Transplantation of Human Umbilical Cord Blood-Derived Cellular Fraction Improves Left Ventricular Function and Remodeling After Myocardial Ischemia/Reperfusion.

Rationale: Human umbilical cord blood (hUCB) contains diverse populations of stem/progenitor cells. Whether hUCB-derived nonhematopoietic cells would induce cardiac repair remains unknown. Objective: To examine whether intramyocardial transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular fraction after a reperfused myocardial infarction in nonimmunosuppressed rats would improve cardiac function and ameliorate ventricular remodeling. Methods and Results: Nonhematopoietic CD45-Lin- cells were isolated from hUCB. Flow cytometry and quantitative polymerase chain reaction were used to characterize this subpopulation. Age-matched male Fischer 344 rats underwent a 30-minute coronary occlusion followed by reperfusion and 48 hours later received intramyocardial injection of vehicle or hUCB CD45-Lin- cells. After 35 days, compared with vehicle-treated rats, CD45-Lin- cell-treated rats exhibited improved left ventricular function, blunted left ventricular hypertrophy, greater preservation of viable myocardium in the infarct zone, and superior left ventricular remodeling. Mechanistically, hUCB CD45-Lin- cell injection favorably modulated molecular pathways regulating myocardial fibrosis, cardiomyocyte apoptosis, angiogenesis, and inflammation in postinfarct ventricular myocardium. Rare persistent transplanted human cells could be detected at both 4 and 35 days after myocardial infarction. Conclusions: Transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular subfraction after a reperfused myocardial infarction in nonimmunosuppressed rats ameliorates left ventricular dysfunction and improves remodeling via favorable paracrine modulation of molecular pathways. These findings with human cells in a clinically relevant model of myocardial ischemia/reperfusion in immunocompetent animals may have significant translational implications.Visual Overview: An online visual overview is available for this article.

N-terminal pro-B-type-natriuretic peptide as a screening tool for pulmonary hypertension in the paediatric population.

BACKGROUND: Although cardiac catheterisation (cath) is the diagnostic test for pulmonary hypertension, it is an invasive procedure. Echocardiography (echo) is commonly used for the non-invasive diagnosis of pulmonary hypertension but maybe limited by lack of adequate signals. Therefore, emphasis has been placed on biomarkers as a potential diagnostic tool. No prior paediatric studies have simultaneously compared N-terminal pro-B-type-natriuretic peptide (NTproBNP) with cath/echo as a potential diagnostic tool. The aim of this study was to determine if NTproBNP was a reliable diagnostic tool for pulmonary hypertension in this population. METHODS: Patients were divided into Study (echo evidence/established diagnosis of pulmonary hypertension undergoing cath) and Control (cath for small atrial septal defect/patent ductus arteriosus and endomyocardial biopsy post cardiac transplant) groups. NTproBNP, cath/echo data were obtained. RESULTS: Thirty-one patients met inclusion criteria (10 Study, 21 Control). Median NTproBNP was significantly higher in the Study group. Echo parameters including transannular plane systolic excursion z scores, pulmonary artery acceleration time and right ventricular fractional area change were lower in the Study group and correlated negatively with NTproBNP. Receiver operation characteristic curve analysis demonstrated NTproBNP > 389 pg/ml was 87% specific for the diagnosis of pulmonary hypertension with the addition of pulmonary artery acceleration time improving the specificity. CONCLUSIONS: NTproBNP may be a valuable adjunctive diagnostic tool for pulmonary hypertension in the paediatric population. Echo measures of transannular plane systolic excursion z score, pulmonary artery acceleration time and right ventricular fractional area change had negative correlations with NTproBNP. The utility of NTproBNP as a screening tool for pulmonary hypertension requires validation in a population with unknown pulmonary hypertension status.

Risk Factors for Red Blood Cell Transfusions in Children Undergoing Cardiac Catheterization.

OBJECTIVE: To identify risk factors associated with risk of red blood cell transfusions (RBCTs) following pediatric cardiac catheterizations. STUDY DESIGN: We performed a review of all pediatric cardiac catheterizations from 2012 to 2017. The primary endpoint was RBCT within 72 hours of pediatric cardiac catheterization. Patient and procedural factors were reviewed. Generalized linear modelling was performed to describe interactions among relevant risk factors. RESULTS: In total, 831 RBCTs occurred within 72 hours of 6028 pediatric cardiac catheterizations (13.8%). Univariate analysis revealed that the prevalence of RBCT was highest among infants (37.6% incidence of RBCT) and among those with higher estimated blood loss as a percent of blood volume (P = .03). Among infants, multivariate analysis revealed that weight (OR 0.72; 95% CI 0.63-0.81), complex 2-ventricle (OR 3.14, 95% CI 2.18-4.57), and single ventricle status (OR 5.21, 95% CI 3.42-8.01) were associated with risk of RBCT. Inpatient infants from intensive care (OR 4.74; 95% CI 3.49-6.49) or stepdown units (OR 2.33; 95% CI 1.58-3.46) were at higher risk. Length of procedure (OR 2.57; 95% CI 2.03-3.26) and oxygen saturation (OR 0.98; 95% CI 0.97-0.99; P < .01) were also associated with RBCTs. CONCLUSIONS: Hospitalized infants with single ventricle or complex 2-ventricle anatomy are at highest risk of RBCT. Length of procedure, blood loss, and oxygen saturations are additional risk factors associated with RBCT. Operators should consider these factors when planning pediatric cardiac catheterizations, particularly when exposure to RBCT is undesirable.

Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs.

RATIONALE: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. OBJECTIVE: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. METHODS AND RESULTS: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV-treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. CONCLUSIONS: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

Desiccation-induced cell damage in bacteria and the relevance for inoculant production.

Plant growth-promoting bacteria show great potential for use in agriculture although efficient application remains challenging to achieve. Cells often lose viability during inoculant production and application, jeopardizing the efficacy of the inoculant. Since desiccation has been documented to be the primary stress factor affecting the decrease in survival, obtaining xerotolerance in plant growth-promoting bacteria is appealing. The molecular damage that occurs by drying bacteria has been broadly investigated, although a complete view is still lacking due to the complex nature of the process. Mechanic, structural, and metabolic changes that occur as a result of water depletion may potentially afflict lethal damage to membranes, DNA, and proteins. Bacteria respond to these harsh conditions by increasing production of exopolysaccharides, changing composition of the membrane, improving the stability of proteins, reducing oxidative stress, and repairing DNA damage. This review provides insight into the complex nature of desiccation stress in bacteria in order to facilitate strategic choices to improve survival and shelf life of newly developed inoculants. KEY POINTS: Desiccation-induced damage affects most major macromolecules in bacteria. Most bacteria are not xerotolerant despite multiple endogenous adaption mechanisms. Sensitivity to drying severely hampers inoculant quality.

Prevalence and Severity of Nonalcoholic Fatty Liver Disease Among Caregivers of Patients With Nonalcoholic Fatty Liver Disease Cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting nearly 1 in 3 Americans.1 Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, has a propensity of fibrosis progression and increased risk of cirrhosis and hepatocellular carcinoma. NASH-related cirrhosis is now the most rapidly growing indication for liver transplantation (LT).2 Disease recurrence and progression to advanced fibrosis after LT are high3; however, the key contributors of these are unknown. We hypothesized that patients with NASH cirrhosis reside in a microenvironment conducive to not only development of NASH but also fibrosis progression, which likely persist after LT and contribute to disease recurrence. The hypothesis was tested by performing vibration-controlled transient elastography (VCTE) in primary caregivers and cohabitants of patients with decompensated cirrhosis awaiting LT.

Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis.

BACKGROUND: Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. GOALS: Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. STUDY: A post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. RESULTS: Hp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme. CONCLUSIONS: Hp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.

Thromboprophylaxis strategies for children with single-ventricle circulations (superior or total cavo-pulmonary connections) after stent implantation.

OBJECTIVE: To define optimal thromboprophylaxis strategy after stent implantation in superior or total cavopulmonary connections. BACKGROUND: Stent thrombosis is a rare complication of intravascular stenting, with a perceived higher risk in single-ventricle patients. METHODS: All patients who underwent stent implantation within superior or total cavopulmonary connections (caval vein, innominate vein, Fontan, or branch pulmonary arteries) were included. Cohort was divided into aspirin therapy alone versus advanced anticoagulation, including warfarin, enoxaparin, heparin, or clopidogrel. Primary endpoint was in-stent or downstream thrombus, and secondary endpoints included bleeding complications. RESULTS: A total of 58 patients with single-ventricle circulation underwent 72 stent implantations. Of them 14 stents (19%) were implanted post-superior cavopulmonary connection and 58 (81%) post-total cavopulmonary connection. Indications for stenting included vessel/conduit stenosis (67%), external compression (18%), and thrombotic occlusion (15%). Advanced anticoagulation was prescribed for 32 (44%) patients and aspirin for 40 (56%) patients. Median follow up was 1.1 (25th-75th percentile, 0.5-2.6) years. Echocardiograms were available in 71 patients (99%), and advanced imaging in 44 patients (61%). Thrombosis was present in two patients on advanced anticoagulation (6.3%) and none noted in patients on aspirin (p = 0.187). Both patients with in-stent thrombus underwent initial stenting due to occlusive left pulmonary artery thrombus acutely post-superior cavopulmonary connection. There were seven (22%) significant bleeding complications for advanced anticoagulation and none for aspirin (p < 0.001). CONCLUSIONS: Antithrombotic strategy does not appear to affect rates of in-stent thrombus in single-ventricle circulations. Aspirin alone may be sufficient for most patients undergoing stent implantation, while pre-existing thrombus may warrant advanced anticoagulation.

Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization: Observations From the NCDR IMPACT Registry (National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment).

BACKGROUND: Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR's (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment). METHODS: Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empirical data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event or death after cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%. RESULTS: The rate of major adverse event or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and 6 independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination, with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent, with a slope of 0.97 (standard error, 0.04; P value [for difference from 1] =0.53) and an intercept of 0.007 (standard error, 0.12; P value [for difference from 0] =0.95). CONCLUSIONS: The creation of a validated risk-standardization model for adverse outcomes after congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement.

Dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FP) to model disease progression in steatohepatitis.

There is a need for further refinement of current histological systems for assessment of hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). This study evaluated hepatic fibrosis in NAFLD using dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FPs). Fifty test cohort subjects and 42 validation cohort subjects with NAFLD and the full spectrum of fibrosis were studied. q-FPs were measured in specific predefined regions of interest (general, vessel, perisinusoid, and vascular septa). Seventy q-FPs had inter- and intraobserver concordance ≥0.8 and were related to the NASH Clinical Research Network fibrosis staging. Of these, 16 q-FPs with the strongest correlations (P < 0.001 for all) were entered in a principal component analysis model (odds ratio [OR] 7.8, P < 0.001), which separated any stage of fibrosis versus no fibrosis, and cirrhosis versus earlier stages with the areas under the receiver operating characteristic curves of 0.88 and 0.93 (P ≤ 0.01 for both), respectively. In an independent multivariable analysis, four q-FPs-the number of collagen strands (OR 8.5, P = 0.004), strand length (OR 12.0, P = 0.02), strand eccentricity (OR 8.3, P = 0.004), and strand solidity (OR 8.0, P = 0.003)-were independently associated with fibrosis stages and were used to model fibrosis along a continuous linear scale using desirability functions; this linear scale of fibrosis measurement was also related to fibrosis stage (P < 0.0001). The robustness of both the multivariable model and the linear scale of measurement was confirmed in the validation cohort. CONCLUSION: The q-FP model provides an accurate reproducible method to evaluate fibrosis in NAFLD along a quantitative and continuous scale. (Hepatology 2017;65:1891-1903).

Premounted stents for branch pulmonary artery stenosis in children: A short term solution.

OBJECTIVE: Define outcomes of premounted stent implantation (PMS) for branch pulmonary artery stenosis (BPAS). BACKGROUND: PMS for BPAS in children raises concern of long term viability, with limited maximal expansion. METHODS: We reviewed our cardiac database over an 11-year period ending in 2013. Primary endpoint was need for surgical stent intervention (SSI). Other endpoints included acute results and repeat interventions (RI). RESULTS: 82 PMS were implanted in 60 children for BPAS. Median weight was 6.3 (25th -75th 4.6-9.8) kg. Median stent diameter was 6 (range 4-9) mm. Acutely, vessel diameter improved from 2.0 (25th -75th 1.6-3.4) to 5.0 (25th -75th 4.2-5.9) mm (p < 0.001), pressure gradient decreased from 41 (25th -75th 29-50) to 11 (25th -75th 7-18) mmHg (n = 47, p < 0.001), RV:Ao pressure ratio decreased from 100% (25th -75th 85-110%) to 59% (25th -75th 49-74%) (n = 40, p < 0.001). Freedom from SSI was 81% at 1 year and 35% at 5 years. Freedom from RI was 50% at 1 year and 14% at 5 years. 86% of PMS underwent SSI during a concomitant planned cardiac surgery. 45% patients had stent redilation, improving stent diameter from 4.6 (25th -75th 4.1-5.4) to 5.7 (25th -75th 4.9-7) mm (p < 0.001). 1 stent (3%) was able to be fractured longitudinally. CONCLUSIONS: PMS is an effective short term solution for BPAS in children. PMS is associated with expected early need for transcatheter reintervention to accommodate for growth, but also has high rates of SSI.

Angiographic follow-up of infants and children undergoing percutaneous carotid artery interventions.

OBJECTIVE: The purpose of this study was to review the outcomes following the percutaneous carotid arterial (PCA) approach in infants and children with congenital heart disease. BACKGROUND: PCA access is becoming more commonly adopted following reports demonstrating it is a safe alternative to surgical carotid cutdown and even the femoral arterial route. However, follow-up outcomes after PCA remain unreported. METHODS: We reviewed all cases with PCA access and follow-up catheterizations which included carotid artery (CA) angiography between May 2012 until December 2016. We examined for evidence of CA stenosis at follow-up angiography and assessed any other CA complications associated with vascular access. RESULTS: There were 61 PCA catheterizations performed in 55 unique patients. Follow-up CA imaging with angiography was available in 43 patients (78%, 43/55). There was no vessel stenosis nor lumen irregularity in 28 (65%) patients. In 15 cases (35%), there was a mild degree of irregularity or narrowing by angiography (median 4.1%, range 2.3%-12.5%). Nine patients underwent repeat PCA catheterizations. Seven of these had no visible vascular stenosis on follow-up angiographic imaging, including a patient who was accessed three separate times from the CA. No statistically significant risk factors for developing mild CA stenosis were identified. CONCLUSIONS: PCA access for pediatric interventional catheterization appears to be safe with a very low rate of mild stenosis, and very few complications. Follow-up outcomes in our series are excellent, with a CA patency rate of 100%, even after multiple procedures. Mild CA stenosis was not associated with patient size or sheath introducer caliber. While the acute results from percutaneous CA catheterization have proven safe in recent literature, longer-term outcomes remain unreported. At our institution, the outcomes following percutaneous carotid access are associated with an excellent patency rate of 100%, even after multiple procedures on the same vessel. A low incidence of mild vessel stenosis can be appreciated on follow-up angiography.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.

RATIONALE: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE: To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS: Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS: Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

Report of the National Heart, Lung, and Blood Institute Working Group: An Integrated Network for Congenital Heart Disease Research.

The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group.

Adjusting for Risk Associated With Pediatric and Congenital Cardiac Catheterization: A Report From the NCDR IMPACT Registry.

BACKGROUND: As US health care increasingly focuses on outcomes as a means for quantifying quality, there is a growing demand for risk models that can account for the variability of patients treated at different hospitals so that equitable comparisons between institutions can be made. We sought to apply aspects of prior risk-standardization methodology to begin development of a risk-standardization tool for the National Cardiovascular Data Registry (NCDR) IMPACT (Improving Pediatric and Adult Congenital Treatment) Registry. METHODS AND RESULTS: Using IMPACT, we identified all patients undergoing diagnostic or interventional cardiac catheterization between January 2011 and March 2013. Multivariable hierarchical logistic regression was used to identify patient and procedural characteristics predictive of experiencing a major adverse event after cardiac catheterization. A total of 19,608 cardiac catheterizations were performed between January 2011 and March 2013. Among all cases, a major adverse event occurred in 378 of all cases (1.9%). After multivariable adjustment, 8 variables were identified as critical for risk standardization: patient age, renal insufficiency, single-ventricle physiology, procedure-type risk group, low systemic saturation, low mixed venous saturation, elevated systemic ventricular end-diastolic pressure, and elevated main pulmonary artery pressures. The model had good discrimination (C statistic, 0.70), confirmed by bootstrap validation (validation C statistic, 0.69). CONCLUSIONS: Using prior risk-standardization efforts as a foundation, we developed and internally validated a model to predict the occurrence of a major adverse event after cardiac catheterization for congenital heart disease. Future efforts should be directed toward further refinement of the model variables within this large, multicenter data set.

A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer.

BACKGROUND & AIMS: The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. METHODS: A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. RESULTS: Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4-8weeks), steatohepatitis (16-24weeks), progressive fibrosis (16weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. CONCLUSIONS: We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. LAY SUMMARY: We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH.

Early catheterization after initiation of extracorporeal membrane oxygenation support in children is associated with improved survival.

OBJECTIVES: The study evaluated the institutional experience with cardiac catheterization on extracorporeal membrane oxygenation (ECMO) support. BACKGROUND: There is scant literature on the outcomes of catheterization on ECMO. METHODS: A retrospective review was performed of all children who underwent catheterization on ECMO from 2003 to 2013. Patients were categorized as cardiomyopathy (CM) or congenital heart disease (CHD). RESULTS: During the study period, 215 children were placed on cardiac ECMO. Of these, 29.8% underwent 75 catheterization procedures while on ECMO support. The median age of the cohort was 1.5 months (range 0 days -16.7 years) and the median weight was 3.9 kg (2.2-63.1 kg). CM patients constituted 18.8% of the cohort and all of them underwent atrial septoplasty (an atrial septal stent in 7/12 and balloon atrial septoplasty or septostomy in 5). The survival to hospital discharge rate was 83% and the transplant-free survival rate was 58.3%. CHD patients constituted 81.2% of the cohort. In this group, transcatheter interventions were performed in 40.4% and subsequent surgical interventions in 40.4%. Survival to hospital discharge rate was 34.6% and transplant free survival rate was 32.7%. Overall, 76.7% underwent transcatheter or surgical interventions. The major catheterization complication rate was 6.7%. The mean ECMO-to-catheterization time was 1.6 days for survivors and 3.5 days for non-survivors (P = 0.034). Survival to discharge was better for the CM group compared to the CHD group (P = 0.01). Among CHD, survival was better with transcatheter interventions compared to no interventions or surgical interventions (P < 0.001). CONCLUSIONS: Cardiac catheterization and transcatheter interventions on ECMO can be performed with low rate of complications. Catheterization was associated with high rate of interventions. Better survival to hospital discharge was associated with transcatheter interventions, earlier performance of catheterization after ECMO and diagnosis of CM. © 2016 Wiley Periodicals, Inc.

SCAI/CCAS/SPA expert consensus statement for anesthesia and sedation practice: Recommendations for patients undergoing diagnostic and therapeutic procedures in the pediatric and congenital cardiac catheterization laboratory.

Current practice of sedation and anesthesia for patients undergoing pediatric congenital cardiac catheterization laboratory (PCCCL) procedures is known to vary among institutions, a multi-society expert panel with representatives from the Congenital Heart Disease Council of the Society for Cardiovascular Angiography and Interventions (SCAI), the Society for Pediatric Anesthesia (SPA) and the Congenital Cardiac Anesthesia Society (CCAS) was convened to evaluate the types of sedation and personnel necessary for procedures performed in the PCCCL. The goal of this panel was to provide practitioners and institutions performing these procedures with guidance consistent with national standards and to provide clinicians and institutions with consensus-based recommendations and the supporting references to encourage their application in quality improvement programs. Recommendations can neither encompass all clinical circumstances nor replace the judgment of individual clinicians in the management of each patient. The science of medicine is rooted in evidence, and the art of medicine is based on the application of this evidence to the individual patient. This expert consensus statement has adhered to these principles for optimal management of patients requiring sedation and anesthesia. What follows are recommendations for patient monitoring in the PCCCL regardless of whether minimal or no sedation is being used or general anesthesia is being provided by an anesthesiologist. © 2016 Wiley Periodicals Inc.

SCAI/CCAS/SPA Expert Consensus Statement for Anesthesia and Sedation Practice: Recommendations for Patients Undergoing Diagnostic and Therapeutic Procedures in the Pediatric and Congenital Cardiac Catheterization Laboratory.

Current practice of sedation and anesthesia for patients undergoing pediatric and congenital cardiac catheterization laboratory (PCCCL) procedures is known to vary among institutions, a multi-society expert panel with representatives from the Congenital Heart Disease Council of the Society for Cardiovascular Angiography and Interventions, the Society for Pediatric Anesthesia and the Congenital Cardiac Anesthesia Society was convened to evaluate the types of sedation and personnel necessary for procedures performed in the PCCCL. The goal of this panel was to provide practitioners and institutions performing these procedures with guidance consistent with national standards and to provide clinicians and institutions with consensus-based recommendations and the supporting references to encourage their application in quality improvement programs. Recommendations can neither encompass all clinical circumstances nor replace the judgment of individual clinicians in the management of each patient. The science of medicine is rooted in evidence, and the art of medicine is based on the application of this evidence to the individual patient. This expert consensus statement has adhered to these principles for optimal management of patients requiring sedation and anesthesia. What follows are recommendations for patient monitoring in the PCCCL regardless of whether minimal or no sedation is being used or general anesthesia is being provided by an anesthesiologist.

Characteristics and safety of interventions and procedures performed during catheterisation of patients with congenital heart disease: early report from the national cardiovascular data registry.

OBJECTIVES: The objective of this study was to report procedural characteristics and adverse events on the data collected in the IMproving Paediatric and Adult Congenital Treatment registry. BACKGROUND: The IMproving Paediatric and Adult Congenital Treatment- registry is a catheterisation registry focussed on paediatric and adult patients with congenital heart disease who are undergoing diagnostic catheterisations and catheter-based interventions. This study reports procedural characteristics and adverse events of patients who have undergone selected catheterisation procedures from January, 2011 to June, 2013. METHODS: Demographic, clinical, procedural, and institutional data elements were collected at participating centres and entered via either a web-based platform or software provided by the American College of Cardiology-certified vendors, and were collected in a secure, centralised database. For the purpose of this study, procedures that were not classified as one of the 'core' IMproving Paediatric and Adult Congenital Treatment procedures originally chosen for additional data collection were identified and selected for further data analysis. RESULTS: During the time frame of data collection, a total of 8021 cases were classified as other procedures and/or multiple procedures. The most commonly performed case types - isolated or in combination with other procedures - were right ventricular biopsy in 3433 (42.8%), conduit/MPA interventions in 979 (12.3%), and systemic pulmonary artery collateral occlusion in 601 (7.5%). For the whole cohort, adverse events of any severity occurred in 957 (12.0%) cases, whereas major adverse events occurred in 113 (1.4%) cases; six patients (0.1%) died in the catheterisation laboratory. CONCLUSIONS: The IMproving Paediatric and Adult Congenital Treatment registry has provided important data on the frequency and spectrum of cardiac catheterisation procedures performed in the present era. For many procedures, more data and work are needed to identify more subtle differences between case categories, especially as it relates to the incidence of major adverse events, and to further develop a risk-adjustment methodology to allow equitable comparisons among institutions.