Seung-Hwan Lee

Comparison of the Efficacy and Safety of Zotarolimus-, Sirolimus-, and Paclitaxel-Eluting Stents in Patients With ST-Elevation Myocardial Infarction

Drug-eluting stents (DESs) are increasingly used for treatment of acute ST-segment elevation myocardial infarction (STEMI), but there are few comparisons of outcomes of various types of DES. We compared the efficacy and safety of zotarolimus-eluting stents (ZESs), sirolimus-eluting stents (SESs), and paclitaxel-eluting stents (PESs) in primary intervention for STEMI. This multicenter, prospectively randomized ZEST-AMI trial included 328 patients at 12 medical centers who were randomly assigned to ZES (n = 108), SES (n = 110), or PES (n = 110) deployment. The primary end point was major adverse cardiac events (death, MI, and ischemia-driven target vessel revascularization) at 12 months. Secondary end points included the individual components of the primary end point, late loss, angiographic restenosis, and stent thrombosis. Baseline clinical and angiographic characteristics were well matched. In-segment late loss (0.28 +/- 0.42 vs 0.46 +/- 0.48 vs 0.47 +/- 0.50 mm, respectively, p = 0.029) and restenosis rate (2.7% vs 15.9% vs 12.3%, respectively, p = 0.027) at 8 months were lowest in the SES group compared to the ZES and PES groups. At 12 months, cumulative incidence rates of primary end points in the ZES, SES, and PES groups were 11.3%, 8.2%, and 8.2%, respectively (p = 0.834). There were 2 acute (in the SES group) and 5 subacute (2 in the SES group and 3 in the PES group) stent thromboses. Incidence of death, recurrent MI, or ischemia-driven target vessel revascularization did not differ among the 3 groups. In conclusion, despite the difference in restenosis rate, the efficacy and safety of the 3 different DESs showed similar, acceptable results in the treatment of STEMI.

Deficiency of developmental endothelial locus-1 (Del-1) aggravates bleomycin-induced pulmonary fibrosis in mice.

Pulmonary fibrosis is a lung disease wherein lung parenchyma is gradually and irreversibly replaced with collagen. The molecular pathogenesis of pulmonary fibrosis is not fully understood and the only effective treatment available is lung transplantation. To test if Del-1, an endogenous anti-inflammatory molecule, may be implicated in the development of pulmonary fibrosis, we induced pulmonary fibrosis in wild type (WT) and Del-1(-/-) mice by intratracheal administration of bleomycin. Del-1 expression in the lung was decreased in the WT mice treated with bleomycin compared to control mice. In addition, bleomycin-induced pulmonary fibrosis increased collagen deposition and TGF-β production in the lung of Del-1(-/-) mice. Finally, Del-1(-/-) mice treated with bleomycin displayed higher weight loss and greater mortality than did WT mice identically treated. These findings suggest that Del-1 may negatively regulate development of pulmonary fibrosis. Further delineation of a role for Del-1 in the development of pulmonary fibrosis will broaden our understanding of the molecular pathogenesis of this disease and hopefully help develop potential therapeutics.

Expression of HMG-CoA reductase in human coronary atherosclerotic plaques and relationship to plaque destabilisation

Background Little is known about hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase expression in human coronary atherosclerotic plaques. Objective To investigate the expression of HMG-CoA reductase in coronary atherectomy tissues obtained from patients with unstable and stable angina and examine the relationship of HMG-CoA with plaque instability. Methods Atherectomy specimens were obtained from 43 patients with unstable (n=22) or stable (n=21) angina who underwent directional coronary atherectomy for de novo coronary artery lesions. The specimens were stained with haematoxylin–eosin and incubated with antibodies specific to HMG-CoA reductase, macrophages, smooth muscle cells and endothelial cells. Histology and immunohistochemistry data were morphometrically evaluated using an image-analysing system. Results Baseline characteristics were similar between the two groups. Immunopositive areas of HMG-CoA reductase, macrophages, endothelial cells and thrombi were significantly greater in patients with unstable angina than those in patients with stable angina. However, the immunopositive area of smooth muscle cells was not different between the two groups. Macrophage-positive areas correlated well with areas of HMG-CoA reductase in patients with unstable angina (r=0.72, p<0.001), but not in patients with stable angina (r=0.02, p=0.937). Conclusion HMG-CoA reductase was present in coronary atherosclerotic plaques and was more commonly expressed in unstable plaques than in stable plaques. Local HMG-CoA reductase in coronary artery lesions may contribute to plaque instability.

Effects of Diabetic Macular Edema on Repeatability of Retinal Nerve Fiber Layer Thickness Measurements at the Macular and Peripapillary Area Using Swept-Source Optical Coherence Tomography.

ABSTRACT Purpose: To investigate the repeatability of macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements made using swept-source optical coherence tomography (SS-OCT) and automated segmentation. Measurements were made in non-diabetic controls and in patients with diabetic retinopathy (DR) with or without diabetic macular edema (DME). Materials and Methods: A total of 131 eyes of 131 participants were included. Fifty-one eyes with DR had no DME (DME[–]), 45 eyes with DR had DME (DME[+]), and 35 eyes were healthy. Measurements of RNFL and full retinal thickness were simultaneously obtained with SS-OCT in the peripapillary area and in the nine Early Treatment Diabetic Retinopathy Study (ETDRS) subfields using the wide three-dimensional mode. All measurements were made twice on the same day by a single examiner to test intra-observer repeatability. Intraclass correlation coefficients (ICCs) and coefficients of repeatability were examined to evaluate repeatability. Results: Average macular and temporal peripapillary RNFL thickness values were greater in the DME[+] group (36.4 ± 13.2 and 83.8 ± 19.4 µm, respectively) than in the control (27.4 ± 3.5 and 73.5 ± 11.4 µm, respectively) and DME[–] (27.9 ± 3.4 µm and 70.3 ± 11.3 µm, respectively) groups (both P < 0.001). The ICCs of average macular (control: 0.982, DME[–]: 0.913, and DME[+]: 0.970) and peripapillary (control: 0.972, DME[–]: 0.973, and DME[+]: 0.958) RNFL thickness measurements indicated good repeatability in all three study groups. Conclusions: Although the ICCs of average RNFL thickness measurements were relatively lower in eyes with DR than in healthy controls, the intra-observer repeatability of SS-OCT RNFL and full retinal thickness measurements is sufficiently reliable for them to be clinically useful.

Developmental endothelial locus-1 inhibits MIF production through suppression of NF-κB in macrophages.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that regulates leukocyte recruitment, thereby playing a pivotal role in the regulation of innate and adaptive immunity and tumor progression. Elevated levels of MIF are associated with numerous inflammatory disorders and cancers. To determine whether developmental endothelial locus-1 (Del-1) regulated MIF, RAW264.7 macrophages were treated with Del-1 and assessed using ELISA. The results showed that MIF was downregulated in macrophages by Del-1, an endogenous anti-inflammatory protein that was previously shown to limit leukocyte adhesion and migration. Treatment of RAW264.7 macrophages with Del-1 inhibited constitutive and lipopolysaccharide (LPS)-induced MIF secretion. Recombinant Del-1 protein attenuated the phosphorylation of IκBα induced by a relatively low concentration of LPS in THP-1 monocytes, but did not inhibit IκBα phosphorylation in response to a relatively high concentration of LPS. Concomitantly, translocation of NF-κB to the nucleus was inhibited by Del-1 in LPS-activated macrophages. In addition, conditioned medium harvested from cells transfected with a Del-1 expression plasmid suppressed NF-κB activation in response to relatively low concentrations of TNF-α, albeit not the activation that was induced by a relatively high concentration of TNF-α. On the other hand, although Del-1 enhanced the macrophage expression of p53, a known negative regulator of MIF production, MIF production was not significantly affected by the level of p53 in mouse bone marrow-derived macrophages. These findings suggested that Del-1 controls NF-κB-activated MIF production in macrophages, and the potential application of Del-1 to therapeutic modalities for chronic inflammation-associated cancers.

Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation

SUMMARY Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity.

Developmental endothelial locus-1 prevents development of peritoneal adhesions in mice

Postoperative peritoneal adhesions, fibrous bands formed in the peritoneal cavity following surgery, represent a common, challenging and costly problem faced by surgeons and patients, for which effective therapeutic options are lacking. Since aberrant inflammation is one of the key mechanisms underlying peritoneal adhesion formation, here we set out to study the role of developmental endothelial locus-1 (Del-1), which has been recently identified as an endogenous inhibitor of inflammation, in the formation of postoperative peritoneal adhesions using a mouse model of peritoneal adhesions induced by ischemic buttons. Del-1-deficient mice had a higher incidence of adhesions, and their adhesions had higher quality and tenacity scores. Del-1 deficiency also led to enhanced inflammation mediators and collagen production. Finally, Del-1 supplementation decreased the incidence and severity of postoperative peritoneal adhesions. Taken together, these results indicate a protective role for Del-1 in postoperative peritoneal adhesion formation.