SCI 발표논문

1. 30282020

   제1저자 기유정 · 교신저자 박경우

   Ki YJ, Park KW, Kang J, Kim CH, Han JK, Yang HM, Kang HJ, Koo BK, Kim HS

   Safety and Efficacy of Second-Generation Drug-Eluting Stents in Real-World Practice: Insights from the Multicenter Grand-DES Registry.

   J Interv Cardiol. 2020;2020:3872704.

   Abstract

   OBJECTIVE In this study, we sought to compare the efficacy and safety of the Xience Prime/Xience V/Promus EES and Biomatrix/Biomatrix Flex/Nobori BES with resolute integrity/resolute ZES using the grand drug-eluting stent (Grand-DES) registry.

   BACKGROUND Currently, new-generation drug-eluting stents (DESs) are used as the standard of care in patients undergoing percutaneous coronary intervention. No study has simultaneously compared everolimus-eluting stent (EES), biolimus-eluting stent (BES), and zotarolimus-eluting stent (ZES).

   METHODS Stent-related composite outcomes (target lesion failure) and patient-related composite outcomes were compared in crude and propensity score-matched analysis.

   RESULTS Of the 17,286 patients in the Grand-DES group, 5,137, 2,970, and 4,990 patients in the EES, BES, and ZES groups completed a three-year follow-up. In the propensity score-matched cohort, the stent-related outcome (EES vs. BES vs. ZES; 5.9% vs. 6.7% vs. 7.1%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%.

   CONCLUSIONS In this robust real-world registry with unrestricted use of EES, BES, and ZES, the three stent groups showed comparable safety and efficacy at the 3-year follow-up.

   PubMed IF 1.4 순환기내과
2. 30272020

   제1저자 조준환 · 교신저자 조현재

   Cho JH, Cho HJ, Lee HY, Ki YJ, Jeon ES, Hwang KK, Chae SC, Baek SH, Kang SM, Choi DJ, Yoo BS, Kim KH, Kim JJ, Oh BH

   Neutrophil-Lymphocyte Ratio in Patients with Acute Heart Failure Predicts In-Hospital and Long-Term Mortality.

   J Clin Med. 2020;9(2):jcm9020557.

   Abstract

   The application of a simple blood test to predict prognosis in acute heart failure (AHF) patients is not well established. Neutrophil-lymphocyte ratio (NLR) is inexpensive and easy to obtain in hospitalized patients using a routine blood test. We evaluate the prognostic implications of NLR as an independent predictor of in-hospital and long-term mortality in AHF patients. Among 5625 patients enrolled in the Korean Acute Heart Failure registry, 5580 patients were classified into quartiles by their NLR level, and analyzed for in-hospital and post-discharge three-year mortality. Patients in the highest NLR quartile had the highest in-hospital and post-discharge three-year mortality. The same results were seen by dividing the aggravating factor into the infection or ischemia group and the non-infection or non-ischemia group. For patients aggravated from infection or ischemia, a cut-off NLR value was 7.0 that increase the risk of in-hospital and post-discharge three-year mortality. In subgroups of patients not aggravated from infection or ischemia, a cut-off NLR value was 5.0 that increase the risk of in-hospital and post discharge three-year mortality. Elevated NLR in AHF patients at the index hospitalization is an independent predictor for in-hospital and post-discharge three-year mortality. Taken together, NLR is a marker for risk assessment of AHF patients.

   PubMed IF 3.3 순환기내과
3. 30262020

   제1저자 오규철 · 교신저자 이해영

   Oh GC, Cho HJ, Lee SE, Kim MS, Kim JJ, Choi JO, Jeon ES, Hwang KK, Chae SC, Baek SH, Kang SM, Yoo BS, Choi DJ, Ahn Y, Kim KH, Cho MC, Oh BH, Lee HY

   Management and Prognosis of Heart Failure in Octogenarians: Final Report from the KorAHF Registry.

   J Clin Med. 2020;9(2):jcm9020501.

   Abstract

   Treatment of heart failure (HF) in the elderly face many difficulties due to lack of robust evidence. We analyzed the outcome of HF in octogenarians using a nationwide HF registry. Among 5625 patients from the Korean Acute Heart Failure (KorAHF) registry, prognosis of octogenarian HF and the association of guideline-directed medical therapy (GDMT) with mortality and readmissions were analyzed. Octogenarian patients (1185, 22.4%) showed a higher mortality, and males were especially at increased risk (HR (hazard ratio) 1.19, 95% CI 1.01-1.40). A J-curve association between blood pressure (BP) and mortality was observed regardless of age, but the nadir value was lower in octogenarians (123.8 vs. 127.9 mmHg for systolic blood pressure (SBP); 67.1 vs. 73.9 mmHg for diastolic blood pressure (DBP), p < 0.001). Use of GDMT in octogenarian patients with HF and reduced ejection fraction (EF) were inadequate (74.3%, 47.1%, and 46.1% in octogenarians vs. 78.4%, 59.8%, and 55.2% in non-elderly for renin-angiotensin system inhibitors, beta-blockers, and aldosterone antagonists, respectively; all p < 0.05). However, those on medications had a significant reduction in 6 month mortality. For octogenarians with HF and preserved EF, angiotensin receptor blocker use reduced hospitalizations for HF in men (HR 0.19, 95% CI 0.04-0.87), but not in women (p-interaction = 0.037). HF in octogenarians were found to have different characteristics compared with the non-elderly. However, adequate use of GDMT was still associated with improved survival, and more attention should be given to prescribing medications with clinical benefits.

   PubMed IF 3.3 순환기내과
4. 30252020

   제1저자 박찬순, 박준빈 · 교신저자 조구영

   Park CS^*, Park JB^*, Park JJ, Park JH, Cho GY

   Impact of sex and myocardial function on association of obesity with mortality in Asian patients with acute heart failure: a retrospective analysis from the STRATS-AHF registry.

   BMJ Open. 2020;10(2):e031608.

   Abstract

   OBJECTIVES Impact of sex and myocardial function on the obesity paradox in heart failure (HF) is unknown. We explored whether sex, myocardial function, and left ventricular (LV) geometry explains the protective association of body mass index (BMI) with mortality, and investigated whether metabolic health status affects this association.

   DESIGN A multicentre cohort study with patients with acute HF admitted from January 2009 to December 2016 with a median follow-up of 33.7 months.

   SETTING Three tertiary hospitals.

   PARTICIPANTS A total of 2021 overweight-to-obese (OW) and 1543 normal-weight (NW) patients with acute HF.

   MEASUREMENTS The primary outcome was all-cause mortality. Patients were categorised as either OW (BMI≥23kg/m²) or NW (BMI<23kg/m²). BMI was used as both categorical and continuous variables. Clinical, laboratory and echocardiographic measures, including LV global longitudinal strain (LV-GLS), LV-ejection fraction, LV geometry, were obtained.

   RESULTS During the follow-up period, 1392 patients died (685 OW and 707 NW). BMI was significantly associated with mortality in univariate (HR=0.929 per kg/m², p<0.001) and multivariate analyses (HR=0.954 per kg/m², p<0.001). In multivariable fractional polynomials, higher BMIs were associated with lower mortality overall and in subgroups by sex, LV-GLS and LV geometry, with a steeper association in men (p-interaction <0.001). In women, there were significant interactions of BMI with LV-GLS (p-interaction=0.044) and age (p-interaction=0.040) for mortality; the protective association of BMI with mortality was confined to subgroups with high LV-GLS (>10.1%) or elderly patients (≥75 years). In men, this association was found in all subgroups without significant interaction. Metabolically healthy obese patients had better survival than metabolically unhealthy obese patients (log-rank p<0.001).

   CONCLUSIONS In women, a significant interaction was observed between BMI and age or LV-GLS in association with mortality, suggesting that sex, ageing and myocardial dysfunction can affect the magnitude of the obesity paradox in HF. Metabolic health status provides prognostic information beyond obesity status.

   TRIAL REGISTRATION NUMBER Registry: ClinicalTrials.gov Number: NCT03513653 (https://clinicaltrials.gov/ct2/show/NCT03513653).

   PubMed IF 2.5 순환기내과
5. 30242020

   제1저자 서원우, 박진주 · 교신저자 최동주

   Seo WW^*, Park JJ^*, Park HA, Cho HJ, Lee HY, Kim KH, Yoo BS, Kang SM, Baek SH, Jeon ES, Kim JJ, Cho MC, Chae SC, Oh BH, Choi DJ

   Guideline-directed medical therapy in elderly patients with heart failure with reduced ejection fraction: a cohort study.

   BMJ Open. 2020;10(2):e030514.

   Abstract

   OBJECTIVES AND DESIGN Guideline-directed medical therapy (GDMT) with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved survival in patients with heart failure with reduced ejection fraction (HFrEF). As clinical trials usually do not include very old patients, it is unknown whether the results from clinical trials are applicable to elderly patients with HF. This study was performed to investigate the clinical characteristics and treatment strategies for elderly patients with HFrEF in a large prospective cohort.

   SETTING The Korean Acute Heart Failure (KorAHF) registry consecutively enrolled 5625 patients hospitalised for acute HF from 10 tertiary university hospitals in Korea.

   PARTICIPANTS In this study, 2045 patients with HFrEF who were aged 65 years or older were included from the KorAHF registry.

   PRIMARY OUTCOME MEASUREMENT All-cause mortality data were obtained from medical records, national insurance data or national death records.

   RESULTS Both beta-blockers and RAS inhibitors were used in 892 (43.8%) patients (GDMT group), beta-blockers only in 228 (11.1%) patients, RAS inhibitors only in 642 (31.5%) patients and neither beta-blockers nor RAS inhibitors in 283 (13.6%) patients (no GDMT group). With increasing age, the GDMT rate decreased, which was mainly attributed to the decreased prescription of beta-blockers. In multivariate analysis, GDMT was associated with a 53% reduced risk of all-cause mortality (HR 0.47, 95% CI 0.39 to 0.57) compared with no GDMT. Use of beta-blockers only (HR 0.57, 95% CI 0.45 to 0.73) and RAS inhibitors only (HR 0.58, 95% CI 0.48 to 0.71) was also associated with reduced risk. In a subgroup of very elderly patients (aged ≥80 years), the GDMT group had the lowest mortality.

   CONCLUSIONS GDMT was associated with reduced 3-year all-cause mortality in elderly and very elderly HFrEF patients.

   TRIAL REGISTRATION NUMBER NCT01389843.

   PubMed IF 2.5 순환기내과
6. 30232020

   제1저자 강민우 · 교신저자 한승석

   Kang MW, Kim J, Kim DK, Oh KH, Joo KW, Kim YS, Han SS

   Machine learning algorithm to predict mortality in patients undergoing continuous renal replacement therapy.

   Crit Care. 2020;24(1):42.

   Abstract

   BACKGROUND Previous scoring models such as the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scoring systems do not adequately predict mortality of patients undergoing continuous renal replacement therapy (CRRT) for severe acute kidney injury. Accordingly, the present study applies machine learning algorithms to improve prediction accuracy for this patient subset.

   METHODS We randomly divided a total of 1571 adult patients who started CRRT for acute kidney injury into training (70%, n = 1094) and test (30%, n = 477) sets. The primary output consisted of the probability of mortality during admission to the intensive care unit (ICU) or hospital. We compared the area under the receiver operating characteristic curves (AUCs) of several machine learning algorithms with that of the APACHE II, SOFA, and the new abbreviated mortality scoring system for acute kidney injury with CRRT (MOSAIC model) results.

   RESULTS For the ICU mortality, the random forest model showed the highest AUC (0.784 [0.744-0.825]), and the artificial neural network and extreme gradient boost models demonstrated the next best results (0.776 [0.735-0.818]). The AUC of the random forest model was higher than 0.611 (0.583-0.640), 0.677 (0.651-0.703), and 0.722 (0.677-0.767), as achieved by APACHE II, SOFA, and MOSAIC, respectively. The machine learning models also predicted in-hospital mortality better than APACHE II, SOFA, and MOSAIC.

   CONCLUSION Machine learning algorithms increase the accuracy of mortality prediction for patients undergoing CRRT for acute kidney injury compared with previous scoring models.

   PubMed IF 11.4 신장내과
7. 30222020

   제1저자 이승표 · 교신저자 손대원

   Lee SP, Suh HY, Park S, Oh S, Kwak SG, Kim HM, Koh Y, Park JB, Kim HK, Cho HJ, Kim YJ, Kim I, Yoon SS, Seo JW, Paeng JC, Sohn DW

   Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

   J Am Coll Cardiol. 2020;75(4):380-390.

   Abstract

   BACKGROUND It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.

   OBJECTIVES The purpose of this study was to demonstrate that ¹¹C-Pittsburgh B compound positron emission tomography (¹¹C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.

   METHODS This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial ¹¹C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.

   RESULTS The degree of myocardial ¹¹C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R² = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial ¹¹C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).

   CONCLUSIONS These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by ¹¹C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

   PubMed IF 22.3 순환기내과
8. 30212020

   제1저자 김진원, 민아름 · 교신저자 임석아

   Kim JW, Min A, Im SA, Jang H, Kim YJ, Kim HJ, Lee KH, Kim TY, Lee KW, Oh DY, Kim JH, Bang YJ

   TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy.

   Cancers (Basel). 2020;12(2):cancers12020334.

   Abstract

   The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.

   PubMed IF 4.8 혈액종양내과
9. 30202020

   제1저자 방영주 · 교신저자 방영주

   Bang YJ, Su WC, Schuler M, Nam DH, Lim WT, Bauer TM, Azaro A, Poon RTP, Hong D, Lin CC, Akimov M, Ghebremariam S, Zhao S, Giovannini M, Ma B

   Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts.

   Cancer Sci. 2020;111(2):536-547.

   Abstract

   Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C_trough >EC₉₀ (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

   PubMed IF 4.9 혈액종양내과
10. 30192020

    제1저자 방영주 · 교신저자 Chen Li-Tzong

    Bang YJ, Li CP, Lee KH, Chiu CF, Park JO, Shan YS, Kim JS, Chen JS, Shim HJ, Rau KM, Choi HJ, Oh DY, Belanger B, Chen LT

    Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.

    Cancer Sci. 2020;111(2):513-527.

    Abstract

    The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).

    PubMed IF 4.9 혈액종양내과
11. 30182020

    제1저자 Hidenori Kato · 교신저자 방영주

    Kato H, de Souza P, Kim SW, Lickliter JD, Naito Y, Park K, Kumar S, Mugundu GM, Bang YJ

    Safety, Pharmacokinetics, and Clinical Activity of Adavosertib in Combination with Chemotherapy in Asian Patients with Advanced Solid Tumors: Phase Ib Study.

    Target Oncol. 2020;15(1):75-84.

    Abstract

    BACKGROUND The WEE1 inhibitor adavosertib (AZD1775) has been investigated in Western patients.

    OBJECTIVE This open-label Phase Ib study (NCT02341456) investigated the safety, pharmacokinetics, and clinical activity of adavosertib in combination with carboplatin alone or paclitaxel plus carboplatin in Asian patients with advanced solid tumors and defined the recommended Phase II dose.

    PATIENTS AND METHODS Nineteen patients received adavosertib 175 mg twice daily (bid) for 2.5 days (five doses) in combination with carboplatin (AUC 5) alone or paclitaxel (175 mg/m²) plus carboplatin, or adavosertib 225 mg bid for 2.5 days in combination with paclitaxel plus carboplatin in 21-day cycles. Preliminary safety and dose-limiting toxicity analyses were performed and dose escalation/de-escalation conducted as appropriate.

    RESULTS Adavosertib 175 mg bid for 2.5 days with carboplatin alone or paclitaxel plus carboplatin was considered tolerable. Two patients receiving adavosertib 225 mg bid in combination with paclitaxel plus carboplatin experienced dose-limiting toxicities (grade 4 sepsis; grade 5 acute respiratory distress syndrome); this regimen was not considered tolerable. Grade ≥ 3 adverse events reported most commonly in any cohort included: anemia; decreased white blood cell count; decreased neutrophil count; neutropenia; decreased platelet count; thrombocytopenia; and febrile neutropenia. Exposure to adavosertib, as determined by pharmacokinetic analysis, in Asian patients was higher than that previously seen in Western patients. A partial response occurred in 2/12 evaluable patients (16.7%) at the recommended Phase II dose.

    CONCLUSIONS Adavosertib 175 mg bid for 2.5 days was chosen as the recommended Phase II dose in combination with paclitaxel and carboplatin in Asian patients.

    PubMed IF 5.1 혈액종양내과
12. 30172020

    제1저자 곽수헌, 황유철 · 교신저자 김재현, 김상용

    Kwak SH, Hwang YC, Won JC, Bae JC, Kim HJ, Suh S, Lee EY, Lee S, Kim SY, Kim JH

    Comparison of the effects of gemigliptin and dapagliflozin on glycaemic variability in type 2 diabetes: A randomized, open-label, active-controlled, 12-week study (STABLE II study).

    Diabetes Obes Metab. 2020;22(2):173-181.

    Abstract

    AIMS The aim of this study was to compare the effect of gemigliptin, a dipeptidyl peptidase-4 inhibitor, and dapagliflozin, a sodium glucose co-transporter-2 inhibitor, on glycaemic variability in type 2 diabetes patients.

    MATERIALS AND METHODS In this randomized, blinded end point, multicentre clinical trial, we enrolled 71 patients with type 2 diabetes who were inadequately controlled with metformin alone or were drug naïve. The participants were randomized to receive gemigliptin 50 mg (n = 35) or dapagliflozin 10 mg (n = 36) daily for 12 weeks. Glycaemic variability was estimated by mean amplitude of glycaemic excursions (MAGE), standard deviation (SD) and coefficient of variation (CV) using a 6-day continuous glucose monitoring system. The primary efficacy endpoint was change in MAGE after 12 weeks compared to baseline.

    RESULTS Intergroup differences in baseline characteristics were not significant. The adjusted mean change (± standard error) in MAGE after 12 weeks in the gemigliptin and dapagliflozin groups was -27.2 ± 4.4 mg/dL and -7.9 ± 4.9 mg/dL, respectively. Between-group comparisons showed a significantly larger reduction in MAGE in the gemigliptin group (-19.2 mg/dL; 95% CI, -31.3 to -7.2; P = .002). Measures of SD and CV also showed a significantly larger reduction in the gemigliptin group. Average glycaemic control, estimated by HbA1c, fasting glucose and safety profiles, was comparable between the two groups.

    CONCLUSIONS Compared to dapagliflozin, gemigliptin significantly improved glycaemic variability, with similar glucose-lowering efficacy and safety profiles in patients with type 2 diabetes who were inadequately controlled with metformin alone or were drug naïve.

    PubMed IF 6.1 내분비대사내과
13. 30162020

    제1저자 양한모, 김주영, 조현재 · 교신저자 김효수

    Yang HM, Kim JY, Cho HJ, Lee JE, Jin S, Hur J, Kwon YW, Seong MW, Choi EK, Lee HY, Lee HS, Jeon M, Kim J, Yang J, Oh S, Suh KS, Yoon SS, Kim KB, Oh BH, Park YB, Kim HS

    NFATc1+CD31+CD45- circulating multipotent stem cells derived from human endocardium and their therapeutic potential.

    Biomaterials. 2020;232:119674.

    Abstract

    Many studies have shown the existence of cardiac stem cells in the myocardium and epicardial progenitor cells in the epicardium. However, the characteristics of stem cells in the endocardium has not been fully elucidated. In this study, we investigated the origin of newly identified cells in the blood and their therapeutic potential. The new population of cells, identified from human peripheral blood, was quite different from previously reported stem cells. These newly identified cells, which we named Circulating Multipotent Stem (CiMS) cells, were multipotent, and therefore differentiated into multiple lineages in vitro and in vivo. In order to determine the origin of these cells, we collected peripheral blood from a group of patients who underwent bone marrow, liver, heart, or kidney transplantation. We identified the endocardium as the origin of these cells because the Short Tandem Repeat profile of CiMS cells from the recipient had changed from the recipient's profile to the donor's profile after heart transplantation. CiMS cells significantly increased after stimuli to the endocardium, such as catheter ablation for arrhythmia or acute myocardial infarction. CiMS cells circulate in human peripheral blood and are easily obtainable, suggesting that these cells could be a promising tool for cell therapy.

    PubMed IF 13.6 순환기내과
14. 30152020

    제1저자 이소령 · 교신저자 최의근

    Lee SR, Choi EK, Kwon S, Jung JH, Han KD, Cha MJ, Oh S, Lip GYH

    Oral Anticoagulation in Asian Patients With Atrial Fibrillation and a History of Intracranial Hemorrhage.

    Stroke. 2020;51(2):416-423.

    Abstract

    Background and Purpose- Warfarin is associated with a better net clinical benefit compared with no treatment in patients with nonvalvular atrial fibrillation (AF) and history of intracranial hemorrhage (ICH). There are limited data on nonvitamin K antagonist oral anticoagulants (NOACs) in these patients, especially in the Asian population. We aimed to compare the effectiveness and safety of NOACs to warfarin in a large-scale nationwide Asian population with AF and a history of ICH. Methods- Using the Korean Health Insurance Review and Assessment database from January 2010 to April 2018, we identified patients with oral anticoagulant naïve nonvalvular AF with a prior spontaneous ICH. For the comparisons, warfarin and NOAC groups were balanced using propensity score weighting. Ischemic stroke, ICH, composite outcome (ischemic stroke+ICH), fatal ischemic stroke, fatal ICH, death from composite outcome, and all-cause death were evaluated as clinical outcomes. Results- Among 5712 patients with AF with prior ICH, 2434 were treated with warfarin and 3278 were treated with NOAC. Baseline characteristics were well-balanced after propensity score weighting (mean age 72.5 years and CHA₂DS₂-VASc score 4.0). Compared with warfarin, NOAC was associated with lower risks of ischemic stroke (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]), ICH (HR, 0.66 [95% CI, 0.47-0.92]), and composite outcome (HR, 0.73 [95% CI, 0.60-0.88]). NOAC was associated with lower risks of fatal stroke (HR, 0.54 [95% CI, 0.32-0.89]), death from composite outcome (HR, 0.53 [95% CI, 0.34-0.81]), and all-cause death (HR, 0.83 [95% CI, 0.69-0.99]) than warfarin. NOAC showed nonsignificant trends toward to reduce fatal ICH compared with warfarin (HR, 0.47 [95% CI, 0.20-1.03]). Conclusions- NOAC was associated with a significant lower risk of ICH and ischemic stroke compared with warfarin. NOAC might be a more effective and safer treatment option for Asian patients with nonvalvular AF and a prior history of ICH.

    PubMed IF 11.1 순환기내과
15. 30142020

    제1저자 소호심 · 교신저자 임종필

    Soh H, Im JP, Han K, Park S, Hong SW, Moon JM, Kang EA, Chun J, Lee HJ, Kim JS

    Crohn's disease and ulcerative colitis are associated with different lipid profile disorders: a nationwide population-based study.

    Aliment Pharmacol Ther. 2020;51(4):446-456.

    Abstract

    BACKGROUND The relationships between lipid profiles and IBD remain elusive.

    AIM To determine the association of IBD with serum lipid profiles.

    METHODS A nationwide population-based study was performed using claims data from the Korean National Healthcare Insurance service. A total of 9 706 026 subjects undergoing medical check-ups in 2009 were enrolled and followed up until 2016. Individuals who developed Crohn's disease (CD) or ulcerative colitis (UC) were identified during follow-up. Adjusted hazard ratio (aHR) by age, sex, body mass index, cigarette smoking, alcohol drinking, exercise, income and underlying comorbidities was calculated to define the impact of serum lipid profiles on developing IBD.

    RESULTS During a median follow-up of 7.3 years, IBD was detected in 7,058 (0.07%) individuals. Compared with the highest quartile of serum total cholesterol (TC) levels, lower TC levels were associated with higher incidence of CD (aHR: Q1, 2.52; Q2, 1.52; Q3, 1.27), but not UC. Lower serum LDL-C levels were associated with higher incidence of CD (aHR: Q1, 1.92; Q2, 1.47; Q3, 1.22), but not UC. Moreover, lower serum HDL-C levels were associated with higher incidence of CD (aHR: Q1, 2.49; Q2, 1.90; Q3, 1.43), but not UC. In contrast, lower serum triglyceride levels were associated with higher incidence of UC (aHR: Q1, 1.22; Q2, 1.19; Q3, 1.19), but not CD.

    CONCLUSIONS Low serum TC, LDL-C and HDL-C levels were associated with CD. Low serum triglyceride levels were related to UC.

    PubMed IF 6.8 소화기내과
16. 30132020

    제1저자 서현정 · 교신저자 김남중

    Suh HJ, Choe PG, Song KH, Park WB, Bang JH, Kim ES, Kim HB, Park SW, Oh MD, Kim NJ

    Prevalence of cryptococcal antigenemia in hospitalized patients with liver cirrhosis.

    Med Mycol. 2020;58(2):207-210.

    Abstract

    The benefits of screening for cryptococcal antigenemia and of preemptive antifungal treatment in HIV-infected patients have been proven. Liver cirrhosis is an important risk factor for cryptococcal infections. Cryptococcal infections are rapidly fatal in patients with liver cirrhosis, especially when diagnosis is delayed. However, screening for cryptococcal antigenemia has not been investigated in these patients. The aim of this study was to investigate the prevalence of cryptococcal antigenemia in hospitalized patients with liver cirrhosis. This prospective study was conducted at Seoul National University Hospital from July 2017 to January 2018. We included patients with liver cirrhosis who were admitted regardless of symptoms or signs suggesting cryptococcal infections. The severity of cirrhosis was evaluated from Child-Pugh and model for end-stage liver disease (MELD) scores. Serum cryptococcal antigenemia was determined using a latex agglutination test. A total of 294 patients were included in the analysis, comprising 104 (35.4%), 100 (34.0%), and 90 (30.6%) patients in Child-Pugh classes A, B, and C, respectively. There were 21 cases of spontaneous bacterial peritonitis, and 14 of hepatic encephalopathy, but none of cryptococcal peritonitis or meningitis. In addition, none of the patient specimens tested positive in the serum cryptococcal latex agglutination test (one-sided 97.5% confidence interval, 0% ∼ 1.2%). Liver cirrhosis is a major risk factor for cryptococcal infections, but the prevalence of serum cryptococcal antigen positivity in patients with liver cirrhosis is very low. Therefore, screening for cryptococcal antigenemia and preemptive antifungal treatment in cirrhotic patients might not be beneficial.

    PubMed IF 3.5 감염내과
17. 30122020

    제1저자 심지수, 이현승 · 교신저자 강혜련, 김혜영

    Shim JS, Lee HS, Park DE, Won Lee J, Bae B, Chang Y, Kim J, Kim HY, Kang HR

    Aggravation of asthmatic inflammation by chlorine exposure via innate lymphoid cells and CD11cintermediate macrophages.

    Allergy. 2020;75(2):381-391.

    Abstract

    BACKGROUND Chlorine is widely used in daily life as disinfectant. However, chronic exposure to chlorine products aggravates allergic T_H 2 inflammation and airway hyperresponsiveness (AHR). Innate lymphoid cells (ILCs) in airways contribute to the inception of asthma in association with virus infection, pollution, and excess of nutrient, but it is not known whether chronic chlorine exposure can activate innate immune cells. The aim of this study was to evaluate the impact of chlorine inhalation on the innate immunity such as ILCs and macrophages in relation with the development of asthma by using murine ovalbumin (OVA) sensitization/challenge model.

    METHODS Six-week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low-dose chlorine exposure by inhalation of naturally vaporized gas of 5% sodium hypochlorite solution. AHR, airway inflammatory cells, from BALF and the population of ILCs and macrophages in the lung were evaluated.

    RESULTS The mice exposed to chlorine with OVA (Cl + OVA group) showed enhanced AHR and eosinophilic inflammation compared to OVA-treated mice (OVA group). The population of T_H 2 cells, ILC2s, and ILC3s increased in Cl + OVA group compared with OVA group. CD11c^int macrophages also remarkably increased in Cl + OVA group compared with OVA group. The deletion of macrophages by clodronate resulted in reduction of ILC2s and ILC3s population which was restored by adoptive transfer of CD11c^int macrophages.

    CONCLUSIONS Chronic chlorine inhalation contributes to the exacerbation of airway inflammation in asthmatic airway by mobilizing pro-inflammatory macrophage into the lung as well as stimulating group 2 and 3 ILCs.

    PubMed IF 11.3 알레르기내과
18. 30112020

    제1저자 이소령, 최유정 · 교신저자 최의근

    Lee SR, Choi YJ, Choi EK, Han KD, Lee E, Cha MJ, Oh S, Lip GYH

    Blood Pressure Variability and Incidence of New-Onset Atrial Fibrillation: A Nationwide Population-Based Study.

    Hypertension. 2020;75(2):309-315.

    Abstract

    Blood pressure variability is a well-known risk factor for cardiovascular disease, but its association with atrial fibrillation (AF) is uncertain. We aimed to evaluate the association between visit-to-visit blood pressure variability and incident AF. This population-based cohort study used database from the Health Screening Cohort, which contained a complete set of medical claims and a biannual health checkup information of the Koran population. A total of 8 063 922 individuals who had at least 3 health checkups with blood pressure measurement between 2004 and 2010 were collected after excluding subjects with preexisting AF. Blood pressure variability was defined as variability independence of the mean and was divided into 4 quartiles. During a mean follow-up of 6.8 years, 140 086 subjects were newly diagnosed with AF. The highest blood pressure variability (fourth quartile) was associated with an increased risk of AF (hazard ratio, 95% CI; systolic blood pressure: 1.06, 1.05-1.08; diastolic blood pressure: 1.07, 1.05-1.08) compared with the lowest (first quartile). Among subjects in the fourth quartile in both systolic and diastolic blood pressure variability, the risk of AF was 7.6% higher than those in the first quartile. Moreover, this result was consistent in both patients with or without prevalent hypertension. In subgroup analysis, the impact of high blood pressure variability on AF development was stronger in high-risk subjects, who were older (≥65 years), with diabetes mellitus or chronic kidney disease. Our findings demonstrated that higher blood pressure variability was associated with a modestly increased risk of AF.

    PubMed IF 9.8 순환기내과
19. 30102020

    제1저자 양민석 · 교신저자 강혜련

    Yang MS, Lee JY, Kim J, Kim GW, Kim BK, Kim JY, Park HW, Cho SH, Min KU, Kang HR

    Searching for the Culprit Drugs for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis from a Nationwide Claim Database in Korea.

    J Allergy Clin Immunol Pract. 2020;8(2):690-695.e2.

    Abstract

    BACKGROUND Ethnic differences exist in relation to culprit drugs for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We wanted to determine culprit drugs for SJS and TEN in Korean population.

    OBJECTIVE To evaluate culprit drugs for SJS and TEN by applying an algorithm for assessment of drug causality for epidermal necrolysis (ALDEN) in a nationwide administrative database.

    METHODS We used the claims database, which included claims data for the entire South Korean population. A retrospective cohort study was conducted by collecting subjects who were first diagnosed with SJS and TEN in 2011. All drugs prescribed to the subjects were reviewed and scored according to the ALDEN score. Drugs with an ALDEN score ≥2 were considered culprit drugs.

    RESULTS A total of 187 subjects were included in the culprit drug analysis; 33 very probable, 101 probable, and 57 possible culprit drugs were identified for SJS and TEN according to the ALDEN score. The most frequently suspected culprit drug was allopurinol (19 cases), followed by carbamazepine (17 cases), lamotrigine (13 cases), amoxicillin (9 cases), and dorzolamide (9 cases). Most cases (78.8%, 52 of 66) associated with the use of allopurinol, carbamazepine, lamotrigine, dorzolamide, and methazolamide occurred between 13 and 44 days after initiating the drug.

    CONCLUSION We applied the ALDEN score to the claims database to identify possible culprit drugs for SJS and TEN in South Korea. This approach could shed light on research and policymaking for drug adverse reactions.

    PubMed IF 6.6 알레르기내과
20. 30092020

    제1저자 이재하, 문미라 · 교신저자 강혜련

    Lee JH, Moon M, Kim YC, Chung SJ, Oh J, Kang DY, Lee SY, Lee KH, Yun J, Kang HR

    A One-Bag Rapid Desensitization Protocol for Paclitaxel Hypersensitivity: A Noninferior Alternative to a Multi-Bag Rapid Desensitization Protocol.

    J Allergy Clin Immunol Pract. 2020;8(2):696-703.

    Abstract

    BACKGROUND Desensitization is used to safely continue treatment with a culprit drug in patients with drug hypersensitivity. Currently, a multi-bag protocol is widely used for rapid desensitization, but performing the desensitization procedure is labor intensive as pharmacists and nurses need to prepare and administer diluted solutions. However, it has not been investigated whether dilution is essential for successful desensitization.

    OBJECTIVE To investigate the efficacy and safety of a nondilution, 1-bag protocol in comparison with a conventional multi-bag protocol for desensitization of patients with paclitaxel hypersensitivity.

    METHODS Patients who underwent paclitaxel desensitization between 2011 and 2018 were analyzed in this retrospective cohort study. The completion rate, time to completion, and occurrence and severity of breakthrough reaction (BTR) between a 1-bag protocol and a multi-bag protocol were compared.

    RESULTS A total of 211 desensitization procedures were performed, of which 207 procedures (98.1%) were completed successfully. The administration time was significantly shorter in the 1-bag protocol group compared with the conventional multi-bag protocol group (266.0 ± 149.3 minutes vs 484.2 ± 178.6 minutes, P < .05) without differences in the completion rate (97.6% vs 98.9%, P = .645), the incidence of BTR (16.1% vs 27.6%, P = .778), and the proportion of severe BTR (2.6% vs 5.7%, P = .134).

    CONCLUSIONS A nondilution, 1-bag protocol is noninferior to a multi-bag rapid desensitization protocol and can be a safe and effective option for paclitaxel desensitization.

    PubMed IF 6.6 알레르기내과
21. 30082020

    제1저자 이주엽 · 교신저자 김나영

    Lee JY, Kim N, Park JH, Nam RH, Lee SM, Song CH, Kim G, Na HY, Choi YJ, Kim JJ, Lee DH

    Expression of Neurotrophic Factors, Tight Junction Proteins, and Cytokines According to the Irritable Bowel Syndrome Subtype and Sex.

    J Neurogastroenterol Motil. 2020;26(1):106-116.

    Abstract

    BACKGROUND/AIMS Emerging evidence shows that the mechanism of irritable bowel syndrome (IBS) is associated with neurotrophic factors and tight junction proteins (TJPs). It is known that there are sex differences in the pathophysiology of IBS. The aim of the present study is to determine expression levels of neurotrophic factors, TJPs, and cytokines according to IBS subtype and sex.

    METHODS From 59 IBS (33 IBS-constipation, 21 IBS-diarrhea, and 5 IBS-mixed) and 36 control patients, colonic mucosa mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1), nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and various TJPs were assessed by real-time polymerase chain reaction. Western blot was performed to determine levels of zonular occludens-1 (ZO-1). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay.

    RESULTS TRPV1, GDNF, and NGF mRNA levels were significantly increased in those with IBS-constipation compared to those in controls (all P < 0.05). However, they showed no significant difference between those with IBS-diarrhea and controls. Expression level of TRPV1 correlated with that of GDNF (r = 0.741, P < 0.001) and NGF (r = 0.935, P < 0.001). ZO-1 RNA expression levels were lower (P = 0.021) in female IBS-diarrhea than those in controls, although they showed no significant differences between male IBS-diarrhea and controls. Serum IL-1β levels in female IBS were significantly higher than those of male IBS, especially in IBS-constipation (P < 0.001).

    CONCLUSIONS Our results suggest that neurotrophic factors and IL-1β are closely related to IBS-constipation and that decrease of ZO-1 is an important factor in female with IBS-diarrhea.

    PubMed IF 3.7 소화기내과
22. 30072020

    제1저자 Mukul Sherekar, 한세원 · 교신저자 Dominic Esposito

    Sherekar M, Han SW, Ghirlando R, Messing S, Drew M, Rabara D, Waybright T, Juneja P, O'Neill H, Stanley CB, Bhowmik D, Ramanathan A, Subramaniam S, Nissley DV, Gillette W, McCormick F, Esposito D

    Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer.

    J Biol Chem. 2020;295(4):1105-1119.

    Abstract

    Neurofibromin is a tumor suppressor encoded by the NF1 gene, which is mutated in Rasopathy disease neurofibromatosis type I. Defects in NF1 lead to aberrant signaling through the RAS-mitogen-activated protein kinase pathway due to disruption of the neurofibromin GTPase-activating function on RAS family small GTPases. Very little is known about the function of most of the neurofibromin protein; to date, biochemical and structural data exist only for its GAP domain and a region containing a Sec-PH motif. To better understand the role of this large protein, here we carried out a series of biochemical and biophysical experiments, including size-exclusion chromatography-multiangle light scattering (SEC-MALS), small-angle X-ray and neutron scattering, and analytical ultracentrifugation, indicating that full-length neurofibromin forms a high-affinity dimer. We observed that neurofibromin dimerization also occurs in human cells and likely has biological and clinical implications. Analysis of purified full-length and truncated neurofibromin variants by negative-stain EM revealed the overall architecture of the dimer and predicted the potential interactions that contribute to the dimer interface. We could reconstitute structures resembling high-affinity full-length dimers by mixing N- and C-terminal protein domains in vitro The reconstituted neurofibromin was capable of GTPase activation in vitro, and co-expression of the two domains in human cells effectively recapitulated the activity of full-length neurofibromin. Taken together, these results suggest how neurofibromin dimers might form and be stabilized within the cell.

    PubMed IF 4.1 혈액종양내과
23. 30062020

    제1저자 이현승 · 교신저자 박흥우

    Lee HS, Park DE, Lee JW, Sohn KH, Cho SH, Park HW

    Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

    Exp Mol Med. 2020;52(1):92-104.

    Abstract

    Nonallergic eosinophilic asthma (NAEA) is a clinically distinct subtype of asthma. Thus far, the pathophysiologic mechanisms underlying NAEA have not been fully elucidated. This study aimed to determine the role of IL-23 in the pathogenesis of NAEA. We developed a murine model of NAEA using recombinant IL-23 (rIL-23) plus a nonspecific airway irritant [polyinosinic-polycytidylic acid (polyI:C) or diesel exhaust particles (DEPs)] and investigated whether IL-23 plays an important role in the development of NAEA. Intranasal administration of rIL-23 (0.1 μg/mouse) plus polyI:C (0.01 μg/mouse) or DEPs (10 μg/mouse) without allergen resulted in methacholine bronchial hyperresponsiveness and eosinophilic airway inflammation in mice, which are characteristic features of NAEA. rIL-23 plus a low dose nonspecific airway irritants induced the release of innate cytokines from airway epithelium, including IL-33, thymic stromal lymphopoietin and IL-1β; these factors activated types 2 and 3 innate lymphoid cells (ILC2s and ILC3s). ILC2s and ILC3s, but not CD4+ T cells (i.e., adaptive immune cells), were important in the development of NAEA. In addition, we observed that IL-23 receptor expressions increased in airway epithelial cells, which suggests the existence of a positive autocrine loop in our murine model of NAEA. To our knowledge, this is the first report in which administration of rIL-23 plus a nonspecific airway irritant (polyI:C or DEPs) without allergen resulted in features of NAEA in mice similar to those found in humans. IL-23 may constitute a therapeutic target for NAEA in humans.

    PubMed IF 17.5 알레르기내과
24. 30052020

    제1저자 이주영 · 교신저자 임종필

    Lee J, Im JP, Han K, Kim J, Lee HJ, Chun J, Kim JS

    Changes in Direct Healthcare Costs before and after the Diagnosis of Inflammatory Bowel Disease: A Nationwide Population-Based Study.

    Gut Liver. 2020;14(1):89-99.

    Abstract

    Background/Aims: We aimed to investigate the differences in direct healthcare costs between patients with and without inflammatory bowel disease (IBD) and changes in direct healthcare costs before and after IBD diagnosis. Methods: This population-based study identified 34,167 patients with IBD (11,014 patients with Crohn's disease and 23,153 patients with ulcerative colitis) and 102,501 age-and sex-matched subjects without IBD (the control group) from the National Health Insurance database using the International Classification of Disease, 10th revision codes and the rare intractable disease registration program codes. The mean healthcare costs per patient were analyzed for 3 years before and after IBD diagnosis, with follow-up data available until 2015. Results: Total direct healthcare costs increased and peaked at $2,396 during the first year after IBD diagnosis, but subsequently dropped sharply to $1,478 during the second year after diagnosis. Total healthcare costs were higher for the IBD patients than for the control group, even in the third year before the diagnosis ($497 vs $402, p<0.001). The costs for biologics for the treatment of IBD increased steeply over time, rising from $720.8 in the first year after diagnosis to $1,249.6 in the third year after diagnosis (p<0.001). Conclusions: IBD patients incurred the highest direct healthcare costs during the first year after diagnosis. IBD patients had higher costs than the control group even before diagnosis. The cost of biologics increased steeply over time, and it can be assumed that biologics could be the main driver of costs during the early period after IBD diagnosis.

    PubMed IF 4.1 소화기내과
25. 30042020

    제1저자 강지훈, Chengbin Zheng · 교신저자 박경우

    Kang J, Zheng C, Park KW, Park J, Rhee T, Lee HS, Han JK, Yang HM, Kang HJ, Koo BK, Kim HS

    Complete Revascularization of Multivessel Coronary Artery Disease Does Not Improve Clinical Outcome in ST-Segment Elevation Myocardial Infarction Patients with Reduced Left Ventricular Ejection Fraction.

    J Clin Med. 2020;9(1):jcm9010232.

    Abstract

    The benefit of complete revascularization (CR) in ST-segment elevation myocardial infarction (STEMI) patients with left ventricular (LV) dysfunction is uncertain. A total of 1314 STEMI patients with multivessel coronary artery disease were analyzed. CR was defined angiographically and by a residual Synergy between PCI with Taxus and Cardiac Surgery trial (SYNTAX) score (SS) <8. Patients with a left ventricular ejection fraction (LVEF) <40% were classified as the reduced LVEF group. The major study endpoints were patient-oriented composite outcome (POCO) and cardiac death during three-year follow-up. Overall, patients that received angiographic CR (579 patients, 44.1%) had significantly lower three-year clinical events compared with incomplete revascularization (iCR). CR reduced three-year POCO and cardiac death rates in the preserved LVEF group (POCO: 13.2% vs. 21.9%, p < 0.001, cardiac death: 1.8% vs. 6.5%, p < 0.001, respectively) but not in the reduced LVEF group (POCO: 26.0% vs. 33.1%, p = 0.275, cardiac death: 15.1% vs. 19.0%, p = 0.498, respectively). Multivariate analysis showed that CR significantly reduced three-year POCO (hazard ration (HR) 0.59, 95% confidence interval (CI) 0.43-0.82) and cardiac death (HR 0.34, 95% CI 0.14-0.80), only in the preserved LVEF group. Additionally, the results were corroborated using the SS-based CR definition. In STEMI patients with multivessel disease, CR did not improve clinical outcomes in those with reduced LVEF.

    PubMed IF 3.3 순환기내과
26. 30032020

    제1저자 문인기, 이서영 · 교신저자 김형관

    Moon I, Lee SY, Kim HK, Han KD, Kwak S, Kim M, Lee HJ, Hwang IC, Lee H, Park JB, Yoon YE, Kim YJ, Cho GY

    Trends of the prevalence and incidence of hypertrophic cardiomyopathy in Korea: A nationwide population-based cohort study.

    PLoS One. 2020;15(1):e0227012.

    Abstract

    Temporal trends of the prevalence and incidence of hypertrophic cardiomyopathy (HCM) have not been well established in Asian populations. Using the Korean National Health Insurance Services database, we identified patients with a confirmed diagnosis of HCM between 2010 and 2016. The annual prevalence and incidence of HCM, and their clinical characteristics were investigated. The prevalence of HCM has increased from 0.016% (n = 6313) in 2010 to 0.031% (n = 13,035) in 2016. During a 7-year period, 13,229 patients were newly diagnosed with HCM. The incidence rate increased from 4.15 (per 100,000 person-years) in 2010 to 5.6 in 2016. The prevalence and incidence of HCM increased with age and peaked during the 70s, with male predominance in all age groups. Chest pain is the most frequent clinical presentation followed by shortness of breath and syncope. Hypertension and dyslipidemia were the two most common comorbidities. Heart failure and atrial fibrillation was diagnosed in about 1/3 and 1/4 of patients with HCM, respectively. The prevalence and incidence of HCM gradually increased from 2010 to 2016, possibly due to heightened recognition of the disease. Given the progressively high incidence of HCM with age and high prevalence of coexisting modifiable risk factors, continued efforts are required to increase awareness regarding HCM-related symptoms and potential complications.

    PubMed IF 2.8 순환기내과
27. 30022020

    제1저자 양예슬, 양보람 · 교신저자 최성희

    Yang YS, Yang BR, Kim MS, Hwang Y, Choi SH

    Low-density lipoprotein cholesterol goal attainment rates in high-risk patients with cardiovascular diseases and diabetes mellitus in Korea: a retrospective cohort study.

    Lipids Health Dis. 2020;19(1):5.

    Abstract

    BACKGROUND Real-world evidence of low-density lipoprotein cholesterol (LDL-C) goal attainment rates for Asian patients is deficient. The objective of this study was to assess the status of dyslipidemia management, especially in high-risk patients with cardiovascular disease (CVD) including stroke and acute coronary syndrome (ACS).

    METHODS This was a retrospective cohort study of 514,866 subjects from the National Health Insurance Service-National Health Screening Cohort database in Korea. Participants were followed up from 2002 to 2015. Subjects with a high-risk of CVD prior to LDL-C measurement and subjects who were newly-diagnosed for high-risk of CVD following LDL-C measurement were defined as known high-risk patients (n = 224,837) and newly defined high-risk patients (n = 127,559), respectively. Data were analyzed by disease status: stroke, ACS, coronary heart disease (CHD), peripheral artery disease (PAD), diabetes mellitus (DM) and atherosclerotic artery disease (AAD).

    RESULTS Overall, less than 50% of patients in each disease category achieved LDL-C goals (LDL-C < 70 mg/dL in patients with stroke, ACS, CHD and PAD; and LDL-C < 100 mg/dL in patients with DM and AAD). Statin use was observed in relatively low proportions of subjects (21.5% [known high-risk], 34.4% [newly defined high-risk]). LDL-C goal attainment from 2009 to 2015 steadily increased but the goal-achiever proportion of newly defined high-risk patients with ACS remained reasonably constant (38.7% in 2009; 38.1% in 2015).

    CONCLUSIONS LDL-C goal attainment rates in high-risk patients with CVD and DM in Korea demonstrate unmet medical needs. Proactive management is necessary to bridge the gap between the recommendations of clinical guidelines and actual clinical practice.

    PubMed IF 6.9 내분비대사내과
28. 30012020

    제1저자 이서연 · 교신저자 김효수

    Lee SY, Yang J, Park JH, Shin HK, Kim WJ, Kim SY, Lee EJ, Hwang I, Lee CS, Lee J, Kim HS

    The MicroRNA-92a/Sp1/MyoD Axis Regulates Hypoxic Stimulation of Myogenic Lineage Differentiation in Mouse Embryonic Stem Cells.

    Mol Ther. 2020;28(1):142-156.

    Abstract

    Hypoxic microenvironments exist in developing embryonic tissues and determine stem cell fate. We previously demonstrated that hypoxic priming plays roles in lineage commitment of embryonic stem cells. In the present study, we found that hypoxia-primed embryoid bodies (Hyp-EBs) efficiently differentiate into the myogenic lineage, resulting in the induction of the myogenic marker MyoD, which was not mediated by hypoxia-inducible factor 1α (HIF1α) or HIF2α, but rather by Sp1 induction and binding to the MyoD promoter. Knockdown of Sp1 in Hyp-EBs abrogated hypoxia-induced MyoD expression and myogenic differentiation. Importantly, in the cardiotoxin-muscle injury mice model, Hyp-EB transplantation facilitated muscle regeneration in vivo, whereas transplantation of Sp1-knockdown Hyp-EBs failed to do. Moreover, we compared microRNA (miRNA) expression profiles between EBs under normoxia versus hypoxia and found that hypoxia-mediated Sp1 induction was mediated by the suppression of miRNA-92a, which directly targeted the 3' untranslated region (3' UTR) of Sp1. Further, the inhibitory effect of miRNA-92a on Sp1 in luciferase assay was abolished by a point mutation in specific sequence in the Sp1 3' UTR that is required for the binding of miRNA-92a. Collectively, these results suggest that hypoxic priming enhances EB commitment to the myogenic lineage through miR-92a/Sp1/MyoD regulatory axis, suggesting a new pathway that promotes myogenic-lineage differentiation.

    PubMed IF 11.4 순환기내과
29. 30002020

    제1저자 박세훈 · 교신저자 이하정

    Park S, Lee HC, Jung CW, Choi Y, Yoon HJ, Kim S, Chin HJ, Kim M, Kim YC, Kim DK, Joo KW, Kim YS, Lee H

    Intraoperative Arterial Pressure Variability and Postoperative Acute Kidney Injury.

    Clin J Am Soc Nephrol. 2020;15(1):35-46.

    Abstract

    BACKGROUND AND OBJECTIVES High BP variability may cause AKI because of inappropriate kidney perfusion. This study aimed to investigate the association between intraoperative BP variability and postoperative AKI in patients who underwent noncardiac surgery.

    DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a cohort study of adults undergoing noncardiac surgery in hospitals in South Korea. We studied three cohorts using the following recording windows for intraoperative BP: discovery cohort, 1-minute intervals; first validation cohort, 5-minute intervals; and second validation cohort, 2-second intervals. We calculated four variability parameters (SD, coefficient of variation, variation independent of mean, and average real variability) based on the measured mean arterial pressure values. The primary outcomes were postoperative AKI (defined by the Kidney Disease Improving Global Outcomes serum creatinine cutoffs) and critical AKI (consisting of stage 2 or higher AKI and post-AKI death or dialysis within 90 days).

    RESULTS In the three cohorts, 45,520, 29,704, and 7435 patients were analyzed, each with 2230 (443 critical), 1552 (444 critical), and 300 (91 critical) postoperative AKI events, respectively. In the discovery cohort, all variability parameters were significantly associated with risk of AKI, even after adjusting for intraoperative hypotension. For example, average real variability was associated with higher risks of postoperative AKI (adjusted odds ratio, 1.13 per 1 SD increment; 95% CI, 1.07 to 1.19) and critical AKI (adjusted odds ratio, 1.13 per 1 SD increment; 95% CI, 1.02 to 1.26). Associations were evident predominantly among patients who also experienced intraoperative hypotension. In the validation analysis with 5-minute-interval BP records, all four variability parameters were associated with the risk of postoperative AKI or critical AKI. In the validation cohort with 2-second-interval BP records, average real variability was the only significant variability parameter.

    CONCLUSIONS Higher intraoperative BP variability is associated with higher risks of postoperative AKI after noncardiac surgery, independent of hypotension and other clinical characteristics.

    PubMed IF 7 신장내과
30. 29992020

    제1저자 장현덕, 이상언, 양지민 · 교신저자 김효수

    Jang HD, Lee SE, Yang J, Lee HC, Shin D, Lee H, Lee J, Jin S, Kim S, Lee SJ, You J, Park HW, Nam KY, Lee SH, Park SW, Kim JS, Kim SY, Kwon YW, Kwak SH, Yang HM, Kim HS

    Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9.

    Eur Heart J. 2020;41(2):239-252.

    Abstract

    AIMS Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels.

    METHODS AND RESULTS The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1.

    CONCLUSION We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.

    PubMed IF 45.3 순환기내과

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