Weon Kim

Cardioprotective Effects of Exenatide in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention Results of Exenatide Myocardial Protection in Revascularization Study

Objective—Experimental evidence suggests that exenatide, a glucagon-like peptide 1 receptor analogue, has significant cardiovascular protective effects in various conditions. We examined whether routine use of exenatide at the time of primary percutaneous coronary intervention would reduce infarct size in patients with ST-segment–elevation myocardial infarction. Approach and Results—Fifty-eight patients with ST-segment–elevation myocardial infarction and thrombolysis in myocardial infarction flow 0 were enrolled in the study and randomly assigned to receive either exenatide or placebo (saline) subcutaneously. Infarct size was assessed by measuring the release of creatine kinase-MB and troponin I during 72 hours and by performing cardiac magnetic resonance imaging at 1 month after infarction. Routine and speckle tracking echocardiography was performed at initial presentation and at 3 days and 6 months after primary percutaneous coronary intervention. The exenatide and control groups had similar results with respect to ischemia time, demographic characteristics, and ejection fraction before primary percutaneous coronary intervention. The releases of creatine kinase-MB and troponin I were significantly reduced in the exenatide group. In 58 patients evaluated with cardiac magnetic resonance, the absolute mass of delayed hyperenhancement was significantly reduced in the exenatide group as compared with the control group (12.8±11.7 versus 26.4±11.6 g; P<0.01). At 6 months, the exenatide group showed a significantly lower value of E/E′ with improved strain parameters. No significant adverse effects of exenatide administration were detected. Conclusions—In patients with ST-segment–elevation myocardial infarction, adjunctive exenatide therapy with primary percutaneous coronary intervention was associated with reduction of infarct size and improvement of subclinical left ventricular function.

A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure.

We sought to compare the platelet responsiveness to clopidogrel between patients with chronic renal failure and those with normal renal function. We conducted a prospective, randomized, open-label, single-center trial. A total of 23 patients with normal renal function received a usual daily dose of 75 mg of clopidogrel (group I, 61 +/- 7 years). Also, 36 patients with chronic renal failure (60 +/- 5 years) were divided into 2 groups according to their daily dose of clopidogrel: a daily dose of 75 mg of clopidogrel for 30 days (group II, n = 18) or a daily dose of 150 mg (group III, n = 18). The primary efficacy variables among the study groups using the VerifyNow P2Y12 assay were the P2Y12 reaction unit value and the percentage of inhibition. A significant difference was found in the P2Y12 reaction unit value among the 3 groups (239 +/- 87 in group I, 308 +/- 70 in group II, 302 +/- 81 in group III (p = 0.013) and in the percentage of inhibition (35 +/- 20 in group I, 21 +/- 16 in group II, 23 +/- 14 in group III, p = 0.026). No significant difference was found in the P2Y12 reaction units or percentage of inhibition between groups II and III. In conclusion, platelet responsiveness to clopidogrel decreased more in patients with chronic renal failure than in those with normal renal function, and this decreased platelet responsiveness to clopidogrel was not improved by an increase in the clopidogrel dosage.

Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells.

Curcumin, a yellow pigment of turmeric in curry, is reported to interfere with nuclear factor (NF)-κB. This study was designed to investigate the underlying pathway of antiinflammation of curcumin on endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with 10 ng/mL tumor necrosis factor (TNF)-α. Curcumin blocked the activation of NF-κB by TNF-α. Curcumin also reduced the intracellular reactive oxygen species (ROS), monocyte adhesion, phosphorylation of c-Jun N-terminal kinase (JNK), p38, and signal transducer and activator of transcription (STAT)-3 in TNF-α-stimulated HUVECs. The expression of intracellular cell adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8 were attenuated by curcumin at both mRNA and protein level. Curcumin, however, did not affect the expression of TNF receptor I and II in TNF-α-stimulated HUVECs. We suggest that curcumin could contribute to protection against the adverse vascular effect of the proinflammatory response through the modulation of p38 and STAT-3 in addition to NF-κB and JNK in endothelial cells.

Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Matrix Metalloproteinase 2–Deficient Mice

Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2+/+ and MMP-2−/− mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2−/− young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti–l-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2−/− mice compared with the age-matched MMP-2+/+ mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2−/− mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow–derived endothelial progenitor cell (EPC)-like c-Kit+ cells from MMP-2−/− showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2−/−. Flow cytometry showed that the numbers of EPC-like CD31+c-Kit+ cells in peripheral blood markedly decreased in MMP-2–deficient mice. Transplantation of bone marrow–derived mononuclear cells from MMP-2+/+ mice restored neovascularization in MMP-2−/− young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization.

Exercise Training Stimulates Ischemia-Induced Neovascularization via Phosphatidylinositol 3-Kinase/Akt-Dependent Hypoxia-Induced Factor-1α Reactivation in Mice of Advanced Age

Background— Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1&agr;–mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results— Aged wild-type mice (MMP-2+/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1&agr;, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2+/+ mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1&agr;. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1&agr; stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice. Conclusions— ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase–dependent mechanism that is mediated by the HIF-1&agr;/vascular endothelial growth factor/MMP-2 pathway in advanced age.

Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinase and Nuclear Factor-kappaB in endothelial cells.

Background: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects that are anti-inflammatory and antiatherothrombotic. It is important to understand the cardioprotective effects of rosuvastatin in order to optimize its additional advantages in the treatment and prevention of cardiovascular diseases. Methods: Human umbilical vein endothelial cells (HUVEC) were treated with tumor necrosis factor (TNF)-α (10 ng/mL) alone or with rosuvastatin (100 μM). The extent of inflammation was determined by U937 adhesion assay as well as analysis of the expression of intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, IL-6, cyclooxygenase (COX)-2, c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), p38, and signal transducer and activator of transcription (STAT)-3. The activation of nuclear factor kappa B (NF-κB) was determined by Western blot. Results: Rosuvastatin decreased the extent of U937 adhesion to TNF-α-stimulated HUVEC. Rosuvastatin inhibited the expressions of ICAM-1, MCP-1, IL-8, IL-6, and COX-2 mRNA and protein levels. The activation of JNK and NF-κB was also blocked by rosuvastatin. The inhibitors of JNK, NF-κB, and STAT-3 produced a statistically significant decrease of the TNF-α induced U937 adhesion and IL-6 protein release. Conclusions: This study suggests that the anti-inflammatory activity of rosuvastatin is accompanied by the inhibition of JNK and NF-κB.

Superoxide-Dependent Cathepsin Activation Is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotensin II Type 1 Receptor Blocker Treatment

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.

Preventive Effects of Exenatide on Endothelial Dysfunction Induced by Ischemia-Reperfusion Injury via KATP Channels

Objective—The purpose of this study was to evaluate whether exenatide administration can prevent impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) injury and whether this effect is mediated by KATP channel opening. Methods and Results—In a double-blind, placebo-controlled, crossover design, 20 volunteers were randomly assigned to 2 groups: subcutaneous exenatide (10 &mgr;g) or placebo administration. At 30 minutes after the study drug administration, endothelium-dependent flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion) injury. Seven days later, both groups were crossed over and received the other treatment (ie, placebo or exenatide) and underwent the same protocol. Pre-IR radial artery diameter, FMD, and baseline radial artery diameter after IR injury were similar between 2 groups (P=no significant difference). After placebo administration, IR significantly blunted FMD (before IR: 12.0±6.23%; after IR: 4.6±3.57%, P=0.02). Exenatide prevented this impairment (FMD before IR: 15.0±7.14%; FMD after IR: 15.0±5.96%, P=no significant difference; P<0.001 compared with placebo). In a separate protocol, this protective effect was completely abolished by pretreatment with glibenclamide (glyburide, 5 mg), a blocker of KATP channels (n=7; FMD before IR: 12.0±2.2%; after IR: 3.2±2.1%, P<0.001). Conclusion—The present study demonstrates that subcutaneous exenatide protects IR-induced endothelial dysfunction through opening of KATP channels in human IR injury model.

Platelet reactivity in patients with chronic kidney disease receiving adjunctive cilostazol compared with a high-maintenance dose of clopidogrel: Results of the Effect of Platelet Inhibition According to Clopidogrel Dose in Patients with Chronic Kidney Disease (PIANO-2 CKD) randomized study

BACKGROUND Chronic kidney disease (CKD) is a factor of low response to clopidogrel. We sought to assess the functional impact of cilostazol in CKD patients with undergoing hemodialysis. METHODS Seventy-four patients with CKD undergoing hemodialysis and percutaneous coronary intervention were enrolled. Patients were randomly assigned to receive clopidogrel (75 mg/d [group 1, n = 24]), high-maintenance dose of clopidogrel (150 mg/d [group 2, n = 25]), or clopidogrel (75 mg/d) with cilostazol (200 mg/d [group 3, n = 25]) for 14 days. Another 50 patients with normal renal function undergoing percutaneous coronary intervention were treated with 75 mg of clopidogrel and served as the control group. Platelet function was evaluated before and after antiplatelet therapy with light transmittance aggregometry and with VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Platelet activation markers (soluble CD40 ligand and soluble P-selectin) were also assessed. RESULTS The baseline platelet function measurements were similar in the 3 groups of patients; however, the CKD groups had significantly higher platelet aggregation activity compared with the control groups. The rate of high on-treatment platelet reactivity was significantly lower in group 3 than in groups 1 and 2 (10% vs 43% vs 32%, respectively; P < .05). After 14 days of antiplatelet therapy, the changes in plasma soluble CD40 ligand and soluble P-selectin levels were significantly higher in group 3 compared with groups 1 and 2 (P < .01); however, there were no significant differences in platelet function and activation markers between groups 1 and 2. CONCLUSIONS Adjunctive cilostazol improves platelet inhibition compared with 75 or 150 mg of clopidogrel in CKD patients undergoing hemodialysis.

Green tea consumption improves endothelial function but not circulating endothelial progenitor cells in patients with chronic renal failure

This study was designed to determine the effect of green tea consumption in patients with chronic kidney disease (CKD) on flow-mediated endothelium-dependent vasodilation (FMD) and the number of circulating endothelial progenitor cells (EPCs). Forty patients with CKD requiring chronic dialysis were enrolled. The patients were divided into two groups: the catechin group that consumed green tea (5 g/day for 1 month) and the control group that consumed water. The number of EPCs, inflammatory markers, oxidative stress, and FMD were determined at baseline and 4 weeks after green tea consumption. Clinical characteristics, oxidative stress, inflammatory markers, and circulating EPCs number were not significantly different. FMD was significantly improved after 4 weeks in the catechin group (from 5.68±2.67% to 8.66±3.46%, p=0.002). Short-term green tea consumption induced a rapid improvement in FMD, but did not improve circulating EPC levels in patients with CKD.