The ethnicity-specific association of biomarkers with the angiographic severity of coronary artery disease

Background

Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays.

Methods

In the Dutch-Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score.

Results

Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p < 0.001 and p = 0.005, respectively). MPO levels were higher in Caucasians than in Indians (32.8 vs. 27.2 ng/ml, p = 0.026), hsTnI levels were higher in Malays than in Caucasians and Indians (33.3 vs. 16.4 and 17.8 ng/l, p < 0.001 and p = 0.029) and hsTnI levels were higher in Chinese than in Caucasians (23.3 vs. 16.4, p = 0.031). We found modifying effects of ethnicity on the association of biomarkers with SYNTAX score. NTproBNP associated more strongly with the SYNTAX score in Malays than Caucasians (β 0.132 vs. β 0.020 per 100 pmol/l increase in NTproBNP, p = 0.032). For MPO levels the association was stronger in Malays than Caucasians (β 1.146 vs. β 0.016 per 10 ng/ml increase, p = 0.017). Differing biomarker cut-off levels were found for the ethnic groups.

Conclusion

When corrected for possible confounders we observe ethnicity-specific differences in biomarker levels. Moreover, biomarkers associated differently with CAD severity, suggesting that ethnicity-specific cut-off values should be considered.     

The Sp1 transcription factor does not directly interact with the HIV-1 Tat protein

The role of Sp1 in regulating the trans-activating activity of the human immunodeficiency virus type 1 (HIV-1) Tat protein has not yet been clearly defined. In fact, studies on the physical and functional interaction between Sp1 and Tat have yielded contradictory results. Here we investigated whether a physical interaction between Sp1 and Tat indeed occurs, exploiting both biochemical and genetic techniques that allow detection of direct protein-protein interactions. Studies performed with the yeast two-hybrid system indicate that Sp1 does not directly interact with the HIV-1 Tat protein. Control experiments demonstrated that both proteins are functionally expressed in the yeast cells. In vitro binding assays further confirmed that Sp1 does not physically bind Tat. These data suggest that in vivo Tat and Sp1 most likely take part of a multicomponent complex and thus encourage the search of the molecule(s) which mediate Tat-Sp1 interaction.     

Association of male pattern baldness with angiographic coronary artery disease severity and collateral development

Objective

We aimed to investigate whether there is an association between male pattern baldness and angiographic coronary artery disease (CAD) severity and collateral development, which has not been reported previously.

Methods

Coronary arteriograms, CAD risk factors, lipid parameters and presence and severity of baldness in 511 male patients were prospectively evaluated. Baldness was classified into five groups. Severity of CAD was evaluated with the Gensini scoring system and collateral development with Rentrop scores.

Results

Although subjects with a higher Gensini score had more frequent and severe baldness, they were older than the group with lower Gensini scores. Bald patients had a higher Gensini score when compared with their non-bald counterparts. In univariate analysis, age more than 60, body mass index more than 30, smoking and baldness were predictors of high Gensini scores. In multivariate analysis, only age more than 60, body mass index more than 30 and smoking were independent predictors of a high Gensini score. There were no differences in terms of presence and severity of baldness in subjects with and without adequate collateral development.

Conclusions

There was no relation between presence, severity and age of occurrence of male pattern baldness and Gensini and Rentrop scores, which are important measures of presence and severity of CAD.     

Association of fibrinogen and plasmin inhibitor,but not coagulation factor XIII gene polymorphisms with coronary artery disease

BackgroundIn the final phase of clot formation, fibrinogen constitutes frame, whereas factor XIII (FXIII) active form is responsible for the covalent cross-linking of fibrin fibres and plasmin inhibitor (PI), thus contributing to clot stability. It could be expected that any change of coagulation factors'' structure affects the clot formation and modulates the atherothrombotic risk. The aim was to determine the frequency of four single nucleotide polymorphisms: (i) A > G in codon 312 of the fibrinogen α-chain gene (rs6050, Thr312AlaFGA), (ii) C > T at position 10034 of the 3 - untranslated region in the fibrinogen γ-chain gene (rs2066865, 10034C > T FGG), (iii) C > T in codon 564 of the FXIII-A subunit gene (rs5982, Pro564LeuFXIII-A), and (iv) C > T in codon 6 of the plasmin inhibitor gene (rs2070863, Arg6TrpPI) in Croatian patients and their association with coronary artery disease (CAD).MethodsWe performed the unrelated case-control association study on the consecutive sample of patients 18 years old, who had undergone coronary angiography for investigation of chest pain and suspected CAD. The cases were patients with confirmed CAD (N=201), and the controls were the subjects with no CAD (N=119). Samples were genotyped using PCR-RFLP analysis.ResultsObserved frequencies of the rare alleles of Thr312Ala FGA, 10034C > T FGG, Leu564Pro FXIII-A and Arg6Trp PI polymorphisms were 21%, 17%, 14%, 20%, respectively. Patients with 10034C > T FGG CC genotype had 3.5 times (95% CI 1.02-12.03) higher adjusted odds for CAD than patients with 10034C > T FGG TT genotype. Patients with Arg6Trp PI CC genotype had 3.86 times (95% CI 1.23-12.12) higher odds for CAD than patients with Arg6Trp PI TT genotype. It seems that those genotype-related higher odds are also male-gender related. No difference was observed regarding any other investigated polymorphism.ConclusionsOur finding suggests that 10034C > T FGG and Arg6Trp PI are associated with CAD.     

Natural history of coronary artery disease in relation to angiographic, hemodynamic and clinical factors

Studying the natural history of coronary artery disease could provide a frame of reference for prognosis and appraisal of treatment for patients having this disease. We studied a total of 465 consecutive patients with angiographically significant coronary artery disease, defined as greater than 50% stenosis in at least one principal artery, who were followed with medical treatment only from 1 to 7 years. Excluding patients with left main coronary disease, there were 73 deaths, of whom 63 were cardiac. The 5-year cumulative survival rates were 72% for the entire group, 87% for single vessel disease, 73% for double vessel disease and 51% for triple vessel disease. In single vessel disease, patients with left anterior descending artery involvement tended to have higher mortality. In double vessel disease, survival was worse with the combination of left anterior descending and right coronary artery involvements than the other 2 combinations. A history of myocardial infarction was not significantly different from angina in 5-year survival rate. Nevertheless, an abnormal Q-wave in ECG was associated with lower survival. History of hypertension and electrocardiographic left ventricular hypertrophy did not affect survival. While congestive heart failure, abnormal resting LVEDP and left ventricular asynergy were all associated with reduced survival. The left ventricular ejection fraction had highly prognostic value, only 42% of patients survived with ejection fraction less than 0.3 at the end of 5 years after angiography.     

Measures of postprandial lipoproteins are not associated with coronary artery disease in patients with type 2 diabetes mellitus

Individuals with type 2 diabetes mellitus (DM) characteristically have elevated fasting and postprandial (PP) plasma triglycerides (TG). Previous case-control studies indicated that PPTG levels predict the presence of coronary artery disease (CAD) in people without DM; however, the data for patients with DM are conflicting. Therefore, we conducted a case-control study in DM individuals, 84 with (+) and 80 without (−) CAD. Our hypothesis was that DM individuals with or without CAD would have similar PPTG levels, but CAD+ individuals would have more small d<1.006 g/L lipoprotein particles. Several markers of PP lipid metabolism were measured over 10 h after a fat load. PP lipoprotein size and particle number were also determined. There was no significant difference in any measure of PP lipid metabolism between CAD+ and CAD−, except for apoB48, which was actually higher in CAD−. We followed 69 CAD− participants for a mean 8.7 years; 33 remained free of any cardiovascular event. There were no PP differences at baseline between these 33 who remained CAD− and either the 36 original CAD− who subsequently developed CAD or the original CAD+ group.PP measurements of TG-rich lipoproteins do not predict the presence of CAD in individuals with DM.     

Association of NT-proBNP and multiple biomarkers with severity of angiographic coronary artery disease in diabetic and pre-diabetic Chinese patients

Background

Little is known about the plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the relationship between the severity of coronary heart disease (CHD) with NT-proBNP and multiple biomarkers in diabetic and pre-diabetic patients, compared to individuals with normal glucose levels.

Methods

Four hundred and fifteen consecutive Chinese patients of both sexes were assigned to three groups on the basis of the new hemoglobin (Hb) A1c (HbA1c) cut-off points for diagnosis of diabetes and pre-diabetes. The three groups were divided into tertiles according to NT-proBNP, hs-CRP, cystatin C, and troponin T levels. Gensini scores were compared among the three groups and biomarker tertiles. Receiver operating characteristic (ROC) curves were used to obtain the angiographic CHD cut-off points for each biomarker. Stepwise multivariate linear correlation analysis was applied to examine the association between the severity of CHD and biomarker levels.

Results

Gensini scores increased with increasing biomarker tertile levels and HbA1c. Gensini scores were significantly different in the middle and upper NT-proBNP tertiles of the diabetic, pre-diabetic and control groups. NT-proBNP had the highest positive and negative predictive values and area under the curve for CHD. Only NT-proBNP was identified as an independent variable for Gensini score.

Conclusions

Plasma NT-proBNP may be an important biomarker to evaluate the severity of CHD and screen for CHD in diabetic or pre-diabetic patients.     

Tissue factor expression and serum level in patients with melanoma does not correlate with disease progression.

Not only does tissue factor (TF) play a crucial role in hemostasis and thrombosis, but it is also involved in tumor progression and metastatic potency in some malignant tumors. We evaluated the clinical relevance of TF expression in melanocytic tumors and TF serum level in patients with malignant melanoma. TF expression in benign and malignant melanocytic lesions was examined by immunoperoxidase staining in 20 nevi, 41 primary, and 24 metastatic melanoma lesions. TF was detected in 94, 95, and 100% of these lesions, respectively. The staining pattern was membranous and cytoplasmic both in nevi and melanoma cells. This finding was confirmed by western blot analysis using cultured human melanocytes, nevi cells, and melanoma cell lines. TF was also expressed on blood vessels in benign and malignant melanocytic lesions. Expression of TF in primary melanoma lesions was not associated with any clinicopathological variables. In addition, the serum level of TF was elevated in 14% of patients with melanoma; however, it was not correlated with disease progression. These results suggest that TF was ubiquitously expressed in melanocytic cells and its expression was not correlated with disease progression and/or metastatic potency of melanoma cells.     

Genetic polymorphisms of the renin-angiotensin system and angiographic extent and severity of coronary artery disease: the CORGENE study

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from –0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = –0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis. Received: 23 April 1996 / Revised: 5 August 1996     

Studies of low density lipoprotein molecular weight in human beings with coronary artery disease

Low density lipoprotein molecular weight (LDL MW) correlates positively with coronary artery disease in cholesterol-fed nonhuman primates. To evaluate this in human beings with coronary artery disease (CAD) we measured LDL MW in 93 volunteers undergoing coronary angiography (47 controls and 46 CAD patients). LDL MW of CAD patients was less than that of controls (patients, 2.79 +/- 0.17 g/mumol; controls, 2.93 +/- 0.19 g/mumol; P less than 0.001). However, LDL MW decreased as plasma triglyceride increased and concentrations of triglyceride were greater in CAD patients than in controls. Since decreased LDL MW is likely to result, in part, from increased plasma triglyceride concentrations, we attempted to determine the effect of triglyceride on the relation of LDL MW to CAD in this study. After covariance adjustment for triglyceride, there was no LDL MW difference between CAD patients and controls. Because LDL heterogeneity has been identified in other studies and was apparent on inspection of agarose column profiles of LDL of these volunteers, we sought differences in the profiles that might distinguish coronary disease cases from controls. No differences could be found. In addition, we used density gradient ultracentrifugation to characterize LDL in more detail in a subset of volunteers who had a wide range of plasma triglyceride concentrations (50 mg/dl to 900 mg/dl). LDL mean hydrated density was inversely related to LDL MW and increased as triglyceride increased. The increase in peak density was reflected in an increase in percent of total protein in LDL found to have d greater than 1.045 g/ml and a decrease in protein in LDL of d 1.035-1.040 g/ml. These interrelationships were not apparently influenced by coronary artery status.     

Relationship between serum high sensitivity C-reactive protein with angiographic severity of coronary artery disease and traditional cardiovascular risk factors

Serum high-sensitivity C-reactive protein (hs-CRP) is predictive of coronary artery disease (CAD). The aim of this study was to examine the possible association of hs-CRP with presence and severity of CAD and traditional CAD risk factors. This case-control study was carried out on 2,346 individuals from September 2011 to May 2013. Of these 1,187 had evidence of coronary disease, and were subject to coronary angiography, and the remainder were healthy controls (n = 1,159). Characteristics were determined using standard laboratory techniques and serum Hs-CRP levels were estimated using enzyme-linked immunosorbent assay (ELISA) kits, and severity of CAD was assessed according to the score of obstruction in coronary artery. Serum hs-CRP levels were higher in those with severe coronary disease, who had stenosis ≥ 50% stenosis of at least one coronary artery (all p < 0.001 vs. individuals in healthy control), and correlated significantly with the score for coronary artery disease (all p < 0.01). After adjustment for conventional risk factors, regression analysis revealed that smoking habits, fasting blood glucose, total cholesterol, high-density lipoprotein, hs-CRP, blood pressure, anxiety, dietary intake of vitamin E, and cholesterol remained as independent determinants for angiographic severity of CAD. The area under the receiving operating characteristic (ROC) curve for serum hs-CRP was 0.869 (CI 95% 0.721–0.872, p < 0.001). The optimal values for the cut-off point was a serum hs-CRP of 2.78 mg/l (sensitivity 80.20%, specificity 85%) to predict severity of CAD. Increased serum hs-CRP levels are significantly associated with angiographic severity of CAD, suggesting its value as a biomarkers for predicting CAD.