Kiyuk Chang

Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging

Magneto-fluorescent silica nanoparticles were conjugated with cetuximab for the targeting and imaging of colon cancer. In this study, cetuximab-conjugated magneto-fluorescent nanoparticles (MFSN-Ctx) could specifically target colon cancer cells that expressed EGFR on their cell membranes, and specific fluorescence was detected. MFSN-Ctx produced significant MRI signal changes in a human colon cancer xenograft mouse model. Intravenous injection of MFSN-Ctx resulted in faster uptake as compared to intraperitoneal injection, indicating that MFSN-Ctx had different kinetic properties in tumors based on the method of injection. The local concentration of MFSN-Ctx in a tumor was amplified by the use of an external magnetic field. These results demonstrate the potential application of MFSN-Ctx for the detection of EGFR-expressing colon cancer using in vivo imaging approaches.

The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm.

Background Coronary spasm seems to be associated with coronary nitric oxide deficiency. Objectives We investigated whether the Glu298Asp polymorphism in the endothelial nitric oxide synthase (eNOS) gene is a definite risk factor for coronary spasm and whether diffuse spasm involving normal‐looking coronary artery correlates significantly with the Glu298Asp polymorphism, in contrast with focal spasm superimposed on an atherosclerotic plaque. Methods A polymerase chain reaction followed by restriction fragment length polymorphism analysis was performed in 118 control participants and in 102 patients with variant angina and a similar degree of atherosclerotic burden. Patients with coronary spasm were divided into diffuse spasm and focal spasm subgroups according to morphological criteria. Results There was a significantly higher incidence of the Glu298Asp polymorphism in the coronary spasm group than in the control group (21.5% compared with 8.5%, P =0.006). Multiple logistic regression analysis using risk factors and the Glu298Asp polymorphism showed that the most important predictive factor for coronary spasm was the Glu298Asp polymorphism (odds ratio 2.83, 95% confidence interval 1.25‐6.41, P = 0.009). The diffuse spasm subgroup had a significantly higher frequency of the Glu298Asp polymorphism than the control group (25.9% compared with 8.5%, P = 0.002). However, the focal spasm subgroup did not differ from the control group in the frequency of Glu298Asp polymorphism. Conclusion The Glu298Asp polymorphism in the eNOS gene is a definite risk factor for coronary spasm, especially for diffuse coronary spasm. This result supports the notion that diffuse coronary spasm is significantly associated with endothelial dysfunction, in contrast to focal spasm. Coron Artery Dis 14:293‐299

Pioglitazone Suppresses Inflammation In Vivo in Murine Carotid Atherosclerosis Novel Detection by Dual-Target Fluorescence Molecular Imaging

Objective—To investigate the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor &ggr; agonist, on plaque matrix metalloproteinase (MMP) and macrophage (Mac) responses in vivo in a molecular imaging study. Methods and Results—In vitro, PIO suppressed MMP-9 protein expression in murine peritoneal Macs (P<0.05). To assess PIOs effects on plaque inflammation, nondiabetic apolipoprotein E−/− mice receiving a high-cholesterol diet (HCD) were administered an MMP-activatable fluorescence imaging agent and a spectrally distinct Mac-avid fluorescent nanoparticle. After 24 hours, mice underwent survival dual-target intravital fluorescence microscopy of carotid arterial plaques. These mice were then randomized to HCD or HCD plus 0.012% PIO for 8 weeks, followed by a second intravital fluorescence microscopy study of the same carotid plaque. In the HCD group, in vivo MMP and Mac target-to-background ratios increased similarly (P<0.01 versus baseline). In contrast, PIO reduced MMP and Mac target-to-background ratios (P<0.01) versus HCD. Changes in MMP and Mac signals correlated strongly (r ≥0.75). Microscopy demonstrated MMP and Mac reductions in PIO-treated mice and a PIO-modulated increase in plaque collagen. Conclusion—Serial optical molecular imaging demonstrates that plaque MMP and Mac activity in vivo intensify with hypercholesterolemia and are reduced by PIO therapy.

High-density lipoprotein cholesterol as a predictor of clinical outcomes in patients achieving low-density lipoprotein cholesterol targets with statins after percutaneous coronary intervention

Background A low level of high-density lipoprotein cholesterol (HDL-C) is strongly associated with cardiovascular events. However, the significance of HDL-C after statin therapy on the outcome of patients who have undergone percutaneous coronary intervention (PCI) with drug eluting stents (DES) is unclear. Objectives To investigate the significance of HDL-C after statin therapy on cardiovascular events in patients with coronary artery disease after DES implantation. Methods Patients who underwent PCI with DES from January 2004 to December 2009 were prospectively enrolled. The follow-up lipid panel of 2693 patients (median lab follow-up duration 225 days) who had continued using statins after PCI and who attained low-density lipoprotein cholesterol (LDL-C) <100 mg/dl was analysed. Major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction, and target vessel revascularisation according to follow-up HDL-C level (40 mg/dl for men or 50 mg/dl for women) were compared with the use of propensity scores matching. Results Median follow-up duration was 832 days. 1585 (58.9%) patients had low follow-up HDL-C and 1108 had high follow-up HDL-C. The low follow-up HDL-C group had significantly higher rates of MACE. Low follow-up HDL-C was a significant independent predictor of MACE (adjusted HR 1.404, 95% CI 1.111 to 1.774, p=0.004). In further analysis with propensity scores matching, overall findings were consistent. Conclusions Raising HDL-C levels may be a subsequent goal after achieving target LDL-C levels in patients with DES implantation.

Long-term outcomes of percutaneous coronary intervention versus coronary artery bypass grafting for unprotected left main coronary bifurcation disease in the drug-eluting stent era

Objectives There are limited data on long-term outcomes (ie, beyond 4 years) for patients with unprotected left main bifurcation disease who underwent percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) in the drug-eluting stent (DES) era. This study therefore compared the treatment effects of PCI and CABG in unprotected left main bifurcation disease. Methods 865 patients with unprotected left main bifurcation disease treated with either PCI using DES (n=556) or CABG (n=309) were evaluated between May 2003 and December 2009. PCI-treated patients were further categorised into simple stenting (n=360) or complex stenting (n=196). Results Median follow-up was 4.2 years (IQR 2.9–5.2 years). After adjusting covariates with multivariate Cox hazard regression model and inverse probability of treatment weighting, the long-term cumulative rates of death (HR 0.95; 95% CI 0.62 to 1.45) or composite of death, Q-wave myocardial infarction, or stroke (HR 0.97, 95% CI 0.64 to 1.48) were not significantly different for patients undergoing PCI or CABG except for target-vessel revascularisation (TVR) (HR 4.42, 95% CI 2.39 to 8.18). The complex stenting group had similar long-term clinical outcomes compared with the simple stenting group except for TVR (HR 1.94, 95% CI 1.22 to 3.10). In further analysis with propensity score matching, overall findings were consistent. Conclusions In patients with unprotected left main bifurcation disease, PCI using DES provides similar long-term (up to 5.2 years) clinical outcomes except for TVR compared with CABG. Complex and simple stenting yielded similar outcomes except for a higher TVR rate in complex stenting.

Decaffeinated green tea extract improves hypertension and insulin resistance in a rat model of metabolic syndrome

BACKGROUND Oxidative stress and endothelial dysfunction are closely associated with hypertension and insulin resistance (IR) in metabolic syndrome (MetS). It is still controversial whether green tea extract (GTE) may have blood pressure (BP) lowering effect. Decaffeinated GTE might be presumed to have strong antioxidative effect and BP-lowering effect as compared with catechins. Thus we investigated whether decaffeinated-GTE could attenuate hypertension and IR by improving endothelial dysfunction and reducing oxidative stress in a rat model of MetS. METHODS AND RESULTS 20 Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 13 weeks old, MetS rats, were randomized into a saline treated group (OLETF; n = 10) and a group treated with decaffeinated-GTE (25 mg/kg/day) (GTE-OLETF; n = 10). Intraperitoneal glucose tolerance tests and BP measurements were performed at 13 and 25 weeks. Decaffeinated-GTE significantly reduced BP (OLETF vs. GTE-OLETF; 130 ± 7 vs. 121 ± 3 mmHg, p = 0.01), fasting/postprandial 2 h glucose (141 ± 18/159 ± 13 vs. 115 ± 7/132 ± 16 mg/dL, p = 0.009/0.002) and insulin levels (4.8 ± 2.3 vs. 2.4 ± 1.3 ng/mL, p < 0.001). Decaffeinated-GTE significantly reduced vascular reactive oxygen species (ROS) formation and NADPH oxidase activity, and improved endothelium dependent relaxation in the thoracic aorta of OLETF rats. Decaffeinated-GTE also suppressed the expression of p47 and p22phox (NADPH oxidase subunits) in the immunohistochemical staining, and stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) and Akt in the immunoblotting of aortas. CONCLUSIONS Decaffeinated-GTE reduced the formation of ROS and NADPH oxidase activity and stimulated phosphorylation of eNOS and Akt in the aorta of a rat model of MetS, which resulted in improved endothelial dysfunction and IR, and eventually lowered BP.

Benefit of β-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention

Objective β-blockers are the standard treatment for myocardial infarction (MI) based on evidence from the pre-thrombolytic era. The aim of this study was to examine the effect of β-blocker treatment in patients with acute MI and preserved systolic function in the era of percutaneous coronary intervention (PCI). Methods We analysed a multicentre registry and identified 3019 patients who presented with acute MI between 2004 and 2009. Patients were treated with PCI, had left ventricular EFs ≥50% according to echocardiograms that were performed during the index PCI, and were alive at the time of discharge. The association between β-blocker use after discharge and mortality (all-cause death and cardiac death) within 3 years was examined. Results Patients who were not treated with β-blockers (n=595) showed higher rates of all-cause death and cardiac death compared to patients treated with β-blockers (10.8% vs 5.7%, p<0.001, 7.6% vs 2.6%, p<0001). The multivariate Cox proportional hazards model showed that β-blocker treatment was associated with a significant reduction in all-cause death (adjusted HR 0.633, 95% CI 0.464 to 0.863; p=0.004) and cardiac death (adjusted HR 0.47, 95% CI 0.32 to 0.70; p<0.001). Comparable results were obtained after propensity score matching. Conclusions β-blocker treatment was associated with reduced long term mortality in patients with acute MI and preserved systolic function who received PCI.

Noninvasive Assessment of Myocardial Inflammation by Cardiovascular Magnetic Resonance in a Rat Model of Experimental Autoimmune Myocarditis

Background— Limited availability of noninvasive and biologically precise diagnostic tools poses a challenge for the evaluation and management of patients with myocarditis. Methods and Results— The feasibility of cardiovascular magnetic resonance (CMR) imaging with magneto-fluorescent nanoparticles (MNPs) for detection of myocarditis and its effectiveness in discriminating inflammation grades were assessed in experimental autoimmune myocarditis (EAM) (n=65) and control (n=10) rats. After undergoing CMR, rats were administered with MNPs, followed by a second CMR 24 hours later. Head-to-head comparison of MNP-CMR with T2-weighted, early and late gadolinium enhancement CMR was performed in additional EAM (n=10) and control (n=5) rats. Contrast-to-noise ratios were measured and compared between groups. Flow cytometry and microscopy demonstrated that infiltrating inflammatory cells engulfed MNPs, resulting in altered myocardial T2* effect. Changes in contrast-to-noise ratio between pre- and post-MNP CMR were significantly greater in EAM rats (1.08±0.10 versus 0.48±0.20; P<0.001). In addition, contrast-to-noise ratio measurement in MNP-CMR clearly detected the extent of inflammation (P<0.001) except for mild inflammation. Compared with conventional CMR, MNP-CMR provided better image contrast (CNR change 8% versus 46%, P<0.001) and detectability of focal myocardial inflammation. Notably, MNP-CMR successfully tracked the evolution of myocardial inflammation in the same EAM rats. Conclusions— Magneto-fluorescent nanoparticle CMR permitted effective visualization of myocardial inflammatory cellular infiltrates and distinction of the extent of inflammation compared with conventional CMR in a preclinical model of EAM. Magneto-fluorescent nanoparticle CMR performs best in EAM rats with at least moderate inflammatory response.

Advances in fluorescence imaging of the cardiovascular system

ConclusionsNIRF molecular imaging strategies are illuminating key biologic aspects of MI and atherosclerosis in vivo. In addition, clinical NIRF reflectance systems are providing intraoperative angiograms and perfusion images that can critically alter the surgical management of coronary artery bypass patients. Advances in NIRF catheter/FMT imaging technology, as well as anticipated clinical trials of NIRF imaging agents, will position fluorescence imaging to play an important role in the molecular diagnosis, risk stratification, and treatment plan of patients with cardiovascular disease.

Impact of diabetes duration on the extent and severity of coronary atheroma burden and long-term clinical outcome in asymptomatic type 2 diabetic patients: evaluation by Coronary CT angiography

AIMS We investigated the association between diabetes duration and the extent and severity of coronary artery disease (CAD) as well as long-term clinical outcomes using coronary computed tomography angiography (CCTA) in asymptomatic type 2 diabetic patients. METHODS AND RESULTS We analysed 933 asymptomatic type 2 diabetic patients without known CAD who underwent CCTA. Patients were divided into three groups according to the duration of diabetes: <5 years, 5-10 years, and ≥10 years. Stenosis by CCTA was scored as none (0%), non-obstructive (1-49%), or obstructive (≥50%) for each coronary artery segment. For these patients, we compared the prevalence, extent, and severity of CAD, including coronary artery calcium score (CACS), atheroma burden obstructive score (ABOS), segment involvement score (SIS), and segment stenosis score (SSS). Major adverse cardiac and cerebrovascular events (MACCE), including all-cause mortality, non-fatal myocardial infarction, and stroke, within a follow-up period were also compared.Patients with longer duration of diabetes possessed higher rates of obstructive CAD (P < 0.001). Patients with longer duration of diabetes also manifested greater degree of CACS, ABOS, SIS, and SSS (P < 0.001 for all) with associated higher rate of MACCE (P = 0.025). Presence of obstructive CAD as assessed by CCTA was an independent predictor of MACCE after adjusting for confounding risk factors (hazard ratio: 1.979, confidence interval: 1.178-3.327, P = 0.010). CONCLUSION In asymptomatic diabetic patients, longer diabetes duration is associated with a higher prevalence, extent, and severity of CAD as well as risk of MACCE. Moreover, greater CAD burden increases the risk of MACCE independent of co-existing CAD risk factors.