Effectiveness of early high-flow nasal oxygen therapy after extubation of patients in the intensive care unit.

PURPOSE: This study aimed to evaluate the impact of early high-flow nasal oxygen (HFNO) therapy initiation using a pre-determined respiratory rate­oxygenation (ROX) index on reducing reintubation rates and duration of intensive care unit (ICU) stay in post-extubated patients. MATERIALS AND METHODS: We enrolled a total of 145 extubated patients (mean age: 67.1 ± 12.9 years; sex: 96 male and 49 female; acute physiology and chronic health evaluation II score: 18.4 ± 6.8 points) classified into two groups: 71 patients admitted to the ICU before establishing extubation criteria and 74 patients after criteria implementation, over a 6-month period. We compared the HFNO reintubation rates and ROX index at 2 h post-extubation before and after implementing early HFNO criteria. RESULTS: The utilization rate of HFNO pre- and post-establishment of early HFNO criteria did not differ significantly (19.7% vs. 17.6%). However, the reintubation rate significantly decreased (11.3% vs. 4.1%, P < 0.05) with early HFNO use. Additionally, significant differences were observed in the total intubation period (5.2 ± 7.0 vs. 2.5 ± 2.7 days, P < 0.05) and ICU duration (8.6 ± 9.7 vs. 5.8 ± 5.6 days, P < 0.05). CONCLUSIONS: Early initiation of HFNO guided by the ROX index threshold post-extubation in patients admitted to ICU is associated with reduced reintubation rates and shorter ICU stays.

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.

Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in Lipopolysaccharide-Induced Experimental Endotoxemia.

Neutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE increases alveolocapillary permeability and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9- to 12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours after LPS injection, survival rate was more than threefold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared with control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was approximately ninefold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin ß1 Augments Angiogenesis in Ischemic Legs.

When injected directly into ischemic tissue in patients with peripheral artery disease, the reparative capacity of endothelial progenitor cells (EPCs) appears to be limited by their poor survival. We, therefore, attempted to improve the survival of transplanted EPCs through intravenous injection and gene modification. We anticipated that overexpression of integrin ß1 will enable injected EPCs to home to ischemic tissue, which abundantly express extracellular matrix proteins, the ligands for integrins. In addition, integrin ß1 has an independent angiogenesis-stimulating function. Human endothelial colony-forming cells (ECFCs; late-outgrowth EPCs) were transduced using a lentiviral vector encoding integrin ß1 (ITGB1) or enhanced green fluorescent protein (GFP). We then locally or systemically injected phosphate-buffered saline or the genetically modified ECFCs (GFP-ECFCs or ITGB1-ECFCs; 1 × 10(5) cells each) into NOD/Shi-scid, IL-2Rγnull mice whose right femoral arteries had been occluded 24 hours earlier. Upregulation of extracellular matrix proteins, including fibronectin, was apparent in the ischemic legs. Four weeks later, blood perfusion of the ischemic limb was significantly augmented only in the ITGB1-ECFC group. Scanning electron microscopy of vascular casts revealed increases in the perfused blood vessels in the ischemic legs of mice in the ITGB1-ECFC group and significant increases in the density of both capillaries and arterioles. Transplanted ECFC-derived vessels accounted for 28% ± 4.2% of the vessels in the ITGB1-ECFC group, with no cell fusion. Intravenous administration of ECFCs engineered to home to ischemic tissue appears to efficiently mediate therapeutic angiogenesis in a mouse model of peripheral artery disease. Significance: The intravenous administration of endothelial colony-forming cells (ECFCs) genetically modified to overexpress integrin ß1 effectively stimulated angiogenesis in ischemic mouse hindlimbs. Transplanted ECFCs were observed in the ischemic leg tissue, even at the chronic stage. Moreover, the cells appeared functional, as evidenced by the improved blood flow. The cell type used (ECFCs), the route of administration (intravenous, not directly injected into the affected area), and the use of ligand-receptor interactions (extracellular matrix and integrins) for homing represent substantial advantages over previously reported cell therapies for the treatment of peripheral artery disease.

An autopsy report of acute myocardial infarction with hypertrophic obstructive cardiomyopathy-like heart.

An 84-year-old woman, who was followed up as hypertrophic obstructive cardiomyopathy (HOCM) in a local hospital, was transferred to our center because of anterior chest pain and diagnosed with acute myocardial infarction (MI). Coronary angiography showed total occlusion of the mid-left anterior descending, and flow was restored after endovascular thrombectomy. An autopsy was performed after she died on hospital day 6. At autopsy, there was no significant stenosis in this vessel and the absence of plaque rupture was confirmed. Likewise, it was unclear asymmetric hypertrophy at autopsy, it could not deny that a sigmoid deformity of the basal septum occurs in elderly patients and can mimic the asymmetric septal hypertrophy of hypertrophic cardiomyopathy. MI was thought to be caused by coronary spasm or squeezing in HOCM-like heart. Therefore, it may be necessary antithrombosis therapy in HOCM-like patients with no history of paroxysmal atrial fibrillation.

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes.

Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.

Much caution does no harm! Organophosphate poisoning often causes pancreatitis.

Organophosphate poisoning (OP) results in various poisoning symptoms due to its strong inhibitory effect on cholinesterase. One of the occasional complications of OP is pancreatitis. A 62-year-old woman drank alcohol and went home at midnight. After she quarreled with her husband and drank 100 ml of malathion, a parasympathomimetic organophosphate that binds irreversibly to cholinesterase, she was transported to our hospital in an ambulance. On admission, activated charcoal, magnesium citrate, and pralidoxime methiodide (PAM) were used for decontamination after gastric lavage. Abdominal computed tomography detected edema of the small intestine and colon with doubtful bowel ischemia, and acute pancreatitis was suspected. Arterial blood gas analysis revealed severe lactic acidosis. The Ranson score was 6 and the APACHE II (Acute Physiology and Chronic Health Evaluation) score was 14. Based on these findings, severe acute pancreatitis was diagnosed. One day after admission, hemodiafiltration (HDF) was started for the treatment of acute pancreatitis. On the third hospital day, OP symptoms were exacerbated, with muscarinic manifestations including bradycardia and hypersalivation and decreased plasma cholinesterase activity. Atropine was given and the symptoms improved. The patient's general condition including hemodynamic status improved. Pancreatitis was attenuated by 5 days of HDF. Ultimately, it took 14 days for acute pancreatitis to improve, and the patient discharged on hospital day 32. Generally, acute pancreatitis associated with OP is mild. In fact, one previous report showed that the influence of organophosphates on the pancreas disappears in approximately 72 hours, and complicated acute pancreatitis often improves in 4-5 days. However, it was necessary to treat pancreatitis for more than 2 weeks in this case. Therefore, organophosphate-associated pancreatitis due to malathion is more severe. Although OP sometime causes severe necrotic pancreatitis or pancreatic pseudocysts, it was thought that the present patient had a good clinical course without these complications due to the appropriate intensive care including nafamostat, antibiotics, fluid resuscitation, and HDF. In conclusion, OP-associated pancreatitis requires careful assessment because it may be aggravated, as in this case.

Postinfarction Cardiac Remodeling Proceeds Normally in Granulocyte Colony-Stimulating Factor Knockout Mice.

Treatment with granulocyte colony-stimulating factor (G-CSF) reportedly mitigates postinfarction cardiac remodeling and dysfunction. We herein examined the effects of G-CSF knockout (G-CSF-KO) on the postinfarction remodeling process in the hearts of mice. Unexpectedly, the acute infarct size 24 hours after ligation was similar in the two groups. At the chronic stage (4 weeks later), there was no difference in the left ventricular dimension, left ventricular function, or histological findings, including vascular density, between the two groups. In addition, expression of vascular endothelial growth factor (VEGF) was markedly up-regulated in hearts from G-CSF-KO mice, compared with wild-type mice. Microarray failed in detecting up-regulation of VEGF mRNA, whereas G-CSF administration significantly decreased myocardial VEGF expression in mice, indicating that G-CSF post-transcriptionally down-regulates VEGF expression. When G-CSF-KO mice were treated with an anti-VEGF antibody (bevacizumab), cardiac remodeling was significantly aggravated, with thinning of the infarct wall and reduction of the cellular component, including blood vessels. In the granulation tissue of bevacizumab-treated hearts 4 days after infarction, vascular development was scarce, with reduced cell proliferation and increased apoptosis, which likely contributed to the infarct wall thinning and the resultant increase in wall stress and cardiac remodeling at the chronic stage. In conclusion, overexpression of VEGF may compensate for the G-CSF deficit through preservation of cellular components, including blood vessels, in the postinfarction heart.

Phenotype and physiological significance of the endocardial smooth muscle cells in human failing hearts.

BACKGROUND: Extravascular smooth muscle cells are often observed in the endocardium of human failing hearts. Here, we characterized the phenotype of those cells and investigated their physiological significance. METHODS AND RESULTS: We examined left ventricular biopsy specimens obtained from 44 patients with dilated cardiomyopathy and 6 nonfailing hearts. In Masson trichrome-stained histological preparations, bundles of smooth muscle cells were seen localized in the endocardium in 23 of the 44 specimens (none of the 6 controls). These cells were immunopositive for α-smooth muscle actin, type 2 smooth muscle myosin, desmin, and calponin, but were negative for embryonic smooth muscle myosin, vimentin, fibronectin, and periostin. This profile is indicative of a late differentiation (contractile) smooth muscle phenotype. Electron microscopy confirmed that phenotype, revealing the cells to contain abundant myofilaments with dense bodies but little rough endoplasmic reticulum or Golgi apparatus. In the endocardial smooth muscle-positive group, the left ventricular end-systolic volume index (73±34 versus 105±50 mL/m(2); P=0.021), left ventricular peak wall stress (164±47 versus 196±43 dynes 10(3)/cm(2); P=0.023), and left ventricular end-systolic meridional wall stress (97±38 versus 121±37 dynes 10(3)/cm(2); P=0.036) were all significantly smaller, and the ejection fraction was larger (41±8.8 versus 33±9.3%; P=0.005) than in the endocardial smooth muscle-negative group. However, no histological parameters differed between the 2 groups. CONCLUSIONS: Endocardial smooth muscle cell bundles in hearts with dilated cardiomyopathy exhibit a mature contractile phenotype and may play a compensatory role mitigating heart failure by reducing left ventricular wall stress and systolic dysfunction.

Restriction of food intake prevents postinfarction heart failure by enhancing autophagy in the surviving cardiomyocytes.

We investigated the effect of restriction of food intake, a potent inducer of autophagy, on postinfarction cardiac remodeling and dysfunction. Myocardial infarction was induced in mice by left coronary artery ligation. At 1 week after infarction, mice were randomly divided into four groups: the control group was fed ad libitum (100%); the food restriction (FR) groups were fed 80%, 60%, or 40% of the mean amount of food consumed by the control mice. After 2 weeks on the respective diets, left ventricular dilatation and hypofunction were apparent in the control group, but both parameters were significantly mitigated in the FR groups, with the 60% FR group showing the strongest therapeutic effect. Cardiomyocyte autophagy was strongly activated in the FR groups, as indicated by up-regulation of microtubule-associated protein 1 light chain 3-II, autophagosome formation, and myocardial ATP content. Chloroquine, an autophagy inhibitor, completely canceled the therapeutic effect of FR. This negative effect was associated with reduced activation of AMP-activated protein kinase and of ULK1 (a homolog of yeast Atg1), both of which were enhanced in hearts from the FR group. In vitro, the AMP-activated protein kinase inhibitor compound C suppressed glucose depletion-induced autophagy in cardiomyocytes, but did not influence activity of chloroquine. Our findings imply that a dietary protocol with FR could be a preventive strategy against postinfarction heart failure.

Resveratrol reverses remodeling in hearts with large, old myocardial infarctions through enhanced autophagy-activating AMP kinase pathway.

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.

Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes.

AIMS: Active autophagy has recently been reported in doxorubicin-induced cardiotoxicity; here we investigated its pathophysiological role. METHODS AND RESULTS: Acute cardiotoxicity was induced in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice by administering two intraperitoneal injections of 10 mg/kg doxorubicin with a 3 day interval. A starvation group was deprived of food for 48 h before each injection to induce autophagy in advance. Doxorubicin treatment caused left ventricular dilatation and dysfunction within 6 days. Cardiomyocyte autophagy appeared to be activated in the doxorubicin group, based on LC3, p62, and cathepsin D expression, while it seemed somewhat diminished by starvation prior to doxorubicin treatment. Unexpectedly, however, myocardial ATP levels were reduced in the doxorubicin group, and this reduction was prevented by earlier starvation. Electron microscopy revealed that the autophagic process was indeed initiated in the doxorubicin group, as shown by the increased lysosomes, but was not completed, i.e. autophagolysosome formation was rare. Starvation prior to doxorubicin treatment partly restored autophagosome formation towards control levels. Autophagic flux assays in both in vivo and in vitro models confirmed that doxorubicin impairs completion of the autophagic process in cardiomyocytes. The activities of both AMP-activated protein kinase and the autophagy-initiating kinase unc-51-like kinase 1 (ULK1) were found to be decreased by doxorubicin, and these were restored by prior starvation. CONCLUSION: Prior starvation mitigates acute doxorubicin cardiotoxicity; the underlying mechanism may be, at least in part, restoration and further augmentation of myocardial autophagy, which is impaired by doxorubicin, probably through inactivation of AMP-activated protein kinase and ULK1.

Asialoerythropoietin, a nonerythropoietic derivative of erythropoietin, displays broad anti-heart failure activity.

BACKGROUND: We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies. METHODS AND RESULTS: Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 µg/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old δ-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner. CONCLUSIONS: The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies.