Yu-Chen Wang

Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor

Objectives Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. Methods and Results Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5]  =  L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine. Conclusions Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.

Concurrent Chemo-Radiotherapy Potentiates Vascular Inflammation: Increased FDG Uptake in Head and Neck Cancer Patients

Concurrent chemo-radiotherapy (CCRT) is the cornerstone of treatment for patients with head and neck cancer. However, the potential risk for cardiovascular complications after combined radiotherapy (RT) and chemotherapy is usually neglected. RT targeting the neck region has been correlated with

Digoxin use is associated with increased risk of stroke in patients with non-valvular atrial fibrillation — a nationwide population-based cohort study

☆ This study has been presented in part at the AHA Sc 2011, Orlando, Florida, USA. ☆☆ Funding sources: This study was supported in part b Taiwan (NSC 100-2314-B-039-042, NSC 101-2314-B-03 039-019), Taiwan Department of Health Clinical Trial and (DOH 101-TD-B-111-004), China Medical University Hosp 006, and DMR-102-007). All the aforementioned funding study design; in the collection, analysis and interpretatio report; or in the decision to submit the paper for publicat ⁎ Corresponding author at: Division of Cardiology, D Medical University Hospital 2, Yuh-Der Road, Taichun 4 22052121x3483; fax: +886 4 22065593. E-mail address: kuancheng.chang@gmail.com (K.-C. C

Reduced door-to-balloon times in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

Background:  Primary percutaneous coronary intervention (PCI) in patients with ST‐elevation myocardial infarction (STEMI) significantly reduces mortality and morbidity, particularly when door‐to‐balloon (D2B) time is < 90 min. We sought to minimize preventable delays by instituting an on‐site cardiology team‐based approach in the emergency department (ED).

Age-dependent impact of new ESC-Guideline recommended door-to-balloon times on mid-term survival in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention

BACKGROUND To investigate the age-dependent impact of the superfast door-to-balloon (D2B) times of ≤60min as recommended by the new ESC Guideline for patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) on mid-term survival rates based on a single center registry dataset. PATIENTS AND METHODS This study enrolled consecutive STEMI patients who underwent PPCI from Jan 1, 2009 through Sep 30, 2013. We compared demographics, clinical characteristics and the D2B-survival relationships between patients aged ≥65 and <65. RESULTS The younger group comprised 242 patients (68%) aged <65 and the elder group consisted of 115 patients (32%) aged ≥65. In patients aged <65, the mortality rate decreased linearly with D2B time shortening (>90min vs. 61-90min vs. ≤60min=14.9% vs. 13.3% vs. 1.2%, P=0.001). Contrarily, shortening of D2B time was not associated with reduced mortality rate in patients aged ≥65 (>90min vs. 61-90min vs. ≤60min=23.5% vs. 19% vs. 18.9%, P=0.99). In younger patients but not the elderly, a D2B time of <60min has sufficient power to predict mortality with a sensitivity of 0.83, specificity of 0.74, and Youden index of 0.57. CONCLUSIONS Our results show that the new ESC Guideline recommendation of D2B time ≤60min is associated with better survival rates in younger STEMI patients undergoing PPCI. Our findings stress the importance of guideline adherence to minimize reperfusion delay to improve survival in these patients.

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo.

Dysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.