Sang Eun Lee

Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes.

Human resistin is a cytokine that induces low-grade inflammation by stimulating monocytes. Resistin-mediated chronic inflammation can lead to obesity, atherosclerosis, and other cardiometabolic diseases. Nevertheless, the receptor for human resistin has not been clarified. Here, we identified adenylyl cyclase-associated protein 1 (CAP1) as a functional receptor for human resistin and clarified its intracellular signaling pathway to modulate inflammatory action of monocytes. We found that human resistin directly binds to CAP1 in monocytes and upregulates cyclic AMP (cAMP) concentration, protein kinase A (PKA) activity, and NF-κB-related transcription of inflammatory cytokines. Overexpression of CAP1 in monocytes enhanced the resistin-induced increased activity of the cAMP-dependent signaling. Moreover, CAP1-overexpressed monocytes aggravated adipose tissue inflammation in transgenic mice that express human resistin from their monocytes. In contrast, suppression of CAP1 expression abrogated the resistin-mediated inflammatory activity both in vitro and in vivo. Therefore, CAP1 is the bona fide receptor for resistin leading to inflammation in humans.

Adipokine resistin is a key player to modulate monocytes, endothelial cells, and smooth muscle cells, leading to progression of atherosclerosis in rabbit carotid artery.

OBJECTIVES We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms. BACKGROUND Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified. METHODS We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed. RESULTS Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Peri-adventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 × vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo. CONCLUSIONS Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis.

Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis : A Network Meta-Analysis of 11 Randomized, Controlled Trials

OBJECTIVES A Bayesian network meta-analysis was performed comparing the efficacy and safety of drug-eluting balloons (DEB), drug-eluting stents (DES), or plain old balloon angioplasty (POBA) for treatment of in-stent restenosis (ISR). BACKGROUND Optimal treatment options for ISR have not been well established. METHODS Randomized, controlled trials comparing DEB, DES, and POBA for the treatment of ISR after percutaneous coronary intervention with bare metal stent or DES were included. The primary outcome was target lesion revascularization (TLR). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. RESULTS This analysis included 2,059 patients from 11 RCTs. The risk of TLR was markedly lower in patients treated with DEB (OR: 0.22, 95% CrI: 0.10 to 0.42) or DES (OR: 0.24, 95% CrI: 0.11 to 0.47) than in those treated with POBA in a random-effects model. In a comparison of DEB and DES, the risk of TLR (OR: 0.92, 95% CrI: 0.43 to 1.90) was similar. The risk of MI or all-cause mortality was lowest in the DEB group compared with the DES and POBA groups, which did not meet statistical significance. The risk of major adverse cardiac events, which was mainly driven by TLR, was also significantly lower in the DEB or and DES group (OR: 0.28, 95% CrI: 0.14 to 0.53) than in the POBA group, but it was similar between the DEB and DES groups (OR: 0.84, 95% CrI: 0.45 to 1.50). The probability of being ranked as the best treatment was 59.9% (DEB), 40.1% (DES), and 0.1% (POBA) in terms of TLR, whereas it was 63.0% (DEB), 35.3% (POBA), and 1.7% (DES) in terms of MI. CONCLUSIONS Local drug delivery by DEB or DES for ISR lesions was markedly better than POBA in preventing TLR, but not for MI or mortality. Among the 2 different strategies of drug delivery for ISR lesions, treatment with DEB showed a trend of less development of MI than did treatment with DES.

A multicentre cohort study of acute heart failure syndromes in Korea: Rationale, design, and interim observations of the Korean Acute Heart Failure (KorAHF) registry

The Korean Acute Heart Failure registry (KorAHF) aims to evaluate the clinical characteristics, management, hospital course, and long‐term outcomes of patients hospitalized for acute heart failure syndrome (AHFS) in Korea.

CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages

Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82(-/-) mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC(+) BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.

Improvement of hyponatraemia during hospitalisation for acute heart failure is not associated with improvement of prognosis: an analysis from the Korean Heart Failure (KorHF) registry

Objective Hyponatraemia predicts poor prognosis in patients hospitalised for acute heart failure (AHF). Yet, the association of hyponatraemia improvement with better postdischarge outcome has not been elucidated. Here, we determined the clinical impact of hyponatraemia improvement during hospitalisation on postdischarge outcome in patients admitted for AHF. Design Prospective cohort study. Setting Nation-wide twenty-four academic hospitals in Korea (mean follow-up of 1.7 years after discharge). Patients 2888 patients hospitalised for AHF. Main outcome measures Primary endpoints were composite of death or rehospitalisation due to heart failure. Results Hyponatraemia was present in 575 of total 2888 patients hospitalised for AHF at admission. Hyponatraemia was normalised in 274 patients (47.7%) at discharge. During mean follow-up of 1.7 years total 735 rehospitalisations and 397 deaths were documented. Persistent hyponatraemia during hospitalisation was significantly associated with increased incidence of composite endpoint of death or rehospitalisation in multivariate analysis compared with normonatraemia at admission (HR 1.345, 95% CI 1.075 to 1.683, p=0.010). However, improvement of hyponatraemia during hospitalisation was not significantly associated with lower incidence of composite endpoint of death or rehospitalisation in multivariate analysis (HR 1.084, 95% CI 0.709 to 1.659, p=0.709). Improved hyponatraemia was not associated with better prognosis in analysis with propensity score matching, either (HR 1.111, 95% CI 0.588 to 2.100, p=0.746). Conclusions In patients hospitalised for AHF, hyponatraemia on admission is associated with a worse prognosis compared with normonatraemia, irrespective of whether hyponatraemia improves during hospitalisation.

Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.

BACKGROUND Angiotensin receptor blockers (ARBs) is an effective and well tolerated first-line antihypertensive drug. Fimasartan is a newly developed ARB that has not been compared with other ARBs with regard to its efficacy and tolerability. OBJECTIVE The goal of this study was to determine the noninferiority of fimasartan to losartan with regard to its efficacy and tolerability in adult Korean patients with mild-to-moderate hypertension. METHODS This was a randomized, multicenter, double-blind, parallel group, dose escalation, Phase III, noninferiority clinical trial. Patients aged 18 to 70 years with mild-to-moderate hypertension were randomized to receive either fimasartan 60/120 mg daily or losartan 50/100 mg daily with optional titration. Antihypertensive efficacy and tolerability were evaluated for 12 weeks. The primary end point was noninferiority of improvement in mean siDBP from baseline to week 12 for fimasartan compared with losartan. The incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were evaluated to assess their tolerability. In addition, some patients whose blood pressure reached goal levels participated in a 24-week extension study for additional assessment of tolerability and efficacy. RESULTS Five hundred six patients were randomly allocated to receive fimasartan (n = 256) or losartan (n = 250). There was no significant difference in baseline demographic characteristics between the 2 treatment groups (fimasartan-treated group-mean age, 53.96 [8.79] years; mean weight, 70.58 [11.73] kg; male, 68.02%; losartan-treated group-mean age, 53.58 [9.61] years; mean weight, 69.80 [11.08] kg; male, 70.17%). At week 12, siDBP was significantly decreased from baseline in both groups (-11.26 [7.53] mm Hg in the fimasartan group and -8.56 [7.72] mm Hg in the losartan group [P < 0.0001]). The between-group difference was 2.70 mm Hg (P = 0.0002), and the lower limit of the 2-sided 95% CI (1.27 mm Hg) was higher than the prespecified noninferiority margin (-2.5 mm Hg). The incidence of ADRs were 7.84% and 10.40% in the fimasartan and losartan groups, respectively (χ(2) test, P = 0.3181). The efficacy of fimasartan was maintained over 24 weeks, and its tolerability was comparable with losartan in the extension study. CONCLUSIONS In this study with eligible adult Korean patients who had mild-to-moderate hypertension, the reduction of siDBP after 12 weeks of treatment with fimasartan 60/120 mg was noninferior to that of losartan 50/100 mg. By post hoc comparison, between-group differences in siDBP were significant in favor of fimasartan, suggesting superiority to losartan. There was no statistically significant difference in tolerability between the groups. This efficacy and tolerability were maintained throughout the additional 12-week extension study.

G-CSF exerts dual effects on endothelial cells—Opposing actions of direct eNOS induction versus indirect CRP elevation

Granulocyte-colony stimulating factor (G-CSF) has been shown to have protective effects in the heart and brain. However, it may also be involved in the acute inflammatory response which may be harmful. The effects of G-CSF on endothelial cells (ECs) and the vasculature are mostly unknown. To study the possible dual effects of G-CSF on ECs, we investigated whether G-CSF induces release of C-reactive protein (CRP) by hepatocytes and whether the direct beneficial effects of G-CSF could protect ECs from the detrimental effects of CRP. G-CSF treatment significantly induced monocytes to produce IL-6, and culture supernatants of G-CSF-stimulated monocytes induced CRP production in hepatocytes. On the other hand, G-CSF directly promoted EC proliferation and migration and reversed the deleterious effects of CRP. In mechanistic analyses, G-CSF increased not only the protein expression of endothelial nitric oxide synthase (eNOS), but also its transcription. Furthermore, it enhanced eNOS phosphorylation and activation, leading to increased production of NO. Thus, G-CSF reversed the attenuated production of NO by CRP. These effects of G-CSF on eNOS transcription, translation, and activation were blunted by the PI3K inhibitor, suggesting that EC protective effects of G-CSF were associated with the activation of the Akt/eNOS pathway. In conclusion, although G-CSF induces an inflammatory reaction leading to CRP production, it has direct beneficial effects protecting ECs from the deleterious effects of CRP through activation of Akt/eNOS pathway, leading to an increase in NO production. Our data suggests that G-CSF may exert dual opposing effects on endothelial cells.

Clinical Characteristics and Outcome of Acute Heart Failure in Korea: Results from the Korean Acute Heart Failure Registry (KorAHF)

Background and Objectives The burden of heart failure has increased in Korea. This registry aims to evaluate demographics, clinical characteristics, management, and long-term outcomes in patients hospitalized for acute heart failure (AHF). Subjects and Methods We prospectively enrolled a total of 5625 consecutive subjects hospitalized for AHF in one of 10 tertiary university hospitals from March 2011 to February 2014. Descriptive statistics were used to determine the baseline characteristics of the study population and to compare them with those from other registries. Results The mean age was 68.5±14.5 years, 53.2% were male, and 52.2% had de novo heart failure. The mean systolic and diastolic blood pressures were 131.2±30.3 mmHg and 78.6±18.8 mmHg at admission, respectively. The left ventricular ejection fraction was ≤40% in 60.5% of patients. Ischemia was the most frequent etiology (37.6%) and aggravating factor (26.3%). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and aldosterone antagonists were prescribed in 68.8%, 52.2%, and 46.6% of the patients at discharge, respectively. Compared with the previous registry performed in Korea a decade ago, extracorporeal membrane oxygenation (ECMO) and heart transplantation have been performed more frequently (ECMO 0.8% vs. 2.8%, heart transplantation 0.3% vs. 1.2%), and in-hospital mortality decreased from 7.6% to 4.8%. However, the total cost of hospital care increased by 40%, and one-year follow-up mortality remained high. Conclusion While the quality of acute clinical care and AHF-related outcomes have improved over the last decade, the long-term prognosis of heart failure is still poor in Korea. Therefore, additional research is needed to improve long-term outcomes and implement cost-effective care.

Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials

Background There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI. Methods and Results Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I2 = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I2 = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I2 = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein. Conclusions High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.