Young Keun Ahn

Triple Versus Dual Antiplatelet Therapy in Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Background— Whether triple antiplatelet therapy is superior or similar to dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention in the era of drug-eluting stents remains unclear. Methods and Results— A total of 4203 ST-segment elevation myocardial infarction patients who underwent primary percutaneous coronary intervention with drug-eluting stents were analyzed retrospectively in the Korean Acute Myocardial Infarction Registry (KAMIR). They received either dual (aspirin plus clopidogrel; dual group; n=2569) or triple (aspirin plus clopidogrel plus cilostazol; triple group; n=1634) antiplatelet therapy. The triple group received additional cilostazol at least for 1 month. Various major adverse cardiac events at 8 months were compared between these 2 groups. Compared with the dual group, the triple group had a similar incidence of major bleeding events but a significantly lower incidence of in-hospital mortality. Clinical outcomes at 8 months showed that the triple group had significantly lower incidences of cardiac death (adjusted odds ratio, 0.52; 95% confidence interval, 0.32 to 0.84; P=0.007), total death (adjusted odds ratio, 0.60; 95% confidence interval, 0.41 to 0.89; P=0.010), and total major adverse cardiac events (adjusted odds ratio, 0.74; 95% confidence interval, 0.58 to 0.95; P=0.019) than the dual group. Subgroup analysis showed that older (>65 years old), female, and diabetic patients got more benefits from triple antiplatelet therapy than their counterparts who received dual antiplatelet therapy. Conclusions— Triple antiplatelet therapy seems to be superior to dual antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with drug-eluting stents. These results may provide the rationale for the use of triple antiplatelet therapy in these patients.

The beneficial effect of high loading dose of rosuvastatin before percutaneous coronary intervention in patients with acute coronary syndrome

BACKGROUND Statin therapy prior to percutaneous coronary intervention (PCI) is associated with reduced mortality and periprocedural myocardial injury after PCI. We studied whether single high dose statin loading is beneficial on the outcome of patients with acute coronary syndrome (ACS) underwent PCI. METHODS Consecutive 445 patients with ACS who underwent PCI were randomly assigned to either the group of no statin treatment before PCI (Control group: n=220, 63+/-11 years, male 62%) or the group of 40 mg rosuvastatin loading before PCI (Rosuvastatin group: n=225, 64+/-10 years, male 60%). Incidence of periprocedural myocardial injury was assessed by analysis of creatinine kinase-MB (CK-MB) and cardiac troponin T before PCI, at 6 h and the next morning after PCI. RESULT There were no significant differences in clinical characteristics between the two groups. After PCI, incidence of periprocedural myocardial injury was higher in control than in rosuvastatin group (11.4% versus 5.8%, p=0.035). Mean preprocedural CK-MB and high sensitivity C-reactive protein were similar between the two groups, whereas after PCI, peak values of both markers were elevated significantly higher in control than in rosuvastatin group. Multivariate analysis revealed that no prior use of statin (OR=2.2; 95% CI=1.1-4.6; p=0.029), procedural complication (OR=3.1; 95% CI=1.4-6.9; p=0.007) and multi-vessel disease (OR=2.6; 95% CI=1.0-6.6; p=0.039) were the independent predictors for periprocedural myocardial infarction. CONCLUSION Single high dose of rosuvastatin prior to PCI reduces periprocedural myocardial injury in patients with ACS.

Multiple predictors of coronary restenosis after drug-eluting stent implantation in patients with diabetes

Objectives: To identify parameters influencing the likelihood of restenosis after implantation of drug-eluting stents (DES) in patients with diabetes. Methods: Stented patients (n  =  840) with DES were retrospectively reviewed for inclusion in the study from the Multicenter PCI Database Registry. From this database, 211 (25.1%) of 840 patients with six-month angiographic follow up had diabetes. Predictors of coronary restenosis were identified with univariate and multivariate logistic regression analyses. Results: Restenosis occurred in 92 of 629 (14.6%) patients without diabetes and in 44 (20.9%) of 211 patients with diabetes (p < 0.001). Multivariate parameters for predicting restenosis in the diabetic group were current smoking (odds ratio (OR) 1.923, 95% confidence interval (CI) 1.055 to 4.725, p  =  0.036), higher C reactive protein concentration (OR 1.031, 95% CI 1.011 to 1.075, p  =  0.043), use of the paclitaxel-eluting stent (OR 2.638, 95% CI 1.338 to 5.200, p  =  0.005), longer stent length (OR 1.065, 95% CI 1.021 to 1.119, p  =  0.033), smaller reference diameter before DES implantation (OR 0.501, 95% CI 0.110 to 0.965, p  =  0.040), smaller reference diameter (OR 0.455, 95% CI 0.120 to 0.814, p  =  0.026) and minimum lumen diameter (OR 0.447, 95% CI 0.068 to 0.876, p  =  0.039) after DES implantation. Conclusion: Even with the introduction of DES, diabetes remains a significant predictor of coronary restenosis, especially in cases of a small baseline vessel size, small vessel size after percutaneous coronary intervention, longer stent length, use of the paclitaxel-eluting stent, current smoking and high C reactive protein concentration.

Preventive effects of the heparin-coated stent on restenosis in the porcine model.

The coronary stent reduces acute coronary arterial occlusion and late restenosis during and after coronary intervention. However, stent thrombosis and restenosis are still major limitations in the widespread use of the coronary stent. Local drug delivery using the heparin‐coated stent may be a new approach, which reduces the incidence of stent thrombosis and restenosis. In order to evaluate the effects of the heparin‐coated stent on stent restenosis, heparin‐coated stents were compared with control stents in a porcine coronary stent restenosis model. Stent overdilation injury (stent:artery = 1.3:1.0) was performed with bare Wiktor stents (group I, n = 10) and heparin‐coated Wiktor stents (group II, n = 20; HEPAMED, Medtronics) in porcine coronary arteries. Follow‐up quan‐titative coronary angiography (QCA) was performed at 4 weeks after stenting, and histo‐pathologic assessments of stented porcine coronary arteries were compared in both groups.

Human cord blood-derived endothelial progenitor cells and their conditioned media exhibit therapeutic equivalence for diabetic wound healing.

Transplantation of human cord blood-derived endothelial progenitor cells (EPCs) is reported to contribute to neovascularization in various ischemic diseases. However, the possible beneficial role and underlying mechanisms in diabetes-impaired wound healing have been less well characterized. In this study, EPC transplantation stimulated keratinocyte and fibroblast proliferation substantially as early as 3 days after injury, leading to significantly accelerated wound closure in streptozotocin-induced diabetic nude mice, compared to PBS control. RT-PCR analysis showed that EPCs secreted various wound healing-related growth factors. Among them, keratinocyte growth factor and platelet-derived growth factor were highly expressed in the EPCs and were present at substantial levels in the EPC-injected dermal tissue. Using EPC-conditioned medium (CM), we found that paracrine factors from EPCs directly exerted mitogenic and chemotactic effects on keratinocytes and fibroblasts. Moreover, injection of EPC-CM alone into the same diabetic wound mice promoted wound healing and increased neovascularization to a similar extent as achieved with EPC transplantation. These results indicate that the beneficial effect of EPC transplantation on diabetic wounds was mainly achieved by their direct paracrine action on keratinocytes, fibroblasts, and endothelial cells, rather than through their physical engraftment into host tissues (vasculogenesis). In addition, EPC-CM was shown to be therapeutically equivalent to EPCs, at least for the treatment of diabetic dermal wounds, suggesting that conditioned medium may serve as a novel therapeutic option that is free from allograft-associated immune rejection concern.

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.

Obesity paradox in Korean patients undergoing primary percutaneous coronary intervention in ST-segment elevation myocardial infarction

The effect of body mass index (BMI) on outcomes after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is not well known. In patients registered in the Korean Acute Myocardial Infarction Registry (KAMIR) between November 2005 and November 2007, 3824 STEMI patients who arrived at hospital within 12h after onset of chest pain and underwent primary PCI were analyzed, and divided into four groups according to their BMI: underweight (BMI<18.5 kg/m(2), n=129); normal weight (18.5 < or =BMI <23.0 kg/m(2), n=1253); overweight (23.0 < or =BMI <27.5 kg/m(2), n=1959); and obese (BMI > or =27.5 kg/m(2), n=483). In-hospital mortality, revascularization in 1 year, mortality in 1 year, and overall mortality were compared between groups. Overweight and obese group were significantly younger, had normal left ventricular ejection fraction, and were more likely to be men with a higher incidence of hypertension, diabetes, and hyperlipidemia. There were no significant differences in symptom-to-door time and door-to-balloon time between groups. Obese patients had significantly lower in-hospital and overall mortalities. Major adverse cardiac events showed a bimodal pattern. Obese STEMI patients treated with primary PCI were associated with lower mortality, which may be explained by better use of medical treatment, hemodynamic stability, and younger age.

Are patients with angiographically near-normal coronary arteries who present as acute myocardial infarction actually safe?

BACKGROUND There is a paucity of data concerning the clinical outcome of patients presenting with acute myocardial infarction (AMI) and near-normal coronary angiograms. The purpose of this study was to evaluate the clinical outcome and the prognosis of the patients with near-normal coronary angiograms who were registered in the Korean Acute Myocardial Infarction Registry (KAMIR). METHODS The subjects were divided into three groups according to findings from coronary angiograms performed between September 2005 and November 2006. Among 8510 consecutive AMI patients, 372 patients (Group I) had near-normal coronary arteries, 6136 patients (Group II) had one- or two-vessel disease, and 2002 patients (Group III) had three-vessel or left main disease. RESULTS Clinical characteristics, in-hospital mortality, and major cardiac adverse events (MACE) were analyzed. Group I was younger, had the lower prevalence of DM, and showed the higher percentage of previous angina history compared to the other two groups. Group III showed a higher incidence of in-hospital mortality, but there was no significant difference between Group I and Group II (2.6% in Group II and 2.2% in Group I, p=0.952). Furthermore, MACE at 1 month, 6 months and 12 months revealed no significant difference between Groups I and II (12 month MACE: 7.8% in Group I and 12.2% in Group II, p=0.359). CONCLUSIONS Patients with near-normal coronary angiograms had similar clinical outcomes and prognosis compared with one- or two-vessel diseased patients presenting with an acute myocardial infarction.

Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways

Here we show that the effect of hypoxia on human umbilical cord blood mesenchymal stem cell (hMSC) migration is via the modulation of focal adhesion kinase (FAK) and its related signaling pathways. Hypoxia increased hMSC migration and cell viability, whereas lactate dehydrogenase (LDH) release was not affected for up to 48 h (data not shown). In addition, hypoxia increased the level of reactive oxygen species (ROS) generation in a time-dependent manner. Hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) were inhibited by the antioxidant (N-acetylcysteine, NAC, 10(-6) M) and (taurine, 4x10(-6) M). Hypoxia-induced endothelial nitric oxide synthase (eNOS) phosphorylation was regulated by p38 MAPK and SAPK/JNK activation. In addition, hypoxia increased the level of hypoxia inducible factor (HIF)-1alpha expression, which was blocked by inhibition of eNOS. Also, hypoxia-induced expression of Flk-1, vascular endothelial growth factor (VEGF), and its secreted form were inhibited by HIF-1alpha small interfering RNA (siRNA). In this hypoxic condition, FAK and Src phosphorylation were increased in a time-dependent manner. Inhibition of Src with specific inhibitor (PP2, 10(-8) M) blocked hypoxia-induced FAK activation. Subsequently, hypoxia-induced FAK phosphorylation was blocked by VEGF siRNA. Finally, hypoxia-induced increase of hMSC migration was inhibited by FAK siRNA. The results indicate that hypoxia increases migration of hMSCs via VEGF-mediated FAK phospholylation and involves the cooperative activity of the ROS, MAPK, eNOS and HIF-1alpha pathways.

Clinical outcomes and optimal treatment for stent fracture after drug-eluting stent implantation.

BACKGROUND Many studies have suggested that in the era of drug-eluting stents (DES) one of the causes of in-stent restenosis is stent fracture (SF). Yet there have been few studies of the major adverse cardiac events and treatment of DES SF. METHODS AND RESULTS From September 2003 to May 2008, 3365 patients received successful stent implantation with DES, of whom 1009 patients underwent a follow-up coronary angiography irrespective of symptoms. Seventeen SFs were detected in 15/1009 patients (1.5%). All SF patients were continued on medication with combination antiplatelet therapy, regardless of angina symptoms. If in-stent restenosis at the fractured site was significant, we performed coronary interventions even in patients without ischemic symptoms. Patients were treated with heterogenous DES for restenosis lesions (5/8 patients), and the rest were treated with either homogenous DES (2 patients), or plain old balloon angioplasty (1 patient) or medical treatment (7 patients). None of the SF patients suffered from cardiac death during a follow-up period of 20.4+/-12.3 months. CONCLUSION If patients with SF were continued on combination antiplatelet therapy irrespective of ischemic symptoms, there would occur a low rate of major adverse cardiac events, especially cardiac death associated with SF.