Hsa-miR-134-5p predicts cardiovascular risk in circulating mononuclear cells and improves angiogenic action of senescent endothelial progenitor cells.

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-ß1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-ß1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-ß1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.

Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.

Comparison of the prognosis among in-hospital survivors of cardiogenic shock based on etiology: AMI and Non-AMI.

BACKGROUND: Current data on post-discharge mortality and rehospitalization is still insufficient among in-hospital survivors of cardiogenic shock (CS), including acute myocardial infarction (AMI) and non-AMI survivors. METHODS: Patients with CS who survived after hospital discharge were selected from the Taiwan National Health Insurance Research Database. Each patient was followed up at 3-year intervals. Mortality and rehospitalization were analyzed using Kaplan-Meier curves and Cox regression models. RESULTS: There were 16,582 eligible patients. Of these, 42.4% and 57.6% were AMI-CS and non-AMI-CS survivors, respectively. The overall mortality and rehospitalization rates were considerably high, with reports of 7.0% and 22.1% at 30 days, 24.5% and 58.2% at 1 year, and 38.9% and 73.0% at 3 years, respectively, among in-hospital CS survivors. Cardiovascular (CV) problems caused approximately 40% mortality and 60% rehospitalization. Overall, the non-AMI-CS group had a higher mortality burden than the AMI-CS group owing to older age and a higher prevalence of comorbidities. In multivariable models, the non-AMI-CS group exhibited a lower risk of all-cause mortality (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.60 to 0.78) and CV mortality (aHR 0.65, 95% CI 0.54 to 0.78) compared to the AMI-CS group. However, these risks diminished and even reversed after one year (aHR 1.13, 95% CI 1.03 to 1.25 for all-cause mortality; aHR 1.27, 95% CI 1.09 to 1.49 for CV mortality).This reversal was not observed in all-cause and CV rehospitalization. For rehospitalization, AMI-CS was associated with the risk of CV rehospitalization in the entire observation period (aHR:0.80, 95% CI:0.76-0.84). CONCLUSIONS: In-hospital AMI-CS survivors had an increased risk of CV rehospitalization and 30-day mortality, whereas those with non-AMI-CS had a greater mortality risk after 1-year follow-up.

Sex-based differences in ischemic cardiovascular and bleeding outcomes following implantation of drug-eluting stent in patients at high bleeding risk.

BACKGROUND: Patients with high bleeding risk (HBR) may exhibit uncertain adherence to dual antiplatelet therapy (DAPT) following drug-eluting stent (DES) implantation. The current population-based cohort study aimed to investigate the sex-based differences in adverse outcomes among the HBR population by analyzing the National Health Insurance Research Database in Taiwan. METHODS: Patients who had HBR features defined by the Academic Research Consortium (ARC) and received DES implantation between January 1, 2007, and December 31, 2017, were enrolled. Propensity score matching was adopted to select 3,981 pairs with similar clinical cardiovascular risks but different sexes. A competing risk model was performed to evaluate the risk of adverse ischemic events (cardiac death, nonfatal myocardial infarction, and ischemic stroke) and any bleeding events in both sexes. Noncardiac death was considered a competing risk. RESULTS: Within a 5-year follow-up, the incidence rates (per 1,000 person-year (95% confidence interval (CI)) of composite ischemic events and any bleeding events in males were respectively 44.09 (40.25-48.30) and 42.55 (38.79-46.68), while those in females were respectively 40.18 (36.51-44.23) and 42.35 (38.57-46.51). After adjustment for clinical variables, male patients had a marginally increased risk in the composite ischemic events (adjusted subdistribution hazard ratio (SHR) = 1.15 (1.00-1.31), p = 0.045) and a similar risk of any bleeding events (adjusted SHR = 1.00 (0.88-1.15), p = 0.946) compared with female patients. CONCLUSIONS: Of the HBR population, males had an increased risk of ischemic outcomes but a similar risk of bleeding compared with females following DES implantation.

QRS Fragmentation in Preserved Ejection Fraction Heart Failure: Functional Insights, Pathological Correlates, and Prognosis.

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P<0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P<0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P<0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P<0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P<0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

Hsa-miR-409-3p regulates endothelial progenitor senescence via PP2A-P38 and is a potential ageing marker in humans.

We explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with siPP2A caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs. Time series analysis showed, in young EPCs treated with hsa-miR-409-3p mimics, PP2A was steadily downregulated for 72 h, while p38/JNK was activated with a peak at 48 hours. The inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis via targeting protein phosphatase 2 catalytic subunit alpha (PPP2CA) gene and regulating PP2A/p38 signalling. Data from human PBMCs suggested hsa-miR-409-3p a potential biomarker for human ageing.

Real-World Analyses of the Treatment Conditions in Patients Initiating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor in Taiwan.

AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a powerful low density lipoprotein cholesterol (LDL-C)-lowering therapy, but this drug is expensive. This study aimed to describe the real-world treatment conditions in patients initiating PCSK9 inhibitor in Taiwan. METHODS: This was a multicenter, retrospective, and observational study. The clinical characteristics, baseline lipid-lowering therapy, and changes in the lipid profile of patients receiving PCSK9 inhibitor treatment were obtained from 11 major teaching hospitals in Taiwan. RESULTS: A total of 296 patients (age 57±13 years, male 73%) who received PCSK9 inhibitor treatments (73.3% alirocumab and 26.7% evolocumab) from 2017 to 2021 were included. Among the patients, 62.8% had history of coronary artery disease, and 27.7% had myocardial infarction. High intensity statin (HIS) monotherapy or HIS＋ezetimibe treatment was used in 32.5% when initiating PCSK9 inhibitor treatment. Among alirocumab users, 21.2% received 75 mg every 3 to 4 weeks, whereas among evolocumab users, 8.9% received 140 mg every 3 to 4 weeks. Almost all the non-standard-dosing PCSK9 inhibitors were paid by the patients themselves but were not reimbursed by the Taiwan National Health Insurance. Overall, the LDL-C levels at baseline and 12 weeks after treatment were 147.4±67.4 and 69.7±58.2 mg/dL (p＜0.01), corresponding to a 49.6%±31.8% LDL-C reduction. CONCLUSIONS: In the real-world practice in Taiwan, the LDL-C reduction efficacy of PCSK9 inhibitors was slightly lower than that reported in the clinical trials. The use of non-standard-dosing PCSK9 inhibitors was not uncommon in Taiwan.

Real-World Data on Comparison of Lipid-Lowering Effects between Alirocumab and Evolocumab in Patients with Hypercholesterolemia.

Background: Even though the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, have been approved to reduce plasma low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease in high-risk patients, real-world data showing comparisons of the lipid-lowering effects between alirocumab and evolocumab are scarce because of the low prescription rates of PCSK9 inhibitors in clinical practice. Methods: Between Feb 2018 and Sep 2021, 22 patients who received alirocumab and 22 patients who received evolocumab at a tertiary medical center were enrolled. The patients' baseline characteristics, prescribed medications, plasma LDL-C levels, and percentages of reduction in LDL-C were compared between alirocumab users and evolocumab users. Results: The alirocumab users more frequently received ezetimibe treatment (72.7% vs. 40.9%, p = 0.03) and had higher baseline LDL-C (165.6 ± 63.2 mg/dL vs. 130.8 ± 56.3 mg/dL, p = 0.04) compared with the evolocumab users. At 6 months of follow-up, the plasma LDL-C levels in the alirocumab users were similar to those in the evolocumab users (79.3 ± 64.0 mg/dL vs. 63.5 ± 44.1 mg/dL, p = 0.48). Additionally, the percentages of LDL-C reduction following treatment were similar between the alirocumab users and evolocumab users (-47.0% ± 45.0% vs. -49.8 ± 24.9%, p = 0.66). Conclusions: The LDL-C lowering effects of alirocumab are similar to those of evolocumab in clinical practice.

2022 Taiwan lipid guidelines for primary prevention.

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Early control of LDL-C to prevent ASCVD later in life is important. The Taiwan Society of Lipids and Atherosclerosis in association with the other seven societies developed this new lipid guideline focusing on subjects without clinically significant ASCVD. In this guideline for primary prevention, the recommended LDL-C target is based on risk stratification. A healthy lifestyle with recommendations for foods, dietary supplements and alcohol drinking are described. The pharmacological therapies for LDL-C reduction are recommended. The aim of this guideline is to decrease the risk of ASCVD through adequate control of dyslipidemia in Taiwan.

Risk of Heart Failure in Patients with ST-Elevation Myocardial Infarction Receiving Drug-Eluting Stent Implantation and Undefined Duration of Antiplatelets.

It remains unknown as to whether the use of new-generation drug-eluting stent (NG-DES) in patients with ST-elevation myocardial infarction (STEMI) who receive an undefined duration of dual antiplatelet therapy (DAPT) reduces the risk of hospitalization for heart failure (HHF). In this population-based retrospective cohort study, we applied propensity score matching to select 6831 pairs of patients with STEMI who had similar baseline characteristics and received either NG-DES or bare-metal stent (BMS) implantation between 1 January 2007 and 31 December 2016. The risk of stent-associated HHF was evaluated, wherein death was considered a competing risk. Rates of cumulative incidence competing risk for HHF at the 1, 2, 3, 4, and 5 year follow-up were lower in the NG-DES group (3.79%, 5.21%, 6.15%, 7.01%, and 8.29%, respectively) than in the BMS group (4.51%, 6.21%, 7.32%, 8.33%, and 9.83%, respectively). NG-DES implantation was associated with a lower risk of HHF than BMS implantation after 5 years, with an adjusted subdistribution hazard ratio of 0.82 (95% confidence interval 0.72−0.92, p = 0.001). These results accord with those of patients who received DAPT for >6 months. Our findings highlight that NG-DESs may reduce HHF risk in patients with STEMI receiving an undefined duration of DAPT.

Real-world data on the prescription of proprotein convertase subtilisin/kexin type 9 inhibitors in high-risk patients in a tertiary medical center.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, are currently approved for clinical use by Taiwan National Health Insurance (NHI) in patients who had a recent atherosclerotic cardiovascular disease with persistent LDL-C levels >135 mg/dL despite high-intensity statin (HIS) or maximally tolerated statin in combination with ezetimibe treatment. Since January 2020 to July 2020, total of 10 patients who had received coronary revascularization received NHI-approved alirocumab or evolocumab in our institution. The mean reduction of LDL-C following PCSK9 inhibitors treatment at 6-month and 12-month were respectively 62.5% and 60.2%. The patients in our study were younger, had more frequently received HIS/ezetimibe, and had higher baseline LDL-C levels with a greater LDL-C reduction following PCSK9 inhibitors treatment compared with those patients in previously studies. Our findings highlight that the NHI's regulation of PCSK9 inhibitors application should be re-evaluation to increase the use of NHI-approved PCSK9 inhibitors in high-risk patients.

Management of Patients with Type V Hyperlipoproteinemia: An Uncommon Phenotype of Dyslipidemia with Chylomicronemia and Severe Hypertriglyceridemia.

Hypertriglyceridemia (HTG) remains a risk-enhancing factor of atherosclerotic cardiovascular disease. We aimed to report real-world data on the management of patients with type V hyperlipoproteinemia (HLP5), an uncommon phenotype of dyslipidemia characterized by fasting chylomicronemia and severe HTG. Between July 2018 and May 2021, 90 patients with HTG, including 83 patients with type IV hyperlipoproteinemia (HLP4) and 7 patients with HLP5, were identified by plasma apolipoprotein B (apoB) and lipoprotein electrophoresis. Patients with HLP5 were younger, had higher total cholesterol (TC) (264.9 ± 26.7 mg/dL vs. 183.9 ± 26.1 mg/dL; p < 0.01) and higher triglyceride (TG) (1296.7 ± 380.5 mg/dL vs. 247.6 ± 96.1 mg/dL; p < 0.01), and had lower high-density lipoprotein cholesterol (HDL-C) (30.6 ± 4.8 mg/dL vs. 40.5 ± 8.7 mg/dL; p < 0.01) and lower low-density lipoprotein cholesterol (LDL-C) (62.9 ± 16.4 vs. 103.0 ± 21.1 mg/dL; p < 0.01) compared with patients with HLP4. Despite an aggressive use of statin and fenofibrate with greater reductions in TG (-65.9 ± 13.7% vs. -27.9 ± 30.5%; p < 0.01) following 6 months of treatment, patients with HLP5 had persistent HTG (440.1 ± 239.0 mg/dL vs. 173.9 ± 94.8 mg/dL; p < 0.01) and an increase in LDL-C (28.3 ± 57.2% vs. -19.5 ± 32.0%; p < 0.01) compared with patients with HLP4. Our findings highlight that the lack of novel TG-lowering medications and management guidelines remains an unmet medical need in patients with HLP5. Closely monitoring lipid profiles, full assessment of individual's risk of cardiovascular disease, and emphasis on medication adherence are of clinical importance.

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

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

Correction: Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003661.].

Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study.

BACKGROUND: Obesity, a known risk factor for cardiovascular disease and heart failure (HF), is associated with adverse cardiac remodeling in the general population. Little is known about how nutritional status modifies the relationship between obesity and outcomes. We aimed to investigate the association of obesity and nutritional status with clinical characteristics, echocardiographic changes, and clinical outcomes in the general community. METHODS AND FINDINGS: We examined 5,300 consecutive asymptomatic Asian participants who were prospectively recruited in a cardiovascular health screening program (mean age 49.6 ± 11.4 years, 64.8% male) between June 2009 to December 2012. Clinical and echocardiographic characteristics were described in participants, stratified by combined subgroups of obesity and nutritional status. Obesity was indexed by body mass index (BMI) (low, ≤25 kg/m2 [lean]; high, >25 kg/m2 [obese]) (WHO-recommended Asian cutoffs). Nutritional status was defined primarily by serum albumin (SA) concentration (low, <45 g/L [malnourished]; high, ≥45 g/L [well-nourished]), and secondarily by the prognostic nutritional index (PNI) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Cox proportional hazard models were used to examine a 1-year composite outcome of hospitalization for HF or all-cause mortality while adjusting for age, sex, and other clinical confounders. Our community-based cohort consisted of 2,096 (39.0%) lean-well-nourished (low BMI, high SA), 1,369 (25.8%) obese-well-nourished (high BMI, high SA), 1,154 (21.8%) lean-malnourished (low BMI, low SA), and 681 (12.8%) obese-malnourished (high BMI, low SA) individuals. Obese-malnourished participants were on average older (54.5 ± 11.4 years) and more often women (41%), with a higher mean waist circumference (91.7 ± 8.8 cm), the highest percentage of body fat (32%), and the highest prevalence of hypertension (32%), diabetes (12%), and history of cardiovascular disease (11%), compared to all other subgroups (all p < 0.001). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were substantially increased in the malnourished (versus well-nourished) groups, to a similar extent in lean (70.7 ± 177.3 versus 36.8 ± 40.4 pg/mL) and obese (73.1 ± 216.8 versus 33.2 ± 40.8 pg/mL) (p < 0.001 in both) participants. The obese-malnourished (high BMI, low SA) group also had greater left ventricular remodeling (left ventricular mass index, 44.2 ± 1.52 versus 33.8 ± 8.28 gm/m2; relative wall thickness 0.39 ± 0.05 versus 0.38 ± 0.06) and worse diastolic function (TDI-e' 7.97 ± 2.16 versus 9.87 ± 2.47 cm/s; E/e' 9.19 ± 3.01 versus 7.36 ± 2.31; left atrial volume index 19.5 ± 7.66 versus 14.9 ± 5.49 mL/m2) compared to the lean-well-nourished (low BMI, high SA) group, as well as all other subgroups (p < 0.001 for all). Over a median 3.6 years (interquartile range 2.5 to 4.8 years) of follow-up, the obese-malnourished group had the highest multivariable-adjusted risk of the composite outcome (hazard ratio [HR] 2.49, 95% CI 1.43 to 4.34, p = 0.001), followed by the lean-malnourished (HR 1.78, 95% CI 1.04 to 3.04, p = 0.034) and obese-well-nourished (HR 1.41, 95% CI 0.77 to 2.58, p = 0.27) groups (with lean-well-nourished group as reference). Results were similar when indexed by other anthropometric indices (waist circumference and body fat) and other measures of nutritional status (PNI and GLIM criteria). Potential selection bias and residual confounding were the main limitations of the study. CONCLUSIONS: In our cohort study among asymptomatic community-based adults in Taiwan, we found that obese individuals with poor nutritional status have the highest comorbidity burden, the most adverse cardiac remodeling, and the least favorable composite outcome.

Ultrasonic microbubble VEGF gene delivery improves angiogenesis of senescent endothelial progenitor cells.

The therapeutic effects of ultrasonic microbubble transfection (UMT)-based vascular endothelial growth factor 165 (VEGF165) gene delivery on young and senescent endothelial progenitor cells (EPCs) were investigated. By UMT, plasmid DNA (pDNA) can be delivered into both young EPCs and senescent EPCs. In the UMT groups, higher pDNA-derived protein expression was found in senescent EPCs than in young EPCs. Consistent with this finding, a higher intracellular level of pDNA copy number was detected in senescent EPCs, with a peak at the 2-h time point post UMT. Ultrasonic microbubble delivery with or without VEGF improved the angiogenic properties, including the proliferation and/or migration activities, of senescent EPCs. Supernatants from young and senescent EPCs subjected to UMT-mediated VEGF transfection enhanced the proliferation and migration of human aortic endothelial cells (HAECs), and the supernatant of senescent EPCs enhanced proliferation more strongly than the supernatant from young EPCs. In the UMT groups, the stronger enhancing effect of the supernatant from senescent cells on HAEC proliferation was consistent with the higher intracellular VEGF pDNA copy number and level of protein production per cell in the supernatant from senescent cells in comparison to the supernatant from young EPCs. Given that limitations for cell therapies are the inadequate number of transplanted cells and/or insufficient cell angiogenesis, these findings provide a foundation for enhancing the therapeutic angiogenic effect of cell therapy with senescent EPCs in ischaemic cardiovascular diseases.

Risk of heart failure following drug-eluting stent implantation in patients with non-ST-elevation myocardial infarction.

BACKGROUND AND AIMS: The association between implanted stent types and heart failure in patients with non-ST-elevation myocardial infarction (NSTEMI) remains unknown. The current study aimed to investigate whether the implantation of a newer-generation drug-eluting stent (NG-DES) compared with that of a bare-metal stent (BMS) in patients with NSTEMI who receive an undefined duration of dual antiplatelet therapy (DAPT) reduces the risk of hospitalization for heart failure (HHF). METHODS: In this nationwide, population-based retrospective cohort study, propensity score matching was used on the Taiwan's National Health Insurance Research Database to select 8,644 pairs of patients with NSTEMI and similar baseline characteristics receiving NG-DES or BMS implantation between January 1, 2007 and December 31, 2016. A competing risk model was constructed to evaluate the risk of HHF in the NG-DES and BMS groups. Death was considered a competing risk. RESULTS: Rates of cumulative incidence competing risk for HHF at 1, 2, 3, 4, and 5-year follow-ups were lower in the NG-DES group (4.11%, 5.63%, 6.72%, 7.65%, and 8.89%, respectively) than in the BMS group (5.89%, 7.81%, 9.25%, 10.8%, and 11.9%, respectively). After adjustment for all clinical variables, NG-DES implantation was associated with a lower risk of HHF than BMS implantation after 5 years, with an adjusted subdistribution hazard ratio of 0.71 (95% CI = 0.64-0.79, p < 0.001). These results are in agreement with those of patients who received DAPT for >6 months. CONCLUSIONS: NG-DESs may reduce HHF risk in patients with NSTEMI who receive an undefined duration of DAPT.

Effect of drug-eluting stents on 1-year risk of new-onset atrial fibrillation in patients with acute myocardial infarction treated with percutaneous coronary intervention.

The use of a drug-eluting stent (DES) in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention is conventional. However, the effect of DES on new-onset atrial fibrillation (AF) after AMI still remains unclear.By using data from Taiwan's National Health Insurance Research Database, a total of 17,741 patients with ST-elevation myocardial infarction (STEMI) and 17,631 patients with non-ST-elevation myocardial infarction (NSTEMI) treated with percutaneous coronary intervention were analyzed to investigate the risk of new-onset AF after index admission of AMI.There were 26.5% (N = 4696) of patients with STEMI and 39.5% (N = 6967) of patients with NSTEMI received DES implantation. Upon 1-year follow-up, we observed that DES placement was associated with a reduced 1-year risk of new-onset AF in the patients with NSTEMI (adjusted hazard ratio [aHR] = 0.74, 95% confidence interval [CI] = 0.59-0.93, P = .009) after adjustment for clinical relevant variables. This benefit was consistent with that in the patients with NSTEMI who were ≥75 years old, had a CHA2DS2-VASc score of ≥2, and did not receive intra-aortic balloon pump insertion (aHR = 0.72, 95% CI = 0.53-0.98, P = .039; aHR = 0.73, 95% CI = 0.586-0.92, P = .006; and aHR = 0.71, 95% CI = 0.56-0.90, P = .004; respectively). However, DES placement had a neutral effect on the risk of new-onset AF in the patients with STEMI.Compared with the use of BMS, the use of DES might reduce the risk of new-onset AF in patients with NSTEMI.

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury.

BACKGROUND: Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemia-reperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia. METHODS: By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α gene-expression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-ß (TGF-ß) and C-reactive protein (CRP) were also determined. RESULTS: The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215-treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215- and MPT0E028-treated rats had a trend in decreased serum TGF-ß levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 µg/mL vs. 961.37 ± 64.94 µg/mL, p < 0.05). CONCLUSIONS: Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-ß and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.