Association of Long Noncoding RNA Expression Signatures with Stress-Induced Myocardial Perfusion Defects.

Stress-induced myocardial perfusion defects found in dipyridamole-thallium-201 single-photon emission computed tomography imaging may indicate vascular perfusion abnormalities and risk of obstructive or nonobstructive coronary heart disease. Besides nuclear imaging and subsequent coronary angiography (CAG), no blood test can indicate whether dysregulated homeostasis is associated with stress-induced myocardial perfusion defects. This study investigated the expression signature of long noncoding RNAs (lncRNAs) and genes involved in vascular inflammation and stress response in the blood of patients with stress-induced myocardial perfusion abnormalities (n = 27). The results revealed an expression signature consisting of the upregulation of RMRP (p < 0.01) and downregulations of THRIL (p < 0.01) and HIF1A (p < 0.01) among patients with a positive thallium stress test and no significant coronary artery stenosis within 6 months after baseline treatment. We developed a scoring system based on the expression signatures of RMRP, MIAT, NTT, MALAT1, HSPA1A, and NLRP3 to predict the need for further CAG among patients with moderate-to-significant stress-induced myocardial perfusion defects (area under the receiver operating characteristic curve = 0.963). Therefore, we identified a dysregulated expression profile of lncRNA-based genes in the blood that could be valuable for the early detection of vascular homeostasis imbalance and personalized therapy.

Impacts of Lesion Characteristics on Procedures and Outcomes of Chronic Total Occlusion Recanalization With Antegrade Guidewire True Lumen Tracking Techniques: A Substudy of Taiwan True Lumen Tracking Registry.

Background: Lesion characteristics were shown to predict procedural success and outcomes in chronic total occlusion (CTO) recanalization. However, diverse techniques involved in these studies might cause potential heterogeneity. Objective: The study aimed to test the impacts of lesion characteristics on CTO intervention with a pure antegrade wiring-based technique. Methods and Results: We studied consecutive 325 patients (64.5 ± 11.1 years, 285 men) with native CTO lesions intervened by a single operator with an antegrade-based technique between August 2014 and July 2020. Forty-seven patients with antegrade procedural failure (20 with pure antegrade wiring failure and 27 with back-up retrograde techniques) were compared to 278 patients with antegrade-only procedural success. With a median follow-up of 30.8 (16.1-48.6) months, 278 patients with procedural success were further assessed for target vessel failure (TVF: cardiac death, target vessel myocardial infarction [MI], and target lesion revascularization [TLR]). Patients with antegrade procedural success had a lower percentage of history with bypass graft (4 vs. 15%, p = 0.004) and lower Multicenter Chronic Total Occlusion Registry of Japan (J-CTO) score (2.1±1.3 vs. 3.4 ± 1.0, p < 0.001), when compared to those with antegrade failure. The J-CTO score was independently associated with procedural failure (odds ratio = 2.5, 95% CI = 1.8-3.4) in multivariate analysis. However, only clinical features, such as female gender (hazard ratio [HR] = 4.3, 95% CI = 1.4-13.1), estimated glomerular filtration rate <60 ml/min/1.73 m2 (HR = 3.2, 95% CI = 1.0-9.9), and old MI (HR = 4.5, 95% CI = 1.5-12.8), but not J-CTO score, could predict long-term TVF in multivariate Cox regression model. Conclusion: The feasibility of the antegrade guidewire-crossing technique for native CTO intervention was highly determined by lesion characteristics. With such a simpler technique, the prognostic impact of lesion complexity shown in studies with multiple recanalization techniques was negligible. This suggested antegrade true lumen tracking techniques deserved to be tried better even for CTO lesions with higher complexity.

Association Between Specificity of Sulfonylureas to Cardiac Mitochondrial KATP Channels and the Risk of Major Adverse Cardiovascular Events in Type 2 Diabetes.

OBJECTIVE: Previous studies have revealed an intraclass difference in major adverse cardiovascular events (MACE) among sulfonylureas. In vitro and ex vivo studies reported several sulfonylureas to exhibit high-affinity blockage of cardiac mitochondrial ATP-sensitive potassium (mitoKATP) channels and could interfere with ischemic preconditioning, the most important mechanism of self-cardiac protection. However, no studies have examined whether these varying binding affinities of sulfonylureas could account for their intraclass difference in MACE. We compared mitoKATP channel high-affinity versus low-affinity sulfonylureas regarding the MACE risk in real-world settings. RESEARCH DESIGN AND METHODS: Using the Taiwan nationwide health care claims database, patients with type 2 diabetes initiating sulfonylurea monotherapy between 2007 and 2016 were included in the cohort study. A total of 33,727 new mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylurea users, respectively, were identified after 1:1 propensity score matching. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) and 95% CI. RESULTS: MitoKATP channel high-affinity sulfonylureas were associated with a significantly increased risk of three-point MACE (aHR 1.21 [95% CI 1.03-1.44]), ischemic stroke (aHR 1.23 [95% CI 1.02-1.50]), and cardiovascular death (aHR 2.61 [95% CI 1.31-5.20]), but not with that of myocardial infarction (aHR 1.04 [95% CI 0.75-1.46]). The duration-response analyses revealed the highest MACE risk to be within 90 days of therapy (aHR 4.67 [95% CI 3.61-6.06]). CONCLUSIONS: Cardiac mitoKATP channel high-affinity sulfonylureas were associated with an increased MACE risk compared with low-affinity sulfonylureas in a nationwide population with diabetes.

A deep learning-based system capable of detecting pneumothorax via electrocardiogram.

PURPOSE: To determine if an electrocardiogram-based artificial intelligence system can identify pneumothorax prior to radiological examination. METHODS: This is a single-center, retrospective, electrocardiogram-based artificial intelligence (AI) system study that included 107 ECGs from 98 pneumothorax patients. Seven patients received needle decompression due to tension pneumothorax, and the others received thoracostomy due to instability (respiratory rate ≥ 24 breaths/min; heart rate, < 60 beats/min or > 120 beats/min; hypotension; room air O2 saturation, < 90%; and patient could not speak in whole sentences between breaths). Traumatic pneumothorax and bilateral pneumothorax were excluded. The ECGs of 132,127 patients presenting to the emergency department without pneumothorax were used as the control group. The development cohort included approximately 80% of the ECGs for training the deep learning model (DLM), and the other 20% of ECGs were used to validate the performance. A human-machine competition involving three physicians was conducted to assess the model performance. RESULTS: The areas under the receiver operating characteristic (ROC) curves (AUCs) of the DLM in the validation cohort and competition set were 0.947 and 0.957, respectively. The sensitivity and specificity of our DLM were 94.7% and 88.1% in the validation cohort, respectively, which were significantly higher than those of all physicians. Our DLM could also recognize the location of pneumothorax with 100% accuracy. Lead-specific analysis showed that lead I ECG made a major contribution, achieving an AUC of 0.930 (94.7% sensitivity, 86.0% specificity). The inclusion of the patient characteristics allowed our AI system to achieve an AUC of 0.994. CONCLUSION: The present AI system may assist the medical system in the early identification of pneumothorax through 12-lead ECG, and it performs as well with lead I ECG alone as with 12-lead ECG.

Profiles of Hospitalized Patients with Angiographic Coronary Heart Disease in Taiwan during 2014-2016: Report of a Tertiary Hospital.

BACKGROUND: The Taiwan Society of Cardiology (TSOC) has established multicenter registries for coronary artery disease (CAD) to investigate clinical characteristics, management and risks for mortality. However, the impacts of newly-emerged evidence-based therapies, including the use of drug-eluting stents (DESs), on patients with CAD in Taiwan remain unclear. METHODS: The Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry is a single-center, prospective, longitudinal registry in Taiwan containing data from 2014-2016. Individuals who were admitted for coronary angiography were enrolled. Patient profiles, management and in-hospital outcome data were collected. RESULTS: We included 3352 patients: 2349 with stable angina and 1003 with acute coronary syndrome (ACS). In the stable angina group, both patients receiving stenting and those receiving medical treatment had a 0.7% mortality rate; DESs were used in 70.4% of the patients receiving stenting. In the ACS group, the patients receiving stenting and those receiving medical treatment had a 4.9% and 10.7% mortality rate, respectively; DESs were used in 63.1% of the patients receiving stenting. In the 2008-2010 Taiwan ACS registry, DESs were used in only 28% of all stenting procedures, and the estimated hospital mortality rate was 1.8%. Multivariate analysis indicated that older age, prior stroke, and cardiogenic shock on admission were associated with an increased risk of in-hospital mortality in the ACS group. CONCLUSIONS: Compared with the Taiwan ACS cohort, the TSGH-CHD registry revealed increased DES use and increased disease complexity and severity after 2010. Although unlikely to significantly improve survival, interventionists seemed to perform high-risk procedures for complex CAD more often in the new DES era.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting ß2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting ß2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

BACKGROUND: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting ß2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. RESEARCH QUESTION: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? STUDY DESIGN AND METHODS: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. RESULTS: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. INTERPRETATION: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

A deep learning algorithm for detecting acute myocardial infarction.

BACKGROUND: Delayed diagnosis or misdiagnosis of acute myocardial infarction (AMI) is not unusual in daily practice. Since a 12-lead electrocardiogram (ECG) is crucial for the detection of AMI, a systematic algorithm to strengthen ECG interpretation may have important implications for improving diagnosis. AIMS: We aimed to develop a deep learning model (DLM) as a diagnostic support tool based on a 12-lead electrocardiogram. METHODS: This retrospective cohort study included 1,051/697 ECGs from 737/287 coronary angiogram (CAG)-validated STEMI/NSTEMI patients and 140,336 ECGs from 76,775 non-AMI patients at the emergency department. The DLM was trained and validated in 80% and 20% of these ECGs. A human-machine competition was conducted. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the performance of the DLM. RESULTS: The AUC of the DLM for STEMI detection was 0.976 in the human-machine competition, which was significantly better than that of the best physicians. Furthermore, the DLM independently demonstrated sufficient diagnostic capacity for STEMI detection (AUC=0.997; sensitivity, 98.4%; specificity, 96.9%). Regarding NSTEMI detection, the AUC of the combined DLM and conventional cardiac troponin I (cTnI) increased to 0.978, which was better than that of either the DLM (0.877) or cTnI (0.950). CONCLUSIONS: The DLM may serve as a timely, objective and precise diagnostic decision support tool to assist emergency medical system-based networks and frontline physicians in detecting AMI and subsequently initiating reperfusion therapy.

Prognostic Effect of Restoring Sinus Rhythm in Patients with New-Onset Atrial Fibrillation during Acute Coronary Syndrome.

BACKGROUND: New-onset atrial fibrillation (NOAF) in acute coronary syndrome (ACS) may be associated with a poor prognosis. However, whether restoring sinus rhythm (SR) at discharge in patients with ACS improves outcomes remains unknown. METHODS: A total of 552 patients with ACS at an emergency department during 2011-2016 were enrolled. According to documented electrocardiography at admission and medical records, the patients were classified into without atrial fibrillation (WAF), NOAF, and prior atrial fibrillation (PAF) groups. Major adverse events (MAEs) were defined as cardiac death, recurrent myocardial infarction, heart failure requiring hospitalization, target lesion revascularization, and stroke. The mean follow-up period of MAEs was 25 ± 15 months. RESULTS: Compared with the NOAF and PAF groups, the WAF group was younger and had a significantly lower heart rate, prior stroke rate, CHA2DS2-VASc score, and lower Global Registry of Acute Coronary Events (GRACE) score in the emergency department (p < 0.001). The patients in the NOAF group had the highest incidence of MAEs (p < 0.001) during follow-up, and those whose SR was restored at discharge had a lower MAE rate than those with AF at discharge (p = 0.001). In multivariable analysis, prior myocardial infarction, GRACE score, use of beta-blockers, and restoring SR at discharge were independent predictors of MAEs in the NOAF group. CONCLUSIONS: The patients with ACS who presented with NOAF had worse outcomes than those with PAF or WAF. The patients with NOAF whose rhythm was restored to SR at discharge were associated with better outcomes than those with AF at discharge.

Effects of Pitavastatin, Atorvastatin, and Rosuvastatin on the Risk of New-Onset Diabetes Mellitus: A Single-Center Cohort Study.

Statins constitute the mainstay treatment for atherosclerotic cardiovascular disease, which is associated with the risk of new-onset diabetes mellitus (NODM). However, the effects of individual statins on the risk of NODM remain unclear. We recruited 48,941 patients taking one of the three interested statins in a tertiary hospital between 2006 and 2018. Among them, 8337 non-diabetic patients taking moderate-intensity statins (2 mg/day pitavastatin, 10 mg/day atorvastatin, and 10 mg/day rosuvastatin) were included. The pitavastatin group had a higher probability of being NODM-free than the atorvastatin and rosuvastatin groups during the 4-year follow-up (log-rank test: p = 0.038). A subgroup analysis revealed that rosuvastatin had a significantly higher risk of NODM than pitavastatin among patients with coronary artery disease (CAD) (adjusted HR [aHR], 1.47, 95% confidence interval [CI], 1.05-2.05, p = 0.025), hypertension (aHR, 1.26, 95% CI, 1.00-1.59, p = 0.047), or chronic obstructive pulmonary disease (COPD) (aHR, 1.74, 95% CI, 1.02-2.94, p = 0.04). We concluded that compared with rosuvastatin, reduced diabetogenic effects of pitavastatin were observed among patients treated with moderate-intensity statin who had hypertension, COPD, or CAD. Additional studies are required to prove the effects of different statins on the risk of NODM.

Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study.

PURPOSE: To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. METHODS: We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). RESULTS: We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). CONCLUSIONS: Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

The association of ischaemic stroke in patients with heart failure without atrial flutter/fibrillation.

PURPOSE: This study evaluated the association between ischaemic stroke (IS) and heart failure (HF) in the absence of atrial fibrillation (AF) or atrial flutter (AFL) using a population-based nation-wide cohort database. METHOD: Newly diagnosed patients with HF without previous stroke and acute myocardial infarction (AMI) were enrolled. Based on the propensity scores matching age, sex and all comorbidities, our studies comprised 12 179 patients with HF and 12 179 patients without HF. Cox proportion hazard regression models and competing-risk regression models were used to evaluate the risk of IS among patients with HF without AF or AFL. RESULTS: In the multivariable analysis, older age (adjusted HR (95% CI)=1.05 (1.04 to 1.05)), male sex (adjusted HR (95% CI)=1.36 (1.24 to 1.50)), diabetes (adjusted HR (95% CI)=2.22 (1.97 to 2.49)) and hypertension (adjusted HR (95% CI)=1.60 (1.41 to 1.82)) were markedly associated with IS in patients with HF. The HF group had a markedly higher risk of IS than did the non-HF group (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66) and AMI (SHR=3.40, 95% CI: 2.71 to 4.28). Additionally, according to the Kaplan-Meier analysis, patients with HF were at a significantly higher risk of cumulative incidence of IS and AMI than did patients with non-HF (p value of log-rank test <0.001). CONCLUSION: This study indicated that HF is a strong independent risk factor for IS, even in the absence of AF or AFL. Clinical physicians should investigate IS through routine screening and careful monitoring of patients with HF.

Acute myocarditis complicated with permanent complete atrioventricular block caused by Escherichia coli bacteremia: A rare case report.

RATIONALE: Acute myocarditis complicated with complete atrioventricular block (CAVB) is rare in clinical scenario. We report an uncommon case of myocarditis complicated with permanent CAVB caused by Escherichia coli (E coli) bacteremia. PATIENT CONCERNS: A 77-year-old woman presented at the emergency department with chest pain, dizziness, nausea, and cold sweats of 1-day duration. She had histories of type 2 diabetes mellitus, hyperlipidemia, and chronic kidney disease with regular medical therapy. DIAGNOSIS: Both blood and urine cultures were positive for E coli. Regional inferior wall motion abnormalities on echocardiography, unexplained life-threatening arrhythmias, newly abnormal electrocardiogram, elevated cardiac troponins, and healthy coronary arteries on angiography were consistent with E coli-induced myocarditis. INTERVENTIONS: The patient received implantation of a dual-chamber pacemaker because of irreversible CAVB. OUTCOMES: The patient was discharged on day 8 and remained asymptomatic at 15 months of follow-up, with ST-segment normalization and normal left ventricular function. LESSONS: This extremely rare case of E coli-induced myocarditis masquerading as acute STEMI and with permanent CAVB sequelae, highlights the importance of sensitivity to non-ischemia etiologies of ST-segment elevation and the potential impact of E coli sepsis on the cardiac conduction system.

Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells.

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.

Risk of adverse cardiovascular events with use of inhaled long-acting bronchodilators in management of chronic obstructive pulmonary disease.

Inhaled long-acting bronchodilators, including long-acting ß2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapy in the treatment of chronic obstructive pulmonary disease (COPD), a disease that poses a heavy burden on morbidity and mortality worldwide. Use of LABAs and LAMAs in patients with COPD, however, has been concerned about an increased risk of adverse cardiovascular events, despite inconsistent findings reported from randomized controlled trials (RCTs) and observational studies. In this review, we detailed the relevant evidence generated from RCTs and observational studies with respect to the risk of cardiovascular disease with use of LABAs and LAMAs in management of COPD, and analyzed the contradictory findings in the literature, as well as recommended future research directions to clear the air regarding the cardiovascular safety of inhaled long-acting bronchodilators.

Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting ß2 agonists (LABAs) and inhaled corticosteroids (ICSs) in a nationwide population with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: This nested case-control study included 65,966 patients with COPD treated with LABAs and ICSs identified from the Taiwan nationwide health care claims database from January 1, 2007, through June 30, 2011. Cases were all patients with a first primary diagnosis of ischemic heart disease, heart failure, stroke, or arrhythmia from inpatient or emergency care settings during follow-up, and each was matched with 4 disease risk score-matched controls from risk sets. The use of tiotropium in the year before the index/event date was measured, stratified by duration since therapy initiation, concomitant COPD medications, and dosage form. Conditional logistic regression models were used to estimate odds ratios of the CVD risk from add-on tiotropium therapy. RESULTS: From the study cohort, with a mean age of 70.3 years (interquartile range, 61.8-79.4 years), 3188 CVD cases (incidence rate, 6.2 [95% CI, 6.0-6.4] cases per 100 person-years) and 12,349 matched controls were identified. The new use of tiotropium was associated with a 1.88-fold (95% CI, 1.44-2.46) increased CVD risk within 30 days of therapy initiation, and the association was sustained up to 60 days after treatment initiation (adjusted odds ratio, 1.71; 95% CI, 1.08-2.70). The risk persisted across all tiotropium regimens, with a case-crossover analysis, and in comparison with new add-on theophylline therapy. CONCLUSION: Tiotropium newly added to LABA/ICS combination therapy was associated with an increased cardiovascular risk in patients with COPD.

Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease: A Nested Case-Control Study.

Importance: The associations between cardiovascular disease (CVD) and inhaled long-acting ß2-agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in chronic obstructive pulmonary disease (COPD) are greatly debated. Pivotal and relevant randomized clinical trials included prior LABA or LAMA users and excluded patients with baseline CVD; therefore, cardiovascular events arising from first-time LABA or LAMA use, if any, could not be observed. There is an urgent need to examine whether new use of and duration since initiating LABAs and LAMAs could act as important determinants of cardiovascular events. Objective: To investigate risk of CVD associated with LABAs and LAMAs, focusing on the initiation and duration of LABA and LAMA therapies. Design, Setting, and Participants: This nested case-control study included 284 220 LABA-LAMA-naïve patients with COPD at least 40 years old (mean age, 71.4 years; 68.9% men), retrieved from the Taiwan National Health Insurance Research Database for health care claims from 2007 to 2011. Exposure: LABA or LAMA use was measured in the year preceding the event or index date, stratified by duration since initiation of LABA or LAMA treatment, new and prevalent users, concomitant COPD medications, and individual agents. Main Outcomes and Measures: Cases with inpatient or emergency care visits for coronary artery disease, heart failure, ischemic stroke, or arrhythmia were identified and individually matched to 4 randomly selected controls. Conditional logistic regressions were performed to estimate odds ratios of CVD from LABA and LAMA treatment. Results: During a mean follow-up of 2.0 years, 37 719 patients with CVD (mean age, 75.6 years; 71.6% men) and 146 139 matched controls (mean age, 75.2 years; 70.1% men) were identified. New LABA and LAMA use in COPD was associated with a 1.50-fold (95% CI, 1.35-1.67; P < .001) and a 1.52-fold (95% CI, 1.28-1.80; P < .001) increased cardiovascular risk within 30 days of initiation, respectively, whereas the risk was absent, or even reduced with prevalent use. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not differ in the CVD risks. The risk persisted in an alternative case-crossover study and remained across subgroups without CVD history or prior exacerbations. Conclusions and Relevance: New initiation of LABAs or LAMAs in patients with COPD is associated with an approximate 1.5-fold increased severe cardiovascular risk, irrespective of prior CVD status and history of exacerbations.

JNK/AP-1 activation contributes to tetrandrine resistance in T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a challenging malignancy with a high relapse rate attributed to drug resistance. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from a Chinese herb, is a potential anti-cancer and anti-leukaemic drug. In this study we investigated the mechanisms of TET resistance in T-ALL cells in vitro. Among the four T-ALL cell lines tested, Jurkat and CEM cells exhibited the lowest and highest resistance to TET with IC50 values at 24 h of 4.31±0.12 and 16.53±3.32 µmol/L, respectively. When treated with TET, the activity of transcription factor activator protein 1 (AP-1) was significantly decreased in Jurkat cells but nearly constant in CEM cells. To avoid cell-specific variation in drug resistance and transcription factor activities, we established a TET-R Jurkat subclone with the estimated IC50 value of 10.90±.92 µmol/L by exposing the cells to increasing concentrations of TET. Interestingly, when treated with TET, TET-R Jurkat cells exhibited enhanced AP-1 and NF-κB activity, along with upregulation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways, whereas the expression of P-gp was not altered. Selective inhibition of JNK but not ERK suppressed AP-1 activity and TET resistance in TET-R Jurkat cells and in CEM cells. These results demonstrate that Jurkat cells acquire TET resistance through activation of the JNK/AP-1 pathway but not through P-gp expression. The JNK/AP-1 pathway may be a potential therapeutic target in relapsed T-ALL.

Chest Pain with Normal Thallium-201 Myocardial Perfusion Image - Is It Really Normal?

BACKGROUND: Thallium-201 myocardial perfusion image (MPI) is commonly used to detect coronary artery disease in patients with chest pain. Although a normal thallium-201 MPI result is generally considered to be a good prognosis and further coronary angiogram is not recommended, there are still a few patients who suffer from unexpected acute coronary events. The aim of this study was to investigate the clinical prognosis in patients with normal thallium-201 MPI. METHODS: From January 2006 to August 2012, a total 22,003 patients undergoing thallium-201 MPI in one tertiary center were screened. Of these, 8092 patients had normal results and were investigated retrospectively. During follow-up, 54 patients underwent coronary angiogram because of refractory typical angina pectoris or unexpected acute coronary events. These 54 patients were divided into 2 groups: group I consisted of 26 (48.1%) patients with angiography-proven significant coronary artery stenosis, and group II consisted of 28 (51.9%) patients without significant stenosis. RESULTS: Patients in group I had a higher prevalence of prior coronary stenting and electrocardiographic features of ST depression compared with patients in group II. The multivariate analysis demonstrated that both prior coronary stenting and ST depression were risk predictors of unexpected acute coronary events in the patients with normal thallium-201 MPI [odds ratio (OR), 5.93; 95% confidence interval (CI): 1.03-34.06, p = 0.05 and OR, 7.10; 95% CI: 1.28-39.51, p = 0.03,respectively]. CONCLUSIONS: Although there is a low incidence of unexpected acute coronary events in patients with chest pain and normal thallium-201 MPI, physicians should be aware of the potentials risk in certain patients in this specific population.

Use of antipsychotics and risk of venous thromboembolism in postmenopausal women. A population-based nested case-control study.

Despite continued uncertainty of venous thromboembolism (VTE) caused from antipsychotic agents, this safety issue has not been examined in postmenopausal women, a population with high usages of antipsychotics and at high risk for VTE. We assessed whether antipsychotic use was associated with an increased VTE risk in women after menopause. We conducted a nested case-control study of all Taiwanese women aged ≥ 50 years (n = 316,132) using a nationwide healthcare claims database between 2000 and 2011. All newly diagnosed VTE patients treated with an anticoagulant or thrombectomy surgery were identified as cases (n = 2,520) and individually matched to select controls (n = 24,223) by cohort entry date, age, cancer diagnosis and major surgery procedure. The odds ratios (ORs) and 95 % confidence interval (CI) of VTE associated with antipsychotics were estimated by multivariate conditional logistic regressions. Current use of antipsychotics was associated with a 1.90-fold (95 % CI = 1.64-2.19) increased VTE risk compared with nonuse in postmenopausal women. The VTE risk existed in a dose-dependent fashion (test for trend, p<0.001), with a more than quadrupled risk for high-dose antipsychotics (adjusted OR = 4.60; 95 % CI = 2.88-7.33). Current parenteral administration of antipsychotics also led to a 3.46-fold increased risk (95 % CI = 2.39-5.00). Conversely, there was no increased VTE risk when antipsychotics were discontinued for > 30 days. In conclusion, current use of antipsychotics is significantly associated with a dose-dependent increased risk of VTE in postmenopausal women, especially for those currently taking high-dose or receiving parenteral antipsychotics.

Risk of Coronary Artery Disease in Patients With Traumatic Intracranial Hemorrhage: A Nationwide, Population-Based Cohort Study.

Traumatic intracranial hemorrhage (ICH) is prevalent worldwide with long-term consequences, including disabilities. However, studies on the association of traumatic ICH with coronary artery disease (CAD) are scant. Therefore, this study explored the aforementioned association in a large-scale, population-based cohort. A total of 128,997 patients with newly diagnosed traumatic ICH and 257,994 age- and sex-matched patients without traumatic ICH from 2000 to 2010 were identified from Taiwan's National Health Insurance Research Database. The Kaplan-Meier method was used for measuring the cumulative incidence of CAD in each cohort. Cox proportional regression models were used for evaluating the risk of CAD in patients with and without traumatic ICH and for comparing the risk between the 2 cohorts. The Kaplan-Meier analysis revealed that the cumulative incidence curves of CAD were significantly higher in patients with traumatic ICH than in those without ICH (log-rank test, P < 0.001). After adjustment for age, sex, and comorbidities, patients with traumatic ICH were associated with a higher risk of CAD compared with those without traumatic ICH (adjusted hazard ratio = 1.16, 95% confidence interval = 1.13-1.20). Compared with the general population, patients with traumatic ICH and having underlying comorbidities, including diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, chronic kidney disease, and congestive heart failure, exhibited multiplicative risks of developing CAD. This cohort study revealed an increased risk of CAD in patients with traumatic ICH. Therefore, comprehensive evaluation and aggressive risk reduction for CAD are recommended in these patients.