Relationship between apolipoprotein(a) isoforms and lipoprotein(a) levels in patients with acute coronary syndrome.

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Genetic determination of lipoprotein(a) and its association with cardiovascular disease: convenient does not always mean better

Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P <or= 1.3 x 10(-7)) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10(-12) and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.

Lipoprotein(a)

Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism

Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) [Lp(a)], a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles.

The increased risk for ischemic heart disease (IHD) associated with subclinical hypothyroidism (SH) has been partly attributed to dyslipidemia. There is limited information on the effect of SH on lipoprotein (a) [Lp(a)], which is considered a significant predictor of IHD. Serum Lp(a) levels are predominantly regulated by apolipoprotein [apo(a)] gene polymorphisms. The aim of our study was to evaluate the Lp(a) levels and apo(a) phenotypes in patients with SH compared to healthy controls as well as the influence of levothyroxine substitution therapy on Lp(a) values in relation to the apo(a) isoform size. Lp(a) levels were measured in 69 patients with SH before and after restoration of a euthyroid state and in 83 age- and gender-matched healthy controls. Apo(a) isoform size was determined by sodium dodecyl sulfate (SDS) agarose gel electrophoresis followed by immunoblotting and development via chemiluminescence. Patients with SH exhibited increased Lp(a) levels compared to controls (median value 10.6 mg/dL vs. 6.0 mg/dL, p = 0.003]), but this was not because of differences in the frequencies of apo(a) phenotypes. There was no association between thyrotropin (TSH) and Lp(a) levels in patients with SH. In subjects with either low (LMW; 25 patients and 28 controls) or high (HMW; 44 patients and 55 controls) molecular weight apo(a) isoforms, Lp(a) concentrations were higher in patients than in the control group (median values 26.9 mg/dL vs. 21.8 mg/dL, p = 0.02 for LMW, and 6.0 mg/dL versus 3.3 mg/dL, p < 0.001 for HMW). Levothyroxine treatment resulted in an overall reduction of Lp(a) levels (10.6 mg/dL baseline vs. 8.9 mg/dL posttreatment, p = 0.008]). This effect was mainly evident in patients with LMW apo(a) isoforms associated with high baseline Lp(a) concentrations (median values 26.9 mg/dL vs. 23.2 mg/dL pretreatment and posttreatment, respectively; p = 0.03). In conclusion, even though a causal effect of thyroid dysfunction on Lp(a) was not clearly demonstrated in patients with SH, levothyroxine treatment is beneficial, especially in patients with increased baseline Lp(a) levels and LMW apo(a) isoforms.

Lipoprotein(a) in various conditions: To keep a sense of proportions

Factors associated with lipoprotein(a) in chronic kidney disease

345 LIPOPROTEIN(A) [Lp(a)] concentration in plasma varies considerably between individuals because it is determined by a series of autosomal alleles at a single locus, encoding its specific protein marker apo-lipoprotein [apo(a)] (a) (1). Apo(a) is highly polymorphic, ranging in molecular weight from 300,000 to 700,000 (2). The polymorphism of apo(a) is complex with as many as 11 isoforms of the molecule having been detected (3). Individuals exhibiting only one isoform are considered homozygotes and those with two heterozygotes. The levels of Lp(a) are controlled more frequently by synthesis than by clearance rate and the observed variations in interindividual plasma Lp(a) levels are because of the differences in the size of the apo(a) glycoprotein (4). It is noteworthy that Lp(a) possesses a striking homology to plasminogen, a protein responsible for the lysis of blood clots; it competes for its binding sites on the endothelium and thus may promote atherosclerosis by interfering with thrombolysis (5). Various prospective epidemiologic studies have demonstrated an association between plasma Lp(a) concentration and coronary heart disease (CHD), whereas others have failed to implicate Lp(a) as a risk factor (6–8). Nevertheless, a strong correlation between Lp(a) and CHD in the presence of increased low-density lipoprotein (LDL) levels has been detected (9). Considering the physiologic role of Lp(a), it should be remembered that apo(a), rich in kringle domains and LDL and rich in cholesterol, are completely different functional systems (2,10). According to a provocative hypothesis, Lp(a) may bridge the two systems, thereby accomplishing functionality (11). Thus, Lp(a) interacting with fibrin, may deliver cholesterol to places of injury or it may be involved in platelet function. Hence, in overt hypothyroidism the usually elevated levels of LDL may be accompanied by elevated levels of Lp(a) suggesting increased atherogenesis (12). However, the influence of thyroid hormones on serum Lp(a) concentration is controversial and because of methodologic difficulties in measuring Lp(a) and to various dose schedules and duration of levothyroxine treatment, remains a matter of dispute (13,14). In this issue of Thyroid, Milionis et al., (15) report an interesting approach to the challenging problem of Lp(a) in patients with subclinical hypothyroidism (SH). They evaluated the serum Lp(a) levels and the apo(a) phenotypes in patients with SH. They found increased Lp(a) levels together with total cholesterol, LDL cholesterol and apo(B) in 69 patients with SH by comparison with 83 euthyroid controls. In contrast, no significant difference in the frequencies of apo(a) phenotypes could be detected between the two study groups. Lp(a) levels were higher in SH patients with high molecular weight (HMW) apo(a) isoform size than in the control group. Replacement treatment with levothyroxine induced an overall decrease of Lp(a), which was more evident in those patients with low molecular weight (LMW) apo(a) isoforms associated with increased baseline Lp(a) levels. However, there was no significant effect in patients with low to moderate Lp(a) levels suggesting that levothyroxine treatment may be beneficial in patients with SH with raised Lp(a) levels and LMW. Taken together, the results may indicate that the increased Lp(a) levels are not the result of genetic predisposition and that thyroid function may be important for Lp(a) metabolism. The findings are at variance with previous data in overt hypothyroidism showing increased small Lp(a) phenotype in patients by comparison with controls, whereas no effect of levothyroxine treatment on Lp(a) levels was registered (16). The discrepancies may be due more to the small number of patients studied and to the polymorphism of apo (a) and less to ethnic differences. There are inconsistent results in the few studies that have investigated Lp(a) levels in SH. Increased Lp(a) levels related to TSH, were mostly found in patients with SH but elevated Lp(a) levels, independent of thyrotropin (TSH) values, have also been reported (17,18). In the light of more recent data, Lp(a) levels were found increased in 25% of patients with SH and no effect of levothyroxine treatment over a 6-month period was registered (19). Furthermore, in the same study a significant association was found between elevated Lp(a) levels and a positive family history for CHD that would seem to indicate a genetic influence (19). In contrast, in another recent study from the Mayo Clinic, thyroid hormone replacement induced a significant decrease of Lp(a) levels resulting

Apolipoprotein [a] (apo[a]) gene size is a major predictor of lipoprotein [a] level. To determine genetic predictors of allele-specific apo[a] levels beyond gene size, we evaluated the upstream C/T and pentanucleotide repeat (PNR) polymorphisms. We determined apo[a] sizes, allele-specific apo[a] levels, and C/T and PNR in 215 Caucasians and 139 African Americans. For Caucasians, apo[a] size affected allele-specific levels substantially greater in subjects with apo[a] < 24 K4; for African Americans, the size effect was smaller than in Caucasians, <24 K4, but did not decrease at higher repeats. In both groups, the level decreased with increasing size of the other allele. Controlling for apo[a] sizes, PNR decreased allele-specific apo[a] levels in Caucasians with increasing PNR > 8. In a multiple regression model, apo[a] allele size and size and expression of the other apo[a] allele (and PNR > 8 for Caucasians) significantly predicted allele-specific apo[a] levels. For a common PNR 8 allele, predicted values were similar in the two ethnicities for small size apo[a]. Allele-specific apo[a] levels were influenced by the other allele size and expression. Observed differences between Caucasians and African Americans in allele-specific apo[a] levels were explained for small apo[a] sizes by the other allele size and PNR; the ethnicity differences remain unexplained for larger sizes.

Sequence polymorphisms in the apolipoprotein(a) gene and their association with lipoprotein(a) levels and myocardial infarction. The ECTIM Study

Leptin is associated with the size of the apolipoprotein(a) particle in African tribal populations living on fish or vegetarian diet

Serum lipoprotein(a) levels and apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in elderly individuals

Lipoprotein(a) [Lp(a)] has enhanced atherothrombotic properties. The ability of Lp(a) levels to predict adverse cardiovascular outcomes in patients undergoing coronary angiography has not been examined. The relationship between serum Lp(a) levels and both the extent of angiographic disease and 3-year incidence of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, and coronary revascularization) was investigated in 2,769 patients who underwent coronary angiography [median Lp(a) 16.4 mg/dl, elevated levels (≥30 mg/dl) in 38%]. An elevated Lp(a) was associated with a 2.3-fold [95% confidence interval (CI), 1.7-3.2, P < 0.001] greater likelihood of having a significant angiographic stenosis and 1.5-fold (95 CI, 1.3-1.7, P < 0.001) greater chance of three-vessel disease. Lp(a)≥30 mg/dl was associated with a greater rate of MACE (41.8 vs. 35.8%, P = 0.005), primarily due to a greater need for coronary revascularization (30.9 vs. 26.0%, P = 0.02). A relationship between Lp(a) levels and cardiovascular outcome was observed in patients with an LDL cholesterol (LDL-C) ≥70-100 mg/dl (P = 0.049) and >100 mg/dl (P = 0.02), but not <70 mg/dl (P = 0.77). Polymorphisms of Lp(a) were also associated with both plasma Lp(a) levels and coronary stenosis, but not a greater rate of MACE. Lp(a) levels correlate with the extent of obstructive disease and predict the need for coronary revascularization in subjects with suboptimal LDL-C control. This supports the need to intensify lipid management in patients with elevated Lp(a) levels.