Left bundle branch area pacing in mildly reduced heart failure: A systematic literature review and meta-analysis.

Cardiac resynchronization therapy (CRT) strategy for heart failure with mildly reduced ejection fraction (HFmrEF) is controversial. Left bundle branch area pacing (LBBAP) is an emerging pacing modality and an alternative option to CRT. This analysis aimed to perform a systematic review of the literature and meta-analysis on the impact of the LBBAP strategy in HFmrEF, with left ventricular ejection fraction (LVEF) between 35% and 50%. PubMed, Embase, and Cochrane Library were searched for full-text articles on LBBAP from inception to July 17, 2022. The outcomes of interest were QRS duration and LVEF at baseline and follow-up in mid-range heart failure. Data were extracted and summarized. A random-effect model incorporating the potential heterogeneity was used to synthesize the results. Out of 1065 articles, 8 met the inclusion criteria for 211 mid-range heart failure patients with an implant LBBAP across the 16 centers. The average implant success rate with lumenless pacing lead use was 91.3%, and 19 complications were reported among all 211 enrolled patients. During the average follow-up of 9.1 months, the average LVEF was 39.8% at baseline and 50.5% at follow-up (MD: 10.90%, 95% CI: 6.56-15.23, p < .01). Average QRS duration was 152.6 ms at baseline and 119.3 ms at follow-up (MD: -34.51 ms, 95% CI: -60.00 to -9.02, p < .01). LBBAP could significantly reduce QRS duration and improve systolic function in a patient with LVEF between 35% and 50%. Application of LBBAP as a CRT strategy for HFmrEF may be a viable option.

Residual Inflammatory Risk and its Association With Events in East Asian Patients After Coronary Intervention.

Background: East Asian population has a low level of inflammation compared with Western population. The prognostic implication of residual inflammatory risk (RIR) remains uncertain in East Asians. Objectives: This study sought to provide an analysis to estimate early-determined RIR and its association with clinical outcomes in East Asian patients with coronary artery disease (CAD). Methods: In an East Asian registry including patients with CAD undergoing percutaneous coronary intervention (PCI) (n = 4,562), RIR status was determined by measuring high-sensitivity C-reactive protein (hsCRP) serially at admission and at 1-month follow-up. Patients were stratified into 4 groups according to hsCRP criteria (≥2 mg/L): 1) persistent low RIR (lowon admission-low1 month: 51.0%); 2) fortified RIR (lowon admission-high 1 month: 10.3%); 3) attenuated RIR (highon admission-low1 month: 20.5%); and 4) persistent high RIR (highon admission-high1 month: 18.3%). The risks of all-cause death, ischemic events, and major bleeding were evaluated. Results: In our cohort, median levels of hsCRP were significantly decreased over time (1.3 to 0.9 mg/L; P < 0.001). Compared with hsCRP on admission, hsCRP at 1 month showed the greater associations with all-cause death and ischemic event. During clinical follow-up, risks of clinical events were significantly different across the groups (log-rank test, P < 0.001). Compared with other RIR groups, persistent high RIR showed the higher risk for all-cause death (HRadjusted, 1.92; 95% CI: 1.44 to 2.55; P < 0.001), ischemic events (HRadjusted, 1.26; 95% CI: 1.02 to 1.56; P = 0.032), and major bleeding (HRadjusted, 1.98; 95% CI: 1.30 to 2.99; P < 0.001), respectively. Conclusions: Approximately one-fifth of East Asian patients with CAD have persistent high RIR, which shows the close association with occurrence of ischemic and bleeding events. (Gyeongsang National University Hospital Registry [GNUH]; NCT04650529).

Serum microRNA-185 Levels and Myocardial Injury in Patients with Acute ST-segment Elevation Myocardial Infarction.

Objective Human microRNA-185 (miR-185) has been reported to act as a regulator of fibrosis and angiogenesis in cancer. However, miR-185 has not been investigated in patients with ST-segment elevation myocardial infarction (STEMI). We hypothesized that the changes in miR-185 levels in STEMI patients are related to the processes of myocardial healing and remodeling. Methods Between January 2011 and December 2013, 145 patients with STEMI (65.9±11.6 years old; 41 women) were enrolled. Initial and discharge serum samples collected from 20 patients with STEMI and mixed sera from 8 healthy controls were analyzed by a microarray. A quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of miR-185 was performed in all 145 patients. The correlation between the miR-185 levels and the clinical, laboratory, angiographic, and echocardiographic parameters was analyzed. Results The microarray analysis revealed a biphasic pattern in miR-185 levels, with an initial decrease followed by an increase at discharge. The miR-185 levels at discharge were significantly correlated with the troponin-I, CK-MB, and area under the curve of CK-MB levels. There was a positive correlation between the transforming growth factor-ß and miR-185 levels at discharge (ρ=0.242, p=0.026). A high wall motion score index and a low ejection fraction, as measured by echocardiography, and high B-type natriuretic peptide level at one month after STEMI were related to high miR-185 levels. Conclusion Our results showed that elevated miR-185 levels at the late stage of STEMI were related to a large amount of myocardial injury and adverse remodeling.

Apparent treatment-resistant hypertension among ambulatory hypertensive patients: a cross-sectional study from 13 general hospitals.

BACKGROUND/AIMS: To examine the prevalence and clinical characteristics of apparent treatment-resistant hypertension among ambulatory hypertensive patients. METHODS: We enrolled adult ambulatory hypertensive patients at 13 well-qualified general hospitals in Korea from January to June 2012. Apparent resistant hypertension was defined as an elevated blood pressure > 140/90 mmHg with the use of three antihypertensive agents, including diuretics, or ≥ 4 antihypertensives, regardless of the blood pressure. Controlled hypertension was defined as a blood pressure within the target using three antihypertensives, including diuretics. RESULTS: Among 16,915 hypertensive patients, 1,172 (6.9%) had controlled hypertension, and 1,514 (8.9%) had apparent treatment-resistant hypertension. Patients with apparent treatment-resistant hypertension had an earlier onset of hypertension (56.8 years vs. 58.8 years, p = 0.007) and higher body mass index (26.3 kg/m2 vs. 24.9 kg/m2, p < 0.001) than those with controlled hypertension. Drug compliance did not differ between groups. In the multivariable analysis, earlier onset of hypertension (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99; p < 0.001) and the presence of comorbidities (OR, 2.06; 95% CI, 1.27 to 3.35; p < 0.001), such as diabetes mellitus, ischemic heart disease, heart failure, and chronic kidney disease, were independent predictors. Among the patients with apparent treatment-resistant hypertension, only 5.2% were receiving ≥ 2 antihypertensives at maximally tolerated doses. CONCLUSION: Apparent treatment-resistant hypertension prevalence is 8.9% among ambulatory hypertensive patients in Korea. An earlier onset of hypertension and the presence of comorbidities are independent predictors. Optimization of medical treatment may reduce the rate of apparent treatment-resistant hypertension.

Comparative analysis of three nutrition scores in predicting mortality after acute myocardial infarction.

OBJECTIVE: We investigated the utility of nutrition scores in predicting mortality and prognostic importance of nutrition status using three different scoring systems in patients with acute myocardial infarction (AMI). METHODS: In total, 1147 patients with AMI were enrolled in this study (72.5 % men; mean age 65.6 years). Patients were divided into three groups according to the geriatric nutritional risk index (GNRI); prognostic nutritional index (PNI); and triglycerides, total cholesterol, and body weight index(TCBI) scores as tertile: low (GNRI ≤ 103.8, n = 382), intermediate (103.8 < GNRI ≤ 112.3, n = 383), and high (GNRI > 112.3, n = 382) GNRI groups; low (PNI ≤ 50.0, n = 382), intermediate (50.0 < PNI ≤ 56.1, n = 383), and high (PNI > 56.1, n = 382) PNI groups; and low (TCBI ≤ 1086.4, n = 382), intermediate (1086.3 < GNRI ≤ 2139.1, n = 383), and high (TCBI > 2139.1, n = 382) TCBI groups. RESULTS: In the GNRI, TCBI, and PNI groups, the cumulative incidence of all-cause death and major adverse cardiovascular events (MACEs) was significantly higher in the low score group, followed by the intermediate and high score groups. Moreover, both intermediate and low PNI groups had a similar cumulative incidence of all-cause death and MACE. The GNRI score (AUC 0.753, 95% CI 0.608~0.745, P = 0.009) had significantly higher areas under the curve (AUCs) than the TCBI (AUC 0.659, 95% CI 0.600~0.719, reference) and PNI (AUC 0.676, 95% CI 0.608~0.745, P = 0.669) scores. CONCLUSIONS: Patients with low nutrition scores were at a higher risk of MACE and all-cause death than patients with high nutrition scores. Additionally, the GNRI had the greatest incremental value in predicting risks among the three different scoring systems used in this study.

Cardiac mortality benefit of direct admission to percutaneous coronary intervention-capable hospital in acute myocardial infarction: Community registry-based study.

ABSTRACT: Appropriate risk stratification and timely revascularization of acute myocardial infarction (AMI) are available in percutaneous coronary intervention (PCI) - capable hospitals (PCHs). This study evaluated whether direct admission vs inter-hospital transfer influences cardiac mortality in patients with AMI. This study was conducted in the PCH where the patients were able to arrive within an hour. The inclusion criteria were AMI with a symptom onset time within 24 hours and having undergone PCI within 24 hours after admission. The cumulative incidence of cardiac death after percutaneous coronary intervention was evaluated in the direct admission versus inter-hospital transfer groups. Among the 3178 patients, 2165 (68.1%) were admitted via inter-hospital transfer. Patients with ST-segment elevation myocardial infarction (STEMI) in the direct admission group had a reduced symptom onset-to-balloon time (121 minutes, P < .001). With a median period of 28.4 (interquartile range, 12.0-45.6) months, the cumulative incidence of 2-year cardiac death was lower in the direct admission group (NSTEMI, 9.0% vs 11.0%, P = .136; STEMI, 9.7% vs 13.7%, P = .040; AMI, 9.3% vs 12.3%, P = .014, respectively). After the adjustment for clinical variables, inter-hospital transfer was the determinant of cardiac death (hazard ratio, 1.59; 95% confidence interval, 1.08-2.33; P = .016). Direct PCH admission should be recommended for patients with suspected AMI and could be a target for reducing cardiac mortality.

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity.

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

Gram-Negative Bacterial Endotoxin LPS Induces NeuGc Loss through Ets1-Dependent Downregulation of Intestine-Specific pcmah Transcript in Porcine Intestinal Cells.

N-glycolylneuraminic acid (NeuGc), a non-human sialic acid derivative synthesized by cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase (CMAH), plays a crucial role in mediating infections by certain pathogens. Although it has been postulated that NeuGc biosynthesis and CMAH expression are downregulated during microbial infection, the underlying mechanisms remain unclear. The present study showed that exposure to lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, leads to loss of NeuGc biosynthesis in pig small intestinal I2I-2I cells. This LPS-induced NeuGc loss was accompanied by decreased CMAH transcript levels, especially intestine-specific 5'pcmah-1. Furthermore, LPS suppressed the activity of the Pi promoter responsible for 5'pcmah-1 by inhibiting DNA binding of Est1. These findings provide insight into the regulatory mechanisms of Neu5Gc biosynthesis during pathogenic infectious events, which may represent a host defense mechanism that protects the self against pathogenic bacterial infections even in non-sanitary environments.

The Impact of platelet-fibrin clot strength on occurrence and clinical outcomes of peripheral artery disease in patients with significant coronary artery disease.

Patients with peripheral artery disease (PAD) have shown the increased risk of cardiovascular (CV) morbidity and mortality. This study sought to evaluate the impact of clot strength on prevalence and major adverse CV events (MACE) of PAD in high-risk patients. We enrolled patients undergoing percutaneous coronary intervention (PCI) (n = 1667) with available platelet-fibrin clot strength [thrombin-induced maximal amplitude (MAthrombin) measured by thromboelastography] and inflammation [high sensitivity C-reactive protein (hs-CRP)]. PAD was defined with abnormal ankle-brachial index (≤ 0.9 or > 1.4). MACE was defined as a composite of CV death, myocardial infarction or stroke. PAD was observed in 201 patients (12.1%). In the multivariate analysis, high clot strength [MAthrombin ≥ 68 mm: odds ratio (OR) 1.70, 95% confidence interval (CI) 1.20 to 2.41, p = 0.003] and enhanced inflammation (hs-CRP ≥ 3.0 mg/L: OR 2.30, 95% CI 1.56 to 3.41, p < 0.001) were associated with PAD occurrence. During the follow-up post-PCI (median, 25 months), MACE was more frequently occurred in patients with vs. without PAD (18.7% vs. 6.4% at 3 years; hazard ratio 1.72, 95% CI 1.03 to 2.87, p = 0.039). Furthermore, combined presence of PAD and high clot strength significantly increased the risk of MACE. In conclusion, this study is the first to show the impact of clot strength on prevalence and clinical outcomes of PAD in coronary artery disease patients undergoing PCI. Whether antithrombotic strategy according to level of this biomarker can improve clinical outcomes in PAD patients deserves the further study.

Head-to-head comparison of prognostic accuracy in patients undergoing noncardiac surgery of dobutamine stress echocardiography versus computed tomography coronary angiography (PANDA trial): A prospective observational study.

BACKGROUND: Dobutamine stress echocardiography (DSE) and coronary computed tomography angiography (CTA) can provide perioperative prognostic information in risk stratification of patients undergoing noncardiac surgery. This study directly compared the prognostic value of DSE and CTA in patients undergoing noncardiac surgery. METHODS: Between 2014 and 2016, 215 patients with more than one clinical risk factor for perioperative cardiovascular (CV) events were enrolled prospectively. They received both DSE and CTA before noncardiac surgery. Perioperative clinical risk was classified according to the revised cardiac risk index (RCRI), DSE results were categorized as abnormal (inducible ischemia and/or nonviable infarction) or not. CTA results were assessed using the severity of stenosis, with significant stenosis being ≥50% of the luminal diameter). After the exclusion, a total of 206 patients remained. Perioperative CV events were defined as CV death, non-fatal myocardial infarction (MI), myocardial injury, pulmonary edema, non-fatal stroke, and systemic embolism within 30 days after surgery. RESULTS: Twenty-four patients (12%) had perioperative cardiac events (1 cardiac death, 10 non-fatal MI, 8 myocardial injury, 11 pulmonary edema, 1 non-fatal stroke, and 1 pulmonary embolism). Following adjustment for baseline RCRI score, abnormal result on DSE (OR, 6.08, 95% CI, 2.41 to 15.31, P < 0.001), significant CAD on CTA (OR, 18.79; 95% CI, 5.24 to 67.42, P < 0.001), and high CACS (OR, 4.19; 95% CI, 1.39 to 12.60, P = 0.011) remained significant predictors of perioperative CV events. CONCLUSIONS: DSE and CTA are independent predictive factors of events in patients undergoing noncardiac surgery. Among them, assessment of significant CAD using CTA might show a higher prognostic value compared with DSE before noncardiac surgery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02250963.

3'-sialyllactose targets cell surface protein, SIGLEC-3, and induces megakaryocyte differentiation and apoptosis by lipid raft-dependent endocytosis.

3'-sialyllactose is one of the abundant components in human milk oligosaccharides (HMOs) that protect infants from various viral infections in early stages of immune system development. 3SL is a combination of lactose and sialic acid. Most sialic acids are widely expressed in animal cells and they bind to siglec proteins. In this study, we demonstrate that 3SL specifically binds to CD33. It induces megakaryocyte differentiation and subsequent apoptosis by targeting cell surface protein siglec-3 (CD33) in human chronic myeloid leukemia K562 cells. The 3SL-bound CD33 was internalized to the cytosol via caveolae-dependent endocytosis. At the molecular level, 3SL-bound CD33 recruits the suppressor of cytokine signaling 3 (SOCS3) and SH2 domain-containing protein tyrosine phosphatase 1 (SHP1). SOCS3 is degraded with CD33 by proteasome degradation, while SHP-1 activates extracellular signal-regulated kinase (ERK) to induce megakaryocytic differentiation and subsequent apoptosis. The present study, therefore, suggests that 3SL is a potential anti-leukemia agent affecting differentiation and apoptosis.

Influence of rabeprazole and famotidine on pharmacodynamic profile of dual antiplatelet therapy in clopidogrel-sensitive patients: The randomized, prospective, PROTECT trial.

Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 µM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 µM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 µM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P= .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P= .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.

Ezetimibe and Rosuvastatin Combination Treatment Can Reduce the Dose of Rosuvastatin Without Compromising Its Lipid-lowering Efficacy.

PURPOSE: The goal of this study was to compare the lipid-lowering efficacy of the combination of ezetimibe and low- or intermediate-intensity statin therapy versus that of high-intensity statin monotherapy. METHODS: This study is a post hoc analysis of an 8-week, randomized, double-blind, Phase III trial. Patients who had hypercholesterolemia and required lipid-lowering treatment were randomly assigned to 1 of 6 treatment groups: rosuvastatin 5 mg (R5, n = 68), rosuvastatin 10 mg (R10, n = 67), rosuvastatin 20 mg (R20, n = 69), and ezetimibe 10 mg combined with rosuvastatin 5 mg (R5 + E10, n = 67), rosuvastatin 10 mg (R10 + E10, n = 68), and rosuvastatin 20 mg (R20 + E10, n = 68) daily. The effects of coadministration of ezetimibe and a low dose of rosuvastatin on lipid parameters and the target achievement rate were compared between the R5 + E10 and R10 treatment groups, the R5 + E10 and R20 treatment groups, and the R10 + E10 and R20 treatment groups. FINDINGS: Reductions in total cholesterol, LDL-C, apolipoprotein B, the apolipoprotein B/A1 ratio, and non-HDL-C were not different between the R5 + E10 and R10 treatment groups (all, P > 0.017), the R5 + E10 and R20 treatment groups (all, P > 0.017), and the R10 + E10 and R20 treatment groups (all, P > 0.017). R5 + E10 treatment showed efficacy comparable to that of R10 or R20 in affording LDL levels <50% of the baseline level (R5 + E10 vs R10, 73.13% vs 62.69% [P = 0.1952]; R5 + E10 vs R20, 73.13% vs 73.91% [P = 0.9180]), LDL-C levels <70 mg/dL (R5 + E10 vs R10, 64.18% vs 55.22% [P = 0.2906]; R5 + E10 vs R20, 64.18% vs 62.32% [P = 0.8220]), and LDL-C levels <50% of the baseline level or <70 mg/dL (R5 + E10 vs R10, 77.61% vs 70.15% [P = 0.3255]; R5 + E10 vs R20, 77.61% vs 78.26% [P = 0.9273]). The R10 + E10 treatment group was better than the R20 treatment group in achieving the target LDL-C level <70 mg/dL (83.82% vs 62.32%; P = 0.0046), even among participants with a baseline LDL-C level >135 mg/dL (77.5% vs 48.8%, respectively; P = 0.0074). IMPLICATIONS: Ezetimibe combined with low- or intermediate-intensity statin therapy has lipid-lowering efficacy comparable to or better than that of high-intensity rosuvastatin monotherapy. The results of the present study indicate that the combination treatment with ezetimibe is advantageous in that it permits dose reduction of rosuvastatin without compromising the lipid-lowering efficacy of rosuvastatin. ClinicalTrials.gov identifier: NCT02205606.

Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity.

Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.

Clinical efficacy of high-flow oxygen therapy through nasal cannula in patients with acute heart failure.

BACKGROUND: High-flow oxygen therapy through nasal cannula (HFNC) could reduce intubation rate and mortality rate among patients with acute respiratory failure. We evaluated the physiological responses and clinical outcomes of HFNC in patients with acute heart failure (AHF). METHODS: A retrospective cohort analysis was performed in single medical tertiary center. Patients with AHF who had a progressive hypoxemia after oxygenation via facemask were divided into intubation group and HFNC group. We analyzed the physiological responses and in-hospital clinical outcomes between two groups. RESULTS: Seventy-three patients of intubation group and 76 patients of HFNC group were included. Baseline characteristics were well-balanced between two groups. There were no differences in changes of mean arterial pressure, heart rate, and pulse oxygen saturation during the first 6 hours. Among HFNC group, 66 of 76 patients (86.8%) were successfully recovered from progressive hypoxemia without endotracheal intubation, and there were no differences in in-hospital clinical outcomes between two groups. CONCLUSIONS: This study showed HFNC group had a similar result of improvement of oxygen saturation and in-hospital clinical outcomes compared with intubation group in AHF. Present study supported HFNC could be considered as initial choice of oxygen therapy in selected patients of AHF.

Erratum to clinical efficacy of high-flow oxygen therapy through nasal cannula in patients with acute heart failure.

[This corrects the article DOI: 10.21037/jtd.2019.01.51.].

Ascochlorin induces caspase-independent necroptosis in LPS-stimulated RAW 264.7 macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Plant-specific fungus of natural compound of Ascochyta viciae has traditionally been used in the treatment of sleeping sickness and tumors. The anti-tumor activities of the compounds obtained from Pisum sativum L were evaluated in this study. AIM OF THE STUDY: In this study, during the prolonged incubation, treatment of the LPS-stimulated tumor-like macrophage RAW 264.7 cells with ASC exhibited the shift of anti-inflammatory behavior to a type of necroptotic cell death named necroptosis. MATERIALS AND METHODS: Ascochlorin (ASC) purified from plant-specific fungus Ascochyta viciae is a natural compound with the trimethyl oxocyclohexyl structure and an anti-cancer and antibiotic agent. The fungus contributes to the Ascochyta blight disease complex of pea (Pisum sativum L). RAW 264.7 cells have been stimulated with LPS and treated with ASC. Cell viability of the LPS-treated RAW 264.7 cells and bone marrow-derived macrophage (BMDM) cells were examined. Flow cytometry analysis with 7AAD and Annexin V was examined for the apoptotic or necroptosis/late-apoptosis. Cleaved caspase-3, -7 and -8 as well as cleaved PARP were assessed with a caspase inhibitor, z-VAD-fmk. LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells were also examined for the cell viabilities. RESULTS: Flow cytometry analysis after Annexin V and 7AAD double staining showed that ASC alone induces apoptosis in RAW 264.7 cells, while it induces necroptosis/late-apoptosis in LPS-treated RAW 264.7 cells. 7AAD and Annexin V positive populations were increased in the LPS-treated cells with ASC. Although viability of LPS-treated cells with ASC was decreased, the amounts of cleaved caspase-3, -7 and -8 as well as cleaved PARP were reduced when compared with ASC-treated cells. Upon ASC treatment, the cleaved caspase-8 level was not changed, however, cleaved caspase-3, -7, and PARP were reduced in LPS-stimulated RAW 264.7 cells treated with ASC, claiming a caspase-8 independent necroptosis of ASC. Furthermore, ASC and LPS-cotreated cells which a caspase inhibitor, z-VAD-fmk, was pretreated, showed the decreased cell viability compared with control cells without the inhibitor. Cell viability of RAW 264.7 cells co-treated with ASC and LPS when treated with z-VAD was decreased. In the LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells, cell viabilities were decreased by 10 µM ASC. CONCLUSION: Prolonged stimulation of ASC with LPS induces the necroptosis in RAW cells. Activated immune cells may share the susceptibility of antitumor agents with the cancer cells.

Association between pulse pressure at discharge and clinical outcomes in patients with acute myocardial infarction: From the KAMIR-Korean-NIH registry.

Pulse pressure (PP) is affected by arterial stiffness and is a predictor of cardiovascular events. However, value and utility of PP assessment in patients with acute myocardial infarction (AMI) remain less clear. We aimed to evaluate the association between PP and cardiovascular events in surviving patients with AMI at discharge. A total of 11 944 surviving patients with AMI at discharge from a Korean nationwide registry were included. Blood pressure was checked just before discharge. Noncardiac death and major adverse cardiovascular events (MACEs) including cardiac death, AMI, and stroke after discharge were analyzed. The median follow-up duration was 368 (IQR 339, 388) days. The rate of MACEs and cardiac death was higher in groups with the lowest PP (PP < 20 mm Hg) and highest PP (PP ≥ 71 mm Hg) and lowest in the group with PP of 31-40 mm Hg. With PP of 31-40 mm Hg as reference, univariate analysis showed a U-shaped association between the risk of MACEs (PP ≤ 20 mm Hg: hazard ratio [HR] 2.3; PP ≥ 71 mm Hg: HR 2.7) or cardiac death (PP ≤ 20 mm Hg: HR 2.6; PP ≥ 71 mm Hg: HR 3.1) and PP. In multivariate analysis, the curve changed from being U-shaped to J-shaped, and HR for PP ≥ 71 mm Hg (1.2 for MACEs and 1.4 cardiac death) decreased and HR for PP < 20 (2.1 for MACEs and 2.4 for cardiac death) did not significantly decrease after adjustment for cardiovascular risk factors. Our findings indicate that PP is a strong independent prognostic factor of MACEs and cardiac death in surviving patients with AMI. Low PP is a more significant independent predictor of MACEs and cardiac death than high PP in surviving patients after AMI.

Intestine specific regulation of pig cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase gene for N-glycolylneuraminic acid biosynthesis.

N-glycolylneuraminic acid (Neu5Gc), a generic form of sialic acid, is enzymatically synthesized by cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase (CMAH). Although expression of pig CMAH gene pcmah encoding CMAH has been reported to be regulated by pathogenic infection and developmental processes, little is known about the mechanisms underlying the regulation of pcmah gene expression. The objective of this study was to determine mechanism(s) involved in intestine specific regulation of pcmah gene by identifying several cis-acting elements and nuclear transcription factors that could directly interact with these cis-acting elements. We identified intestine specific promoter region (Pi) of pcmah gene located at upstream regions of the 5'flanking region of exon 1a and found that the promoter region is responsible for the transcriptional regulation of 5'pcmah-1. Based on reporter assays using serially constructed luciferase genes with each deleted promoter, we demonstrated that the Pi promoter activity was more active in intestinal IPI-2I cells than that in kidney PK15 cells, corresponding to both mRNA expression patterns in the two cell lines. In addition, we found that Sp1 transcription factor was necessary for basal activity of Pi promoter and that Ets-1 contributed to intestine-specific activity of Pi promoter. This study helps us understand transcriptional regulation of pcmah in the intestine of pig tissues. It also allows us to consider potential roles of Neu5Gc in interaction with environmental factors present in the intestinal tissue during pathogenic infection and developmental process.

Influence of Amlodipine on Haemostatic Measurements during Clopidogrel Treatment in Patients with Coronary Artery Disease.

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5-47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: -847 dyne/cm2; ∆95% CI: -1,632 to -62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with 'PRU ≥ 160 on-amlodipine' in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302-1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.