A Novel Antioxidant, Hydrogen-Rich Coral Calcium Alters Gut Microbiome and Bile Acid Synthesis to Improve Methionine-and-Choline-Deficient Diet-Induced Non-Alcoholic Fatty Liver Disease.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has dramatically increased in recent years, and it is highly associated with metabolic diseases, as well as the development of hepatocellular carcinoma. However, effective therapeutic strategies for the treatment of NAFLD are still scarce. Although hydrogen-rich water shows beneficial effects for hepatic steatosis, the inconvenience limits the application of this antioxidant. In light of this, hydrogen-rich coral calcium (HRCC) was developed due to its convenience and quantifiable characteristics. However, the effects of HRCC on NAFLD are still unknown. In the present study, we found that HRCC treatment improved methionine-and-choline-deficient diet (MCD)-induced hepatic steatosis, increased aspartate aminotransferase and alanine aminotransferase levels, and elevated hepatic inflammatory factor expressions in mice. In addition to the increased expressions of antioxidative enzymes, we found that HRCC increased the expressions of bile acid biosynthesis-related genes, including Cyp8b1 and Cyp27a1. Increased hepatic bile acid contents, such as muricholic acids, 23 nor-deoxycholic acid, glycoursodeoxycholic acid, and cholic acids, were also confirmed in MCD mice treated with HRCC. Since the biogenesis of bile acids is associated with the constitution of gut microbiome, the alterations in gut microbiome by HRCC were evaluated. We found that HRCC significantly changed the constitution of gut microbiome in MCD mice and increased the contents of Anaerobacterium, Acutalibacter, Anaerosacchariphilus, and Corynebacterium. Taken together, HRCC improved MCD-induced NAFLD through anti-inflammatory mechanisms and by increasing antioxidative activities. Additionally, HRCC might alter gut microbiome to change hepatic bile acid contents, exerting beneficial effects for the treatment of NAFLD.

Rapid intervention team strategy improves intervention quality for patients undergoing hemodialysis with arteriovenous shunt dysfunction or failure.

BACKGROUND: Vascular access dysfunction is a great burden for hemodialysis patients. Early intervention of a dysfunctional arteriovenous shunt is associated with higher technical success and may improve midterm patency. This trial aimed to estimate the feasibility of a new system, the "rapid intervention team" (RIT) strategy. METHODS: We recruited hemodialysis patients who visited our hospital because of arteriovenous shunt dysfunction or failure to undergo an RIT strategy from September 1, 2019 to December 31, 2022. In addition, we included a control group comprising patients who underwent percutaneous intervention for arteriovenous shunt dysfunction or failure before this strategy was implemented from February 1, 2017 to December 31, 2022. Case number, time to intervention, all-cause mortality, cumulative survival rate, and number of patients who required temporary dialysis catheter insertion and recreation were compared between the two groups. The primary endpoints were double-lumen insertion, a composite outcome involving permanent catheter insertion, and the need for recreation. The secondary endpoint was all-cause mortality. RESULTS: We enrolled 1054 patients, including 544 (51.6%) and 510 (48.4%) in the RIT and control groups, respectively. Even with the coronavirus disease of 2019 (COVID-19) pandemic, the number of cases significantly increased after the implementation of the RIT strategy (from 216 in 2019 to 828 in 2022, p for trend <0.001). The RIT group had a shortened time to intervention ( p for trend <0.001). The implementation of the RIT strategy was significantly associated with a reduced risk of insertion of a temporary double-lumen catheter and recreation of vascular access (1% vs 6% and 1% vs 28%, respectively; both p < 0.01). The cumulative survival rate was not significantly different between the RIT and control groups ( p = 0.16). CONCLUSION: The implementation of the RIT strategy improves the quantity and quality of percutaneous transluminal intervention for arteriovenous shunt dysfunction or failure in patients undergoing hemodialysis.

Exercise capacity-hemodynamics mismatch in elderly patients with pulmonary hypertension: A nationwide multicenter study from Taiwan Society of Cardiology Pulmonary Hypertension Registry (TAIPANS).

Background: Demographics of pulmonary hypertension (PH) has changed a lot over the past forty years. Several recent registries noted an increase in mean age of PH but only a few of them investigated the characteristics of elderly patients. Thus, we aimed to analyze the characteristics of PH in such a population in this study. Methods: This multicenter study enrolled patients diagnosed with PH in group 1, 3, 4, and 5 consecutively from January 1, 2019 to December 31, 2020. A total of 490 patients was included, and patients were divided into three groups by age (≤45 years, 45-65 years, and >65 years). Results: The mean age of PH patients diagnosed with PH was 55.3 ± 16.3 years of age. There was higher proportion of elderly patients classified as group 3 PH (≤45: 1.3, 45-65: 4.5, >65: 8.1 %; p = 0.0206) and group 4 PH (≤45: 8.4, 45-65: 14.5, >65: 31.6 %; p < 0.0001) than young patients. Elderly patients had shorter 6-min walking distance (6 MWD) (≤45 vs. >65, mean difference, 77.8 m [95% confidence interval (CI), 2.1-153.6 m]), lower mean pulmonary arterial pressure (mPAP) (≤45 vs. >65, mean difference, 10.8 mmHg [95% CI, 6.37-15.2 mmHg]), and higher pulmonary arterial wedge pressure (PAWP) (≤45 vs. 45-65, mean difference, -2.1 mmHg [95% CI, -3.9 to -0.3 mmHg]) compared to young patients. Elderly patients had a poorer exercise capacity despite lower mPAP level compared to young population, but they received combination therapy less frequently compared to young patients (triple therapy in group 1 PH, ≤45: 16.7, 45-65: 11.3, >65: 3.8 %; p = 0.0005). Age older than 65 years was an independent predictor of high mortality for PH patients. Conclusions: Elderly PH patients possess unique hemodynamic profiles and epidemiologic patterns. They had higher PAWP, lower mPAP, and received combination therapy less frequently. Moreover, ageing is a predictor of high mortality for PH patients. Exercise capacity-hemodynamics mismatch and inadequate treatment are noteworthy in the approach of elderly population with PH.

Taiwan Association for the Study of the Liver-Taiwan Society of Cardiology Taiwan position statement for the management of metabolic dysfunction- associated fatty liver disease and cardiovascular diseases.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

Blood pressure levels within normotensive range are independently associated with increased risk of arterial stiffness in adults without hypertension or prehypertension.

BACKGROUND AND AIMS: High blood pressure (BP) indices, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) predict cardiovascular diseases and mortality. However, the association of these BP indices with arterial stiffness (AS) in the normotensive population (BP < 120/80 mmHg) remains unclear. METHODS AND RESULTS: Study participants who underwent health checkups at a tertiary referred center were recruited between November 2018 to December 2019. 2129 participants were enrolled after excluding those aged <18 years old, with elevated BP, history of hypertension, cardiovascular disease, and stroke, or with incomplete data. The brachial-ankle pulse wave velocity (baPWV) values were examined for evaluation of AS. Participants with higher blood pressure indices had significantly higher baPWV. Multiple linear regression revealed that all BP indices were positively associated with baPWV. According to the binary logistic regression analysis, participants in the higher SBP and MAP quartiles were significantly related to AS. The odds ratio (OR) for SBP Q2, Q3 and Q4 vs. Q1 were 6.06, 10.06 and 17.78 whereas the OR for MAP Q2, Q3 and Q4 vs. Q1 were: 5.07, 5.28 and 10.34. For DBP and PP, only participants belonging to the highest quartile were associated with AS(OR for DBP Q4 vs. Q1: 2.51; PP Q4 vs Q1: 1.94). CONCLUSIONS: BP indices were linearly related to the baPWV. Normotensive participants with higher quartiles of SBP, DBP, MAP, and PP, remained associated with increased AS. The SBP and MAP levels exhibited a more prominent relationship with AS.

2023 Expert Consensus of the Taiwan Society of Cardiology on the Diagnosis and Treatment of Cardiac Amyloidosis.

Cardiac amyloidosis is one form of systemic amyloidosis caused by abnormal amyloid fibrils deposited in the extracellular space of the myocardium causing heart failure because of restrictive cardiomyopathy and conduction disturbances. The incidence and prevalence of cardiac amyloidosis are higher than previously noted, particularly among special populations. The most common forms of cardiac amyloidosis are light chain and transthyretin amyloid cardiomyopathy. Even though more than 70% of patients with systemic amyloidosis have cardiac amyloidosis, the diagnosis is often delayed, suggesting significant gaps in the knowledge of cardiac amyloidosis and a lack of multidisciplinary teamwork in our daily practice. The Taiwan Society of Cardiology Heart Failure Committee organized experts to draft the "Expert Consensus on the diagnosis and treatment of cardiac amyloidosis." This statement aims to help clinicians and healthcare professionals improve early diagnosis and management of cardiac amyloidosis in Taiwan. The expert panel met virtually to review the data and discuss the consensus statements. Our review provided practical information about diagnostic methods and algorithms, clinical clues and red-flag signs, cardiac amyloidosis per se and its comorbidities treatment modalities, and follow-up plans for asymptomatic transthyretin gene carriers. We especially innovate two acronyms, "HFpEF MUTED CALL" and "HFmrEF MUST COUNT", to help in the early diagnosis and screening of transthyretin amyloid cardiomyopathy as shown in the Central Illustration.

Rationale and Study Design of the TSOC-Fully Organized Registry for the Management of Symptomatic ACS Study (T-FORMOSA Study).

Background: Successful implementation of practice guidelines has been challenging in the treatment of acute coronary syndrome (ACS), leaving room for improvement. A nationwide registry can provide more information than that recorded in the National Health Insurance Research Database (NHIRD). Methods: We conducted a prospective, nationwide, multi-center ACS full spectrum registry involving 3600 patients admitted to hospitals within 24 hours of the onset of myocardial infarction with ST-segment elevation or ACS without ST-segment elevation. In total, 41 sites including medical centers and regional hospitals were selected across Taiwan. The data for each patient are collected at 3 time points for the main study: during hospitalization, 6 months, and 12 months after the discharge. The milestone for first patient in was reached on January 7, 2022, and complete enrollment is expected before October 2023. The primary aims of the main study are to determine the degree of guideline-directed medical therapies and to identify prognostic predictors associated with 1-year composite outcomes, including death, myocardial infarction, stroke, and unplanned coronary revascularization in ACS patients. Thereafter, the patient data will be analyzed every 3 to 5 years for up to 20 years after discharge using the NHIRD in the extended study. Conclusions: We hypothesized that a greater increase in the implementation of guideline-directed medical therapies can be observed. The results of the current study will add new and important information regarding a broad spectrum of ACS to drive further investigations.

Nephrolithiasis is associated with the severity of coronary artery calcification, but not with coronary artery stenosis.

PURPOSE: Emerging data have indicated that nephrolithiasis is possibly associated with subclinical coronary artery disease (CAD). Considering that a significant proportion of obstructive CAD in non-elderly individuals occurs in those without detectable calcium score (CACS), this study aimed to investigate whether nephrolithiasis is still associated with CAD as assessed by coronary computed tomography (CT)-derived luminal stenosis [using Gensini score (GS)]. METHODS: A total of 1170 asymptomatic adults without known CAD who underwent health examinations were recruited. Nephrolithiasis was assessed using abdominal ultrasonography (US). Individuals with a self-reported stone history, but no evidence of nephrolithiasis were excluded. The CACS and GS were measured using 256-slice coronary CT. RESULTS: Nearly half of these patients had a CACS > 0 (48.1%), and a higher prevalence of nephrolithiasis was observed than in those who had zero CACS (13.1% vs. 9.7%). However, no significant intergroup difference in GS was detected. A greater proportion of stone formers than non-stone formers had a higher risk category, whereas no significant difference was noted in Gensini category. Multiple linear regression analyses showed that the CACS independently predicted the presence of nephrolithiasis after adjustment. Importantly, we found that stone formers had a nearly threefold higher risk than non-stone formers of developing severe coronary calcification (CAC > 400). CONCLUSIONS: Nephrolithiasis was significantly associated with coronary artery calcification presence and severity, but not coronary luminal stenosis in patients without known CAD. Accordingly, the relationship between stone disease and CAD remains controversial, and additional studies are imperative to validate these findings.

2023 Consensus of Taiwan Society of Cardiology on the Pharmacological Treatment of Chronic Heart Failure.

The prevalence of heart failure is increasing, causing a tremendous burden on health care systems around the world. Although mortality rate of heart failure has been significantly reduced by several effective agents in the past 3 decades, yet it remains high in observational studies. More recently, several new classes of drugs emerged with significant efficacy in reducing mortality and hospitalization in chronic heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). To integrate these effective therapies and prioritize them in the management of Asian patients, Taiwan Society of Cardiology has recently appointed a working group to formulate a consensus of pharmacological treatment in patients with chronic heart failure. Based on most updated information, this consensus provides rationales for prioritization, rapid sequencing, and in-hospital initiation of both foundational and additional therapies for patients with chronic heart failure.

The Effects of Post-Acute Care in Patients with Heart Failure in Taiwan: A Single Center Experience.

Background: The National Health Insurance Administration in Taiwan has promoted the heart failure post-acute care (HF-PAC) program as a means to provide proactive integrated care within the optimal treatment timeframe to enhance functional recovery after acute decompensated heart failure (HF). Objectives: The aim of this program was to reduce HF readmission rates, improved medication prescription rates, and improve the quality of life in HF patients. Methods: Patients who had a reduced left ventricular ejection fraction (LVEF) of ≤ 40% were included and followed up for 6 months after discharge. They underwent cardiac rehabilitation and physiological, and nutritional status evaluations. The main clinical outcomes of the HF-PAC program were guideline-directed medical therapy prescription rate and 6-month readmission rate. Results: A total of 122 patients were recruited from June 2018 to December 2020 at a medical center in southern Taiwan. The patients' activities of daily living, nutritional status, quality of life and LVEF were significantly improved during the HF-PAC program. More than 95% of the patients received guideline-directed medical prescriptions at the end of the HF-PAC program. The cardiovascular-related 6-month re-admission rate after the HF-PAC program ended was 27.7%, and it could be predicted by the New York Health Association functional class [hazard ratio (HR) 95% confidence interval (95% CI) = 4.12 (1.36-12.46)], value of the Mini Nutritional Assessment - Short Form [HR (95% CI) = 0.46 (0.31-0.68)] and LVEF [HR (95% CI) = 0.95 (0.91-0.99)]. Conclusions: By incorporating multidisciplinary healthcare teams, the HF-PAC program improves the guideline- directed medical therapy prescription rate, thus improving patients' cardiac function, physical activity recovery, the quality of life, and also reduces their readmission rate.

Management of Restenosis after Stenting in Left Main Coronary Artery Disease.

Background: The optimal alternative treatment strategy to coronary artery bypass graft surgery (CABG) for in-stent restenosis (ISR) in left main (LM) coronary artery disease remains uncertain. Methods: We retrospectively screened all intervention reports from an intervention database and extracted those mentioning an LM stent. We then manually confirmed reports involving LM ISR and divided them into two groups, those in which the patient received a new drug-eluting stent (new-DES) strategy, and those in which the patient received a drug-coated balloon (DCB) only. A composite endpoint of major adverse cardiovascular events (MACEs) and each individual endpoint were compared. We also performed a brief analysis of similar designed studies. Results: Between the new-DES (n = 40) and DCB-only (n = 22) groups, during median respective follow-up times of 581.5 and 642.5 days, no significant statistical differences were detected in MACEs (50.0% vs. 50.0%, p = 0.974), cardiovascular death (27.5% vs. 13.6%, p = 0.214), nonfatal myocardial infarction (30.0% vs. 31.8%, p = 0.835), or target lesion revascularization (35.0% vs. 45.5%, p = 0.542). We analyzed four similar studies and found comparable MACE findings (odds ratio: 0.85, 95% CI: 0.44-1.67). Conclusions: Our findings support both DCB angioplasty and repeat DES implantation for LMISR lesions in patients who were clinically judged to be unsuitable for CABG; the treatments achieved comparable clinical results in terms of MACEs in the medium term.

Estimating time and transportation costs associated with lung cancer screening and diagnostic lung procedures in Taiwan: a cross-sectional survey in a medical centre.

OBJECTIVES: Earlier research has evaluated the non-medical costs after lung cancer diagnosis. This study estimated the time costs and transportation costs associated with low-dose CT (LDCT) screening and diagnostic lung procedures in Taiwan. DESIGN: Cross-sectional study. SETTING: A tertiary referral medical centre. PARTICIPANTS AND INTERVENTIONS: The study participants were individuals aged 50-80 years who underwent LDCT screening or diagnostic lung procedures between 2021 and 2022. Participants completed a questionnaire including items on time spent on receiving care, time spent on travel and its cost and time taken off from work by the participant and any accompanying caregiver. OUTCOME MEASURES: Time costs were valued using the age- and sex-specific average daily wage for employed participants/caregivers. Costs of informal healthcare sector consisted of time cost of the participant, transportation cost and time cost of the caregiver. RESULTS: A total of 209 participants who underwent LDCT screening (n=84) or non-surgical (n=12) or surgical (n=113) diagnostic lung procedures for the first time were enrolled. Considering the purchasing power parity, the average costs of informal healthcare sector were US$126.4 (95% CI 101.6 to 151.2), US$290.7 (95% CI 106.9 to 474.5) and US$749.8 (95% CI 567.3 to 932.4), respectively, for LDCT screening, non-surgical procedures and surgical procedures. CONCLUSIONS: This study estimated time and transportation costs associated with LDCT screening and diagnostic lung procedures, which could be used for future analysis of cost-effectiveness of lung cancer screening in Taiwan.

2023 Guidelines of the Taiwan Society of Cardiology on the Diagnosis and Management of Chronic Coronary Syndrome.

Coronary artery disease (CAD) covers a wide spectrum from persons who are asymptomatic to those presenting with acute coronary syndromes (ACS) and sudden cardiac death. Coronary atherosclerotic disease is a chronic, progressive process that leads to atherosclerotic plaque development and progression within the epicardial coronary arteries. Being a dynamic process, CAD generally presents with a prolonged stable phase, which may then suddenly become unstable and lead to an acute coronary event. Thus, the concept of "stable CAD" may be misleading, as the risk for acute events continues to exist, despite the use of pharmacological therapies and revascularization. Many advances in coronary care have been made, and guidelines from other international societies have been updated. The 2023 guidelines of the Taiwan Society of Cardiology for CAD introduce a new concept that categorizes the disease entity according to its clinical presentation into acute or chronic coronary syndromes (ACS and CCS, respectively). Previously defined as stable CAD, CCS include a heterogeneous population with or without chest pain, with or without prior ACS, and with or without previous coronary revascularization procedures. As cardiologists, we now face the complexity of CAD, which involves not only the epicardial but also the microcirculatory domains of the coronary circulation and the myocardium. New findings about the development and progression of coronary atherosclerosis have changed the clinical landscape. After a nearly 50-year ischemia-centric paradigm of coronary stenosis, growing evidence indicates that coronary atherosclerosis and its features are both diagnostic and therapeutic targets beyond obstructive CAD. Taken together, these factors have shifted the clinicians' focus from the functional evaluation of coronary ischemia to the anatomic burden of disease. Research over the past decades has strengthened the case for prevention and optimal medical therapy as central interventions in patients with CCS. Even though functional capacity has clear prognostic implications, it does not include the evaluation of non-obstructive lesions, plaque burden or additional risk-modifying factors beyond epicardial coronary stenosis-driven ischemia. The recommended first-line diagnostic tests for CCS now include coronary computed tomographic angiography, an increasingly used anatomic imaging modality capable of detecting not only obstructive but also non-obstructive coronary plaques that may be missed with stress testing. This non-invasive anatomical modality improves risk assessment and potentially allows for the appropriate allocation of preventive therapies. Initial invasive strategies cannot improve mortality or the risk of myocardial infarction. Emphasis should be placed on optimizing the control of risk factors through preventive measures, and invasive strategies should be reserved for highly selected patients with refractory symptoms, high ischemic burden, high-risk anatomies, and hemodynamically significant lesions. These guidelines provide current evidence-based diagnosis and treatment recommendations. However, the guidelines are not mandatory, and members of the Task Force fully realize that the treatment of CCS should be individualized to address each patient's circumstances. Ultimately, the decision of healthcare professionals is most important in clinical practice.

Optimal body composition indices cutoff values based on all-cause mortality in the elderly.

The cutoffs of body composition indices are inconclusive in older populations. This study is designed toward determining the optimal cutoffs of the body composition indices based on the association with all-cause mortality. During 2009 and 2010, a cohort population of 1200 was enrolled in central western Taiwan. Of the 1200 subjects, 428 older subjects (mean age: 72.5 ± 5.4 yrs.; 47.7 % were women) were censored in this study. The waist circumference (WC) and body mass index (BMI) were measured using standard anthropometric methods. A multi-frequency bioelectrical impedance analysis device was utilized to estimate each participant's body composition indices, including percent body fat (PBF) and skeletal muscle mass index (SMMI). All claims records of death from 2009 to 2018 in the National Health Insurance Research Databank were identified. A receiver operating characteristic curve method and the highest Youden index were used to identify the optimal cutoffs. A Cox proportional hazards regression analysis was used to model associations between each of the recommended cutoff values with all-cause mortality. The all-cause mortality rate was 20.09 % after a follow-up period of 5.86 ± 2.39 person-years. The significant indices cutoff value was identified to be WC (86.7 cm) for older women and BMI (23.8 kg/m2) and as WC (77.6 cm), and SMMI (8.7 kg/m2) for older men. The recommended optimal cutoffs of the body composition indices were gender-specific and can be utilized to predict the risk of all-cause mortality.

2022 Taiwanese Dermatological Association (TDA), Taiwanese Association for Psoriasis and Skin Immunology (TAPSI), and Taiwan Society of cardiology (TSOC) joint consensus recommendations for the management of psoriatic disease with attention to cardiovascular comorbidities.

Psoriatic disease is a chronic inflammatory disorder with skin and joint manifestations. Due to the persistent inflammatory state exhibited by patients with psoriasis, multiple systemic comorbidities occur more frequently in patients with psoriasis than in the general population, and the risk of cardiovascular (CV) diseases is significantly increased. As the pathophysiology of psoriatic disease is becoming better understood, the sharing of underlying pathogenic mechanisms between psoriatic and CV diseases is becoming increasingly apparent. Consequently, careful attention to CV comorbidities that already exist or may potentially develop is needed in the management of patients with psoriasis, particularly in the screening and primary prevention of CV disease and in treatment selection due to potential drug-drug and drug-disease interactions. Furthermore, as the use of effective biologic therapy and more aggressive oral systemic treatment for psoriatic disease is increasing, consideration of the potential positive and negative effects of oral and biologic treatment on CV disease is warranted. To improve outcomes and quality of care for patients with psoriasis, the Taiwanese Dermatological Association, the Taiwanese Association for Psoriasis and Skin Immunology, and the Taiwan Society of Cardiology established a Task Force of 20 clinicians from the fields of dermatology, cardiology, and rheumatology to jointly develop consensus expert recommendations for the management of patients with psoriatic disease with attention to CV comorbidities.

Effects of Cilostazol on Angiogenesis in Diabetes through Adiponectin/Adiponectin Receptors/Sirtuin1 Signaling Pathway.

Cilostazol is an antiplatelet agent with vasodilating effects that functions by increasing the intracellular concentration of cyclic adenosine monophosphate. We have previously shown that cilostazol has favorable effects on angiogenesis. However, there is no study to evaluate the effects of cilostazol on adiponectin. We investigated the effects of cilostazol on angiogenesis in diabetes in vitro and in vivo through adiponectin/adiponectin receptors (adipoRs) and the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling pathway. Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cocultured under high glucose (HG) conditions. Adiponectin concentrations in the supernatants were significantly increased when HASMCs were treated with cilostazol but not significantly changed when only HUVECs were treated with cilostazol. Cilostazol treatment enhanced the expression of SIRT1 and upregulated the phosphorylation of AMPK in HG-treated HUVECs. By sequential knockdown of adipoRs, SIRT1, and AMPK, our data demonstrated that cilostazol prevented apoptosis and stimulated proliferation, chemotactic motility, and capillary-like tube formation in HG-treated HUVECs through the adipoRs/SIRT1/AMPK signaling pathway. The phosphorylation of downstream signaling molecules, including acetyl-CoA carboxylase (ACC) and endothelial nitric oxide synthase (eNOS), was downregulated when HUVECs were treated with a SIRT1 inhibitor. In streptozotocin-induced diabetic mice, cilostazol treatment could improve blood flow recovery 21-28 days after inducing hindlimb ischemia as well as increase the circulating of CD34+CD45dim cells 14-21 days after operation; moreover, these effects were significantly attenuated by the knockdown of adipoR1 but not adipoR2. The expression of SIRT1 and phosphorylation of AMPK/ACC and Akt/eNOS in ischemic muscles were significantly attenuated by the gene knockdown of adipoRs. Cilostazol improves HG-induced endothelial dysfunction in vascular endothelial cells and enhances angiogenesis in diabetic mice by upregulating the expression of adiponectin/adipoRs and its SIRT1/AMPK downstream signaling pathway.

Higher platelet count, even within normal range, is associated with increased arterial stiffness in young and middle-aged adults.

BACKGROUND: Platelet counts and mean platelet volume (MPV) are related to cardiovascular disease, but a thorough investigation into the connection between increased arterial stiffness, MPV, and platelet counts is lacking. This study aimed to explore the association of platelet count and MPV with arterial stiffness in young and middle-aged adults. METHODS: A total of 2464 participants who underwent health checkups at National Cheng Kung University Hospital, Taiwan from November 2018 to December 2019 were included. We excluded participants aged <18 or >50 years; who are pregnant; on medication for dyslipidemia; with abnormal platelet count, incomplete data, and past history of hematologic disorders. We examined the association of platelet counts and MPV values with brachial-ankle pulse wave velocity (baPWV) levels and increased arterial stiffness. RESULTS: Platelet count was significantly higher in participants with increased arterial stiffness than in those without. The multiple linear regression model revealed that platelet counts were positively associated with baPWV levels (ß = 1.88, 95% confidence interval (CI): 0.96 to 2.80). In the binary logistic regression analysis, subjects in the higher platelet counts quartiles had a higher risk of developing increased arterial stiffness (Q2 vs. Q1: odds ratio (OR): 1.54, 95% CI: 1.05 to 2.27; Q3 vs. Q1: OR: 1.57, 95% CI: 1.06 to 2.33; and Q4 vs. Q1: OR: 2.23, 95% CI: 1.50 to 3.30). In contrast, MPV levels were not associated with arterial stiffness. CONCLUSIONS: Platelet count in midlife was positively associated with baPWV levels. Participants in higher platelet quartiles were at risk for increased arterial stiffness.

Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vitro, cilostazol treatment increased PCSK9 expression in vehicle-treated HepG2 cells but decreased PCSK9 expression in palmitic acid-treated HepG2 cells. In vivo, cilostazol treatment increased the serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice. The expressions of PCSK9-relevant microRNAs also showed similar results. Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrates the therapeutic potential of cilostazol in clinical settings.

Effect of 1PC111, a Fixed-dose Combination of Pitavastatin and Ezetimibe, Versus Pitavastatin or Ezetimibe Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia or Mixed Dyslipidemia: A Randomized, Double-blind, Multicenter, Phase III Study.

PURPOSE: This study aimed to show that the efficacy of 1PC111 is superior to that of either ezetimibe or pitavastatin alone (monotherapy) for the treatment of hypercholesterolemia. METHODS: This was a multicenter, randomized, double-blind, Phase III study. Patients with hypercholesterolemia or mixed dyslipidemia were randomized to receive 1PC111 (which was a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg), pitavastatin 2 mg, or ezetimibe 10 mg daily for 12 weeks. The primary end point was the difference in the percent change in LDL-C from baseline to week 12 between the 1PC111 and each monotherapy group. The secondary end points were the percent change in other lipid profiles from baseline to each visit. All patients were assessed for adverse events until end of study. FINDINGS: A total of 388 patients were randomly assigned to the 1PC111 (n = 128), pitavastatin (n = 132), or ezetimibe (n = 128) group. Generally, baseline characteristics were similar among the 3 groups. A statistically significant decrease in the LDL-C level at week 12 was observed in the 1PC111 group (-50.50% [14.9%]) compared with either the pitavastatin (-36.11% [11.4%]; P < 0.001) or ezetimibe (-19.85% [12.4%]; P < 0.001) group. Also, there was a statistically significant difference between 1PC111 and each monotherapy group in the reduction in total cholesterol, non-HDL-C, and apolipoprotein B levels. Moreover, there was a trend toward more efficient lowering of LDL-C levels in elderly patients (age ≥65 years) than in younger patients (age <65 years) by 1PC111 treatment. In patients given a class I recommendation for atherosclerotic cardiovascular disease prevention, the percentage of patients achieving the LDL-C target of <100 mg/dL at week 12 was significantly higher in the 1PC111 group than in both monotherapy groups (P < 0.001). Overall, the incidence of adverse events was similar among 3 groups. IMPLICATIONS: 1PC111 was more effective in improving lipid profiles and achieving the LDL-C goal than pitavastatin or ezetimibe alone for hypercholesterolemia treatment. Furthermore, 1PC111 may provide more benefit in treating elderly patients. CLINICALTRIALS: gov identifier: NCT04643093.

Coral Hydrate, a Novel Antioxidant, Improves Alcohol Intoxication in Mice.

Alcohol-drinking culture may cause individuals to periodically experience unpleasant hangovers. In addition, ethanol catabolism stimulates the production of free radicals that may cause liver injury and further lead to the development of chronic alcoholic fatty liver disease. Although a number of studies have suggested that hydrogenated water may be consumed to act as free radical scavenger, its instability limits its application. In this study, we used coral hydrate (i.e., hydrogenated coral materials) as a more stable hydrogen source and evaluated its effects in a murine model of alcohol intoxication. In solution, coral hydrate exhibited much more stable redox potential than did hydrogenated water. Furthermore, administration of coral hydrate by oral gavage significantly prolonged the time to fall asleep and decreased the total sleep time in mice that received intraperitoneal injection of ethanol. The mice receiving coral hydrate also had lower plasma ethanol and acetaldehyde levels than controls. In line with this observation, hepatic expression of alcohol dehydrogenase, acetaldehyde dehydrogenase, catalase and glutathione peroxidase were all significantly increased by the treatment. Meanwhile, alcohol-induced upregulation of pro-inflammatory factors was attenuated by the administration of coral hydrate. Taken together, our data suggest that coral hydrate might be an effective novel treatment for alcohol intoxication.