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BackgroundChronic kidney disease (CKD) is a strong risk factor for cardiovascular disease. Electrocardiogram (ECG) is the basic test for screening cardiovascular disease. However, the impact of ECG abnormalities on cardiovascular prognosis in patients with CKD is largely unknown.MethodsA total of 1,295 patients with CKD (stage 3, 4, and 5) who underwent ECG between 2013 and 2015 were selected from the tertiary hospital in Korea. ECG abnormalities were defined using the Minnesota classification. Five-year major adverse cerebrocardiovascular event (MACCE), a composite of death, myocardial infarction (MI) and stroke, was analyzed after excluding 251 patients (n=1,044) with prior MI or stroke.ResultsThe higher the CKD stage, the higher the proportion of patients with a major ECG abnormality. Five-year MACCE incidences were 34%, 23.9%, and 21.7% in patients with major, minor and no ECG abnormalities. MACCE and MI incidences were significantly higher in patients with severe ECG abnormalities (log-rank p < 0.001). Major ECG abnormalities were significantly associated with MACCE (adjusted HR 1.48, 95% CI 1.11-1.97). In particular, atrial fibrillation, atrial premature complex, and QT interval prolongation were identified as important ECG diagnoses. The accuracy of cardiovascular risk stratification was improved when ECG diagnosis was added to the conventional SCORE model (net reclassification index 0.09).ConclusionsMajor ECG abnormality was a significant predictor of cardiovascular events in CKD patients. ECG diagnosis can be useful in evaluating the risk of cardiovascular disease in CKD patients when applied in addition to the conventional risk stratification model.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), neutrophil gelatinase-associated lipocalin (NGAL), and matrix metalloproteinase-9 (MMP-9) are inflammatory biomarkers involved in plaque destabilization resulting in acute coronary syndrome (ACS). This study aimed to investigate the diagnostic value of a combination of biomarkers to discriminate plaque ruptures in the setting of ACS. Eighty-five ACS patients with optical coherence tomography (OCT) images of the culprit plaque were included and categorized into two groups: ACS with plaque rupture (Rupture group, n = 42) or without plaque rupture (Non-rupture group, n = 43) verified by OCT. A discriminative model of plaque rupture using several biomarkers was developed and validated. The Rupture group had higher white blood cell (WBC) counts and peak creatine kinase-myocardial band (CK-MB) levels (13.39 vs. 2.69 ng/mL, p = 0.0016). sLOX-1 (227.9 vs. 51.7 pg/mL, p

Background: Identification of subclinical target organ damage (TOD) at early stage is important for the reduction in cardiovascular risk. This study was performed to assess the association between ...

Background The effect of chronic total occlusion (CTO) revascularization on survival remains controversial. Furthermore, data regarding outcome differences for CTO revascularization based on left ventricular systolic function (LVSF) are limited. The differential outcomes from CTO revascularization in patients with preserved LVSF (PLVSF) versus reduced LVSF (RLVSF) were assessed. Methods A total of 2,173 CTO patients were divided into either a PLVSF (n = 1661, Ejection fraction ≥ 50%) or RLVSF (n = 512, Results Patients with RLVSF had a mean 37% ejection fraction (EF) and 19% had EF p p = 0.0019], which was mainly driven by a reduction in cardiac death. The difference in survival probability was greater and became more pronounced over time in patients with RLVSF than with PLVSF (1-year, p = 0.197; 3-years, p = 0.048; 5-years, p = 0.036). Conclusions SCR was associated with better survival benefit than OMT regardless of LVSF. The benefit was greater and became more significant over time in patients with RLVSF versus PLVSF. Graphic abstract

Background Hypertriglyceridemia is an important feature of dyslipidemia in type 1 and type 2 diabetic patients and associated with the development of atherosclerotic cardiovascular disease. Recently, variability of lipid profile has been suggested as a residual risk factor for cardiovascular disease. This study compared the clinical impact of serum triglyceride variability, and their cumulative exposure estimates on cardiovascular prognosis in diabetic patients. Methods A total of 25,933 diabetic patients who had serum triglyceride levels measured at least 3 times and did not have underlying malignancy, myocardial infarction (MI), and stroke during the initial 3 years (modeling phase) were selected from three tertiary hospitals. They were divided into a high/low group depending on their coefficient of variation (CV) and cumulative exposure estimate (CEE). Incidence of major adverse event (MAE), a composite of all-cause death, MI, and stroke during the following 5 years were compared between groups by multivariable analysis after propensity score matching. Results Although there was a slight difference, both the high CV group and the high CEE group had a higher cardiovascular risk profile including male-dominance, smoking, alcohol, dyslipidemia, and chronic kidney disease compared to the low groups. After the propensity score matching, the high CV group showed higher MAE incidence compared to the low CV group (9.1% vs 7.7%, p = 0.01). In contrast, there was no significant difference of MAE incidence between the high CEE group and the low CEE group (8.6% vs 9.1%, p = 0.44). After the multivariable analysis with further adjustment for potential residual confounding factors, the high CV was suggested as an independent risk predictor for MAE (HR 1.19 [95% CI 1.03–1.37]). Conclusion Visit-to-visit variability of triglyceride rather than their cumulative exposure is more strongly related to the incidence of MAE in diabetic patients.

With advances in deep learning and natural language processing (NLP), the analysis of medical texts is becoming increasingly important. Nonetheless, despite the importance of processing medical texts, no research on Korean medical-specific language models has been conducted. The Korean medical text is highly difficult to analyze because of the agglutinative characteristics of the language, as well as the complex terminologies in the medical domain. To solve this problem, we collected a Korean medical corpus and used it to train the language models. In this paper, we present a Korean medical language model based on deep learning NLP. The model was trained using the pre-training framework of BERT for the medical context based on a state-of-the-art Korean language model. The pre-trained model showed increased accuracies of 0.147 and 0.148 for the masked language model with next sentence prediction. In the intrinsic evaluation, the next sentence prediction accuracy improved by 0.258, which is a remarkable enhancement. In addition, the extrinsic evaluation of Korean medical semantic textual similarity data showed a 0.046 increase in the Pearson correlation, and the evaluation for the Korean medical named entity recognition showed a 0.053 increase in the F1-score.

Background: Decreased TIMI flow following percutaneous coronary intervention (PCI) is associated with poor clinical outcomes. However, predicting slow TIMI flow after PCI is limited. Herein, we investigated predicting slow TIMI flow based on the lipid core burden (LCB) of target lesion by using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS). Methods and Results: This study retrospectively evaluated 636 patients who underwent NIRS-IVUS guided PCI from a single tertiary center registry. Total patients were divided into decreased TIMI flow group (n=90, TIMI 0, 1, and 2) and normal TIMI flow group (n=546, TIMI 3). The extent of LCB in the treatment zone was calculated as the maximal LCB index (maxLCBi) measured by NIRS for each of the 4-mm longitudinal segments in the treatment zone. In three-month composite events including all-cause death, myocardial infarction, stent thrombosis, and re-intervention, decreased TIMI flow group showed worse clinical outcomes compared to normal TIMI flow group (5.6% vs. 1.5%, log-rank p=0.010). To investigate the correlation between TIMI flow and lipid core burden, a receiver-operating characteristic analysis was performed, and a high LCBi group was defined as maxLCBi 4mm ≥353. Multivariate logistic regression analysis revealed that high LCBi group was strongly associated with decreased TIMI flow (OR 2.223, 95% CI 1.341-3.685, p=0.002). Conclusions: High LCBi measured by NIRS-IVUS could be considered an independent predictor for decreased TIMI flow. Furthermore, a high value for LCBi could lead to worse clinical outcomes.

Mature cardiomyocytes (CMs) obtained from human pluripotent stem cells (hPSCs) have been required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. Here, we found that FGF4 and ascorbic acid (AA) induce differentiation of BG01 human embryonic stem cell–cardiogenic mesoderm cells (hESC-CMCs) into mature and ventricular CMs. Co-treatment of BG01 hESC-CMCs with FGF4+AA synergistically induced differentiation into mature and ventricular CMs. FGF4+AA-treated BG01 hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes and potential cardiac biomarkers proved in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated BG01 hESC-CMs in response to hypoxia based on transcriptome analyses. This study demonstrates that it is feasible to model hypoxic stress in vitro using hESC-CMs matured by soluble factors.

Background Statin therapy reduces the risk of cardiovascular events across a broad spectrum of patients; however, it increases the risk of new-onset diabetes (NOD). Although the highest dose pitavastatin is considered to not be associated with NOD, there are limited data regarding the impact of long-term highest dose pitavastatin use on the development of NOD in patients at high risk of developing diabetes. Therefore, we prospectively compared the differences in the development of NOD between the lowest and the highest dose of pitavastatin in patients at high risk of developing diabetes during a 3-year follow-up. Methods This post hoc analysis of a prospective, single-blinded, randomized study compared the risk of NOD between the highest dose of pitavastatin (4 mg) and the lowest dose of pitavastatin (1 mg) over a 3-year follow-up in patients with acute coronary syndrome. Among 1044 patients of the original study, 667 patients at high risk of developing type 2 diabetes mellitus were in the subgroup analysis. The primary endpoint was a comparison of the differences in the cumulative incidence of NOD in the pitavastatin 1 mg and 4 mg groups during a 3-year follow-up. Results With propensity score matching, there were no significant differences in baseline demographic characteristics between the 2 groups. Incidence of NOD was similar between the pitavastatin 1 mg and 4 mg groups [12 of 289 patients (4.2%) and 8 of 289 patients (2.8%), respectively; p = 0.36]. In a prespecified analysis, there were no significant differences in NOD events according to sex, age, diagnosis, body mass index, glucose intolerance, or dyslipidemia. Conclusions Administration of highest-dose pitavastatin did not increase the risk of NOD in patients at high risk of developing diabetes during the 3-year follow-up. Moreover, various risk factors for NOD such as metabolic syndrome components, glucose intolerance, dyslipidemia, obesity, or hypertension did not affect the development of NOD during pitavastatin administration. Thus, the highest dose pitavastatin can be safely used in patients with metabolic syndrome who are at high risk of developing diabetes. Trial registration Clinical Trial registration information. URL: https://clinicaltrials.gov/ct2/show/NCT02545231. Unique identifier: NCT02545231

Background and aims Metabolic syndrome (MetS) is a cluster of multiple risk factors including central obesity that may lead to cardiac damage and cardiovascular events. We investigated whether visceral obesity induces cardiac structural and functional remodeling independently from central obesity and other risk factors in subjects with suspected MetS. Methods and results We studied 229 participants with suspected MetS. Visceral fat area (VFA) was measured by bioelectrical impedance analysis. Left ventricular (LV) mass index, early diastolic velocity of mitral annulus (e′), and LV global longitudinal strain (GLS) were measured by echocardiography. Subjects were categorized into high and low VFA group (VFAh and VFAl). MetS was more prevalent in the VFAh than in the VFAl (p = 0.004). The VFAh had a higher waist circumference (WC) than the VFAl (p Conclusions Visceral obesity assessed by VFA was well correlated with parameters of MetS. Visceral obesity, but not central obesity measured by WC, was independently associated with structural and functional cardiac remodeling in subjects with suspected MetS. It suggests that visceral obesity should be considered as an important risk factor for cardiac damage in dysmetabolic subjects. Trial registration NCT02077530 (date of registration: November 1, 2013).

Decreased thrombolysis in myocardial infarction (TIMI) flow is associated with poor clinical outcomes. However, its predictors are not fully known. A combination of near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS) could be used to detect lesions at high risk of slow TIMI flow. This study evaluated 636 consecutive patients undergoing target-lesion NIRS-IVUS imaging prior to percutaneous coronary intervention (PCI). The maximal lipid core burden index over 4-mm segments (maxLCBI4mm) per target vessel was calculated. The primary endpoint was the association between maxLCBI4mm and post-interventional TIMI flow. A high lipid core burden index (LCBI) cut-off point was determined using receiver-operating characteristic analysis. Decreased TIMI flow (TIMI less than 3) occurred in 90 patients and normal TIMI flow in 546 patients. The decreased TIMI flow group showed significantly higher incidence of cardiovascular events (5.6% vs. 1.5%, log-rank p = 0.010) in three months of composite events including cardiac death, myocardial infarction, stent thrombosis, and target lesion revascularization. In multivariable analysis, a high LCBI (≥354) was independently associated with slow TIMI flow (OR, 2.59 (95% CI, 1.33–5.04), p = 0.005). High LCBI measured using NIRS-IVUS imaging was an independent predictor of decreased post-PCI TIMI flow. Performing PCI for high-LCBI lesions may necessitate adjunctive measures to prevent suboptimal post-PCI reperfusion.

BACKGROUND With advances in deep learning and natural language processing, analyzing medical texts is becoming increasingly important. Nonetheless, a study on medical-specific language models has not yet been conducted given the importance of medical texts. OBJECTIVE Korean medical text is highly difficult to analyze because of the agglutinative characteristics of the language as well as the complex terminologies in the medical domain. To solve this problem, we collected a Korean medical corpus and used it to train language models. METHODS In this paper, we present a Korean medical language model based on deep learning natural language processing. The proposed model was trained using the pre-training framework of BERT for the medical context based on a state-of-the-art Korean language model. RESULTS After pre-training, the proposed method showed increased accuracies of 0.147 and 0.148 for the masked language model with next sentence prediction. In the intrinsic evaluation, the next sentence prediction accuracy improved by 0.258, which is a remarkable enhancement. In addition, the extrinsic evaluation of Korean medical semantic textual similarity data showed a 0.046 increase in the Pearson correlation. CONCLUSIONS The results demonstrated the superiority of the proposed model for Korean medical natural language processing. We expect that our proposed model can be extended for application to various languages and domains.

The generation of mature ventricular cardiomyocytes (CMs) resembling adult CMs from human pluripotent stem cells (hPSCs) is necessary for disease modeling and drug discovery. To investigate the effect of self-organizing capacity on the generation of mature cardiac organoids (COs), we generated cardiac mesoderm cell-derived COs (CMC-COs) and CM-derived COs (CM-COs) and evaluated COs. CMC-COs exhibited more organized sarcomere structures and mitochondria, well-arranged t-tubule structures, and evenly distributed intercalated discs. Increased expressions of ventricular CM, cardiac metabolic, t-tubule formation, K+ ion channel, and junctional markers were confirmed in CMC-COs. Mature ventricular-like function such as faster motion vector speed, decreased beats per min, increased peak-to-peak duration, and prolonged APD50 and APD90 were observed in CMC-COs. Transcriptional profiling revealed that extracellular matrix-integrin, focal adhesion, and LEFTY-PITX2 signaling pathways are upregulated in CMC-COs. LEFTY knockdown affected ECM-integrin-FA signaling pathways in CMC-COs. Here, we found that high self-organizing capacity of CMCs is critical for the generation of mature and ventricular COs. We also demonstrated that LEFTY-PITX2 signaling plays key roles for CM maturation and specification into ventricular-like CM subtype in CMC-COs. CMC-COs are an attractive resource for disease modeling and drug discovery.

Background The fact that medical terms require special expertise and are becoming increasingly complex makes it difficult to employ natural language processing techniques in medical informatics. Several human-validated reference standards for medical terms have been developed to evaluate word embedding models using the semantic similarity and relatedness of medical word pairs. However, there are very few reference standards in non-English languages. In addition, because the existing reference standards were developed a long time ago, there is a need to develop an updated standard to represent recent findings in medical sciences. Objective We propose a new Korean word pair reference set to verify embedding models. Methods From January 2010 to December 2020, 518 medical textbooks, 72,844 health information news, and 15,698 medical research articles were collected, and the top 10,000 medical terms were selected to develop medical word pairs. Attending physicians (n=16) participated in the verification of the developed set with 607 word pairs. Results The proportion of word pairs answered by all participants was 90.8% (551/607) for the similarity task and 86.5% (525/605) for the relatedness task. The similarity and relatedness of the word pair showed a high correlation (ρ=0.70, P Conclusions Korean medical word pair reference standard sets for semantic similarity and relatedness were developed based on medical documents from the past 10 years. It is expected that our word pair reference sets will be actively utilized in the development of medical and multilingual natural language processing technology in the future.

BACKGROUND The fact that medical terms require special expertise and are becoming increasingly complex makes it difficult to employ natural language processing techniques in medical informatics. Several human-validated reference standards for medical terms have been developed to evaluate word embedding models using the semantic similarity and relatedness of medical word pairs. However, there are very few reference standards in non-English languages. In addition, because the existing reference standards were developed a long time ago, there is a need to develop an updated standard to represent recent findings in medical sciences. OBJECTIVE We propose a new Korean word pair reference set to verify embedding models. METHODS From January 2010 to December 2020, 518 medical textbooks, 72,844 health information news, and 15,698 medical research articles were collected, and the top 10,000 medical terms were selected to develop medical word pairs. Attending physicians (n=16) participated in the verification of the developed set with 607 word pairs. RESULTS The proportion of word pairs answered by all participants was 90.8% (551/607) for the similarity task and 86.5% (525/605) for the relatedness task. The similarity and relatedness of the word pair showed a high correlation (ρ=0.70, Pρ=0.12 vs with medical text for the similarity task, ρ=0.47; namu, ρ=0.02 vs with medical text for the relatedness task, ρ=0.30). CONCLUSIONS Korean medical word pair reference standard sets for semantic similarity and relatedness were developed based on medical documents from the past 10 years. It is expected that our word pair reference sets will be actively utilized in the development of medical and multilingual natural language processing technology in the future. CLINICALTRIAL

An increase in antibiotic usage is considered to attribute to the emergence of antimicrobial resistance. Although experts are counting on the antimicrobial stewardship programs to reduce antibiotic usage, their effect remains uncertain. In this study, we aimed to evaluate the impact of antibiotic usage and forecast the prevalence of hospital-acquired extended spectrum β-lactamase (ESBL) - producing Escherichia coli (E. coli) using time-series analysis. Antimicrobial culture information of E. coli was obtained using a text processing technique that helped extract free-text electronic health records from standardized data. The antimicrobial use density (AUD) of antibiotics of interest was used to estimate the quarterly antibiotic usage. Transfer function model was applied to forecast relationship between antibiotic usage and ESBL-producing E. coli. Of the 1,938 hospital-acquired isolates, 831 isolates (42.9%) were ESBL-producing E. coli. Both the proportion of ESBL-producing E. coli and AUD increased over time. The transfer model predicted that ciprofloxacin AUD is related to the proportion of ESBL-producing E. coli two quarters later. In conclusion, excessive use of antibiotics was shown to affect the prevalence of resistant organisms in the future. Therefore, the control of antibiotics with antimicrobial stewardship programs should be considered to restrict antimicrobial resistance.

Although lowering low-density lipoprotein cholesterol (LDL-C) levels following acute myocardial infarction (MI) is the cornerstone of secondary prevention, the attainment of recommended LDL-C goals remains suboptimal in real-world practice. We sought to investigate recurrent adverse events in post-MI patients. From the Korea Acute Myocardial Infarction-National Institutes of Health registry, a total of 5049 patients with both measurements of plasma LDL-C levels at index admission and at the one-year follow-up visit were identified. Patients who achieved an LDL-C reduction ≥ 50% from the index MI and an LDL-C level ≤ 70 mg/dL at follow-up were classified as target LDL-C achievers. The primary endpoint was a two-year major adverse cardiac and cerebrovascular event (MACCE), including cardiovascular mortality, recurrent MI, and ischemic stroke. Among the 5049 patients, 1114 (22.1%) patients achieved the target LDL-C level. During a median follow-up of 2.1 years, target LDL-C achievers showed a significantly lower incidence (2.2% vs. 3.5%, log-rank p = 0.022) and a reduced adjusted hazard of MACCE (0.63; p = 0.041). In patients with acute MI, achieving a target LDL-C level was associated with a lower incidence and a reduced hazard of recurrent clinical events. These results highlight the need to improve current practices for managing LDL-C levels in real-world settings.

Pathology reports contain the essential data for both clinical and research purposes. However, the extraction of meaningful, qualitative data from the original document is difficult due to the narrative and complex nature of such reports. Keyword extraction for pathology reports is necessary to summarize the informative text and reduce intensive time consumption. In this study, we employed a deep learning model for the natural language process to extract keywords from pathology reports and presented the supervised keyword extraction algorithm. We considered three types of pathological keywords, namely specimen, procedure, and pathology types. We compared the performance of the present algorithm with the conventional keyword extraction methods on the 3115 pathology reports that were manually labeled by professional pathologists. Additionally, we applied the present algorithm to 36,014 unlabeled pathology reports and analysed the extracted keywords with biomedical vocabulary sets. The results demonstrated the suitability of our model for practical application in extracting important data from pathology reports.

BACKGROUND Existing bacterial culture test results for infectious diseases are written in unrefined text, resulting in many problems, including typographical errors and stop words. Effective spelling correction processes are needed to ensure the accuracy and reliability of data for the study of infectious diseases, including medical terminology extraction. If a dictionary is established, spelling algorithms using edit distance are efficient. However, in the absence of a dictionary, traditional spelling correction algorithms that utilize only edit distances have limitations. OBJECTIVE In this research, we proposed a similarity-based spelling correction algorithm using pretrained word embedding with the BioWordVec technique. This method uses a character-level N-grams–based distributed representation through unsupervised learning rather than the existing rule-based method. In other words, we propose a framework that detects and corrects typographical errors when a dictionary is not in place. METHODS For detected typographical errors not mapped to Systematized Nomenclature of Medicine (SNOMED) clinical terms, a correction candidate group with high similarity considering the edit distance was generated using pretrained word embedding from the clinical database. From the embedding matrix in which the vocabulary is arranged in descending order according to frequency, a grid search was used to search for candidate groups of similar words. Thereafter, the correction candidate words were ranked in consideration of the frequency of the words, and the typographical errors were finally corrected according to the ranking. RESULTS Bacterial identification words were extracted from 27,544 bacterial culture and antimicrobial susceptibility reports, and 16 types of spelling errors and 914 misspelled words were found. The similarity-based spelling correction algorithm using BioWordVec proposed in this research corrected 12 types of typographical errors and showed very high performance in correcting 97.48% (based on F1 score) of all spelling errors. CONCLUSIONS This tool corrected spelling errors effectively in the absence of a dictionary based on bacterial identification words in bacterial culture and antimicrobial susceptibility reports. This method will help build a high-quality refined database of vast text data for electronic health records.

BACKGROUND De-identifying personal information is critical when using personal health data for secondary research. The Observational Medical Outcomes Partnership Common Data Model (CDM), defined by the nonprofit organization Observational Health Data Sciences and Informatics, has been gaining attention for its use in the analysis of patient-level clinical data obtained from various medical institutions. When analyzing such data in a public environment such as a cloud-computing system, an appropriate de-identification strategy is required to protect patient privacy. OBJECTIVE This study proposes and evaluates a de-identification strategy that is comprised of several rules along with privacy models such as k-anonymity, l-diversity, and t-closeness. The proposed strategy was evaluated using the actual CDM database. METHODS The CDM database used in this study was constructed by the Anam Hospital of Korea University. Analysis and evaluation were performed using the ARX anonymizing framework in combination with the k-anonymity, l-diversity, and t-closeness privacy models. RESULTS The CDM database, which was constructed according to the rules established by Observational Health Data Sciences and Informatics, exhibited a low risk of re-identification: The highest re-identifiable record rate (11.3%) in the dataset was exhibited by the DRUG_EXPOSURE table, with a re-identification success rate of 0.03%. However, because all tables include at least one “highest risk” value of 100%, suitable anonymizing techniques are required; moreover, the CDM database preserves the “source values” (raw data), a combination of which could increase the risk of re-identification. Therefore, this study proposes an enhanced strategy to de-identify the source values to significantly reduce not only the highest risk in the k-anonymity, l-diversity, and t-closeness privacy models but also the overall possibility of re-identification. CONCLUSIONS Our proposed de-identification strategy effectively enhanced the privacy of the CDM database, thereby encouraging clinical research involving multiple centers.

Elderly patients treated with percutaneous coronary intervention (PCI) have a higher risk of both ischemic and bleeding complications than younger patients. However, few studies have reported how genetic information of elderly patients treated with PCI affects clinical outcomes. We investigated the impact of genetic variants on clinical outcomes in elderly patients. Correlations between single-nucleotide polymorphisms (CYP2C19 and P2Y12 receptor gene G52T polymorphism) and clinical outcomes were analyzed in 811 elderly patients (≥75 years of age) from a prospective multicenter registry. The primary endpoint was a composite of myocardial infarction and death. Secondary endpoints were an individual event of death, cardiac death, myocardial infarction, stent thrombosis, target lesion revascularization, stroke, and major bleeding (Bleeding Academic Research Consortium ≥3). Regarding CYP2C19, patients with poor metabolizers had a significantly higher risk for the primary endpoint (hazard ratio [HR] 2.43; 95% confidence interval [95% CI] 1.12-5.24; p=0.024) and secondary endpoints (death and cardiac death). Regarding P2Y12 G52T, the TT group had a significantly higher occurrence of major bleeding than the other groups (HR 3.87; 95% CI 1.41-10.68; p=0.009). In conclusion, poor metabolizers of CYP2C19 and TT groups of P2Y12 G52T may be significant predictors of poor clinical outcomes in elderly patients.

What is known and objective Pre-treatment of clopidogrel 600 mg is better than 300 mg loading for reducing periprocedural myocardial infarction (PMI). We aimed to evaluate pre-treatment methods for preventing PMI among patients undergoing conventional coronary angiography (CAG) for stable angina pectoris. Materials and methods The study analyzed 402 patients who underwent percutaneous coronary intervention (PCI) during 2010 - 2011 at three Korean hospitals. Clopidogrel-naive patients received routine maintenance therapy (75 mg/day for ≥ 5 days) and were randomly assigned to a 300-mg reload (RL) or only the maintenance dose (MD). Patients who received a loading dose (LD; 600 mg at 2 - 24 hours before the procedure) were entered into a non-randomized group. Results After excluding patients who showed an abnormal creatinine kinase myocardial band (CK-MB) level, the study included 233 patients in the LD group, 85 patients in the RL group and 84 patients in the MD group. The LD group had a significantly higher rate of PMI (LD: 21, RL: 3, MD: 0 cases; p = 0.007) and a significant increase in the mean CK-MB levels after 8 hours (p = 0.016) and 24 h (p = 0.01). However, there was no difference in PMI between the RL and MD groups. Furthermore, no significant differences between the three groups were observed in the P2Y12 reaction unit (PRU) values (p = 0.57). Albeit not significantly, the LD group had a higher rate of moderate-to-severe GUSTO bleeding within 7 days. What is new and conclusion Clopidogrel maintenance is better than 600-mg loading for preventing PMI, and the RL protocol did not further prevent PMI. .

PURPOSE: To evaluate the feasibility of coronary iodine concentration (CIC) by using spectral CT in the assessment of the outcome of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). MATERIALS AND METHODS: In total, 50 consecutive patients underwent preprocedural coronary CT angiography with spectral CT prior to their staged PCI for CTO between June 2017 and July 2018. Iodine density maps, referred to as iodine-no-water maps throughout, with spectral CT provided the CIC at proximal CTO (CTO-CIC). Depending on the outcome of PCI, all CTO lesions were divided into two groups: failed PCI and successful PCI. The receiver operating characteristic curve was used to determine the cutoff values of CTO-CIC in the assessment of the outcome of PCI for CTO. RESULTS: Of the 50 CTO lesions in 50 patients, 34 (68%) and 16 (32%) were assigned to the successful PCI and failed PCI groups, respectively. The mean CTO-CIC was significantly less in the failed PCI group than in the successful PCI group (1.3 mg/mL ± 0.9 [standard deviation] vs 5.2 mg/mL ± 2.5; P < .001). A low CTO-CIC (≤ 2.5 mg/mL) predicted failed PCI with 87% sensitivity, 79% specificity, 79% positive predictive value, and 90% negative predictive value. At multivariable analysis, the low CTO-CIC was significantly associated with the failed PCI (odds ratio, 27.0; 95% confidence interval: 4.9, 147.6; P < .0001). CONCLUSION: The CTO-CIC determined by using spectral CT may be useful in the assessment of the outcome of staged PCI for CTO. See also the commentary by Rubinshtein and Blankstein in this issue. © RSNA, 2020

Thymosin Beta4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

UNSTRUCTURED Common data model (CDM) is a data representation standard that unifies the observational database scheme for each medical institution and allows an analysis using the same tools. Although the analysis for CDM data does not directly examine a medical institution’s original data, it is essential to establish a policy that considers the CDM database operating environment because privacy issues cannot be avoided. The observational medical outcomes partnership common data model (OMOP CDM) defined by Observational Health Data Sciences and Informatics, a nonprofit organization, eliminates most personal information when constructing the database by design principles. When transforming the database of the medical institution to the OMOP CDM structure, the original data “source_value” is maintained to minimize information loss, which may cause the re-identification of the individual. This review presents a de-identification strategy for the original data, which can be considered when operating a CDM database in a public computing environment such as cloud computing. Furthermore, we evaluate the re-identification risk to the CDM database based on the proposed strategy using privacy models such as k-anonymity, l-diversity, and t-closeness. The analysis shows that the CDM database is highly anonymized on average (the highest re-identification record ration is 11.3 %), but every table in the CDM database contains one or more re-identifiable records. It has been confirmed that the risk of re-identification is reduced significantly by applying a de-identification strategy.

There have been limited clinical trials comparing drug eluting stents (DESs) and drug coated balloons (DCBs) in the treatment of femoropopliteal artery disease. This two centre retrospective and prospective cohort study sought to compare DES with DCB for the treatment of native femoropopliteal artery disease.A total of 288 limbs (242 patients) with native femoropopliteal artery disease were treated with DESs (Zilver PTX; 102 limbs) or DCBs (IN.PACT Admiral; 186 limbs) in two Korean endovascular centres between 19 January 2013 and 5 May 2018 and followed for a median duration of 19.6 months. The primary endpoint was primary clinical patency. Propensity score matching (PSM, 162 limbs) and inverse probability weighted (IPW) adjustment were performed to adjust for confounding baseline characteristics.The DCB group had fewer lesions with Trans-Atlantic Inter-Society Consensus (TASC) II type C/D (55.9% vs. 70.6%, p = .021) or total occlusions (43.5% vs. 77.5%, p .001) and showed shorter lesion lengths (164.2 ± 105.4 mm vs. 194.8 ± 86.8 mm, p = .009) than the DES group. After PSM, baseline clinical and lesion characteristics of the two groups were comparable except for larger reference vessel diameter in the DES group (5.4 ± 0.6 vs. 5.1 ± 0.7, p = .025). Adjunctive atherectomy was performed in 32.1% of the DCB group and in 2.5% of the DES group (p .001). The provisional stenting was required in 14.8% of the DCB group. At two year follow up, the DCB group showed higher primary clinical patency (74.6% vs. 56.7%, hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.27-0.96, p = .032) and freedom from target lesion revascularisation (85.9% vs. 71.3%, HR 0.39, 95% CI 0.17-0.89, p = .021) than the DES group. Survival from all cause death did not differ between groups (87.6% vs. 92.1%, HR 1.85, 95% CI 0.62-5.52, p = .26).In this two centre cohort, DCBs with selective use of adjunctive atherectomy achieved more favourable outcomes than DESs for native femoropopliteal artery disease.

Thymosin &beta, 4 (T&beta, 4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with T&beta, 4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with T&beta, 4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, T&beta, 4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with T&beta, 4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with T&beta, 4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the T&beta, 4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with T&beta, 4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with T&beta, 4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

Background The current guidelines recommend both repeat stenting and drug-coated balloons (DCB) for in-stent restenosis (ISR) lesions, if technically feasible. However, real-world clinical data on the interventional strategies in patients with left main bifurcation (LMB)-ISR have not been elucidated. Methods Seventy-five patients with LMB-ISR, who underwent percutaneous coronary intervention (PCI) between January 2009 and July 2015, were retrospectively reviewed for the present study (repeat drug eluting stent [DES] implantation [n = 51], DCB angioplasty [n = 24]). Results Analysis of the baseline characteristics showed that the patients in the DCB group had a lower incidence of non-ST segment elevation myocardial infarction/ST segment elevation myocardial infarction at the index PCI (8.3% vs. 25.5%; p = 0.12), higher low-density lipoprotein-cholesterol level (92.9 mg/dL vs. 81.7 mg/dL; p = 0.09), and more “stent-in-stent” lesions (25% vs. 7.8%; p = 0.07) than those in the DES group. A smaller post-procedural minimal target lesion lumen diameter was also noted in the DCB group than in the DES group (2.71 mm vs. 2.85 mm; p = 0.03). The cumulative incidence rates of major adverse cardiac events (MACEs) were similar between both groups (median follow-up duration, 868 days; MACE rate, 25% in the DCB group vs. 25.5% in the DES group; p = 0.96). The multivariate Cox regression analysis indicated that the true bifurcation of ISR was an independent risk predictor of MACEs (hazard ratio, 4.62; 95% confidence interval, 1.572–13.561; p Conclusions DES and DCB showed comparable long-term clinical results in patients with LMB-ISR lesions.

BACKGROUND AND OBJECTIVES The Sapien 3 (S3) valve has not been compared to the Sapien XT (SXT) valve in Korea. We compared procedural and clinical outcomes between the 2 devices. METHODS A total of 189 patients who underwent transcatheter aortic valve replacement (TAVR) with S3 (n=95) or SXT (n=94) valve was analyzed. The primary endpoint was cardiovascular mortality at 1 year. The median follow-up duration was 438 days. RESULTS The Society of Thoracic Surgeons score was similar between the 2 groups. The device success rate (90.4% vs. 97.9%; p=0.028) was higher in the S3 than in the SXT. The S3 showed significantly fewer cases of moderate or severe paravalvular leakage (PVL) (16.7% vs. 0.0%; p=0.001) than the SXT. However, effective orifice area (EOA) (2.07±0.61 vs. 1.70±0.49 cm²; p

Background Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. Methods Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. Results The optimal conditions for S-GECS was determined to be 1052 GECS cells/mm2 and a 48 h culture period to produce spheroids. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl2-induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. Conclusions Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).

Platelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Searching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.Nine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (The PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.ClinicalTrials.gov Identifier: NCT04734028.

Background As body fat composition and metabolism differ between men and women, we evaluated sex-related differences in the association among epicardial adipose tissue (EAT), secretome profile, and myocardial function of subjects with suspected metabolic syndrome. Methods We evaluated 277 participants (men, n = 140; 56.1 ± 4.7 years) who underwent conventional echocardiography and two-dimensional speckle tracking from the Seoul Metabolic Syndrome cohort. EAT was measured from the right ventricular free wall perpendicular to the aortic annulus at end systole. Global longitudinal strain (GLS) was obtained from 18 apical segments. Apolipoprotein A1, apolipoprotein B, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) levels were measured using immunoturbidimetry assay. Results Mean age, body mass index, and hs-CRP level did not differ by sex. Waist circumference, fasting blood glucose level, and triglyceride/high-density lipoprotein cholesterol ratio were higher, and apolipoprotein AI and adiponectin levels were lower in men. No significant difference in mean EAT thickness was found (7.02 ± 1.81 vs. 7.13 ± 1.70 mm, p = 0.613). Men had a higher left ventricular (LV) mass index and lower GLS. EAT thickness was associated with hs-CRP level in men alone (ß = 0.206, p = 0.015). LV mass index (ß = 2.311, p = 0.037) and function represented by e′ (ß = − 0.279, p = 0.001) and GLS (ß = − 0.332, p Conclusions In middle-aged subjects with suspected metabolic syndrome, EAT was associated with inflammation represented by hs-CRP level, LV mass, and subclinical myocardial dysfunction only in men, suggesting that the inflammatory activity of EAT induced myocardial remodeling and dysfunction in middle-aged subjects but was attenuated in women. Trial registration NCT02077530 (date of registration: November 1, 2013)

Background/Aims: Although epigallocatechin-3-gallate (EGCG), which is found in high contents in the dried leaves of green tea, has been reported to have an an ti-platelet effect, synergistic effects of EGCG in addition to current anti-platelet medications remains to be elucidated. Methods: Blood samples were obtained from 40 participants who took aspirin (ASA, n = 10), clopidogrel (CPD, n = 10), ticagrelor (TCG, n = 10) and no anti-plate let medication (Control, n = 10). Ex vivo platelet aggregation and adhesion under various stimulators were analyzed by multiple electrode aggregometry (MEA) and Impact-R systems. PAC-1 and P-selectin expressions in human platelets were ana lyzed by flow cytometry. Results: In MEA analysis, adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP)-induced platelet aggregations were lower in the CPD and the TCG groups; arachidonic acid (AA)-induced platelet aggregation was low er in the ASA group, whereas collagen (COL)-induced platelet aggregations were comparable among four groups. EGCG significantly reduced ADP- and COL-in duced platelet aggregation in dose-dependent manner (ADP, p = 0.04; COL, p < 0.01). There were no additional suppressions of platelet aggregation stimulated by AA in the ASA group, and by ADP in the CPD and TCG groups. Moreover, EGCG suppressed shear stress-induced platelet adhesion on Impact-R, and had no effect on P-selectin and PAC-1 expressions. Conclusions: Ex vivo treatment of EGCG inhibited platelet adhesion and aggrega tion without changes in P-selectin and PAC-1 expression. There was no additional suppressions in platelet aggregation stimulated by AA in the ASA group and ADP in the CPD and TCG groups.

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI). The relationship of platelet reactivity and genetic polymorphism with clinical outcomes with newer-generation drug-eluting stents is unclear. We analysed 4,587 patients for the most powerful single-nucleotide polymorphisms (CYP2C19, CYP2C9, ABCB1, PON1, and P2Y12) related to on-treatment platelet reactivity (OPR). The optimal cut-off value of high OPR for major adverse thrombotic events was 266. CYP2C19 was significantly associated with high OPR and the number of CYP2C19*R (*2 or *3) alleles was proportional to the increased risk of high OPR. Death, myocardial infarction (MI), stroke, stent thrombosis, and bleeding events were assessed during a 1-year follow-up period. Primary endpoints were death and non-fatal MI. The cumulative 1-year incidence of death and stent thrombosis was significantly higher in patients with CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3 (Group 3) than in patients with CYP2C19*1/*1 (Group 1). Multivariate Cox proportional hazard model showed that cardiac death risk was significantly higher in Group 3 than in Group 1 (hazard ratio 2.69, 95% confidence interval 1.154–6.263, p = 0.022). No association was reported between bleeding and OPR. Thus, CYP2C19 may exert a significant impact on the prognosis of PCI patients even in the era of newer-generation drug-eluting stents.

Nanotopography plays a pivotal role in the regulation of cellular responses. Nonetheless, little is known about how the gradient size of nanostructural stimuli alters the responses of endothelial progenitor cells without chemical factors. Herein, the fabrication of gradient nanopattern plates intended to mimic microenvironment nanotopography is described. The gradient nanopattern plates consist of nanopillars of increasing diameter ranges [120–200 nm (GP 120/200), 200–280 nm (GP 200/280), and 280–360 nm (GP 280/360)] that were used to screen the responses of human endothelial colony-forming cells (hECFCs). Nanopillars with a smaller nanopillar diameter caused the cell area and perimeter of hECFCs to decrease and their filopodial outgrowth to increase. The structure of vinculin (a focal adhesion marker in hECFCs) was also modulated by nanostructural stimuli of the gradient nanopattern plates. Moreover, Rho-associated protein kinase (ROCK) gene expression was significantly higher in hECFCs cultured on GP 120/200 than in those on flat plates (no nanopillars), and ROCK suppression impaired the nanostructural-stimuli-induced vinculin assembly. These results suggest that the gradient nanopattern plates generate size-specific nanostructural stimuli suitable for manipulation of the response of hECFCs, in a process dependent on ROCK signaling. This is the first evidence of size-specific nanostructure-sensing behavior of hECFCs. Significance Nano feature surfaces are of growing interest as materials for a controlled response of various cells. In this study, we successfully fabricated gradient nanopattern plates to manipulate the response of blood-derived hECFCs without any chemical stimulation. Interestingly, we find that the sensitive nanopillar size for manipulation of hECFCs is range between 120 nm and 200 nm, which decreased the area and increased the filopodial outgrowth of hECFCs. Furthermore, we only modulate the nanopillar size to increase ROCK expression can be an attractive method for modulating the cytoskeletal integrity and focal adhesion of hECFCs.

A novel tissue engineering strategy using 3D bio-print technology has become a promising therapeutic method for acute myocardial infarction (AMI) in an animal model. However, the application of 3D bio-printed tissue remains limited due to poor graft survival. Therefore, it is a scientific priority to enhance graft survival by precisely adjusting the 3D environment of encapsulated cells. In this study, novel transplantable 3D cardiac mesh (cMesh) tissue with a porous mesh structure was presented using human cardiomyocytes, human cardiac fibroblasts, and gelatin-methacryloyl-collagen hydrogel. Cardiomyocytes and cardiac fibroblasts were well spreaded. The cardiomyocytes were connected with a gap junction channel in bio-printed cMesh and a 3D cardiac patch with an aggregated structure. Porous cMesh demonstrated structural advantages by increased phosphorylation of mTOR, AKT, and ERK signals associated with cell survival. Transplanted cMesh in rats with AMI improved long-term graft survival, vessel formation, and stabilization, reduced fibrosis, increased left ventricle thickness, and enhanced cardiac function. Our results suggest that porous cMesh provides structural advantages and a positive therapeutic effect in an AMI animal model.

Background: Previous studies have shown conflicting results on the benefits of deferred stenting (DS) in infarct size and the incidence of microvascular obstruction in patients with ST elevation myocardial infarction (STEMI). However, effect of DS on left ventricular (LV) function was not known. We aimed to evaluate whether DS improve LV function and relevant clinical outcomes after STEMI, using follow-up data from the INNOVATION study (NCT02324348). Methods: In total, 114 patients were randomly assigned to DS group or immediate stenting (IS) group at a 1:1 ratio. LV functional remodeling indices and MACE (major adverse cardiac events: a composite of death, non-fatal MI, unplanned target vessel revascularization, or hospitalization due to heart failure) were compared between DS and IS groups. Results: Serial echocardiographic analyses were completed in 89 subjects (78%). There were no significant changes in LV volume in either group. While LV ejection fraction and wall motion score index (WMSI) improved in both groups during follow-up, the increments were not statistically different between the 2 groups (4.3 ± 8.2 vs 3.2 ± 7.1, P = .504 for ΔLV ejection fraction; –0.16 ± 0.25 vs –0.16 ± 0.25, P = .99 for ΔWMSI). However, E/e′’ was decreased and e′ was increased only in the DS group (–3.31 ± 5.60 vs –0.46 ± 3.10, P = .005 for ΔE/e′; 0.77 ± 1.71 vs –0.22 ± 1.64, P = .009 for Δe′). The incidence of major adverse cardiac events was numerically lower in the DS group than in the IS group without a statistical significance at 1-year follow-up. Conclusions: Routine DS improved LV diastolic function but not systolic function compared with IS in patients with STEMI.

Background: No large-scale study has compared the clinical and angiographic predictors of cardiovascular events in patients with left main bifurcation (LMB) and non-LMB stenting after second-generation DES implantation. Herein, we investigated differential clinical and angiographic factors for predicting outcomes in LMB versus non-LMB stenting. Methods: A total of 2648 patients with bifurcation lesions treated with second-generation DESs from the retrospective patient cohort were divided into an LMB group (n = 935) and a non-LMB group (n = 1713). The primary outcome was the 7-year incidence of target lesion failure (TLF), defined as the composite of cardiac death, myocardial infarction, and target lesion revascularization. Results: The incidence of TLF was 9.8%. Those in the LMB group were associated with a higher risk of TLF (14.2% versus 7.5%, p &lt, 0.001) than those in the non-LMB group. Regarding the LMB group, independent predictors of TLF were chronic kidney disease (CKD), reduced left ventricular ejection fraction (LVEF), and two-stenting. Regarding the non-LMB group, CKD, reduced LVEF, old age, diabetes, and small diameter of the main vessel stent were independent predictors of TLF. Conclusions: The two-stent strategy could potentially increase TLF for the LMB lesions, and achieving the maximal diameter of the main vessel stent could result in better clinical outcomes for non-LMB lesions.

Adipose-derived stem cells (ASCs) have potential of differentiating into endothelial lineage and are easily obtainable, therefore they are promising candidates for stem cell therapy. Thymosin beta 4 (Tb4) is G-actin sequestering protein that exerts a broad range of functions such as cell migration and angiogenesis. In this study, we investigated the effects of Tb4 on angiogenic and endothelial differentiation potential of ASCs. Exogenous treatment of Tb4 (100 ng/mL) induced a significant increase in endogenous mRNA expression of Tb4, and morphological changes with increased cell length in ASCs. In addition, Tb4-treated ASCs showed significantly higher endothelial differentiation potential than untreated ASCs after the induction of endothelial differentiation for 3 weeks. The expression of endothelial markers such as PDGFRb and CD144 were significantly enhanced by the treatment of Tb4 with the endothelial differentiation induction media compared to untreated ASCs. Indeed, Tb4-treated ASCs expressed higher expression of angiogenic genes including Ang-1, vWF, Tie1, CXCR4, uPAR, FGFR4, IGFR2, and VE-Cadherin than untreated ASCs, both cultured in the endothelial differentiation induction media. Moreover, a scratch wound healing assay revealed that the treatment of Tb4 significantly increased cell migration compared to untreated and Tb4-siRNA transfected ASCs. In the microbead sprouting assay, the treatment of Tb4 significantly augmented the number of sprouts per bead and the length of sprouts compared to untreated and Tb4-siRNA transfected ASCs. Futhermore, transplantation of ASCs with Tb4 induced neovascularization improved the blood flow in mouse ischemic hind limb models, compared to sham, ASC-transplanted, and Tb4-transplanted groups. Taken together, therapeutic application of ASCs with Tb4 could be useful to enhance endothelial differentiation and neovascularization.

Integration of adipose-derived stem cells (ASCs) and cell sheet engineering technology has received much interest in the regenerative medicine. First of all, sphere formation of ASCs (sph-ASCs) were successfully produced by poly-2-hydroxyethyl methacrylate (poly-HEMA)-coated plates as we previously reported. Sph-ASCs showed increased expression of angiogenic growth factors and cytokine secretion compared to adherent ASCs. Significantly increased expression of HIF-1α and decreased expression of cleaved caspase-3 were detected in sph-ASCs compared to adherent ASCs. Moreover, ASC sheets were formed using thermo-responsive plates and sph-ASCs were seeded to produce ASC sheets covered with sph-ASCs (sph-ASC sheets). After 48 hrs of incubation, the cross-section of sph-ASC sheets revealed mixed and multi-layered of sph-ASCs and ASC sheets. Sph-ASC sheets showed the positive expression of HIF-1α and angiogenic markers such as FGF-2, CD31, PDGFb, and CD144, especially higher in sph-ASC-covered sites. In addition, cytokine arrays of secretome revealed that sph-ASCs and sph-ASC sheets showed augmented angiogenic potential compared to adherent ASCs. Furthermore, four groups of AMI induction only (sham), intramyocardial injection of sph-ASC, ASC sheet transplantation, and sph-ASC sheet transplantation were compared using acute myocardial infarction (AMI) rat models. After 6 weeks of transplantation, echocardiography revealed that significantly improved ejection fraction and fraction shortening in sph-ASC sheet group compared to sham, sph-ASC, and ASC sheet groups. In conclusion, transplantation of sph-ASC sheets showed enhanced neovascularization in AMI animal models. These results indicated that the use of ASC sheets as a novel tissue engineering approach to improve the cardiac and vascular function.