Synergistic Effect of Lipoprotein-Associated Phospholipase A2 with Classical Risk Factors on Coronary Heart Disease: A Multi-Ethnic Study in China.

AIMS: We evaluated the synergistic effect of lipoprotein-associated phospholipase A2 (Lp-PLA2) in association with classical risk factors in predicting coronary heart disease (CHD) and demonstrated the diagnostic value of Lp-PLA2 for predicting coronary stenotic lesions in subjects with CHD. METHODS: Blood samples were acquired from 911 consecutive adult subjects (662 males and 249 females) from 11 ethnic groups. Lp-PLA2 plasma levels were detected using a commercially available turbidimetric immunoassay (TIA). CHD in patients was confirmed using coronary angiography, and the severity of coronary atherosclerosis was assessed using the Gensini scoring system. RESULTS: A binary logistic regression was performed to analyse the relationships between Lp-PLA2 and other risk factors. A multivariate logistic regression analysis revealed that Lp-PLA2 levels were significantly associated with CHD (OR, 1.882; 95% CI, 1.369-2.587, p=0.000).The area under the receiver operating characteristic curve for Lp-PLA2 was 0.589 (95%CI, 0.549-0.629, p=0.000).The synergism between Lp-PLA2 and other risk factors was also investigated. The proportion of CHD attributable to the interaction between Lp-PLA2 and age was as high as 64%. CONCLUSIONS: Lp-PLA2 levels in human plasma were positively associated with the severity of CHD, and there was a clear positive interaction between Lp-PLA2 and classical risk factors in predicting CHD.

Meteorological parameters and the onset of chest pain in subjects with acute ST-elevation myocardial infarction: an eight-year, single-center study in China.

OBJECTIVE: The purpose of this study was to investigate the influence of weather on the occurrence of acute ST-elevation myocardial infarction in Chinese subjects. METHODS: Weather and climate data, as well as the occurrence of STEMI, were monitored at 2 am, 8 am, 2 pm, and 8 pm between 2003 and 2010. Generalized additive Poisson models were utilized to plot the numbers of patients with STEMI within 6 hour intervals against climatological variations, after accounting for the effects of the hour and season. RESULTS: The inclusion of meteorological conditions, including observed atmospheric pressure (hPa, hectopascal) variations during the previous three hours and temperature (°C, degrees Celsius), significantly affected the occurrence of STEMI, as measured every six hours. Compared with the 50th percentile of atmospheric pressure variations, the RRs (95% CI) for the first percentile, 10th percentile, 25th percentile, 75th percentile, 90th percentile, and 99th percentile of atmospheric pressure variation over lag 0 were 1.66 (1.36∼2.03), 1.47 (1.30∼1.67), 1.22 (1.12∼1.33), 1.16 (1.07∼1.25), 1.27 (1.13∼1.43), and 1.16 (0.92∼1.46), respectively. Compared to the 50th percentile of temperature, the RRs (95% CI) for the first percentile, 10th percentile, 25th percentile, 75th percentile, 90th percentile, and 99th percentile of temperature over lag 0 were 0.58 (0.40∼0.83), 0.60 (0.46∼0.78), 0.69 (0.57∼0.83), 1.33 (1.14∼1.56), 1.39 (1.13∼1.71), and 1.17 (0.84∼1.63), respectively. CONCLUSIONS: Based on the eight-year, single-center study, significant relationships were observed among the occurrence of STEMI and atmospheric pressure variations during the previous three hours and temperature after account for long-term time trends.

Hemoglobin A1c risk score for the prediction of coronary artery disease in subjects with angiographically diagnosed coronary atherosclerosis.

OBJECTIVE: To develop a risk score by incorporating Hemoglobin A1c(HbA1c) with traditional risk factors for the prediction of coronary artery disease (CAD) in Chinese subjects. METHODS: A total of 196 consecutive subjects (131 males and 65 females) aged 38-89 years who underwent coronary angiography were enrolled in this study. HbA1c risk score sheets for the prediction of CAD were developed using age, gender and HbA1c. A receiver-operating characteristic curve analysis was used to determine the optimum cut-off levels of the HbA1c risk score for predicting CAD. RESULTS: In the ROC curve analysis, the optimal cut-off value of the HbA1c score for predicting CAD was 5.1, with a sensitivity of 72.0% and a specificity of 75.5% (area under the curve 0.781, 95% confidence interval 0.709 to 0.854, p=0.000). CONCLUSIONS: The HbA1c score system is a simple and feasible method that can be used for the prediction of CAD. Large-scale studies are needed to further substantiate these results.

[Initial experience of percutaneous coronary intervention guided by computed tomography coronary angiography derived roadmap and magnetic navigation system].

OBJECTIVE: To evaluate the feasibility, efficacy and safety of the percutaneous coronary intervention (PCI)guided by computed tomography (CT) coronary angiography derived roadmap and magnetic navigation system (MNS). METHODS: During June 2011 and May 2012, thirty consecutive patients receiving elective PCI were enrolled, coronary artery disease was primarily diagnosed by dual-source CT coronary angiography (DSCT-CA) at outpatient clinic and successively proved by coronary artery angiography in the hospital. Target vessels from pre-procedure DSCT-CA were transferred to the magnetic navigation system, and consequently edited, reconstructed, and projected onto the live fluoroscopic screen as roadmap. Parameters including characters of the target lesions, time, contrast volume, radiation dosage for guidewire crossing, and complications of the procedure were recorded. RESULTS: Thirty patients with 36 lesions were recruited and intervened by PCI. Among the target lesions, sixteen were classified as type A, 11 as type B1, 8 as type B2, 1 as type C. The average length of the target lesions was (22.0 ± 9.8) mm, and the average stenosis of the target lesions was (81.3 ± 10.3)%. Under the guidance of CT roadmap and MNS, 36 target lesions were crossed by the magnetic guidewires, with a lesion crossing ratio of 100%. The time of placement of the magnetic guidewires was 92.5 (56.6 - 131.3) seconds. The contrast volume and the radiation dosage for guidewire placement were 0.0 (0.0 - 3.0) ml and 235.0 (123.5 - 395.1) µGym(2)/36.5 (21.3 - 67.8) mGy, respectively. Guidewires were successfully placed in 21 (58.3%) lesions without contrast agent. All enrolled vessels were successfully treated, and there were no MNS associated complications. CONCLUSIONS: It is feasible, effective and safe to initiate PCI under the guidance of CT derived roadmap and MNS. This method might be helpful for the guidewire placement in the treatment of total occlusions.

Renin-angiotensin-aldosterone system gene polymorphisms and coronary artery disease: detection of gene-gene and gene-environment interactions.

OBJECTIVE: The objective of this study was to explore the association between coronary artery disease and genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) pathway. In addition, we examined the interactions between demographic and lifestyle risk factors (environmental factors including age, sex, smoking status, alcohol intake) and RAAS polymorphisms on disease risk. METHODS: A total of 1089 subjects who underwent coronary angiography were enrolled in this study. Eight RAAS polymorphisms were genotyped in this population: the G2350A (rs4343) polymorphism in exon 17 of the angiotensin converting enzyme (ACE) gene, 1166A→C (rs5186) and 573C/T (rs5182) in the angiotensin II type 1 receptor (AGTR1) gene, the -344C→T transversion (rs1799998) in the aldosterone synthase (CYP11B2) gene, and the G-217A (rs5049), G-6A (rs5051), M235T (rs699; T4072C), and T174M (rs4762; C3889T) polymorphisms in the angiotensinogen (AGT) gene. Subjects with coronary heart disease were defined as those with at least 50% stenosis in at least one major coronary artery, and, the severity of coronary atherosclerosis was defined by the Gensini scoring system. RESULTS: Compared to the subjects with AA genotype, the subjects with AG + GG genotype of rs1799998 had significant lower gensini score (p=0.029). After adjusting for age, gender, cigarette smoking, and alcohol intake status, the AG genotype (OR 0.717 95%CI 0.541-0.950, p=0.021) and the AG + GG genotype (OR 0.730 95%CI 0.559-0.954, p=0.021) distributions of rs1799998 were significantly different between the cases and controls compare to the AA genotype. Subjects with three at-risk loci had increased risk of coronary artery disease compared to subjects carrying 0 or 1 risk-associated polymorphism (OR [95% CI]:1.579 [1.077-2.316], p=0. 019), and the significance of the association was not reduced after adjusting for age, sex, cigarette smoking, or alcohol intake (adjusted OR [95% CI]: 1.673 [1.116-2.507], p=0.013). The results of multifactor-dimensionality reduction analysis revealed an interaction effect of CYP11B2 -344C→T, age, and smoking status on the risk of coronary heart disease (training OR [95% CI]: 3.7685 [2.8463-4.9895], p<0.0001; testing OR [95% CI]: 2.7583 [1.2038-6.3203], p=0.015). CONCLUSIONS: Subjects who carried the G allele of the rs1799998 polymorphism significantly associated with coronary heart disease and severity of coronary atherosclerosis estimated by the Gensini score in the whole population of the study. And, multiple RAAS gene polymorphisms are associated with coronary artery disease. The interaction of the CYP11B2 -344C→T polymorphism (rs1799998), age, and smoking status is also associated with enhanced risk of coronary artery disease.

Inhibitory effect of hepatocyte growth factor on cardiomyocytes apoptosis is partly related to reduced calcium sensing receptor expression during a model of simulated ischemia/reperfusion.

Calcium-sensing receptors (CaSR) are G-protein coupled receptors which maintain systemic calcium haemeostasis, participate in hormone secretion, activation of iron channel, cell apoptosis, proliferation and differentiation. Previous studies have show CaSR induce apoptosis in isolated rat adult heart and in normal rat neonatal cardiomyocytes by G-protein-PLC-IP3 signaling transinduction. A few of studies had demonstrated that CaSR induce apoptosis in cultured neonatal rat cardiomyocytes during ischemia/reperfusion. Hepatocyte growth factor (HGF), as a mesenchymally derived heterodimeric glycoprotein, play vital role in mitogenesis, angiogenesis, cellular motility and growth and anti-apoptosis after postinfarction heart failure via activation of transmembrane tyrosine kinase cell surface receptor c-Met. However, little knowledge exists about whether anti-apoptotic role of HGF in preventing cardiomyocytes injury induced by ischemia/reperfusion is associated with downregulation of CaSR expression. We incubated primary neonatal rat ventricular cardiomyocytes in ischemia-mimetic solution for 2 h, then reincubated them in normal culture medium for 24 h to establish a model of simulated ischemia/reperfusion (I/R). Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The expression of CaSR mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, we analyzed the expression of Caspase-3, Bcl-2 and Phosphoinositide 3-kinase (PI3K) by Western blotting. The simulated I/R enhances the expression of CaSR and cardiomyocyte apoptosis. GdCl3, a specific activator of CaSR, further increase the expression of CaSR and Cardiomyocyte apoptosis, along with upregulation of Caspase-3, downregulation of Bcl-2 and inhibiting PI3K phosphorylation. Combination of GdCl3 with LY294002 (a selective PI3K inhibitor) increased Cardiomyocytes apoptosis but did not increased CaSR expression. Treatment of HGF decreased I/R- and GdCl3-induced apoptosis by suppressing Caspase-3 and promoting Bcl-2 and PI3K phosphorylation expression in accordance with downregulation of CaSR expression. HGF exerts protective role in I/R-induced apoptosis at least in part by inhibiting CaSR expression along with promoting Bcl-2, suppressing Caspase-3 expression and stimulating PI3K phosphorylation signaling pathway.

Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction.

AIM: To investigate the relationship between free triiodothyronine (FT3) and the international normalized ratio (the ratio of the prothrombin time of a patient to the normal sample, INR) in Chinese euthyroid subjects with acute ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 231 consecutive patients (177 males, 54 females) with STEMI were enrolled. Anthropometric and laboratory measurements, including heart rate, respiratory rate, blood pressure, body temperature, platelet count, INR, prothrombin time, activated partial thromboplastin time, FT3, free thyroxine (FT4), and thyroid-stimulating hormone, were collected from all the patients. The levels of FT3 and FT4 were measured with a full-automatic immune analyzer. The INR was determined using a coagulation analyzer. RESULTS: Patients were classified into 4 groups according to their quartile FT3 and FT4 levels: 0.40-3.09 (n=52), 3.10-3.69 (n=56), 3.70-4.29 (n=64) and 4.30-7.10 (n=59) for FT3; 4.9-14.8 (n=57), 14.9-16.8 (n=58), 16.9-18.7 (n=57) and 18.8-29.0 (n=59) for FT4. Subjects with a high FT3 level had significantly lower values of INR than those with a low FT3 level (P=0.01). Multiple linear regression analysis revealed decreased serum FT3 as an independent risk factor for elevated INR values (ß=-0.139, P=0.025). The value of INR was similar among the 4 groups according to the quartile FT4 levels (P=0.36). CONCLUSION: Free triiodothyronine was negatively associated with INR in the patients with acute STEMI and normal thyroid function.

Severity of coronary atherosclerosis is an independent predictor of the left ventricular ejection fraction.

1. We studied the association between the level of the left ventricular ejection fraction and the severity of coronary atherosclerosis. 2. The study population consisted of 850 consecutive patients who underwent coronary angiography for suspected or known coronary atherosclerosis. Anthropometric measurements including the body mass index, blood pressure, blood lipids, blood glucose and leucocyte count were taken. The severity of coronary atherosclerosis was defined by the Gensini score. 3. When the level of the left ventricular ejection fraction was examined as a categorical variable classified by quartile values, subjects with a high left ventricular ejection fraction level had significantly lower Gensini scores than those with a low left ventricular ejection fraction level (P=0.000). Spearman's correlation analysis suggested that the left ventricular ejection fraction was significantly negatively associated with Gensini score (r= -0.213, P=0.000). Multiple stepwise linear regression analysis showed that the Gensini score was significantly independently associated with the left ventricular ejection fraction level (ß= -0.194, P=0.000). Furthermore, multivariable stepwise logistic regression analysis showed that the Gensini score was the independent risk factor for dysfunction of left ventricular ejection (OR=2.048, 95% CI=1.517-2.763). 4. The severity of coronary atherosclerosis was defined by the Gensini score. This was a strong and statistically highly significant predictor of the left ventricular ejection fraction level and dysfunction of left ventricular ejection independent of other major risk factors including age, body mass index, blood pressure, fasting blood glucose, blood lipid and leucocyte count.

[Activation of calcium-sensing receptors is associated with apoptosis in cardiomyocytes under simulated ischemia/reperfusion].

OBJECTIVE: To examine the association of activation of calcium-sensing receptors (CaSR) with apoptosis in cardiomyocytes under simulated ischemia/reperfusion. METHODS: Ventricular cardiomyocytes of neonatal rats were incubated in ischemia-mimetic solution for 2 h, then re-incubated in normal culture medium for 24 h to establish a model of simulated ischemia/reperfusion (I/R). Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL assay). The expression of CaSR mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of Caspase -3 and Bcl-2 was detected by Western blotting. RESULT: The simulated I/R enhanced the expression of CaSR and cardiomyocyte apoptosis. GdCl(3), a specific activator of CaSR, further increased the expression of CaSR and cardiomyocyte apoptosis, along with upregulation of Caspase-3 and downregulation of Bcl-2. CONCLUSION: CaSR is associated with I/R injury and apoptosis in neonatal rat ventricular cardiomyocytes via suppressing Bcl-2 and promoting Caspase -3 expression.

Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups.

Despite advances in surgical and reperfusion therapy, there is no effective therapy currently exists to prevent the progressive decline in cardiac function following myocardial infarction. Hepatocyte growth factor has potent angiogenic and anti-apoptotic activities. The aim of this study was to investigate the therapeutic effect and dose-effect relationship on postinfarction heart failure with different doses of adenovirus-mediated human hepatocyte growth factor (Ad(5)-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad(5), 1 ml); (b) low-dose group (1 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (c) medium-dose group (5 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (d) high-dose group (1 x 10(10) Pfu/ml Ad(5)-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad(5)-HGF were transferred in three therapeutic groups via right coronary artery. Four and seven weeks after LAD ligation, gate cardiac perfusion imaging was performed to evaluate cardiac perfusion and left ventricular ejection fraction (LVEF). Seven weeks after surgery, the apoptotic index of cardiocyte was observed by TUNEL, the expression of Bcl-2, Bax, alpha-SMA and Factor VIII in the border zones were evaluated by immunohistochemistry, respectively. Four weeks after myocardial infarction, no significant difference was observed among four groups. Three weeks after Ad(5)-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 x 10(10) Pfu Ad(5)-HGF transfer. TUNEL assay showed that 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad(5) group, especially after 1 x 10(10) Pfu Ad(5)-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF groups compared with the null-Ad(5) group. The vessel density of Factor VIII(+) and alpha-SMA(+) was increased in Ad(5)-HGF groups compared with the null-Ad(5) group. There were no significant differences in angiogenesis, reducing apoptosis and ameliorating heart function between the 1 x 10(9) Pfu Ad(5)-HGF group and the null-Ad(5) group. Although no statistical difference was observed between 1 x 10(10) Pfu and 5 x 10(9) Pfu Ad(5)-HGF groups, the cardiac protective effects of 1 x 10(10) Pfu Ad(5)-HGF treatment were greater than 5 x 10(9) Pfu Ad(5)-HGF treatment. Different doses of Ad5-HGF injected via noninfarct-related artery could induce angiogenesis, reduce apoptosis and ameliorate heart function, and the cardiac protective effects of 1 x 10(10) Pfu Ad5-HGF is of most significance.

[Clinical study on the coronary artery interventions guided by the magnetic navigation system].

OBJECTIVE: To investigate the efficacy and safety of the magnetic navigation system used in the real world percutaneous coronary artery intervention. METHODS: All lesions detected by the coronary artery angiography in the magnetic-navigation catheter lab indicated for percutaneous coronary artery intervention (PCI) were included and treated under the guidance of the magnetic navigation system. The characteristics of the target lesion, process of the procedure, time and dosage of the X-ray exposure, and procedure-related complication were recorded and analyzed. RESULTS: One hundred and twenty one patients with 138 lesions were recruited and intervened by PCI during the period from April 2006 to June 2008. Thirty lesions were classified as type A, 50 as type B1, 36 as type B2, 22 as type C (including seven total occlusions). The average stenosis of the target lesions was (85.3 +/- 10.0)%, mean length was (21.1 +/- 10.0) mm. Under the guidance of the magnetic navigation system, 134 target lesions were passed by the magnetic guide-wires, the lesion passing ratio was 97.1%. The X-ray exposure time, X-ray dosage and the contrast volume used during the period of the wire placement were (55.9 +/- 35.4) seconds, (98.0 +/- 86.1) mGy/(490.0 +/- 422.2) microGym(2) and (8.0 +/- 5.4) ml, respectively. A total of 164 stents were implanted in the vessels where the target lesions were passed by the magnetic wires. There was no magnetic navigation system associated complication. Magnetic guide-wires failed to pass four target lesions, two of which were chronic total occlusions (CTOs), and the other two were calcified subtotal occlusions. CONCLUSIONS: It is feasible and safe to adopt the magnetic navigation system for the real-world coronary artery intervention. The magnetic guide-wire possesses a high lesion-passing ratio. The CTOs and calcified subtotal occlusions are not ideal lesions for use of the magnetic navigation system.

[Hepatocyte growth factor attenuates ischemia/reperfusion induced cardiomyocyte apoptosis via downregulating calcium sensing receptor expression].

OBJECTIVE: To examine whether the anti-apoptotic effect of hepatocyte growth factor (HGF) in cardiomyocytes underwent ischemia/reperfusion (I/R) is associated with downregulation of calcium sensing receptor (CaSR) mRNA expression. METHODS: Neonatal rat cardiomyocytes were isolated and randomly divided into 7 groups: control, I/R, GdCl(3), GdCl(3) + NiCl(2) + CdCl(2), GdCl(3) + LY294002, GdCl(3) + HGF, GdCl(3) + HGF + LY294002.I/R was established by incubating primary neonatal rat ventricular cardiomyocytes in ischemia-mimetic solution for 2 h, then reincubated in normal culture medium for 24 h. Cardiomyocyte apoptosis was detected by TUNEL. The expression of CaSR mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of Caspase-3, Bcl-2 and Phosphoinositide-3 Kinase (PI3K) was analyzed by Western blot. RESULTS: I/R enhanced the expression of CaSR mRNA (I/R: 2.62 ± 0.41, control: 1.00 ± 0.31, P < 0.01) and cardiomyocyte apoptosis [I/R: (15.32 ± 2.54)%, control: (2.90 ± 1.45)%, P < 0.01]. GdCl(3) further increased the expression of CaSR mRNA (GdCl(3): 4.46 ± 0.62, I/R: 2.62 ± 0.41, P < 0.01) and cardiomyocyte apoptosis [GdCl(3): (25.36 ± 2.60)%, I/R: (15.32 ± 2.54)%, P < 0.01], along with upregulation of Caspase-3 (GdCl(3): 1.93 ± 0.28, I/R: 1.50 ± 0.21, P < 0.01), downregulation of Bcl-2 (GdCl(3): 0.82 ± 0.18, I/R: 1.71 ± 0.30, P < 0.01) and PI3K phosphorylation inhibition (I/R: 0.87 ± 0.08, GdCl(3): 0.61 ± 0.07, P < 0.01). Combination of GdCl(3) with LY294002 further enhanced cardiomyocytes apoptosis [GdCl(3) + LY294002: (32.6 ± 3.42)%, GdCl(3): (25.36 ± 2.60)%, P < 0.01] but did not affect CaSR mRNA expression (GdCl(3) + LY294002: 4.27 ± 0.56, GdCl(3): 4.46 ± 0.62, P > 0.05). HGF decreased I/R- and GdCl(3)-induced apoptosis [GdCl(3) + HGF: (11.8 ± 1.89)%, GdCl(3): (25.36 ± 2.60)%, P < 0.05] by suppressing Caspase-3 (GdCl(3) + HGF: 1.12 ± 0.23, (GdCl(3): 1.93 ± 0.28, P < 0.05; GdCl(3) + HGF + LY294002: 1.87 ± 0.31, GdCl(3) + LY294002: 3.86 ± 0.47, P < 0.05) and promoting Bcl-2 (GdCl(3) + HGF: 2.56 ± 0.54, GdCl(3): 0.82 ± 0.18, P < 0.05; GdCl(3) + HGF + LY294002: 1.68 ± 0.28, GdCl(3) + LY294002: 0.68 ± 0.13, P < 0.05) and PI3K phosphorylation expression (GdCl(3) + HGF: 2.87 ± 0.21, GdCl(3): 0.61 ± 0.07, P < 0.05; GdCl(3) + HGF + LY294002: 2.01 ± 0.14, GdCl(3) + LY294002: 0.44 ± 0.10, P < 0.05) in accordance with downregulation of CaSR mRNA expression (GdCl(3) + HGF: 1.46 ± 0.37, GdCl(3): 4.46 ± 0.62, P < 0.01). CONCLUSION: HGF exerts protective role in I/R-induced apoptosis at least in part by inhibiting CaSR mRNA expression along with promoting Bcl-2, suppressing Caspase-3 expression and stimulating PI3K phosphorylation signaling pathway.

Association of the mutation for the human carboxypeptidase E gene exon 4 with the severity of coronary artery atherosclerosis.

OBJECTIVE: To test the hypothesis that the identification of mutation in the carboxypeptidase E (CPE) gene which leads to marked hyperproinsulinaemia is consistent with a possible role for mutations in CPE in the development of coronary atherosclerosis. METHODS: The study subjects consisted of 1084 consecutive patients (812 males and 272 females) who will undergo coronary angiography. The severity of coronary atherosclerosis was defined by the Gensini's score system. The proinsulin level was measured using highly sensitive two-site sandwich ELISA methods. Screening for mutations of the 4th exon and exon-intron junctional region of the CPE gene was performed by polymerase chain reaction followed by bidirectional sequencing. RESULTS: Sequencing of the CPE gene exon 4 in 1084 consecutive patients revealed 2 genetic variants, the G-to-A substitution at nucleotide 2855 in exon 4 (synonymous mutation) and A-to-G substitution at nucleotide 2925 in intron 4. Although the proinsulin level was not influenced by the presence of the two point mutation, the Gensini score was significantly influenced by the presence of the A2925G mutant (P = 0.023). Furthermore, we found a higher prevalence of subjects with the A2925G heterozygous mutant among higher Gensini score subjects than it among lower Gensini score subjects, and this difference reached statistical significance (P = 0.006, OR 1.465, 95%CI 1.116-1.924). In addition, the frequency distribution of the G2855A mutant was differed in the higher Gensini score subjects than it in the lower Gensini score subjects belonging to high-risk category as smokers, and the statistical significance was reached (P = 0.043, OR 2.075, 95%CI 1.024-4.207). CONCLUSIONS: In the present study, the severity of the coronary atherosclerosis estimated by Gensini score was significantly influenced by the presence of the A2925G mutant and G2855A mutant of the CPE gene, and the exactly mechanism underlying the association needs further study.

Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease.

OBJECTIVE: Therapeutic angiogenesis is a new strategy for treatment of vascular insufficiency. Hepatocyte growth factor (HGF)-induced angiogenesis has been applied to induce the neovascularization of ischemic adult tissues in preclinical studies. This report summarizes a phase I clinical trial on the safety of adenovirus-mediated human HGF (Ad-HGF) gene transfer to treat clinically significant coronary artery disease. METHODS: The 18 patients with severe and diffused triple vessel disease determined by coronary angiography, 1-3 of the main coronary arteries not amenable to bypassing grafting and to catheter-based revascularization were assigned to 3 study groups according to the dose of Ad-HGF (from low to high), and the total dose as follows: 5 x 10(9) pfu (group A, n = 6); 1 x 10(10) pfu (group B, n = 6); 2 x 10(10) pfu (group C, n = 6). Arterial gene transfer was performed by over-the wire balloon to the distal of the accessible artery or otherwise the ostium of the target vessels by diagnostic coronary catheter. General safety parameters and cardiac-specific parameters were measured through the preoperative period and on day 7, 21, and 35 postoperatively. The safety and tolerance of Ad-HGF for patients were evaluated according to functional and cytological assessments. RESULTS: During the acute phase up to day 35 and at 11-14 months of follow-up there were no serious adverse events. A mild fever during the first 3 days was not present at day 4, and no long term or paroxysmal fever was found. There were no acute alterations in hemodynamic parameters and the electrocardiogram remained normal. No serious pericardial effusion was reported and there were no arrhythmia on Holter registrations. Moreover, the serum levels of HGF were not changed and the serum anti-adenovirus in the patients was not detected up to day 35. CONCLUSIONS: The present study demonstrates that it is feasible to safely use an adenovirus gene-transfer vector to deliver the human hepatocyte growth factor gene to individuals with clinically significant coronary artery disease by direct intracoronary injection. However, a great deal of additional work must be done before administration of Ad-HGF can be recommended for clinical practice.

Association of serum sodium concentration with coronary atherosclerosis in China: follow-up study.

AIM: The aim of this study was to test the hypothesis that lower serum sodium may be associated with increased cardiovascular events and all-cause mortality by means of long-term follow-up of subjects with coronary atherosclerosis in a prospective, hospital-based epidemiological study in China. METHODS: A prospective, hospital-based epidemiological design was used. The study population consisted of 1069 consecutive patients who were scheduled to undergo coronary angiography for suspected or known coronary atherosclerosis. The severity of coronary atherosclerosis was defined using Gensini's score system. Age, sex-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the quartiles of serum sodium concentration were estimated with Cox proportional hazard models, using quartile 1 as the reference. Cox proportional hazard models were also constructed to estimate the hazard ratios and 95% confidence intervals for all-cause mortality and final end-point events by serum sodium quartile and to adjust for potentially confounding variables. Multivariate models were adjusted for the following variables: age, sex, smoking status, alcohol consumption, body mass index, blood pressure, potassium, chloride, total cholesterol, triglycerides, fasting blood glucose, urea, creatinine, uric acid, and Gensini's score. RESULTS: During the median 2.86 years (3011.66 person-years) of follow-up, 176 final end-point events were documented. These events included 79 deaths and 97 readmissions for coronary heart disease. There was a statistically significant inverse association of serum sodium with all-cause mortality (P<0.001). After full adjustment comparing the highest serum sodium quartile to the lowest, there was a non-significant inverse association with all-cause mortality, with an adjusted hazard ratio (95% CI) of 0.67 (0.25-1.80). After adjustment for age and sex, the hazard ratio and 95% CI for final end-point events across increasing quartiles of serum sodium concentration were 1.00, 0.85 (0.59-1.22), 0.52 (0.34-0.82), and 0.31 (0.19-0.49). After full adjustment comparing the highest serum sodium quartile to the lowest, there was a statistically significant inverse association with final end-point events, with an adjusted hazard ratio (95% CI) of 0.46 (0.26-0.81). CONCLUSION: The serum sodium concentration showed a statistically significant negative association with coronary events and all-cause mortality in subjects with coronary atherosclerosis; the actual mechanism underlying this association needs further study.

Smoking and coronary atherosclerosis: follow-up study in China.

1. The aim of the present study was to explore the association between the total number of cigarettes smoked in life and the severity of and mortality due to coronary atherosclerosis. 2. The study population comprised 1096 consecutive patients (820 men and 276 women) who underwent coronary angiography for suspected or known coronary atherosclerosis. Anthropometric and plasma measurements (body mass index, blood pressure and blood lipid, blood glucose and pro-insulin levels) were made. The number of cigarettes smoked during previous years was estimated. The severity of coronary atherosclerosis was defined by the Gensini score system. 3. At baseline, a significant positive association was observed between the number of cigarettes smoked and Gensini score (r = 0.213; P = 0.000), pro-insulin (r = 0.072; P = 0.017), total leucocyte count (r = 0.179; P = 0.000) and neutrophil count (r = 0.164; P = 0.000), whereas an inverse correlation was found between the number of cigarettes smoked and High-density lipoprotein-cholesterol (r = -0.150; P = 0.000). 4. When participants were divided into five categories based on the baseline number of cigarettes smoked, an independent association between baseline number of cigarettes smoked and all-cause mortality was observed in a multivariate analysis of Cox proportional hazards models, with a hazard ratio (95% confidence interval) of 1.328 (1.086-1.623; P = 0.006) during a median follow up of 2.86 years. 5. The number of cigarettes smoked was a highly significant predictor of coronary atherosclerosis and an independent risk factor for mortality in subjects with atherosclerosis in this Chinese population.

Hepatocyte growth factor plays a critical role in the regulation of cytokine production and induction of endothelial progenitor cell mobilization: a pilot gene therapy study in patients with coronary heart disease.

1. There is growing evidence of the beneficial effects of hepatocyte growth factor (HGF) in myocardial infarction, heart failure and occlusive peripheral arterial disease. The aim of the present study was to evaluate the effects of intracoronary administration of an adenovirus vector encoding the human HGF gene (Ad-HGF) on serum levels of cytokines and mobilization of CD34(+) and CD117(+) cells in patients with coronary heart disease. 2. Twenty-one patients with severe coronary artery disease were recruited to the study: 11 patients received both a stent and administration of Ad-HGF; the remaining 10 patients received a stent alone and served as the control group. Blood samples were obtained from the femoral vein before and then 6 and 24 h, 3 and 6 days and 2 weeks after treatment for the isolation of serum and peripheral blood mononuclear cells. Intracoronary administration of Ad-HGF in patients with coronary heart disease resulted in high levels of HGF gene expression, as well as its receptor c-met, compared with the control group, as demonstrated by real-time reverse transcription-polymerase chain reaction. In addition, serum levels of HGF, vascular endothelial growth factor, monocyte chemoattractant protein-1 and interleukin (IL)-10 were increased and serum levels of IL-8 were decreased in patients administered Ad-HGF compared with the control group. The percentage of CD34(+) and CD117(+) cells in the peripheral blood increased in patients administered Ad-HGF. 3. In conclusion, HGF gene therapy may play an important role in the regulation of cytokines and the induction of endothelial progenitor cell mobilization in patients with coronary heart disease.

Helicobacter pylori infection is associated with decreased serum levels of high density lipoprotein, but not with the severity of coronary atherosclerosis.

OBJECTIVE: The objective of this survey was to study the association between Helicobacter pylori infection and the severity of coronary atherosclerosis. METHODS: The study population consisted of 961 consecutive patients (711 males and 250 females) who underwent coronary angiography for suspected or known coronary atherosclerosis. The patients' body mass index, blood pressure, the blood lipid, blood glucose, leukocyte count (10(9)/L), neutrophil count (10(9)/L), and Helicobacter pylori-specific IgG antibodies were performed. Coronary angiograms were scored according to vessel score and Gensini's score. RESULTS: A significant association between H. pylori infection and coronary atherosclerosis as well as its severity was not find in this cross section study (p = 0.858). And, the level distribution of vessel score (p = 0.906) and Gensini's score (p = 0.905) were similar in the seropositivity group and seronegativity group of Helicobacter pylori infection. However, the level of fasting high-density lipoprotein cholesterol (mmol/L) (p = 0.013) was significantly lower in the seropositivity group than that in the seronegativity group of Helicobacter pylori infection. CONCLUSIONS: In conclusion, in the present study, a significantly correlation between Helicobacter pylori seropositivity and angiographically evaluated severity of atherosclerosis was not find. And, the present study showed a good correlation between Helicobacter pylori infection and decreased HDL cholesterol. However, the exact mechanisms need further study.

Proinsulin is an independent predictor of the angiographical characteristics of coronary atherosclerosis.

OBJECTIVE: The objective of this survey was to study the association between circulating proinsulin level and the severity of coronary atherosclerosis. METHODS: The study population consisted of 1,039 consecutive patients (775 males and 264 females) who underwent coronary angiography for suspected or known coronary atherosclerosis. The patients' anthropometric and plasma measurements including body mass index, blood pressure, blood lipid, blood glucose, and proinsulin level were performed. The severity of coronary atherosclerosis was defined by the Gensini's score system. RESULTS: When proinsulin level was examined as a categorical variable classified by quartile values, subjects with a high proinsulin level had significantly higher values of Gensini's score than those with a low proinsulin level (p = 0.000). The Spearman correlation analysis suggests that the Gensini's score was significantly correlated with proinsulin level (r = -0.177, p = 0.000). Multiple stepwise linear regression analysis demonstrated that glucose (beta= 0.136, p = 0.000), age (beta= 0.189, p = 0.000), proinsulin (beta= 0.135, p=0.000), SBP (mm Hg) (beta= -0.061, p = 0.043), fasting low-density lipoprotein cholesterol (mmol/l) (beta= 0.141, p = 0.003), and total cholesterol (beta= -0.105, p = 0.029) are significantly independently associated with the Gensini's score. CONCLUSIONS: Proinsulin is a strong and statistically highly significant pre- dictor of coronary atherosclerosis independent of the other major risk factors including age, body mass index, blood pressure, fasting blood glucose, and blood lipid. The exact mechanisms need further study.

Association of human carboxypeptidase E exon5 gene polymorphisms with angiographical characteristics of coronary atherosclerosis in a Chinese population.

AIM: To explore the association between 801C>T and 847C>T polymorphisms of the human carboxypeptidase E (CPE) gene exon5, which could cause hyperproinsulinemia, and the angiographical characteristics of coronary atherosclerosis. METHODS: In total, 1044 consecutive patients who underwent coronary angiography for suspected or known coronary atherosclerosis were examined with respect to their genotypes, insulin, proinsulin level, and other risk factors of coronary atherosclerosis. The angiographical characteristics of coronary atherosclerosis (ie the severity of coronary heart disease) were defined by Gensinios score (GS) system. RESULTS: The results showed that the genotype frequencies of CC, CT, and TT at 801C>T locus were significantly different among the patients of the 4 groups who were classified by quartile values of GS (P=0.033). However, the frequency of the 847T allele was 0 for all the patients. The ordinal logistic regression analysis revealed that the increased risk of angiographical characteristics of coronary atherosclerosis were associated with CPE 801CT/TT variant genotypes [adjusted odds ratio (OR)=1.23, 95% confidence interval (CI) =0.93-1.63 for 801CT and adjusted OR=3.13, 95% CI=1.18-8.28 for 801TT] compared with the 801CC wild-type homozygotes. A stratification analysis showed that the effects of the CPE 801TT genotype were more evident among subgroups with relatively older (> or = 60 years) patients, males, and smokers. Furthermore, an analysis of covariance controlling age, sex, and body mass index indicated that differences of blood glucose, insulin, insulin resistance, and the proinsulin level between 801C>T genotype groups were not statistically significant. CONCLUSION: These findings indicate that the 801C>T polymorphism in the CPE exon5 gene may contribute to the angiographical characteristics of coronary atherosclerosis in the Chinese population.