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The ventricular arrhythmia (VA)–chronic obstructive pulmonary disease (COPD) association and related risk factors remain unclear. Using 2001–2012 data from National Health Insurance Research Database, we retrospectively reviewed 71,838 patients diagnosed as having COPD and 71,838 age- and sex-matched controls. After adjustments for comorbidities, medication, urbanization level, and monthly income, patients with COPD had higher incidence rates of VA than did the controls (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 1.45 [1.25–1.68]). More hospitalization or emergency visits because of acute COPD exacerbation (aHRs [95% CIs] for first, second, and third visits: 1.28 [1.08–1.50], 1.75 [1.32–2.32], and 1.88 [1.46–2.41], respectively) and asthma–COPD overlap (aHR [95% CI]: 1.49 [1.25–1.79]) were associated with high VA risk in patients with COPD. In the multivariate analysis, heart failure (aHR [95% CI]: 2.37 [1.79–3.14]), diabetes (aHR [95% CI]:1.64 [1.29–2.08]), age ≥75 (aHR [95% CI]: 2.48 [1.68–3.67]), male (aHR [95% CI]: 1.69[1.34–2.12]), and class III antiarrhythmic drug use (aHR [95% CI]: 2.49 [1.88–3.28]) are the most significant risk factors of new onset of VA in patients with COPD.

This study investigated differences in the utilization of healthcare services between subjects with mitral valve prolapse (MVP) and comparison subjects using data from Taiwan&rsquo, s National Health Insurance population-based database, 138,493 patients with MVP (study group) and 138,493 matched patients without MVP (comparison group). We calculated the utilization of healthcare services in the year 2016 for each study sample. Patients with MVP had more outpatient cardiological services during the year (5.3 vs. 0.7, p &lt, 0.001) and higher outpatient cardiology costs (US$226.0 vs. US$30.8, p &lt, 0.001) than patients without MVP. As expected, patients with MVP had a longer inpatient stay (0.5 vs. 0.1, p &lt, 0.001) and higher inpatients costs (US$158.0 vs. US$22.9, p &lt, 0.001) than patients without MVP for cardiology services. Furthermore, patients with MVP also had more outpatient non-cardiology services (20.8 vs. 16.5, p &lt, 0.001) and associated costs (US$708.3 vs. US$518.7, p &lt, 0.001) than patients without MVP in the year 2016. Multiple regression analysis indicated that patients with MVP had higher total costs for all healthcare services than patients without MVP after adjusting for the urbanization level, monthly income, and geographic region. This study demonstrated that healthcare utilization by patients with MVP is substantially higher than comparison patients. Future studies are encouraged to explore MVP treatment with less expensive modalities while maintaining care quality and without jeopardizing patient outcomes.

Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-β1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.

// Pai-Feng Kao 1, 6, * , Ju-Chi Liu 1, 6, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 6 , Tsung-Yeh Yang 1 , Wen-Rui Hao 1 , Ying-Chin Lin 2, 3 and Szu-Yuan Wu 4, 5, 6, 7 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, New Taipei, Taiwan 3 Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 6 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: influenza vaccination; atrial fibrillation; ischemic stroke Received: June 11, 2017 Accepted: July 26, 2017 Published: November 09, 2017 ABSTRACT Purpose: Atrial fibrillation (AF) is associated with the risk of ischemic stroke, regardless of the administration of appropriate antithrombotic prophylaxis. This study investigated whether influenza vaccination is associated with the risk of ischemic stroke, to determine a solution to reduce this risk in patients with AF. Methods: We used data from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients diagnosed as having AF (n = 14 454) before January 1, 2005; these patients were followed until December 31, 2012. The index date was January 1, 2005. A propensity score was derived using a logistic regression model to estimate the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A Cox proportional hazard model was used to calculate the hazard ratios (HRs) of ischemic stroke in vaccinated and unvaccinated patients with AF. Results: We included 6570 patients (2547 [38.77%] with and 4023 [61.23%] without influenza vaccination). The adjusted HRs (aHRs) of ischemic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.59, 0.50, and 0.55; P < 0.001, P < 0.001, and P < 0.001, respectively). Conclusions: Influenza vaccination might exert a dose-response effect against ischemic stroke in patients with AF who have risk factors for ischemic stroke by reducing the incidence of ischemic stroke, particularly in those aged 65–74 and ≥75 y.

Background This study investigated whether lipopolysaccharide (LPS) increase protease-activated receptor-2 (PAR-2) expression and enhance the association between PAR-2 expression and chemokine production in human vascular endothelial cells (ECs). Methods The morphology of ECs was observed through microphotography in cultured human umbilical vein ECs (EA. hy926 cells) treated with various LPS concentrations (0, 0.25, 0.5, 1, and 2 μg/mL) for 24 h, and cell viability was assessed using the MTT assay. Intracellular calcium imaging was performed to assess agonist (trypsin)-induced PAR-2 activity. Western blotting was used to explore the LPS-mediated signal transduction pathway and the expression of PAR-2 and adhesion molecule monocyte chemoattractant protein-1 (MCP-1) in ECs. Results Trypsin stimulation increased intracellular calcium release in ECs. The calcium influx was augmented in cells pretreated with a high LPS concentration (1 μg/mL). After 24 h treatment of LPS, no changes in ECs viability or morphology were observed. Western blotting revealed that LPS increased PAR-2 expression and enhanced trypsin-induced extracellular signal-regulated kinase (ERK)/p38 phosphorylation and MCP-1 secretion. However, pretreatment with selective ERK (PD98059), p38 mitogen-activated protein kinase (MAPK) (SB203580) inhibitors, and the selective PAR-2 antagonist (FSLLRY-NH2) blocked the effects of LPS-activated PAR-2 on MCP-1 secretion. Conclusions Our findings provide the first evidence that the bacterial endotoxin LPS potentiates calcium mobilization and ERK/p38 MAPK pathway activation and leads to the secretion of the pro-inflammatory chemokine MCP-1 by inducing PAR-2 expression and its associated activity in vascular ECs. Therefore, PAR-2 exerts vascular inflammatory effects and plays an important role in bacterial infection-induced pathological responses. Electronic supplementary material The online version of this article (10.1186/s12929-017-0393-1) contains supplementary material, which is available to authorized users.

ObjectiveTo investigate anticoagulant adherence and its associated factors, including demographics, clinical variables, atrial fibrillation (AF) severity, knowledge, satisfaction with services, perceived barriers, perceived benefits, symptom severity and self-efficacy in patients with AF.DesignThis is a cross-sectional study.Participants and settingA convenient sample of patients with AF were recruited from cardiology clinics of two teaching hospitals in Taiwan.MeasuresData were collected using the study questionnaires, including the AF-related symptom subscale of the AF Severity Scale, the Knowledge of Warfarin Anticoagulation Treatment Scale, the Satisfaction Scale about Service and Warfarin Treatment, the perceived benefits subscale of the Beliefs about Anticoagulation Survey, the Concerns about Anticoagulation Therapy Scale, The Self-efficacy for Appropriate Medication Use Scale and the short-form Adherence to Refills and Medications Scale.ResultsA total of 151 patients with AF participated in the study; 53 treated with warfarin and 98 treated with novel oral anticoagulants (NOACs). The difference in adherence to warfarin (mean=8.6; SD=1.6) and NOACs (mean=8.9; SD=2.0) was statistically insignificant. Multiple linear regression analysis showed that perceived barriers (β=0.18, p=0.017) and self-efficacy (β=−0.48, p(2,149)=38.11, pConclusionWe found no better adherence to NOACs compared with warfarin. Patients with greater self-efficacy and perceived fewer barriers showed better adherence to anticoagulation therapy.

Background: The association between atrial fibrillation (AF) and inflammation has been established. Diabetes mellitus (DM) is associated with increase inflammation and is an independent important risk factor of AF. Moreover, rhinosinusitis is an inflammation of the paranasal sinuses and nasal cavity. However, the association of rhinosinusitis as a risk factor of AF is unknown. The present study aimed to examine the association between rhinosinusitis, DM and AF. Methods: A total of 229,100 patients with the diagnosis of rhinosinusitis were identified as the study cohort from the Taiwan National Health Insurance Research Database from January 1, 2001, through December 31, 2012. The comparison cohort consisted of patients without rhinosinusitis and were match for age and sex with the study cohort at a ratio of 1:1. Incidence and hazard ratio (HR) of AF were calculated by Multivariable Cox regression models. Results: The incidence rate of AF was 142.4 per 10,000 person-years (95% CI 136.8-148.0) for the study cohort and 116.5 (95% CI 111.4-121.6) for the comparison cohort. Adjusted HR was 1.17 (95% CI 1.11-1.25) for the total study cohort, 1.18 (95% CI 1.11-1.25) for patients with acute sinusitis and 1.14 (95% CI 1.00-1.31) for chronic sinusitis. In subgroup analysis, HR for patients with DM was 1.23 (95% CI 1.09-1.39) for total study cohort, 1.20 (95% CI 1.06-1.37) for acute sinusitis and 1.44 (95% CI 1.13-1.84) for chronic sinusitis. The risk was less significant for patients with metformin use more than 28 days. HR 1.09 (95% CI 0.94-1.26) for total study cohort, 1.08 (95% CI 0.93-1.26) for acute sinusitis and 1.18 (95% CI 0.85-1.63) for chronic sinusitis. Conclusion: Rhinosinusitis was associated with the risk of AF. Sinusitis patients with DM had a higher risk than patients without DM. The use of metformin might reduce the risk of AF in DM patients. Further clinical investigation is warranted. Disclosure H. Liu: None. Y. Fang: None. T. Lee: None. J. Liu: None.

Some cohort studies showed the possibility of renin-angiotensin-aldosterone system (RAAS) blockade in preventing future osteoporotic fractures. The study aimed to evaluate the association between angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and future osteoporotic fracture in a hypertensive population. We queried the Taiwan Longitudinal Health Insurance Database between 2001 and 2012. We used propensity score matching and the total cohort was made up of 57,470 participants (28,735 matched-pairs using or not using RAAS blockers). The mean follow-up period was 6 years. The number of incident fractures was 3757. Hazard ratios (HRs) [95% confidence interval (CI)] of ACEIs and ARBs use with incident fractures were calculated. The incidence of future osteoporotic fracture was significantly lower in the ACEI and ARB user groups but not in the group using an ACEI plus ARB concomitantly, when compared with RAAS blocker nonusers. Comparing ACEI users with RAAS blocker non-users and ARB users with RAAS blocker non-users, the HRs for composite fractures were 0.70 (0.62–0.79) and 0.58 (0.51–0.65), respectively. Sensitivity analysis confirmed a lower incidence of future osteoporotic fracture in patients taking an ACEI for >55 cumulative defined daily doses (cDDDs) and those who received an ARB for >90 cDDDs. These results suggested a lower incidence of future osteoporotic fracture in a hypertensive population who were using an ACEI or ARB compared with RAAS blocker nonusers but not in the group taking an ACEI and ARB concomitantly.

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I’s antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 μM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-β1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-β1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.

// Ju-Chi Liu 1, 4, * , Tsung-Yeh Yang 1, * , Yi-Ping Hsu 1 , Wen-Rui Hao 1 , Pai-Feng Kao 1, 4 , Li-Chin Sung 1, 4 , Chun-Chao Chen 1 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * Co-first authors, These authors contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, COPD, lung cancer Received: March 09, 2016 Accepted: July 09, 2016 Published: August 09, 2016 ABSTRACT Purpose: Chronic obstructive pulmonary disease (COPD) is associated with increased lung cancer risk. We evaluated the association of statin use with lung cancer risk in COPD patients and identified which statins possess the highest chemopreventive potential. Results: After adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income according to propensity scores, lung cancer risk in the statin users was lower than that in the statin nonusers (adjusted hazard ratio [aHR] = 0.37). Of the individual statins, lovastatin and fluvastatin did not reduce lung cancer risk significantly. By contrast, lung cancer risk in patients using rosuvastatin, simvastatin, atorvastatin, and pravastatin was significantly lower than that in statin nonusers (aHRs = 0.41, 0.44, 0.52, and 0.58, respectively). Statins dose-dependently reduced lung cancer risk in all subgroups and the main model with additional covariates (nonstatin drug use). Materials and Methods: The study cohort comprised all patients diagnosed with COPD at health care facilities in Taiwan ( n = 116,017) between January 1, 2001 and December 31, 2012. Our final study cohort comprised 43,802 COPD patients: 10,086 used statins, whereas 33,716 did not. Patients were followed up to assess lung cancer risk or protective factors. In addition, we also considered demographic characteristics, namely age, sex, comorbidities (diabetes, hypertension, dyslipidemia, and Charlson comorbidity index [CCI]), urbanization level, monthly income, and nonstatin drug use. The index date of statin use was the COPD confirmation date. To examine the dose–response relationship, we categorized statin use into four groups in each cohort: 365 cumulative defined daily doses (cDDDs). Patients receiving < 28 cDDDs were defined as nonstatin users. Conclusions: Statins dose-dependently exert a significant chemopreventive effect against lung cancer in COPD patients. Rosuvastatin, simvastatin, and atorvastatin exhibited the highest chemopreventive potential.

// Ju-Chi Liu 1, 4, * , Wen-Rui Hao 1, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 4 , Pai-Feng Kao 1, 4 , Chao-Feng Lin 1 , Alexander T.H. Wu 6 , Kevin Sheng-Po Yuan 7 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan 6 Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, chronic obstructive pulmonary disease, colon cancer Received: March 22, 2016 Accepted: June 27, 2016 Published: August 12, 2016 ABSTRACT Purpose: We evaluated the chemopreventive effect of statins on colon cancer in patients with chronic obstructive pulmonary disease (COPD) and identified the statin exerting the strongest chemopreventive effect. Methods: Using the National Health Insurance Research Database, we identified patients who received a COPD diagnosis in Taiwan between January 1, 2001, and December 31, 2012, and included them in the study cohort. Each patient was followed to assess the colon cancer risk and protective factors. A propensity score was derived using a logistic regression model to estimate the effect of statins by accounting for covariates predicted during the intervention (statins). To examine the dose–response relationship, we categorized statin doses into four groups in each cohort [ 365 cumulative defined daily dose]. Results: Compared with the statin nonusers, the adjusted hazard ratio (aHR) for colon cancer decreased in the statin users (aHR = 0.52, 95% confidence interval = 0.44, 0.62). Hydrophilic statins exerted a stronger preventive effect against colon cancer. Regarding the statin type, lovastatin, pravastatin, and fluvastatin nonsignificantly reduced the colon cancer risk in the patients with COPD. Compared with the statin nonusers, the aHRs for colon cancer decreased in the individual statin users (rosuvastatin, simvastatin, and atorvastatin: aHRs = 0.28, 0.64, and 0.65, respectively). In the sensitivity analysis, statins dose-dependently reduced the colon cancer risk. Conclusions: Statins dose-dependently exert significant chemopreventive effects on colon cancer in patients with COPD, with rosuvastatin exerting the largest chemopreventive effect.

Cloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care.Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.Cloud-based BP system does not require any technical skills and is therefore suitable for every age group. BackgroundLess than 50% of patients with hypertensive disease manage to maintain their blood pressure (BP) within normal levels. ObjectiveThe aim of this study is to evaluate whether cloud BP system integrated with computerized physician order entry (CPOE) can improve BP management as compared with traditional care. MethodsA randomized controlled trial done on a random sample of 382 adults recruited from 786 patients who had been diagnosed with hypertension and receiving treatment for hypertension in two district hospitals in the north of Taiwan. Physicians had access to cloud BP data from CPOE. Neither patients nor physicians were blinded to group assignment. The study was conducted over a period of seven months. ResultsAt baseline, the enrollees were 50% male with a mean (SD) age of 58.18 (10.83) years. The mean sitting BP of both arms was no different. The proportion of patients with BP control at two, four and six months was significantly greater in the intervention group than in the control group. The average capture rates of blood pressure in the intervention group were also significantly higher than the control group in all three check-points. ConclusionsCloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care. This system does not require any technical skills and is therefore suitable for every age group. The praise and assurance to the patients from the physicians after reviewing the Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.

PURPOSE Hypnotic use might cause altered inflammatory processes, which have been suggested as being related to the mechanisms of arteriovenous fistula (AVF) failure. Therefore, we examined the association between the risk of AVF failure and hypnotic use in patients receiving hemodialysis (HD). METHODS A nested case-control study was conducted using data from the National Health Insurance Research Database of Taiwan. From 34 165 HD patients, 3676 patients receiving percutaneous transluminal angioplasty or surgical thrombectomy for AVF failure were matched to 14 704 control patients according to sex, age (±1 year), and the year of initial HD therapy. The risk of AVF failure was estimated based on conditional logistic regression after adjustment for the timing of AVF creation, HD frequency, comorbidities, and prescribed medications. Hypnotic use was measured prior to the date of AVF failure of case patients and the date of pseudo-AVF failure of controls. RESULTS Compared with matched controls, case patients were more likely to be exposed to hypnotics 30 days or an average daily defined dose > 0.5 within 90 days before the date of AVF failure, with an adjusted odds ratio of 1.21 (95% confidence interval [CI]: 1.09-1.35, p

Tanshinone IIA is the main effective component of Salvia miltiorrhiza, known as “Danshen,” which has been used in many therapeutic remedies in traditional Chinese medicine. However, the direct effects of tanshinone IIA on vascular endothelial cells have not yet been fully described. In the present study, we demonstrated that tanshinone IIA increased heme oxygenase-1 (HO-1) expression in human umbilical vein endothelial cells. Western blot analyses and experiments with specific inhibitors indicated tanshinone IIA enhanced HO-1 expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt and the subsequent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In addition, tanshinone IIA inhibited cyclic strain induced interleukin-8 (IL-8) expression. HO-1 silencing significantly abrogated the repressive effects of tanshinone IIA on strain-induced IL-8 expression, which suggests HO-1 has a role in mediating the effects of tanshinone IIA. This study reports for the first time that tanshinone IIA inhibits cyclic strain-induced IL-8 expression via the induction of HO-1 in endothelial cells, providing valuable new insight into the molecular pathways that may contribute to the effects of tanshinone IIA.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect.

Depressive symptoms are linked to increased morbidity and mortality, and impaired health status in patients with heart failure. Elevating resilience may mitigate the negative consequences associated with depressive symptoms. However, the role of resilience in the relationship between depressive symptoms and health status in patients with heart failure remains unknown.To examine the relationships among depressive symptoms, resilience, and physical and psychological health status in patients with heart failure and to determine whether resilience plays a mediating or moderating role in the relationship between depressive symptoms and physical and psychological health status.Cross-sectional study design.Cardiac outpatient clinics in hospitals in Northern Taiwan.The sample comprised 128 community-dwelling and medically stable patients with echocardiographically documented heart failure.Hierarchical multiple regressions were conducted to determine whether depressive symptoms and resilience are associated with physical and psychological health status. The moderating role of resilience was examined by testing the significance of the interaction between depressive symptoms and resilience. The mediating role of resilience was analyzed using the PROCESS procedure in SPSS.Depressive symptoms were significantly associated with both physical and psychological health status (both p.01) in patients with heart failure after adjustment for sociodemographic variables, comorbidities, and the New York Heart Association functional class. Furthermore, resilience mediated the relationship between depressive symptoms and psychological health status (b=-0.05; confidence interval: -0.01, -0.001) but not that between depressive symptoms and physical health status (b=-0.004; confidence interval: -0.003, 0.003).Depressive symptoms are risk factors for poor health status in patients with heart failure. However, enhancing resilience may facilitate improving psychological health status in patients with depression and heart failure. Future studies should investigate further the design and feasibility of resilience-focused interventions for patients with depression and heart failure.

Although previous clinical trials demonstrated that ticagrelor could reduce cardiovascular events and mortality versus clopidogrel in patients with acute coronary syndrome (ACS), the real-world evidence of its clinical impacts on East Asian Diabetic population has rarely been investigated.Between November 2013 and June 2015, 1534 patients were recruited into the Acute Coronary Syndrome-Diabetes Mellitus Registry of the Taiwan Society of Cardiology (TSOC ACS-DM registry). After propensity score matching, a total of 730 patients undergoing successful revascularization and discharged on ticagrelor (N = 365) or clopidogrel (N = 365) were analyzed. The primary and secondary endpoints were all-cause mortality and re-hospitalization, respectively. The all-cause death associated with ticagrelor vs clopidogrel was 3.6% vs 7.4% (adjusted hazard ratio (HR) 0.34 [0.15-0.80]; P = .0138) at 24 months. The re-hospitalization rate at 24 months was 38.9% vs 39.2% (P = .3258).For diabetic patients with ACS, ticagrelor provided better survival benefit than clopidogrel without an increase of re-hospitalization in 24 months after successful percutaneous coronary intervention. This study in real-world circumstance provided valuable complementary data to externally validate platelet inhibition and patient outcomes (PLATO) finding especially in Asian diabetic population.

Chronic obstructive pulmonary disease (COPD) patients are at a higher risk of development of lung cancer. Frequent exacerbations of COPD trigger the disease course to chronic inflammation which likely plays a role in the pathogenesis of lung cancer. Previous studies showed influenza virus infection is one of important causes for exacerbations of COPD. Therefore, the aim of this study was to know whether influenza vaccination could reduce the incidence of lung cancer in patients with COPD. This cohort study enrolled patients (≥55 years old) with a recorded diagnosis of COPD between January 1, 2000 and December 31, 2012 by using the Taiwan Health Insurance Database. A propensity score was calculated to reduce vaccine therapy selection bias. Cox proportional hazard regressions were used to investigate the association between the influenza vaccination and lung cancer incidence after adjusting for known confounding factors. Besides, we categorized the patients into 4 groups according to vaccination status (unvaccinated, total number of vaccinations: 1, 2–3, ≥4) to evaluate the dose-dependent effect on reducing lung cancer occurrence of lung cancer in COPD patients. Our study comprised of 28,752 eligible individuals from the COPD cohort database. Among them, 51% (14,630) received influenza vaccination; the rest (49%) of the COPD patients did not receive influenza vaccination. We observed that COPD patients receiving influenza vaccination had a lower risk of lung cancer (adjusted HR = 0.40, 95% CI (0.35–0.45), P

In Taiwan, the incidence of non-ST segment elevation acute coronary syndrome (NSTE-ACS) continues to increase in recent years. The purpose of this guideline is to help health care professionals in Taiwan to use adequate tests and treatments for management of NSTE-ACS. For rapid diagnosis, in addition to history and physical examination, 0/3 h rapid diagnosis protocol with high sensitivity cardiac troponin assay is recommended in this guideline. Dual antiplatelet and anticoagulation therapies are important parts in the initial treatment. Risk stratification should be performed to identify high risk patients for early coronary angiography. Through evaluation of the coronary anatomy and other clinical factors, the decision for coronary revascularization, either by percutaneous coronary intervention or coronary artery bypass grafting, should be decided by the heart team. The duration of dual antiplatelet therapy should be given for at least 12 months after discharge. Other secondary preventive medications are also recommended for long term use. Keywords: Acute coronary syndrome, Guideline, Taiwan

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol.

Cafestol, a diterpene molecule found in the berries of Coffea arabica L. (Rubiaceae), has been shown to exercise anti-angiogenic and anti-tumorigenic effects. However, cafestol's cellular mechanism has yet to be fully investigated. We previously demonstrated that urotensin II enhanced interleukin-8 secretion by endothelial cells, thereby increasing endothelial cell proliferation. Urotensin II may also participate in angiogenesis and tumor infiltration by macrophages. However, the effects of cafestol on urotensin II-induced interleukin-8 expression and cellular proliferation have not been determined. Here, we showed that pretreatment with cafestol inhibited urotensin II-stimulated endothelial cell proliferation. Further experiments demonstrated that cafestol increased translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of enhanced heme oxygenase-1. Moreover, cafestol inhibited expression of urotensin II-induced interleukin-8. Cafestol's inhibitory effects on interleukin-8 expression and cellular proliferation induced by urotensin II were significantly abrogated by heme oxygenase-1 silencing, suggesting it may be involved in mediating the effects of cafestol. This study reports that cafestol inhibits urotensin II-induced interleukin-8 expression and cell proliferation via Nrf2/heme oxygenase-1-dependent mechanism in endothelial cells. These findings provide novel insight into the signaling pathways that may be important in mediating the effects of cafestol.

A high efficient time-shift correlation algorithm was proposed to deal with the peak time uncertainty of P300 evoked potential for a P300-based brain-computer interface (BCI). The time-shift correlation series data were collected as the input nodes of an artificial neural network (ANN), and the classification of four LED visual stimuli was selected as the output node. Two operating modes, including fast-recognition mode (FM) and accuracy-recognition mode (AM), were realized. The proposed BCI system was implemented on an embedded system for commanding an adult-size humanoid robot to evaluate the performance from investigating the ground truth trajectories of the humanoid robot. When the humanoid robot walked in a spacious area, the FM was used to control the robot with a higher information transfer rate (ITR). When the robot walked in a crowded area, the AM was used for high accuracy of recognition to reduce the risk of collision. The experimental results showed that, in 100 trials, the accuracy rate of FM was 87.8% and the average ITR was 52.73 bits/min. In addition, the accuracy rate was improved to 92% for the AM, and the average ITR decreased to 31.27 bits/min. due to strict recognition constraints.

This study investigated how lycopene affected urotensin-II- (U-II-) induced cardiomyocyte hypertrophy and the possible implicated mechanisms. Neonatal rat cardiomyocytes were exposed to U-II (1 nM) either exclusively or following 6 h of lycopene pretreatment (1–10 μM). The lycopene (3–10 μM) pretreatment significantly inhibited the U-II-induced cardiomyocyte hypertrophy, decreased the production of U-II-induced reactive oxygen species (ROS), and reduced the level of NAD(P)H oxidase-4 expression. Lycopene further inhibited the U-II-induced phosphorylation of the redox-sensitive extracellular signal-regulated kinases. Moreover, lycopene treatment prevented the increase in the phosphorylation of serine-threonine kinase Akt and glycogen synthase kinase-3beta (GSK-3β) caused by U-II without affecting the protein levels of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). However, lycopene increased the PTEN activity level, suggesting that lycopene prevents ROS-induced PTEN inactivation. These findings imply that lycopene yields antihypertrophic effects that can prevent the activation of the Akt/GSK-3βhypertrophic pathway by modulating PTEN inactivation through U-II treatment. Thus, the data indicate that lycopene prevented U-II-induced cardiomyocyte hypertrophy through a mechanism involving the inhibition of redox signaling. These findings provide novel data regarding the molecular mechanisms by which lycopene regulates cardiomyocyte hypertrophy.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 μM) for 12 h and then treated with DOX (1 μM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 μM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 μM). Furthermore, nicorandil (3 μM) enhanced nuclear factor erythroid 2–related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.

Rationale: Acute myocardial infarction (AMI) secondary to spontaneous coronary artery dissection (SCAD) is a rare condition. SCAD can be underdiagnosed on a coronary angiography (CAG). Therefore, the application of intravascular imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT) is crucial for ensuring an accurate diagnosis and treatment. Patients concerns: A 72-year-old woman had an evolving AMI with ST elevation in the inferior leads (II, III, and aVF). Diagnoses: An emergent CAG showed that a double lumen had developed in the middle portion of the left circumflex artery. An IVUS examination revealed a coronary artery dissection and intramural hematoma. Interventions: First, the patient was treated with conservative management. We later placed a stent in response to the progression of the intramural hematoma observed during the IVUS follow-up. Outcomes: The patient remained symptom free after discharge. CAG with OCT at the 1-year follow-up after stent implantation showed in-stent restenosis with dissection flap with residual false lumen at the proximal site of stent. We treated this lesion with another stent. Lessons: From this case, we learned that in patients with AMI, SCAD should be considered as a possible diagnosis and that intravascular imaging tool can successfully guide clinical decision making and the treatment strategies.

Background Vaccination against influenza may decrease the risk of an acute cardiovascular event in the elderly. The purpose of this study was to test the hypothesis that influenza vaccination could reduce hospitalizations for heart failure (HF) in patients with chronic obstructive pulmonary disease (COPD). Methods Using Taiwan National Health Insurance Research Dataset (NHIRD) 2000 to 2007, this cohort study comprised patients with a recorded diagnosis of COPD (n = 25,609) between January 1, 2000 and December 31, 2007. Each patient was followed up until the end of 2007. Cox proportional hazard regression analysis was used to evaluate the HF-free survival rates after adjusting for known confounding factors. Results We found that patients with COPD but no history of a cardiovascular event had a lower risk of hospitalization for HF after receiving influenza vaccination. After adjusting for potential confounders, there was a possible decrease in HF admission for the vaccinated group [hazard ratio (HR), 0.44, 95% confidence interval (CI), 0.35–0.55]. When stratified in terms of the patients' ages, the adjusted HR for hospitalization due to HF was 0.36 (95% CI, 0.28–0.46) for vaccinated patients over 64 years of age; however, the adjusted HR for HF in patients under 55 years of age who had received vaccination was not significant. Conclusion Our data show that there was a lower rate of hospitalization from HF in patients with COPD receiving influenza vaccination, but only in patients older than 65 years.

Research has indicated that inflammation promote all phases of atherosclerosis. The current study tested the hypothesis that rhinosinusitis is a risk marker for myocardial infarction (MI). Data on the general population were obtained from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005). The study cohort comprised patients who had received a recorded diagnosis of rhinosinusitis ( N = 52,930) between January 1, 2004 and December 31, 2004. The comparison group consisted of patients who had not received a rhinosinusitis diagnosis, and who were matched for age and sex with the study group at a ratio of 4 controls to 1 study patient (1:4) ( N = 211,720). Each patient's condition was followed using database entries until the end of 2006. Cox proportional hazard regressions were used to evaluate the 3-year MI-free survival rates, after adjusting for known confounding factors. We found that patients with rhinosinusitis were more likely than the control group to have MI, after adjusting for potential confounders [adjusted hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.44 ∼ 2.40]. Of the total 264 650 patients, 290 experienced MI during the 3-year follow-up period, including 8 acute sinusitis patients, 77 chronic sinusitis patients, and 205 control patients. The incidence rate of MI was 6.19 (95% CI 5.01–7.65) per 10,000 person-years for rhinosinusitis patients, compared to 3.51 (95% CI, 3.06–4.02) for the control patients. From this study, rhinosinusitis may be associated with MI. Further research in this important area of public health is warranted.

The aim of the study was to investigate the longitudinal transition trajectory of gout and its comorbidities in male patients with gout in different age groups. A total of 3973 male patients who received a new diagnosis of gouty arthritis were identified from the Taiwan Longitudinal Health Insurance Database and divided into two age cohorts (

Purpose The risk of hemorrhagic stroke in patients with atrial fibrillation (AF) is low but the consequences of its occurrence are extremely severe. In this study, we investigated the association of influenza vaccination with the risk of hemorrhagic stroke to develop an efficient strategy for reducing this risk in patients with AF. Methods In this study, data were retrieved from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients who received a diagnosis of AF ( n =14,454) before January 1, 2005 (index date) and were followed until December 31, 2012. Propensity scores were calculated using a logistic regression model to determine the effects of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) for hemorrhagic stroke in vaccinated and unvaccinated patients with AF. Results The study population comprised 6570 patients who did (2547 [38.77%]) and did not receive (4023 [61.23%]) influenza vaccination. The adjusted HRs (aHRs) for hemorrhagic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs=0.97 [0.59–1.60], 0.51 [0.30–0.87], and 0.72 [0.50–1.03], respectively). Conclusions Influenza vaccination exerts dose–response and synergistic protective effects against hemorrhagic stroke in patients with AF who have a high risk of hemorrhagic stroke (i.e., male sex, age≥75years, Charlson comorbidity index ≥3, and hypertension) and reduces the incidence of hemorrhagic stroke.

This study investigated microcirculatory-blood-flow responses in nude mice following the injection of CT26 tumor cells by analyzing the frequency content of skin blood-flow signals recorded on the skin surface. CT26 cells were injected subcutaneously (10^4/100 μl) into the right back flank of each 7-week-old mouse. Three-minute laser Doppler flowmetry (LDF) signals were measured in 60 nude mice. The data sequences were obtained at 1, 2, and 3 weeks after injecting CT26 cells. Mouse tissue samples were cut into sections and examined microscopically to determine the condition of cancer metastasis. Spectral analysis performed after 1 week revealed a significant decrease in the relative energy contribution of the endothelium-related frequency band, and significant increases in those of the myogenic and respiration-related frequency bands of the LDF signals in the metastasis group (n=12). To the best of our knowledge, this is the first study demonstrating the feasibility of evaluating metastasis in animal subjects based on changes in noninvasively measured LDF parameters. Changes in the LDF spectral indexes can be attributed to differences in the microcirculatory regulatory activities. The present measurements performed on the skin surface provide a noninvasive and real-time method for evaluating the microcirculatory responses induced by implanting CT26 tumor cells.

Elderly patients with chronic kidney disease (CKD) are at a higher risk of hospitalization for cardiovascular diseases (CVD). Previous studies have reported the beneficial effects of the influenza vaccine in patients with CVD. However, the effects of influenza vaccination on the reduction of hospitalizations for heart failure (HF) in elderly patients with CKD remain unclear.This cohort study comprised elderly patients (≥ 55 years of age) with a recorded diagnosis of CKD (n = 4406) between January 1, 1999 and December 31, 2008. Each patient was followed-up until the end of 2008. The hazard ratio (HR) and 95% confidence interval (CI) for the association between the influenza vaccination and the first HF hospitalization were analyzed. In addition, the patients were categorized into four groups based on their vaccination status (unvaccinated and total number of vaccinations: 1, 2-3, and ≥ 4).We found that elderly patients with CKD receiving influenza vaccination exhibited a lower risk of HF hospitalization (adjusted HR, 0.31; 95% CI, 0.26-0.39, p0.001). The protective effects of influenza vaccination remained consistent regardless of the age group (55-64, 65-74, ≥ 75), sex, and influenza seasonality. When the patients were stratified according to the total number of vaccinations, the adjusted HRs for HF hospitalization were 0.60 (0.47-0.77), 0.30 (0.23-0.41), and 0.10 (0.06-0.16) for patients who received 1, 2-3, and ≥ 4 vaccinations during the follow-up period, respectively.The results revealed that elderly patients with CKD receiving annual influenza vaccination are at a lower risk of HF hospitalization.

Background Statins have been reported to prevent adverse cardiovascular events in patients with myocardial infarction (MI). However, the association of statin use and the risk of pneumonia requiring hospitalization in MI patients remains unclear. Methods A nested case-control study was conducted by using data from the National Health Insurance Research Database of Taiwan. Among 24,975 patients with MI, 2686 case patients with pneumonia requiring hospitalization were age- and sex-matched with 10,726 control patients using the incidence density sampling approach. Duration and dosage of statin use were obtained from pharmaceutical claims. Conditional logistic regression analyses were used to estimate the risk of hospitalization for pneumonia associated with statin use adjusted for patient’s demographics, medical conditions and prescribed medications. Results Statin use was associated with a 15 % reduced risk of pneumonia requiring hospitalization among MI patients (adjusted odds ratio [aOR] = 0.85, 95 % confidence interval [CI] = 0.77–0.95, P = 0.004). The association was more significant for MI patients unexposed to statin pretreatment (aOR = 0.76, 95 % CI = 0.64–0.90, P = 0.001). Statins also exhibited favorable benefits in a time- and dose-dependent manner. The results were consistent in various subgroup analysis of the patients who were female, age ≥ 65 years, a low CHADS2 (i.e. congestive heart failure, hypertension, diabetes mellitus, previous stroke and age > 75 years old) score, and fewer comorbidities. Atorvastatin, fluvastatin and simvastatin were the most common prescribed statins and had similar effects. Conclusions Statins might be considered as an adjunctive therapy to reduce the risk of hospitalization for pneumonia for MI patients under thorough evaluation of individual comorbidities, previous statin use and optimal dosage. Electronic supplementary material The online version of this article (doi:10.1186/s12872-016-0202-x) contains supplementary material, which is available to authorized users.

International classification of diseases, ninth revision, clinical modification (ICD-9-CM) codes. (DOC 31Â kb)

Title of data: Anatomical therapeutic chemical (ATC) classification system codes for drugs. (DOC 31Â kb)

Anatomical therapeutic chemical (ATC) classification system codes for drugs and defined daily dose (DDD) for statins. (DOC 32Â kb)

A high efficient time-shift correlation algorithm was proposed to deal with the peak time uncertainty of P300 evoked potential for a P300-based brain-computer interface (BCI). The time-shift correlation series data were collected as the input nodes of an artificial neural network (ANN), and the classification of four LED visual stimuli was selected as the output node. Two operating modes, including fast-recognition mode (FM) and accuracy-recognition mode (AM), were realized. The proposed BCI system was implemented on an embedded system for commanding an adult-size humanoid robot to evaluate the performance from investigating the ground truth trajectories of the humanoid robot. When the humanoid robot walked in a spacious area, the FM was used to control the robot with a higher information transfer rate (ITR). When the robot walked in a crowded area, the AM was used for high accuracy of recognition to reduce the risk of collision. The experimental results showed that, in 100 trials, the accuracy rate of FM was 87.8% and the average ITR was 52.73 bits/min. In addition, the accuracy rate was improved to 92% for the AM, and the average ITR decreased to 31.27 bits/min. due to strict recognition constraints.

Background: Nicorandil, a mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel opener, exerts protective effects on the cardiovascular system. This study examined the effect of nicorandil on cyclic strain-induced interleukin-8 (IL-8) expression in human umbilical vein endothelial cells (HUVECs). Methods: Cultured HUVECs were exposed to cyclic strain in the presence or absence of nicorandil (1-10 μmol/l); we then analyzed IL-8 expression. We also assessed the effects of nicorandil on heme oxygenase-1 (HO-1) expression and cyclic strain-modulated IL-8 expression after HO-1 silencing in HUVECs. Summary: HUVECs exposed to cyclic strain showed increased IL-8 messenger RNA expression and protein secretion. Nicorandil (1-10 μmol/l) inhibited cyclic strain-induced IL-8 expression, whereas 5-hydroxydecanoate (100 μmol/l), a selective inhibitor of the mitoKATP channel, completely reversed the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression. We demonstrated that nicorandil increased HO-1 expression in HUVECs. In addition, cobalt protoporphyrin (10 μmol/l), an inducer of HO-1 expression, mimicked the effects of nicorandil and inhibited IL-8 expression under cyclic strain, whereas zinc protoporphyrin IX (10 μmol/l), an inhibitor of HO-1 expression, antagonized the effect of nicorandil. HO-1 silencing significantly abrogated the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression, suggesting that HO-1 plays a role in the mechanism of action of nicorandil. Key Messages: This study is the first to report that nicorandil inhibits cyclic strain-induced IL-8 expression through the induction of HO-1 expression in HUVECs. This finding provides valuable new insight into the molecular pathways contributing to the vasoprotective effects of nicorandil.

Summary 1. Tanshinone IIA, one of the active components of the Radix of Salvia miltiorrhiza, is used in traditional Chinese medicine to treat cardiovascular diseases. However, the intracellular mechanism of action of tanshinone IIA remain to be determined. The aims of the present study were to test the hypothesis that tanshinone IIA alters strain-induced endothelin (ET)-1 expression and nitric oxide (NO) production, as well as to identify the putative signalling pathways involved, in human umbilical vein endothelial cells (HUVEC). 2. Cultured HUVEC were exposed to cyclic strain in the presence of 1–10 μmol/L tanshinone IIA. Expression of ET-1 was examined by reverse transcription–polymerase chain reaction and ELISA. Phosphorylation of endothelial NO synthase (eNOS) and activating transcription factor (ATF) 3 was assessed by western blot analysis. 3. Tanshinone IIA (3 and 10 μmol/L) inhibited strain-induced ET-1 expression. In contrast, NO production, eNOS phosphorylation and ATF3 expression were enhanced by tanshinone IIA. The eNOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 100 μmol/L), the phosphatidylinositol 3-kinase inhibitor LY294002 (5 μmol/L) and the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; 10 μmol/L) inhibited tanshinone IIA-induced increases in ATF3 expression. Moreover, treatment of HUVEC with either an NO donor (3,3-bis [aminoethyl]-1-hydroxy-2-oxo-1-triazene; 500 μmol/L) or an ATF3 activator (carbobenzoxy-l-leucyl-l-leucyl-l-leucinal; 5 μmol/L) resulted in the repression of strain-induced ET-1 expression. The inhibitory effect of tanshinone IIA on strain-induced ET-1 expression was significantly attenuated by l-NAME, ODQ and the transfection of small interfering RNA for ATF3. 4. In conclusion, tanshinone IIA inhibits strain-induced ET-1 expression by increasing NO and upregulating ATF3 in HUVEC. The present study provides important new insights into the molecular pathways that may contribute to the beneficial effects of tanshinone IIA in the cardiovascular system.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener that combines an organic nitrate and a nicotinamide group which respectively confer to nicorandil the additional properties of being a nitric oxide (NO) donor and antioxidant; it also induces vasodilation, decreases the blood pressure, and protects the heart. However, the intracellular mechanism of nicorandil remains to be delineated. The aims of this study were to test the hypothesis that nicorandil alters strain-induced endothelin-1 secretion and NO production, and to identify the putative underlying signaling pathways in human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were exposed to cyclic strain in the presence of nicorandil; endothelin-1 expression was examined by reverse-transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Activation of extracellular signal-regulated protein kinase (ERK), endothelial NO synthase (eNOS), and activating transcription factor (ATF)-3 was assessed by Western blot analysis. We show that nicorandil inhibited strain-induced endothelin-1 expression. Nicorandil also inhibited strain-increased reactive oxygen species formation and ERK phosphorylation. On the contrary, NO production, eNOS phosphorylation, and ATF3 expression were enhanced by nicorandil; however, L-NAME (an inhibitor of eNOS) and LY294002 (an inhibitor of phosphatidylinositol 3-kinase) inhibited nicorandil-increased ATF3 expression. Moreover, treatment of HUVECs with either an NO donor (NOC18; 3,3-bis[aminoethyl]-1-hydroxy-2-oxo-1-triazene) or an ATF3 activator (MG-132; carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) resulted in repression of strain-induced endothelin-1 expression. Furthermore, L-NAME, and small interfering RNA transfection of eNOS also partially attenuated the inhibitory effect of nicorandil on strain-induced endothelin-1 expression. We demonstrate for the first time that nicorandil inhibits strain-induced endothelin-1 secretion via an increase in NO and upregulation of ATF3 in HUVECs. This study provides important new insights into the molecular pathways that may contribute to the beneficial effects of nicorandil in the cardiovascular system.

Background and Purposes The metabolic syndrome (MS) and abnormal nocturnal blood pressure (BP) dipping are both associated with increased risk of cardiovascular events. An association between MS and arterial stiffness was reported. This study aimed to examine the relationship between arterial stiffness as determined by the Cardio-Ankle Vascular Index (CAVI) and the nocturnal BP dipping pattern in normotensive individuals with one or more risk components of MS. Methods and Results A total of 73 normotensive individuals who met at least one of the five National Cholesterol Education Program Adult Treatment Panel III criteria were included. The MS score was calculated according to the GISSI Study. Ambulatory BP was recorded every 30 minutes for a 48-hour period. Individuals with MS and those without MS did not significantly differ in CAVI ( p = 0.040) or nocturnal systolic blood pressure (SBP) dipping ( p = 0.909). Controlling for age, CAVI was not significantly correlated with the MS score ( p = 0.067). CAVI significantly correlated with the magnitude ( ρ = 0.29, p = 0.014) and the percentage ( ρ = 0.29, p = 0.013) of nocturnal SBP dipping. CAVI independently predicted the magnitude of nocturnal SBP reduction ( β = 0.364, p = 0.002) even after adjusting for age and nighttime SBP. The extreme dippers had significantly higher CAVI values than the nondippers ( p = 0.012) and a trend toward higher CAVI than the dippers ( p = 0.031). Conclusion MS is associated with neither arterial stiffness nor nocturnal dipping pattern in normotensives. However, in normotensive individuals with risk components of the MS, arterial stiffness is related to an extreme dipping pattern.