Young Won Yoon

Lipoprotein(a) and LDL Particle Size Are Related to the Severity of Coronary Artery Disease

Background: The pathophysiological role and metabolic pathway of Lp(a) have not been clearly defined. An association between Lp(a) and oxidative low-density lipoprotein (LDL) were recently reported. And small dense LDL (sd-LDL) were associated with circulating malondialdehyde-modified LDL. We investigated the relationships between serum Lp(a) level and LDL particle size in coronary artery disease (CAD) patients. Further, we investigated the relationships of sd-LDL and Lp(a) with the extent and severity of CAD. Methods: A total of 490 patients (mean: 60.5 ± 11.5 years old) who underwent coronary angiography to evaluate chest pain were investigated. Patients were classified into two groups, a CAD group (n = 256), who had significant stenosis observed by coronary angiogram, and a control group (n = 234), who had normal, or minimal coronary arteries. CAD severity was measured by Gensini scores. The distribution of the LDL subfraction was analyzed using a Quantimetrix Lipoprint LDL System. Results: The serum Lp(a) concentration was correlated with the fraction of sd-LDL (r = 0.193, p < 0.001) and mean LDL size (r = 0.160, p = 0.003). The Lp(a) level and mean LDL particle size were significantly correlated with a high Gensini score. LDL particle size in the CAD group was smaller than in the control group (26.74 ± 0.64 vs. 26.43 ± 0.93 nm, p < 0.001). The Gensini score was significantly higher in small LDL with high Lp(a) level groups. Conclusion: The positive correlation of the level of Lp(a) and sd-LDL fraction were demonstrated. The mechanism of this association is not clearly defined; we can suggest that it may stem from the individual atherogenic condition that linked to increased oxidative stress. Both increased Lp(a) and sd-LDL fraction were correlated with the severity of CAD.

Usefulness of brachial-ankle pulse wave velocity as a predictive marker of multiple coronary artery occlusive disease in Korean type 2 diabetes patients

Multiple coronary artery occlusive disease (multiple CAOD) is the most fatal and frequently observed coronary artery disease in type 2 diabetes patients, but no simple, non-invasive screening tool is available yet. The aim of this study is to evaluate the arterial stiffness in type 2 diabetes patients using brachial-ankle pulse wave velocity (baPWV), to demonstrate the correlation between arterial stiffness and multiple CAOD, and to suggest the cutoff point of baPWV for predicting multiple CAOD in Korean type 2 diabetes patients. One hundred and eighty-one diabetes and 262 non-diabetes patients were enrolled in the study. Routine anthropometric and serologic data were collected. baPWV was measured the day before coronary angiography, and the severity of CAOD was assessed with Gensini score after angiography. baPWV and Gensini score were significantly increased in diabetes patients and Gensini score had a positive correlation with baPWV. Subjects in the highest tertile of baPWV showed odds ratio of 3.06 for multiple CAOD compared to the lowest tertile. In ROC curve, baPWV at 1635 cm/s showed 73% sensitivity and 75% specificity with AUC 0.76 in diabetes patients in detecting multiple CAOD. Therefore, baPWV may be utilized a screening tool for predicting multiple CAOD, especially in type 2 diabetes patients.

Significance of Small Dense Low-Density Lipoprotein as a Risk Factor for Coronary Artery Disease and Acute Coronary Syndrome

Small dense LDL (sd-LDL) has recently emerged as an important coronary artery disease (CAD) risk factor. This study was performed to investigate how LDL particle size is related to CAD and acute coronary syndrome (ACS). Blood samples were collected from 504 patients that underwent coronary angiography to evaluate chest pain. The LDL particle size of these samples was measured. The mean LDL particle size was smaller in patients with angiographically proven CAD than in the controls (26.41 ± 0.95 vs 26.73 ± 0.64 nm, p < 0.001), and was negatively correlated with the Framingham risk score (r = -0.121, p = 0.007). Patients with more extensive CAD had smaller LDL particles. LDL particle size was also smaller in patients with acute coronary syndrome as compared to non-ACS patients (26.09 ± 1.42 vs 26.54 ± 0.63 nm, p = 0.011). These results suggest that sd-LDL is independently associated with the incidence and extent of CAD, and can be a risk factor for the development of ACS in the Korean population.

Incidence and natural history of coronary artery aneurysm developing after drug-eluting stent implantation.

AIMS There is a growing concern about the occurrence of coronary artery aneurysms (CAAs) after drug-eluting stent (DES) implantation and their long-term course. We assessed the occurrence and the factors affecting the long-term outcome of DES-associated CAA. METHODS AND RESULTS We analyzed 3,612 consecutive patients (4,419 lesions) who underwent follow-up angiography after DES implantation. All 34 CAAs (0.76% per lesion) in 29 patients (0.8% per patient) were detected at follow-up, and the mean elapsed time from DES implantation to CAA diagnosis was 414 ± 213 days. Angiographically, CAAs developed almost exclusively in complex (type B2/C) de novo lesions (30 [88.2%] of 34 lesions), and lesion length was significantly greater in patients with CAA than without CAA (26.9 ± 9.03 vs 23.1 ± 7.14 mm; P = .004). Myocardial infarction with stent thrombosis occurred in 5 patients with CAA (17.2%), 4 of whom were on aspirin only without clopidogrel. CONCLUSION Although CAAs rarely develop after DES implantation and show mostly favorable clinical courses, long-term maintenance of clopidogrel therapy might be required to minimize occurrence of adverse clinical events resulting from stent thrombosis.

Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy

Advanced glycation endproducts (AGEs) have been reported to play a role in neointimal formation and increase the rate of in-stent restenosis (ISR) in the diabetic coronary artery disease patients treated with stents, but the potential pathogenic mechanisms of AGEs in vascular smooth muscle cell proliferation remain unclear. We sought to determine the AGEs related pathobiological mechanism of diabetic vasculopathy. Rat aortic smooth muscle cell (RAoSMC) culture was done with different concentrations of AGEs and proliferation was assessed. Immunohistochemistry for receptor of AGEs (RAGE) was performed with human carotid atheroma. Western blotting was performed to assess the activation of MAP kinase system in the cultured RAoSMC. AGEs increased RAoSMC proliferation and were associated with increased phosphorylation of ERK and p38 kinase by time and dose dependent manner. The MAP kinase activity was decreased by RNA interference for RAGE. AGEs stimulation increased reactive oxygen species (ROS) generation in cultured RAoSMC. From this study it is concluded that AGEs played a key role in RAoSMC proliferation via MAP kinase dependent pathways. Activation of vascular smooth muscle cell (VSMC) proliferation by MAP kinase system and increased formation of ROS may be the possible mechanisms of AGEs induced diabetic vasculopathy.

Left Atrial Strain Assessed by Speckle Tracking Imaging Is Related to New-Onset Atrial Fibrillation After Coronary Artery Bypass Grafting

BACKGROUND Left atrial (LA) dysfunction was recently proposed as an important factor in the development of postoperative atrial fibrillation (POAF). LA strain analysis by 2-dimensional (2D) speckle tracking imaging is emerging as a new tool to evaluate LA function. We aimed to evaluate the correlation of LA dysfunction assessed by 2D speckle tracking imaging with the occurrence of POAF after coronary artery bypass grafting (CABG). METHODS In this study, 53 patients (mean age 66 ± 9 years) undergoing elective isolated CABG were enrolled. Conventional transthoracic echocardiography and 2D speckle tracking strain analysis were performed before surgery. POAF was detected with continuous electrocardiography monitoring throughout hospitalization (mean duration 17 ± 10 days). RESULTS POAF occurred in 13 of 53 patients (24%). Patients with POAF were significantly older than patients with normal sinus rhythm after surgery (71 ± 5 vs 64 ± 10 years, P = 0.026). Compared with patients with normal sinus rhythm, patients with POAF had a significantly larger LA volume index (32.6 ± 5.1 vs 27.3 ± 7.2 mL/m(2), P = 0.018), lower value of LA global strain (25.4 ± 10.4 vs 36.8 ± 7.6%, P = 0.001), and strain rate (1.2 ± 0.6 vs 1.6 ± 0.8 seconds, P = 0.024). By multivariate logistic regression analysis, only LA global strain (odds ratio, 1.12; 95% confidence interval, 1.00-1.24; P = 0.040) was an independent predictor of POAF after CABG. CONCLUSIONS Preoperative LA global strain measured by 2D speckle tracking strain analysis is associated with the development of POAF after CABG.

Serum Levels of Advanced Glycation End Products Are Associated with In-Stent Restenosis in Diabetic Patients

The formation of advanced glycation end products (AGEs), in various tissues has been known to enhance immunoinflammatory reactions and local oxidant stresses in long standing diabetes. Recently, AGEs have been reported to play a role in neointimal formation in animal models of arterial injury. We attempted to determine whether the serum levels of AGEs are associated with coronary restenosis in diabetic patients. Blood samples were collected from diabetic patients with coronary artery disease undergoing stent implantation and the serum levels of AGEs were analyzed by the fluorescent intensity method. The development of in-stent restenosis (ISR) was evaluated by a 6-month follow-up coronary angiography. A total of 263 target lesions were evaluated, in 203 patients. The ISR rate in the high-AGE (>170 U/ml) group (40.1%) was significantly higher than in the low-AGE group (≤170 U/ml) (19.6%) (p<0.001). Furthermore, multivariate analysis revealed that a high level of serum AGEs is an independent risk factor for the development of ISR (odds ratio, 2.659; 95% CI, 1.431-4.940; p=0.002). The serum levels of AGEs constitute an excellent predictive factor for ISR, and should be one of the guidelines for medical therapy and interventional strategy to prevent ISR in diabetic patients.

Oncogenic H-Ras Up-regulates Expression of Ku80 to Protect Cells from γ-Ray Irradiation in NIH3T3 Cells

The Ras activation contributes to radioresistance, but the mechanism is unclear. This article shows that the expression of the dominant-positive H-Ras increased the Ku80 level, which is one of the key enzymes involved in repairing dsDNA breaks (DSB). After exposing the cells to ionizing radiation and analyzing them using an electrophoretic mobility shift assay and pulsed-field gel electrophoresis, it was found that activated H-Ras expression in NIH3T3 cells increases the DNA-binding activity of Ku80 and increases the DSB repair activity. Ku80 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DSBs and suppress the oncogenic H-Ras-mediated resistance of the cells to gamma-ray irradiation, whereas Ku80 overexpression in the NIH3T3 cells significantly increased the radioresistance. These results suggest that the Ku80 expression induced by oncogenic H-Ras seems to play an important role in protecting cells against gamma-ray irradiation.

Significant association of coronary stent fracture with in-stent restenosis in sirolimus-eluting stents

BackgroundSeveral reports have suggested that stent fractures in sirolimus-eluting stents (SESs) might be related to in-stent restenosis (ISR). However, the role of stent strut fracture in ISR has not been clearly elucidated. Therefore, we investigated the association of the SES fracture and ISR. MethodsFrom 2003 to 2006, SES implantations with follow-up coronary angiography (CAG) for 628 lesions in 557 patients were analyzed. We reviewed clinical and procedural factors that might affect SES fracture and ISR. The median time interval from stent implantation to follow-up CAG was 9 months (range: 2–30 months). ResultsISR occurred in 38 patients (5.7%), and 21 stent fractures (3.3%) were identified by follow-up CAG. Fourteen cases occurred in the left anterior descending artery, and seven occurred in the right coronary artery. The binary ISR rate in the stent fracture group was higher compared with that of the nonfracture group (38.1% vs. 4.6%, P<0.001). Predictors of ISR as estimated by multivariate analysis were a stent diameter less than 2.75 mm [odds ratio (OR)=2.76, P=0.012], a stent length over 28 mm (OR=3.30, P=0.024), and stent fracture (OR=11.03, P<0.001) after controlling for the angiographic and clinical risk factors of ISR. ConclusionStent fracture was an independent predictor of ISR and may be one of the crucial mechanisms of ISR after implantation of an SES.

Senescence-dependent MutS alpha dysfunction attenuates mismatch repair.

DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSα complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSα to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSα dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978–89)