Polymorphisms in the neurokinin-2 receptor gene are associated with angiotensin-converting enzyme inhibitor-induced cough.

BACKGROUND AND OBJECTIVE: Treatment with angiotensin-converting enzyme (ACE) inhibitors can induce chronic cough in many patients. Genetic variations in the neurokinin 2 receptor gene (NK2R) are significantly associated with cough sensitivity to capsaicin. METHODS: This study assessed the relationship between genetic polymorphisms in the NK2R gene and chronic cough in 91 patients taking ACE inhibitors. Patients included in the study did not have chest abnormalities, postnasal drip, gastroesophageal reflux or a recent history of upper respiratory infection. RESULTS: We detected two single nucleotide polymorphisms in the NK2R gene (i.e., Gly231Glu and Arg375His). The allelic frequencies at amino acid 231 were 36.3% for Gly/Gly, 49.5% for Gly/Glu and 14.3% for Glu/Glu. The allelic frequencies at amino acid 375 were 74.7% for Arg/Arg, 24.2% for Arg/His and 1.1% for His/His. The prevalence of chronic cough in patients with the amino acid 231 genotype was 33.3% in Gly/Gly homozygotes, 24.4% in Gly/Glu heterozygotes and 0% in Glu/Glu homozygotes. There was a statistically significant association between chronic cough and the Glu/Glu allele (P = 0.028) when the data were analyzed with a recessive model. In addition, there was a significant inverse linear association between the number of Glu231 alleles and ACE inhibitor-related cough (P = 0.026). The prevalence of chronic cough in patients with the amino acid 375 genotype was 22.1% in Arg/Arg homozygotes, 31.8% in Arg/His heterozygotes and 0% in His/His homozygotes, although none of these association were statistically significant. CONCLUSION: Our findings indicate that the Gly231Glu polymorphism is associated with a lower prevalence of ACE inhibitor-related cough.

Prognostic significance of asymptomatic coronary artery disease in patients with diabetes and need for early revascularization therapy.

AIMS: Information on the clinical outcome of patients with diabetes with silent myocardial ischaemia is limited. We compared the clinical and angiographic characteristics, and the clinical outcomes of diabetic patients with asymptomatic or symptomatic coronary artery disease (CAD). METHODS: Three hundred and ten consecutive diabetic patients with CAD were divided into two groups according to the presence of angina and followed for a mean of 5 years. Fifty-six asymptomatic patients with a positive stress test and CAD on coronary angiography were compared with 254 symptomatic patients, 167 with unstable angina and 87 with chronic stable angina. RESULTS: Although the severity of coronary atherosclerosis was similar in asymptomatic and symptomatic patients, revascularization therapy was performed less frequently in the asymptomatic than the symptomatic patients (26.8 vs. 62.0%; P < 0.001). Asymptomatic patients experienced a similar number of major adverse cardiac events (MACEs; death, non-fatal myocardial infarction, and revascularization; 32 vs. 28%; P = 0.57), but had higher cardiac mortality than symptomatic patients (26 vs. 9%; P < 0.001). However, patients who underwent revascularization therapy at the time of CAD diagnosis in these two groups showed similar MACE and cardiac mortality (20.0 vs. 22.5%, 6.7 vs. 5.3%, respectively; all P > 0.05). CONCLUSIONS: This study suggests that diabetic patients with asymptomatic CAD have a higher cardiac mortality risk than those with symptomatic CAD, and that lack of revascularization therapy may be responsible for the poorer survival.

Association of endothelial constitutive nitric oxide synthase gene polymorphism with acute coronary syndrome in Koreans.

OBJECTIVE: To examine the effects of two polymorphisms of the endothelial constitutive nitric oxide synthase (ecNOS) gene, 4a/4b(A:B) located in intron 4 and Glu298Asp(G:T) located in exon 7, on the development of acute coronary syndromes (ACS). METHODS: 164 patients with ACS and 142 control participants were investigated for genotype and conventional risk factors. Genotype was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Genotype and allele frequencies of the A:B polymorphism in the ACS group (0.15:0.85 for AA+AB:BB, 0.09:0.91 for A:B) differed from those in the control group (0.26:0.74 for AA+AB:BB, 0.15:0.85 for A:B). However, genotype and allele frequencies of the G:T polymorphism in the ACS group (0.22:0.78 for TT+TG:GG, 0.11:0.89 for T:G) were similar to those in the control group (0.17:0.83 for TT+TG:GG, 0.09:0.91 for T:G). Multiple logistic regression analysis showed that the non-BB (AA+AB) and the non-BB+GG genotypes were significant protective factors against ACS (odds ratios 0.49 and 0.34, 95% confidence intervals 0.26 to 0.93 and 0.14 to 0.83, respectively). In addition, linear association analysis showed that the percentage of ACS patients was significantly lower in the genotype group non-BB+GG than in the genotype group BB+non-GG (39.6% v 62.7%, p = 0.01). CONCLUSIONS: The non-BB genotype of the ecNOS 4a/4b gene polymorphism is a protective factor against the development of ACS. The GG genotype of the ecNOS Glu298Asp polymorphism exerts a benefit in addition to the non-BB genotype in the Korean population.

The association of cholesteryl ester transfer protein polymorphism with high-density lipoprotein cholesterol and coronary artery disease in Koreans.

Cholesteryl ester transfer protein (CETP) is a key protein involved in high-density lipoprotein cholesterol (HDL-C) metabolism. It is known to affect plasma HDL-C levels, and its genetic regulation may be involved in the development of coronary artery disease (CAD). The aim of this study was to determine the frequency of the CETP Taq1B polymorphism in Koreans, and to investigate its relationship with plasma HDL-C levels and CAD. One-hundred and nineteen patients with significant CAD and 106 controls were examined with respect to their genotypes, lipid profiles and other risk factors of CAD. The genotype frequencies of B1B1:B1B2:B2B2 in males and females were 35.5%:50%:14.5% and 34.7%:42.6%:22.7%, respectively, which is comparable to previous reports in other ethnic groups. The B1B1 homozygote was associated with significantly lower HDL-C levels in females (p = 0.049) and non-smoking males (p = 0.037). After controlling for gender, body mass index (BMI) and smoking, the TaqIB polymorphism was still significantly associated with HDL-C levels (p = 0.046) and explained 5.4% of the HDL-C variation in this study. By univariate analysis, the B1B1 homozygote was a significant predictor of CAD (p = 0.043), and this was confirmed by multivariate analysis with traditional risk factors, i.e. the B1B1 homozygote was an independent predictor of CAD (p = 0.026, odds ratio = 1.97, 95% confidence interval: 1.08-3.57). In conclusion, the B1B1 homozygote of the CETP Taq1B polymorphism is associated with low HDL-C levels in females and non-smoking males, and may be an independent genetic risk factor of CAD in the Korean population.

Vitamin C prevents radiation-induced endothelium-dependent vasomotor dysfunction and de-endothelialization by inhibiting oxidative damage in the rat.

1. The present study was undertaken to determine whether endothelial function or morphology was altered in aortic rings of rats after irradiation, to investigate the mechanism of radiation effects on the endothelium and to examine the effect of vitamin C treatment against radiation-induced damage of the endothelium. 2. Female Sprague-Dawley rats were randomized into four groups (control, radiation, radiation + vitamin C, radiation + vitamin C + NG-nitro-L-arginine methyl ester (L-NAME); n = 10 for each group and n = 7 for the control group) and were irradiated with 10 Gy of 137Cs as a radiation source. Segments of the thoracic aorta were obtained and isometric tension, levels of 8-hydroxydeoxyguanosine (OH-dG) and immunohistochemical staining were measured. 3. Irradiation significantly impaired the acetylcholine-induced vasodilation of aortic segments, an effect that could be prevented by pretreatment with vitamin C (500 mg/kg per day). This beneficial effect of vitamin C was abolished by the addition of L-NAME (100 microg/kg per day), an inhibitor of nitric oxide (NO) synthesis. Irradiation significantly increased the level of OH-dG in the aorta (1.02 +/- 0.27 vs 2.61 +/- 0.78 OH-dG/105 deoxyguanosine (dG) for control and irradiated tissues, respectively; P < 0.01), an increase that was prevented by vitamin C treatment (1.59 +/- 0.23 OH-dG/105 dG; P < 0.01). Irradiation caused significant de-endothelialization (von Willebrand factor (vWF) staining was 93 +/- 7 vs 100% in irradiated and control tissues, respectively; P < 0.05) and this was prevented by vitamin C treatment (vWF staining 98 +/- 3%; P < 0.05). 4. Radiation caused endothelial damage and impaired NO production through oxidative injury, resulting in a selective impairment of endothelial-dependent vasodilation that could be prevented by vitamin C, partly through anti-oxidant mechanisms.

Off-pump coronary artery bypass may decrease the patency of saphenous vein grafts.

BACKGROUND: There is concern that a hypercoagulable status is caused after coronary artery bypass grafting without cardiopulmonary bypass (off-pump coronary artery bypass grafting, or OPCAB) and may potentially endanger the patency of the anastomosis. The aims of this study were: (1) to compare 1-year graft patency after OPCAB with that of conventional coronary artery bypass grafting (CABG) and that of on-pump beating CABG; and (2) to demonstrate any differences in patency of various conduits among the three groups. METHODS: We analyzed the results of 122 consecutive OPCAB cases (group 1) compared with those of 65 consecutive conventional CABG cases (group II) and those of 19 consecutive on-pump beating CABG cases (group III). In group I, coronary angiography (CAG) was performed immediately postoperatively and 1 year after surgery. In groups II and III, CAG was performed 1 year after surgery. Graft patency was graded as grade A (excellent), grade B (fair), or grade O (occluded). RESULTS: The average number of distal anastomoses in groups I, II, and III were 3.1 +/- 1.1, 3.7 +/- 0.9, and 3.6 +/- 0.9, respectively. In group I, postoperative CAG was performed in 92% of patients (112/122) before discharge. The patency rate (grade A + B) was 96.4% (162/168) for arterial grafts, and 85.6% (160/187) for saphenous vein grafts (SVG). One-year follow-up CAG was performed in 74% of patients (90/122). The patency rate was 97.8% (132/135) for arterial grafts and 67.9% (106/156) for SVG. In group II, 1-year follow-up CAG was performed in 65% of patients (42/65). The patency rate (grade A + B) was 93.5% (43/46) for arterial grafts and 88.3% (98/111) for SVG. In group III, 1-year follow-up CAG was performed in 89% of patients (17/19). The patency rate (grade A + B) was 100% (19/19) for arterial grafts and 86.8% (33/38) for SVG. CONCLUSIONS: Our results demonstrate that the patency rate ot SVG after OPCAB was significantly lower than that of arterial grafts in the early postoperative CAG (p < 0.001), and was also significantly lower than those of SVG of group II (p < 0.001) and group III (p < 0.01) in the postoperative 1-year CAG, although there was no significant difference in 1-year patency of arterial grafts among the three groups. Our data suggest that a specific perioperative anticoagulant therapy may be advisable in patients undergoing OPCAB with SVG.

Correlation of Fas and Fas ligand expression with rejection status of transplanted heart in human.

BACKGROUND: Activation of pro-apoptotic systems has been proven in rejection model of animal heart transplantation. The role of Fas and Fas ligand (FasL) in graft rejection is not fully understood, and the expression changes of these genes in human transplanted heart have not been elucidated. METHODS: Endomyocardial biopsy samples were taken from 13 consecutive patients undergoing heart transplantation at various times, and they were classified into rejection (REJ, grade 3A or more) and lack of rejection (TOL, grade 1B or less) by International Society of Heart and Lung Transplantation rejection grade. Semiquantitative reverse transcription-polymerase chain reaction and immunohistochemistry were performed to evaluate the status of Fas and FasL expression in each sample. RESULTS: Fas was constitutively expressed both in REJ and TOL specimens (expression levels normalized by glyceraldehyde-3-phosphate dehydrogenase expression in semiquantitative reverse transcription-polymerase chain reaction of REJ vs. TOL, 0.842+/-0.096 vs. 0.848+/-0.103, P=0.776); however, FasL expression was detected in 66% of REJ samples and 40% of TOL samples. Normalized levels of FasL expression were 0.591+/-0.494 (REJ) and 0.383+/-0.507 (TOL) (P<0.05). FasL was expressed by cardiomyocytes as well as graft-infiltrating cells. CONCLUSIONS: This up-regulation of FasL may be one of possible mechanisms of apoptosis in rejection process of human cardiac allograft.

Effect of hypercholesterolemia on macrophage infiltration after balloon injury to rabbit iliac artery.

Both hypercholesterolemia and vascular injury have been reported to induce macrophage infiltration, but their combined effect and the mechanism by which hypercholesterolemia enhances the infiltration remain to be clarified in vivo. To evaluate the effect of hypercholesterolemia on macrophage infiltration after vascular injury, the iliac arteries of hypercholesterolemic (HC) and normocholesterolemic (NC) rabbits were examined 2h, 1 day, 3 days, 7 days, and 14 days after balloon injury using immunohistochemical staining for macrophages, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1. Nuclear factor kappa-B (NF-kappaB) activation was also evaluated in fresh frozen iliac arteries using the electrophoretic mobility shift assay method. The fundamental difference between HC and NC was the amount of macrophage infiltration seen in HC from 7 days after balloon injury. Two out of 4 HC iliac arteries on the 7th day, and 3 out of 4 HC iliac arteries on the 14th day were positively stained with ICAM-1 in regenerated endothelium and neointima, whereas there were no positively stained NC iliac arteries. Neither HC nor NC tissues showed positive staining with VCAM-1. NF-kappaB was activated in HC 7 and 14 days after balloon injury, but not in NC. In conclusion, in vivo hypercholesterolemia induces macrophage infiltration after balloon injury and it is mediated by increased NF-kappaB activation promoting ICAM-1 expression.