Patterns of Circadian Variation in 24-Hour Ambulatory Blood Pressure, Heart Rate, and Sympathetic Tone Correlate with Cardiovascular Disease Risk: A Cluster Analysis.

To investigate whether specific time series patterns for blood pressure (BP), heart rate (HR), and sympathetic tone are associated with metabolic factors and the 10-year risk of atherosclerotic cardiovascular disease (ASCVD). A total of 989 patients who underwent simultaneous 24-hour ambulatory BP and Holter electrocardiogram monitoring were enrolled. The patients were categorized into sixteen groups according to their circadian patterns using the consensus clustering analysis method. Metabolic factors, including cholesterol profiles and apolipoprotein, were compared. The 10-year ASCVD risk was estimated based on the Framingham risk model. Overall, 16 significant associations were found between the clinical variables and cluster groups. Age was commonly associated with all clusters in systolic BP (SBP), diastolic BP (DBP), HR, and sympathetic tone. Metabolic indicators, including diabetes, body mass index, total cholesterol, high-density lipoprotein, and apolipoprotein, were associated with the four sympathetic tone clusters. In the crude analysis, the ASCVD risk increased incrementally from clusters 1 to 4 across SBP, DBP, HR, and sympathetic tone. After adjustment for multiple variables, however, only sympathetic tone clusters 3 and 4 showed a significantly high proportion of patients at high risk (≥7.5%) of 10-year ASCVD (odds ratio (OR) = 5.90, 95% confidential interval (CI) = 1.27-27.46, and P value = 0.024 and OR = 15.28, 95% CI = 3.59-65.11, and P value < 0.001, respectively). Time series patterns of BP, HR, and sympathetic tone can serve as an indicator of aging. Circadian variations in sympathetic tone can provide prognostic information about patient metabolic profiles and indicate future ASCVD risk.

CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis.

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.

A Genetic Risk Score for Atrial Fibrillation Predicts the Response to Catheter Ablation.

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.

Machine Learning for the Prediction of New-Onset Diabetes Mellitus during 5-Year Follow-up in Non-Diabetic Patients with Cardiovascular Risks.

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.

Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure.

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.

Hyperuricaemia and development of type 2 diabetes mellitus in Asian population.

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.

Impact of diabetes mellitus on 5-year clinical outcomes in patients with chronic total occlusion lesions.

BACKGROUND: Diabetes mellitus (DM) is a major predictor of cardiovascular morbidity and mortality. However, there are limited data on the impact of DM in patients who have chronic total occlusion (CTO) lesion on long-term outcomes. PATIENTS AND METHODS: A total of 822 CTO patients who underwent coronary angiography, treated by either percutaneous coronary intervention or optimal medical therapy, were enrolled and divided into two groups: (i) diabetic group (n=363) and (ii) nondiabetic group (n=459). Individual and composite major clinical outcomes were compared up to 5 years. RESULTS: Propensity score matching analysis was carried out generating two groups (298 pairs, n=596, C-statistic=0.655) with balanced baseline characteristics. Up to 5 years, the DM group showed a higher trend toward revascularization (19.5 vs. 13.5%, P=0.051) and major adverse cardiovascular events (MACE) (24.7 vs. 19.1%, P=0.097) compared with the nondiabetic group. However, there was no difference in the incidence of death and myocardial infarction between the two groups. Subgroup analysis showed that the chronic kidney disease (CKD) subgroup was associated with a higher incidence of all-cause death, cardiac death, myocardial infarction, revascularization, and MACE in comparison with diabetic patients without CKD and nondiabetic patients, respectively (total MACE: 39 vs. 20.5 vs. 19.2% , P=0.001). Insulin-dependent diabetic patients had a significantly higher incidence of MACE (hazard ratio=1.58; 95% confidence interval: 1.04-2.40; P=0.03) compared with the nondiabetic patients. CONCLUSION: Diabetic patients with CTO were associated with a trend toward a higher incidence of revascularization and total MACE up to 5 years. Insulin-dependent and diabetic patients with CKD subgroups had a significantly higher incidence of total MACE.

Five-year major clinical outcomes according to severity of coronary artery spasm as assessed by intracoronary acetylcholine provocation test.

BACKGROUND: Long-term clinical outcome data according to severity of coronary artery spasm (CAS) as assessed by an intracoronary acetylcholine provocation test are limited in series of Asian patients. AIM: To investigate 5-year clinical outcomes in patients with CAS according to CAS severity. METHODS: In total, 5873 consecutive patients with insignificant coronary artery disease (<70% fixed stenosis) who underwent an acetylcholine provocation test were enrolled and divided into four groups according to CAS severity during the acetylcholine provocation test: negative, borderline positive, moderately positive and severely positive. CAS severity was assessed by quantitative coronary angiography. We investigated 5-year clinical outcomes according to CAS severity. RESULTS: Over a follow-up period of up to 5 years, before adjustment, the severely-positive CAS group showed a significantly higher incidence of major adverse cardiac events (MACE; composite of death, myocardial infarction and de novo revascularization) (hazard ratio [HR]: 1.834, 95% confidence interval [CI]: 1.047-3.211; P=0.033), total death (HR: 3.124, 95% CI: 1.047-9.322; P=0.041), myocardial infarction (HR: 3.190, 95% CI: 1.069-9.519; P=0.037) and recurrent angina (HR: 1.762, 95% CI: 1.363-2.278; P<0.001) compared with the negative group. However, after adjustment for baseline confounders, only the incidence of recurrent angina (HR: 1.323, 95% CI: 1.014-1.726; P=0.039) was significantly higher in the severely-positive CAS group compared with the negative group. CONCLUSIONS: The severity of CAS in the positive group was not associated with an increased incidence of MACE after adjustment for covariates compared with the negative group, but the severely-positive CAS group was associated with a higher incidence of recurrent angina compared with the negative group.

Selective ß1-Blockers Are Not Associated With New-onset Diabetes Mellitus in Hypertensive Patients.

BACKGROUND: Although ß-blockers are known to increase new-onset diabetes mellitus (DM), previous evidence have been controversial. It has been suggested that newer vasodilatory ß-blockers yield better glycemic control than older nonselective agents. The aim of this study was to evaluate the diabetogenicity of currently used newer ß-blockers based on ß1 receptor selectivity in a series of Asian population. METHODS: We investigated a total of 65,686 hypertensive patients without DM from 2004 to 2014. Patients with hemoglobin (Hb) A1c ≤6.0%, fasting blood glucose ≤110 mg/dL, and no history of diabetes or diabetic treatment were enrolled for analysis. Patients were divided into the ß-blockers group and non-ß-blockers group. Propensity score matching (PSM) analysis using a logistic regression model was performed to adjust for potential confounders. The primary end point was the cumulative incidence of new-onset DM, defined as a fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5%, and major adverse cardiac and cerebral events (MACCE), defined as a composite of total death, nonfatal myocardial infarction, and cerebrovascular accidents. We investigated predictors of new-onset DM and MACCE based on 2 models, including clinical risk factors and co-medications, respectively. RESULTS: Mean follow-up duration was 30.91 ± 23.14 months in the entire group before adjustment. The ß-blockers group had a significantly higher incidence of new-onset DM and MACCE than the non-ß-blockers group. After PSM, analysis of a total of 2284 patients (1142 pairs, C-statistic = 0.752) showed no difference between the 2 groups in new-onset DM or MACCE. In multivariate analysis after PSM, baseline HbA1c, stroke, heart failure, nonselective ß-blockers, and age were independent predictors of new-onset DM. Selective ß1-blockers did not increase new-onset DM after adjustment for other antihypertensive medication and statins. CONCLUSIONS: In the era of newer ß-blockers, selective ß1-blockers were not associated with new-onset DM. More evidence is needed to verify this relationship and the underlying mechanisms.

A novel interaction perturbation analysis reveals a comprehensive regulatory principle underlying various biochemical oscillators.

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.

Three-Year Major Clinical Outcomes of Angiography-Guided Single Stenting Technique in Non-Complex Left Main Coronary Artery Diseases.

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.

Influence of Sex on the Association Between Epicardial Adipose Tissue and Left Atrial Transport Function in Patients With Atrial Fibrillation: A Multislice Computed Tomography Study.

BACKGROUND: Epicardial adipose tissue (EAT) is known to play an important role in atrial fibrillation substrate remodeling; however, the influence of sex on the association between EAT and left atrial (LA) transport function has not been elucidated. METHODS AND RESULTS: Of the 514 patients who underwent an index atrial fibrillation ablation procedure, 123 postmenopausal women with no history of hormone replacement therapy and 123 men who were matched for age, body mass index, type of atrial fibrillation, and CHADS2 score were enrolled. Before the procedure, LA volume, LA emptying fraction, and EAT volume were assessed using multislice computed tomography. Blood samples were obtained from a coronary sinus for analysis of serum adiponectin level before the ablation procedure. There were no differences in baseline demographics and laboratory findings between sexes. Compared with men, women had significantly less total EAT (P<0.001) and higher serum adiponectin levels (P=0.022) but higher proportions of periatrial EAT to total EAT volume (P/T EAT ratio, P<0.001), lower LA emptying fraction (P=0.042), and lower LA voltage (P=0.034). The ratio of periatrial to total EAT volume correlated significantly with LA emptying fraction and LA voltage in both sexes, whereas total EAT volume and serum adiponectin level did not. On multivariate analysis, increased LA volume and higher periatrial:total EAT volume ratio were independent predictors of decreased LA emptying fraction in both sexes. CONCLUSIONS: Compared with matched men, postmenopausal women with atrial fibrillation had higher periatrial adiposity, which was independently correlated with decreased LA voltage and LA transport function.

Routine Angiographic Follow-Up versus Clinical Follow-Up after Percutaneous Coronary Intervention in Acute Myocardial Infarction.

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.

Three-year follow-up of patients with acetylcholine-induced coronary artery spasm combined with insignificant coronary stenosis.

BACKGROUND: Coronary artery spasm (CAS) and significant coronary stenosis are known to be major causes of myocardial ischemia. However, their association and the impact of insignificant coronary stenosis (ICS) on long-term clinical outcomes of CAS patients are largely unknown. METHODS: A total of 2797 patients without significant coronary artery disease (CAD) who underwent the acetylcholine (ACH) provocation test between November 2004 and October 2010 were enrolled. Significant CAS was defined as having ≥70% of temporary narrowing by ACH test and ICS as having <70% of fixed stenosis on angiography. Patients were divided into two groups: ICS group (n=764) and non-ICS group (n=845). To adjust potential confounders, a propensity score matching (PSM) analysis was performed using the logistic regression model. Primary endpoint was the composite of total death, myocardial infraction (MI), de novo percutaneous coronary intervention (PCI), and cerebrovascular accidents (CVA). Secondary endpoint was the incidence of recurrent angina requiring repeat coronary angiography (CAG) at 3years. RESULTS: After PSM analysis, two well-balanced groups (548 pairs, total=1096) were generated. The baseline clinical characteristics were similar between the two groups. During the ACH test, compared with the non-ICS group, the ICS group had smaller spastic narrowing diameter (0.69±0.35 vs. 0.73±0.37, P=0.039) and incidence of ST-segment depression (4.0% vs. 0.9%, P=0.001). The incidence of primary and secondary endpoints was similar between the two groups up to 3years. CONCLUSIONS: Although, the ICS group was expected to have more adverse long-term clinical outcomes, it was not associated with the increased incidence of major adverse clinical outcomes compared with the non-ICS group up to 3years. Longer term follow-up studies are needed.

Routine angiographic follow-up versus clinical follow-up in patients with multivessel coronary artery diseases following percutaneous coronary intervention with drug-eluting stents: a nested case-control study within a Korean population.

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.

Context-independent essential regulatory interactions for apoptosis and hypertrophy in the cardiac signaling network.

Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure and are known to be regulated by complex interactions in the underlying intracellular signaling network. Previous experimental studies were successful in identifying some key signaling components, but most of the findings were confined to particular experimental conditions corresponding to specific cellular contexts. A question then arises as to whether there might be essential regulatory interactions that prevail across diverse cellular contexts. To address this question, we have constructed a large-scale cardiac signaling network by integrating previous experimental results and developed a mathematical model using normalized ordinary differential equations. Specific cellular contexts were reflected to different kinetic parameters sampled from random distributions. Through extensive computer simulations with various parameter distributions, we revealed the five most essential context-independent regulatory interactions (between: (1) αAR and Gαq, (2) IP3 and calcium, (3) epac and CaMK, (4) JNK and NFAT, and (5) p38 and NFAT) for hypertrophy and apoptosis that were consistently found over all our perturbation analyses. These essential interactions are expected to be the most promising therapeutic targets across a broad spectrum of individual conditions of heart failure patients.

Changes in Left Atrial Transport Function in Patients Who Maintained Sinus Rhythm After Successful Radiofrequency Catheter Ablation for Atrial Fibrillation: A 1-Year Follow-Up Multislice Computed Tomography Study.

BACKGROUND: Functional remodeling of left atrium (LA) after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) has not been fully elucidated. This study aimed to determine the impact of RFCA on LA transport function in patients who maintained sinus rhythm (SR) after AF ablation. METHODS AND RESULTS: A total of 96 patients (paroxysmal AF [PAF] = 52) who maintained SR during 1 year after AF ablation were enrolled. Multislice computed tomography was performed to determine LA volume (LAV) and LA emptying fraction (LAEF) at pre-RFCA and 1-year post-RFCA. Creatine kinase-MB (CK-MB) and troponin-T levels were analyzed 1-day post-RFCA. At 1-year post-RFCA, mean LAV and LAEF decreased in overall patients. Based on LAEF change (ΔLAEF) cutoff of 5.0%, LAEF reduced in 41 patients (worsened group) and improved or showed no change in 55 patients (preserved group). Compared with preserved group, worsened group had a higher proportion of PAF, higher levels of CK-MB and troponin-T, and additional LA ablation. ΔLAEF was inversely correlated with CK-MB and troponin-T levels. Subgroup analysis showed that LAEF significantly decreased in PAF patients who underwent additional LA ablation. Multivariate analysis revealed that high baseline LAEF and additional LA ablation were independent predictors for worsened LAEF. CONCLUSIONS: Although SR was maintained for 1 year after AF ablation, LAEF as well as LAV decreased. The extent of LAEF deterioration was significantly associated with the amount of iatrogenic myocardial damage. Our data indicate that extensive atrial ablation may lead to LA functional deterioration, especially in patients with PAF.

Systems biological approaches to the cardiac signaling network.

Recent systems biological studies of cardiac systems have greatly advanced our understanding of cardiac physiology with a particular focus on the excitation-contraction coupling. With these advancements, there is a growing interest in systems analysis of the cardiac signaling network because its dynamical property is closely associated with cardiac diseases. In this article, we review recent attempts at computational modeling of the cardiac signaling network and provide a system-level perspective on the analysis of the large-scale cardiac signaling network. We discuss why the systems biological approach is useful and what novel insights it can provide for the development of personalized therapeutic strategies for cardiac diseases in the post-genomic era.

The switching role of ß-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes.

How cell fate (survival or death) is determined and whether such determination depends on the strength of stimulation has remained unclear. In this study, we discover that the cell fate of cardiomyocytes switches from survival to death with the increase of ß-adrenergic receptor (ß-AR) stimulation. Mathematical simulations combined with biochemical experimentation of ß-AR signalling pathways show that the gradual increment of isoproterenol (a non-selective ß1/ß2-AR agonist) induces the switching response of Bcl-2 expression from the initial increase followed by a decrease below its basal level. The ERK1/2 and ICER-mediated feed-forward loop is the hidden design principle underlying such cell fate switching characteristics. Moreover, we find that ß1-blocker treatment increases the survival effect of ß-AR stimuli through the regulation of Bcl-2 expression leading to the resistance to cell death, providing new insight into the mechanism of therapeutic effects. Our systems analysis further suggests a novel potential therapeutic strategy for heart disease.

Spinal cord injury after conducting transcatheter arterial chemoembolization for costal metastasis of hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) has been used widely to treat patients with unresectable hepatocellular carcinoma. However, this method can induce various adverse events caused by necrosis of the tumor itself or damage to nontumor tissues. In particular, neurologic side effects such as cerebral infarction and paraplegia, although rare, may cause severe sequelae and permanent disability. Detailed information regarding the treatment process and prognosis associated with this procedure is not yet available. We experienced a case of paraplegia that occurred after conducting TACE through the intercostal artery to treat hepatocellular carcinoma that had metastasized to the rib. In this case, TACE was attempted to relieve severe bone pain, which had persisted even after palliative radiotherapy. A sudden impairment of sensory and motor functions after TACE developed in the trunk below the level of the sternum and in both lower extremities. The patient subsequently received steroid pulse therapy along with supportive care and continuous rehabilitation. At the time of discharge the patient had recovered sufficiently to enable him to walk by himself, although some paresthesia and spasticity remained.