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Background: Although ticagrelor is known to increase the bleeding risk compared to clopidogrel in East Asian patients, its clinical benefits in patients with acute myocardial infarction (AMI) without high bleeding risk (HBR) remains unknown., Methods: A total of 7,348 patients who underwent successful percutaneous coronary intervention (PCI) from the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), between November 2011 and December 2015, were divided into two groups according to the Academic Research Consortium for HBR criteria (KAMIR-HBR, 2,469 patients; KAMIR-non HBR, 4,879 patients). We compared in-hospital major adverse cardiovascular events (MACEs, defined as a composite of cardiac death, non-fatal myocardial infarction, or stroke), and the thrombolysis in myocardial infarction (TIMI) major bleeding between ticagrelor and clopidogrel in the KAMIR-HBR and the KAMIR-non HBR groups, respectively., Results: After propensity score matching, ticagrelor had a higher incidence of in-hospital TIMI major bleeding than clopidogrel in all patients (odds ratio [OR], 1.683; 95% confidence interval [CI], 1.010-2.805; P = 0.046) and the KAMIR-HBR group (OR, 3.460; 95% CI, 1.374-8.714; P = 0.008). However, there was no significant difference in in-hospital TIMI major bleeding between ticagrelor and clopidogrel in the KAMIR-non HBR group (OR, 1.436; 95% CI, 0.722-2.855; P = 0.303). No differences were observed in the cumulative incidences of in-hospital and 6-month MACEs between ticagrelor and clopidogrel in both groups., Conclusions: The bleeding risk of ticagrelor was attenuated in Korean patients with AMI without HBR. Appropriate patient selection could reduce in-hospital bleeding complications associated with ticagrelor in Korean patients with AMI who underwent successful PCI., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

We proposed a novel material named sodium hypochlorite (NaClO) solution as a source of activation for amorphous indium-gallium-zinc oxide (a-IGZO) thin-film transistors (TFTs). We reduced the activation temperature from 300 to 150 °C using NaClO solution (concentration: 50%) and obtained satisfactory electrical characteristics of a-IGZO TFTs. The field-effect mobility, threshold voltage, on/off ratio, subthreshold swing, and threshold voltage ( V th ) shift under negative bias illumination stress ( V G = -20 V and V D = 10.1 V for 10,000 s) of NaClO (50%)-activated a-IGZO TFTs were 10.41 cm 2 /V·s, 1.51 V, 2.78 × 10 8 , 0.37 V/dec, and -5.43 V, respectively. Also, the V th shifts of the NaClO (50%)-activated a-IGZO TFTs (150 °C) under the positive bias stress test decreased from 5.01 to 1.87 V ( V G = 20 V and V D = 10.1 V for 10,000 s) compared with that of only-annealed (300 °C) a-IGZO TFTs. Also, the mechanism of NaClO activation for a-IGZO TFTs is clarified through photo-assisted oxygen radical (POR) and heat-driven oxygen radical (HOR) effects. The POR and HOR effects generated the reactive oxygen species (ROS) from NaClO solution (50%), which activated a-IGZO TFTs at a low temperature (150 °C). When the NaClO solution (50%) was exposed to external energy, it generated ROS such as hydroxyl radicals (OH • ), hydroperoxyl radicals (HO 2 • ), and oxygen radicals (O • ), which promoted the formation of strong metal-oxide bonds in a-IGZO TFTs. Furthermore, NaClO solution (50%) was applied to a-IGZO TFTs on a flexible polyimide substrate and electrohydrodynamic printing process for selective deposition.

In this study, the oxygen scavenger layer (OSL) is proposed as a back channel in the bilayer channel to enhance both the electrical characteristics and stability of an amorphous indium-gallium-zinc oxide thin-film transistor (a-IGZO TFT) and also to enable its fabrication at low temperature. The OSL is a hafnium (Hf)-doped a-IGZO channel layer deposited by radio-frequency magnetron cosputtering. Amorphous IGZO TFTs with the OSL, even if annealed at a low temperature (200 °C), exhibited improved electrical characteristics and stability under positive bias temperature stress (PBTS) compared to those without the OSL, specifically in terms of field-effect mobility (31.08 vs 9.25 cm 2 /V s), on/off current ratio (1.73 × 10 10 vs 8.68 × 10 8 ), and subthreshold swing (0.32 vs 0.43 V/decade). The threshold voltage shift under PBTS at 50 °C for 10,000 s decreased from 9.22 to 2.31 V. These enhancements are attributed to Hf in the OSL, which absorbs oxygen ions from the a-IGZO front channel near the interface between a-IGZO and the OSL.

Exposure to microgravity affects human physiology in various ways, and astronauts frequently report skin-related problems. Skin rash and irritation are frequent complaints during space missions, and skin thinning has also been reported after returning to Earth. However, spaceflight missions for studying the physiological changes in microgravity are impractical. Thus, we used a previously developed 3D clinostat to simulate a microgravity environment and investigate whether physiological changes of the skin can be reproduced in a 3D in vitro setting. Our results showed that under time-averaged simulated microgravity (taSMG), the thickness of the endothelial cell arrangement increased by up to 59.75%, indicating skin irritation due to vasodilation, and that the diameter of keratinocytes and fibroblast co-cultured spheroids decreased by 6.66%, representing skin thinning. The α1 chain of type I collagen was upregulated, while the connective tissue growth factor was downregulated under taSMG. Cytokeratin-10 expression was significantly increased in the taSMG environment. The clinostat-based 3D culture system can reproduce physiological changes in the skin similar to those under microgravity, providing insight for understanding the effects of microgravity on human health before space exploration.

Stretchable organic light-emitting diodes are ubiquitous in the rapidly developing wearable display technology. However, low efficiency and poor mechanical stability inhibit their commercial applications owing to the restrictions generated by strain. Here, we demonstrate the exceptional performance of a transparent (molybdenum-trioxide/gold/molybdenum-trioxide) electrode for buckled, twistable, and geometrically stretchable organic light-emitting diodes under 2-dimensional random area strain with invariant color coordinates. The devices are fabricated on a thin optical-adhesive/elastomer with a small mechanical bending strain and water-proofed by optical-adhesive encapsulation in a sandwiched structure. The heat dissipation mechanism of the thin optical-adhesive substrate, thin elastomer-based devices or silicon dioxide nanoparticles reduces triplet-triplet annihilation, providing consistent performance at high exciton density, compared with thick elastomer and a glass substrate. The performance is enhanced by the nanoparticles in the optical-adhesive for light out-coupling and improved heat dissipation. A high current efficiency of ~82.4 cd/A and an external quantum efficiency of ~22.3% are achieved with minimum efficiency roll-off.

Background: Epidemiologic studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with an increased risk of developing cardiovascular diseases, including arrhythmia. However, the cellular and molecular mechanisms by which PM exposure causes arrhythmia and the component that is mainly responsible for this adverse effect remains to be established. In this study, the arrhythmogenicity of mobilized organic matter from two different types of PM collected during summer (SPM) and winter (WPM) seasons in the Seoul metropolitan area was evaluated. In addition, differential effects between polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (oxy-PAHs) on the induction of electrophysiological instability were examined., Results: We extracted the bioavailable organic contents of ambient PM, measuring 10 μm or less in diameter, collected from the Seoul metropolitan area using a high-volume air sampler. Significant alterations in all factors tested for association with electrophysiological instability, such as intracellular Ca 2+ levels, reactive oxygen species (ROS) generation, and mRNA levels of the Ca 2+ -regulating proteins, sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a), Ca 2+ /calmodulin-dependent protein kinase II (CaMK II), and ryanodine receptor 2 (RyR2) were observed in cardiomyocytes treated with PM. Moreover, the alterations were higher in WPM-treated cardiomyocytes than in SPM-treated cardiomyocytes. Three-fold more oxy-PAH concentrations were observed in WPM than SPM. As expected, electrophysiological instability was induced higher in oxy-PAHs (9,10-anthraquinone, AQ or 7,12-benz(a) anthraquinone, BAQ)-treated cardiomyocytes than in PAHs (anthracene, ANT or benz(a) anthracene, BaA)-treated cardiomyocytes; oxy-PAHs infusion of cells mediated by aryl hydrocarbon receptor (AhR) was faster than PAHs infusion. In addition, ROS formation and expression of calcium-related genes were markedly more altered in cells treated with oxy-PAHs compared to those treated with PAHs., Conclusions: The concentrations of oxy-PAHs in PM were found to be higher in winter than in summer, which might lead to greater electrophysiological instability through the ROS generation and disruption of calcium regulation.

Background: Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting., Methods: A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year., Results: The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively)., Conclusion: Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection., Methods: Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%)., Results: Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection., Conclusions: A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection., (Published by Elsevier Inc.)

Aims: Most immunosuppressive drugs provide targeted immunosuppression by selective inhibition of lymphocyte activation and proliferation. This study evaluated whether a change in the lymphocyte to neutrophil ratio (LNR) is related to acute rejection., Methods: In 74 cardiac transplant recipients peripheral blood lymphocyte and neutrophil counts were measured soon after (baseline) and three, six, and 12months after heart transplantation. The primary endpoint was the incidence of acute rejection., Results: Significant acute rejection after heart transplantation occurred in 20 patients (27%) during a median follow-up of 49.4 [IQR 37.4-61.1] months. LNR significantly increased over time (0.1149±0.1354 at baseline, 0.2330±0.2266 at 3months, 0.2961±0.2849 at 6months, and 0.3521±0.2383 at 12months; P<0.001), especially during the first 3months in the group without acute rejection. The area under the curve of the change in LNR during the first three months (ΔLNR) for acute rejection was 0.565 (95% CI 0.420 to 0.710, P=0.380) on ROC curve analysis. The best cutoff value of Δ LNR to differentiate those with and without acute rejection was ≤0.046 by ROC curve analysis. Kaplan-Meier analysis revealed that the low ΔLNR group (≤0.046) had a significantly higher rate of acute rejection than the high ΔLNR group (>0.046) (37.5% vs. 19.0%, log-rank: P=0.0358). The low ΔLNR for the first 3months was an independent predictor of clinically significant acute rejection after adjusting for cytomegalovirus donor seropositive and recipient seronegative., Conclusions: The results of this study suggest that ΔLNR over the first 3months after heart transplantation is a strong and independent predictor of acute rejection after heart transplantation. ΔLNR can be used as an early biomarker for predicting of acute rejection after heart transplantation., (Published by Elsevier B.V.)

The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0 mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1 μM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1 %, respectively, in the presence of pioglitazone (1.0 mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0 mg/kg) decreased by pioglitazone (35.8 %). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0 mg/kg) was significantly higher (25.3 %) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0 mg/kg) significantly decreased (23.9 %) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone.

Background: The preprocedural neutrophil-lymphocyte ratio (NLR) is related to adverse outcomes in patients with coronary artery disease. We hypothesized that high NLR is a predictor of cardiac death after percutaneous coronary intervention (PCI). The objective of this investigation was to assess the associations of NLR, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the occurrence of cardiac death after PCI., Materials and Methods: The NLR, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary end point was cardiac death., Results: The median NLR was 2.3 (interquartile range: 1.5-4.1). There were 21 cardiac death events during a mean follow-up duration of 25.8 months. With the NLR cutoff level set to 3.3 using the receiver-operating characteristic curve, the sensitivity and specificity for differentiating between the group with cardiac death and the group without cardiac death were 85.7% and 59.3%, respectively. Kaplan-Meier analysis revealed that the higher NLR group (≥3.3) had a significantly higher cardiac death rate than the lower NLR group (<3.3) (11.1% versus 1.4%, log-rank: P < 0.0001). This value was more useful in patients with heart failure (NT-proBNP ≥ 300ng/L) or myocardial injury (hs-cTnT ≥ 100ng/L)., Conclusions: The outcomes of the current study demonstrate that high NLR is a predictor of cardiac death after PCI, especially in patients with heart failure or myocardial injury., (Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Low triiodothyronine (T3) levels and subclinical myocardial injury may be associated with adverse cardiac and cerebrovascular (CCV) events in individuals without clinically apparent coronary heart disease (CHD). The aim of this study was to determine the associations of a low T3 level and subclinical myocardial injury with the development of adverse CCV events in individuals without clinically apparent CHD., Methods: T3 and high-sensitivity cardiac troponin T (hs-cTnT) levels were analyzed in 250 patients with chest pain free of CHD and heart failure. The primary end point was the composite of sudden cardiac death, ischemic stroke, newly developed atrial fibrillation, pericardial effusion and thrombosis., Results: Throughout a mean follow-up of 15.6 months, the primary end point happened in 17 patients (6.8%). Kaplan-Meier analysis disclosed a notably higher overall occurrence rate in patients with hs-cTnT levels ≥0.014 ng/mL and in patients with T3 <60 ng/dL. An exaggerated hazard was observed in patients with combined high hs-cTnT and low T3 levels. After adjustment, the hazard ratio for overall events in patients with high hs-cTnT/low T3 versus normal hs-cTnT/T3 was 11.72 (95% confidence interval, 2.83-48.57; P = 0.001)., Conclusions: In patients with chest pain without clinically obvious CHD, high hs-cTnT combined with low T3 was associated with adverse cardiac/CCV events and was an independent predictor of overall events even after adjustment. These data suggest the importance of systemic factors, such as low T3 syndrome, in the development of adverse cardiac/CCV events beyond advancing clinical atherosclerotic coronary disease in patients with chest pain.

The aim of this study was to evaluate the prognostic value of serum total bilirubin on the development of adverse outcomes after percutaneous coronary intervention (PCI) besides high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP). Serum total bilirubin, hs-cTnT, and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary endpoint was cardiac death. There were 21 events of cardiac death during a mean of 25.8 months of follow-up. When the serum total bilirubin cut-off level (median value) was set to 0.58 mg/dL using the receiver operating characteristic curve, the sensitivity was 95.2 % and the specificity was 51.0 % for differentiating between the group with cardiac death and the group without cardiac death. Kaplan-Meier analysis revealed that the lower serum total bilirubin group (<0.58 mg/dL) had a significantly higher cardiac death rate than the higher serum total bilirubin group (≥0.58 mg/dL) (10.4 vs. 0.6 %, log-rank: P = 0.0001). In conclusion, low serum total bilirubin is a predictive marker for cardiac death after PCI.

Background: This study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats., Methods: We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors. We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4., Results: Atorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC50) values were 47.0, 5.2, 15.0 and 3.3 μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123. The area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite-parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC0-∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group., Conclusion: The increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Introduction: Lateral internal sphincterotomy (LIS) is a safe and effective surgical treatment, commonly used in patients with chronic anal fissures (CAFs). Although LIS is a simple surgical technique, it may cause several complications. Open LIS is usually performed through an incision made in the intersphincteric groove; radial or circumferential incisions, used according to the surgeon's preference. However, differences in clinical outcomes and wound healing, based on type of skin incision, are unclear. We investigated incision site wound healing and other clinical outcomes, after open LIS, according to the type of skin incision employed., Methods: We retrospectively reviewed the data of the electronic medical records of 602 patients who underwent open LIS for CAFs between March 2005 and February 2010 at Yang Hospital, Seoul, Korea., Results: Of the 602 patients, 298 patients received radial incisions and 304 received circumferential incisions. Circumferential incisions of the anus reduced the wound healing time compared to radial incisions (19.1 vs. 24.0 days, p < 0.001). There were no significant differences between the groups in wound complications such as perianal abscess, fistula, or cellulitis. Clinical outcomes including recurrence, persistence of fissures, and continence problems were also similar between the groups., Conclusions: Our study shows that circumferential skin incisions, during LIS, are associated with shorter healing times than radial incisions., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to determine the associations of brachial-ankle pulse wave velocity (baPWV), high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the development of adverse outcomes after percutaneous coronary intervention (PCI)., Methods: The baPWV, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary endpoint was cardiac death., Results: There were 21 events of cardiac death during a mean of 25.8 months of follow-up. When the baPWV cut-off level was set to 1672 cm/s using the receiver operating characteristic curve, the sensitivity was 85.7% and the specificity was 60.1% for differentiating between the group with cardiac death and the group without cardiac death. Kaplan-Meier analysis revealed that the higher baPWV group (≥1672 cm/s) had a significantly higher cardiac death rate than the lower baPWV group (<1672 cm/s) (11.4% vs. 1.4%, log-rank: P<0.0001). This value was more useful in patients with myocardial injury (hs-cTnT≥0.1 ng/mL) or heart failure (NT-proBNP≥450 pg/mL)., Conclusions: The results of this study show that high baPWV is a predictive marker for cardiac death after PCI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this study was to determine the association of pulse wave velocity or left ventricular diastolic function with the development of cardiovascular (CV) events., Methods: Brachial-ankle pulse wave velocity (baPWV) and E/E' were analyzed in 185 patients. The primary end point was CV events including ischemic stroke, coronary arterial disease (CAD), peripheral arterial disease and aortic dissection., Results: There were 30 CV events during a mean follow-up period of 19.8 months. When the baPWV cutoff level was set to 1704 cm/s using the receiver operating characteristic curve, the sensitivity was 70/92% and the specificity 63/62% for differentiating between the group with and without CV events or ischemic stroke. In univariate analysis with the Cox proportional hazard model, higher baPWV was a predictor for CV events and ischemic stroke events. However, high E/E' (>15) was not a predictor for CV, ischemic stroke events or CAD. A higher baPWV was an independent predictor for CV and ischemic stroke risk after adjusting for age, sex, hypertension and diabetes in the Cox proportional hazard analysis. In subgroup analysis, diabetic patients with a baPWV >1704 cm/s had a high CV event and ischemic stroke risk., Conclusions: The results of this study show that higher baPWV was a predictive marker for CV events, especially ischemic stroke. The subgroup analysis suggests that antiplatelet therapy may be needed in diabetic patients with a high baPWV for prevention of ischemic stroke.

Heart dysfunctions have been shown to be associated with altered concentrations of thyroid hormones. However, the relation between thyroid hormones and subclinical myocardial injury in those without clinically apparent coronary heart disease is not well-established. We examined the correlation between altered levels of thyrotropin, free thyroxine, and triiodothyronine (T3) and high-sensitivity cardiac troponin T (hs-cTnT) in 250 patients (mean age 60 years; 42% men) with chest pain, who were free of coronary heart disease and heart failure. These patients were examined in the emergency room or outpatient department of the cardiovascular center of Chosun University Hospital. Multivariate logistic regression models were used for statistical analysis. The baseline values of T3 were associated with elevated hs-cTnT levels (r = -0.428, p <0.001), a significantly negative correlation. We did not observe any significant correlation between the thyrotropin or free thyroxine and hs-cTnT levels. When the T3 cutoff was set at 74.6 ng/dl using the receiver operating characteristic curve, the sensitivity and specificity was 70% and 69%, respectively, for differentiating between groups with and without myocardial injury. After adjusting for traditional risk factors, the odds ratio for an elevated hs-cTnT level (≥0.014 ng/ml) for patients with T3 <74.6 ng/dl was 6.95 (95% confidence interval 3.09 to 15.66) compared to patients with T3 ≥74.6 ng/dl. In conclusion, the T3 levels were negatively related to hs-cTnT levels among patients without clinically obvious coronary heart disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 μM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-∞)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-∞) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect-time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions.

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg; P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3% at 0.3 mg/kg, 9.3% at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2%). The AUC and Cmax of norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P-glycoprotein (P-gp) efflux pump in small intestine. Therefore, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases.

The pharmacokinetic changes of tolbutamide were studied after oral administration to normal rabbits and mild and medium folate-induced renal failure rabbits. Tolbutmide 50 mg/kg was orally administered to the rabbits. The plasma concentrations of tolbutamide were significantly increased (p<0.05) at 9 to 24 hr in mild and medium folate-induced renal failure rabbits compared with those in normal rabbits. Therefore, the area under the plasma concentration-time curves (AUC) was significantly higher (p<0.05 and p<0.01 respectively) in mild and medium folate-induced renal failure rabbits (2906 microg/ml x hr and 4074 microg/ml x hr) than that in normal rabbits (2295 microg/ml x hr). The cumulative urinary excretion of tolbutamide was significantly decreased (p<0.05) in medium folate-induced renal failure rabbits (3.3 mg) compared with the normal rabbits (5.9 mg). The elimination rate constant (Kel) of tolbutamide was significantly slower in medium folate-induced renal failure rabbits (0.027 hr(-1)) than that in normal rabbits(0.044 hr(-1)). The terminal half-life of tolbutamide in medium folate-induced renal failure rabbits (25.5 hr) was significantly longer (p<0.01) than in normal rabbits (15.7 hr). These results could be considered as possibly due to inhibited excretion of tolbutamide metabolites or retarded metabolism of tolbutamide.