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Abstract: Cardiac rehabilitation programs (CR) are standard treatment for patients with coronary artery disease (CAD), yet a large variation in risk factor and lipoprotein changes exists. We investigated the role of three common genetic polymorphisms (CETP Taq1B, LIPC −514 and apo E) associated with alterations of lipoprotein metabolism, in patients before and after standardized CR. Three-hundred and seven patients were recruited for this study. DNA samples were collected and all three genotypes were determined for every patient. While the hepatic lipase LIPC promoter polymorphism and apo E genotype showed little or no correlation with response to CR, CETP Taq1B showed significant association with changes in plasma lipid and lipoproteins. The B1 homozygotes for CETP Taq1B genotype showed significant reduction in TC (−0.25±0.07, p <0.01), LDL-C (−0.15±0.06, p <0.050) and TG (−0.20±0.08, p <0.05). B2 carriers showed no significant change in these parameters. HDL-C, exercise capacity and BMI improved independent of genotype. Individuals with the B1B1 genotype appear to respond well to CR, whereas B2 carriers exhibit marginal gains in lipoprotein risk factors. Although the B2 carriers had similar benefits in exercise capacity and weight reduction, long-term consequences of little or no change in lipoprotein risk factors require further investigation to establish appropriate management strategies. [Copyright &y& Elsevier]

Objectives: We evaluated the relative and combined value of oxidative stress biomarkers for predicting cardiovascular mortality in patients undergoing selective coronary angiography. Background: Oxidative stress participates in all stages of cardiovascular disease, from lipoprotein modification to plaque rupture, and biomarkers of oxidative stress predict development of coronary artery disease (CAD). Oxidative stress biomarkers merit investigation for the value they may offer for long-term cardiovascular risk prediction. Methods: Myeloperoxidase (MPO), nitrotyrosine, oxidized low-density lipoprotein, and antioxidant capacity were measured in a prospective cohort of 885 selective coronary angiography patients followed up for >13 years for cardiovascular mortality. Results: MPO independently predicted CAD, and top tertile MPO levels predicted a 2.4-fold risk of cardiovascular mortality (95% confidence interval [CI]: 1.47 to 2.98), compared with patients with lowest tertile MPO levels. MPO also improved risk model discrimination and patient risk category classification. Elevations in multiple oxidative stress biomarkers predicted increased mortality risk; however, the strongest risk prediction was achieved by assessing MPO and C-reactive protein (CRP) together. Patients with either MPO or CRP elevated had 5.3-fold higher cardiovascular mortality risk (95% CI: 1.86 to 14.9), and patients with high levels of both MPO and CRP had a 4.3-fold risk compared with patients with only elevated marker (95% CI: 2.26 to 8.31). These results remained significant with adjustment for cardiovascular risk factors and baseline disease burden. Conclusions: MPO accurately predicted cardiovascular mortality risk in coronary angiography patients. Considering MPO and CRP together may improve long-term risk assessment and CAD patient outcomes. [Copyright &y& Elsevier]

Abstract: Purpose: Cyclosporine A (CsA), Rapamycin (RAPA), Tacrolimus (FK-506) and Mycophenolate mofetil (MMF) are immunosuppressants that are widely used in solid organ transplant patients. However, some of these drugs have been reported to cause dyslipidemia in patients. Our aim was to determine the effects of these drugs on in vitro cholesteryl ester transfer protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma. Methods: We measured CETP activity in human normolipidemic plasma with and without drug treatment, by measuring the incorporation of labeled cholesteryl ester into lipoproteins. To further confirm the result, we also measured recombinant CETP (rCETP) activity with and without drug treatment. We measured HL and LPL activity in post-heparin normal human plasma in the presence and absence of the drugs by measuring the release of fatty acids from radiolabeled triolein. Results: We found an increase in CETP activity in human normolipidemic plasma and rCETP treated with CsA and RAPA. By contrast, CETP activity was not altered significantly in the presence of FK-506 and MMF. LPL activity in post-heparin normal human plasma was suppressed following the co-incubation with CsA, RAPA, FK-506 or MMF whereas HL activity remained unaffected. Conclusions: The increase in CETP activity and suppression in LPL activity following CsA and RAPA treatment observed in the present study may be associated with elevated LDL cholesterol levels and hypertriglyceridemia seen in patients administered these drugs. [Copyright &y& Elsevier]

The purpose of this study was to test the effect of modulating the expression of the human low-density lipoprotein receptor (LDLr) in human embryonic kidney (293T) cells on Cyclosporin A (CsA) cellular uptake and CsA-mediated cytotoxicity. LDLr expression was modulated using RNA interference (RNAi) and an LDLr overexpression plasmid. One of the small-interfering RNA (siRNA) constructs, LDLr-792, showed a 60% decrease in LDLr protein expression. The downregulation effect was specific as transfection with an annexin V (AxV) siRNA construct did not decrease LDLr expression levels. AxV and ABCA1 expression levels were not affected in the cells transfected with LDLr-792 (LDLrLOW cells) compared to the controls. At a functional level, fluorescent low-density lipoprotein (LDL) (DiI-LDL) internalization in the LDLrLOW cells was decreased (30%) compared to control cells. We tested the dose-dependent cytotoxicity induced by CsA using a respiration assay. We found a decrease in CsA-mediated cytotoxicity in the range of CsA doses studied (1–10 µg/mL) in the LDLrLOW cells compared to the pSHAG-transfected cells, reaching a statistical significance at 10 µg/mL CsA. At higher CsA doses we found a significant decrease in LDLr expression. When the control and LDLrLOW cells were treated with another cytotoxic drug, gentamycin, there was no difference in the cell viability, suggesting that this effect is specific for CsA. We confirmed the association of LDLr expression levels with CsA uptake by overexpressing the LDLr. The LDLr overexpressing cells showed an enhanced uptake of radiolabelled CsA. Taken together these results suggest that CsA internalization and cytotoxicity are affected by the LDL receptor expression levels. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2349–2361, 2008 [ABSTRACT FROM AUTHOR]

We have reassessed the clinical and biochemical status of a large Canadian kindred with LCAT deficiency 25 years after the initial investigations. There have been no vascular events or death in this family over the 25 years. Both the homozygous (N = 2) and heterozygous (N = 9) patients had highly abnormal lipid profiles with low HDL-C (extreme in the homozygotes); apo B levels were high in the heterozygotes. Lipoprotein and hepatic lipase activities were low in the homozygotes and several heterozygotes. In the two homozygotes the carotid intima media thickness (IMT) was above 75th percentile expected for age and gender. However, the IMT abnormalities were much more pronounced in the heterozygotes, four of whom also had detectable plaques. The homozygotes had only minimal increases in IMT, no plaques, no IMT changes over the last 4 years and normal endothelial function.We conclude that, in this kindred, no significant vascular changes were observed in the homozygotes. However, heterozygocity for LCAT deficiency is associated with both an atherogenic lipid profile and vascular abnormalities. [Copyright &y& Elsevier]

Variation in the APOA5 gene has been shown to be associated with triglyceride levels in several independent population studies. It was our objective to determine if a relationship existed between selected genotypes or haplotypes of the APOA5 gene and findings on selective coronary angiography (SCA) in an independent cohort. The Vancouver SCA Cohort consists of individuals referred for angiography between 1993 and 1995. DNA was extracted from 537 patients and analyzed for the -1131T>C and the c.56C>G polymorphisms which define three common haplotypes of the APOA5 gene. Plasma triglycerides and the fractional esterification rate in apoB-depleted lipoproteins (FERHDL), an index of high-density lipoprotein (HDL) composition, were significantly higher (P = 0.01 and P = 0.001, respectively), and HDL cholesterol (HDL-C) was significantly lower (P = 0.03) in Caucasians with genotypes containing the minor allele of the -1131T>C polymorphism compared to the homozygotes for the major allele. However, there was no relationship between the c.56C>G polymorphism of the APOA5 gene and any of the measured lipid and lipoprotein parameters. Subjects homozygous for the common haplotype APOA5*1 had decreased triglyceride levels and FERHDL (P = 0.04 and P < 0.001, respectively) and increased HDL-C levels (P = 0.01) compared to subjects with all other haplogenotypes. Multivariate linear regression analysis indicated that the -1131T>C polymorphism remained an independent predictor of triglyceride, HDL-C, and FERHDL following adjustment of several variables including age, gender, body mass index, diabetes, lipid lowering and β-blocker medication. The APOA5*1/*1 haplogenotype remained an independent predictor of HDL-C and FERHDL following adjustment of the same variables. The relationship between APOA5 genotype or haplogenotype and FERHDL remained significant even after the addition of both HDL-C and triglyceride to the model. However, there was no association between APOA5 gene polymorphisms or haplotypes and coronary artery disease as determined by angiography. [Copyright &y& Elsevier]

Discusses the identification of a lipoprotein lipase cofactor-binding site by chemical cross-linking and transfer of apolipoprotein C-II-responsive lipolysis from lipoprotein lipase to hepatic lipase. Construction of apolipoprotein C-II activation site chimeras; Specific activity of chimeras; Kinetic analysis.