Th-W54:4 Risk of angiographically-assessed coronary artery disease associated with LDL and HDL particle sizes in women

Thurs&ty, June 22, 2006: Workshop Th- W54 Lipoprotein particle NCEPIII guidelines), and insulin resistance (by HOMA). We used a multilocus polymerase chain reaction (PCR)-based assay and sequonome method to genotype 72 SNPs in promoters, exons or introns of 36 genes associated with lipoprotein phenotype. The associations between gene variants, their phenotype, and longevity were examined. Results: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly greater in probands (p<0.001), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein-A1 and B ( A P t - A 1 , B). This phenotype was also typical of their offspring but not of the age-matched controls. HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension, cardiovascular disease (CVD), and the metabolic syndrome (p<0.008) (1). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly greater in offspring and controls without the metabolic syndrome (p<0.0001). A significant overrepresentation of 2-3 fold in the frequency of homozygosity in the favorable genotype for cholesteryl ester transfer protein (CETP) gene codon 405 isoleucine to valine variant (CETP W ) , apolipoprotein C-3 (APOC-3) A (-641) C promoter variant (APOC-3 CC), and genotype of deletion at the 3" UTR +2019 in the adiponectin (ADIPOQ) gene were observed. In addition to the favorable lipid profile, subjects with these genotypes have very large lipoprotein particle sizes, specifically larger particle sizes of high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL), and increased HDL levels (2). Conclusions: Exceptional longevity is associated with enrichment in the several genotypes, and significant measurable phenotype. These genotypes and their associated phenotype may play a role in conferring survival to exceptionally old age by increasing lipoprotein particle size, insulin sensitivity and providing protection from the metabolic syndrome and cardiovascular disease. References [1] Baxzilai N, Atzmon G, Schechter C., Schaefer E., Cupples AL, Lipton R, Cheng S, Shuldiner AR. "'Unique lipoprotein phenoytype and genotype associated with exceptional longevity." JAMA 2003:290:2030-40 [2] Atzmon G, Rincon M, Rabizadeh R BarziDJ N. "'Biological evidence for inheritance of exceptional longevity." Mech. Ageing Dev. 2005 Feb: 126(2):341-5 F u n d i n g : This work has been supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, RO1 (AG-18728-01A1), the General Clinical Research Center (M01-RR12248), the Diabetes Research and Training Center (DK 20541) at the Albert Einstein College of Medicine,

I Th-W54:3 I L D L D E N S I T Y

PREDICTS INTIMA-MEDIA T H I C K N E S S IN A F R E E - L I V I N G P O P U L A T I O N . T H E P R E S E N C E A N D P R O G R E S S I O N OF L E S I O N S IN C A R O T I D A R T E R I E S (PLIC) S T U D Y

A. Zambon I , S. Raselli 2 , G.D. Norata 2, L. Grigore 2 , F. Maggi 2, D. V i a n d l o 1 M. Marchiori 1 A.L. Catapano 2 . 1Department of Medical and

Surgical Sciences, Universi~ of PcMova, Italy: 2Department of Pharmacological Sciences arm Center for the Study of Atherosclerosis, Universi~ of Milan, Italy Objective: Small, dense LDL (s-d LDL) are associated with premature cardiovascular disease (CVD). Carotid intima-media thickness (IMT) is a sutrogate index of atherosclerosis. The PLIC study aims to: i) verify the presence and progression of carotid lesions and IMT in a large cohort, and ii) investigate how IMT relates to classic and emerging CVD risk factors. We present data from a randomly selected PLIC cohort without signs or history of CVD nor on any lipid-lowering therapy. Methods: IMT was evaluated by B-mode ultrasonography in both common carotid arteries and measured as the mean of 10 standardized points. RF is the LDL flotation rate by ultracentrifugation (UC). Results: n=156, age 53-4- lyrs, BM126.6-4-0.4 kg/m 2, PAS 132 -4-1.5 mmHg, PAD 82-t-0.8 mmHg, LDL-C 144-t-3 mg/dL, HDL-C 56-t-1 mg/dL, triglycerides 108-t-6, glucose 89-t-1 mg/dL. In a linear stepwise regression analysis, including all major CVD risk factors, age, LDL-RF and HDL-C are the only independent predictors of IMT (p<0.0001, p=0.018, p=0.023 respectively). In a multivariate analysis with all lipoprotein subclasses, the cholesterol in two UC fractions corresponding to remnants-like particles (RLP) and small-dense LDL, accounts for 32.3%, p<0.0001, and 24.3% p=0.003, of IMT respectively. Leukocytes from subjects with prevalence of s-d LDL, show a 27 fold greater RNA expression of monocyte chemoattractant protein- 1 (MCP- 1). Conclusions: In a free-living population, LDL peak density, age and HDL-C predict IMT. Only 10-12% of the overall LDL-C, caxried in the RLP

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and s-d LDL, is strongly associated with the degree of IMT and increased leukocyte MCP-1 expression.

I Th-W54:4 I R I S K OF A N G I O G R A P H I C A L L Y - A S S E S S E D CORONARY ARTERY DISEASE ASSOCIATED WITH L D L A N D H D L P A R T I C L E S I Z E S IN W O M E N

P. Blackburn 1"2"3, I. Lemieux I , B. Lamaxche 4 , J. Bergeron 5 , P. Perron 2, G. Tremblay 2, D. Gaudet 2, J.E Despr6s 1. 1 Qudbec Heart bzstitute, Lcn,al Hospital Researeh Center; Qudbec, CamMa: 2 Chicoutimi Universi~ Hospital, Chicoutinti, CamMa: 3 Universitd Du Qudbec gt Chicoutinti, Chicoutimi, CancMa: 41nstitute On Nutraceutieals and Functional Foods, Laval Universi~, Qudbec, Canada: 5Lipid Research Center; CHUL Research Center; Qudbec, Cattclda Objective: LDL peak particle diameter and the proportion of small and large LDL particles predict ischemic heart disease. The presence of small HDL particles has also been associated with features of the metabolic syndrome. The aim of the present study was to quantify, in women, the respective and potentially additive contributions of LDL and HDL particle chaxacteristics to the risk of coronary artery disease (CAD). Methods: We analyzed the baseline data of 239 women on whom CAD was assessed by angiography. LDL and HDL chaxacteristics were respectively assessed by 2-16% and 4-30% polyacrylamide gradient gel electrophoresis. Results: Women with CAD were characterized by significantly different LDL and HDL particle characteristics compared to women without CAD (p<0.01). Women with large LDL particles (>255 rA) and small HDL part i d e s (<80.2 A, the 50th percentile) had an increased risk of CAD (OR 2.3, 95% CI: 1.2 to 4.5; p=0.01) compared with women chaxacterized by both large LDL and HDL particles. Small LDL particles in the absence of small HDL particles resulted in a 2.9-fold increase in CAD risk, which did not reach statistical significance (p=0.06). Finally, women having both small LDL and HDL particles showed the highest risk of CAD (OR 6.9, 95% CI: 2.0 to 24.1; p<0.003). Similar results were obtained when calculating the proportion of small LDL in the presence of small HDL particles. Conclusions: Results suggest that both small LDL and HDL phenotypes are predictive of an increased CAD risk in women. Funding: Canadian Diabetes Association.

ITh-W54:5

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I L D L P A R T I C L E S I Z E A N D T H E R I S K OF F U T U R E i

C H D IN A P P A R E N T L Y H E A L T H Y M E N A N D W O M E N : THE EPIC-NORFOLK PROSPECTIVE POPULATION STUDY

B.J. Arsenault I , I. Lemieux I , J.P. Despr~s I , S.M. Boekholdt 2 , N.J. Wareham 3, S.A. Bingham 4 , K.-T. Khaw 5. 1Lcn'al Hospital Research

Center; Qudbec, Canada: 2Academic Medical Center; Amsterdam, tile Netherlands: 3MRC Epidemiology Unit, Cambridge, United Kingdom: 4MRC Dunn Nutrition Unit, Canal)ridge, United Kingdom: 5btstitute of Public Health and PrJmary Care, Cambridge, United Kittgdom Small LDL particle size has been shown to predict an increased risk of CHD in both prospective and case-control studies. The present study examined, in a nested case-control study performed in the prospective EPIC-Norfolk cohort study, the association of LDL particle size to future CHD in apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CHD over 10 year follow-up. Cases (n=1035) were matched to 1920 controls who remained free of CHD, by age, gender and enrollment time. Baseline LDL particle size was measured using 2-16% non denaturing polyacrylamide gradient gel electrophoresis. LDL peak particle size was smaller in cases than in matched controls (259-t-5 vs. 260-t-5 ~ , P<0.001). Accordingly, the proportion of small LDL particles (<255 A) was higher in cases than in controls (29.8-4-18.7 vs. 26.1-4-17.2%, P<0.001). The unadjusted odds ratio for future CHD by percentage of small LDL (as continuous variable, per 10% points) was 1.12 (95%CI, 1.07 to 1.17; P<0.001) The odds ratio for future CHD remained significant after adjustment for traditional risk factors (OR, 1.09; 95%CI, 1.04 to 1.14; P<0.001) whereas it did not reach statistical significance after adjustment for HDL-cholesterol and triglyceride levels (OR, 1.04; 95%CI, 0.99 to 1.09; NS). A m o n g apparently healthy men and women, an increased proportion of small LDL particles predicts an increased risk of future CHD, although adjustment for HDL-cholesterol and triglyceride levels had a major impact on the relation of LDL particle size to CHD events.

XIV bzterTmtional Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006