Anti-inflammatory response-based risk assessment in acute type A aortic dissection: A national multicenter cohort study.

Background: Early identification of patients at high risk of operative mortality is important for acute type A aortic dissection (TAAD). We aimed to investigate whether patients with distinct risk stratifications respond differently to anti-inflammatory pharmacotherapy. Methods: From 13 cardiovascular hospitals, 3110 surgically repaired TAAD patients were randomly divided into a training set (70%) and a test set (30%) to develop and validate a risk model to predict operative mortality using extreme gradient boosting. Performance was measured by the area under the receiver operating characteristic curve (AUC). Subgroup analyses were performed by risk stratifications (low versus middle-high risk) and anti-inflammatory pharmacotherapy (absence versus presence of ulinastatin use). Results: A simplified risk model was developed for predicting operative mortality, consisting of the top ten features of importance: platelet-leukocyte ratio, D-dimer, activated partial thromboplastin time, urea nitrogen, glucose, lactate, base excess, hemoglobin, albumin, and creatine kinase-MB, which displayed a superior discrimination ability (AUC: 0.943, 95 % CI 0.928-0.958 and 0.884, 95 % CI 0.836-0.932) in the derivation and validation cohorts, respectively. Ulinastatin use was not associated with decreased risk of operative mortality among each risk stratification, however, ulinastatin use was associated with a shorter mechanical ventilation duration among patients with middle-high risk (defined as risk probability >5.0 %) (ß -1.6 h, 95 % CI [-3.1, -0.1] hours; P = 0.048). Conclusion: This risk model reflecting inflammatory, coagulation, and metabolic pathways achieved acceptable predictive performances of operative mortality following TAAD surgery, which will contribute to individualized anti-inflammatory pharmacotherapy.

Prognostic Implication of Pulmonary Arterial Pressure in Surgical Repair of Predominantly Congenital Mitral Valve Regurgitation-Based Intracardiac Abnormalities.

INTRODUCTION: Knowledge is limited regarding the significance of pulmonary arterial pressure (PAP) in predominantly congenital mitral valve regurgitation (MR)-based intracardiac abnormalities. METHODS: From a prospective cohort, we included 200 patients with congenital MR regardless of other associated intracardiac abnormalities (mean age 60.4 months, 67% female, systolic PAP (sPAP) 54.2 mm Hg) surgically repaired in 2012-2019 and followed up to 2020 (median 30.0 months). Significant pulmonary hypertension (PH) was defined as sPAP >50 mm Hg at rest or mean PAP >25 mm Hg on right heart catheterization. By perioperative sPAP changes, patients were stratified as group I (pre-normotension to post-normotension), group II (pre-hypertension to post-normotension), or group III (pre-hypertension to post-hypertension). Primary outcomes were the recurrence of MR (defined as the regurgitation grade of moderate or greater) and the progression of MR (defined as any increase in the magnitude of regurgitation grade after surgery). Cox proportional hazard and Kaplan-Meier curve were performed. RESULTS: There was no association between preoperative PH and the recurrent MR (adjusted hazard ratios [aHR]: 1.146 [95% CI: 0.453-2.899]) and progressive MR (aHR: 1.753 [95% CI: 0.807-3.804]), respectively. There were no significant differences among group I, group II, and group III in the recurrent MR but in the progressive MR. A dose dependency was identified for preoperative sPAP with recurrent MR (aHR: 1.050 [95% CI: 1.029-1.071]) and progressive MR risks (aHR: 1.037 [95% CI: 1.019-1.055]), respectively. CONCLUSIONS: Preoperative higher sPAP is associated with worse outcomes, warranting heightened attention to the identification of perioperative sPAP.

Identification of variants of ISL1 gene promoter and cellular functions in isolated ventricular septal defects.

Ventricular septal defects (VSDs) are the most common congenital heart defects (CHDs). Studies have documented that ISL1 has a crucial impact on cardiac growth, but the role of variants in the ISL1 gene promoter in patients with VSD has not been explored. In 400 subjects (200 patients with isolated and sporadic VSDs: 200 healthy controls), we investigated the ISL1 gene promoter variant and performed cellular functional experiments by using the dual-luciferase reporter assay to verify the impact on gene expression. In the ISL1 promoter, five variants were found only in patients with VSD by sequencing. Cellular functional experiments demonstrated that three variants decreased the transcriptional activity of the ISL1 promoter (P < 0.05). Further analysis with the online JASPAR database demonstrated that a cluster of putative binding sites for transcription factors may be altered by these variants, possibly resulting in change of ISL1 protein expression and VSD formation. Our study has, for the first time, identified novel variants in the ISL1 gene promoter region in the Han Chinese patients with isolated and sporadic VSD. In addition, the cellular functional experiments, electrophoretic mobility shift assay, and bioinformatic analysis have demonstrated that these variants significantly alter the expression of the ISL1 gene and affect the binding of transcription factors, likely resulting in VSD. Therefore, this study may provide new insights into the role of the gene promoter region for a better understanding of genetic basis of the formation of CHDs and may promote further investigations on mechanism of the formation of CHDs.

Effect of cardiopulmonary bypass reoxygenation on myocardial dysfunction following pediatric tetralogy of Fallot repair.

BACKGROUND: Little is known regarding the effect of cardiopulmonary bypass (CPB) reoxygenation on cardiac function following tetralogy of Fallot repair. We hypothesized that hyperoxic reoxygenation would be more strongly associated with myocardial dysfunction in children with tetralogy of Fallot. METHODS: We investigated the association of perfusate oxygenation (PpO2) associated with myocardial dysfunction among children aged 6-72 months who underwent complete repair of tetralogy of Fallot in 2012-2018. Patients were divided into two groups: lower PpO2 group (≤ 250 mmHg) and higher PpO2 (> 250 mmHg) group based on the highest value of PpO2 during aortic occlusion. The odd ratio (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression models. RESULTS: This study included 163 patients perfused with lower PpO2 and 213 with higher PpO2, with median age at surgery 23.3 (interquartile range [IQR] 12.5-39.4) months, 164 female (43.6%), and median body mass index 15.59 (IQR 14.3-16.9) kg/m2. After adjustment for baseline, clinical and procedural variables, patients with higher PpO2 were associated with higher risk of myocardial dysfunction than those with lower PpO2 (OR 1.770; 95% CI 1.040-3.012, P = 0.035). Higher PpO2, lower SpO2, lower pulmonary annular Z-score, and longer CPB time were independent risk factors for myocardial dysfunction. CONCLUSIONS: Association exists between higher PpO2 and myocardial dysfunction risk in patients with tetralogy of Fallot, highlighting the modulation of reoxygenation during aortic occlusion to reduce cardiovascular damage following tetralogy of Fallot repair. TRIAL REGISTRATION: Clinical Trials. gov number NCT03568357. June 26, 2018.

Genetic analysis of the CITED2 gene promoter in isolated and sporadic congenital ventricular septal defects.

Ventricular septal defect (VSD) is the most common congenital heart defect. Previous studies have reported genetic variations in the encoding region of CITED2 highly associated with cardiac malformation but the role of CITED2 gene promoter variations in VSD patients has not yet been explored. We investigated the variation of CITED2 gene promoter and its impacts on gene promoter activity in the DNA of paediatric VSD patients. A total of seven variations were identified by Sanger sequencing in the CITED2 gene promoter region in 400 subjects, including 200 isolated and sporadic VSD patients and 200 healthy controls. Using dual-luciferase reporter assay, we found four of the 7 variations identified significantly decreased the transcriptional activity of the CITED2 gene promoter in HEK-293 cells (P < .05). Further, a bioinformatic analysis with the JASPAR databases was performed and a cluster of putative binding sites for transcription factors was created or disrupted by these variations, leading to low expression of CITED2 protein and development of VSD. Our study for the first time demonstrates genetic variations in the CITED2 gene promoter in the Han Chinese population and the role of these variations in the development of VSD, providing new insights into the aetiology of CHD.

Effect of perfusate oxygenation on inflammatory response in congenital heart disease children from low versus high altitude.

OBJECTIVE: To examine the altitude differences in the optimal perfusate oxygenation (PpO2) in patients who underwent cardiac surgery. METHODS: We included children (aged 1 month to 18 years) with congenital heart diseases surgically repaired between 2012 and 2018. We included only patients who underwent cardiac surgery with arrested heart cardiopulmonary bypass. Primary outcome was severe systemic inflammatory response syndrome (SIRS). Logistic regression was used to evaluate the association between arterial PpO2 on continuous and categorical scales and severe SIRS by altitude. We established PpO2 thresholds that equated to a risk probability of roughly 0.185 or greater for developing severe SIRS in each group of altitude. RESULTS: Among 3918 patients from low altitudes and 2384 from high altitudes, high-altitude patients were older (median, 42.3 [interquartile range 22.8-75.8] vs 37.1 [17.7-69.1] months, P < .001) and had lower arterial PpO2 (289 [237-342] vs 301 [246-362] mm Hg, P < .001). Greater PpO2 was associated with increased risk of severe SIRS overall (adjusted odds ratio, 1.221 [95% confidence interval, 1.167-1.278] per standard deviation increase), with a stronger monotonic associations for low-altitude patients than for high-altitude patients (adjusted odds ratio, 1.302 [95% confidence interval, 1.229-1.379] vs adjusted odds ratio, 1.083 [95% confidence interval, 1.003-1.170] per standard deviation increase) (Pinteraction = .0003). A PpO2 level of 310 mm Hg identified low-altitude patients with a risk probability of roughly 0.185 or greater of severe SIRS, whereas the cutoffs ranged from 200 mm Hg to 325 mm Hg for high-altitude patients. CONCLUSIONS: This study suggests altitude differences in the association of arterial PpO2 with inflammatory response following pediatric cardiac surgery.

Loop isolation-based uploading preconditioning to protect heart from damage: a proof-of-concept study.

BACKGROUND: Little is known on the role of indirect clamp releasing in coronary artery bypass grafting (CABG). Loop isolation-based uploading preconditioning (LiuPhD) was modified to protect the heart from damage and the question of whether this can attenuate reperfusion injury after global myocardial ischemia was examined. METHODS: A post-hoc comparative analysis was conducted of a prospective single-arm trial on the use of the LiuPhD strategy for 60 multivessel-disease patients undergoing isolated first-time elective on-pump CABG versus 1:1 propensity score-matched patients from the historical database of the same center. RESULTS: A total of 120 matched patients had a median age of 62.0 (interquartile range [IQR] 55.8-69.0) years, 27 (22.5%) women, 35 (29.2%) with left main disease, and median follow-up of 18.5 (10.9-35.4) months. The LiuPhD group had shorter post-bypass times than conventional controls (10 [6-13] vs 14 [10-19] mins; p = 0.003). The LiuPhD group had similar needs in terms of composite cardiac-specific interventions (38/60 vs 44/60; p = 0.29). At follow-up of safety, the risk for composite major adverse cardiac and cerebrovascular events was similar between groups (event-free survival: 82.3% vs 73.8%; hazard ratio 1.00 [0.39, 2.54], p log-rank test = 0.99). CONCLUSION: The LiuPhD strategy is associated with short post-bypass times, comparable risk of myocardial injury, and similar safety compared with conventional direct clamp releasing.

Haematocrit differences modify the association of cardiopulmonary bypass reoxygenation with acute kidney injury after paediatric Tetralogy of Fallot repair.

BACKGROUND: Little is known regarding the potential impact of haematocrit differences in the association between cardiopulmonary bypass reoxygenation and acute kidney injury following Tetralogy of Fallot repair. METHODS: We investigated the association of perfusate oxygenation during aortic occlusion associated with acute kidney injury between 204 normal and 248 higher haematocrit children with Tetralogy of Fallot, aged 1 month-18 years, who were surgically repaired in 2012-2018. Normal and higher haematocrit children were defined as having a preoperative haematocrit within and above age- and sex-specific reference intervals, respectively. Acute kidney injury was determined as a binary variable according to the Kidney Disease Improving Global Outcomes criteria. RESULTS: After adjusting for baseline and clinical covariates, a significant interaction between the haematocrit and continuous perfusate oxygenation on acute kidney injury was found (pinteraction = 0.049): a higher perfusate oxygenation was associated with a greater acute kidney injury risk among higher haematocrit children (adjusted odds ratio = 1.50, 95% confidence interval = [1.02, 2.22] per SD, p = 0.038) but not among normal haematocrit children (adjusted odds ratio = 0.91, 95% confidence interval = [0.51, 1.63] per SD, p = 0.73). After a similar adjustment, there was a marginal interaction between tertiles of perfusate oxygenation and haematocrit on acute kidney injury (pinteraction = 0.09): the middle and top tertiles of perfusate oxygenation were associated with a trend towards increased acute kidney injury risks among higher haematocrit children (adjusted odds ratio = 1.69, 95% confidence interval = [0.61, 4.66]; adjusted odds ratio = 2.25, 95% confidence interval = [0.84, 5.99], respectively) but not among normal haematocrit children (adjusted odds ratio = 1.16, 95% confidence interval = [0.46, 2.94]; adjusted odds ratio = 0.45, 95% confidence interval = [0.15, 1.36], respectively) compared with the bottom tertile. CONCLUSION: Preoperative haematocrit differences significantly modify the association of perfusate oxygenation with acute kidney injury, highlighting differential control of reoxygenation for different haematocrit children with Tetralogy of Fallot in the management of cardiopulmonary bypass.

Association Between Perfusate Oxygenation and Acute Lung Injury in Tetralogy of Fallot Surgery.

PURPOSE: Little is known regarding precise estimates of the association between perfusate oxygenation (PpO2) and acute lung injury (ALI) following tetralogy of Fallot repair. The objective is to investigate PpO2 and the risk of ALI following tetralogy of Fallot repair in pediatric patients. METHODS: We conducted a nested case-control study within a prospective Chinese TedaICH cohort including 134 ALI patients aged 1 month to 18 years undergoing complete repair of tetralogy of Fallot, and each was matched to two controls. We selected the highest PpO2 during aortic crossclamp as the exposure. Conditional logistic regression was used to quantify the association between PpO2 and overall ALI risk by covariates of interest. We identified and integrated the risk covariates to build ALI nomograms and internally validated the nomograms using bootstrapping. RESULTS: After adjusting for covariates, continuously and categorically higher PpO2 values were associated with ALI risk (all P < 0.05), especially for those with a z-score of pulmonary annulus < -4.0 (P = 0.002), McGoon ratio < 1.5 (P = 0.029), and major aortopulmonary collateral arteries (P = 0.005), despite no statistical heterogeneity (all P interaction >0.05). Younger age, lower oxyhemoglobin saturation, untreated minor aortopulmonary collateral arteries, transannular patch, larger transpulmonary gradient, major transfusion, and longer cardiopulmonary bypass time were independent risk factors for ALI (all P < 0.05). Combining the PpO2 nomogram provided further risk discriminative information on ALI diagnosis compared with the covariate-based nomogram alone in the training cohort (AUC 0.865, 95% CI [0.828-0.903] vs. 0.869 [0.832-0.906], respectively) with no statistical significance (P = 0.445). CONCLUSIONS: The findings suggested an association between high PpO2 and ALI risk, and more importance should be attached to independent risk factors for ALI.

Derivation and Validation of a Nomogram to Predict In-Hospital Complications in Children with Tetralogy of Fallot Repaired at an Older Age.

Background We aimed to develop and validate a prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age. Methods and Results A total of 513 pediatric patients from the Tianjin data set formed a derivation cohort, and 158 pediatric patients from the Hefei and Xiamen data sets formed validation cohorts. We applied least absolute shrinkage and selection operator analysis for variable selection and logistic regression coefficients for risk scoring. We classified patients into different risk categorizations by threshold analysis and investigated the association with in-hospital complications using logistic regression. In-hospital complications were defined as death, need for extensive pharmacologic support (vasoactive-inotrope score of ≥20), and need for mechanical circulatory support. We developed a nomogram based on risk classifier and independent baseline variables using a multivariable logistic model. Based on risk scores weighted by 11 preoperative and 4 intraoperative selected variables, we classified patients as low, intermediate, and high risk in the derivation cohort. With reference to the low-risk group, the intermediate- and high-risk groups conferred significantly higher in-hospital complication risks (adjusted odds ratio: 2.721 [95% CI, 1.267-5.841], P=0.0102; 9.297 [95% CI, 4.601-18.786], P<0.0001). A nomogram integrating the ARIAR-Risk classifier (absolute and relative low risk, intermediate risk, and aggressive and refractory high risk) with age and mean blood pressure showed good discrimination and goodness-of-fit for derivation (area under the receiver operating characteristic curve: 0.785 [95% CI, 0.731-0.839]; Hosmer-Lemeshow test, P=0.544) and external validation (area under the receiver operating characteristic curve: 0.759 [95% CI, 0.636-0.881]; Hosmer-Lemeshow test, P=0.508). Conclusions A risk-classifier-oriented nomogram is a reliable prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age, and strengthens risk/benefit-based decision-making.

Minimally invasive perventricular versus open surgical ventricular septal defect closure in infants and children: a randomised clinical trial.

BACKGROUND: Robust evidence is lacking regarding the clinical efficacy, safety and cardiopulmonary performance of perventricular closure. This study investigated the perioperative efficacy, safety and cardiorespiratory performance of perventricular closure of perimembranous ventricular septal defects (pmVSDs). METHODS: Operation-naïve infants and young children aged 5-60 months with isolated pmVSDs were randomised to receive either standard open surgical or minimally invasive perventricular closure via direct entry into the ventricle with a catheter from a subxiphoid incision. The primary outcomes included complete closure at discharge, major and minor adverse events and the changes in perioperative cardiorespiratory performance from baseline. Complete closure was mainly analysed in the modified intention-to-treat (mITT) population, with sensitivity analyses for the ITT, per-protocol (PP) and as-treated (AT) populations (non-inferiority margin -5.0%). RESULTS: We recruited 200 patients with pmVSDs for this study (mean age 24.38 months, range 7-58 months, 104 girls), of whom 100 were randomly allocated to one of the study groups. The non-inferiority of perventricular to surgical closure regarding complete closure at discharge was not shown in the ITT (absolute difference -0.010 (95% CI -0.078 to 0.058)) and mITT populations (-0.010 (95% CI -0.069 to 0.048)), but was shown in the PP (0.010 (95% CI -0.043 to 0.062)) and AT populations (0.048 (95% CI -0.009 to 0.106)). Perventricular closure reduced the rate of compromising cardiac haemodynamics, electrophysiological responses, cardiomyocyte viability, respiratory mechanics, ventilatory and gas exchange function and oxygenation and tissue perfusion compared with surgical closure (all between-group P<0.05). CONCLUSIONS: For infants and young children with pmVSD, perventricular closure reduced the rate of postoperative cardiorespiratory compromise compared with surgical closure, but the non-inferiority regarding complete closure should be interpreted in the context of the specific population. TRIAL REGISTRATION NUMBER: NCT02794584 ;Results.