Apolipoprotein(a) size polymorphism in young adults with ischemic stroke
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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Lipoprotein (a) as a risk factor for ischemic stroke: A meta-analysis
2015, AtherosclerosisCitation Excerpt :Stroke subtypes significantly contributed to heterogeneity assessed by meta-regression; stroke due to large artery atherosclerosis and stroke due to undetermined etiology reported significantly higher ORs (QM = 6.89; p = 0.03; beta = 0.008; se = 0.003). Four studies [47,48,54,56] dichotomized Lp(a) levels at 30 mg/dl (clinical cut-off) or 14 mg/dl, respectively, three studies [27,49,58] compared highest vs. lowest tertile or quartile, respectively, and three studies [45,55,57] reported risk differences for continuous increase in Lp(a), see eTable 6 in the supplement. Four studies reported sex-specific ORs [27,47,48,56].
Lipoprotein(a), ferritin, and albumin in acute phase reaction predicts severity and mortality of acute ischemic stroke in north indian patients
2013, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :The levels peaked at poststroke day 7 and dropped significantly in the following 6 months but were still higher than control values. These findings are in accordance with a case control study by Jurgens et al25 in which serum Lp(a) values were significantly higher in patients with ischemic stroke compared to those in healthy individuals (median 95 v 50 mg/dL)25 and a study by Peynet et al26 who evaluated Lp(a) concentration and apo(a) isoform size in 90 young patients with acute cerebral ischemia. One study by Dhamija et al27 also had similar findings.
Apolipoprotein(a) Isoforms and the Risk of Vascular Disease. Systematic Review of 40 Studies Involving 58,000 Participants
2010, Journal of the American College of CardiologyCitation Excerpt :Statistical tests were 2-sided and used a significance threshold of p < 0.05. A total of 40 relevant studies (9,12,14,19,21,22,25,29–59) reporting on 58,334 individuals were identified (Table 2). Twenty-seven studies were based in Europe, 5 in East Asia, 2 in the U.S., 3 in South Asia, and 2 in the Middle East; 1 study was multinational (with centers in Austria, Germany, Israel, Wales, China, and India).
Lipoprotein (a) and risk of ischemic stroke in young adults
2007, Journal of the Neurological SciencesCitation Excerpt :Some studies including small numbers of subjects showed higher levels of Lp(a) in stroke patients [12–14]. Other case-control studies failed to demonstrate any independent association of increased Lp(a) level with ischemic stroke [15,16]. On the other hand, raised Lp(a) was found to be an independent predictor of recurrent ischemic stroke in a cohort of 301 children followed up for 44 months [17].
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