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John Sunwoo,1 Patjanaporn Chalacheva,1 Maha Khaleel,2 Payal Shah,2 Richard Sposto,3 Roberta M Kato,4 Jon Detterich,5 Lonnie K Zeltzer,6 John C Wood,1,5 Thomas D Coates,2 Michael CK Khoo1 1Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; 2Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 3Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 4Division of Pediatric Pulmonology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 5Division of Pediatric Cardiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 6Pediatric Pain and Palliative Care Program, Department of Pediatrics, Division of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA Purpose: The purpose of this work was to noninvasively detect and quantify microvascular blood flow changes in response to externally applied pain in humans. The responsiveness of the microvasculature to pain stimulation might serve as an objective biomarker in diseases associated with altered pain perception and dysregulated vascular functions. The availability of such a biomarker may be useful as a tool for predicting outcome and response to treatments, particularly in diseases like sickle cell anemia where clinical manifestations are directly linked to microvascular perfusion. We, therefore, developed a method to distinguish the blood flow response due to the test stimulus from the blood flow measurement that also includes concurrent flow changes from unknown origins.Subjects and methods: We measured the microvascular blood flow response in 24 healthy subjects in response to a train of randomly spaced and scaled heat pulses on the anterior forearm. The fingertip microvascular perfusion was measured using laser Doppler flowmetry. The cross-correlation between the heat pulses and the blood flow response was computed and tested for significance against the null distribution obtained from the baseline recording using bootstrapping method.Results: We estimated correlation coefficients, response time, response significance, and the magnitude of vasoreactivity from microvascular blood flow responses. Based on these pain response indices, we identified strong responders and subjects who did not show significant responses.Conclusion: The cross-correlation of a random pattern of painful stimuli with directly measured microvascular flow can detect vasoconstriction responses in a noisy blood flow signal, determine the time between stimulus and response, and quantify the magnitude of this response. This approach provided an objective measurement of vascular response to pain that may be an inherent characteristic of individual human subjects, and may also be related to the severity of vascular disorders. Keywords: objective quantification of pain, randomized heat pulse train, laser Doppler flowmetry, cross-correlation, bootstrap test, vasoreactivity

Objective: Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non‐invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood‐oxygen‐level‐dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. Methods: This was a cross‐sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6–38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end‐tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7–8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence‐weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel‐wise PlVR values across the placenta. Results: PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non‐linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. Conclusions: We present, for the first time, a non‐invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high‐risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Sickle cell anemia is caused by a single mutation in the gene encoding the beta subunit of hemoglobin. Due to this mutation, sickle cell hemoglobin (HbS) polymerizes under hypoxic conditions, decreasing red blood cell deformability and leading to multiple pathological effects that cause substantial morbidity and mortality. Several pre-clinical and human studies have demonstrated that the anion nitrite has potential therapeutic benefits for patients with sickle cell disease. Nitrite is reduced to nitric oxide (NO) by deoxygenated hemoglobin contributing to vasodilation, decreasing platelet activation, decreasing cellular adhesion to activated endothelium, and decreasing red cell hemolysis; all of which could ameliorate patient morbidities. Previous work on extracellular hemoglobin has shown that solution phase HbS reduces nitrite to NO faster than normal adult hemoglobin (HbA), while polymerized HbS reduces nitrite slower than HbA. In this work, we compared the rate of nitrite reduction to NO measured by the formation of nitrosyl hemoglobin in sickle and normal red blood cells at varying hemoglobin oxygen saturations. We found the overall rate of nitrite reduction between normal and sickle red blood cells was similar and confirmed this result under partially oxygenated conditions, but normal red blood cells reduced nitrite faster than sickle red blood cells under anoxia where HbS polymerization is maximal. These results are consistent with previous work using extracellular hemoglobin where the rate of reduction by solution phase HbS makes up for the slower reduction by polymer phase HbS under partially oxygenated conditions, but the polymer phase kinetics dominates in the complete absence of oxygen., Competing Interests: Declaration of competing interest DKS and EA are a co-inventors on patent and/or patent applications related to sodium nitrite as a therapeutic. AG gets research support from Forma Therapeutics, serves on the advisory board for Pfizer, and receives royalties from Wolters Kluwer. Other authors do not declare any competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: The ability to predict sudden cardiac death (SCD) in children and adolescents with hypertrophic cardiomyopathy (HCM) is currently inadequate. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is associated with SCD events in adults with HCM., Objective: To examine the prognostic significance of LGE in patients with HCM who are younger than 21 years., Design, Setting, and Participants: This multicenter, retrospective cohort study was conducted from April 8, 2015, to September 12, 2022, in patients with HCM who were younger than 21 years and had undergone CMR imaging across multiple sites in the US, Europe, and South America. Observers of CMR studies were masked toward outcomes and demographic characteristics., Exposure: Natural history of HCM., Main Outcome and Measures: The primary outcome was SCD and surrogate events, including resuscitated cardiac arrest and appropriate discharges from an implantable defibrillator. Continuous and categorical data are expressed as mean (SD), median (IQR), or number (percentage), respectively. Survivor curves comparing patients with and without LGE were constructed by the Kaplan-Meier method, and likelihood of subsequent clinical events was further evaluated using univariate and multivariable Cox proportional hazards models., Results: Among 700 patients from 37 international centers, median (IQR) age was 14.8 (11.9-17.4) years, and 518 participants (74.0%) were male. During a median (IQR) [range] follow-up period of 1.9 (0.5-4.1) [0.1-14.8] years, 35 patients (5.0%) experienced SCD or equivalent events. LGE was present in 230 patients (32.9%), which constituted an mean (SD) burden of 5.9% (7.3%) of left ventricular myocardium. The LGE amount was higher in older patients and those with greater left ventricular mass and maximal wall thickness; patients with LGE had lower left ventricular ejection fractions and larger left atrial diameters. The presence and burden of LGE was associated with SCD, even after correcting for existing risk stratification tools. Patients with 10% or more LGE, relative to total myocardium, had a higher risk of SCD (unadjusted hazard ratio [HR], 2.19; 95% CI, 1.59-3.02; P < .001). Furthermore, the addition of LGE burden improved the performance of the HCM Risk-Kids score (before LGE addition: 0.66; 95% CI, 0.58-0.75; after LGE addition: 0.73; 95% CI, 0.66-0.81) and Precision Medicine in Cardiomyopathy score (before LGE addition: 0.68; 95% CI, 0.49-0.77; after LGE addition: 0.73; 95% CI, 0.64-0.82) SCD predictive models., Conclusions and Relevance: In this retrospective cohort study, quantitative LGE was a risk factor for SCD in patients younger than 21 years with HCM and improved risk stratification.

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p = 0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration., Competing Interests: Declaration of Competing Interest The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the U.S. Department of Health and Human Services; or Mezzion Pharma Co. Ltd., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The burden of pulmonary disease in children with CHD remains under-recognised. Studies have examined children with single ventricle and two ventricle heart disease and documented a decreased forced vital capacity. Our study sought to further explore the pulmonary function of children with CHD., Methods: A retrospective review was performed of spirometry in CHD patients over a 3-year period. Spirometry data were corrected for size, age, and gender and analysed using z-scores., Results: The spirometry of 260 patients was analysed. About 31% had single ventricle (n = 80, 13.6 years (interquartile range 11.5-16.8)) and 69% had two ventricle circulation (n = 180, 14.4 years (interquartile range 12.0-17.3)). Single ventricle patients were found to have a lower median forced vital capacity z-score compared to two ventricle patients (p = 0.0133). The prevalence of an abnormal forced vital capacity was 41% in single ventricle patients and 29% in two ventricle patients. Two ventricle patients with tetralogy of Fallot and truncus arteriosus had similar low forced vital capacity comparable to single ventricle patients. The number of cardiac surgeries predicted an abnormal forced vital capacity in two ventricle patients except tetralogy of Fallot patients., Conclusion: Pulmonary morbidity in patients with CHD is common with a decreased forced vital capacity noted in single ventricle and two ventricle patients. Forced vital capacity is lower in patients with single ventricle circulation; however, two ventricle patients with tetralogy of Fallot or truncus arteriosus have similar lung function in comparison to the single ventricle group. The number of surgical interventions was predictive of forced vital capacity z-score in some but not all two ventricle patients and not predictive in single ventricle patients suggesting a multifactorial to pulmonary disease in children with CHD.

The Single Ventricle Reconstruction (SVR) Trial was a randomized prospective trial designed to determine survival advantage of the modified Blalock-Taussig-Thomas shunt (BTTS) vs the right ventricle to pulmonary artery conduit (RVPAS) for patients with hypoplastic left heart syndrome. The primary aim of the long-term follow-up (SVRIII) was to determine the impact of shunt type on RV function. In this work, we describe the use of CMR in a large cohort follow up from the SVR Trial as a focused study of single ventricle function. The SVRIII protocol included short axis steady-state free precession imaging to assess single ventricle systolic function and flow quantification. There were 313 eligible SVRIII participants and 237 enrolled, ages ranging from 10 to 12.5 years. 177/237 (75%) participants underwent CMR. The most common reasons for not undergoing CMR exam were requirement for anesthesia (n = 14) or ICD/pacemaker (n = 11). A total of 168/177 (94%) CMR studies were diagnostic for RVEF. Median exam time was 54 [IQR 40-74] minutes, cine function exam time 20 [IQR 14-27] minutes, and flow quantification time 18 [IQR 12-25] minutes. There were 69/177 (39%) studies noted to have intra-thoracic artifacts, most common being susceptibility artifact from intra-thoracic metal. Not all artifacts resulted in non-diagnostic exams. These data describe the use and limitations of CMR for the assessment of cardiac function in a prospective trial setting in a grade-school-aged pediatric population with congenital heart disease. Many of the limitations are expected to decrease with the continued advancement of CMR technology., (© 2023. The Author(s).)

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Background: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS., Methods: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention., Conclusions: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (P ET CO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of P ET CO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD., Competing Interests: The authors declare no conflicts of interest.

It has been long known that blood health heavily influences optimal physiological function. Abnormalities affecting the physical properties of blood have been implicated in the pathogenesis of various disorders, although the exact mechanistic links between hemorheology and clinical disease manifestations remain poorly understood. Often overlooked in current medical practice, perhaps due to the promises offered in the molecular and genetic era, the physical properties of blood which remain a valuable and definitive indicator of circulatory health and disease. Bridging this gap, the current manuscript provides an introduction to hemorheology. It reviews the properties that dictate bulk and microcirculatory flow by systematically dissecting the biomechanics that determine the non-Newtonian behavior of blood. Specifically, the impact of hematocrit, the mechanical properties and tendency of red blood cells to aggregate, and various plasma factors on blood viscosity will be examined. Subsequently, the manner in which the physical properties of blood influence hemodynamics in health and disease is discussed. Special attention is given to disorders such as sickle cell disease, emphasizing the clinical impact of severely abnormal blood rheology. This review expands into concepts that are highly topical; the relation between mechanical stress and intracellular homeostasis is examined through a contemporary cell-signaling lens. Indeed, accumulating evidence demonstrates that nitric oxide is not only transported by erythrocytes, but is locally produced by mechanically-sensitive enzymes, which appears to have intracellular and potentially extracellular effects. Finally, given the importance of shear forces in the developing field of mechanical circulatory support, we review the role of blood rheology in temporary and durable mechanical circulatory support devices, an increasingly utilized method of life support. This review thus provides a comprehensive overview for interested trainees, scientists, and clinicians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alexy, Detterich, Connes, Toth, Nader, Kenyeres, Arriola-Montenegro, Ulker and Simmonds.)

Low forced vital capacity (FVC) is associated with decreased exercise capacity in CHD. Multiple prior cardiac surgeries have been associated with low FVC. We seek to understand the relationship between low FVC, number of cardiac surgeries and cardiopulmonary response leading to decreased exercise capacity. Retrospective chart review of demographics, surgical history and exercise testing including spirometry was performed in patients with CHD. Single ventricle patients were excluded. Low FVC was defined as a Z-score below the lower limit of normal. Exercise parameters were expressed as a percent of predicted. There were 93 patients with 2 ventricle CHD identified over 34 months with cardiopulmonary exercise testing. The FVC Z-score directly correlated with peak V̇O 2 % (R 2  = 0.07, p < 0.05), and the O 2 pulse% (R 2  = 0.25, p < 0.0001). The VE/VCO 2 was inversely related to the FVC Z-score (R 2  = 0.11, p < 0.01). Patients with minimum three prior surgeries had decreased peak VO 2 % (63.7 vs. 72.8, p < 0.05), decreased peak O 2 pulse% (80.8 vs. 97.9, p < 0.01) and a lower mean FVC Z-score (- 1.9 vs - 0.38, p < 0.01). The FVC Z-score and number of surgeries both predicted peak V̇O 2 % in multivariate analysis. Our study demonstrated that low FVC and three or more prior cardiac surgeries were associated with lower exercise capacity and lower stroke volume response. More cardiac surgeries were also associated with low FVC. However, both low FVC and the number of surgeries were independent predictors of exercise capacity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite significant improvements in the management of Fontan circulation in patients with single ventricle physiology, long-term outcomes continue to be suboptimal. Conversion to biventricular circulation is increasingly gaining popularity, particularly in the subset of patients who are not ideal Fontan candidates. Meticulous image-guided planning, extensive preoperative discussions, and a team-based approach are required for successful execution of complex biventricular conversion. A segmental approach to the anatomy of the heart defect allows methodical planning of the technique of biventricular conversion. Ventricular size and function continue to be the Achilles heel of successful biventricular repair. Long-term studies comparing outcomes in patients converted to biventricular circulation to those in patients with Fontan physiology are required to appropriately tailor management approaches to an individual patient., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background & Aims: Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored., Methods: A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed., Results: Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m 2 , with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/μl for congestive hepatic fibrosis score [CHFS] 0-2b, p  = 0.009), higher bilirubin (1.7 ± 2.2 vs . 0.9 ± 0.7 mg/dl, p  = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs . 0.4 ± 0.1, p <0.01 [AUC: 0.69] and FIB-4: 0.6 ± 0.4 vs . 0.4 ± 0.2, p <0.01 [AUC: 0.69]), and worse overall survival (median 2 years follow-up post-biopsy, p  = 0.027). Regression modelling of temporal changes in platelet counts before and after biopsy correlated with fibrosis severity ( p  = 0.005)., Conclusions: In this large, relatively homogeneous adolescent population in terms of age, ethnicity, and Fontan duration, bridging fibrosis was observed in 35% of patients within the first decade post-Fontan. Bridging fibrosis was associated with worse survival. Changes in platelet counts, even years before biopsy, and APRI/FIB-4 scores had modest discriminatory power in identifying patients with advanced fibrosis. Steatosis may represent an additional risk factor for disease progression in obese patients. Further prospective studies are necessary to develop strategies to screen for FALD in the adolescent population., Lay Summary: In this study, the prevalence of Fontan-associated liver disease (FALD) in the young adult population and clinical variables that may be predictive of fibrosis severity or adverse outcomes were explored. Several lab-based, non-invasive markers of bridging fibrosis in FALD were identified, suggesting that these values may be followed as a prognostic biomarker for FALD progression in the adolescent population., Competing Interests: The authors have no conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Objectives: Ebstein anomaly and tricuspid valve dysplasia (EA/TVD) carry high perinatal mortality. Past studies have focused on cardiac predictors of mortality; we sought to describe the fetal echo (FE) extracardiac Dopplers in this cohort and determine their association with perinatal mortality., Method: Fetuses with EA/TVD at 23 centers from 2005-2011 were included for retrospective study. Doppler pattern and velocity of the umbilical artery (UA), umbilical vein (UV), ductus venosus (DV), and middle cerebral artery (MCA) were collected. Bivariate and multivariate analyzes were performed. The primary outcome measure was perinatal mortality, defined as fetal demise or neonatal death., Results: Of 190 cases that met eligibility criteria, alterations were seen in 50% of UA, 16% of UV, 48% of DV, and 8% of MCA Doppler indices on the last FE (median 27.4 weeks). Independent predictors of perinatal mortality included abnormal UA Doppler pattern of absence or reversed end diastolic flow (OR 9.7) and UV velocity z score <1 (OR 2.5), in addition to diagnosis <32 weeks (OR 4.2) and tricuspid valve (TV) annulus z score ≥6 (OR 5.3)., Conclusion: Abnormal UA Doppler pattern and decreased UV velocity are independent predictors of perinatal mortality in EA/TVD fetuses and should be used to refine mortality risk and guide perinatal management., (© 2020 John Wiley & Sons, Ltd.)

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers., (© 2020 Wiley Periodicals LLC.)

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD., (© 2020 by The American Society of Hematology.)

Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion. In this study, we determined the effect of mental stress on microvascular blood flow and autonomic nervous system reactivity. Sickle cell patients and controls performed mentally stressful tasks, including a memory task, conflict test and pain anticipation test. Blood flow was measured using photoplethysmography, autonomic reactivity was derived from electrocardiography and perceived stress was measured by the State-Trait Anxiety Inventory questionnaire. Stress tasks induced a significant decrease in microvascular blood flow, parasympathetic withdrawal and sympathetic activation in all subjects. Of the various tests, pain anticipation caused the highest degree of vasoconstriction. The magnitude of vasoconstriction, sympathetic activation and perceived stress was greater during the Stroop conflict test than during the N-back memory test, indicating the relationship between magnitude of experimental stress and degree of regional vasoconstriction. Baseline anxiety had a significant effect on the vasoconstrictive response in sickle cell subjects but not in controls. In conclusion, mental stress caused vasoconstriction and autonomic nervous system reactivity in all subjects. Although the pattern of responses was not significantly different between the two groups, the consequences of vasoconstriction can be quite significant in SCD because of the resultant entrapment of sickle cells in the microvasculature. This suggests that mental stress can precipitate a VOC in SCD by causing neural-mediated vasoconstriction., (Copyright© 2020 Ferrata Storti Foundation.)

Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference). Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland-Altman plots. Linear regression was used to evaluate proportional bias. Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2-44); median anthracycline dose: 225 mg/m 2 (25-642)]. Echocardiography overestimated mean EF by 4.9% ( P < 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR ( t = 3.1, P < 0.001). There was no difference between mean EF derived from Vivio and from CMR (-0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF < 45% (sensitivity 14.3%), Echo EF < 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF < 45% or EF < 50% (sensitivity 85.7%)]. Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 24(13); 3119-25. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients., (© 2017 Wiley Periodicals, Inc.)

Purpose: We sought a human blood T 2 -oximetery calibration curve over the wide range of hematocrits commonly found in anemic patients applicable with T 2 relaxation under spin tagging (TRUST)., Methods: Blood was drawn from five healthy control subjects. Ninety-three in vitro blood transverse relaxation (T 2b ) measurements were performed at 37°C over a broad range of hematocrits (10-55%) and oxygen saturations (14-100%) at 3 Tesla (T). In vivo TRUST was performed on 35 healthy African American control subjects and 11 patients with chronic anemia syndromes., Results: 1/T 2 rose linearly with hematocrit (r 2  = 0.96), for fully saturated blood. Upon desaturation, 1/T 2 rose linearly with the square of the oxygen extraction, (1-Y) 2 , and the slope was linearly proportional to hematocrit (r 2  = 0.88). The resulting bilinear model between 1/T 2 , (1-Y) 2 , and hematocrit had a combined r 2 of 0.96 and a coefficient of variation of 6.1%. Using the in vivo data, the bilinear model had significantly lower bias and variability than existing calibrations, particularly for low hematocrits. In vivo Bland Altman analysis demonstrated clinically relevant bias that was -6% (absolute saturation) for hematocrits near 30% and rose to + 6% for hematocrits near 45%., Conclusion: This work introduces a robust bilinear calibration model that should be used for MRI oximetry. Magn Reson Med 77:2364-2371, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Studies performed in the last decades have highlighted the need to better understand the contribution of the endothelium, vascular function, oxidative stress, inflammation, coagulation, hemolysis and vascular adhesion mechanisms to the pathophysiology of acute vaso-occlusive like events and chronic organ damages in sickle cell disease (SCD). Although SCD is a hemorheological disease, a few works focused on the contribution of blood viscosity, plasma viscosity, red blood cell deformability and aggregation in the pathophysiology of SCD. After a brief description of basic hemorheology, the present review focuses on the role of the hemorheological abnormalities in the causation of several SCD complications, mainly in sickle cell anemia and hemoglobin (Hb) SC disease. Several genetic and cellular modulators of blood rheology in SCD are discussed, as well as unresolved questions and perspectives.

Sickle cell disease (SCD) is characterized by sudden onset of painful vaso-occlusive crises (VOC), which occur on top of the underlying chronic blood disorder. The mechanisms that trigger VOC remain elusive, but recent work suggests that autonomic dysfunction may be an important predisposing factor. Heart-rate variability has been employed in previous studies, but the derived indices have provided only limited univariate information about autonomic cardiovascular control in SCD. To circumvent this limitation, a time-varying modeling approach was applied to investigate the functional mechanisms relating blood pressure (BP) and respiration to heart rate and peripheral vascular resistance in healthy controls, untreated SCD subjects and SCD subjects undergoing chronic transfusion therapy. Measurements of respiration, heart rate, continuous noninvasive BP and peripheral vascular resistance were made before, during and after the application of cold face stimulation (CFS), which perturbs both the parasympathetic and sympathetic nervous systems. Cardiac baroreflex sensitivity estimated from the model was found to be impaired in nontransfused SCD subjects, but partially restored in SCD subjects undergoing transfusion therapy. Respiratory-cardiac coupling gain was decreased in SCD and remained unchanged by chronic transfusion. These results are consistent with autonomic dysfunction in the form of impaired parasympathetic control and sympathetic overactivity. As well, CFS led to a significant reduction in vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups. This blunting of the baroreflex control of peripheral vascular resistance during elevated sympathetic drive could be a potential factor contributing to the triggering of VOC in SCD., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

The risk for pulmonary hypertension (PH) in thalassemia major (TM) patients remains controversial. We report echocardiography results from 60 TM patients: we evaluated the association between tricuspid regurgitation velocities (TRV), iron stores, and serologic markers of hemolysis and arginine dysregulation. Patients were enrolled from August 2004 until May 2009. All parameters were inversely weighted by the number of exams. TRV was comparable between sexes and it was uncorrelated with age. At the first exam, TR velocities at the upper limits of normal (2.5-2.7m/s) were observed in 8 patients. An abnormal TRV (2.9m/s) was found in 1 patient. Borderline increases in TRV were associated with a reduced global arginine bioavailability (R=-0.399 P=0.005), increased anemia (hemoglobin: R=-0.219 P=0.0461), cardiac index (R=0.223 P=0.0481), and diastolic dysfunction (E/A: R=0.289 P=0.0088; E/E': R=0.223 P=0.0453), but not hemolysis, iron overload and systolic function evaluated by Magnetic Resonance Imaging, and splenectomy. Well-transfused TM patients have a lower risk for PH than thalassemia intermedia patients. However, they do have vascular stressors that raise their lifetime PH risk to levels higher than for the general population. Consequently, we support recommendations for annual echocardiographic screening and cardiac catheterization for persistent TRV above 3m/s., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate outcomes for neonates with critical congenital heart disease (CHD) requiring emergent neonatal cardiac intervention (ENCI)., Methods: Neonates < 30 days of age that underwent ENCI at <48 h of age were retrospectively enrolled over a 2-year period., Results: Forty-seven neonates met inclusion criteria for ENCI comprising nine cardiac defects that underwent 25 catheterizations and 22 cardiothoracic surgeries. The main groups were d-transposition of the great arteries (DTGA) and total anomalous pulmonary venous return (TAPVR). Prenatal detection was 38% overall: higher for single ventricle (86%) and heterotaxy (75%) than for DTGA (28%) or TAPVR (13%). Mortality was 11.1% (2/18) in prenatally diagnosed versus 13.8% (4/29) in postnatally diagnosed neonates (p = 0.86). Prenatal detection was associated with shorter mean hospital stay: 16.8 versus 30.3 days (p = 0.03). Prenatally diagnosed patients had lower preoperative inotropic scores (p = 0.02), less acidosis (pH; p = 0.09), but decreased likelihood of spontaneous labor (p = 0.01), lower gestational age (p = 0.01), and lower birth weight (p = 0.01)., Conclusions: Fewer deaths occurred in neonates with prenatal detection of their critical CHD requiring ENCI. However, there was no statistical difference in survival demonstrated for prenatally diagnosed neonates in this small cohort. Prenatal detection did improve preoperative clinical status and shorten hospital length of stay., (© 2014 John Wiley & Sons, Ltd.)

Consumption of red wine is associated with a decreased risk of several cardiovascular diseases (e.g., coronary artery disease, stroke), but unfortunately literature reports regarding ethanol's effects on hemorheological parameters are not concordant. In the present study, red blood cell (RBC) deformability was tested via laser ektacytometry (LORCA, 0.3-30 Pa) using two approaches: 1) addition of ethanol to whole blood at 0.25%-2% followed by incubation and testing in ethanol-free LORCA medium; 2) addition of ethanol to the LORCA medium at 0.25%-6% then testing untreated native RBC in these media. The effects of ethanol on deformability for oxidatively stressed RBC were investigated as were changes of RBC aggregation (Myrenne Aggregometer) for cells in autologous plasma or 3% 70 kDa dextran. Significant dose-related increases of RBC deformability were observed at 0.25% (p < 0.05) and higher concentrations only if ethanol was in the LORCA medium; no changes occurred for cells previously incubated with ethanol then tested in ethanol-free medium. The impaired deformability of cells pre-exposed to oxidative stress was improved only if ethanol was in the LORCA medium. RBC aggregation decreased with concentration at 0.25% and higher for cells in both autologous plasma and dextran 70. Our results indicate that ethanol reversibly improves erythrocyte deformability and irreversibly decreases erythrocyte aggregation; the relevance of these results to the health benefits of moderate wine consumption require further investigation.

Background and Purpose: Abnormal cerebral microstructure has been documented in term neonates with congenital heart disease, portending risk for injury and poor neurodevelopmental outcome. Our hypothesis was that preterm neonates with congenital heart disease would demonstrate diffuse cerebral microstructural abnormalities when compared with critically ill neonates without congenital heart disease. A secondary aim was to identify any association between microstructural abnormalities, white matter injury (eg, punctate white matter lesions), and other clinical variables, including heart lesions., Materials and Methods: With the use of tract-based spatial statistics, an unbiased, voxelwise method for analyzing diffusion tensor imaging data, we compared 21 preterm neonates with congenital heart disease with 2 cohorts of neonates without congenital heart disease: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit., Results: Compared with term neonates without congenital heart disease, preterm neonates with congenital heart disease had microstructural abnormalities in widespread regions of the central white matter. However, 42% of the preterm neonates with congenital heart disease had punctate white matter lesions. When neonates with punctate white matter lesions were excluded, microstructural abnormalities remained only in the splenium. Preterm neonates with congenital heart disease had similar microstructure to preterm neonates without congenital heart disease., Conclusions: Diffuse microstructural abnormalities were observed in preterm neonates with congenital heart disease, strongly associated with punctate white matter lesions. Independently, regional vulnerability of the splenium, a structure associated with visual spatial function, was observed in all preterm neonates with congenital heart disease.

Patients with chronic anemia develop compensatory ventricular dilation, even when maintained on chronic transfusion regimens. It is important to characterize these effects to interpret pathological changes in cardiac dimensions and function introduced by iron overload and sickle cell vasculopathy. Our primary goal was to compare biventricular dimensions and function assessed by cardiovascular magnetic resonance (CMR) in pediatric, chronically-transfused sickle-cell disease (SCD) and thalassemia major (TM) patients who had normal cardiac iron levels. Moreover, we explored systematic sex differences in ventricular dimensions in both populations. We identified 261 studies suitable for analysis from 64 patients with SCD (34 females) and 49 patients with TM (20 females). All demographic and CMR parameters were inversely weighted by the number of exams. In both populations, males had larger left and right ventricular dimensions than females, with a more marked effect observed in patients with SCD. Compared to patients with TM, patients with SCD showed significantly greater biventricular dilation and left ventricular hypertrophy. This difference could not be explained by different hemoglobin levels, cardiac iron overload, and systolic blood pressure. The left ventricular (LV) ejection fraction (EF) for the males and the right ventricular (RV) EF for both the sexes were comparable between SCD and TM groups, while females with SCD had significantly lower LV EF than females with TM. Our results represent important baseline findings that place changes introduced by iron overload as well as systemic and pulmonary vasculopathy in proper context., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Simple chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen-carrying capacity, reducing demands for high cardiac output. While transfusion decreases factors associated with vasoocclusion, including percent hemoglobin (Hb)S, reticulocyte count, and circulating cell-free Hb, it increases blood viscosity, which reduces microvascular flow. The hematocrit-to-viscosity ratio (HVR) is an index of red blood cell oxygen transport effectiveness that varies with shear stress and balances the benefits of improved oxygen capacity to viscosity-mediated impairment of microvascular flow. We hypothesized that transfusion would improve HVR at high shear despite increased blood viscosity, but would decrease HVR at low shear., Study Design and Methods: To test this hypothesis, we examined oxygenated and deoxygenated blood samples from 15 sickle cell patients on CTT immediately before transfusion and again 12 to 120 hours after transfusion., Results: Comparable changes in Hb, hematocrit (Hct), reticulocyte count, and HbS with transfusion were observed in all subjects. Viscosity, Hct, and high-shear HVR increased with transfusion while low-shear HVR decreased significantly., Conclusion: Decreased low-shear HVR suggests impaired oxygen transport to low-flow regions and may explain why some complications of sickle cell anemia are ameliorated by CTT and others may be made worse., (© 2012 American Association of Blood Banks.)

Objective: We sought to evaluate the impact of mode of delivery (MOD) on early outcome for neonates diagnosed prenatally with major forms of congenital heart disease (CHD)., Methods: We retrospectively studied infants admitted, over a 2-year period, to a single institution for cardiac intervention. Infants were grouped on the basis of timing of diagnosis (prenatal/postnatal) and MOD--planned (induced labor or planned cesarean delivery) versus spontaneous labor. Multivariate logistic regression was used to evaluate independent predictors for MOD and early outcomes., Results: Of 329 patients, 45% received a prenatal diagnosis of CHD. A prenatal diagnosis of CHD increased the likelihood for planned delivery [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.6 to 4.5, p < 0.001]. Newborns prenatally diagnosed with CHD were more likely to have been delivered between 8 am and 6 pm, Monday through Friday (OR 2.3, 95% CI 1.1 to 4.8, p = 0.019). However, MOD had no statistical impact on Apgar score, duration of pre-operative intubation, and survival to surgery or to discharge. The Risk Adjustment for Congenital Heart Surgery 1 surgical mortality score was the only independent predictor of hospital mortality., Conclusions: In our experience, although a prenatal diagnosis of CHD decreased the likelihood of spontaneous labor, MOD had no demonstrable impact on neonatal outcome., (© 2012 John Wiley & Sons, Ltd.)

Iron cardiomyopathy is a leading cause of death in transfusion-dependent thalassemia major (TM) patients and MRI (T2*) can recognize preclinical cardiac iron overload, but, is unavailable to many centers. We evaluated the ability of 12-lead electrocardiography to predict cardiac iron loading in TM. 12-lead electrocardiogram and cardiac T2* measurements were performed prospectively, with a detectable cardiac iron cutoff of T2*less than 20 ms. Patients with and without cardiac iron were compared using two-sample statistics and against population norms using age and gender-matched Z-scores. 45/78 patients had detectable cardiac iron. Patients having cardiac iron were older and more likely female but had comparable liver iron burdens and serum ferritin. Increased heart rate (HR) and prolonged corrected QT interval (QT(c)) were present, regardless of cardiac iron status. Repolarization abnormalities were the strongest predictors of cardiac iron, including QT/QT(c) prolongation, left shift of T-wave axis, and interpretation of ST/T-wave morphology. Recursive partitioning of the data for females using T-axis and HR and for males using QT, HR, and T-axis produced algorithms with AUROC's of 88.3 and 87.1, respectively. Bradycardia and repolarization abnormalities on 12-lead electrocardiography were the most specific markers for cardiac iron in thalassemia major. Changes in these variables may be helpful to stratify cardiac risk when cardiac MRI is unavailable. However, diagnostic algorithms need to be vetted on larger and more diverse patient populations and longitudinal studies are necessary to determine reversibility of the observed abnormalities., (Copyright © 2011 Wiley-Liss, Inc.)

Large placental chorioangiomas (>4 cm) can precipitate severe polyhydramnios, fetal anemia, growth restriction, high-output cardiac failure, hydrops, and fetal demise. We report a case of a large chorioangioma that was treated in a stepwise fashion with amnioreduction to ameliorate maternal discomfort, followed by fetoscopic laser ablation of the feeding vessels after rapid evolution of heart failure. Although amnioreduction was helpful in improving maternal symptoms, we suspect that the drop in intrauterine pressure from the amniotic fluid decompression may have resulted in increased tumor perfusion, thereby promoting fetal deterioration due to a 'steal' phenomenon. Close scrutiny of the fetal status via ultrasound is required, particularly if amnioreduction is necessary, and definitive treatment should be considered once early signs of heart failure develop. Fetoscopic laser ablation of the feeding vessels is a feasible definitive treatment of a large chorioangioma in cases in which perfusion of the tumor is via a superficial nonterminus umbilical artery. Future reports should describe the anatomy of the blood supply to the chorioangioma, in the hopes that further guidelines for surgical candidacy may be established., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To assess postnatal prevalence of congenital heart disease (CHD) in surviving twins treated for twin-twin transfusion syndrome (TTTS) with laser surgery., Methods: Patients who underwent laser surgery for TTTS at a single institution were prospectively enrolled between January 2009 and May 2010. Preoperative fetal echocardiography was performed. Perinatal outcomes were obtained via postnatal echocardiograms and review of medical records. CHD was defined as unequivocal structural cardiac pathology; patent foramen ovale and patent ductus arteriosus were excluded., Results: Fifty pregnancies with TTTS were enrolled, with the following Quintero stage distribution: stage I, 10%; stage II, 22%; stage III, 50%; and stage IV, 18%. Of the 88 fetuses born alive, 84 patients (95.5%) completed postnatal cardiac evaluation. Overall postnatal prevalence of CHD was 15.5% (13 of 84): 15.6% of recipient twins and 15.4% of donor twins. Three patients required cardiac intervention during infancy. Among liveborn twins with CHD, the overall prenatal detection rate was 30.8% (4/13), comprising 16.7% (1/6) of donors compared with 42.9% (3/7) of recipients., Conclusion: Following successful laser surgery for TTTS, an increased and comparable postnatal prevalence of CHD occurs among both former recipients and donors., (Copyright © 2011 John Wiley & Sons, Ltd.)

Integrins are a diverse family of heterodimeric (alphabeta) adhesion receptors recently shown to be concentrated within synapses and involved in the consolidation of long-term potentiation. Whether neuronal types or anatomical systems in the adult rat brain are coded by integrin type was studied in the present experiments by mapping the relative densities of mRNAs for nine alpha and four beta subunits. Expression patterns were markedly different and in some regions complementary. General results and areas of notable labeling were as follows: alpha1-limited neuronal expression, neocortical layer V, hippocampal CA3; alpha3 and alpha5-diffuse neuronal and glial labeling, Purkinje cells, hippocampal stratum pyramidale, locus coeruleus (alpha3); alpha4- discrete limbic regions, olfactory cortical layer II, hippocampal CA2; alpha6-most prominently neuronal, neocortical subplate, endopiriform, subiculum; alpha7-discrete, all neocortical layers, hippocampal granule cells and CA3, cerebellar granule and Purkinje cells, all efferent cranial nerve nuclei; alpha8-discrete neuronal, deep cortex, hippocampal CA1, basolateral amygdala, striatum; alphaV-all cortical layers, striatum, Purkinje cells; beta4-dentate gyrus granule cells; beta5-broadly distributed, neocortex, medial amygdala, cerebellar granule and Purkinje cells, efferent cranial nerve nuclei; alpha2, beta2, and beta3-mRNAs not detected. These results establish that brain subfields express different balances of integrin subunits and thus different integrin receptors. Such variations will determine which matrix proteins are recognized by neurons and the types of intraneuronal signaling generated by matrix binding. They also could generate important differences in synaptic plasticity across brain systems.