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Publication Record


Endothelial-Dependent Vasomotor Dysfunction in Infants After Cardiopulmonary Bypass.
Krispinsky LT, Stark RJ, Parra DA, Luan L, Bichell DP, Pietsch JB, Lamb FS
(2020) Pediatr Crit Care Med 21: 42-49
MeSH Terms: Acetylcholine, Biomarkers, Cardiac Surgical Procedures, Cardiopulmonary Bypass, Cardiovascular Diseases, Child, Child, Preschool, Cytokines, Endothelium, Vascular, Heart Defects, Congenital, Humans, Infant, Microcirculation, Nitric Oxide, Pilot Projects, Postoperative Complications, Prospective Studies, Severity of Illness Index, Vascular Resistance, Vasodilator Agents, Vasomotor System
Show Abstract · Added July 2, 2019
OBJECTIVES - Cardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.
DESIGN - Single-center prospective observational cohort pilot study.
SETTING - Pediatric cardiac ICU at a tertiary children's hospital.
PATIENTS - Children less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.
MEASUREMENTS AND MAIN RESULTS - Laser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).
CONCLUSIONS - Cutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.
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21 MeSH Terms
Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.
Osipovich AB, Gangula R, Vianna PG, Magnuson MA
(2016) Development 143: 4595-4607
MeSH Terms: Acetylation, Animals, Apoptosis, Carrier Proteins, Cell Cycle, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chromatin, Embryonic Development, Embryonic Stem Cells, Gene Expression Regulation, Heart Defects, Congenital, Histones, Methyltransferases, Mice, Mice, Knockout, Myocytes, Cardiac, Neural Tube, Promoter Regions, Genetic, RNA, Untranslated, Transcription, Genetic
Show Abstract · Added November 30, 2016
SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.
© 2016. Published by The Company of Biologists Ltd.
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22 MeSH Terms
Brain in Congenital Heart Disease Across the Lifespan: The Cumulative Burden of Injury.
Marelli A, Miller SP, Marino BS, Jefferson AL, Newburger JW
(2016) Circulation 133: 1951-62
MeSH Terms: Brain, Brain Injuries, Child, Child Development, Cost of Illness, Heart Defects, Congenital, Humans, Longevity, Risk Factors
Show Abstract · Added March 26, 2019
The number of patients surviving with congenital heart disease (CHD) has soared over the last 3 decades. Adults constitute the fastest-growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has been focused largely on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes mellitus, and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. Against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions.
© 2016 American Heart Association, Inc.
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MeSH Terms
Cognitive and attentional functioning in adolescents and young adults with Tetralogy of Fallot and d-transposition of the great arteries.
Murphy LK, Compas BE, Reeslund KL, Gindville MC, Mah ML, Markham LW, Jordan LC
(2017) Child Neuropsychol 23: 99-110
MeSH Terms: Adolescent, Adult, Attention, Child, Cognition, Female, Heart Defects, Congenital, Humans, Male, Tetralogy of Fallot, Transposition of Great Vessels, Young Adult
Show Abstract · Added March 24, 2020
The objective of this study is to investigate cognitive and attentional function in adolescents and young adults with operated congenital heart disease. Previous research has indicated that children with congenital heart disease have deficits in broad areas of cognitive function. However, less attention has been given to survivors as they grow into adolescence and early adulthood. The participants were 18 non-syndromic adolescents and young adults with tetralogy of Fallot and d-transposition of the great arteries that required cardiac surgery before the age of 5 years, and 18 healthy, unaffected siblings (11-22 years of age for both groups). Cases with congenital heart disease and their siblings were administered Wechsler Intelligence scales and reported attention problems using the Achenbach System of Empirically Based Assessments. Cases were compared to both healthy siblings and established norms. Cases performed significantly lower than siblings on full scale IQ and processing speed, and significantly lower than norms on perceptual reasoning. Cases also reported more attention problems compared to both siblings and norms. Effect sizes varied with medium-to-large effects for processing speed, perceptual reasoning, working memory, and attention problems. Findings suggest that neurocognitive function may continue to be affected for congenital heart disease survivors in adolescence and young adulthood, and that comparisons to established norms may underestimate neurocognitive vulnerabilities.
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MeSH Terms
Parenteral Prostanoid Use at a Tertiary Referral Center: A Retrospective Cohort Study.
Hay BR, Pugh ME, Robbins IM, Hemnes AR
(2016) Chest 149: 660-6
MeSH Terms: Adult, Cause of Death, Cohort Studies, Comorbidity, Connective Tissue Diseases, Death, Sudden, Endothelin Receptor Antagonists, Familial Primary Pulmonary Hypertension, Female, Guideline Adherence, HIV Infections, Heart Defects, Congenital, Heart Failure, Humans, Hypertension, Pulmonary, Infusions, Parenteral, Male, Middle Aged, Patient Selection, Phosphodiesterase 5 Inhibitors, Practice Guidelines as Topic, Prostaglandins, Quality Improvement, Retrospective Studies, Severity of Illness Index, Tertiary Care Centers
Show Abstract · Added March 8, 2020
BACKGROUND - Evidence-based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many patients with PAH die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize patients with PAH who died without receiving PP.
METHODS - We conducted a single-center retrospective cohort analysis of consecutive patients with PAH between 2008 and 2012. Clinical data and cause of death were compared between patients with PAH treated with PP (PAH-PP) and those who were not but were not documented as poor PP candidates (PAH-nonPP).
RESULTS - Of the 101 patients who received a diagnosis of PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) whereas 30 were not considered candidates or refused PP therapy. Compared with PAH-PP, PAH-nonPP had a longer 6-min walk distance, had a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be diagnosed as functional class IV, and had significantly lower right atrial pressure. None of the PAH-nonPP died of progressive PAH.
CONCLUSIONS - We found that most patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH-related causes. Our data suggest that at large pulmonary hypertension (PH) centers, the vast majority of patients who are appropriate candidates receive PP therapy.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Association between perioperative dexmedetomidine and arrhythmias after surgery for congenital heart disease.
Shuplock JM, Smith AH, Owen J, Van Driest SL, Marshall M, Saville B, Xu M, Radbill AE, Fish FA, Kannankeril PJ
(2015) Circ Arrhythm Electrophysiol 8: 643-50
MeSH Terms: Adrenergic alpha-2 Receptor Agonists, Arrhythmias, Cardiac, Bradycardia, Cardiac Surgical Procedures, Chi-Square Distribution, Child, Child, Preschool, Dexmedetomidine, Female, Heart Defects, Congenital, Humans, Incidence, Infant, Infant, Newborn, Logistic Models, Male, Multivariate Analysis, Odds Ratio, Propensity Score, Retrospective Studies, Risk Factors, Tachycardia, Tennessee, Time Factors, Treatment Outcome
Show Abstract · Added April 11, 2017
BACKGROUND - Dexmedetomidine is commonly used after congenital heart surgery and may be associated with a decreased incidence of postoperative tachyarrhythmias. Using a large cohort of patients undergoing congenital heart surgery, we examined for an association between dexmedetomidine use in the immediate postoperative period and subsequent arrhythmia development.
METHODS AND RESULTS - A total of 1593 surgical procedures for congenital heart disease were performed. Dexmedetomidine was administered in the immediate postoperative period after 468 (29%) surgical procedures. When compared with 1125 controls, the group receiving dexmedetomidine demonstrated significantly fewer tachyarrhythmias (29% versus 38%; P<0.001), tachyarrhythmias receiving intervention (14% versus 23%; P<0.001), bradyarrhythmias (18% versus 22%; P=0.03), and bradyarrhythmias receiving intervention (12% versus 16%; P=0.04). After propensity score matching with 468 controls, the arrhythmia incidence between groups became similar: tachyarrhythmias (29% versus 31%; P=0.66), tachyarrhythmias receiving intervention (14% versus 17%; P=0.16), bradyarrhythmias (18% versus 15%; P=0.44), and bradyarrhythmias receiving intervention (12% versus 9%; P=0.17). After excluding controls exposed to dexmedetomidine at a later time in the hospitalization, dexmedetomidine was associated with increased odds of bradyarrhythmias receiving intervention (odds ratio, 2.18; 95% confidence interval, 1.02-4.65). Furthermore, there was a dose-dependent increase in the odds of bradyarrhythmias (odds ratio, 1.04; 95% confidence interval, 1.01-1.07) and bradyarrhythmias receiving intervention (odds ratio, 1.05; 95% confidence interval, 1.01-1.08).
CONCLUSIONS - Although dexmedetomidine exposure in the immediate postoperative period is not associated with a clinically meaningful difference in the incidence of tachyarrhythmias after congenital heart surgery, it may be associated with increased odds of bradyarrhythmias.
© 2015 American Heart Association, Inc.
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25 MeSH Terms
Neonatal carotid repair at ECMO decannulation: patency rates and early neurologic outcomes.
Duggan EM, Maitre N, Zhai A, Krishnamoorthi H, Voskresensky I, Hardison D, Tice J, Pietsch JB, Lovvorn HN
(2015) J Pediatr Surg 50: 64-8
MeSH Terms: Brain, Carotid Arteries, Evoked Potentials, Auditory, Brain Stem, Extracorporeal Membrane Oxygenation, Female, Heart Defects, Congenital, Humans, Infant, Newborn, Ligation, Male, Postoperative Period, Retrospective Studies, Vascular Patency
Show Abstract · Added October 1, 2015
PURPOSE - Neonates placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) undergo either carotid repair or ligation at decannulation. Study aims were to evaluate carotid patency rates after repair and to compare early neurologic outcomes between repaired and ligated patients.
METHODS - A retrospective study of all neonates without congenital heart disease (CHD) who had VA-ECMO between 1989 and 2012 was completed using our institutional ECMO Registry. Carotid patency after repair, neuroimaging studies, and auditory brainstem response (ABR) testing at time of discharge were examined.
RESULTS - 140 neonates were placed on VA-ECMO during the study period. Among survivors, 84% of carotids repaired and imaged remained patent at last study. No significant differences were observed between infants in the repaired and ligated groups regarding diagnosis, ECMO duration, or length of stay. A large proportion (43%) developed a severe brain lesion after VA-ECMO, but few failed their ABR testing. Differences in early neurologic outcomes between the two groups of survivors were not significant.
CONCLUSIONS - At this single institution, carotid patency is excellent following repair at ECMO decannulation. No increased incidence of severe brain lesions or greater neurosensory impairment in the repair group was observed. Further studies are needed to investigate the effects of ligation on longer-term neurocognitive outcomes.
Copyright © 2015 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Repair of anomalous aortic origin of a coronary artery in 113 patients: a Congenital Heart Surgeons' Society report.
Poynter JA, Bondarenko I, Austin EH, DeCampli WM, Jacobs JP, Ziemer G, Kirshbom PM, Tchervenkov CI, Karamlou T, Blackstone EH, Walters HL, Gaynor JW, Mery CM, Pearl JM, Brothers JA, Caldarone CA, Williams WG, Jacobs ML, Mavroudis C, Congenital Heart Surgeons’ Society AAOCA Working Group
(2014) World J Pediatr Congenit Heart Surg 5: 507-14
MeSH Terms: Aorta, Thoracic, Cardiac Surgical Procedures, Child, Coronary Vessel Anomalies, Heart Defects, Congenital, Humans, Registries
Show Abstract · Added February 12, 2015
BACKGROUND - Anomalous aortic origin of a coronary artery (AAOCA) encompasses a wide morphologic spectrum, which has impeded consensus regarding indications for the diverse repair strategies. We constructed a profile of current surgical techniques and explore their application to morphologic variants.
METHODS - Patients<30 years old (n=113) with isolated AAOCA who underwent operations at 29 Congenital Heart Surgeons Society (CHSS) institutions from 1998 to 2012 were identified from the CHSS AAOCA Registry. Operative findings were related to surgical techniques at index repairs by cross-tabulation.
RESULTS - Anomalous origin of the left main or left anterior descending coronary artery was present in 33 (29%) patients and of the right coronary artery in 78 (69%) patients; 2 arteries originated directly above the commissure between the left and right sinuses. There were 101 (89%) interarterial and intramural (IA/IM) arteries, 10 (9%) were interarterial but not intramural (IA/NIM) and 2 (2%) were neither interarterial nor intramural. Intramural arteries were unroofed in 100 (88%) operations, usually with intimal tacking after incision (n=47) or excision (n=25) of the common wall. Coronary reimplantation (n=11), pulmonary artery relocation (n=7; 5 for IA/NIM), simple ostioplasty (without unroofing; n=3), coronary artery bypass grafting (n=2), and ostial window (n=1) were less common. In 37 (33%) operations, a valvar commissure was taken down; 33 were resuspended.
CONCLUSION - Current surgical repair of AAOCA is individualized to morphology, particularly the presence of intramural and/or interarterial segments. This report is foundational for future planned CHSS studies that will examine interventional and noninterventional outcomes and ultimately guide management of AAOCA.
© The Author(s) 2014.
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7 MeSH Terms
Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease.
Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, Hofmann-Bowman MA, Mortlock DP, Rogers MB, Sadeghi MM, Aikawa E
(2014) Arterioscler Thromb Vasc Biol 34: 2387-93
MeSH Terms: Aortic Valve, Aortic Valve Stenosis, Bicuspid Aortic Valve Disease, Biomedical Research, Calcinosis, Cardiac Surgical Procedures, Heart Defects, Congenital, Heart Valve Diseases, Heart Valve Prosthesis Implantation, Hemodynamics, Humans, Signal Transduction
Show Abstract · Added January 20, 2015
Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.
© 2014 American Heart Association, Inc.
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12 MeSH Terms
Potential drug targets for calcific aortic valve disease.
Hutcheson JD, Aikawa E, Merryman WD
(2014) Nat Rev Cardiol 11: 218-31
MeSH Terms: Aortic Valve, Bicuspid Aortic Valve Disease, Calcinosis, Heart Defects, Congenital, Heart Valve Diseases, Humans, Prognosis
Show Abstract · Added February 12, 2015
Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. Therefore, we discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.
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7 MeSH Terms