Lack of change of lipoprotein (a) concentration with improved glycemic control in subjects with type II diabetes.

Recently, lipoprotein (a) [Lp(a)] has been identified as a major risk factor for coronary heart disease. No data are available on the effect of improved metabolic control on plasma Lp(a) concentrations in subjects with type II diabetes mellitus, a group at high risk for coronary heart disease. We examined the effects of improved metabolic control on plasma lipid and lipoproteins and Lp(a) concentrations in 12 subjects before and after 21 days of tight metabolic control. Glycosylated hemoglobin declined from 8.9% to 6.9% (P less than .002). Lp(a) increased slightly from 21.4 to 25.8 mg/dL (P = .119) with improved metabolic control. There were no significant differences in total, low-density, or high-density cholesterol values, although the decline in triglyceride concentrations was statistically significant. The distribution of apolipoprotein (a) [apo (a)] isoforms in subjects with type II diabetes mellitus was not unusual and the apo (a) isoform patterns did not change with improved metabolic control. Although the number of subjects was small, there was no decline in Lp(a) concentrations with improved control and thus the effect of glycemic control on Lp(a) concentrations may be much smaller in type II than in type I diabetes. These results suggest that diabetic subjects with elevated Lp(a) concentrations should have intensive management of conventional cardiovascular risk factors such as high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and blood pressure.     

Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?

High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evaluated by measuring the ability of Lp(a) particles of distinct apo(a) isoform content to compete with plasminogen for fibrin binding during plasminogen activation by fibrin-bound tissue-type plasminogen activator. The rate of plasmin generation was most efficiently inhibited by an isoform with a molecular weight (M(r)) of approximately 540 Kd. An isoform with M(r) approximately 590 Kd produced a less pronounced effect, whereas the isoform with M(r) approximately 610 Kd failed to inhibit plasminogen activation. These effects were directly proportional to the amount of Lp(a) bound to the carboxy-terminal lysine residues of degraded fibrin. The relative affinity of the binding (kd range, 16 to 180 nmol/L) reflected the ability of individual Lp(a) isoforms to inhibit the binding of plasminogen (kd, 600 nmol/L). The question of the influence of kringle sequence variability on the binding to fibrin was not addressed by the present work. These data suggest that apo(a) isoform types with high affinity for fibrin may influence the ability of Lp(a) to interfere with fibrinolysis and contribute thereby to the association of elevated levels of Lp(a) with atherosclerotic and thrombotic risks.     

Lipoprotein(a) and coronary heart disease risk

Although retrospective case-control studies continue to indicate that plasma lipoprotein(a) [Lp(a)] concentrations are associated with coronary heart disease (CHD), several large population-based prospective studies have failed to confirm that Lp(a) is an independent risk factor. However, evidence exists from several studies to suggest that elevated plasma Lp(a) increases the CHD risk associated with more traditional risk factors. Although identification of the functional role of Lp(a) in atherogenesis has been thwarted by the physical, chemical, and genetic complexity of Lp(a), the structural similarity of Lp(a) to both the fibrinolytic proenzyme plasminogen and low-density lipoprotein (LDL) has suggested a prothrombotic or atherogenic role (or both) for this lipoprotein. Because the clinical determination and application of plasma Lp(a) concentration poses several challenges, we cannot recommend its routine measurement at this time. Rather, plasma Lp(a) determinations should be limited to either patients at high risk for the development of CHD or patients at borderline risk for the development of CHD in whom uncertainty may exist about how aggressively to treat modifiable risk factors such as elevated LDL cholesterol.     

A critical evaluation of the role of Lp(a) in cardiovascular disease: can Lp(a) be useful in risk assessment?

Lp(a) is a structurally complex particle which resembles LDL, but which also contains the distinctive glycoprotein apo(a). Apo(a) is characterized by a variable number of repeated kringle domains, which gives rise to differently-sized Lp(a) isoforms in the population. Although epidemiological studies indicate that elevated Lp(a) concentration and/or small apo(a) isoform sizes increase the risk of coronary heart disease (CHD), a causal role for Lp(a) in CHD remains unproven. This is largely due to the difficulty in establishing a relevant animal model to probe Lp(a) function, and the lack of intervention studies in which Lp(a) concentrations are lowered and outcomes followed. The accumulation of apo(a)/Lp(a) in arterial lesions has provided the rationale for numerous in vitro studies aimed at dissecting its function in this milieu. These studies have resulted in the proposal of numerous proatherogenic, prothrombotic and antifibrinolytic roles for both native and modified apo(a)/Lp(a). Although characterization of Lp(a) in the general population is not presently justified, Lp(a) analysis in patients at risk for CHD may be warranted.     

Corticotropin-induced reduction of plasma lipoprotein(a) concentrations in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism

Lipoprotein(a) [Lp(a)], a strong independent cardiovascular risk factor, consists of the unique apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein particle. Apo(a) contains a widely differing number of the plasminogen-like kringle IV, a size polymorphism that is codominantly inherited. In addition to powerful genetic control, renal failure is known to influence the plasma Lp(a) concentration. There is still a lot to be learned about the mode and site of catabolism of Lp(a), and there is no readily applicable Lp(a)-lowering treatment available. Therefore, it was of interest to study further the Lp(a)-lowering effect of corticotropin (ACTH) that has been demonstrated in small studies. The main purpose of the present study was to investigate the influence of ACTH on different apo(a) isoforms. Short-term treatment with ACTH decreased the plasma Lp(a) concentration in all 26 study participants. The two study groups (12 healthy individuals and 14 hemodialysis patients) responded similarly, with a median decrease in plasma Lp(a) of 39% and 49%, respectively. In subjects with two clearly separable apo(a) bands, apo(a) phenotyping and densitometric scanning of the bands before and after treatment with ACTH revealed a change in the proportion of apo(a) isoforms, ie, a shift toward the isoform with lower molecular weight. This was observed in seven of nine investigated subjects (four of five healthy individuals and three of four hemodialysis patients).     

Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk

In 2010, more than 45 years after the initial discovery of lipoprotein(a) [Lp(a)] by Kare Berg, an European Atherosclerosis Society Consensus Panel recommended screening for elevated Lp(a) in people at moderate to high risk of atherosclerotic cardiovascular disease (CVD). This recommendation was based on extensive epidemiological findings demonstrating a significant association between elevated plasma Lp(a) levels and coronary heart disease, myocardial infarction, and stroke. In addition to those patients considered to be at moderate to high risk of heart disease, statin-treated patients with recurrent heart disease were also identified as targeted for screening of elevated Lp(a) levels. Taken together, recent findings have significantly strengthened the notion of Lp(a) as a causal risk factor for CVD. It is well established that Lp(a) levels are largely determined by the size of the apolipoprotein a [apo(a)] gene; however, recent studies have identified several other LPA gene polymorphisms that have significant associations with an elevated Lp(a) level and a reduced copy number of K4 repeats. In addition, the contribution of other genes in regulating Lp(a) levels has been described. Besides the strong genetic regulation, new evidence has emerged regarding the impact of inflammation as a modulator of Lp(a) risk factor properties. Thus, oxidized phospholipids that possess a strong proinflammatory potential are preferentially carried on Lp(a) particles. Collectively, these findings point to the importance of both phenotypic and genotypic factors in influencing apo(a) proatherogenic properties. Therefore, studies taking both of these factors into account determining the amount of Lp(a) associated with each individual apo(a) size allele are valuable tools when assessing a risk factor role of Lp(a).     

Molecular analysis of apo(a) fragmentation in polygenic hypercholesterolemia: characterization of a new plasma fragment pattern

Hypercholesterolemia is frequently associated with elevated Lp(a) levels, an independent risk factor for coronary, cerebrovascular, and peripheral vascular disease. A portion of apolipoprotein(a) [apo(a)] circulates as a series of fragments derived from the N-terminal region of apo(a). The relationship of elevated lipoprotein(a) [Lp(a)] levels to those of circulating apo(a) fragments in polygenic hypercholesterolemia is indeterminate. Therefore, plasma Lp(a) and plasma and urinary apo(a) fragment levels were measured by ELISA in 82 patients with polygenic type IIa hypercholesterolemia (low density lipoprotein cholesterol >/=4.13 mmol/L and triglycerides <2.24 mmol/L) and in 90 normolipidemic subjects. Lp(a) levels were significantly elevated in patients compared with control subjects (0.35+/-0.4 and 0.24+/-0.31 mg/mL, respectively; median 0.13 and 0.11 mg/mL, respectively; P=0.039), although apo(a) isoform distribution did not differ. Patients displayed significantly higher plasma and urinary apo(a) fragment levels than did control subjects (respective values were as follows: 4.97+/-5.51 and 2.15+/-2.57 [median 2.85 and 1.17] microg/mL in plasma, P<0.0001; 75+/-86 and 40+/-57 [median 38 and 17] ng/mg urinary creatinine in urine, P<0.0001). The ratio of plasma apo(a) fragments to Lp(a) levels was also significantly higher in patients than in control subjects (1.93+/-1.5% and 1.75+/-2.36%, respectively; P<0.0001). We conclude that increased plasma Lp(a) levels in polygenic hypercholesterolemia are associated with elevated circulating levels of apo(a) fragments but that this increase is not due to decreased renal clearance of apo(a) fragments. Furthermore, we identified a new pattern of apo(a) fragmentation characterized by the predominance of a fragment band whose size was related to that of the parent apo(a) isoform and that was superimposed on the series of fragments described previously by Mooser et al (J Clin Invest. 1996; 98:2414-2424). This new pattern was associated with small apo(a) isoforms and did not discriminate between hypercholesterolemic and normal subjects. However, this new apo(a) fragment pattern may constitute a novel marker for cardiovascular risk.     

Genetic basis and pathophysiological implications of high plasma Lp(a) levels.

Lipoprotein(a) or Lp(a) is a genetic variant of plasma low density lipoproteins (LDL) containing apoB100 covalently linked to apolipoprotein(a) or apo(a), the specific marker of Lp(a). Lp(a) is heterogeneous in size and density, accounting in part for the marked size polymorphism of apo(a), 300 to 800 kDa. The apo(a) size polymorphism is related to the different number of kringle repeats which are structurally similar although not identical to the kringle 4 of plasminogen. Recent studies on a genomic level have indicated that the apo(a) gene contains at least 19 different alleles varying in length between 48 and 190 kb, partially impacting on the plasma levels of Lp(a). High plasma levels of Lp(a) have been found to be associated with an increased prevalence of premature atherosclerotic cardiovascular disease by mechanism(s) yet to be established. Both atherogenic and thrombogenic potentials have been postulated and have been related to the LDL-like and plasminogen-like properties of Lp(a), respectively.     

Predictors of plasma lipoprotein(a) concentration in the West of Scotland Coronary Prevention Study cohort

An elevated plasma lipoprotein(a) (Lp(a)) concentration is an independent risk factor for coronary heart disease (CHD). Plasma Lp(a) levels are believed to be predominantly controlled by the APO(a) gene, which encodes the apo(a) glycoprotein moiety of the Lp(a) particle. However, other parameters in the lipoprotein profile as well as co-existing disease states or personal traits have been proposed as co-varieties. In order to examine these potential controlling factors in greater detail than previously possible, 1760 unrelated Caucasian subjects were studied, from which were identified 907 with a single expressing APO(a) allele. This strategy was followed to obviate the difficulty in dealing with the co-expression of different apo(a) isoforms and the resulting compound plasma Lp(a) level. After cube-root transformation of the plasma Lp(a) levels to normalise their distribution, a series of correlates were computed. There was no good correlation between Lp(a) concentration and any other measured lipid or lipoprotein in the lipid profile or with any other variable examined, with the important exception of the length of the expressed apo(a) isoform (r = -0.491, P = 0.0001). We conclude that in this population the plasma Lp(a) concentration is not predicted by the plasma lipid profile, alcohol intake, or smoking status but is predicted, albeit incompletely, by the length polymorphism of the APO(a) gene.     

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

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.     

Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is a strong and independent risk factor for coronary heart disease. We assessed the potential relationship between plasma Lp(a) levels, apo(a) phenotypes and coronary heart disease in a population of NIDDM patients. Seventy-one patients with coronary heart disease, who previously have had transmural myocardial infarction, or significant stenosis on coronary angiography, or positive myocardial thallium scintigraphy, or in combination, were compared with 67 patients without coronary heart disease, who tested negatively upon either coronary angiography, myocardial thallium scintigraphy or a maximal exercise test. The prevalence of plasma Lp(a) levels elevated above the threshold for increased cardiovascular risk (>0.30 g/l) was significantly higher (p=0.005) in patients with coronary heart disease (33.8%) compared to the control group (13.4%). The relative risk (odds ratio) of coronary heart disease among patients with high Lp(a) concentrations was 3.1 (95% confidence interval, 1.31–7.34;p=0.01). The overall frequency distribution of apo(a) phenotypes differed significantly between the two groups (p=0.043). However, the frequency of apo(a) isoforms of low apparent molecular mass (700 kDa) was of borderline significance (p=0.067) between patients with or without coronary heart disease (29.6% and 16.4%, respectively). In this Caucasian population of NIDDM patients, elevated Lp(a) levels were associated with coronary heart disease, an association which was partially accounted for by the higher frequency of apo(a) isoforms of small size. In multivariate analyses, elevated levels of Lp(a) were independently associated with coronary heart disease (odds ratio 3.48, p=0.0233).Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - IDDM insulin-dependent diabetes mellitus - CHD coronary heart disease - Lp(a) lipoprotein(a) - apo(a) apolipoprotein(a) - apoB apolipoprotein B - HMGCoA reductase hydroxymethylglutaryl coenzyme A reductase     

High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men

Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (>/=50% stenosis) in 576 white and African American men and women. Only in white men were Lp(a) levels significantly higher among patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL, respectively; P:=0.004), and only in this group was the presence of small apo(a) isoforms (<22 kringle 4 repeats) associated with CAD (P:=0.043). Elevated Lp(a) levels (>/=30 mg/dL) were found in 26% of whites and 68% of African Americans, and of those, 80% of whites but only 26% of African Americans had a small apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were significantly associated with CAD (P:<0.01) in African American and white men but not in women. This association remained significant after adjusting for age, diabetes mellitus, smoking, hypertension, HDL cholesterol, LDL cholesterol, and triglycerides. We conclude that elevated levels of Lp(a) with small apo(a) isoforms independently predict risk for CAD in African American and white men. Our study, by determining the predictive power of Lp(a) levels combined with apo(a) isoform size, provides an explanation for the apparent lack of association of either measure alone with CAD in African Americans. Furthermore, our results suggest that small apo(a) size confers atherogenicity to Lp(a).     

Lipoprotein(a): resurrected by genetics

Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25–35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high‐risk patients with already maximally reduced low‐density lipoprotein cholesterol levels can dramatically reduce major coronary events.     

国人健康男女及冠心病患者血浆脂蛋白(a)水平

为了了解国人人群脂蛋白(a)的分布及水平,探讨脂蛋白(a)与冠心病及其它血脂与载脂蛋白的关系,本文应用单价抗载脂蛋白(a)及抗载脂蛋白B抗体夹心酶联法测定668名健康人血浆脂蛋白(a),测得(?);122.34±141.97mg/L,M为81.07mg/L(0～1 250mg/L),呈典型的正偏态分布,无性别年龄差异,与其它脂类及载脂蛋白不相关。48例冠心病患者血浆脂蛋白(a)水平及>200mg/L的频率分布均明显高于同年龄对照组,提示高脂蛋白(a)水平是致动脉粥样硬化的一个独立危险因素。     

Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis

Lipoprotein(a) [Lp(a)], comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis. Lp(a) is the major plasma lipoprotein carrier of oxidized phospholipids, is pro-inflammatory, inhibits plasminogen activation, and promotes smooth muscle cell proliferation, as defined mostly through in vitro studies. Although Lp(a) is not expressed in commonly studied laboratory animals, mouse and rabbit models transgenic for Lp(a) and apo(a) have been developed to address their pathogenicity in vivo. These models have provided significant insights into the pathophysiology of Lp(a), particularly in understanding the mechanisms of Lp(a) in mediating atherosclerosis. Studies in Lp(a)-transgenic mouse models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation. Furthermore, rabbit models have shown that Lp(a) promotes atherosclerosis and vascular calcification. However, many of these models have limitations. Mouse models need to be transgenic for both apo(a) and human apolipoprotein B-100 since apo(a) does not covalently associated with mouse apoB to form Lp(a). In established mouse and rabbit models of atherosclerosis, Lp(a) levels are low, generally <20 mg/dL, which is considered to be within the normal range in humans. Furthermore, only one apo(a) isoform can be expressed in a given model whereas over 40 isoforms exist in humans. Mouse models should also ideally be studied in an LDL receptor negative background for atherosclerosis studies, as mice don’t develop sufficiently elevated plasma cholesterol to study atherosclerosis in detail. With recent data that cardiovascular disease and calcific aortic valve stenosis is causally mediated by the LPA gene, development of optimized Lp(a)-transgenic animal models will provide an opportunity to further understand the mechanistic role of Lp(a) in atherosclerosis and aortic stenosis and provide a platform to test novel therapies for cardiovascular disease.     

Lipoprotein(a): an elusive cardiovascular risk factor

Lipoprotein (a) [Lp(a)], is present only in humans, Old World nonhuman primates, and the European hedgehog. Lp(a) has many properties in common with low-density lipoprotein (LDL) but contains a unique protein, apo(a), which is structurally different from other apolipoproteins. The size of the apo(a) gene is highly variable, resulting in the protein molecular weight ranging from 300 to 800 kDa; this large variation may be caused by neutral evolution in the absence of any selection advantage. Apo(a) influences to a major extent metabolic and physicochemical properties of Lp(a), and the size polymorphism of the apo(a) gene contributes to the pronounced heterogeneity of Lp(a). There is an inverse relationship between apo(a) size and Lp(a) levels; however, this pattern is complex. For a given apo(a) size, there is a considerable variation in Lp(a) levels across individuals, underscoring the importance to assess allele-specific Lp(a) levels. Further, Lp(a) levels differ between populations, and blacks have generally higher levels than Asians and whites, adjusting for apo(a) sizes. In addition to the apo(a) size polymorphism, an upstream pentanucleotide repeat (TTTTA(n)) affects Lp(a) levels. Several meta-analyses have provided support for an association between Lp(a) and coronary artery disease, and the levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with cardiovascular disease or with preclinical vascular changes. Further, there is an interaction between Lp(a) and other risk factors for cardiovascular disease. The physiological role of Lp(a) is unknown, although a majority of studies implicate Lp(a) as a risk factor.     

Transgenic rabbits expressing human apolipoprotein (a).

Elevated plasma levels of lipoprotein (a) [Lp(a)] constitutes an independent risk factor for coronary heart disease, stroke, and restenosis. Over the past years, our understanding of the genetics, metabolism and pathophysiology of Lp(a) have increased considerably. However, the precise mechanism(s) by which this atherogenic lipoprotein mediates the development of atherosclerosis remains unclear. This is partly due to the lack of appropriate animal models since apolipoprotein (a) [apo(a)], a distinct component of Lp(a) is found only in primates and humans. Development of transgenic mice expressing human apo(a) has provided an alternative means to investigate many aspects of Lp(a). However, human apo(a) in transgenic mice can not bind to murine apoB to form Lp(a) particles. In this aspect, we generated transgenic rabbits expressing human apo(a). In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was associated with rabbit apo B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). Our study suggests that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a).     

Ascorbic acid supplementation does not lower plasma lipoprotein(a) concentrations

Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are associated with premature coronary heart disease (CHD). Lp(a) is a lipoprotein particle consisting of low-density lipoprotein (LDL) with apolipoprotein (apo) (a) attached to the apo B-100 component of LDL. It has been hypothesized that ascorbic acid supplementation may reduce plasma levels of Lp(a). The purpose of this study was to determine whether ascorbic acid supplementation at a dose of 1 g/day would lower plasma concentrations of Lp(a) when studied in a randomized, placebo-controlled, blinded fashion. One hundred and one healthy men and women ranging in age from 20 to 69 years were studied for 8 months. Lp(a) values at baseline for the placebo group (n = 52) and the ascorbic acid supplemented group (n = 49) were 0.026 and 0.033 g/l, respectively. The 8-month concentrations were 0.027 g/l (placebo) and 0.038 g/l (supplemented group). None of these values were significantly different from each other. In addition, no difference in plasma Lp(a) concentration was seen between the placebo and supplemented groups when only subjects with an initial Lp(a) value of > or = 0.050 g/l were analyzed. Our data indicate that plasma Lp(a) concentrations are not significantly affected by ascorbic acid supplementation in healthy human subjects.     

Lipoprotein(a) as a cardiovascular risk factor

Lipoprotein(a) [Lp(a)] is a class of lipoprotein particles having the lipid composition of plasma low-density lipoprotein (LDL), but with a distinct protein moiety comprised of two proteins linked together by a disulfide bridge. The two proteins are apoB100, the protein moiety of LDL, and apo(a), a heavily glycosylated protein that is specific for Lp(a). Apo(a) has a strong structural similarity to plasminogen and has a wide-size polymorphism that has a genetic origin and is partially responsible for the size and density heterogeneity of Lp(a). High plasma levels of Lp(a) are associated with an increased risk for cardiovascular disease that is related to the atherogenic and thrombogenic potentials of this lipoprotein enhanced by the presence of other risk factors, among which are high plasma levels of LDL or low levels of high-density lipoprotein. The factors determining the plasma levels of Lp(a) have not been clearly identified except for an association with different alleles of the apo(a) gene, which is located in the long arm of chromosome 6. Currently there are no generally accepted ways to normalize the plasma levels of Lp(a) by either dietary and/or pharmacologic means. Until further progress in this area is made, patients with high plasma levels of Lp(a) should be advised to correct modifiable risk factors in order to decrease the cardiovascular pathogenicity of this lipoprotein class.     

Convergent evolution of apolipoprotein(a) in primates and hedgehog

Apolipoprotein(a) [apo(a)] is the distinguishing protein component of lipoprotein(a), a major inherited risk factor for atherosclerosis. Human apo(a) is homologous to plasminogen. It contains from 15 to 50 repeated domains closely related to plasminogen kringle four, plus single kringle five-like and inactive protease-like domains. This expressed gene is confined to a subset of primates. Although most mammals lack apo(a), hedgehogs produce an apo(a)-like protein composed of highly repeated copies of a plasminogen kringle three-like domain, with complete absence of protease domain sequences. Both human and hedgehog apo(a)-like proteins form covalently linked lipoprotein particles that can bind to fibrin and other substrates shared with plasminogen. DNA sequence comparisons and phylogenetic analysis indicate that the human type of apo(a) evolved from a duplicated plasminogen gene during recent primate evolution. In contrast, the kringle three-based type of apo(a) evolved from an independent duplication of the plasminogen gene approximately 80 million years ago. In a type of convergent evolution, the plasminogen gene has been independently remodeled twice during mammalian evolution to produce similar forms of apo(a) in two widely divergent groups of species.