Outcomes following percutaneous coronary intervention and coronary artery bypass grafting surgery in Chinese, South Asian and White patients with acute myocardial infarction: administrative data analysis.

BACKGROUND: Little is known on whether there are ethnic differences in outcomes following percutaneous coronary intervention (PCI) and coronary artery bypass grafting surgery (CABG) after acute myocardial infarction (AMI). We compared 30-day and long-term mortality, recurrent AMI, and congestive heart failure in South Asian, Chinese and White patients with AMI who underwent PCI and CABG. METHODS: Hospital administrative data in British Columbia (BC), Canada were linked to the BC Cardiac Registry to identify all patients with AMI who underwent PCI (n = 4729) or CABG (n = 1687) (1999-2003). Ethnicity was determined from validated surname algorithms. Logistic regression for 30-day mortality and Cox proportional-hazards models were adjusted for age, sex, socio-economic status, severity of coronary disease, comorbid conditions, time from AMI to a revascularization procedure and distance to the nearest hospital. RESULTS: Following PCI, Chinese had higher short-term mortality (Odds Ratio (OR): 2.36, 95% CI: 1.12-5.00; p = 0.02), and South Asians had a higher risk for recurrent AMI (OR: 1.34, 95% CI: 1.08-1.67, p = 0.007) and heart failure (OR 1.81, 95% CI: 1.00-3.29, p = 0.05) compared to White patients. Risk of heart failure was higher in South Asian patients who underwent CABG compared to White patients (OR (95% CI) = 2.06 (0.92-4.61), p = 0.08). There were no significant differences in mortality following CABG between groups. CONCLUSIONS: Chinese and South Asian patients with AMI and PCI or CABG had worse outcomes compared to their White counterparts. Further studies are needed to confirm these findings and investigate potential underlying causes.

Cholesterol ester transfer protein (CETP) Taq1B polymorphism influences the effect of a standardized cardiac rehabilitation program on lipid risk markers.

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.

Lecithin: cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year follow-up.

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.

APOA5 gene polymorphism modulates levels of triglyceride, HDL cholesterol and FERHDL but is not a risk factor for coronary artery disease.

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 (FER(HDL)), 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 FER(HDL) (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 FER(HDL) following adjustment of several variables including age, gender, body mass index, diabetes, lipid lowering and beta-blocker medication. The APOA5*1/*1 haplogenotype remained an independent predictor of HDL-C and FER(HDL) following adjustment of the same variables. The relationship between APOA5 genotype or haplogenotype and FER(HDL) 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.

Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus or the metabolic syndrome have a unique dyslipidemia characterized by hypertriglyceridemia; elevated blood levels of apolipoprotein B; small, dense low-density lipoprotein (LDL) cholesterol; and low levels of high-density lipoprotein (HDL) cholesterol, in particular HDL(2)-C. Treatment of the dyslipidemia associated with these disorders should focus on correcting the abnormal lipoprotein levels as well as LDL and HDL heterogeneity. Statins and fibrates are useful for treating elevated LDL in patients with and without diabetes or the metabolic syndrome. In addition, thiazolidinediones or niacin in combination with a statin show promise for correcting defects in LDL and HDL heterogeneity. The ultimate goal of treatment in this patient population is to prevent the development and progression of coronary artery disease.

Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia.

Metabolic abnormalities associated with the metabolic syndrome are also present in patients with type 2 diabetes mellitus and in those with familial combined hyperlipidemia (FCHL). These abnormalities include central obesity, insulin resistance with hyperinsulinemia, hypertension, increased plasma triglycerides, and decreased high-density lipoprotein cholesterol levels. Other characteristics associated with FCHL include the presence of small, dense low-density lipoprotein cholesterol and increased apolipoprotein B. Patients with these abnormalities are at an increased risk for premature coronary artery disease. Treatment of the dyslipidemia associated with type 2 diabetes and FCHL with a combination of a statin and a thiazolidinedione or niacin offers the most comprehensive modality to correct the various lipid abnormalities.

Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia.

OBJECTIVE: Familial combined hyperlipidemia (FCHL) is associated with variable lipid and lipoprotein phenotypes arbitrarily defined as type IIa, IIb, and IV based on plasma total cholesterol and triglyceride levels. This study sought to characterize consistent lipoprotein and lipid abnormalities across the 3 lipoprotein phenotypes in 62 patients with documented FCHL (IIa [n=14], IIb [n=19], and IV [n=29]) and 44 healthy individuals. METHODS AND RESULTS: The lipoprotein cholesterol distribution was determined over 38 fractions obtained by density gradient ultracentrifugation. As expected, FCHL patients with hypertriglyceridemia (IIb and IV) had higher cholesterol levels in VLDL than IIa, whereas IIa showed higher cholesterol in the big, buoyant LDL and in HDL. LDL cholesterol was higher in IIb than IV; most of the increase in LDL cholesterol was associated with big, buoyant LDL rather than small, dense LDL (sdLDL). The differences in lipoproteins between phenotypes were attributable to changes in VLDL and big, buoyant LDL levels. Comparison of the FCHL patients with healthy individuals showed a significant elevation in plasma apolipoprotein B levels and sdLDL in all 3 FCHL phenotypes. CONCLUSIONS: Although triglyceride and cholesterol levels are variable by lipoprotein phenotype, sdLDL and elevated plasma apolipoprotein B levels are consistent characteristics of FCHL shared by the 3 different lipoprotein phenotypes.

Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet.

Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.

Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene.

Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly(188)-->Glu LPL and the stable Ile(194)-->Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile(194)-->Thr substitution interferes with access of lipid substrate to the catalytic pocket. These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis.