LncRNA MALAT1-targeting antisense oligonucleotide ameliorates the AngII-induced vascular smooth muscle cell proliferation and migration via Nrf2/GPX4 antioxidant pathway.

ABSTRACT: The high level of oxidative stress induced by angiotensin II (AngII) is the main pathophysiological process that promotes the proliferation and migration of vascular smooth muscle cells (VSMCs) and induces vascular remodeling. LncRNA Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) has been determined to play an important role in the modulation of oxidative stress and the development of cardiovascular diseases. Nevertheless, the function and underlying mechanism of MALAT1 in restenosis induced by hypertensive angioplasty remain unclear. AngII increased the expression of MALAT1 in VSMCs. We found that anti-sense oligonucleotide lncRNA MALAT1 (ASO-MALAT1) could inhibit AngII induced reactive oxygen species (ROS) production and VSMCs proliferation and migration by inducing the expression of glutathione peroxidase 4 (GPX4), which can be reversed by siRNA-GPX4. And GPX4 overexpression can inhibit the proliferation and migration of VSMCs induced by AngII. In addition, we found that the process by which MALAT1 knockdown induces GPX4 expression involves nuclear factor erythrocyte 2 related factor 2 (Nrf2). Overexpression of Nrf2 can increase the expression of GPX4, and down-regulation of GPX4 by ML385 (Nrf2 inhibitor) blocked the protective effect of ASO-MALAT1 on AngII-induced proliferation and migration of VSMCs. Ferrostatin-1 (Fer-1, ip 5mg/kg per day for 2 weeks), a GPX4 agonist, significantly inhibited neointimal formation in spontaneously hypertensive rat (SHR) by the inhibition of oxidative stress. In conclusion, these data imply that ASO-MALAT1 suppresses the AngII-induced oxidative stress, proliferation and migration of VSMCs by activating Nrf2/GPX4 antioxidant signaling. GPX4 may be a potential target for the therapeutic intervention of hypertensive vascular restenosis.

Random forest for prediction of contrast-induced nephropathy following coronary angiography.

The majority of prediction models for contrast-induced nephropathy (CIN) have moderate performance. Therefore, we aimed to develop a better pre-procedural prediction tool for CIN following contemporary percutaneous coronary intervention (PCI) or coronary angiography (CAG). A total of 3469 patients undergoing PCI/CAG between January 2010 and December 2013 were randomly divided into a training (n = 2428, 70%) and validation data-sets (n = 1041, 30%). Random forest full models were developed using 40 pre-procedural variables, of which 13 variables were selected for a reduced CIN model. CIN developed in 78 (3.21%) and 37 of patients (3.54%) in the training and validation datasets, respectively. In the validation dataset, the full and reduced models demonstrated improved discrimination over classic Mehran, ACEF CIN risk scores (AUC 0.842 and 0.825 over 0.762 and 0.701, respectively, all P < 0.05) and common estimated glomerular filtration rate. Compared to that for the Mehran risk score model, the full and reduced models had significantly improved fit based on the net reclassification improvement (all P < 0.001) and integrated discrimination improvement (P = 0.001, 0.028, respectively). Using the above models, 2462 (66.7%), 661, and 346 patients were categorized into low (< 1%), moderate (1% to 7%), and high (> 7%) risk groups, respectively. Our pre-procedural CIN risk prediction algorithm (http://cincalc.com) demonstrated good discriminative ability and was well calibrated when validated. Two-thirds of the patients were at low CIN risk, probably needing less peri-procedural preventive strategy; however, the discriminative ability of CIN risk requires further external validation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400295.

Simple pre-procedure risk stratification tool for contrast-induced nephropathy.

BACKGROUND: A few simple and pre-procedural risk models have been developed for predicting contrast-induced nephropathy (CIN), which allow for early administration of preventative strategies before coronary angiography (CAG). The study aims to develop and validate simple pre-procedure tools for predicting risk of CIN following CAG. METHODS: We retrospectively analyzed the data from 3,469 consecutive patients undergoing CAG, who were randomly assigned to a development dataset (n=2,313) and a validation dataset (n=1,156). CIN was defined as an increase in serum creatinine (SCr) ≥0.5 mg/dL from baseline within 72 hours after CAG. Multivariate logistic regression was applied to identify independent predictors of CIN to develop risk models. The possible predictors included age >75 years, hypotension, acute myocardial infarction (AMI), SCr ≥1.5 mg/dL, and congestive heart failure (CHF). RESULTS: The incidences of CIN were 3.20% and 3.55% in the training and validation dataset respectively. Compared to classical Mehran' and ACEF CIN risk score, the new score across the validation dataset exhibited similar discrimination and predictive ability on CIN (c-statistic: 0.829, 0.832, 0.812 respectively) and in-hospital mortality (c-statistic: 0.909, 0.937, 0.866 respectively) (all P>0.05). CONCLUSIONS: The easy-to-use pre-procedural prediction model only containing 5 factors had similar predictive ability on CIN and mortality.

Novel risk model for predicting acute adverse drug reactions following cardiac catheterization from TRUST study (The Safety and toleRability of UltraviSt in Patients Undergoing Cardiac CaTheterization).

BACKGROUND: Acute drug reactions (ADRs) are common complications of contrast administration following cardiac catheterization. Serious reactions may be life threatening. However, few risk models for predicting ADRs exist. The study aims to develop a novel tool for predicting the risk of ADRs [occurring within 1 hour in patients undergoing coronary angiography or percutaneous coronary intervention (PCI)]. METHODS: A total of 17,139 consecutive patients included in the TRUST study were randomly (2:1) assigned to a development data set (n=11,426) or a validation data set (n=5,713). Multivariate logistic regression was applied to identify independent predictors of contrast-induced nephropathy (CIN), including age, contrast dose, premedication, and prehydration. The performance of our model was assessed using the c-statistic for discrimination and the Hosmer-Lemeshow test for calibration. RESULTS: The overall incidence of ADRs was 42 (0.37%) in the development data set: 0.09% in the low-risk category (score: 0-2), 0.36% in the moderate-risk category (score: 3-4), and 1.78% in the high-risk category (score ≥5). The risk score across the subgroup of the study population exhibited good discrimination and predictive ability for ADRs (c-statistic: 0.694). Meanwhile, the calibration was also demonstrated to be accurate by the Hosmer-Lemeshow goodness-of-fit test (P=0.305). CONCLUSIONS: Our data showed that our simple risk model showed good discrimination and predictive ability of ADRs following cardiac catheterization.

Procalcitonin could be a reliable marker in differential diagnosis of post-implantation syndrome and infection after percutaneous endovascular aortic repair.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is an emerging treatment modality, which has been rapidly embraced by clinicians treating thoracic aortic disease. However, the clinical manifestations of systemic inflammatory response after TEVAR as post-implantation syndrome (PIS) resemble the perioperative infection. This study aimed to evaluate changes and diagnostic value of procalcitonin (PCT) and other traditional inflammatory markers for infections after TEVAR. METHODS: We conducted a prospective clinical study that enrolled 162 consecutive aortic dissection cases, who underwent TEVAR in our institution between July 2011 and November 2012. The PCT, C-response protein (CRP), erythrocyte sedimentation rate (ESR) and blood routine examination were monitored before the operation and on days 1, 2, 3 and 5 after the operation. The diagnosis of infection was confirmed by the infection control committee with reference to Hospital Acquired Infection Diagnostic Criteria Assessment, released by the Ministry of Health of the People's Republic of China. RESULTS: Post endovascular repair of thoracic aorta, PCT changes significantly at different time points (χ(2) = 13.225, P = 0.021), without significant difference between the PIS group and the control group (0.24 ± 0.04 vs.0.26 ± 0.10, P = 0.804). PCT values were significantly higher in the first day after TEVAR than the preoperative levels (0.18 ± 0.03 vs. 0.11 ± 0.02, P < 0.001). Compared with PIS patients, the level of PCT, CRP, White blood cell (WBC) and neutrophil (NEU) in the infection patients elevated significantly (relatively χ(2) = 6.062, P = 0.048; χ(2) = 6.081, P = 0.048; χ(2) = 11.030, P = 0.004; χ(2) = 14.632, P = 0.001). According to the ROC analysis, the PCT levels in the first day after TEVAR (AUC = 0.785, P = 0.012) had better predictive values of infection than WBC, NEU CRP and ESR (AUC = 0.720, P = 0.040; AUC = 0.715, P = 0.045; AUC = 0.663, P = 0.274; AUC = 0.502, P = 0.991). The best predictive index was the changes of PCT between preoperative and postoperative (PCT), which possess AUC as 0.803 (P = 0.014). And PCT = 0.055 could be considered as an infection diagnosis cutoff value with a sensitivity of 83.3% and specificity 69.0%. CONCLUSIONS: PCT provides better diagnostic value of infection compared with other inflammatory markers. The potential applications of PCT in differential diagnosis of PIS and infection after percutaneous TEVAR deserve further studies.

Totally percutaneous thoracic endovascular aortic repair with the preclosing technique: a case-control study.

BACKGROUND: The conventional thoracic endovascular aortic repair (TEVAR) involves groin incisions under general or epidural anesthesia. As technology moves towards less invasive procedures, a total percutaneous approach is desirable. In this study, we describe a Preclosing technique and investigate its safety and efficacy for femoral access sites management, and evaluate its advantages as compared to those of traditional surgical cutdown approaches. METHODS: The Preclosing technique involves two or multiple 6 F Perclose Proglide devices deployed in the femoral artery before upsizing to a 20-25 F sheath. The sutures were secured to close the arteriotomy at the end of the procedure. The medical records of patients who underwent thoracic endovascular aortic repairs using the Preclosing technique between December 2009 and November 2010 (group A) were compared with those using surgical femoral cutdown from January 2008 to November 2009 (group B). Outcome measures included rates of technical success, early complications, anesthesia method, procedure time, cardiac care unit (CCU) stay, time from procedure to discharge, hospital stay, procedure expense, hospital cost. RESULTS: Between the two groups, there were no significant differences in baseline characteristics, in the endograft models or profiles. The technical success rate was 100.0% (85/85) in group A vs. 97.4% (147/151) in group B (P < 0.05). There was no access-related mortality in both groups. Compared with group B, the incidence of early complications were fewer in group A, 9.4% (8/85) vs. 22.5% (34/151) (P < 0.01). Local anesthesia with conscious sedation was used more often in group A, 68.2% (58/85) vs. 51.7% (78/151) in group B (P < 0.01). The procedure duration was shorter, (96 ± 33) minutes in group A vs. (127 ± 41) minutes in group B (P < 0.01). The length of the CCU stay, the duration from procedure to discharge, and the hospital stay were both reduced in group A, (117.3 ± 88.3) hours, (7.5 ± 5.3) days and (15.3 ± 6.8) days vs. (132.7 ± 115.5) hours, (10.5 ± 5.0) days and (19.5 ± 7.8) days in group B (P < 0.01). The procedure cost was RMB (109,000 ± 30,000) Yuan in group A vs. RMB (108,000 ± 25,000) Yuan in group B (P = NS). The hospital cost was RMB (130,000 ± 35,000) Yuan in group A vs. RMB (128,000 ± 33,000) Yuan in group B (P = NS). CONCLUSIONS: Total percutaneous TEAVR with the Preclosing technique is safe and effective with meticulous technique and appropriate patient selection. The Preclosing technique decreases access-related complications, depends less on general anesthesia and the surgeon's cooperation, saves procedure time and shortens the CCU/hospital stay. With these advantages, the use of two percutaneous closure devices increases the hospital cost only slightly.