the association between hyperlipidemia and cerebrovascular diseases since some reports found raised cholesterol [42], raised triglycerides and decreased HDL cholesterol [43], [44] in

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