Mesenchymal stem cells may alleviate angiotensin II-induced myocardial fibrosis and hypertrophy by upregulating SFRS3 expression.

INTRODUCTION AND OBJECTIVES: The development of cardiac fibrosis (CF) and hypertrophy (CH) can lead to heart failure. Mesenchymal stem cells (MSCs) have shown promise in treating cardiac diseases. However, the relationship between MSCs and splicing factor arginine/serine rich-3 (SFRS3) remains unclear. In this study, our objectives are to investigate the effect of MSCs on SFRS3 expression, and their impact on CF and CH. Additionally, we aim to explore the function of the overexpression of SFRS3 in angiotensin II (Ang II)-treated cardiac fibroblasts (CFBs) and cardiac myocytes (CMCs). METHODS: Rat cardiac fibroblasts (rCFBs) or rat cardiac myocytes (rCMCs) were co-cultured with rat MSCs (rMSCs). The function of SFRS3 in Ang II-induced rCFBs and rCMCs was studied by overexpressing SFRS3 in these cells, both with and without the presence of rMSCs. We assessed the expression of SFRS3 and evaluated the cell cycle, proliferation and apoptosis of rCFBs and rCMCs. We also measured the levels of interleukin (IL)-ß, IL-6 and tumor necrosis factor (TNF)-α and assessed the degree of fibrosis in rCFBs and hypertrophy in rCMCs. RESULTS: rMSCs induced SFRS3 expression and promoted cell cycle, proliferation, while reducing apoptosis of Ang II-treated rCFBs and rCMCs. Co-culture of rMSCs with these cells also repressed cytokine production and mitigated the fibrosis of rCFBs, as well as hypertrophy of rCMCs triggered by Ang II. Overexpression of SFRS3 in the rCFBs and rCMCs yielded identical effects to rMSC co-culture. CONCLUSION: MSCs may alleviate Ang II-induced cardiac fibrosis and cardiomyocyte hypertrophy by increasing SFRS3 expression in vitro.

Correlation between blood albumin and hospital death and long-term death in ICU patients with heart failure: data from the medical information mart for intensive care III database.

BACKGROUND: Elevated circulating levels of albumin (ALB) are often associated with improved prognosis in patients with heart failure (HF). However, investigations of its association with hospital death and long-term death in HF patients in the intensive care unit (ICU) are limited. AIM: We examined whether increased blood ALB levels (first value at admission and maximum and minimum values in the ICU) were related to a greater risk of hospital death and long-term death in ICU patients with HF. METHODS: For the first time, we analyzed 4084 ICU patients with HF admitted to the ICU in The Medical Information Mart for Intensive Care III (MIMIC-III) database. RESULTS: Among 4084 HF patients, 774 (18.95%), 1056 (25.86%) and 1720 (42.12%) died in the hospital, within 30 days and 1 year, respectively. We conducted a logistic regression analysis and found significant inverse associations between blood ALB concentration and risk of hospital death, 30-day death and 1-year death when the covariates including age, sex, myocardial infarction (MI), hypertension, diabetes, valvular diseases, atrial fibrillation, stroke and chronic kidney disease (CKD) were adjusted. We additionally used a smooth curve for univariate analysis to establish an association between blood ALB concentration and death risk. Surprisingly, we observed U-shaped correlations between blood ALB concentration and hospital mortality, 30-day mortality and 1-year mortality. We found that the "inflection point" for the blood ALB concentration at the lowest risk of death was 3.5 g/dL. We further observed that a higher blood ALB concentration (albumin-max) did not contribute to a reduced risk of death (hospital death, 30-day death and 1-year death) in HF patients with an albumin concentration >3.5 g/dL. CONCLUSIONS: A lower blood ALB concentration contributed to a greater risk of hospital death and long-term death in HF patients admitted to the ICU, further suggesting that nutritional support in the ICU is highly important for improving the short-term and long-term mortality of HF patients. However, in HF patients without hypoproteinaemia (>3.5 g/dL), the impact of increased serum ALB on patient prognosis still needs to be demonstrated.

The association between blood albumin level and cardiovascular complications and mortality risk in ICU patients with CKD.

BACKGROUND: Studies involving the association of blood albumin with prognosis in patients with chronic kidney disease (CKD) during intensive care unit (ICU) were scarce. AIM: We investigated whether reduced blood albumin level independently associated with an increased risk of cardiovascular (CV) complications and 1-year mortality risk in ICU patients with CKD. METHODS: The Medical Information Mart for Intensive Care III (MIMIC-III) database was used. Disease diagnosis and death information among a number of 925 ICU patients with CKD, who have been measured for blood biochemistry, were recorded. Here, multivariable logistic regression Models were structured to evaluate the associations between blood albumin levels (first value on admission, maximum and minimum value during ICU) and risks for CV complications and 1-year mortality among these CKD patients. RESULTS: In 925 CKD patients, the number of CV complication with heart failure (HF), myocardial infarction (MI) or stroke was 470 (50.8%). 406 (43.9%) patients were dead during the follow-up of 1 year after patients were discharged. Our smooth curve results suggested a curvilinear relation on association between blood albumin level and risk of CV complications. The "inflection point" of blood albumin level that patients were at highest risk of CV complications was 3.4 g/dL. The almost linear relationship with a downward trend was observed on the association between blood albumin level and 1-year mortality risk. We found that reduced blood albumin level contributed to lower risk for CV complications and higher risk for 1-year mortality respectively when blood albumin levels in CKD patients were below 3.4 g/dL. Additionally, albumin therapy had an obvious modifying effect on the independent association, suggesting a possible improved effect of albumin therapy on risk of CV complications and 1-year mortality risk in these CKD patients. CONCLUSIONS: Our study reported that reduced blood albumin levels in CKD patients during ICU were related to lower risk for CV complications and increased risk of 1-year mortality.

Neutrophil Gelatinase-Associated Lipocalin Contributes to Increased Risk of Cardiovascular Death After Acute Coronary Syndrome.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to reflect early renal dysfunction. We investigated the predictive significance of serum NGAL in predicting cardiovascular (CV) death in an old-age population with coronary heart disease (CHD). METHODS: In total, 633 CHD patients with a stable clinical condition were enrolled. The measurements of serum NGAL and other laboratory indices were performed within 24 hours after admission. Adjusted analysis was used to assess relationships between serum NGAL and CV death during the 10-year follow-up period. RESULTS: Multivariate logistic regression analysis demonstrated that elevated NGAL levels were related to a higher prevalence of CV disease history [quartile 4, 2.41 (1.60-4.59), P-trend <0.001]. The Kaplan-Meier curve indicated that patients with high NGAL levels tended to have a higher rate of CV death than patients with low NGAL levels. A multivariate Cox model suggested that increased levels of NGAL were independently linked with elevated risk of CV death (HR=2.62, 95% CI 1.51-4.96, P<0.001) during the 10-year follow-up period, after adjusting for related confounding factors using sensitivity analysis. Furthermore, the receiver operating characteristics (ROC) curve demonstrated that serum NGAL (AUC=0.917, 95% CI 0.895-0.940, P<0.001) had an ideal predictive value in predicting CV death. CONCLUSION: Serum levels of NGAL were elevated in patients with CHD and may be a new parameter that could independently predict CV death in these patients, which may strengthen its potential application in clinical practice.

The Relationship Between Interleukin-4 Levels and Cardiovascular Events in Patients with Chronic Kidney Disease.

BACKGROUND: Cardiovascular diseases (CVDs) are the main cause of death in patients with chronic kidney disease (CKD). Interleukin-4 (IL-4) is considered an inflammatory cytokine. However, few studies have investigated the association between serum IL-4 and cardiovascular events in CKD. This study investigated whether serum IL-4 levels were associated with an increased risk of cardiovascular (CV) events in patients with CKD. PATIENTS AND METHODS: A total of 302 patients with stage 1-5 CKD were followed up for a mean of 32 (range=4-36) months for end points (CV events). Serum IL-4 levels were measured at baseline. The independent relationship between serum IL-4 and the risk of CV events was assessed with multivariate Cox regression analysis. RESULTS: The average age of this cohort (N=302) was 65.4 years. A total of 69.9% of them were male. CV events numbered 41 (13.6%) during the follow-up period. The Kaplan-Meier analysis showed that the rate of CV events was higher in patients with CKD with IL-4 levels above the mean (126.2 pg/mL) than in those with IL-4 levels below the mean. The multivariate Cox proportional hazard analysis revealed that serum IL-4 (HR=1.650, 95% CI 1.266-2.210, P<0.001) was associated with CV events in these patients with CKD. Sensitivity analysis showed that the association between serum IL-4 and CV events was not affected by the use of anti-inflammatory medication. The significant association between higher IL-4 levels and increased risk of CV events existed in patients with CKD3-5 but not in patients with CKD1-2 by using the stratified analysis. CONCLUSION: Higher serum IL-4 levels were associated with an increased risk of CV events during follow-up. Elevated serum IL-4 levels may help clinicians predict early CV events in patients with CKD.

Neuroventilatory efficiency and extubation readiness in critically ill patients.

INTRODUCTION: Based on the hypothesis that failure of weaning from mechanical ventilation is caused by respiratory demand exceeding the capacity of the respiratory muscles, we evaluated whether extubation failure could be characterized by increased respiratory drive and impaired efficiency to generate inspiratory pressure and ventilation. METHODS: Airway pressure, flow, volume, breathing frequency, and diaphragm electrical activity were measured in a heterogeneous group of patients deemed ready for a spontaneous breathing trial. Efficiency to convert neuromuscular activity into inspiratory pressure was calculated as the ratio of negative airway pressure and diaphragm electrical activity during an inspiratory occlusion. Efficiency to convert neuromuscular activity into volume was calculated as the ratio of the tidal volume to diaphragm electrical activity. All variables were obtained during a 30-minute spontaneous breathing trial on continuous positive airway pressure (CPAP) of 5 cm H2O and compared between patients for whom extubation succeeded with those for whom either the spontaneous breathing trial failed or for those who passed, but then the extubation failed. RESULTS: Of 52 patients enrolled in the study, 35 (67.3%) were successfully extubated, and 17 (32.7%) were not. Patients for whom it failed had higher diaphragm electrical activity (48%; P < 0.001) and a lower efficiency to convert neuromuscular activity into inspiratory pressure and tidal volume (40% (P < 0.001) and 53% (P < 0.001)), respectively. Neuroventilatory efficiency demonstrated the greatest predictability for weaning success. CONCLUSIONS: This study shows that a mixed group of critically ill patients for whom weaning fails have increased neural respiratory drive and impaired ability to convert neuromuscular activity into tidal ventilation, in part because of diaphragm weakness. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01065428.

[A pilot study of diaphragmatic function evaluated as predictors of weaning in chronic obstructive pulmonary disease patients].

OBJECTIVE: To evaluate the predictive performance of neuro-mechanical coupling (NMC) and neuro-ventilatory coupling (NVC) in the weaning outcome in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sixteen patients were enrolled when the criteria for their first spontaneous breathing trial (SBT) was met. A 30-minute SBT was attempted, with the measurement of electrical activity of the diaphragm (Edi), NMC, NVC, NVC × NMC, index of rapid shallow breathing (f/Vt), airway occlusion pressure (P(0.1)) and f/Vt × P(0.1) at 0, 5 and 30 min. The receiver operating characteristic (ROC) curve was calculated to evaluate the predictive performance of each index. RESULTS: Successful weaning (S group) was observed in 6 patients while weaning failure (F group) in 10 patients. (1) The predictive capacity of Edi: at 30 min of SBT, Edi showed higher values in the F group (P < 0.05), the area under the ROC curves (AUC) was 0.817(P < 0.05). (2) The predictive capacity of NVC and NMC: at 5, 30 min of SBT, NVC and NMC showed higher values in the S group (P < 0.05); at 30 min of SBT NVC presented the largest AUC than any other time of SBT (0.822, P < 0.05), while the AUC of NMC was 0.800(P > 0.05). (3) The predictive capacity of NVC × NMC: at 30 min of SBT, the AUC of NVC × NMC was larger than NVC (0.864, P < 0.05), showing greater sensitivity (100.0%) and specificity (83.3%). (4) The predictive capacity of f/Vt and P(0.1): f/Vt and f/Vt × P(0.1) presented poor predictive performance in the failed patients. CONCLUSIONS: Edi, NVC and NVC × NMC were good predictor for the weaning outcome in patients with COPD.

[Effects of neurally adjusted ventilatory assist on subject-ventilator synchrony in rabbits with acute respiratory distress syndrome].

OBJECTIVE: To observe the effects of neurally adjusted ventilatory assist (NAVA) on subject-ventilator synchrony in rabbits with acute respiratory distress syndrome (ARDS). METHODS: The rabbit model of ARDS was induced by intratracheal infusion of hydrochloric acid. After sufficient recruitment, the rabbits were randomly divided into 2 groups: pressure support ventilation (PSV) group and NAVA group. The parameters of subject-ventilator synchrony such as ventilation trigger, ventilation switching and magnitude of assist were observed at 0, 1, 2, 3 h respectively. RESULTS: (1) Ventilation trigger: 1) trigger delay: the trigger delay in the NAVA group were markedly lower than the PSV group at 0, 1, 2, 3 h (P < 0.05); as ventilation time elapsed, the trigger delay changed neither in NAVA nor in PSV group (P > 0.05). 2) Ineffective trigger index: the ineffective trigger index was 17.7% ± 13.7% in the PSV group. While all neural efforts were trigger, there was no ineffective trigger observed in the NAVA group. (2) Off-cycle delay: the off-cycle delay were significantly lower in the PSV group than that in the NAVA group at 0, 1, 2, 3 h (P < 0.05); as the ventilation time elapsed, the off-cycle delay changed neither in the NAVA group nor in the PSV group (P > 0.05). (3) Magnitude of assist: in the NAVA group, peak EAdi and peak pressure were markedly correlated (determination coefficient 0.86 ± 0.07, P < 0.05). But pressure delivery during the PSV group was not correlated with EAdi (P > 0.05). CONCLUSION: As compared with PSV, NAVA can improve subject-ventilator synchrony in rabbits with ARDS.

[Effects of neurally adjusted ventilatory assist on prevention of ventilator-induced diaphragmatic dysfunction in acute respiratory distress syndrome rabbits].

OBJECTIVE: To evaluate the effect of neurally adjusted ventilatory assist (NAVA) on prevention of ventilator-induced diaphragmatic dysfunction (VIDD) in ARDS rabbits. METHODS: Twenty New Zealand white rabbits were randomly divided into 4 groups: (1) control group (n = 5); (2) Volume control (VC) group (n = 5); (3) Pressure support (PSV) group (n = 5); (4) NAVA group (n = 5). In VC, PSV and NAVA groups, the rabbits were killed and the diaphragm was removed after 4 hours of ventilation. Animals in the control group were not mechanically ventilated, and the diaphragm was also removed immediately after anesthetizing. In all rabbits, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) of diaphragm were measured. Structure of diaphragm was observed by light microscope, electron microscope, constituent ratio and mean cross-sectional area (CSA) of diaphragm fiber. RESULTS: (1) MDA: Compared with the control [(0.15 ± 0.06) nmol/mg], PSV group [(0.30 ± 0.11) nmol/mg], there was no significant difference in MDA of diaphragm in NAVA group [(0.28 ± 0.19) nmol/mg] (F = 2.730, P > 0.05). MDA in VC group [(0.40 ± 0.16) nmol/mg] was significantly higher than the control group (P < 0.05). (2) SOD: Compared with control [(111 ± 12) U/mg], PSV group [(93 ± 4) U/mg], there was no significant difference in SOD of diaphragm in NAVA group [(94 ± 9) U/mg] (F = 4.422, P > 0.05). SOD in VC group [(80 ± 21) U/mg] was significantly lower than the control group (P < 0.05). (3) GSH: Compared with control [(5.3 ± 1.0) mg/g] and PSV group [(4.5 ± 1.2) mg/g], there was no significant difference in GSH of diaphragm in NAVA group [(5.6 ± 1.0) mg/g] (F = 3.001, P > 0.05). GSH in VC group [(3.3 ± 1.7) mg/g] is significantly lower than control and NAVA groups (P < 0.05). (4) Light microscope: In VC group, many changes were observed in the muscle, such as myelofibrosis, necrosis, and some of muscle fibers became atrophy, but these were no obvious changes of pathological structure in control, PSV or NAVA groups. (5) Electron microscope: In control, PSV and NAVA groups, the ultrastructure of diaphragm was normal. Different from the above 3 groups, some abnormal ultrastructure was observed in VC group, including disrupted myofibrils, swollen mitochondria. (6) CSA of diaphragm fiber: Compared with control and PSV group, there was no significant difference in CSA of diaphragm fiber in NAVA group (P > 0.05); The CSA of type II fibers in VC group was markedly lower than control group (P < 0.05). CONCLUSIONS: Compared with volume control ventilation, NAVA may mitigate diaphragmatic oxidative stress, atrophy and injury, and prevent VIDD better than VC.

Effects of pulmonary stretch reflex on lung injury in rabbits with acute respiratory distress syndrome.

BACKGROUND: Pulmonary stretch reflex plays an important role in regulation of respiratory movement. This study aimed to evaluate the effect of pulmonary stretch reflex on lung injury in rabbits with acute respiratory distress syndrome (ARDS). METHODS: ARDS rabbits were given intratracheal infusion of hydrochloric acid and ventilated with neurally adjusted ventilatory assistance (NAVA) with a tidal volume (VT) of 6 mL/kg and the electrical activity of diaphragm (EAdi)-determined positive end expiratory pressure. After isolation of the bilateral vagus nerve trunk, the rabbits were randomized into two groups: sham operation (SHAM) group (n=5) and bilateral vagotomy (VAG) group (n=5). Gas exchange and respiratory mechanics were detected at baseline, after lung injury and 1, 2, and 3 hours after ventilation respectively. Pulmonary permeability index, pathological changes and inflammatory response were also measured. RESULTS: Compared with the SHAM group, PaO2/FiO2 in the VAG group decreased significantly 2 and 3 hours after ventilation (P<0.05). There was no significant difference in PaCO2 between the SHAM and VAG groups (P>0.05), and the VAG group had a high VT, peak pressure (Ppeak), and mean pressure (Pm) compared with the SHAM group 1, 2, 3 hours after ventilation (P<0.05). Compared to the SHAM group, dead space fraction (VD/VT) and respiratory system elastance (Ers) in the VAG group increased (P<0.05) and static pulmonary compliance (Cst) decreased markedly (P<0.05) after ventilation for 3 hours. Lung wet/dry weight ratio (W/D) (8.4±1.2 vs. 6.6±1.0), lung injury score (6.3±1.8 vs. 3.8±1.3), tumor necrosis factor-α (TNF-α) (779±372 pg/mL vs. 355±130 pg/mL) and interleukin-8 (IL-8) (169±21 pg/mL vs. 118±17 pg/mL) increased significantly in the VAG group compared with the SHAM group (P<0.05). CONCLUSION: Lung injury is aggravated after bilateral vagotomy, demonstrating that pulmonary stretch reflex may have protective effect on the lung.

[Effects of electrical activity of diaphragm on the titration of positive end-expiratory pressure in a model of acute respiratory distress syndrome].

OBJECTIVE: To explore the relationship of electrical activity of diaphragm (EAdi) and positive end-expiratory pressure (PEEP) in a rabbit model of acute respiratory distress syndrome (ARDS). METHODS: The rabbit model of ARDS was induced by an intratracheal infusion of hydrochloric acid. After a sufficient amount of recruitment maneuvers (RM), the level: the PEEP levels were (10.4 ± 1.0) cm H2O in EAdi group and (9.7 ± 2.1) cm H2O in rabbits were divided into 2 groups: (1) PEEP titration with EAdi (EAdi group); (2) PEEP titration with maximum oxygenation (maximum oxygenation group). The tidal volume was 6 ml/kg in 2 groups. Pulmonary mechanics, gas exchange and hemodynamic were observed in two groups at baseline, after lung injury and ventilation 1, 2, 3 h respectively. RESULTS: (1) PEEP maximum oxygenation group. There was no significant difference between two groups (P > 0.05). (2) Pulmonary mechanics:there was no significant difference in peak pressure (Ppeak) and mean pressure (Pm) between two groups at ventilation 1, 2, 3 h (P > 0.05). (3) Gas exchange: at ventilation 1, 2, 3 h, the oxygenation index (PaO2/FiO2) in EAdi group was higher than that of after lung injury (P < 0.05) and there was no significant difference in PaO2/FiO2 and partial pressure of arterial carbon dioxide (PaCO2) between two groups (P > 0.05). (4) Hemodynamic: at ventilation 1, 2, 3 h, the heart rate (HR) and mean artery pressure (MAP) in EAdi group had no significant differences with baseline, after lung injury and maximum oxygenation group (P > 0.05). CONCLUSION: EAdi may be an ideal method for PEEP titration at post-RM in an ARDS model.

[Effects of neurally adjusted ventilatory assist on patient-ventilator synchrony in patients with acute respiratory distress syndrome].

OBJECTIVE: To observe the effect of neurally adjusted ventilatory assist (NAVA) on patient-ventilator synchrony in patients with acute respiratory distress syndrome (ARDS). METHODS: Eighteen patients with ARDS were enrolled in the study. Each patient underwent both an incremental pressure support ventilation (PSV) and NAVA run randomly in 4 steps. The PSV level was gradually increased 5 cm H2O (1 cm H2O = 0.098 kPa) every 5 min from 5 cm H2O until to 20 cm H2O. Incremental NAVA was individually set in steps of 0.2 - 1.0 cm H2O/microV every 5 min to determine the NAVA level predicted to give an airway pressure in each step equivalent to that of PSV. Parameters in patient-ventilator synchrony such as ventilation trigger, ventilation switching and ventilation maintenance were observed at the same time during PSV(PSV1-PSV4) and NAVA(NAVA1-NAVA4). RESULTS: (1) Ventilation trigger:(1) trigger delay: with progressive increases in PSV, the trigger delays increased significantly (P < 0.05). With increasing NAVA, the trigger delay did not increase significantly (P > 0.05) and each of them was shorter than that of PSV in each corresponding step (P < 0.05). (2) Ineffective trigger: At PSV1, the ineffective triggers accounted for 2. 3% of the neural respiratory rate (NRR), but the ineffective triggers added up to 22% in PSV4 significantly (P < 0.05). All neural efforts were triggered and there were not ineffective triggers at all level in NAVA. (2) Off cycle delay: the off cycle delays in PSV2 - PSV4 increased significantly when compared with PSV1 (P < 0.05). With increasing NAVA, the off cycle delays did not increase significantly (P > 0.05) and each of them was shorter than that of PSV in each corresponding step (P < 0.05). (3) Magnitude of assist [tidal volume (VT)]: The VT [(361 +/- 69) ml] in NAVA1 was equivalent to the VT[(361 +/- 121) ml] in PSV1(P > 0.05). The VT [(417 +/- 71) ml, (427 +/- 80) ml, respectively] in NAVA3-NAVA4 was significantly lower than the VT[(604 +/- 141) ml, (675 +/- 108) ml, respectively] in PSV3-PSV4 (P < 0.05). (4)Respiratory muscle loading: Increasing NAVA and PSV level reduced the magnitude of diaphragm electrical activity (EAdi) and the pressure-time products of esophagus (PTPes) (P < 0.05), but there was no significant difference in each corresponding step of PSV and NAVA(P > 0.05). CONCLUSIONS: Compared with PSV, the ventilation cycle and the magnitude of assist in NAVA matched the patient's breathing pattern. NAVA improved patient-ventilator synchrony in patients with ARDS.