Coronary Artery Disease: Humphries S

Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Anonymous00206, Anonymous00207. · European Society of Cardiology · G Ital Cardiol (Rome). · Pubmed #18383763 No free full text.

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Hamsten A, Syvänne M, Silveira A, Luong LA, Nieminen MS, Humphries S, Frick MH, Taskinen MR. · King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden. · Thromb Haemost. · Pubmed #10744143 No free full text.

Abstract: Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.

Li P, Sanders J, Hawe E, Brull D, Montgomery H, Humphries S. · Cardiovascular Department, Second Affiliated Hospital of Jiangxi Medical College, Nanchang 330006, China. · Chin Med J (Engl). · Pubmed #16117883 links to  free full text

Abstract: BACKGROUND: Heme-oxygenase 1 (HO-1) is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO) and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different (GT)n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery (CABG) as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein (CRP) and fibrinogen and their relationship to HO-1 genotype. METHODS: Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG. RESULTS: Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen (r = 0.48, P < 0.0001; r = 0.41, P < 0.0001 respectively), with a significant correlation between CRP and fibrinogen (r = 0.61, P < 0.0001). All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP (r = 0.34, P = 0.0009) but not with peak fibrinogen (r = 0.15, P = 0.13), while peak CRP and peak fibrinogen were significantly correlated (r = 0.415, P < 0.0001). HO-1 allelic repeats ranged from 22-42, with (GT)25 and (GT)32 being the two most common alleles, and subsequently divided into three groups according to previous published work: <30 (GT)n were designated as S (short), 30-37 (GT)n as M (middle) and long repeats with >37 (GT)n as L (long); allele frequency 0.35, 0.58 and 0.07 respectively. Baseline CRP differed by genotype: those carrying at least one long allele having higher CRP than those with no long allele (3.76 +/- 0.79 vs. 2.07 +/- 0.17, P = 0.013). Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele (3.83 +/- 0.79 vs. 3.51 +/- 0.88, P = 0.006). CONCLUSIONS: There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.

Gudnason V, Kakko S, Nicaud V, Savolainen MJ, Kesäniemi YA, Tahvanainen E, Humphries S. · UCLMS, UK. · Eur J Clin Invest. · Pubmed #10092998 No free full text.

Abstract: BACKGROUND: Variation at the cholesteryl ester transfer protein (CETP) gene locus has been implicated in determining the levels and activity of CETP, apoAI and high-density lipoprotein (HDL) plasma concentration and the risk of developing coronary artery disease. STUDY DESIGN: The effects of two common polymorphisms of CETP, TaqIB in intron 1 and isoleucine 405 to valine (I405-->V) in exon 14, were examined in a sample of 822 men age 18-28 years from 11 countries in Europe who had participated in a study (the European Atherosclerosis Research Study II) of the offspring of myocardial infarction sufferers before the age of 55 years and age-matched control subjects. RESULTS: The frequency of the rare TaqIB allele (B2) and the rare V405 allele was 0.44 and 0.28 respectively and was the same in different regions of Europe. There was a moderate linkage disequilibrium between the two polymorphisms in all the regions (D' = +0.31, P < 0.001), explained by the preferential association between the two common alleles, B1 and I405. There was a statistically significant association of the rare alleles for both the polymorphisms with lower activity of CETP (P < 0.001), 11.2% lower for the TaqIB and 7.0% lower for the I405-->V polymorphism. The TaqIB polymorphism explained 9.1% (P < 0.001) and I405-->V explained 3.7% (P < 0.001) of the variance in CETP activity, and in combination these genotypes explained 12.0% of the variance (P < 0.001). Overall, subjects whose fathers had had an early coronary heart disease had 2.4% higher plasma CETP activity than those without such family history, which became statistically significant when adjusted for the effect of the genotypes (P = 0.015), but the significance disappeared after adjustment for the effect of lipids. There was a statistically significant effect of the TaqIB polymorphism on both plasma HDL cholesterol and apoAI level (P < 0.001), with those homozygous for the rare B2 allele having the highest level. Those individuals homozygous for the rare V405 allele had the highest HDL and apoAI levels, although these effects only reached statistical significance for HDL (P < 0.03). CONCLUSION: These results suggest that the TaqIB and I405-->V polymorphisms represent two independent functional variations in the CETP gene that may affect the activity of CETP and thus plasma levels of HDL.