Chang, Su Min

Farmer, John A.

Lakkis, Nasser

Yazbek, Naji

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256A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC March 19,2003 
Para Ei!E/ PBOI EZEI PBOI Ei!E/ PBOl EZEl PBOI 
met SlOmg S80mg AlOmg ABOmg PlOmg P40mg LlOmg L40mg 
er (“=67) (“~67) (“~65) (“~62) (“=71) (n=67) (“=66) (“=66) 
LDL- -45.5 -44.7 -53.4 -53.8 -33.6 -31.1 -34.2 -30.5 
C’ 
HDL 8.6 a.2 9.0”’ 2.8 6.4 6.1 7.9 4.8 
-C’ 
TG” -26.1 -22.6 -31 .l -30.6 -22.9 -19.2 -18.8 -15.3 
‘Mean % change “Median % change *“P<O.O5 vs high dose StatIn (A60) 
1083-143 Does Pretreatment With Statins Before Percutaneus 
Coronary Intervention Reduce Myonecrosis? 
Su Min Chanq, Naji Yazbek, John A. Farmer, Nasser Lakkis, Baylor College of Medicine, 
Houston, TX 
Background: Cardiac enzyme elevation peri PCI carnes a worse outcome. Objective 
Determine if pretreatment with statins prior to PCI reduces enzyme elevation periPCl and 
other cardiac events (CE). Methods: 119 consecutive pts ( 63 on statins prior to PCI , 56 
not )underwent PCI were followed for 6 months. We compared the peri PCI cardiac 
enzyme elevation above 3 times normal and 6 months CE rate (death, peri PCI myocar- 
dial infarctlon (Ml), non fatal MI, target vessels revasculanzation (TVR) and unstable 
angina requiring hospitalization) Of not pretreated pts ,72% were on statins at follow up 
as compared to 98 % of pretreated pts. Results: Pretreated Patlents had more history of 
Ml or revascularization (63% vs 43%, p=O.O15), hyperllpidemia (60% vs 48% p=O.OOl), 
hypertension (83% vs 49% p=O.OZ) .The rest of baseline characteristics were similar 
including use of glycoprotein Ilb/llla inhibitors (60% vs 68% p=NS) and type of lesions. 
Pretreatment with statins had less periprocedure enzyme elevation (2% vs IO % p= 0.04) 
and lower CE rate at 6 months (21% vs 41% p=O.O15). After adjusting for 15 baseline 
characteristics, use of StatIns prior to PCI was associated with a decrease in the risk of 
enzyme elevation and CE. (OR 0.2, Cl 0.06-0.63, p=O.O06). Age > 65 years and type b2/ 
C lesions predicted worse outcome. Conclusion: Statins therapy prior to PCI may 
reduce periprocedure cardiac enzyme elevation and subsequent cardiac events. These 
results need to be confirmed in prospective randomized trials. 
StatIns n=63 
PeriPCl enzyme elevation 
death 
Non periPCl MI 
lvR 
1 
ip/. 
4 
6% 
4 
6% 
1 
2% 
USA 3 
5% 
CE 13 
21% 
No Statins n =56 
6 
10% 
2 
4% 
3 
6% 
6 
10% 
7 
13% 
24 
41% 
1083-144 Statins Potentiate the Anticoagulant Effects of Low 
Molecular Weight Heparin 
Sirisha Puppala, Katherine Zamecki, Jennifer Zimmer, Rohit R. Arora, Biren Bhatt, Jesse 
Houghton, Mir Chowdhury, Charles R. Spillert. New Jersey Medical School, Newark, NJ 
Background: Pravastatin sodium (PS) has been shown to have an anticoagulant effect in 
patrents. We have shown that PS has anticoagulant effects which are unrelated to a tis- 
sue factor pathway. Whether PS can potentlate the anticoagulant effects of low molecu- 
lar weight heparln (LMWH, Dalteparin) IS discussed. 
Methods: One milliliter of titrated whole blood (CWB) was incubated for 10 minutes at 37 
degrees with the following: 20 ~1 water (control); 16 Kg/ml PS; 0.25 U/ml LMWH; 16 pgl 
ml PS and 0.25 U/ml LMWH combined. The clotting time (set) was determined on a Son- 
oclot Coagulation Analyzer, a miniviscometer, which is sensitive to early fibrin polymer 
generation. 
Results: The clotting times are as follows: control 355 f 74; PS 462 * 75; 
LMWH 636 * 191 and PS + LMWH 610 * 119. All values were significantly different from 
each other (~‘0.05 or less). 
Conclusion: PS prolongs clotting time as does LMWH when compared to the control. In 
addition. the combination of PS and LMWH prolongs clotting time when compared to 
either alone. The enhanced anticoagulant effects of this combination of drugs may also 
cxcur when used clinically. A rapid clinical blood clotting assay capable of monitoring 
these apparently beneficial effects would be an asset. 
1083-145 Variability in the ASCAl Gene but Not HMG-CoA 
Reductase Predicts Low-Density Lipoprotein Lowering 
Effects of Statins 
Gualberto Ruano. Chad Messer, Bradley Dain, Richard Judson. Carol Reed, Antonio 
Gotto. Genaissance Pharmaceuticals, New Haven, CT, Weill Cornell Medical College, 
New York, NY 
Background: ABCAI (ATP-binding cassette, sub-family A_ABCl_, member 1) is 
involved in Tangier disease and is known to play a role in cholesterol homeostasis but 
not in statin treatment. HMGCR (HMGCoA reductase) is the target for statins. We inves- 
tigated whether variability in these genes may be wolved in statin response using the 
STRENGTH study, &htin fisponse &am&d by @?ne+c &plotype Markers, a phar- 
macogenetic study of statin efficacy). 
Methods 425 patients with hyperlipidemla were randomly assigned to 6 weeks of treat- 
ment with one of three statins: 8Omg/day simvastatin (N=l48), EOmgiday atowastatin 
(N=l39) or 40mg/day pravastatin (N=l38). We sequenced the ABCAl and HMGCA 
genes in 679 hyperlipidemlc patients plus 93 other individuals. We constructed haplotype 
markers from unphased genotypes (Drysdale, et al, PNAS, 97:19, 2000). Each marker 
was tested for an associarion with LDL reduction using ANCOVA models. Permutation 
tests were used to adjust for the multiple markers considered. 
Results: We discovered 179 SNPs Including 30 novel, non-synomymous SNPs in 
ABCA1. We found a significant association between an ABCAl haplotype marker and 
LDL reduction by statin treatment (P~O.0001) The association is also seen in the Individ- 
ual statin groups with p-values ranging from 0.04 to 0.003. The marker Includes 
GLU(1192) ASP plus 4 other SNPs. Patients with tl copy of the marker respond wth 
10% less LDL reduction than those without the marker. There were no differences in 
basellne lipids or HDL response between individuals based on this marker. 
For HMGCR, sequencing in our cohort revealed 51 SNPs. We detected no association 
between haplotype markers of HMGCR and statln response. 
Conclusion: Genes involved in cholesterol and lipid metabolic dwases should be can- 
dldates for pharmacogenetic analysis of drug response. Drug targets. although useful for 
drug screening, may not influence interindiwdual differences in drug response. 
ORAL CONTRIBUTIONS 
804 Genetic Determinants of Atherosclerosis 
Monday, March 31, 2003, 9:15 a.m.-10:30 a.m. 
McCormick Place, Room S103 
9:15 a.m. 
804-l LOX-l Polymorphism as a Susceptibility Genetic Marker 
for Atherosclerosis 
Ruaaiero Manaq Fabrizio Clementi, Gianmarco Contino, Giovanni B. Forleo. Paola 
Borgiani, Annalisa Botta, Annamaria Nardone, Gaetano Chiricolo, Massimo Marchei, 
Alessia Romeo, Sabina Guarino, Clarissa Cola, Maria Rosaria D’Apice, Masslmo 
Federici, lbrahim Fahdi, Renato Laura, Francesco Romeo, Giuseppe Novelli. Jawahar L. 
Mehta, University of Tor Vergata, Rome, Italy, University of Arkansas for Medical 
Sciences, Little Rock, AR 
Background and Objectives: Atherosclerosis is the principal process contributing to the 
pathogenesis of coronary artery disease (CAD), cerebral infarctlon. and penpheral vas- 
cular disease. A large number of risk factors such as hypertension. hypercholester- 
olemia, diabetes, obesity, smoking and shear stress leads to endothelial activation and/ 
or dysfunction, which elicit a series of cellular interactions that culminate in atherogene- 
sis. Several biochemical and functional studies suggest that a lectm-like receptor for oxi- 
dized low-density-lipoprotein (ox-DL), termed LOX-l. may be involved in atherogenesis. 
A recent linkage study performed in a mouse model, identified LOX-l as candidate sus- 
ceptibility gene for human atherosclerosis. Aim of this study is to investigate the role of 
the LOX-1 gene in human atherosclerosis susceptibility through association studies in 
different populations. 
Mated&and Methods: We screened a group of 164 Italian individuals with angiographlc 
CAD phenotype (CAD; n=66) or without any angiographically demonstrable disease 
(CAD-free; w76) and a group of 35 individuals from Arkansas (CAD, n=14; CAD-free, 
n=21). 
Results: We charaderized five dtfferent SNPs (SNP l-5) at the LOX-l locus I” these 
populations. We demonstrated that SNP4 (A to G transltion) correlates with CAD with a 
high degree of specificity in the Italian population (X’ = 7,37: P. 0.007; ldf) and repro- 
duced this association also in the American group (X*=5.1 I; P. 0.0237; ldf). 
Conclus;on:On the basis of these data on the prevalence of LOX-l SNPs in two different 
angiographically documented CAD populations, we think that LOX-l may be a potent 
candidate gene for atherogenesls and endothelial dysfunction in response to ox-LDL. 
Work supported by the Italian Ministry of Universrty and Research (MIUR) 
9:30 a.m. 
804-2 Genetic Determinants of Nicotine-Induced 
Angiogenesis 
Edwin Chanq, Yan Wang, Hanh M. Bui. Johannes Jacobi, Christopher Heeschen, James 
J. Jang, John P. Cooke, Stanford University Medical School, Stanford, CA 
Background: Nicotine is a potent angiogenic agent which Induces tumor angiogenesis 
and plaque neovascularizatlon. The angiogenic effect of nicotine occurs at concentra- 
tions similar to those found in plasma of moderate smokers. Nlcotlne action is medlated 
by endothelial nicotlnic cholinergic receptors (nAChR). We hypothesize that stimulation 
of the nAChR activates signal transduction pathways and transcriptional pathways that 
an? distinct from other anglogenic factors. Methods: We identified nicotine-regulated 
genes by using subtraction hybndization technology to isolate the differentrally expressed 
genes. We also employed high-throughput microarray transcriptional profiling to examine 
and validate gene expression profiles. Human micro vascular endothelial cells were 
treated with vehicle or nicotine (IO-‘M), and were subjected to PCR-selected subtraction 
hybridization. Results: Nicotine increased proliferative but decreased apoptotlc indices in 
sub confluent proliferatmg endothelial cells (HUVEC and HCAECs) with respect to 
untreated cells. Hexamethonium blocked the anti-apoptotic effect of nicotine. In nicotine 


Does pretreatment with statins before percutaneus coronary intervention reduce myonecrosis? 

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Does pretreatment with statins before percutaneus coronary intervention reduce myonecrosis?

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