MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells.

Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3'-untranslated region (3'-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.

MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.

Endothelial, platelet, and macrophage microparticle levels do not change acutely following transcatheter aortic valve replacement.

BACKGROUND: Patients with severe aortic stenosis have increased levels of prothrombotic and proinflammatory microparticles (MP), and MPs actively regulate pathological processes that lead to atherothrombotic cardiovascular events. Shear stress is a validated stimulus of MP production, and abnormal shear stress in aortic stenosis increases MP release in ex-vivo studies. We hypothesized that in patients with severe aortic stenosis, percutaneous replacement of the aortic valve (TAVR) would reduce abnormal shear stress and would decrease levels of circulating MPs. FINDINGS: The experimental protocol utilized flow cytometry (FC) and nanoparticle tracking analysis (NTA) to quantify circulating plasma MP levels in aortic stenosis patients at baseline and 5 days after TAVR. The baseline and 5 day MP counts measured by FC were 6.10⋅10(5) ± 1.21⋅10(5) MP/µL and 5.74⋅10(5) ± 9.54⋅10(4) MP/µL, respectively (p = 0.91). The baseline and 5 day MP counts measured by NTA were 9.29⋅10(13) ± 1.66⋅10(13) MP/µL and 3.95⋅10(14) ± 3.11⋅10(14) MP/µL, respectively (p = 0.91). When MPs were stratified by cell source, there was no difference in pre/post TAVR endothelial, platelet, or leukocyte MP levels. CONCLUSION: Levels of circulating MPs do not change acutely following TAVR therapy for aortic stenosis. Trial registered at clinicaltrials.gov NCT02193035 on July 11, 2014.

Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.

RATIONALE: We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification. OBJECTIVE: We tested the hypothesis that macrophage-derived MVs contribute directly to microcalcification. METHODS AND RESULTS: Macrophages associated with regions of calcified vesicular structures in human carotid plaques (n=136 patients). In vitro, macrophages released MVs with high calcification and aggregation potential. MVs expressed exosomal markers (CD9 and TSG101) and contained S100A9 and annexin V. Silencing S100A9 in vitro and genetic deficiency in S100A9-/- mice reduced MV calcification, whereas stimulation with S100A9 increased calcification potential. Externalization of phosphatidylserine after Ca/P stimulation and interaction of S100A9 and annexin V indicated that a phosphatidylserine-annexin V-S100A9 membrane complex facilitates hydroxyapatite nucleation within the macrophage-derived MV membrane. CONCLUSIONS: Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.

MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling.

RATIONALE: The rapid induction and orchestration of new blood vessels are critical for tissue repair in response to injury, such as myocardial infarction, and for physiological angiogenic responses, such as embryonic development and exercise. OBJECTIVE: We aimed to identify and characterize microRNAs (miR) that regulate pathological and physiological angiogenesis. METHODS AND RESULTS: We show that miR-26a regulates pathological and physiological angiogenesis by targeting endothelial cell (EC) bone morphogenic protein/SMAD1 signaling in vitro and in vivo. MiR-26a expression is increased in a model of acute myocardial infarction in mice and in human subjects with acute coronary syndromes. Ectopic expression of miR-26a markedly induced EC cycle arrest and inhibited EC migration, sprouting angiogenesis, and network tube formation in matrigel, whereas blockade of miR-26a had the opposite effects. Mechanistic studies demonstrate that miR-26a inhibits the bone morphogenic protein/SMAD1 signaling pathway in ECs by binding to the SMAD1 3'-untranslated region, an effect that decreased expression of Id1 and increased p21(WAF/CIP) and p27. In zebrafish, miR-26a overexpression inhibited formation of the caudal vein plexus, a bone morphogenic protein-responsive process, an effect rescued by ectopic SMAD1 expression. In mice, miR-26a overexpression inhibited EC SMAD1 expression and exercise-induced angiogenesis. Furthermore, systemic intravenous administration of an miR-26a inhibitor, locked nucleic acid-anti-miR-26a, increased SMAD1 expression and rapidly induced robust angiogenesis within 2 days, an effect associated with reduced myocardial infarct size and improved heart function. CONCLUSIONS: These findings establish miR-26a as a regulator of bone morphogenic protein/SMAD1-mediated EC angiogenic responses, and that manipulating miR-26a expression could provide a new target for rapid angiogenic therapy in ischemic disease states.

Bone marrow-derived Kruppel-like factor 10 controls reendothelialization in response to arterial injury.

OBJECTIVE: The objective of this study was to investigate the role of Kruppel-like factor (KLF) 10, a zinc-finger transcription factor, in bone marrow (BM)-derived cell responses to arterial endothelial injury. Accumulating evidence indicates that BM-derived progenitors are recruited to sites of vascular injury and contribute to endothelial repair. APPROACH AND RESULTS: In response to carotid artery endothelial denudation, KLF10 mRNA expression was markedly increased in both BM and circulating lin(-) progenitor cells. To examine the specific role of KLF10 in arterial reendothelialization, we used 2 models of endothelial denudation (wire- and thermal-induced injury) of the carotid artery in wild-type (WT) and KLF10(-/-) mice. WT mice displayed higher areas of reendothelialization compared with KLF10(-/-) mice after endothelial injury using either method. BM transplant studies revealed that reconstitution of KLF10(-/-) mice with WT BM fully rescued the defect in reendothelialization and increased lin(-)CD34(+)kinase insert domain receptor(+) progenitors in the blood and injured carotid arteries. Conversely, reconstitution of WT mice with KLF10(-/-) BM recapitulated the defects in reendothelialization and peripheral cell progenitors. The media from cultured KLF10(-)/(-) BM progenitors was markedly inefficient in promoting endothelial cell growth and migration compared with the media from WT progenitors, indicative of defective paracrine trophic effects from KLF10(-)/(-) BM progenitors. Finally, BM-derived KLF10(-/-) lin(-) progenitors from reconstituted mice had reduced CXC-chemokine receptor 4 expression and impaired migratory responses. CONCLUSIONS: Collectively, these observations demonstrate a protective role for BM-derived KLF10 in paracrine and homing responses important for arterial endothelial injury and highlight KLF10 as a possible therapeutic target to promote endothelial repair in vascular disease states.

Stent thrombosis: understanding and managing a critical problem.

OPINION STATEMENT: Coronary artery stent thrombosis (ST), defined as the thrombotic occlusion of a stented segment, is an infrequent but serious complication of percutaneous coronary intervention (PCI). The clinical consequences of ST are severe, because acute stent occlusion results in myocardial infarction and death in up to 45% of cases. Specific patient and procedural characteristics increase the risk of ST, but optimized interventional techniques and antiplatelet therapies have the potential to decrease ST and improve cardiovascular outcomes following PCI.

Mortality and other outcomes of patients with coronavirus disease pneumonia admitted to the emergency department: A prospective observational Brazilian study.

BACKGROUND: The first cases of coronavirus disease (COVID-19) in Brazil were diagnosed in February 2020. Our Emergency Department (ED) was designated as a COVID-19 exclusive service. We report our first 500 confirmed COVID-19 pneumonia patients. METHODS: From 14 March to 16 May 2020, we enrolled all patients admitted to our ED that had a diagnosis of COVID-19 pneumonia. Infection was confirmed via nasopharyngeal swabs or tracheal aspirate PCR. The outcomes included hospital discharge, invasive mechanical ventilation, and in-hospital death, among others. RESULTS: From 2219 patients received in the ED, we included 506 with confirmed COVID-19 pneumonia. We found that 333 patients were discharged home (65.9%), 153 died (30.2%), and 20 (3.9%) remained in the hospital. A total of 300 patients (59.3%) required ICU admission, and 227 (44.9%) needed invasive ventilation. The multivariate analysis found age, number of comorbidities, extension of ground glass opacities on chest CT and troponin with a direct relationship with all-cause mortality, whereas dysgeusia, use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker and number of lymphocytes with an inverse relationship with all-cause mortality. CONCLUSIONS: This was a sample of severe patients with COVID-19, with 59.2% admitted to the ICU and 41.5% requiring mechanical ventilator support. We were able to ascertain the outcome in majority (96%) of patients. While the overall mortality was 30.2%, mortality for intubated patients was 55.9%. Multivariate analysis agreed with data found in other studies although the use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker as a protective factor could be promising but would need further studies. TRIAL REGISTRATION: The study was registered in the Brazilian registry of clinical trials: RBR-5d4dj5.

Correction: Mortality and other outcomes of patients with coronavirus disease pneumonia admitted to the emergency department: A prospective observational Brazilian study.

[This corrects the article DOI: 10.1371/journal.pone.0244532.].

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.

Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.

Awake Prone Positioning in COVID-19 Hypoxemic Respiratory Failure: Exploratory Findings in a Single-center Retrospective Cohort Study.

BACKGROUND: Awake prone positioning has been widely used in patients with COVID-19 respiratory failure to avoid intubation despite limited evidence. Our objective was to evaluate if prone positioning is associated with a reduced intubation rate when compared to usual care. METHODS: This was a retrospective cohort study in the emergency department of a large quaternary hospital in Sao Paulo. We retrieved data from all admitted patients in need of oxygen supplementation (>3 L/min) and tachypnea (>24 ipm) from March 1 to April 30, 2020, excluding those who had any contraindication to the prone position or who had an immediate need for intubation. The primary endpoint was endotracheal intubation up to 15 days. Secondary outcomes included a 6-point clinical outcome ordinal scale, mechanical ventilation-free days, admission to the intensive care unit, and need of hemodialysis and of vasoactive drugs, all assessed at or up to 15 days. We analyzed unadjusted and adjusted effect estimates with Cox proportional hazards models, logistic regression, quantile regression, and sensitivity analyses using propensity score models. RESULTS: Of 925 suspected COVID-19 patients admitted off mechanical ventilation, 166 patients fulfilled inclusion and exclusion criteria: 57 were exposed to prone positioning and 109 to usual care. In the intervention group, 33 (58%) were intubated versus 53 (49%) in the control group. We observed no difference in intubation rates in the univariate analysis (hazard ratio = 1.21, 95% confidence interval [CI] = 0.78 to 1.88, p = 0.39) nor in the adjusted analysis (hazard ratio = 0.90, 95% CI = 0.55 to 1.49, p = 0.69). Results were robust to the sensitivity analyses. Secondary outcomes did not differ between groups. CONCLUSIONS: Awake prone positioning was not associated with lower intubation rates. Caution is necessary before widespread adoption of this technique, pending results of clinical trials.

Potential of transcatheter aortic valve replacement to improve post-procedure renal function.

BACKGROUND: Baseline comorbidities including renal dysfunction are frequently found in patients treated with transcatheter aortic valve replacement (TAVR) and may increase the risks of acute kidney injury (AKI), although some of them may actually improve renal function. We aimed to evaluate the potential of TAVR to acutely improve post-procedure renal function. METHODS: This is a prospective single-center registry of consecutive patients with severe symptomatic aortic stenosis treated by transfemoral TAVR. Creatinine levels were determined at baseline and daily until hospital discharge. AKI was defined according to VARC-2 criteria. Patients who had improvement of creatinine levels >25% were classified as having TAVR induced renal function improvement (TIRFI). RESULTS: A total of 69 patients undergoing TAVR were included, with a mean age of 83.0±7.4 years, being 24.6% diabetics, with a median STS score of 9.2 (5.1-21.6). Using the VARC-2 criteria, the majority of patients (64.6%) did not have renal impairment, while AKI was detected in 35.4% of the patients. Importantly, in those with prior severe renal dysfunction (clearance <30mL/min/1.73m2) or diabetes, AKI reached up to 50% and 56.3% of the patients, respectively. Conversely, acute kidney recovery (TIRFI) occurred in 12 patients (18.5%) being >50% in 1 patient (1.5%), and at hospital discharge the majority of the patients (88.6%) left the hospital in their original or better renal function categories. CONCLUSION: Despite multiple comorbidities in a selected TAVR-population and the use of contrast media, TAVR did not impair renal function in a majority of patients, with a significant proportion of them rather having acute renal function improvement.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.

Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.

Very late outcomes of drug-eluting stents coated with biodegradable polymers: insights from the 5-year follow-up of the randomized PAINT trial.

BACKGROUND: Few studies have examined the very long-term outcomes after implantation of drug-eluting stents (DES) coated with biodegradable polymers (BP). This report presents the 5-year clinical follow-up of patients treated with BP-DES in the randomized PAINT trial. METHODS: The PAINT study is a prospective, multicenter randomized controlled trial that allocated 274 patients for treatment with two BP-DES formulations [paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES)] or bare metal stents (BMS) in a 1:2:2 ratio, respectively. The primary end-point of this sub-study was defined as the composite of the major cardiac adverse events (MACE) cardiac death, myocardial infarction (MI) or ischemia-driven target vessel revascularization (TVR) at 5 years. RESULTS: The 5-year MACE rates were different among the groups: 35.3%, 22.5% and 16.9% for BMS, PES and SES, respectively (P<0.05 for both DES vs. bare stent comparisons). The primary end-point was mainly driven by TVR: 31.8%, 14.1% and 12.2% for bare stents, PES and SES, respectively (P<0.05 for both DES vs. bare stent comparisons). The incidence of stent thrombosis (ST) was null for BMS during the entire follow-up. There was no definite or probable ST in the SES group after the second year, while one patient (1.0%) presented with a definite ST episode in the PES group between 4 and 5 years. CONCLUSIONS: The tested biodegradable-polymer coated stents releasing either paclitaxel or sirolimus, compared with same bare metal platform, sustained their effectiveness in reducing combined major adverse cardiac events and re-intervention without an increase in ST during 5 years of follow-up.

Prevalence of high platelet reactivity in aspirin-treated patients referred for coronary angiography.

BACKGROUND: Aspirin (ASA) reduces adverse events in coronary artery disease (CAD) patients by inhibiting platelets. Some CAD patients have high platelet reactivity (HPR) despite ASA therapy and these individuals have increased risk of adverse events. OBJECTIVE: The purpose of this study was to determine the prevalence of HPR in ASA-treated patients referred for coronary angiography and to assess whether the HPR correlates with the severity of CAD. METHODS: This single center investigation enrolled 115 consecutive ASA-treated patients with stable CAD. ADP- and collagen-induced platelet reactivity were evaluated by light transmittance aggregometry (LTA). Patients with greater than 70% ADP- and collagen-induced aggregation were determined to have HPR and, in this group, ASA compliance was assessed by examining blood salicylate levels. Mean age was 60.9 years and average ASA dose was 164.2 mg. RESULTS: Smoking and DM were present in 28.7% and 31.5% respectively. HPR was found in 14 patients (13%) however 7 of the 14 patients (50%) with HPR had low serum salicylate levels (< 2.0 µg/mL) suggesting medication noncompliance. Of the entire cohort, 6.5% of patients had HPR and detectable serum salicylate levels suggesting reduced ASA efficacy. HPR correlated with number and severity of coronary stenosis (p = 0.04). CONCLUSION: In a general population of ASA-treated patients referred for coronary angiography, elevated platelet reactivity is prevalent (13%) with 50% related to noncompliance and 50% related to reduced aspirin efficacy.

Low educational status, smoking, and multidisciplinary team experience predict hospital length of stay after bariatric surgery.

OBJECTIVE: The objective of the present study was to identify new risk factors associated with longer hospitalization following bariatric surgery. METHODS: Patient clinical, social, and biochemical data in addition to multidisciplinary team experience were analyzed in a cohort that included all patients undergoing bariatric surgery at our hospital. The primary outcome was length of hospital stay (LOS). Mortality was recorded to validate the obesity surgery mortality risk score (OS-MRS). RESULTS: This study included 299 sequential patients, 41 ± 10 years of age, and BMI of 50 ± 8 kg/m(2) who underwent bariatric surgery. Two thirds (196) of patients were hypertensive, a third (86) were diabetic and a third (91) were current or former smokers. Overall, LOS was 8 ± 5 days. The predictors of a longer LOS were smoking (P < 0.05) and less multidisciplinary team experience (P < 0.05). Looking at only the last three years of data, LOS was 6 ± 5 days, and the predictors of a longer LOS were low educational attainment (P < 0.02) and smoking (P < 0.01) but not team experience. The global mortality was 2.6%, with the OS-MRS identifying a high-risk group. CONCLUSION: Excluding the initial learning phase, longer LOS independent predictors were patient low educational attainment and smoking. These predictors can help guide care to reduce complications.

Implante percutâneo de prótese valvar aórtica ­ experiência com o dispositivo reposicionável LotusTM / Percutaneous aortic valve implantation ­ an experience with the LotusTM repositionable device

Introdução: A válvula aórtica transcateter de segunda geração LotusTM foi desenhada para proporcionar ao intervencionista o controle completo de sua liberação durante o procedimento. O presente estudo apresenta a experiência inicial e os desfechos hospitalares de pacientes tratados com essa prótese no Brasil. Métodos: Registro observacional, retrospectivo, que incluiu pacientes com estenose aórtica grave sintomáticos, considerados de alto risco cirúrgico, tratados em sete centros.Resultados: Receberam o dispositivo 31 pacientes, sendo 61,3% do sexo feminino, com idade de 82,9 ± 6,9 anos e escore STS de 6,5 ± 4,1%. A área valvar aórtica foi de 0,73 ± 0,18 cm2 e o gradiente médio de 51,7 ± 13,9 mmHg. Todos os procedimentos foram realizados pela via transfemoral, e a pré-dilatação foi necessária em 65% dos casos. A taxa de sucesso do procedimento foi de 96,7%. Não houve complicação vascular com necessidade de intervenção cirúrgica e nem casos de acidente vascular cerebral. O gradiente médio após o procedimento foi de 10,5 ± 5,8 mmHg e não foram observadas regurgitações aórticas de graus moderado/importante. A taxa de implante de marca-passo definitivo foi de 38,7%, e a permanência hospitalar de 8,5 ± 4,8 dias. Conclusões: Na experiência inicial com o implante da válvula aórtica LotusTM, os resultados hospitalares demostraram a segurança e a eficácia do dispositivo, além de ausência de regurgitação aórtica relevante

Background: The second-generation LotusTM transcatheter aortic valve was designed to provide the interventional cardiologist with complete control of its release during the procedure. This study presents the initial experience and in-hospital outcomes of patients treated with this prosthesis in Brazil. Methods: This observational and retrospective study included patients with symptomatic severe aortic stenosis considered at high surgical risk, treated in seven centers. Results: The device was used in 31 patients, 61.3% female, aged 82.9 ± 6.9 years, and with STS score of 6.5 ± 4.1%. The aortic valve area was 0.73 ± 0.18 cm2 and the mean gradient was 51.7 ± 13.9 mmHg. All procedures were performed by the transfemoral access route, and pre-dilation was necessary in 65% of cases. The success rate of the procedure was 96.7%. There were no vascular complications requiring surgical intervention nor cases of stroke. The mean gradient after the procedure was 10.5 ± 5.8 mmHg; no cases of moderate to severe aortic regurgitation were observed. The rate of permanent pacemaker implantation was 38.7%, and mean in-hospital length of stay was 8.5 ± 4.8 days. Conclusions: In the initial experience with the use of the LotusTM aortic valve, in-hospital results demonstrated the safety and efficacy of the device; no cases of significant aortic regurgitation were observed