NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype.

Hypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (Nox) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5-but not NOX1, NOX2, or NOX4-with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human Nox5 in endothelial cells developed-upon aging-severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype. Nox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.

Tumor Necrosis Factor Superfamily 14 (LIGHT) Restricts Neovascularization by Decreasing Circulating Endothelial Progenitor Cells and Function.

Tumor necrosis factor superfamily 14 (TNFSF14) is also known as the LT-related inducible ligand (LIGHT). It can bind to the herpesvirus invasion mediator and lymphotoxin-ß receptor to perform its biological activity. LIGHT has multiple physiological functions, including strengthening the synthesis of nitric oxide, reactive oxygen species, and cytokines. LIGHT also stimulates angiogenesis in tumors and induces the synthesis of high endothelial venules; degrades the extracellular matrix in thoracic aortic dissection, and induces the expression of interleukin-8, cyclooxygenase-2, and cell adhesion molecules in endothelial cells. While LIGHT induces tissue inflammation, its effects on angiogenesis after tissue ischemia are unclear. Thus, we analyzed these effects in the current study. In this study, the animal model of hind limb ischemia surgery in C57BL/6 mice was performed. Doppler ultrasound, immunohistochemical staining, and Western blotting were employed to analyze the situation of angiogenesis. In addition, human endothelial progenitor cells (EPCs) were used for in vitro studies to analyze the possible mechanisms. The results in the animal study showed that LIGHT injection inhibited angiogenesis in ischemic limbs. For the in vitro studies, LIGHT inhibited the expression of integrins and E-selectin; decreased migration and tube formation capabilities, mitochondrial respiration, and succinate dehydrogenase activity; and promoted senescence in EPCs. Western blotting revealed that the impairment of EPC function by LIGHT may be due to its effects on the proper functioning of the intracellular Akt signaling pathway, endothelial nitrite oxide synthase (eNOS), and mitochondrial respiration. In conclusion, LIGHT inhibits angiogenesis after tissue ischemia. This may be related to the clamped EPC function.

2023 TAMIS/TSOC/TACVPR Consensus Statement for Patients with Acute Myocardial Infarction Rehabilitation.

Cardiac rehabilitation is a comprehensive intervention recommended in international and Taiwanese guidelines for patients with acute myocardial infarction. Evidence supports that cardiac rehabilitation improves the health-related quality of life, enhances exercise capacity, reduces readmission rates, and promotes survival in patients with cardiovascular disease. The cardiac rehabilitation team is comprehensive and multidisciplinary. The inpatient, outpatient, and maintenance phases are included in cardiac rehabilitation. All patients admitted with acute myocardial infarction should be referred to the rehabilitation department as soon as clinically feasible. Pre-exercise evaluation, including exercise testing, helps physicians identify the risks of cardiac rehabilitation and organize appropriate exercise prescriptions. Therefore, the Taiwan Myocardial Infarction Society (TAMIS), Taiwan Society of Cardiology (TSOC), and Taiwan Academy of Cardiovascular and Pulmonary Rehabilitation (TACVPR) address this consensus statement to assist healthcare practitioners in performing cardiac rehabilitation in patients with acute myocardial infarction.

Assessing the facilities and healthcare services for heart failure: Taiwan versus European countries.

BACKGROUND/PURPOSE: The present study was designed to evaluate the local cardiology infrastructure and services for heart failure (HF) care in Taiwan hospitals and to compare the HF care with the hospitals in European countries. METHODS: Available data from a total of 98 medical centers and regional hospitals in Taiwan were analyzed. Each facility was given a single copy of the questionnaire between September and December 2019, and service records were extracted from the National Health Insurance Database. European data were adopted from the 2017 European Society of Cardiology Atlas. RESULTS: The number of cardiologists per million populations in Taiwan was 57.4, and it was lower than the European median (72.8). The median percentages of interventional and electrophysiologists among cardiologists were 64% and 15% in Taiwan, which were both higher than the European median values (12% and 5%, respectively). The accessibility rates to implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) in Taiwan were both higher (3.4 and 3.0 centers per million populations) comparing to those in European countries (median 1.6 and 1.5 centers per million populations). Comparing to 67 hospitals without HF care teams in Taiwan, 31 hospitals (31.6%) with HF teams have significantly more cardiology staff, enhanced procedural capabilities with more alternatives on oral or intravenous HF relevant medications. CONCLUSION: Our analysis clearly demonstrated discrepancies in cardiology subspecialties and CRT/ICD accessibilities between European countries and Taiwan. Variations in HF-focused services and facilities plus HF-directed medications have demonstrated significant differences among Taiwanese hospitals with or without HF care team.

Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction.

BACKGROUND: Metabolic disorders such as obesity and diabetes mellitus can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than vascular endothelial growth factor-vascular endothelial growth factor receptor-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. METHODS: We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-knockout [KO]) and their wild-type littermates to a fast food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We used crosslinking immunoprecipitation- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy donors and donors with obesity/type 2 diabetes mellitus. RESULTS: We identified an antiobesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (THBS1/TSP1), an antiangiogenic and proinflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from donors with obesity or type 2 diabetes mellitus, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway. CONCLUSIONS: Our study suggests a novel mechanism by which ECs, through the AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.

Cardiogenic shock in Taiwan from 2003 to 2017 (CSiT-15 study).

BACKGROUND: This study investigated temporal trends in the treatment and mortality of patients with cardiogenic shock (CS) in Taiwan in relation to acute myocardial infarction (AMI) accreditation implemented in 2009 and the unavailability of percutaneous ventricular assist devices. METHODS: Data of patients diagnosed as having CS between January 2003 and December 2017 were collected from Taiwan's National Health Insurance Research Database. Each case was followed from the date of emergency department arrival or hospital admission for the first incident associated with a CS diagnosis up to a 1-year interval. Measurements included demographics, comorbidities, treatment, mortality, and medical costs. Using an interrupted time-series (ITS) design with multi-level mixed-effects logistic regression model, we assessed the impact of AMI accreditation implementation on the mortality of patients with AMI and CS overall and stratified by the hospital levels. RESULTS: In total, 64 049 patients with CS (mean age:70 years; 62% men) were identified. The incidence rate per 105 person-years increased from 17 in 2003 to 25 in 2010 and plateaued thereafter. Average inpatient costs increased from 159 125 points in 2003 to 240 993 points in 2017, indicating a 1.5-fold increase. The intra-aortic balloon pump application rate was approximately 22-25% after 2010 (p = 0.093). Overall, in-hospital, 30-day, and 1-year mortality declined from 60.3%, 63.0%, and 69.3% in 2003 to 47.9%, 50.8% and 59.8% in 2017, respectively. The decline in mortality was more apparent in patients with AMI-CS than in patients with non-AMI-CS. The ITS estimation revealed a 2% lower in-hospital mortality in patients with AMI-CS treated in district hospitals after the AMI accreditation had been implemented for 2 years. CONCLUSIONS: In Taiwan, the burden of CS has consistently increased due to high patient complexity, advanced therapies, and stable incidence. Mortality declined over time, particularly in patients with AMI-CS, which may be attributable to advancements in AMI therapies and this quality-improving policy.

Circulating TNFSF14 (Tumor Necrosis Factor Superfamily 14) Predicts Clinical Outcome in Patients With Stable Coronary Artery Disease.

Objective- Basic research indicates that TNFSF14 (tumor necrosis factor superfamily 14) may be involved in the pathogenesis of atherosclerosis. Given the requirements of new biomarkers for risk classification in coronary artery disease (CAD), we conducted a longitudinal analysis to investigate if TNFSF14 levels are associated with the risk of cardiovascular events among patients with stable CAD. Approach and Results- In total, 894 patients with CAD were enrolled in a multicenter prospective study. The primary outcome was the occurrence of cardiovascular death, nonfatal myocardial infarction, and stroke. The secondary outcome was the occurrence of all-cause death, nonfatal myocardial infarction, stroke, revascularization, and hospitalization because of angina or heart failure. During the mean follow-up period of 22±9 months, 32 patients reached the primary outcome and 166 patients reached the secondary outcome. Kaplan-Meier analysis showed that the event-free survival was significantly different in the first and fourth quartile groups in subjects categorized by TNFSF14 levels. In multivariate Cox proportional hazard regression analysis, TNFSF14 was independently associated with the risk of cardiovascular events after adjustment for various relevant factors (adjusted hazard ratio, 1.14; 95% CI, 1.04-1.25). In the validation cohort of 126 multivessel patients with CAD, TNFSF14 was confirmed to provide good prognostic predictive value for composite cardiovascular events (adjusted hazard ratio, 1.11; 95% CI, 1.04-1.19). Conclusions- This is the first study to demonstrate that increased TNFSF14 levels were independently associated with the occurrence of cardiovascular events in patients with stable CAD. Future studies are worthy to validate if TNFSF14 could be a novel prognostic biomarker for CAD outcomes over different populations.

2020 Consensus Statement of the Taiwan Hypertension Society and the Taiwan Society of Cardiology on Home Blood Pressure Monitoring for the Management of Arterial Hypertension.

To facilitate the applications of home blood pressure (HBP) monitoring in clinical settings, the Taiwan Hypertension Society and the Taiwan Society of Cardiology jointly put forward the Consensus Statement on HBP monitoring according to up-to-date scientific evidence by convening a series of expert meetings and compiling opinions from the members of these two societies. In this Consensus Statement as well as recent international guidelines for management of arterial hypertension, HBP monitoring has been implemented in diagnostic confirmation of hypertension, identification of hypertension phenotypes, guidance of anti-hypertensive treatment, and detection of hypotensive events. HBP should be obtained by repetitive measurements based on the " 722 " principle, which is referred to duplicate blood pressure readings taken per occasion, twice daily, over seven consecutive days. The " 722" principle of HBP monitoring should be applied in clinical settings, including confirmation of hypertension diagnosis, 2 weeks after adjustment of antihypertensive medications, and at least every 3 months in well-controlled hypertensive patients. A good reproducibility of HBP monitoring could be achieved by individuals carefully following the instructions before and during HBP measurement, by using validated BP devices with an upper arm cuff. Corresponding to office BP thresholds of 140/90 and 130/80 mmHg, the thresholds (or targets) of HBP are 135/85 and 130/80 mmHg, respectively. HBP-based hypertension management strategies including bedtime dosing (for uncontrolled morning hypertension), shifting to drugs with longer-acting antihypertensive effect (for uncontrolled evening hypertension), and adding another antihypertensive drug (for uncontrolled morning and evening hypertension) should be considered. Only with the support from medical caregivers, paramedical team, or tele- monitoring, HBP monitoring could reliably improve the control of hypertension.

2019 Consensus Statement of the Taiwan Hypertension Society and the Taiwan Society of Cardiology on Renal Denervation for the Management of Arterial Hypertension.

Sympathetic overactivity, an essential mechanism of hypertension, in driving sustained hypertension derives mostly from its effects on renal function. Percutaneous renal denervation (RDN) is designed to disrupt renal afferent and efferent sympathetic nerves to achieve sustained blood pressure (BP) reduction. Since 2017 onward, all three proof-of-concept, sham-controlled RDN trials demonstrated that RDN achieved consistent and clinically meaningful BP reductions [approximately 10 mmHg in office systolic BP (SBP) and 6-9 mmHg in 24-hour SBP] compared to sham operation in patients with mild to moderate or uncontrolled hypertension. There were no serious adverse events. The registry data in Taiwan showed similar 24-hour BP reductions at 12 months following RDN. The Task Force considers RDN as a legitimate alternative antihypertensive strategy and recommends 1) RDN should be performed in the context of registry and clinical studies (Class I, Level C) and 2) RDN should not be performed routinely, without detailed evaluation of various causes of secondary hypertension and renal artery anatomy (Class III, Level C). RDN could be performed in patients who fulfill either of the following BP criteria: 1) office BP ≥ 150/90 mmHg and daytime ambulatory SBP ≥ 135 mmHg or diastolic BP (DBP) ≥ 85 mmHg, irrespective of use of antihypertensive agents (Class IIa, Level B), or 2) 24-hour ambulatory SBP ≥ 140 mmHg and DBP ≥ 80 mmHg, irrespective of use of antihypertensive agents (Class IIa, Level B), with eligible renal artery anatomy and estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2. Five subgroups of hypertensive patients are deemed preferred candidates for RDN and dubbed "RDN i2": Resistant hypertension, patients with hypertension-mediated organ Damage, Non-adherent to antihypertensive medications, intolerant to antihypertensive medications, and patients with secondary (2ndary) causes being treated for ≥ 3 months but BP still uncontrolled. The Task Force recommends assessment of three aspects, dubbed "RAS" (R for renal, A for ambulatory, S for secondary), beforehand to ascertain whether RDN could be performed appropriately: 1) Renal artery anatomy eligibility assessed by computed tomography or magnetic resonance renal angiography if not contraindicated, 2) genuine uncontrolled BP confirmed by 24-hour Ambulatory BP monitoring, and 3) Secondary hypertension identified and properly treated. After the procedure, 24-hour ambulatory BP monitoring, together with the dose and dosing interval of all BP-lowering drugs, should be obtained 6 months following RDN. Computed tomography or magnetic resonance renal angiography should be obtained 12 months following RDN, given that renal artery stenosis might not be clinically evident.

MicroRNA-92a Mediates Endothelial Dysfunction in CKD.

CKD is an independent risk factor for cardiovascular disease (CVD). The accumulation of uremic toxins in CKD induces oxidative stress and endothelial dysfunction. MicroRNA-92a (miR-92a) is induced by oxidative stress in endothelial cells (ECs) and involved in angiogenesis and atherosclerosis. We investigated a role for oxidative stress-responsive miR-92a in CKD. Our study of patients at three clinical sites showed increased serum miR-92a level with decreased kidney function. In cultured ECs, human CKD serum or uremic toxins (such as indoxyl sulfate), compared with non-CKD serum, induced the levels of miR-92a and suppressed the expression of miR-92a targets, including key endothelial-protective molecules. The antioxidant N-acetylcysteine inhibited these vasculopathic properties. In rats, adenine-induced CKD associated with increased levels of miR-92a in aortas, serum, and CD144+ endothelial microparticles. Furthermore, CD144+ microparticles from human uremic serum contained more miR-92a than those from control serum. Additional analysis showed a positive correlation between serum levels of miR-92a and indoxyl sulfate in a cohort of patients with ESRD undergoing hemodialysis. Collectively, our findings suggest that the uremic toxins accumulated in CKD can upregulate miR-92a in ECs, which impairs EC function and predisposes patients to CVD.

Systemic Inflammatory Response Syndrome is an Independent Predictor of One-Year Mortality in Patients with Acute Myocardial Infarction.

BACKGROUND: Convincing evidence suggests that inflammatory biomarkers are associated with an increased risk among patients with acute myocardial infarction (AMI). However, the impact of systemic inflammatory response (SIRS) on one-year clinical outcomes remains uncertain. Herein we investigated the impact of SIRS on one-year mortality and major adverse cardiovascular events (MACE) in patients with AMI. METHODS: We conducted a retrospective study that enrolled patients admitted due to AMI and who received coronary artery intervention from January 2012 to June 2014. SIRS was defined according to standard criteria as having two or more of the following: (1) body temperature < 36 or > 38 °C, (2) heart rate > 90 beats per minute, (3) respiratory rate > 20, or (4) white blood cell count < 4000/mm3 or > 12,000/mm3. The primary endpoint was one-year mortality. The secondary endpoint was a one-year MACE, including revascularization, AMI, and stroke. RESULTS: A total of 330 AMI patients were enrolled in the study, and 121 study subjects (36.6%) met the SIRS criteria. AMI patients with SIRS on admission had significantly increased one-year all-cause mortality (control vs. SIRS: 21.1% vs. 33.1%, p = 0.026) and one-year MACE (35.9% vs. 53.7%, p = 0.022). Patients with SIRS had a higher incidence of one-year non-fatal myocardial infarction, but not non-fatal stroke. After multivariable adjustment, SIRS [hazard ratio (HR) = 1.773, 95% confidence interval (CI) = 1.097-2.886, p = 0.019] and age (HR = 1.038, 95% CI = 1.018-1.058, p < 0.001) were associated with enhanced risk of one-year mortality. CONCLUSIONS: This study revealed that AMI patients with SIRS on initial admission were associated with increased risk of one-year all-cause mortality.

Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a.

BACKGROUND: Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. METHODS AND RESULTS: Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1ß. CONCLUSIONS: Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

Association between use of oral-antidiabetic drugs and the risk of aortic aneurysm: a nested case-control analysis.

BACKGROUND: Pleiotropic effects on cardiovascular protection have been suggested in several oral antidiabetic drugs (OAD). The impacts of OADs on aortic aneurysm (AA) growth have been found in animal studies, but the evidence of their beneficial effects for AA protection in human are lacking. We investigated the relationship between OAD therapy and the risk of developing AA. METHODS: We conducted a nested case-control analysis using the database extracted from Taiwan's National Health Insurance Research Database. The database consists of 1.2 million diabetic patients representing the majority of the type 2 diabetes population in Taiwan from 2000 to 2013. Cases were identified as those with either inpatient or outpatient diagnosis code of AA. One control was selected for each case matching on duration of follow-up, age, sex, urbanization, monthly income, severity of diabetes, and risk factor for AA. We identified variable classes of OADs, including metformin, sulfonylureas, thiazolidinedione (TZD), alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors prior to the development of AA. RESULTS: A total of 4468 cases diagnosed with AA and 4468 matched controls were identified. Metformin use, sulfonylurea use, and TZD were associated with lower risk of developing AA, odds ratio [OR] 0.72 (95 % confidence interval [CI] 0.64-0.80), 0.82 (95 % CI 0.74-0.92), and 0.82 (95 % CI 0.69-0.98), respectively. The effects of metformin and sulfonylurea on AA were dose responsive. Neither alpha-glucosidase inhibitors (OR 0.95; 95 % CI 0.81-1.11) nor DPP-4 inhibitors (OR 0.85; 95 % CI 0.68-1.07) was significantly associated with AA events. CONCLUSIONS: Metformin, sulfonylurea, and TZD treated patients were associated with lower risks of AA development, but not DPP-4 inhibitors or alpha-glucosidase inhibitor. The protective effects of hypoglycemic agents are further confirmed by the dose responsive relations in metformin and sulfonylurea groups.

CHADS2 score predicts risk of contrast-induced nephropathy in stable coronary artery disease patients undergoing percutaneous coronary interventions.

BACKGROUND/PURPOSE: To investigate the correlation between the CHADS2 score and risk of contrast-induced nephropathy (CIN), we conducted a retrospective study in patients who underwent elective percutaneous coronary intervention (PCI) and compared its accuracy with previous scoring systems. METHODS: A total of 539 patients who underwent elective PCI were enrolled. Based on their underlying diseases, such as hypertension, diabetes, and kidney disease, CHADS2 score, R2CHADS2 score, and Mehran's risk score were calculated for each patient. Incidence of CIN was defined as a rise in serum creatinine >0.5 mg/dL or >25% increase in baseline within 48 hours after PCI. All study participants were followed up until October 2014, or until the occurrence of major adverse cardiovascular events (MACEs). RESULTS: Overall, 55 cases (10.2%) of CIN and 90 cases (16.7%) of MACEs were identified after participants were followed up for 1.57 ± 1.46 years. The study cohort was divided into three groups according to CHADS2 scores: score 0, score 1-2, and score 3-6. In multivariate analysis, an increase of 1 point in the CHADS2 score was independently associated with a 37% increase in the risk of CIN (odds ratio, 1.37; 95% confidence interval, 1.00-1.87; p = 0.048) and a 49% increase in MACEs (hazard ratio, 1.49; 95% confidence interval, 1.18-1.88, p = 0.001). In pairwise comparison, the discriminatory performance of CHADS2 score was not inferior to either R2CHADS2 score (p = 0.226) or Mehran's risk score (p = 0.075). CONCLUSION: CHADS2 score could be a simple and useful predictor for CIN in patients undergoing elective PCI.

Association of Serum Bilirubin with SYNTAX Score and Future Cardiovascular Events in Patients Undergoing Coronary Intervention.

BACKGROUND: Bilirubin has emerged as an important endogenous antioxidant molecule, and increasing evidence shows that bilirubin may protect against atherosclerosis. The SYNTAX score has been developed to assess the severity and complexity of coronary artery disease. The aim of this study was to evaluate whether serum bilirubin levels are associated with SYNTAX scores and whether they could be used to predict future cardiovascular events in patients undergoing coronary intervention. METHODS: Serum bilirubin levels and other blood parameters in patients with at least 12-h fasting states were determined. The primary endpoint was any composite cardiovascular event within 1 year, including death, nonfatal myocardial infarction, and target-vessel revascularization. RESULTS: In total, 250 consecutive patients with stable coronary artery disease (mean age 70 ± 13) who had received coronary intervention were enrolled. All study subjects were divided into two groups: group 1 was defined as high SYNTAX score (> 22), and group 2 was defined as low SYNTAX score (≤ 22). Total bilirubin levels were significantly lower in the high SYNTAX score group than in the low SYNTAX score group (0.51 ± 0.22 vs. 0.72 ± 0.29 mg/dl, p < 0.001). By multivariate analysis, serum total bilirubin levels were identified as an independent predictor for high SYNTAX score (adjusted odds ratio: 0.28, 95% confidence interval 0.04-0.42; p = 0.004). Use of the Kaplan-Meier analysis demonstrated a significant difference in 1-year cardiovascular events between high (> 0.8 mg/dl), medium (> 0.5, ≤ 0.8 mg/dl), and low (≤ 0.5 mg/dl) bilirubin levels (log-rank test p = 0.011). CONCLUSIONS: Serum bilirubin level is associated with SYNTAX score and predicts future cardiovascular events in patients undergoing coronary intervention.

The Association Between Insomnia and Increased Future Cardiovascular Events: A Nationwide Population-Based Study.

OBJECTIVES: Insomnia may increase the risk of cardiovascular disease (CVD), but the reported magnitude of the associations between sleep characteristics and CVD is inconsistent. We investigated the association between insomnia and the risk of developing acute myocardial infarction (AMI) and/or stroke by using a nationwide, population-based cohort database in Taiwan. METHODS: The analyses were conducted using information from a random sample of 1 million people enrolled in the nationally representative Taiwan National Health Insurance Research Database. A total of 44,080 individuals who were 20 years or older, including 22,040 people who had diagnosis of insomnia during the study period and an age-, sex-, comorbidity-matched group of 22,040 people without insomnia, were enrolled in our study. The study end points were the occurrence of cardiovascular events including AMI or stroke during follow-up. RESULTS: During a 10-year follow-up, 302 AMI events and 1049 stroke events were identified. The insomnia group had a higher incidence of AMI (2.25 versus 1.08 per 1000 person-years) and stroke (8.01 versus 3.69 per 1000 person-years, p < .001). Cox proportional hazard regression model analysis showed that insomnia was independently associated with a higher risk of future AMI (hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.31-2.16, p < .001), stroke (HR = 1.85, 95% CI = 1.62-2.12, p < .001), and the composite event index (HR = 1.81, 95% CI = 1.61-2.05, p < .001), after adjusting for age, sex, and comorbidities. CONCLUSIONS: Insomnia is associated with an increased risk of future cardiovascular events.

Fainting After Chest Pain.

UNLABELLED: Variant angina presenting acute chest pain and ST elevation on electrocardiogram accounts for an underdiagnosed scenario in acute coronary syndrome and contributes to syncope as a consequence of ventricular arrhythmia. Here, we report a case of a 48-year-old man with a recent onset of chest pain and palpitations followed by syncope. Holter monitoring documented 2 episodes of evolving ST elevation associated with non-sustained ventricular tachycardia. Emergent cardiac catheterization indicated insignificant coronary narrowing. A non-invasive brachial artery ultrasound, which demonstrated endothelial dysfunction that was salvaged by exogenic nitrate, was used instead of intracoronary provocation. There was no clinical or electrocardiographic recurrence of variant angina after vasodilator treatment. In conclusion, variant angina represents an important but overlooked etiology for syncope. Holter monitoring facilitates the diagnostic and prognostic assessment in patients with syncope precipitated by chest pain. KEY WORDS: Flow-mediated vasodilation; Holter monitoring; Variant angina; Ventricular arrhythmia.

Rapid Resolution of Severe Myocardial Dysfunction in a Patient with Rheumatoid Arthritis by Intravenous Immunoglobulin and Steroid Treatment.

UNLABELLED: A 64-year-old man with rheumatoid arthritis (RA) presented to our emergency department with severe chest tightness and dyspnea. His electrocardiography (ECG) showed multiple premature atrial complexes (PACs) with wide QRS, and transthoracic echocardiography revealed severe hypokinesis of the left ventricle. The patient later developed sudden cardiovascular collapse with presumed fulminant myocarditis and cardiogenic shock. Further investigation showed that coronary angiogram, viral studies and autoimmune vasculitis markers were all negative. After high-dose intravenous immunoglobulin (IVIG) and systemic steroid were administered, a dramatic improvement of clinical conditions was observed, with an increase of the left ventricular ejection fraction (LVEF) from 10% to 42% within one week, and a resolution of the wide QRS on the ECG. The rapid recovery from left ventricular dysfunction by treatment with IVIG and systemic steroid suggests immunotherapy might be effective in RA patients with acute fulminant myocarditis. KEY WORDS: Fulminant myocarditis; Intravenous immunoglobulin; Rheumatoid arthritis; Systemic steroid.

Bridging the STRONG Gap: Call to Optimize Heart Failure Treatment After Hospitalization in Women and Men in Taiwan.

The benefits of rapidly up-titrating evidence-based treatments following heart failure (HF) hospitalizations were demonstrated in the The Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) trial and emphasized in contemporary HF guidelines. We aimed to assess up-titration patterns of guideline-directed medical treatments in the Taiwanese HF population. Combining data from the Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry and the Treatment with Angiotensin Receptor neprilysin inhibitor for Taiwan Acute Heart Failure (TAROT-AHF) study cohort, we formed the "Taiwan real-world cohort". We compared these data with subgroups of patients with left ventricular ejection fraction ≤40% in the STRONG-HF trial. Patients in the Taiwan cohort exhibited similar blood pressure, heart rate and N-terminal pro B-type natriuretic peptide levels at discharge compared with those in the STRONG-HF trial. A higher proportion of patients in the STRONG-HF high-intensity care group received up-titrations compared with those in the usual care group and the Taiwan cohort. Composite all-cause mortality or HF hospitalization at 180 days for patients in the high-intensity care group, usual care group, and Taiwan cohort were 17.4%, 23.7%, and 31.9%, respectively, with differences largely contributed by HF hospitalization (10.1%, 17.9%, and 27.6%, respectively), whereas all-cause mortality rates were similar (11.0%, 9.6%, and 9.3%, respectively). Gender did not affect this trend. In conclusion, our data highlights a treatment gap between the STRONG-HF trial and real-world practices in Taiwan, urging prompt optimization of HF therapy.