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cholesterol-rich diet without and with adventitia showed similar hyperplastic intima lesions and distribution of collagen. KCl-induced vasoconstriction was significantly reduced in carotid arteries without adventitia ( 0.59/-0.08 g vs 0.25 /-0.06 g, p0.05). Ach-induced relaxation was unchanged. Conclusion: Histological and functional properties of carotid arteries in rabbits on a cholesterol-rich diet are influenced by adventitial cells (Supported by NSFC grant 39725013 ). Cell Cycle Protein Expression in Stenosed Arteriovenous Fistulas for Hemodialysis Ruben Dammers, Rick De Graaf, Tryfon Vainas, Jan H Tordoir, Peter J Kitslaar, Arnold P Hoeks. University Hospital Maastricht, Maastricht, Netherlands; University of Maastricht, Maastricht, Netherlands P232 Objectives. Renal failure (RF) patients rely on arteriovenous fistulas (AVFs) for hemodialysis vascular access. Intimal hyperplasia (IH) results in frequent interventions and/or failure of the AVF. The extent of IH depends on the interplay between cyclins and cyclin dependent kinases (p.e. CDK2), positively regulating cell cycle progression. CDK activity is negatively modulated by the interaction with CDK inhibitory proteins, such as p21 and p27. Little is known about the expression of these proteins in the development of IH in AVFs. Methods. Of 18 failed AVFs (patency duration: 765 160 days) of 16 RF patients (8 male) stenotic segments were compared to 5 healthy left-over veins and arteries. The nuclear proteins p21, p27, and CDK2 were immunohistochemically stained on paraffin embedded 5 m tissue sections. To compare the percentages of positively stained cells an ANOVA with Bonferroni correction was used. Correlation coefficients were calculated, corrected for age. Findings. Results are summarized in the table. The percentage of p21-positive cells was significantly less in AVFs compared to healthy segments (p0.001). CDK2 activity was more pronounced in AVFs (p0.001). Between healthy veins and AVFs the percentage of p27-positive cells was not different, but in AVFs it was higher compared to healthy arteries (p0.05). AVF patency correlated with the number of p27-positive cells (r-0.612, p0.026). Conclusion. p21 is downregulated in stenotic segments of AVFs and is thus correlated to the development of IH in AVFs. Furthermore, p27 inversely correlated with the patency, suggesting p27 to have a more regulatory function in IH development. Future research is needed to decide whether p21 is an appropriate target for therapeutical intervention to prevent IH in AVFs. Consequences of Chronically Elevated Plasma Fibrinogen Levels on Thrombosis in Genetically Hypercoagulable Mice P233 Bryce A Kerlin, Brian Cooley, Susan Lord, Hartmut Weiler. Medical College of Wisconsin, Milwaukee, WI; University of North Carolina, Chapel Hill, NC; Blood Research Institute of The Blood Center, Milwaukee, WI Elevated plasma fibrinogen (hyperfibrinogenemia) is associated with cardiovascular disease and may increase the probability of developing arterial vascular disease. Epidemiological studies remain inconclusive with respect to the question whether elevated plasma fibrinogen is only associated with disease, or constitutes indeed a causative risk factor for disease initiation and progression. In order to investigate the cause-effect relationship between hyperfibrinogenemia and thrombosis, we examined a transgenic mouse model of familial hyperfibrinogenemia in which plasma fibrinogen levels are approximately 2-fold higher than in normal mice secondary to the presence of an extra copy of the genetic locus carrying all three fibrinogen genes (HiFib-mice). HiFib-mice maintained under standard husbandry conditions did not exhibit an increased propensity for microvascular thrombosis and/or fibrin deposition, yet showed augmented fibrin degradation products (D-Dimer). Experimentally induced permanent stasis of blood flow in the carotid artery did not cause formation of fibrin-platelet thrombi in excess of those formed in wild type mice. Platelet thrombus formation after arterial injury induced by ferric chloride was indistinguishable from that observed in normal mice. HiFib-mice were then crossed with a second genetically engineered mouse strain that exhibits a hypercoagulable state due to reduced thrombomodulin function. Superimposed hyperfibrinogenemia did not modify the prothrombotic phenotype of thrombomodulin-deficient mice. In conclusion, in mice, pre-existing hyperfibrinogenemia does not induce a marked prothrombotic state, and does not appear to alter the incidence/severity of experimentally induced thrombosis. Identification of the Proteoglycan-Binding Site of Apolipoprotein B48-Containing Lipoproteins Maria J Gustafsson, Christofer Flood, Jan Boren. Wallenberg Laboratory, Göteborg, Sweden P234 The retention of lipoproteins is a key step in atherogenesis. The binding of LDL to proteoglycans to the extracellular matrix (ECM) is mediate through residues 3359–3369 in apoB100. Despite the fact that apoB48 lacks this binding site, lipoproteins containing apoB48 have been shown to bind to proteoglycans in vitro. To identify the principal glycosaminoglycan binding site of apoB48, we made a series of mutations in the human apoB gene, expressed the mutated genes in rat McArdle 7777 cells, isolated the recombinant human LDL, and determined their abilities to bind to the smooth muscle cell proteoglycans, decorin and biglycan. We found that when mutating all of the basic amino acids in residues 18 –24 or 225–227 of apoB, the assembly of lipoproteins was affected and there was no secretion Downloaded of human apoB. from However, recombinant http://atvb.ahajournals.org/ Poster Presentations a-41 apoB48 with residues 87, 88 and 90 mutated were secreted, but the interaction to the proteoglycans was abolished. We also generated transgenic mice expressing apoB 80, with or without residues 3359–3369 mutated. Characterization of wild-type apoB80 and RK3359 – 3369SA apoB80 showed that apoB80-containing LDL had a higher affinity for ECM than apoB100, and that RK3359–3369SA apoB80 displayed the same proteoglycan binding affinity as apoB48. Immunoaffinity studies indicated that the proteoglycan-binding site of apoB48 is masked in apoB100. These results indicate that residues 87, 88 and 90 in apoB48 interacts with artery wall proteoglycans, and that this binding site is nonfunctional in apoB100. P235 Protective Effect of Apolipoprotein E2 on Angiographically Determined Heart Disease in African Americans is Mediated through Serum Lipoprotein Cholesterol Lars Berglund, Roberta G Reed, Jill Rubin, Steve Holleran, Rajasekhar Ramakrishnan, Thomas A Pearson. Columbia University, New York, NY; Bassett Research Institute, Cooperstown, NY; University of Rochester, Rochester, NY We studied the relationship of apolipoprotein E (apoE) isoforms to coronary heart disease (CHD) in 226 African Americans (AA) and 334 Caucasians (C) undergoing diagnostic coronary angiography. Presence of CHD was defined as 50% stenosis in at least one artery. Allele frequencies were 12% E2, 62% E3, 26% E4 in AA, and 8% E2, 78% E3, 14% E4 in C. ApoE2/4 heterozygotes were excluded from analysis. Among AA, CHD was present in 9 of 34 E2 carriers, significantly smaller (P0.05) in proportion compared to 39 of 82 E3/3 and 43 of 93 E4 carriers, suggesting a protective effect of the E2 allele. Among C, the CHD proportions were 23 of 39 E2 carriers, 121 of 205 E3/3 and 40 of 75 E4 carriers, not significantly different from one another. Case-control differences were significant in both ethnic groups (P0.02 for AA and P0.01 for C) for LDL cholesterol with cases having higher LDL cholesterol levels than controls. In AA, HDL cholesterol was lower among cases than controls (P0.03). In AA but not in C, LDL in E2 carriers was lower than in non-E2 carriers (P0.005). Since lipid levels were predictive of CHD in both ethnic groups and E2 carriers had more favorable lipid levels, a multiple logistic regression was done to determine if E2 had a separate protective effect beyond its effect on lipid levels. After adjusting for lipid levels, the association between apoE2 and CHD was no longer significant (the P value in AA went from 0.04 to 0.18). Thus, the protective effect of apoE2 seen in AA could be explained by the favorable lipid profile in E2 carriers, while in C, the absence of such an effect could be due to the lack of effect of apoE2 on the lipid profile Differential Effects of Atorvastatin and Fenofibrate on HDL Kinetics in Overweight Subjects P236 Hugh R Barrett, Anthony G Johnson, June Ji, Kevin D Croft, Adrian Serone, Gerald F Watts. University of Western Australia, Perth, Australia; GlaxoSmithKline, King of Prussia, PA; GlaxoSmithKline, Sydney, Australia Overweight (OW) and obesity are associated with increased risk for cardiovascular disease (CVS) and this may be related to low plasma concentrations of high-density lipoproteins (HDL), and hence to depressed reverse cholesterol transport (RCT). Statins and fibrates are commonly used in OW, dyslipidemic patients and have been shown to reduce CVS risk in clinical trials. However, the precise mechanisms of action involved and the specific effects on HDL metabolism of these agents have not yet been fully established. Therefore, the aim of this study was to examine the effect of Atorvastatin (AT) and Fenofibrate (FF) on HDL kinetics. We studied 12 dyslipidemic OW men (BMI27 kg/m 2 , plasma cholesterol (C) 6.03/-0.23 mmol/L, HDL cholesterol (HDLC) 0.96/-0.05 mmol/L, triglyceride (TG) 2.29/-0.29 mmol/L, apoB 1.13/- 0.03 mmol/L, apoAI 1.14/-0.04 mmol/L) in a double-blind, randomized, placebo controlled, cross-over trial. Subjects were treated once daily with micronised FF (200mg), AT (40mg) or placebo (P) for 6-week periods with 2-week washouts. HDL apoAI turnover was measured following iv administration of d 3-leucine. HDL apoAI was isolated using PAGE and isotopic enrichment measured with GCMS. Metabolic parameters were estimated by compartment modeling. Compared with reference data, HDL apoAI fractional catabolic rate (FCR) was higher in the OW subjects, but apoAI production rate (PR) was normal. Compared with P, AT reduced plasma C 41% (p0.001), TG 35% (p0.002) and apoB 42% (p0.001). FF treatment reduced plasma TG 28% (p0.004), apoB 12% (p0.015) and increased HDLC 7% (p0.005). Compared with P, FF increased HDL apoAI concentration 5% (p0.046) and apoAI PR 14% (p0.037). HDL apoAI FCR did not differ between P, AT or FF. Although AT and FF both reduced plasma TG concentrations, only AT significantly lowered plasma C. In contrast to AT, FF was associated with increased plasma HDLC and apoAI concentrations; this effect was related to increased PR of apoAI and may be due to increased apoAI transcription with FF. This mechanism of action may account for the favourable effect of FF on RCT and a specific CVS benefit of PPAR- agonists compared with statins. P237 Plasma ApoA-I Kinetics in Complete Hepatic Lipase Deficiency in Humans Isabelle Ruel, Patrick Couture, Jeffrey Cohn, Benoit Lamarche. Nutraceuticals and Functional Foods Institute, Sainte-Foy, QC, Canada; Lipid Research Center, CHUL, Sainte-Foy, QC, Canada; Hyperlipidemia and Atherosclerosis Research Group, Montreal, QC, Canada Complete hepatic lipase (HL) deficiency in humans is a rare monogenic disorder associated with increased plasma apoA-I and HDL cholesterol levels, and with a marked triglyceride (TG) enrichment of HDL particles. It has been documented that in the presence of active intravascular HL, the TG-enrichment of HDL is associated with an enhanced metabolic clearance of HDL apoA-I. The aim of the study was to test the hypothesis that the catabolic rate of plasma apoA-I is reduced in complete HL deficiency. The female proband of a kindred with HL deficiency and 2 of her younger brothers were found to have undetectable HL activity, which was accompanied by the presence of -VLDL and elevated plasma apoA-I and HDL-TG concentrations. by guest All 3 subjects on April were4, E32013 homozygotes. The in vivo kinetic of apoA-I was studied
a-42 Arterioscler Thromb Vasc Biol. Vol 22, No 5 in the 3 patients with complete HL deficiency and in 6 male and female control subjects using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h in fasting state. The apoA-I (d1.25 g/L) tracer/tracee enrichment curve over time was determined by gas chromatography-mass spectrometry and fitted to a monoexponential function to determine the rate of apoA-I production and catabolism. The mean fractional catabolic rate of plasma apoA-I was reduced in HL deficient patients compared to control subjects (0.118 0.007 vs. 0.173 0.054 pools/day, P0.06). As a result, the residence time of plasma apoA-I was 34 % greater among HL deficient patients compared to controls. On the other hand, the production rate of plasma apoA-I was similar between the two groups (9.70 3.66 vs. 9.56 2.63 mg/kg/day in HL deficient and control subjects respectively, P0.9). Similar trends were observed when men and women were analyzed separately. These data confirm that the accumulation of TG-enriched HDL particles in patients with complete HL deficiency is largely due to a reduction in the catabolic rate of apoA-I Niacin Non-Competitively Inhibits Hepatocyte Diacylglycerol Acyltransferase, a Key Enzyme for Triglyceride Synthesis Shobha H Ganji, S Tavintharan, Daming Zhu, Vaijinath S Kamanna, Moti L Kashyap. VA Healthcare System, Long Beach, CA; University of California at Irvine, Irvine, CA P238 Background: Niacin is a widely used lipid regulating agent with a broad spectrum beneficial effect on lipoproteins in dyslipidemic patients. Previously, we have shown that it increases the degradation of hepatic apolipoprotein B (apo B, the major apolipoprotein of atherogenic lipoproteins) by inhibiting triacylglycerol (TG) synthesis from fatty acids and glycerol. In this study, we hypothesized that niacin inhibits diacylglycerol acyltransferase (DGAT), a key enzyme for TG synthesis. Methods: Human hepatoma cells (Hep G2) grown in DMEM containing 10% FBS were used to prepare microsomes by ultracentrifugation at 100,000 g. Microsomal DGAT activity in the absence or presence of niacin was measured by assessing the formation of TG using 14C-oleoyl-CoA and dioleoylglycerol as substrates. Enzyme kinetic parameters, including Km, Vmax, Lineweaver and Burk (LB) plot for competitive/non-competitive inhibition, and IC-50 were determined. Results: DGAT activity measurement at various concentrations of oleoyl-CoA showed a Km value of 8.3 M . Addition of niacin (0–3 mM) to the assay reaction mixture (at 30 min, 25 C) significantly reduced DGAT activity by 40–50%. Dose-response studies with niacin showed an IC-50 of 0.3 mM. To assess the competitive or non-competitive type of inhibition, the rate of reaction of DGAT was measured at various concentrations of substrate (oleoyl-CoA; 2.5–20 M) in the absence or presence of niacin. LB plot of DGAT inhibition by niacin showed a non-competitive pattern of inhibition. There was a decrease in Vmax values with niacin while the Km remained constant in control and in presence of niacin. Conclusions: These data define DGAT as a major target for the mechanism of action of niacin. We suggest that the direct inhibition of DGAT by niacin results in the observed increased apo B degradation leading to a reduction of hepatic atherogenic lipoprotein secretion. DGAT inhibitors therefore may represent a new class of drugs that regulate atherogenic lipoproteins by this mechanism. P239 Combination of a Novel Inhibitor of the Apical Sodium-Bile Acid Cotransporter, SC-435, and Atorvastatin Reduces LDL-Cholesterol through Decreased Secretion and Enhanced Clearance of LDL ApoB Dawn E Telford, John R Burnett, P Hugh R Barrett, Bradley T Keller, Murray W Huff. The John P Robarts Research Institute, London, ON, Canada; University of Western Australia, Perth, WA, Australia; University of Western Australia, Perth, Australia; Pharmacia Corp, St. Louis, MO Discovery of the ileal apical sodium-bile acid cotransporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially, a new class of cholesterol lowering agents. Recently, we showed that SC-435, a novel ASBT inhibitor, significantly reduced LDL-cholesterol (C) in miniature pigs. In the present study we tested the hypothesis that combining SC-435 with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate LDL-C reduction and the regulation of apoB metabolism. ApoB kinetic studies were performed in miniature pigs after 21 days treatment with SC-435 (5 mg/kg/d) and atorvastatin (3 mg/kg/d)(SC-435 A) or placebo (n6/group). Pigs were fed a diet containing fat (35% of energy) and C (400 mg/d). SC-435 A decreased plasma total C by 23% (2.22 vs 2.89 mmol/L, p0.004) and LDL-C by 40% (0.86 vs 1.44, p0.0004). Other plasma lipids were unchanged. Autologous 131I-VLDL, 125I-LDL and 3H-leucine were injected simultaneously and apoB kinetic parameters determined by multicompartmental analysis (SAAM II). SC-435 A had little effect on VLDL apoB kinetics. LDL apoB decreased by 35% (6.6 vs 10.1 mg/kg, p0.004), due to a 45% (0.060 vs 0.044 h-1, p0.05) increase in the LDL apoB fractional catabolic rate (FCR). Furthermore, LDL direct synthesis was decreased by 17% (0.26 vs 0.32 mg/kg/h, p0.05), whereas conversion of VLDL apoB to LDL was unchanged. SC-435 A significantly decreased hepatic concentrations of free C (-12%; 2.3 vs 2.0 mg/g) and esterified C (-47%; 0.18 vs 0.35), increased hepatic 7-alpha OHase activity 2.3-fold (p0.03) and increased hepatic LDL receptor mRNA 1.8-fold (p0.05). As monotherapy, SC-435 (10 mg/kg/d) decreased LDL apoB by 10% (8.7 vs 9.8; p0.035), due entirely to a 17% (0.052 vs 0.044; p0.032) increase in LDL apoB FCR. Atorvastatin monotherapy (3 mg/kg/d) decreased LDL apoB by 29% (4.7 vs 6.8; p0.0004), due primarily to a 22% (0.23 vs 0.30; p0.004) reduction in LDL apoB production. We conclude that SC-435 A potentiates the reduction of LDL-C and LDL apoB due to their complementary mechanisms of action. P240 Female Swine Develop Greater Carotid Atherosclerosis than do Male Swine Care and Use Committee of the University of Missouri approved all procedures. Sexually mature female (n16) and male (n16) Sinclair miniature swine between the ages of 9 and 12 months were housed in a temperature-controlled room (20 to 22 C) with a 12-hour light/dark cycle. Pigs were fed once daily for 12 weeks a high fat, high cholesterol diet consisting of Purina Minipig chow supplemented to contain 2% cholesterol, 17.1% coconut oil, 2.3% corn oil, and 0.7% sodium cholate. Total, low-density, and high-density lipoprotein (HDL) cholesterol were analyzed in plasma obtained from blood samples taken following an overnight fast on days 0 and 84. On day 84 pigs were anesthetized intramuscularly with atropine, ketamine, and xylazine and the chest was opened to achieve euthanasia. The common carotid arteries were harvested 5 mm above and below their origin from the brachiocephalic artery and fixed in neutral buffered 10% formalin. Arterial samples were opened longitudinally, stained with Sudan IV, flattened under a glass plate, and photographed digitally. The area of positive Sudan IV staining was calculated as a percent of total luminal area (percent Sudanophilia) utilizing ImagePro Plus. Cross sections of the arterial wall were taken from the most intensely Sudanophilic portion of each sample and processed routinely through paraffin embedment. Five micron sections were stained with Verhoeff’s method for elastin and the maximal intimal thickness was measured by digital light microscopy. Results and Conclusions: The percent Sudanophilia was greater in female (37.7 /- 28.4) than male (10.5 /- 9.6, P 0.002) pigs. The maximal intimal thickness was greater in female (384 /- 333 microns) than male (192 /- 148 microns, P 0.05) pigs. There was no difference in HDL on day 0, however HDL on day 84 was lower in female (76 /- 14) than male (89/- 15, P 0.02) pigs and correlated inversely with percent Sudanophilia (R -0.56) and maximal intimal thickness (R-0.39) Differential Lipid Binding of the N-terminal Domain of ApoE Isoforms Paul M Weers, Robert O Ryan. Children’s Hospital Oakland Research Institute, Oakland, CA P241 Apolipoprotein E (apoE) is a 34 kDa protein that is involved in plasma lipid homeostasis through its interaction with the low density lipoprotein receptor family. The protein contains two independently folded and functional domains, a 22-kDa N-terminal (NT) and a 10-kDa C-terminal domain. The NT domain (residues 1–183) undergoes a conformational reorganization of its four helices upon binding to a lipid surface. Three common isoforms exist (apoE2, apoE3 and apoE4), differing in cysteine and arginine content at position 112 and 158. They also differ in biophysical properties, which may be related to isoform-specific correlations with heart disease and Alzheimer’s disease. We therefore examined the lipid binding properties of the NT domain of apoE2, apoE3 and apoE4 using model lipid surfaces. The ability of the protein to interact with large unilamellar phospholipid vesicles composed of anionic dimyristoylphosphatidylglycerol (DMPG) or zwitterionic dimyristoylphosphatidylcholine (DMPC) was investigated. Incubation of apoE-NT with vesicle dispersions results in their transformation into discoidal complexes. Based on the rate of DMPG vesicle transformation, the interaction of apoE4-NT was much stronger than apoE3-NT, while apoE2-NT showed the weakest interaction. The transformation of DMPC vesicles by apoE-NT was poor at pH 7.2 but transformation rates increased dramatically at pH 3. However, no differences in the interaction of apoE-NT isoforms with DMPC vesicles were observed under these conditions. Fluorescent dye experiments with 8-anilino-1-naphthalene sulfonate revealed increased exposure of the hydrophobic interior at pH 3 for all isoforms, indicating adoption of a molten globule-like state. In this state, isoform-specific differences in tertiary structure may be diminished. This study shows that differences in the biophysical properties of apoE-NT isoforms may result into distinct interactions with various lipid substrates. P242 Lipoprotein Lipase Is One of the Important Determinant Factors for LDL Particle Sizes and Triglycerides and HDL Metabolism, but not Cholesterol Ester Transfer Protein in Healthy Japanese Hiroshi Mokuno, Haruyo Yamashita, Kazunori Shimada, Eriko Seki, Yoshitaka Iwama, Testurou Miyazaki, Yoshirou Watanabe, Hiroyuki Daida. Juntendo University, Tokyo, Japan Production of small, dense LDL, high levels of triglycerides (TG) and low levels of HDL cholesterol (Chol) have been reported for atherogenic lipid profile in insulin resistant metabolism. To determine the lipid metabolic enzyme attributing to this lipid profile, we measured fasting serum lipoprotein lipase (LPL) and cholesterol ester transfer protein (CETP) by ELISA in 237 healthy Japanese subjects. LDL size was determined by non-denature gradient PAGE. Correlation analysis of LPL mass (mean S.D. : 43.713 ng/ml) and CETP mass (1.920.57 mg/ml) was performed with age (489 yo), BMI (23.062.9), LDL Chol (11632 mg/dl), TG (10887 mg/dl), HDL Chol (6618 mg/dl), glucose (9413 mg/dl) and LDL size (26.30.9 nm). In result, LPL had positive correlation with HDL Chol (r0.48) and LDL size (r0.26) and negative correlation with BMI (r-0.26), TG (r-0.34) and glucose (r-0.24) significantly (p0.01, respectively). In contrast, CETP positively correlated with only LDL Chol (r0.25, p0.01). These results indicated that LPL is associated with not only TG and HDL metabolism and also LDL size and glucose metabolism. LPL may be important lipid enzyme determining atherogenic lipid profile in insulin resistance, compared with CETP. P243 Atorvastatin Reduces VLDL ApoE and Total Plasma ApoE Production in Patients with Combined Hyperlipidemia Jeffrey S Cohn, Michel Tremblay, Rami Batal, Helene Jacques, Lyne Veilleux, Claudia Rodriguez, P Hugh R Barrett, Lise Bernier, Orval Mamer, Jean Davignon. Clinical Research Institute of Montreal, Montreal, QC, Canada James Turk, Tom Thomas, Michael Sturek, M Harold Laughlin. University of Missouri, Atorvastatin, a synthetic HMG-CoA reductase inhibitor, significantly lowers plasma cholesterol Columbia, MO and low-density lipoprotein (LDL) cholesterol levels and reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of Objective: The objective of this study was to examine the influence of gender upon carotid atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo atherosclerosis induced by an atherogenic diet inDownloaded swine. Materialsfrom and Methods: http://atvb.ahajournals.org/ The Animal rates of plasma by guest apoE production on April and 4, catabolism 2013 in 6 patients with combined hyperlipidemia,
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