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Abstract Aims Heart failure with reduced ejection fraction (HFrEF) significantly impacts health‐related quality of life (HR‐QoL). Existing HR‐QoL questionnaires can show inconsistencies, potentially misrepresenting patient self‐reports. This study examines the variation in HR‐QoL measurement tools for HFrEF patients, identifying related determinants. Methods and results We retrospectively analysed 134 hospitalized patients with acute decompensated HFrEF at a Taiwanese tertiary centre's Heart Failure Post‐Acute‐Care (HF‐PAC) programme. Participants completed the EuroQol‐5 dimension (EQ‐5D) questionnaire, the EQ‐5D visual analogue scale (VAS), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Utility values were obtained from the EQ‐5D questionnaire. Demographic features were depicted using descriptive statistics, while multivariate regression was used to ascertain relationships between HR‐QoL measurements and determinants. Average scores for EQ‐5D, MLHFQ, EQ‐5D utility, and VAS were 6.1 ± 1.6, 21.8 ± 21.3, 81.7 ± 27.0, and 59.5 ± 14.6, respectively. Significant correlations were observed among the three tools. The New York Heart Association functional class showed a notable association with all tool scores. Other associations encompassed EQ‐5D with coronary artery disease, mineralocorticoid receptor antagonists, and the 6 min walk test; EQ‐5D VAS with chronic kidney disease; and MLHFQ with age. Conclusions This study illuminates the variance in HR‐QoL measurement tools for Taiwanese HFrEF patients. Using a range of these tools is beneficial in unveiling diverse determinants and approaching comprehensive patient‐centred care. However, for a more precise HR‐QoL assessment in Taiwanese HFrEF patients, recalibrating the EQ‐5D‐derived utility scores might be necessary, emphasizing the importance of patient‐specific considerations within the HF‐PAC programme.

Previous studies have suggested a possible association between carbon monoxide poisoning (COP) and hypothyroidism, but the evidence is limited. Therefore, the aim of this study was to further investigate this relationship. Using data from the Taiwan National Health Research Database, we identified 32,162 COP patients and matched with 96,486 non-COP patients by age and index date for an epidemiological study. The risk of hypothyroidism was compared between the two cohorts until 2018. Independent predictors of hypothyroidism were analyzed using competing risk analysis. An animal study was also conducted to support the findings. COP patients had an increased risk of hypothyroidism compared to non-COP patients in the overall analysis (adjusted hazard ratio [AHR]= 3.88; 95 % confidence interval [CI]: 3.27−4.60) and in stratified analyses by age, sex, and comorbidities. The increase in the overall risk persisted even after more than six years of follow-up (AHR= 4.19; 95 % CI: 3.18−5.53). Independent predictors of hypothyroidism, in addition to COP, included age ≥65 years, female sex, hyperlipidemia, and mental disorder. The animal study showed damages in the hypothalamus, pituitary gland, and thyroid, as well as altered hormone levels 28 days after COP exposure. The epidemiological results showed an increased risk of hypothyroidism in COP patients, which was further supported by the animal study. These findings suggest the need for close monitoring of thyroid function in COP patients, especially in those who are age ≥65 years, female, and have hyperlipidemia or mental disorder.

IntroductionAlthough angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation.MethodsThis multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness.ResultsOut of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28–3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings.ConclusionARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

Abstract Background Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta‐blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta‐blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. Methods and results Using a novel echo‐guided mini‐invasive surgery, MR was created in 12‐weeks‐old Sprague–Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two‐week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR‐induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR‐induced chamber dilatation (end‐systolic volume and end‐diastolic volume; MR vs. MR + Carvedilol; P

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.

Abstract The predictive value of the prognostic nutritional index (PNI) for the long-term prognosis of patients with acute coronary syndrome (ACS) remains uncertain. Medline, Embase, Cochrane Library, and Google Scholar were searched from inception until January 2023 to study the relationship between all-cause mortality risk and PNI in patients receiving percutaneous coronary intervention for ACS (i.e., primary outcome). Thirteen observational studies were included in this meta-analysis. Analysis of seven studies using PNI as a categorical variable showed a pooled hazard ratio (HR) of all-cause mortality of 2.97 (95% CI 1.65 to 5.34, p = 0.0003, I2 = 89%, n = 11,245) for patients with a low PNI. The meta-analysis also showed a higher risk of major adverse cardiovascular events (MACEs) in patients with a low PNI (HR 2.04; 95% CI 1.59 to 2.61; p

BackgroundPostoperative infectious complications (PICs) are major concerns. Early and accurate diagnosis is critical for timely treatment and improved outcomes. Presepsin is an emerging biomarker for bacterial infections. However, its diagnostic efficacy for PICs across surgical specialties remains unclear.MethodsIn this study, a systematic search on MEDLINE, Embase, Google Scholar, and Cochrane Library was performed on September 30, 2023, to identify studies that evaluated presepsin for diagnosing PICs. PIC is defined as the development of surgical site infection or remote infection. Pooled sensitivity, specificity, and hierarchical summary receiver operating characteristic (HSROC) curves were calculated. The primary outcome was the assessment of the efficacy of presepsin for PIC diagnosis, and the secondary outcome was the investigation of the reliability of procalcitonin or C-reactive protein (CRP) in the diagnosis of PICs.ResultsThis meta-analysis included eight studies (n = 984) and revealed that the pooled sensitivity and specificity of presepsin for PIC diagnosis were 76% (95% confidence interval [CI] 68%–82%) and 83% (95% CI 75%–89%), respectively. The HSROC curve yielded an area under the curve (AUC) of 0.77 (95% CI 0.73–0.81). Analysis of six studies on procalcitonin showed a combined sensitivity of 78% and specificity of 77%, with an AUC of 0.83 derived from the HSROC. Meanwhile, data from five studies on CRP indicated pooled sensitivity of 84% and specificity of 79%, with the HSROC curve yielding an AUC of 0.89.ConclusionPresepsin exhibits moderate diagnostic accuracy for PIC across surgical disciplines. Based on the HSROC-derived AUC, CRP has the highest diagnostic efficacy for PICs, followed by procalcitonin and presepsin. Nonetheless, presepsin demonstrated greater specificity than the other biomarkers. Further study is warranted to validate the utility of and optimize the cutoff values for presepsin.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023468358.

Background Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)–related PAH. Methods and Results During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD‐related PAH. Next‐generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR‐21, miR‐139‐5p, miR‐155‐5p, let‐7f‐5p, miR‐328‐3p, miR‐330‐3p, and miR‐103a‐3p in patients with CHD‐related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR‐21 exhibited the highest expression in patients with CHD‐related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD‐related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR‐21. Suppressing miR‐21 rescued the shear stress–induced downregulation of the RAS/phosphatidylinositol 3‐kinase/protein kinase B pathway, leading to a mitigation of apoptosis. Conclusions Our study identified a pronounced expression of transpulmonary exosomal miR‐21, particularly in patients with CHD‐related PAH, through next‐generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR‐21 in the pathophysiology of PAH.

Abstract Background The implication of sepsis-induced cardiomyopathy (SIC) to prognosis is controversial, and its association with mortality at different stages remains unclear. We conducted a systematic review and meta-analysis to understand the association between SIC and mortality in septic patients. Methods We searched and appraised observational studies regarding the mortality related to SIC among septic patients in PubMed and Embase from inception until 8 July 2021. Outcomes comprised in-hospital and 1-month mortality. We adopted the random-effects model to examine the mortality risk ratio in patients with and without SIC. Meta-regression, subgroup, and sensitivity analyses were applied to examine the outcome’s heterogeneity. Results Our results, including 20 studies and 4,410 septic patients, demonstrated that SIC was non-statistically associated with increased in-hospital mortality, compared to non-SIC (RR 1.28, [0.96–1.71]; p = 0.09), but the association was statistically significant in patients with the hospital stay lengths longer than 10 days (RR 1.40, [1.02–1.93]; p = 0.04). Besides, SIC was significantly associated with a higher risk of 1-month mortality (RR 1.47, [1.17–1.86]; p

BackgroundPeople living with HIV (PLWH) have an increased risk of developing cardiovascular diseases (CVD). As speckle-tracking echocardiography (STE) has been used to detect subclinical myocardial abnormalities, this study aims to detect early cardiac impairment among Asian PLWH using STE and to investigate the associated risk factors.MethodsWe consecutively recruited asymptomatic PLWH without previous CVD from a medical center of Taiwan, and their cardiac function was evaluated by conventional echocardiogram and STE. Enrolled PLWH were classified as antiretroviral therapy (ART)-experienced and ART-naive, and multivariable regressions were used to assess the association between myocardial strain and risk factors including traditional CVD and HIV-associated factors.ResultsA total of 181 PLWH (mean age: 36.4 ± 11.4 years, 173 males) were recruited and conventional echocardiogram parameters were within normal ranges. Decreased myocardial strain across the myocardium was found, with a mean left ventricular (LV) global longitudinal strain of −18.7 ± 2.9%. The LV strain in the ART-experienced group (−19.0 ± 2.9%) was significantly better than the ART-naive group (−17.9 ± 2.8%), despite a younger age and lesser CVD risk factors in the ART-naive group. Hypertension [B = 1.92, 95% confidence interval (95% CI) 0.19–3.62, p = 0.029] and ART-naive with both low and high viral loads (VL) (B = 1.09, 95% CI 0.03–2.16, p = 0.047; and B = 2.00, 95% CI, 0.22–3.79, p = 0.029) were significantly associated with reduced myocardial strain.ConclusionThis is the first and largest cohort using STE to investigate myocardial strain in Asian PLWH. Our results suggest that hypertension and detectable VL are associated with impaired myocardial strain. Thus, timely ART administration with VL suppression and hypertension control are crucial in preventing CVD when making the management parallel with the improved life expectancy of PLWH on ART.

ObjectiveAs a standard therapy, tyrosine kinase inhibitors (TKIs) improved survival in patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation. However, treatment-related cardiotoxicity, particularly arrhythmia, cannot be ignored. With the prevalence of EGFR mutations in Asian populations, the risk of arrhythmia among patients with NSCLC remains unclear.MethodsUsing data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified patients with NSCLC from 2001 to 2014. Using Cox proportional hazards models, we analyzed outcomes of death and arrhythmia, including ventricular arrhythmia (VA), sudden cardiac death (SCD), and atrial fibrillation (AF). The follow-up duration was three years.ResultsIn total, 3876 patients with NSCLC treated with TKIs were matched to 3876 patients treated with platinum analogues. After adjusting for age, sex, comorbidities, and anticancer and cardiovascular therapies, patients receiving TKIs had a significantly lower risk of death (adjusted HR: 0.767; CI: 0.729–0.807, p < 0.001) than those receiving platinum analogues. Given that approximately 80% of the studied population reached the endpoint of mortality, we also adjusted for mortality as a competing risk. Notably, we observed significantly increased risks of both VA (adjusted sHR: 2.328; CI: 1.592–3.404, p < 0.001) and SCD (adjusted sHR: 1.316; CI: 1.041–1.663, p = 0.022) among TKI users compared with platinum analogue users. Conversely, the risk of AF was similar between the two groups. In the subgroup analysis, the increasing risk of VA/SCD persisted regardless of sex and most cardiovascular comorbidities.ConclusionsCollectively, we highlighted a higher risk of VA/SCD in TKI users than in patients receiving platinum analogues. Further research is needed to validate these findings.

BackgroundAlthough prognostic nutritional index (PNI) has been frequently applied in patients with malignancy or those during postoperative recovery, whether it is also an optimal indicator of the risk of contrast-induced nephropathy (CIN) in patients receiving coronary angiography remains uncertain. This meta-analysis aimed at investigating the clinical association of PNI with the risk of CIN in patients receiving coronary angiography or percutaneous coronary intervention.MethodsEmbase, Medline, Cochrane Library, and Google scholar were searched for studies until January 2023. The relationship between CIN risk and PNI (i.e., low vs. high) (primary outcome) as well as other variables (secondary outcomes) were analyzed using a random-effects model.ResultsOverall, 10 observational studies with 17,590 patients (pooled incidence of CIN: 18%) were eligible for analysis. There was a higher risk of CIN in patients with a low PNI compared to those with a high PNI [odd ratio (OR) = 3.362, 95% confidence interval (CI): 2.054 to 5.505, p

COVID-19 has not only affected the respiratory but the cardiovascular system. Taiwan has encountered a less severe COVID-19 pandemic. We reported the current situation in Taiwan. In this study, we retrospectively analyzed the data from our cardio-oncology program since October of 2019 to April of 2020 (the initial months of COVID-19 pandemic). In our cardio-oncology program, newly diagnosed breast cancer patients preparing for epirubicin therapy were included. Echocardiography, 6-min walking distance and major adverse cardiovascular events (MACEs) were recorded. To evaluate whether the social atmosphere affects cardio-oncology care, we analyzed the objective (physical) and subjective (emotional) parameters before and after January 21, 2020, when the first case of COVID-19 was confirmed in Taiwan. There was no significant decrease in patients’ return ratio and LVEFs. However, there was a trend of subjective shortness of breath reported by the patients but no decline in 6 MWT. Notably, none of the enrolled patients reported MACEs during the COVID pandemic. We observed an impact of anxiety on patients receiving epirubicin but it did not influence their return ratio.

Abstract Background With the development of HiC technology, more and more HiC sequencing data have been produced. Although there are dozens of packages that can turn sequencing data into contact maps, there is no appropriate tool to query contact maps in order to extract biological information from HiC datasets. Results We present HiCmapTools, a tool for biologists to efficiently calculate and analyze HiC maps. The complete program provides multi-query modes and analysis tools. We have validated its utility on two real biological questions: TAD loop and TAD intra-density. Conclusions HiCmapTools supports seven access options so that biologists can quantify contact frequency of the interest sites. The tool has been implemented in C++ and R and is freely available at https://github.com/changlabtw/hicmaptools and documented at https://hicmaptools.readthedocs.io/ .

Aortic stenosis (AS) is the most prevalent valvular disease in the elderly population and the prevalence of atrial fibrillation (AF) increases in the elderly population. Transcatheter aortic valve replacement (TAVR) becomes an important treatment for patients with AS at high surgical risk. This metanalysis aimed to compare the efficacy and safety of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) in patients with AF undergoing TAVR. We searched the different databases for articles published before January 31, 2022. In total, 7 studies including 25,255 patients were analyzed. Data on demographics, comorbidities, CHA2DS2-VASc score, Society of Thoracic Surgeons (STS) score, and incidences of all-cause mortality, major bleeding, intracranial hemorrhage (ICH), stroke, and thromboembolic events were obtained and analyzed. The VKA group had a lower CHA2DS2-VASc score (3.2 ± 1.2 vs 3.3 ± 1.2; P

Abstract Aims In contrast to Western patients with breast cancer, Asian patients are relatively younger at diagnosis, and most are free from traditional cardiovascular risk factors. Despite trastuzumab‐related major adverse cardiac and cerebrovascular event (MACCE) being reported, its incidence and predictors remain unknown in Taiwan. Methods and results Through a three‐hospital retrospective cohort study, we analysed the incidence of MACCE in 386 breast cancer patients' exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13 502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab non‐users, the incidence of MACCE was measured with a median follow‐up of 36 months. In the hospital‐based study, among 386 patients receiving trastuzumab, the 5‐year incidences of MACCE and heart failure (HF) were 5.4 and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67 and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246–1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than non‐users. Conclusions From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use.

Abstract Background With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia–Pacific region. Methods A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars. Results The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia–Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment. Conclusions Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia–Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.

Gonadotropin-releasing hormone (GnRH) therapy has been known to increase risks of major adverse cardiovascular and cerebrovascular events (MACCEs). Herein, we aim to estimate whether regular use of aspirin attenuates risks of MACCEs in prostate cancer patients receiving GnRHs. Using Taiwanese National Health Insurance Research Database (NHIRD), we identified 7719 patients diagnosed with prostate cancer who were either aspirin-naïve, received irregular or regular aspirin from 2008 to 2015. Through a multivariable logistic regression model, we investigated the impact of aspirin on MACCEs. Compared with nonusers and irregular users, most patients receiving regular aspirin were older and had more comorbidities. The crude incidence of one-year MACCEs was lowest in aspirin nonusers but highest in irregular users of aspirin compared with regular users of aspirin (2.65% vs. 4.41% vs. 2.85%, p=0.0099). After adjusting for age, cancer stage and comorbidities, irregular aspirin users had a higher risk of one-year MACCEs (adjusted OR: 1.33; 95% CI: 0.93-1.90, p=0.1139) than aspirin nonusers, but conversely, there was a trend of reducing the risk of MACCEs among those who received regular aspirin (adjusted OR: 0.79; 95% CI: 0.44-1.42, p=0.4256). In the subgroup analysis, there were age- and cancer stage-independent higher risks of MACCEs in patients who took aspirin irregularly compared to those in patients who did not take aspirin. The risks were attenuated in patients receiving regular aspirin. Collectively, regular use of aspirin presented a trend of reducing risks of MACCEs in prostate cancer patients receiving GnRHs. However, irregular use of aspirin diminished the benefits.

Abstract Aims The Registry to Evaluate Early and Long‐Term PAH Disease Management (REVEAL) risk scores differentiate survivals in patients with pulmonary arterial hypertension (PAH). However, measurements of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) in the peripheral blood may not adequately reflect early‐stage decompensated heart failure (HF). Given that right heart catheterization (RHC) can facilitate measurements of intracardiac NT‐proBNP, in this study our aim was to evaluate the predictive role of right ventricular (RV) NT‐proBNP measurements in patients with PAH. Methods and results We prospectively collected intracardiac blood samples for NT‐proBNP measurements from patients diagnosed with World Health Organization Group I PAH during RHC. Clinical information including the aetiology of PAH (idiopathic, connective tissue disease, or congenital heart disease) and REVEAL scores were recorded. The primary endpoint was hospitalization for decompensated HF; median duration of follow‐up was 28 months. Among the 62 patients evaluated, 12 reached the designated endpoint. REVEAL risk scores were higher among patients hospitalized for HF. We detected no significant differences in plasma NT‐proBNP levels in peripheral circulation, in the right atrium, or in pulmonary arterial blood; however, significantly higher levels of NT‐proBNP were detected in the RV in patients diagnosed with PAH. RV NT‐proBNP was a sensitive predictor (cut‐off value 1500 pg/mL) of subsequent hospitalization for HF. Our findings indicate that RV NT‐proBNP levels add predictive value to REVEAL scores with respect to future hospitalization due to HF. Conclusions Right ventricular NT‐proBNP levels combined with REVEAL 2.0 could predict the development of subsequent HF in patients with PAH and may be a potential biomarker.

Background: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. Methods: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician’s choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. Results: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49–100] days vs. 112 [86–138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319–2507] pg/mL vs. 570 [206–1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. Conclusions: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the newly discovered virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had been noticed to have high morbidity and mortality. Apart from pneumonia, COVID-19 can also cause damage to the cardiovascular system, and co-occurring with cardiovascular injury leads to a poorer prognosis. Besides, amid the pandemic of COVID-19, the management of critical cardiovascular events needs to further account for the highly infectious coronavirus, prompt and optimal treatments, clinician's safety, and healthcare provider's capacity. This review article aims to provide more comprehensive and appropriate guidance for the management of critical cardiovascular disease, including ST-segment elevation myocardial infarction (STEMI), non-STEMI acute coronary syndrome, cardiogenic shock, acute heart failure, cardiopulmonary resuscitation, and advanced care planning, during the COVID-19 epidemic.

With an increasing prevalence, peripheral arterial disease (PAD), cause by atherosclerosis is a new threat to public health beyond coronary artery disease and involves aberrant vascular endothelial cell proliferation and angiogenesis. The degree of vascular remodeling is influenced by the processes described. MicroRNA-21 (miR-21) has been found to play a critical role in cellular functions, including angiogenesis. Nevertheless, the effect of miR-21 on endothelial cells in response to hypoxia is largely unknown. Using wild-type C57BL/6J and miR-21–/– mice, we compared the capability of angiogenesis in response to hindlimb hypoxic/ischemia. In an in vitro study, we further studied whether overexpression of miR-21 mitigates hypoxia-induced apoptosis and impaired angiogenesis. Also, we prospectively collected the sera of patients with limb ischemia and followed the clinical information, including major adverse limb events (MALEs). Using laser Doppler perfusion imaging and CD31 staining, compared with miR-21–/– mice, wild-type mice expressed a significantly higher capability of angiogenesis and less apoptosis following 28 days of hindlimb hypoxic/ischemic surgery. In our in vitro study, after 24 h of hypoxia, proliferation, migration, and tube formation were significantly impaired in cells treated with the miR-21 inhibitor but rescued by the miR-21 mimic. Mechanistically, by suppressing PTEN/PI3K/AKT, miR-21 promoted angiogenesis and suppressed apoptosis in endothelial cells post hypoxia. In patients with limb ischemia, the high expression of circulating miR-21 was associated with less subsequent MALE. Collectively, miR-21 could be a biomarker associated with the endogenous ability of angiogenesis and reflect subsequent MALE in patients. Additionally, abolishing miR-21 impairs angiogenesis and promotes apoptosis post limb ischemia. Further studies are required to elucidate the clinical applications of miR-21.

Although androgen deprivation therapy (ADT) has been proposed to be associated with a higher risk of venous thromboembolisms (VTEs), whether gonadotropin-releasing hormones (GnRHs), such as both agonists and antagonists, are also associated with VTEs remain unclear. Using the Taiwan Cancer Registry (TCR) linked with the National Health Insurance Research Database, we identified patients diagnosed with prostate cancer from 2008 to 2015. Patients who received GnRH were 1:1 propensity score matched with non-GnRH users by age and cancer stage at diagnosis and clinical stage. Cox regression analysis was applied to estimate the incidences of VTEs with death as a competing event at the 5-year follow-up. The VTE incidence among GnRH users was 1.13% compared with 0.98% among non-users. After adjusting with potential confounding factors, the risk of VTEs showed borderline statistical significance among GnRH users and non-users. Notably, in the subgroup analysis among patients receiving GnRH therapy, those younger than 70 years old or at an earlier stage (stage I/II) were at a higher risk of VTEs. Different from previous studies, our findings highlighted critical concerns regarding the cardiac safety of GnRH therapies in prostate cancer patients at a relatively younger age or at an earlier stage.

Atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral artery disease, carries a high morbidity and mortality. Risk factor control is especially important for patients with ASCVD to reduce recurrent cardiovascular events. Clinical guidelines have been developed by the Taiwan Society of Cardiology, Taiwan Society of Lipids and Atherosclerosis, and Diabetes Association of Republic of China (Taiwan) to assist health care professionals in Taiwan about the control of hypertension, hypercholesterolemia and diabetes mellitus. This article is to highlight the recommendations about blood pressure, cholesterol, and sugar control for ASCVD. Some medications that are beneficial for ASCVD were also reviewed. We hope the clinical outcomes of ASCVD can be improved in Taiwan through the implementation of these recommendations. Keywords: Atherosclerosis, Risk factors, Performance guide

Pulmonary arterial hypertension (PAH) is characterized as a progressive and sustained increase in pulmonary vascular resistance, which may induce right ventricular failure. In 2014, the Working Group on Pulmonary Hypertension of the Taiwan Society of Cardiology (TSOC) conducted a review of data and developed a guideline for the management of PAH.4 In recent years, several advancements in diagnosis and treatment of PAH has occurred. Therefore, the Working Group on Pulmonary Hypertension of TSOC decided to come up with a focused update that addresses clinically important advances in PAH diagnosis and treatment. This 2018 focused update deals with: (1) the role of echocardiography in PAH; (2) new diagnostic algorithm for the evaluation of PAH; (3) comprehensive prognostic evaluation and risk assessment; (4) treatment goals and follow-up strategy; (5) updated PAH targeted therapy; (6) combination therapy and goal-orientated therapy; (7) updated treatment for PAH associated with congenital heart disease; (8) updated treatment for PAH associated with connective tissue disease; and (9) updated treatment for chronic thromboembolic pulmonary hypertension. Keywords: Guideline, Pulmonary arterial hypertension, Pulmonary hypertension

This research demonstrates the preparation of composite membranes containing graphene oxide (GO) and investigates the separation mechanisms of various salts and bovine serum albumin (BSA) solutions. A microporous polyvinylidene fluoride–polyacrylic acid–GO (PVDF-PAA-GO) separation layer was fabricated on non-woven support. The GO-incorporating composite resulted in enlarged pore size (0.16 μm) compared with the control membrane (0.12 μm). The zeta potential of the GO composite was reduced to –31 from –19 mV. The resulting membranes with and without GO were examined for water permeability and rejection efficiency with single salt and BSA solutions. Using the non-woven/PVDF-PAA composite, the permeance values were 88–190 kg/m2hMPa, and the salt rejection coefficients were 9–28% for Na2SO4, MgCl2, MgSO4, and NaCl solutions. These salt removals were based on the Donnan exclusion mechanism considering the ion radii and membrane pore size. Incorporating GO into the separation layer exhibited limited impacts on the filtration of salt solutions, but significantly reduced BSA membrane adhesion and increased permeance. The negatively charged protein reached almost complete removal (98.4%) from the highly negatively charged GO-containing membrane. The GO additive improved the anti-fouling property of the composite membrane and enhanced BSA separation from the salt solution.

Background: EMPEROR-Reduced trial provides promising evidence on the efficacy of empagliflozin adding to the standard treatment in patients with heart failure and reduced ejection fraction (HFrEF). This study aimed to investigate the cost-effectiveness of add-on empagliflozin vs. standard therapy alone in HFrEF from the perspective of the Asia-Pacific healthcare systems.Methods: A Markov model was constructed to simulate HFrEF patients and to project the lifetime direct medical costs and quality-adjusted life years (QALY) of both therapies. Transitional probabilities were derived from the EMPEROR-Reduced trial. Country-specific costs and utilities were extracted from published resources. Incremental cost-effectiveness ratio (ICER) against willingness to pay (WTP) threshold was used to examine the cost-effectiveness. A series of sensitivity analyses was performed to ensure the robustness of the results.Results: The ICERs of add-on empagliflozin vs. standard therapy alone in HFrEF were US$20,508, US$24,046, US$8,846, US$53,791, US$21,543, and US$20,982 per QALY gained in Taiwan, Japan, South Korea, Singapore, Thailand, and Australia, respectively. Across these countries, the probabilities of being cost-effective for using add-on empagliflozin under the WTP threshold of 3-times country-specific gross domestic product per capita were 93.7% in Taiwan, 95.6% in Japan, 96.3% in South Korea, 94.2% Singapore, 51.9% in Thailand, and 95.9% in Australia. The probabilities were reduced when shortening the time horizon, assuming the same cardiovascular mortality for both treatments, and setting lower WTP thresholds.Conclusion: Adding empagliflozin to HFrEF treatment is expected to be a cost-effective option among the Asia-Pacific countries. The cost-effectiveness is influenced by the WTP thresholds of different countries.

Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function—especially when strained—and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF.

Introduction: With the aging of the population, hip fractures have become a major public health issue in the elderly. It is important to examine the loss of activities of daily living (ADL) and the quality of life (QoL) among the elderly after repair of hip fracture. The correlation between ADL and QoL over time after hip fracture surgery was also our major concern. Methods: A prospective study enrolling 117 geriatric patients undergoing hip fracture surgery in a tertiary medical center was conducted between 2017 and 2018. All participants were evaluated with the EuroQol-5D for assessing QoL and the Barthel index for measuring ADL function at baseline, 3-and 6-month follow-ups after hip fracture surgery. Results: The mortality rate among geriatric patients after hip fracture surgery was 5.5% at 3 months and 9.1% at 6 months. In addition, both ADL function and QoL significantly deteriorated after 6 months of follow-up without improvement with time. After the 6-month follow-up, only 20% of geriatric patients undergoing repair for hip fracture were able to recover baseline ADL. The QoL at the 6-month follow-up was correlated with both cross-sectional and longitudinal ADL function after repair for hip fracture among geriatric patients. Conclusion: Functional impairment is common among geriatric patients after hip fracture surgery. Poor ADL could predict and reflect poor QoL after the 6-month follow-up. More emphasis should be put on preventing functional loss after hip fracture surgery in order for better QoL among geriatric patients undergoing hip fracture surgery.

Background Mitral regurgitation (MR) is a major contributor for heart failure (HF) and atrial fibrillation. Despite the advancement of MR surgeries, an effective medical therapy to mitigate MR progression is lacking. Sodium glucose cotransporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality but the mechanism is unclear. We hypothesized that dapagliflozin (DAPA), a sodium glucose cotransporter 2 inhibitor, can improve cardiac hemodynamics in MR‐induced HF. Methods and Results Using a novel, mini‐invasive technique, we established a MR model in rats, in which MR induced left heart dilatation and functional decline. Half of the rats were randomized to be administered with DAPA at 10 mg/kg per day for 6 weeks. After evaluation of electrocardiography and echocardiography, hemodynamic studies were performed, followed by postmortem tissue analyses. Results showed that DAPA partially rescued MR‐induced impairment including partial restoration of left ventricular ejection fraction and end‐systolic pressure volume relationship. Despite no significant changes in electrocardiography at rest, rats treated with DAPA exhibited lower inducibility and decreased duration of pacing‐induced atrial fibrillation. DAPA also significantly attenuated cardiac fibrosis, cardiac expression of apoptosis, and endoplasmic reticulum stress‐associated proteins. Conclusions DAPA was able to suppress cardiac fibrosis and endoplasmic reticulum stress and improve hemodynamics in an MR‐induced HF rat model. The demonstrated DAPA effect on the heart and its association with key molecular contributors in eliciting its cardio‐protective function, provides a plausible point of DAPA as a potential strategy for MR‐induced HF.

Right ventricular impairment is a predictor of cardiovascular outcomes in patients with degenerative mitral regurgitation. However, the time course of right ventricular functional changes post-surgical mitral valve repair remains largely unknown. Herein, using right ventricular-focused echocardiography, we aimed to investigate right ventricular reserve and its impact on hospitalization for heart failure after mitral valve repair. In this prospective study, we enrolled 108 patients scheduled to undergo surgical repair of degenerative mitral regurgitation. Echocardiography, including right ventricular strain analysis, was performed prior to, and one month and six months post mitral valve repair. Right ventricular strain that improved one month post-surgery was defined as reserved right ventricular. In addition, any cardiovascular outcomes comprising heart failure that required admission were recorded. The median follow-up duration is 31 months. Despite a significant improvement in mitral valve regurgitant volume post-operatively, left ventricular ejection fraction (LVEF) at six months was similar to LVEF at baseline. There was a transient decrease in LV longitudinal strain at one month that was recovered six months post mitral valve repair. Regarding the right ventricular, in contrast with conventional right ventricular parameters, including right ventricular tissue Doppler S′, fractional area change and tricuspid annular plane systolic excursion (TAPSE), only resolution of right ventricular strain at one month predicted the subsequent myocardial recovery. Furthermore, patients with reserved right ventricular had a lower risk of hospitalization for heart failure compared to those with non-reserved right ventricular. Collectively, the early resolution of right ventricular strain is associated with the improvement in right ventricular function (measured by TAPSE) and in heart failure hospitalization in patients who had undergone surgical mitral valve repair for degenerative mitral regurgitation.

Despite no significant differences of growth differentiation factor-15 expressions in peripheral, right atrial, and right ventricular blood, in the pulmonary arterial blood, there was a significantly high level of growth differentiation factor-15 in Group I pulmonary arterial hypertension patients subsequently developing heart failure. During right heart catheterization, collecting pulmonary blood samples is suggested to measure growth differentiation factor-15.

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral drug in the class of nucleotide analogs, has been particularly tailored for treatment of coronavirus infections. However, to which extent RDV is able to modify various types of membrane ion currents remains largely uncertain. In this study, we hence intended to explore the possible perturbations of RDV on ionic currents endogenous in pituitary GH3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH3 cells the exposure to RDV concentration-dependently depressed the peak or late components of IK(DR) elicitation with effective IC50 values of 10.1 or 2.8 μM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of IK(DR) on the basis of the first-order reaction was yielded to be 3.04 μM. Upon the existence of RDV, the steady-state inactivation curve of IK(DR) was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of IK(DR) failed to be overcome by further addition of either α,β-methylene ATP or cyclopentyl-1,3-dipropylxanthine. The RDV addition also lessened the strength of M-type K+ current with the IC50 value of 2.5 μM. The magnitude of voltage hysteresis of IK(M) elicited by long-lasting triangular ramp pulse was diminished by adding RDV. Membrane electroporation-induced current in response to large hyperpolarization was enhanced, with an EC50 value of 5.8 μM. Likewise, in Jurkat T-lymphocytes, adding RDV declined IK(DR) amplitude concomitantly with the raised rate of current inactivation applied by step depolarization. Therefore, in terms of the RDV molecule, there appears to be an unintended activity of the prodrug on ion channels. Its inhibition of both IK(DR) and IK(M) occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.

With the advancement of computed tomography pulmonary angiography, differentiating between acute and chronic thrombus in pulmonary embolism has become more feasible. However, whether pulmonary embolism with chronic thrombus contributes to a higher mortality than pulmonary embolism with acute thrombus remains undetermined. Additionally, the clinical features of patients with chronic thrombus are largely unknown. Herein, we aimed to investigate the incidence and outcomes of patients with pulmonary embolism and chronic thrombus. This retrospective study included patients with pulmonary embolism from 2008 to 2016 at National Cheng Kung University Hospital. After excluding patients with tumor emboli or other etiologies and a lack of computed tomography images, we identified 205 patients with acute thrombus and 58 patients with chronic thrombus. Patients with chronic thrombus initially presented mainly with dyspnea, and the etiology was not related to recent surgery. Patients with chronic thrombus had a significantly higher incidence of elevated right ventricular systolic pressure detected by echocardiography and a higher incidence of subsequent events due to residual pulmonary embolism. Despite no differences in clinically recurrent pulmonary embolism, patients with chronic thrombus presented with a higher risk of all-cause and pulmonary embolism-related mortality than patients with acute thrombus. Chronic thrombus (hazard ratio: 2.03, p = 0.03), simplified pulmonary embolism severity index, anticoagulant use, and body mass index were the independent factors for all-cause mortality. Our findings suggest that using computed tomography pulmonary angiography for identifying patients with pulmonary embolism and chronic thrombus, which was associated with a higher risk of mortality, is pivotal for early intervention in addition to anticoagulant use.

Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.

Electrocardiograms (ECGs) provide important information for diagnosing cardiovascular diseases. In clinical practice, the conventional Ag/AgCl electrode is generally used; however, it is not suitable for long-term ECG measurement because of the risk of allergic reactions on the skin and the dying issue of electrolytic gels. In previous studies, several dry electrodes have been proposed to address these issues. However, most dry electrodes, which are the mode of conductive materials, have to contact the skin well and are easily affected by motion artifacts in daily life. In the smart clothes developed in this study, a noncontact electrode was used to assess the biopotential across the clothes to prevent skin irritation and discomfort. Moreover, a three-dimensional parametric model based on anthropometric data was built, and the technique of customized product design was introduced into the smart clothes development process to reduce the influence of motion artifacts. The experimental results show that the proposed smart clothes can maintain a good ECG signal quality stably under motion from different activities.

Objective: Obstetrician–gynecologists are the main providers of women's healthcare. However, workforce shortages and excessive workloads among these providers have been encountered in many countries. While most past studies on this subject have investigated the spatial distribution of obstetrics–gynecology clinics, few have focused on their temporal availability, especially on the national level. Materials and methods: The weekly opening time schedules (divided into morning, afternoon, and evening sessions) of all obstetrics–gynecology clinics in Taiwan were extracted from the web site of Taiwan's National Health Insurance Administration in July 2015. The numbers of open sessions were then analyzed and stratified by urbanization level and practice type. Results: Among 742 obstetrics–gynecology clinics in Taiwan, 521 were located in urban areas, 194 in suburban areas, and 27 in rural areas. The numbers of open sessions per week in suburban areas were higher than those in urban and rural areas (16.7 ± 2.6 vs. 15.9 ± 3.1 and 15.9 ± 2.7). Group practices had more open sessions per week than solo practices (16.8 ± 2.8 vs. 15.8 ± 3.0). With respect to after-hours services in rural areas, only two rural obstetrics–gynecology clinics remained open on Sunday mornings, while none remained open on Sunday afternoons and evenings. Conclusion: Obstetrics–gynecology clinics in Taiwan offered great temporal availability. In addition to the remarkable urban–rural disparity in the distribution of obstetrics–gynecology clinics, the availability of services on Sundays in rural areas demands special attention.

The shortage and maldistribution of pediatricians affected after-hours pediatric services, especially in rural areas. Our study aimed to examine the urban-rural disparity in geographical and temporal availability of the pediatrician workforce in Taiwan by analyzing opening time schedules of all pediatric clinics throughout the country. Methods: The opening time schedules of nonhospital pediatric clinics were downloaded from the website of the National Health Insurance Administration in Taiwan for analysis. The geographical and temporal availability of pediatric clinics was calculated and stratified by urbanization level and opening time, which was divided into daytime and evening sessions over 1 week. Each of 368 towns in Taiwan was also regarded as a unit of measurement to estimate the local availability of at least one pediatric clinic open in after-hours sessions. Results: Among 1483 nonhospital pediatric clinics in Taiwan, the overwhelming majority were situated in urban (65.8%) and suburban (30.6%) areas. On average, a pediatric clinic provided 16.3 (standard deviation = 3.04) sessions of services per week. One-third (34.7%, n = 50) of 144 suburban towns and over three-fourths (77.4%, n = 120) of 155 rural towns had no pediatric clinic. Most pediatric clinics remained open on weekday evenings (91.1%) and during Saturday daytime (91.8%). The percentage of open clinics gradually decreased over the weekend: Saturday evening (58.1%), Sunday daytime (33.4%), and Sunday evening (19.4%). Rural pediatric clinics remained closed mostly on weekends. On Sunday evenings, pediatric clinics were open only in 5.2% of rural towns, with a decline of 77.1%, whereas they were open in 78.3% of urban towns, with a decline of 18.2%. Conclusion: Pediatric clinics in Taiwan were unevenly distributed between urban and rural areas. The disparity of pediatric services became more obvious at weekends. The consequences of undersupplied rural pediatric care deserve further investigation.

Background: How sex and age influence post-myocardial infarction (post-MI) outcomes remains unclear. This study evaluated the influence of sex and age on drug therapy, echocardiographic parameters, and outcomes in post-MI patients undergoing percutaneous coronary intervention (PCI). Methods: We retrospectively enrolled 643 patients with first acute MI who underwent successful PCI and two echocardiographic examinations within 1 year after MI. Clinical characteristics and 4-year follow-up outcomes were compared between sexes and age groups. Primary endpoints were cardiovascular mortality and hospitalization for heart failure (HF). Results: Compared with males, female patients with MI, particularly older females, had more systemic diseases. Younger females received fewer guideline-directed therapies. Older patients presented with higher left ventricular volume and mass index but no significant differences in left ventricular ejection fraction. The Kaplan–Meier analysis revealed increased mortality in both younger and older females. Elderly patients, particularly older females, exhibited significantly higher post-MI HF incidence but no difference in recurrent MI, ventricular arrhythmia, or revascularization. Conclusions: In MI patients receiving PCI, outcome differences between sexes are age-dependent. Age influences outcome more heavily in females than in males. Females are likely to exhibit worse overall survival, and older females are at higher risk of post-MI HF. Keywords: MI, Age, Gender, Cardiac structure

Tolvaptan (TLV), an oral non-peptide antagonist of vasopressin V2 receptor, has been increasingly used for managements in patients with hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion. However, none of the studies have thus far been investigated with regard to its possible perturbations on membrane ion currents in endocrine or neuroendocrine cells. In our electrophysiological study, the whole-cell current recordings showed that the presence of TLV effectively and differentially suppressed the amplitude of delayed rectifier K+ (IK(DR)) and M-type K+ current (IK(M)) in pituitary GH3 cells with an IC50 value of 6.42 and 1.91 μM, respectively. This compound was also capable of shifting the steady-state activation curve of IK(M) to less depolarized potential without any appreciable change in the gating charge of this current. TLV at a concentration greater than 10 μM also suppressed the amplitude of erg-mediated K+ current or the activity of large-conductance Ca2+-activated K+ channels; however, this compound failed to alter the amplitude of hyperpolarization-activated cation current in GH3 cells. In vasopressin-preincubated GH3 cells, TLV-mediated suppression of IK(M) remained little altered. Under current-clamp condition, we also observed that addition of TLV increased the firing of spontaneous action potentials in GH3 cells and further addition of flupirtine could reverse TLV-mediated elevation of the firing. In Madin-Darby canine kidney (MDCK) cells, the K+ current elicited by long ramp pulse was also effectively subject to inhibition by this compound. Findings from the present study were thus stated as saying that the suppression by TLV of multiple type K+ currents could be direct and independent of its antagonism of vasopressin V2 receptors. Our study also reveals an important aspect that should be considered when assessing aquaretic effect of TLV or its structurally similar compounds.

BackgroundCardiovascular events are the leading cause of perioperative complications among patients undergoing noncardiac surgery. However, the role of echocardiography for preoperative cardiac risk stratification prior to major noncardiac surgery is still controversial.MethodsThis retrospective study included a total of 1453 patients (51% male; age, 67 ± 16) who underwent intermediate- or high-risk major abdominal surgery or orthopedic surgery at two medical centers in South Taiwan between February 2013 and June 2016. All patients underwent preoperative transthoracic echocardiography (TTE). All of the included patients were followed up for 56 days after surgery. The primary endpoints were major adverse events (MAEs), i.e., all-cause mortality and major adverse cardiovascular-cerebral events (MACCEs).ResultsA total of 35 patients (2.4%) reached the primary endpoint: 24 patients (1.6%) died, and 17 patients (1.2%) had MACCEs. Patients with postsurgery MAEs had higher average E/e' values, a lower Left ventricular (LV) ejection fraction, and higher prevalence of significant mitral regurgitation (MR) and moderate-advanced chronic kidney disease (CKD). Multivariate analysis showed that the modified Lee index and significant MR were independent prognostic predictors of MAEs.ConclusionPreoperative identification of significant MR on TTE is associated with increased MAEs at 56 days compared with that predicted by the modified Lee index alone in patients undergoing intermediate- or high-risk noncardiac surgery.

Esaxerenone (ESAX; CS-3150, Minnebro®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible perturbations of ESAX on the transient, late and persistent components of voltage-gated Na+ current (INa) identified from pituitary GH3 or MMQ cells. GH3-cell exposure to ESAX depressed the transient and late components of INa with varying potencies. The IC50 value of ESAX required for its differential reduction in peak or late INa in GH3 cells was estimated to be 13.2 or 3.2 μM, respectively. The steady-state activation curve of peak INa remained unchanged during exposure to ESAX; however, recovery of peak INa block was prolonged in the presence 3 μM ESAX. In continued presence of aldosterone (10 μM), further addition of 3 μM ESAX remained effective at inhibiting INa. ESAX (3 μM) potently reversed Tef-induced augmentation of INa. By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent INa measured at high or low threshold was enhanced by the presence of tefluthrin (Tef), in combination with the appearance of the figure-of-eight hysteretic loop; moreover, hysteretic strength of the current was attenuated by subsequent addition of ESAX. Likewise, in MMQ lactotrophs, the addition of ESAX also effectively decreased the peak amplitude of INa along with the increased current inactivation rate. Taken together, the present results provide a noticeable yet unidentified finding disclosing that, apart from its antagonistic effect on MR receptor, ESAX may directly and concertedly modify the amplitude, gating properties and hysteresis of INa in electrically excitable cells.

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one) is a novel and selective activator of KCNQ2/KCNQ3 K+ channels. However, it remains largely unknown whether this compound can modify any other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH3 lactotrophs were investigated in this study. QO-40 stimulated Ca2+-activated K+ current (IK(Ca)) with an EC50 value of 2.3 μM in these cells. QO-40-stimulated IK(Ca) was attenuated by the further addition of GAL-021 or paxilline but not by linopirdine or TRAM-34. In inside-out mode, this compound added to the intracellular leaflet of the detached patches stimulated large-conductance Ca2+-activated K+ (BKCa) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BKCa channels. The KD value required for the QO-40-mediated decrease in the slow component at the mean closure time was 1.96 μM. This compound shifted the steady-state activation curve of BKCa channels to a less positive voltage and decreased the gating charge of the channel. The application of QO-40 also increased the hysteretic strength of BKCa channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing α-hSlo, QO-40 stimulated BKCa channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BKCa channel to increase the amplitude of IK(Ca) in GH3 cells.

FTY720 (fingolimod), a modulator of sphingosine-1-phosphate receptors, is known to produce the immunomodulatory actions and to be beneficial for treating the relapsing multiple sclerosis. However, whether it exerts any effects on membrane ion currents in immune cells remains largely unknown. Herein, the effects of FTY720 on ionic currents in Jurkat T-lymphocytes were investigated. Cell exposure to FTY720 suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 1.51 μM. Increasing the FTY720 concentration not only decreased the IK(DR) amplitude but also accelerated the inactivation time course of the current. By using the minimal reaction scheme, the effect of FTY720 on IK(DR) inactivation was estimated with a dissociation constant of 3.14 μM. FTY720 also shifted the inactivation curve of IK(DR) to a hyperpolarized potential with no change in the slope factor, and recovery from IK(DR) became slow during the exposure to this compound. Cumulative inactivation for IK(DR) in response to repetitive depolarizations was enhanced in the presence of FTY720. In SEW2871-treated cells, FTY720-induced inhibition of IK(DR) was attenuated. This compound also exerted a stimulatory action on the activity of intermediate-conductance Ca2+-activated K+ channels in Jurkat T-lymphocytes. However, in NSC-34 neuronal cells, FTY720 did not modify the inactivation kinetics of KV3.1-encoded IK(DR), although it suppressed IK(DR) amplitude in these cells. Collectively, the perturbations by FTY720 on different types of K+ channels may contribute to the functional activities of immune cells, if similar findings appear in vivo.

The entrapment of a ruptured catheter balloon during percutaneous coronary intervention (PCI) is rare, but it can lead to life-threatening complications, such as myocardial infarction (MI) and lethal arrhythmias. Ruptured balloon entrapment usually occurs in either tortuous, calcified, or angulated coronary lesions without adequate balloon deflation. The avoidance of drastic balloon pull-out and the use of appropriate catheter-based retrieval techniques could prevent surgical intervention. Herein, we describe two cases of ruptured coronary balloon entrapment during emergency or elective PCI. We successfully removed the ruptured and entrapped balloons through nonsurgical techniques. Coronary interventionists should be aware of the possibility of balloon entrapment during complex coronary interventions; they should also become familiar with nonsurgical catheter-based methods for the retrieval of ruptured and entrapped balloons.

Syphilis, the “great imitator” of skin diseases, remains a public health problem worldwide. Coinfection by the human immunodeficiency virus (HIV) and syphilis is common and has important clinical consequences. HIV infection may alter the classical clinical course and manifestations of syphilis. We herein report two young men who presented with fever and generalized ulceronecrotic lesions, which mimic hemorrhagic chicken pox, eczema herpeticum, or vasculitis. Malignant syphilis (lues maligna) was diagnosed according to clinical presentation, serology, and pathology. HIV infection was subsequently confirmed later. Excellent resolution of skin lesion was achieved after appropriate antibiotics therapy.

BackgroundPatients with unprovoked venous thromboembolism (VTE) are at an increased risk of mortality, but whether their cardiovascular risks also increase remains to be determined. We aimed to investigate the factors associated with overall mortality and major adverse cardiovascular events in patients with unprovoked VTE. Methods and ResultsWe identified 2154 patients newly diagnosed with unprovoked VTE from Taiwan's National Health Insurance Database between 2000 and 2013, excluding those with reversible etiologies, underlying cancer, or autoimmune diseases. These patients with VTE were compared with an age‐, sex‐, and cardiovascular risk‐matched cohort of 4308 controls. The risk of mortality and major adverse cardiovascular events in patients with VTE was 2.23 (CI, 1.93–2.57; P