Effects of exercise on lipoprotein(a).

Exploring Avenues for Raising HDL Cholesterol

The catabolism of lipoprotein(a), Lp(a), remains unclear. Very recently we observed that estrogen, a hormone known to increase low-density lipoprotein (LDL) receptor activity, reduced serum Lp(a) levels in a man with familial hypercholesterolemia (FH) (JAMA 267: 2328, 1992). In the present study, we attempted to further evaluate this Lp(a)-lowering action of estrogen in men without FH. Seven men, aged 61-84 yr, treated with estrogen for prostatic cancer were the subjects and seven men who underwent surgical treatment without estrogen therapy served as controls. Fasting blood was collected before and 1-3 months after estrogen therapy, and serum Lp(a) levels and lipoprotein profiles were determined. Estrogen treatment caused significant changes in serum lipoproteins, i.e., decreases in LDL-cholesterol, and increases in high-density lipoprotein (HDL)-cholesterol. Serum triglyceride levels tended to increase. Serum apo A-1 underwent a two-fold increase, while apo B did not change. Serum Lp(a) levels ranged from 8 to 62 mg/dl. After estrogen treatment serum Lp(a) was reduced markedly, with a mean reduction of 81% (71-95%). Serum lipids, lipoproteins and Lp(a) did not change significantly in the controls. The results demonstrated a regulating effect of estrogen on serum Lp(a) levels, and the findings further suggested that Lp(a) is removed via LDL receptors. However, previous studies have shown that maneuvers causing a decrease in LDL-cholesterol do not always cause a reduction in serum Lp(a). Thus, our findings suggested the possible presence of a receptor which is estrogen-inducible and different from the LDL receptor.

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.

There are so many studies that suggest the changes in lipid profiles and lipoprotein (a) [Lp(a)] are associated with early atherosclerosis in rheumatoid arthritis (RA). But there are some opposite studies also. Because of marked ethnicity differences in the distribution of Lp(a), we aimed to investigate the associations of Lp(a) levels and lipid changes in Turkish RA patients. There were 30 women and 20 men, a total of 50 patients with RA (mean age 47.6 +/- 13.2 years), included and 21 healthy women and 14 healthy men (mean age 45.7 +/- 14.5 years) were recruited as a control (C) group. Serum Lp(a), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were analysed for each group. Analysis of six different studies was performed. In the RA and C groups, mean serum Lp(a) levels were 39.7 +/- 64.4 and 10.5 +/- 13.4 mg/dl, respectively (P=0.001). Mean TC levels were 189.2 +/- 142.5 and 174.0 +/- 29.3 mg/dl (P=0.294), mean TG levels were 121.4 +/- 65.4 and 106.5 +/- 80.0 mg/dl (P=0.030), mean HDL-C levels were 44.5 +/- 10.0 and 47.7 +/- 4.8 mg/dl (P=0.014) and mean LDL-C levels were 94.3 +/- 35.3 and 102.0 +/- 24.6 mg/dl (P=0.98), respectively. Analysis of the six studies showed Lp(a) level was higher and HDL level was lower in RA patients than in healthy controls. Patients with RA may have altered lipid profiles from one country to another one. Especially in Turkey, higher serum Lp(a), lower HDL-C and higher TG levels may be found in RA patients instead of some findings of other countries showing different results. Ethnicity may be a reason for these findings.

To further understand lipoprotein (a) [Lp(a)] and atherosclerosis, we measured serum Lp(a), lipoprotein, and apolipoprotein levels in 55 patients (males, 24-73 years old) on maintenance hemodialysis, and compared them with those of 82 controls (males, 21-81 years old). The serum Lp(a) levels in patients on maintenance hemodialysis were significantly higher than those of the normal controls, while serum total cholesterol (TC), high-density lipoprotein-cholesterol, (HDL-C), HDL2-C, HDL3-C, apolipoprotein (apo) Al, apo All levels, and lecithin-cholesterol acyltransferase (LCAT) activities were significantly (p < 0.05) reduced in the patient group. The frequency distribution of serum Lp(a) levels in the patients was different from that in the control group, and no prognostic tendency of serum Lp(a) levels was noted by the etiology of renal failure as histologically determined by the renal biopsies. In the patient group, we also found that serum Lp(a) levels negatively correlated with serum triglycerides (TG) and total protein (TP) concentrations (p < 0.05), but no correlation was found between the duration of hemodialysis therapy or patient age and the serum levels of TC, TG, apo B and Lp(a) levels when tested for simple regression. Significant (p < 0.05) positive correlations were also found between TP and serum TG, apo B, and LCAT activities. These opposing tendencies of Lp(a) and serum TG, apo B, when measured against TP concentrations, indicate that serum TP levels may not affect serum lipoprotein and Lp(a) levels in the same direction. These data suggest that hemodialysis or end-stage renal disease itself, rather than hypoproteinemia, may hold the key to high serum Lp(a) levels in hemodialysis patients.

Lipoprotein(a), type 2 diabetes and nephropathy; the mystery continues

Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels. In 16654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr <2.5 mmol/L and Lp(a) <80th cohort percentile was used as reference category. In the EPIC-Norfolk and CCHS cohorts, individuals with an Lp(a) ≥80th percentile were at increased CVD risk compared with those with Lp(a) <80th percentile for any LDL-Ccorr levels ≥2.5 mmol/L. In contrast, for LDL-Ccorr <2.5 mmol/L, the risk associated with elevated Lp(a) attenuated. However, there was no interaction between LDL-Ccorr and Lp(a) levels on CVD risk in either cohort. Lipoprotein(a) and LDL-C are independently associated with CVD risk. At LDL-C levels below <2.5 mmol/L, the risk associated with elevated Lp(a) attenuates in a primary prevention setting.

Effects of Increasing High-Density Lipoprotein Cholesterol and Decreasing Low-Density Lipoprotein Cholesterol on the Incidence of First Acute Coronary Events (from the Air Force/Texas Coronary Atherosclerosis Prevention Study)

Serum lipoprotein(a) {Lp(a)} is accepted as a potent risk factor for atherosclerotic disease. C4b binding protein (C4bp), a regulatory protein in complement system, plays important roles in blood coagulation and fibrinolysis, and is identical with proline-rich protein. Our previous study showed a positive correlation between serum Lp(a) and C4bp levels (Nagata et al., J. Jpn. Atheroscler. Soc., 20: 651-655, 1992). Both the serum amyloid A (SAA) and serum amyloid P (SAP) components are precursors of the amyloid A and P proteins, which are the main amyloid components deposited in the tissue of secondary amyloidosis. In human blood, SAP binds with C4bp, and SAA binds with HDL lipoprotein.We examined effects of oral administration of niceritrol (750mg/day, for 16 weeks) on serum lipids, apolipoproteins, Lp(a), C4bp, SAP, and SAA in 26 patients (12 males and 14 females) who had high serum Lp(a) levels (>30mg/dl) and the following cerebrovascular diseases: cerebral infarction (16 patients), cerebral bleeding (8 patients), and subarachinoidal hemorrhage (2 patients).Niceritrol therapy decreased total cholesterol and triglyceride levels, confirming previous reports. HDL-cholesterol levels had increased 4 weeks after administration, but the increases after 16 weeks were not significant. Apolipoproteins B and C-III levels had decreased after 16 weeks, but other apolipoproteins showed no significant change.Niceritrol obviously lowered serum Lp(a) levels; the percentage decrease from the pre-treatment level was 22±8% (12±4mg/dl) after administration for 16 weeks. Lp(a) levels rebounded to pre-treatment levels 4 weeks after niceritrol therapy was discontinued. C4bp levels had also decreased after 4 weeks, but the decreases after 16 weeks were not significant. However, the percentage decreased in Lp(a) and C4bp levels showed a positive correlation. In addition, both SAA and SAP levels decreased after 16 weeks, and the decreases, in percentage terms, percentage were positively correlated. Niceritorol therapy lowered the serum levels of C4bp, SAA, and SAP as well as Lp(a). We speculate that niceritrol suppressed the production of these proteins in the liver.

Studies have shown that phosphatidylinositol (PI) can stimulate reverse cholesterol transport by enhancing the flux of cholesterol into HDL and by promoting the transport of high density lipoprotein-cholesterol (HDL-C) to the liver and bile. The goal of this study was to determine the safety and therapeutic value of PI after oral administration to normolipidemic human subjects. We performed a randomized 2 week study in 16 normolipidemic subjects. Subjects received either 2.8 or 5.6 g of PI, with or without food. PI was well tolerated by all subjects. PI significantly affected the levels of HDL-C and triglyceride in the plasma of subjects receiving PI with food. The lower dose showed a 13% increase in HDL-C, whereas the high dose showed an increase of 18% over the 2 week period. Both low- and high-dose groups showed significant increases in plasma apolipoprotein A-I. The high dose of PI also decreased plasma triglycerides by 36% in the fed subjects. These data suggest that after only 2 weeks, PI may have a comparable therapeutic value to niacin, with negligible side effects.

BackgroundLipoprotein (a) (LP (a) is an independent cardiovascular risk factor that is not widely studied in people of sub-Saharan African origin. The aim of this report is to determine the frequency of occurrence of elevated Lp (a) and possible relationship with total cholesterol (TCHOL), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), C reactive protein (CRP) and serum uric acid (SUA).MethodsThis is a cross sectional study carried out in 200 Nigerian patients with type 2 DM and 100 sex and age matched healthy Controls aged between 32-86 years. We determined the frequency of occurrence of elevated Lp (a) levels in the study subjects and compared clinical and biochemical variables between type 2 diabetic patients and non-diabetic patients. Clinical and biochemical parameters were also compared between subjects with type 2 DM who had elevated LP (a) and normal LP (a) levels. Long term glycaemic control using glycosylated haemoglobin was determined and compared in the study subjects. Test statistics used include chi square, correlation coefficient analysis and Student's t test.ResultsThe mean Lp(a) concentration differed significantly between type 2 diabetic patients and the Control subjects (18.7 (5.8) mg/dl vs 23 (6.8) mg/dl, 0.00001). Similarly, the prevalence of high LP (a) levels in type 2 DM patients was significantly higher than that of the Control subjects (12.5% vs 4%, p-0.019). The mean levels of the lipid profile parameters (TCHOL, LDL-C, TG, LDL/HDL) and CRP were significantly higher in DM patients than in the Control subjects. The mean LP (a) levels were comparable in both sexes and in DM subjects with and without hypertension. TG was the only parameter that differed significantly between subjects with elevated Lp (a) levels and those with normal Lp (a) levels. There was a significant positive correlation (r) between Lp(a) levels and TG, LDL-C. TCHOL, LDL/HDL and uric acid. No association was found between Lp(a) and clinical parameters such as age and anthropometric indices.ConclusionWe have showed that Lp (a), CRP and other CVS risk factors cluster more in patients with DM than non DM patients. Serum Lp (a) levels are not associated with anthropometric and glycaemic indices.

Several studies have indicated that residual cardiovascular risk might be associated with elevated lipoprotein(a) [Lp(a)] even in the setting of controlled low-density lipoprotein cholesterol (LDL-C). We aimed to prospectively examine the association between Lp(a) and unfavorable functional outcome among patients with acute ischemic stroke when Lp(a) and LDL-C were discordant. Based on samples from the Infectious Factors, Inflammatory Markers and Prognosis of Acute Ischemic Stroke study, 973 patients with baseline plasma Lp(a) levels were included. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score of 3-6) at 6months. Logistic regression models were used to estimate the risk for the primary outcome. Discordance analyses were performed, using difference in percentile units (>10units), to detect the relative risk when Lp(a) and LDL-C were discordant. In total, 201 (20.7%) participants experienced major disability or death at 6months. The multivariable-adjusted odds ratio (OR) for the highest quartile was 1.88 [95% confidence interval (CI): 1.16-3.04] compared with the lowest quartile. Each 1-SD higher log-Lp(a) was associated with a 23% increased risk (95% CI: 2%-47%) for the primary outcome. Compared with the concordant group, the high Lp(a)/low LDL-C discordant group was associated with increased risk for the primary outcome (adjusted OR: 1.59, 95% CI: 1.01-2.52). Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6months. Discordantly high Lp(a)/low LDL-C was associated with an unfavorable functional outcome, supporting the predictive potential of plasma Lp(a) after ischemic stroke, especially when discordant with LDL-C. Key messages What is already known on this topic Previous studies have indicated that a positive association between increased lipoprotein(a) [Lp(a)] and cardiovascular disease risk remained even in patients who achieved controlled low-density lipoprotein cholesterol (LDL-C) levels. The findings of studies exploring the association between Lp(a) and unfavorable clinical outcomes of stroke were inconsistent, and whether Lp(a) can predict the risk of unfavorable functional outcome in stroke patients when Lp(a) and LDL-C levels are discordant remains unknown. What this study adds Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6months beyond LDL-C levels in acute ischemic stroke patients. How this study might affect research, practice, or policy The combination of LDL-C-lowering therapies and Lp(a)-lowering therapies may have better clinical efficacy for patients with ischemic stroke, and it is of great clinical interest to further explore this possibility in dedicated randomized trials.

Lipoprotein(a) and other lipoproteins in hypothyroid patients before and after thyroid replacement therapy

Should Lipoprotein(a) be Measured in Youth?

An Evidence-Based Review of Exercise and Metabolic Syndrome