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Recently, meta-analysis studies reported that hyperuricaemia is associated with higher incidence of type 2 diabetes mellitus (T2DM), however, there are limited data on the Asian population. The aim of this observational study is to estimate the long-term impact of hyperuricaemia on the new-onset T2DM and cardiovascular events. This study is based on a single-centre, all-comers, and large retrospective cohort. Subjects that visited from January 2004 to February 2014 were enrolled using the electronic database of Korea University Guro Hospital. A total of 10 505 patients without a history of T2DM were analyzed for uric acid, fasting glucose and haemoglobin (Hb) A1c level. Inclusion criteria included both Hb A1c <5.7% and fasting glucose level <100 mg/dL without T2DM. Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dL in men, and ≥6.5 mg/dL in women. To adjust baseline confounders, a propensity score matching (PSM) analysis was performed. The impact of hyperuricaemia on the new-onset T2DM and cardiovascular events were compared with the non-hyperuricaemia during the 5-year clinical follow-up. After PSM, baseline characteristics of both groups were balanced. In a 5-year follow-up, the hyperuricaemia itself was a strong independent predictor of the incidence of new-onset T2DM (HR, 1.78; 95% CI, 1.12 to 2.8). Hyperuricaemia was a strong independent predictor of new-onset T2DM, which suggests a substantial implication for a correlation between uric acid concentration and insulin resistance (or insulin sensitivity). Also, hyperuricaemia is substantially implicated in cardiovascular risks and the further long-term cardiovascular events in the crude population, but it is not an independent predictor of long-term cardiovascular mortality in the matched population. [ABSTRACT FROM AUTHOR]

Intestinal-type gastric cancer often results from Helicobacter pylori infection through intestinal metaplasia, a transdifferentiated premalignant phenotype. Because H. pylori virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with H. pylori infection and function during gastric carcinogenesis in normal gastric epithelial cells and gastric cancer cell lines. Infection of HFE 145 cells with CagA + H. pylori increased expression of CDX1, as well as the epithelial-to-mesenchymal transition (EMT) markers Snail and Slug, increased invasion and migration, but those effects were not found in HFE 145 cells infected with CagA-deficient H. pylori . CDX1 overexpression increased expression of the intestinal markers Villin, sucrose isomaltase (SI), and MUC2, induced spheroid formation, and enhanced expression of the stem cell markers CD44, SOX2, Oct4, and Nanog, while CDX1 knockdown inhibited proliferation and intestinal stemness. Treatment of CDX1-expressing cells with metformin, an antidiabetic drug known to decrease the risk of gastric cancer, decreased expression of EMT and stemness markers, and reduced spheroid formation. In a murine xenograft model, combining metformin or shCDX1 with cisplatin reduced tumor growth, increased caspase-3 cleavage, and reduced expression of CD44 and MMP-9 to a greater degree than cisplatin alone. Patients with more advanced intestinal metaplasia staging exhibited higher CDX1 expression than those with earlier intestinal metaplasia staging ( P = 0.039), and those with H. pylori tended to have more CDX1 expression than noninfected patients ( P = 0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/SOX2 expression. Our findings indicate CagA + H. pylori -induced CDX1 expression may enhance gastric cancer tumorigenesis and progression, and support therapeutic targeting of CDX1 in gastric cancer. IMPLICATIONS: This study shows that CDX1 contributes to the tumorigenesis and progression of gastric cancer and suggests the potential of targeting CDX1 to treat this malignancy., (©2019 American Association for Cancer Research.)

Background and Objectives: The association of susceptibility loci for atrial fibrillation (AF) with AF recurrence after ablation has been reported, although with controversial results. In this prospective cohort analysis, we aimed to investigate whether a genetic risk score (GRS) can predict the rhythm outcomes after catheter ablation of AF., Methods: We determined the association between 20 AF-susceptible single nucleotide polymorphisms (SNPs) and AF recurrence after catheter ablation in 746 patients (74% males; age, 59±11 years; 56% paroxysmal AF). A GRS was calculated by summing the unweighted numbers of risk alleles of selected SNPs. A Cox proportional hazard model was used to identify the association between the GRS and risk of AF recurrence after catheter ablation., Results: AF recurrences after catheter ablation occurred in 168 (22.5%) subjects with a median follow-up of 23 months. The GRS was calculated using 5 SNPs (rs1448818, rs2200733, rs6843082, rs6838973 at chromosome 4q25 [ PITX2 ] and rs2106261 at chromosome 16q22 [ ZFHX3 ]), which showed modest associations with AF recurrence. The GRS was significantly associated with AF recurrence (hazard ratio [HR] per each score, 1.13; 95% confidence interval [CI], 1.03-1.24). Patients with intermediate (GRS 4-6) and high risks (GRS 7-10) showed HRs of 2.00 (95% CI, 0.99-4.04) and 2.66 (95% CI, 1.32-5.37), respectively, compared to patients with low risk (GRS 0-3)., Conclusions: Our novel GRS using 5 AF-susceptible SNPs was strongly associated with AF recurrence after catheter ablation in Korean population, beyond clinical risk factors. Further efforts are warranted to construct a generalizable, robust genetic prediction model which can guide the optimal treatment strategies., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019. The Korean Society of Cardiology.)

Purpose: Many studies have proposed predictive models for type 2 diabetes mellitus (T2DM). However, these predictive models have several limitations, such as user convenience and reproducibility. The purpose of this study was to develop a T2DM predictive model using electronic medical records (EMRs) and machine learning and to compare the performance of this model with traditional statistical methods., Materials and Methods: In this study, a total of available 8454 patients who had no history of diabetes and were treated at the cardiovascular center of Korea University Guro Hospital were enrolled. All subjects completed 5 years of follow up. The prevalence of T2DM during follow up was 4.78% (404/8454). A total of 28 variables were extracted from the EMRs. In order to verify the cross-validation test according to the prediction model, logistic regression (LR), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), and K-nearest neighbor (KNN) algorithm models were generated. The LR model was considered as the existing statistical analysis method., Results: All predictive models maintained a change within the standard deviation of area under the curve (AUC) <0.01 in the analysis after a 10-fold cross-validation test. Among all predictive models, the LR learning model showed the highest prediction performance, with an AUC of 0.78. However, compared to the LR model, the LDA, QDA, and KNN models did not show a statistically significant difference., Conclusion: We successfully developed and verified a T2DM prediction system using machine learning and an EMR database, and it predicted the 5-year occurrence of T2DM similarly to with a traditional prediction model. In further study, it is necessary to apply and verify the prediction model through clinical research., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2019.)

Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure (HF), a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive mathematical model of the cardiac signaling network by integrating all available experimental evidence. Attractor landscape analysis of the network model identifies distinct sets of control nodes that effectively suppress apoptosis and hypertrophy of cardiomyocytes under ischemic or pressure overload-induced HF, the two major types of HF. Intriguingly, our system-level analysis suggests that intervention of these control nodes may increase the efficacy of clinical drugs for HF and, of most importance, different combinations of control nodes are suggested as potentially effective candidate drug targets depending on the types of HF. Our study provides a systematic way of developing mechanism-based therapeutic strategies for HF.

There is limited long-term comparative clinical outcome data concerning angiography- versus intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) in non-complex left main coronary artery (LMCA) disease treated with the single stenting technique in the drug-eluting stent (DES) era.The aim of this study was to investigate whether angiography-guided stenting is comparable to IVUS-guided stenting during 3-year clinical follow-up periods in patients with non-complex LM disease treated with the single stenting technique.A total of 196 patients treated with either angiography-guided (n = 74) or IVUS-guided (n = 122) PCI were included. The primary outcome was the occurrence of major adverse cardiac events (MACE) defined as total death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and non-target vessel revascularization (Non-TVR). To adjust for any potential confounders, propensity score (PS) adjusted analysis was performed.During 3-year follow-up, the PS adjusted Cox-proportional hazard ratio (HR) was not significantly different between the two groups for total death, cardiac death, and MI. Also, TLR and the combined rates of TVR and non-TVR were not significantly different. Finally, MACE was not significantly different between the two groups (HR: 0.63, 95% Confidence interval (CI): 0.33-1.17; P = 0.149).Angiography-guided PCI for non-complex LMCA diseases treated with the single stenting technique showed comparable results compared with IVUS-guided PCI in reducing clinical events during 3-year clinical follow-up in the DES era. Although IVUS guided PCI is the ideal strategy, angiography-guided PCI can be an option for LMCA PCI in some selected cases.

Background: Biochemical oscillations play an important role in maintaining physiological and cellular homeostasis in biological systems. The frequency and amplitude of oscillations are regulated to properly adapt to environments by numerous interactions within biomolecular networks. Despite the advances in our understanding of biochemical oscillators, the relationship between the network structure of an oscillator and its regulatory function still remains unclear. To investigate such a relationship in a systematic way, we have developed a novel analysis method called interaction perturbation analysis that enables direct modulation of the strength of every interaction and evaluates its consequence on the regulatory function. We have applied this new method to the analysis of three representative types of oscillators., Results: The results of interaction perturbation analysis showed different regulatory features according to the network structure of the oscillator: (1) both frequency and amplitude were seldom modulated in simple negative feedback oscillators; (2) frequency could be tuned in amplified negative feedback oscillators; (3) amplitude could be modulated in the incoherently amplified negative feedback oscillators. A further analysis of naturally-occurring biochemical oscillator models supported such different regulatory features according to their network structures., Conclusions: Our results provide a clear evidence that different network structures have different regulatory features in modulating the oscillation frequency and amplitude. Our findings may help to elucidate the fundamental regulatory roles of network structures in biochemical oscillations.

Purpose: Differences in the utility of routine angiographic follow-up (RAF) and clinical follow-up (CF) after percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are not well understood. The present study aimed to compare the 3-year clinical outcomes of RAF and CF in AMI patients who underwent PCI with drug-eluting stents (DES)., Materials and Methods: A total of 774 consecutive AMI patients who underwent PCI with DES were enrolled. RAF was performed at 6 to 9 months after index PCI (n=425). The remaining patients were medically managed and clinically followed (n=349); symptom-driven events were captured. To adjust for any potential confounders, a propensity score matched analysis was performed using a logistic regression model, and two propensity-matched groups (248 pairs, n=496, C-statistic=0.739) were generated. Cumulative clinical outcomes up to 3 years were compared between RAF and CF groups., Results: During the 3-year follow-up period, the cumulative incidences of revascularization [target lesion revascularization: hazard ratio (HR), 2.40; 95% confidence interval (CI), 1.18-4.85; p=0.015, target vessel revascularization (TVR): HR, 3.33; 95% CI, 1.69-6.58; p=0.001, non-TVR: HR, 5.64; 95% CI, 1.90-16.6; p=0.002] and major adverse cardiac events (MACE; HR, 3.32; 95% CI, 1.92-5.73; p<0.001) were significantly higher in the RAF group than the CF group. However, the 3-year incidences of death and myocardial infarction were not different between the two groups., Conclusion: RAF following index PCI with DES in AMI patients was associated with increased incidences of revascularization and MACE. Therefore, CF seems warranted for asymptomatic patients after PCI for AMI., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2017)

Objective: The difference in the usefulness of routine angiographic follow-up (RAF) and clinical follow-up (CF) after a percutaneous coronary intervention (PCI) in multivessel coronary artery disease (MVD) patients has not been well clarified as yet., Patients and Methods: A total of 642 consecutive MVD patients who underwent PCI with drug-eluting stents (DES) were enrolled. RAF was performed at 6-9 months after the index PCI (n=374) and others were medically managed and clinically followed (n=268). Patients who experienced clinical events including death, myocardial infarction (MI), and ischemia-driven PCI before 1 year were excluded. To adjust for any potential confounders, a propensity scorematched analysis was carried out using the logistic regression model and two propensity-matched groups (193 pairs, n=386, C-statistic=0.744) were generated. Cumulative clinical outcomes up to 3 years were compared between the RAF group and the CF group., Results: During the 3-year follow-up period, the cumulative incidence of revascularization [target lesion revascularization: odds ratio (OR), 4.21; 95% confidence interval (CI), 1.67-10.6; P=0.001) and target vessel revascularization (TVR: OR, 4.69; 95% CI, 2.00-11.0; P<0.001, target vessel revascularization: OR, 4.69; 95% CI, 2.00-1011.0; P<0.001] and major adverse cardiovascular events (composite of death, repeat PCI and MI: OR, 2.96; 95% CI, 1.62-105.42, P<0.001) were significantly higher in the RAF group compared with the CF group. However, the 3-year incidence of death (OR, 1.41; 95% CI, 0.44-104.53; P=0.558) or MI (OR, 2.58; 95% CI, 0.79-108.37; P=0.102) was not different between the two groups. In MVD patients treated with second-generation DESs, the incidence of repeat revascularization (target lesion revascularization and target vessel revascularization) was not different between the two groups., Conclusion: Conclusion RAF following index PCI with DES in multivessel CAD patients was associated with increased incidence of revascularization and major adverse cardiovascular events. However, in MVD patients treated with second-generation DESs, repeat revascularization incidence was similar between two different follow-up strategies up to 3 years.