Scott E Klewer

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• Caryl, N. E., June, C., Culbert, M. H., Hellinger, R. D., Hoyer, A. W., Klewer, S. E., & Seckeler, M. D. (2024). Incidence of Radiation-Associated Cancer in Patients With Congenital Heart Disease. The American journal of cardiology, 210, 65-68.
• Andrews, J. G., Strah, D., Downing, K. F., Kern, M. C., Oster, M. E., Seckeler, M. D., Goudie, A., Nembhard, W. N., Farr, S. L., & Klewer, S. E. (2023). Cardiology Care and Loss to Follow-Up Among Adults With Congenital Heart Defects in CH STRONG. The American journal of cardiology, 197, 42-45.
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  Many of the estimated 1.4 million adults with congenital heart defects (CHDs) in the United States are lost to follow-up (LTF) despite recommendations for ongoing cardiology care. Using 2016 to 2019 CH STRONG (Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG) data, we describe cardiac care among community-based adults with CHD, born in 1980 to 1997, identified through state birth defects registries. Our estimates of LTF were standardized to the CH STRONG eligible population and likely more generalizable to adults with CHD than clinic-based data. Half of our sample were LTF and more than 45% had not received cardiology care in over 5 years. Of those who received care, only 1 in 3 saw an adult CHD physician at their last encounter. Not knowing they needed to see a cardiologist, being told they no longer needed cardiology care, and feeling "well" were the top reasons for LTF, and only half of respondents report doctors discussing the need for cardiac follow-up.
• Downing, K. F., Klewer, S. E., Nembhard, W. N., Goudie, A., Oster, M. E., & Farr, S. L. (2023). Healthcare and Socioeconomic Outcomes Among Young Adults With Congenital Heart Defects and Functional Cognitive Disabilities, CH STRONG 2016 to 2019. The American journal of cardiology, 201, 229-231.
• Downing, K. F., Nembhard, W. N., Rose, C. E., Andrews, J. G., Goudie, A., Klewer, S. E., Oster, M. E., & Farr, S. L. (2023). Survival From Birth Until Young Adulthood Among Individuals With Congenital Heart Defects: CH STRONG. Circulation, 148(7), 575-588.
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  Limited population-based information is available on long-term survival of US individuals with congenital heart defects (CHDs). Therefore, we assessed patterns in survival from birth until young adulthood (ie, 35 years of age) and associated factors among a population-based sample of US individuals with CHDs.
• Farr, S. L., Galindo, M., Downing, K. F., Nembhard, W. N., Klewer, S. E., Judge, A. S., Bolin, E. H., Benavides, A., & Oster, M. E. (2023). Reproductive Health Counseling and Concerns Among Women with Congenital Heart Defects With and Without Disabilities. Journal of women's health, 32(7), 740-746.
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  Women with disabilities are less likely to receive reproductive health counseling than women without disabilities. Yet, little is known about reproductive health counseling and concerns among women with congenital heart defects (CHD) and disabilities. We used population-based survey data from 778 women aged 19 to 38 years with CHD to examine contraceptive and pregnancy counseling and pregnancy concerns and experiences by disability status, based on six validated questions on vision, hearing, mobility, cognition, self-care, and living independently. Multivariable Poisson regression was used to examine adjusted prevalence ratios between disability status and each outcome, adjusted for CHD severity, age, race/ethnicity, place of birth (Arkansas, Arizona, Georgia), and insurance type. Women with disabilities ( = 323) were 1.4 and 2.3 times more likely than women without disabilities ( = 455) to receive clinician counseling on safe contraceptive methods and avoiding pregnancy because of their CHD. Women with CHD and disabilities, compared to those without disabilities, were more likely to be concerned about their ability to have children (aPR = 1.2) and to have delayed or avoided pregnancy (aPR = 2.2); they were less likely to have ever been pregnant (aPR = 0.7). Associations differed slightly across specific disability types. All associations remained after excluding 71 women with chromosomal anomalies. Among women with CHD, reproductive counseling, concerns, and experiences differ by disability status.
• García, D., Huntsman, J., Sisk, D., Price, A. M., Schock, S. N., Klewer, S. E., & Seckeler, M. D. (2023). Congenital left atrial appendage ostial stenosis in an extremely premature infant diagnosed by transthoracic echocardiography. Echocardiography (Mount Kisco, N.Y.), 40(6), 587-591.
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  Congenital left atrial appendage ostial stenosis is a very rare congenital cardiac condition. We present the case of an extremely premature infant with congenital left atrial appendage ostial stenosis diagnosed by transthoracic echocardiographic imaging.
• June, C., Culbert, M. H., Meziab, O., Caryl, N. E., Klewer, S. E., & Seckeler, M. D. (2023). Additional Burden of Esophageal and Gastric Varices on Hospitalized Patients With Moderate or Severe Congenital Heart Disease. The American journal of cardiology, 209, 163-164.
• Klewer, S. E. (2023). COVID-19–Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease. JACC: Advances, Volume 2, IDecember 2023(Issue 10), Article number 100701.
• Kops, S. A., Strah, D. D., Andrews, J., Klewer, S. E., & Seckeler, M. D. (2023). Contemporary pregnancy outcomes for women with moderate and severe congenital heart disease. Obstetric medicine, 16(1), 17-22.
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  Women with congenital heart disease (CHD) are surviving into adulthood, with more undergoing pregnancy.
• Takamatsu, C., Ibrahim, R., Corban, M. T., Klewer, S. E., & Seckeler, M. D. (2023). Transcatheter Treatment of Right Ventricular Outflow Tract Compression by a Pseudoaneurysm in Tetralogy of Fallot. JACC. Cardiovascular interventions, 16(15), 1931-1934.
• Broberg, C. S., Kovacs, A. H., Sadeghi, S., Rosenbaum, M. S., Lewis, M. J., Carazo, M. R., Rodriguez, F. H., Halpern, D. G., Feinberg, J., Galilea, F. A., Baraona, F., Cedars, A. M., Ko, J. M., Porayette, P., Maldonado, J., Sarubbi, B., Fusco, F., Frogoudaki, A. A., Nir, A., , Chaudhry, A., et al. (2021). COVID-19 in Adults With Congenital Heart Disease. Journal of the American College of Cardiology, 77(13), 1644-1655.
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  Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications.
• Combs, D., Edgin, J. O., Klewer, S., Barber, B. J., Morgan, W. J., Hsu, C. H., Abraham, I., & Parthasarathy, S. (2020). OSA and Neurocognitive Impairment in Children With Congenital Heart Disease. Chest, 158(3), 1208-1217.
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  Children with congenital heart disease (CHD) have an increased risk of neurocognitive impairment. No prior studies have evaluated the role of OSA, which is associated with neurocognitive impairment in children without CHD.
• Farr, S. L., Klewer, S. E., Nembhard, W. N., Alter, C., Downing, K. F., Andrews, J. G., Collins, R. T., Glidewell, J., Benavides, A., Goudie, A., Riehle-Colarusso, T., Overman, L., Riser, A. P., & Oster, M. E. (2020). Rationale and design of CH STRONG: Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG. American heart journal, 221, 106-113.
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  Studies of outcomes among adults with congenital heart defects (CHDs) have focused on those receiving cardiac care, limiting generalizability. The Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG (CH STRONG) will assess comorbidities, health care utilization, quality of life, and social and educational outcomes from a US population-based sample of young adults living with CHD.
• Janardhanan, R., Seckeler, M. D., Seckeler, M. D., Klewer, S. E., Kern, M. C., Kelly, T., Janardhanan, R., & Fox, K. A. (2020). Multimodality imaging for diagnosis and procedural planning for a ruptured sinus of Valsalva aneurysm.. Journal of cardiovascular computed tomography, 14(6), e139-e142. doi:10.1016/j.jcct.2019.09.018
• Kops, S. A., Andrews, J. G., Klewer, S. E., & Seckeler, M. D. (2020). Effect of comorbid neuropsychiatric disorders on children and adolescents undergoing surgery for moderate and severe congenital heart disease. Journal of cardiac surgery, 35(11), 3048-3052.
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  Children and adolescents with congenital heart disease (CHD) are at an increased risk of neuropsychiatric disorders (NPDs). The purpose of this study is to determine how a comorbid NPD affects hospital outcomes and costs for CHD patients undergoing cardiac surgery.
• Kurepa, D., Boyar, V., Zaghloul, N., Beachy, J., Zaytseva, A., Teng, D., Cooper, R., Klewer, S., & Amodio, J. (2020). Structured Neonatal Point-of-Care Ultrasound Training Program. American journal of perinatology.
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   Point-of-care ultrasound (POC US) has been increasingly used by intensive care physicians. Growing use of POC US necessitates defining distinct clinical indications for its application, as well as structured POC US training programs. Homogeneous approach to POC US education combined with rigorous quality assurance should further enable POC US to become standard-of-care clinical tool. This study aimed to present the first, innovative, and structured POC US program in neonatal-perinatal medicine field. In addition, we reviewed the availability of the POC US training programs across different medical specialties.
• Seckeler, M. D., Bliss, A., Rischard, F., & Klewer, S. E. (2020). Early bioprosthetic tricuspid valve stenosis due to size mismatch in Ebstein anomaly-Successful transcatheter treatment. Journal of cardiac surgery, 35(11), 3138-3140.
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  Patients with congenital heart disease are surviving well into adulthood thanks to advances in medical and clinical care. We present a patient with Ebstein anomaly who underwent surgical tricuspid valve replacement and suffered early valve stenosis due to her unique anatomy. This case highlights the importance of the "unnatural" anatomy that can be encounter in this challenging patient population.
• Seckeler, M. D., Parthasarathy, S., Morgan, W. J., Klewer, S. E., Hsu, C. H., Fernandez, V., Combs, D., Barber, B. J., Andrews, J., Seckeler, M. D., Parthasarathy, S., Morgan, W. J., Klewer, S. E., Hsu, C. H., Fernandez, V., Combs, D., Barber, B. J., & Andrews, J. (2020). Abstract 14771: Obstructive Sleep Apnea is Associated With Cardiac Dysfunction in Children With Congenital Heart Disease. Circulation, 142(Suppl_3). doi:10.1161/circ.142.suppl_3.14771
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  Introduction: Obstructive sleep apnea (OSA) is associated with cardiac dysfunction in children without congenital heart disease (CHD). Children with CHD are at increased risk for OSA and may be susceptible to further cardiovascular consequences due to OSA but the extent and nature of such cardiovascular effects of OSA are unknown. Methods: Children (6-17 years old) with corrected CHD without current cyanosis or Down syndrome were recruited from pediatric cardiology clinic. Home sleep tests were done to determine the presence and severity of OSA. OSA was defined as an obstructive apnea hypopnea index (oAHI) ≥1. Mild OSA was defined as an oAHI of ≥1 to
• Vanderpool, R. R., Seckeler, M. D., Rischard, F. P., Klewer, S. E., Vanderpool, R. R., Seckeler, M. D., Vanderpool, R., Seckeler, M. D., Rischard, F., & Klewer, S. E. (2020). Long-term hemodynamic benefits after ‘treat-to-close’ for intracardiac shunts and pulmonary hypertension. European Respiratory Journal, 56. doi:10.1183/13993003.congress-2020.4048
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  Background: Patients with congenital heart defects and systemic-to-pulmonary pre-tricuspid shunts (PTS) may develop pulmonary arterial hypertension (PAH) from chronic volume overload. PTS patients with PAH can undergo medical therapy followed by closure (treat-to-close) with safe short-term outcomes. This may result in improved pulmonary resistance, compliance and RV function, but severe distal vascular disease may persist. Aims and Objectives: To examine longitudinal hemodynamic changes in pulmonary vascular load and RV function from diagnosis, post-shunt closure and long-term follow up in patients with PTS with PAH. Methods: PTS subjects with PAH who underwent treat-to-close and had at least one early post-closure and late resting and exercise cath were identified. RV afterload (Ea, Ca, resting PVR, exercise α and linear PQ), RV contractility (Ees) and RV-PA coupling (Ees/Ea) were analyzed. Results: 3 subjects (2 ASDs, 1 PAPVR) were included. Closure resulted in short- and long-term reduction in mean PA pressure, PVR (Fig A and B) and global afterload with improved RV-PA coupling (Fig C). Exercise PQ and α remained abnormal (Fig C). Conclusions: Treat-to-close for PTS with PAH provides short- and long-term improvements suggesting benefit of this aggressive approach. However, distal vascular disease remains despite near normalization of global afterload and chronic medical therapy may still be needed.
• Yell, J., Boyer, P. J., Bernardi, A., Klewer, S., & Seckeler, M. D. (2020). Improvement in Pulmonary Vascular Resistance After Relief of Fontan Circuit Obstruction. The Journal of invasive cardiology, 32(10), E254-E257.
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  Patients with single-ventricle congenital heart disease undergo staged surgical palliations leading to a final Fontan procedure. After Fontan, cardiac index (CI) is primarily determined by pulmonary vascular resistance (PVR). Lower Fontan pressure has been achieved after relieving obstruction within the Fontan circuit, but to date the effect on PVR has not been quantified. We hypothesized that there would be significant reduction in PVR after relief of obstruction within the Fontan circuit; the purpose of this study is therefore to describe the change in PVR after relief of Fontan obstruction.
• Kern, M. C., Janardhanan, R., Kelly, T., Fox, K. A., Klewer, S. E., & Seckeler, M. D. (2019). Multimodality imaging for diagnosis and procedural planning for a ruptured sinus of Valsalva aneurysm. Journal of Cardiovascular Computed Tomography, 30450-2.
• Kuo, P. H., Klewer, S. E., Witte, M. H., Mustacich, D. J., Moedano, L., Lau-braunhut, S., Kylat, R. I., Kuo, P. H., Klewer, S. E., Bernas, M. J., Behan, S., Bedrick, A. D., & Barber, B. J. (2019). Whole-body lymphangioscintigraphy and SPECT/CT in children with lymphatic complications after surgery for complex congenital heart disease.. Lymphology, 52(4), 157-165.
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  The number of patients surviving repair of complex congenital heart disease (CCHD) has increased due to improved surgical techniques, post operative management and outpatient care. Likewise, this growing patient population has demonstrated an increasing number and complexity of complications involving the lymphatic system. To evaluate the peripheral and central lymphatic system, whole-body lymphangioscintigraphy (LAS) is considered as the initial imaging evaluation of choice. To date, very few publications exist on the value of lymphatic imaging techniques in infants and small children with lymphatic complications following surgery for congenital heart disease. A retrospective review of medical records from 2008 to 2018 was performed for pediatric patients referred for lymphatic complications after CCHD surgery at an academic medical center. LAS and SPECT/CT was performed using intradermal bipedal injections of Tc 99m labeled filtered sulfur colloid, and in some patients also bilateral hand injections, followed by dynamic imaging and whole- body planar imaging typically up to 180 minutes post injection. Clinical decision making and outcomes were recorded. LAS and SPECT/CT were performed without complication in pediatric patients with prior surgery for CCHD. LAS successfully localized various lymphatic abnormalities such as lymphatic obstruction, reflux, and leaks, which were further delineated by SPECT/CT. LAS findings directed further evaluation with more definitive studies, management and prognosis. Five of the ten patients had follow up outcome data - 2 years and up to 10 years. LAS and SPECT/CT are safe and effective techniques for the initial evaluation of lymphatic abnormalities in pediatric patients with CCHD. LAS, particularly with further 3D localization by SPECT/CT, provides functional imaging of peripheral and central lymphatic flow and thus provides guidance for medical therapy, non operative interventional management, and surgical therapy for these diverse, debilitating, and often life threatening disorders.
• Riser, A. P., Riehle-colarusso, T., Overman, L., Oster, M. E., Nembhard, W. N., Klewer, S. E., Goudie, A., Glidewell, J., Farr, S. L., Downing, K. F., Collins, R. T., Benavides, A., Andrews, J., & Alter, C. (2019). Abstract 11112: Rationale and Design of Ch Strong: Congenital Heart Survey to Recognize Outcomes, Needs, and Well-beinG. Circulation.
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  Introduction: Studies of long-term outcomes among adults with congenital heart defects (CHD) have typically focused on those receiving care at specialty centers, limiting generalizability. The obje...
• Seckeler, M. D., White, S. C., Klewer, S. E., & Ott, P. (2019). Transjugular Transseptal Approach for Left Ventricular Pacing Lead in an Adult With Criss-Cross Heart. JACC. Clinical electrophysiology, 5(8), 998-999.
• White, S. C., Seckeler, M. D., White, S. C., Seckeler, M. D., Klewer, S. E., Gilpatrick, M. M., & Andrews, J. (2019). Cost of Childhood Chest Pain Evaluation is Higher in Emergency Departments with Fewer Pediatric Resources. Pediatrics, 144, 314-314. doi:10.1542/peds.144.2_meetingabstract.314
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  Purpose: Chest pain is a common chief complaint in children presenting to emergency departments and pediatric cardiologists. Despite the low incidence of cardiac pathology in children with chest pain, costly evaluations with uncertain benefits persist. The purpose of this study is to assess resource utilization across hospitals with varying levels of pediatric resources and compare clinical outcomes. Our hypothesis is that hospitals with fewer pediatric resources will generate higher costs without increased rates of specific diagnoses. Methods: We performed a secondary analysis of emergency department …
• Allen, L. A., Adler, E. D., Bayes-Genis, A., Brisco-Bacik, M. A., Chirinos, J. A., Claggett, B., Cook, J. L., Fang, J. C., Gustafsson, F., Ho, C. Y., Kapur, N. K., Klewer, S. E., Kociol, R. D., Lanfear, D. E., Vardeny, O., & Sweitzer, N. K. (2018). When the VEST Does Not Fit: Representations of Trial Results Deviating From Rigorous Data Interpretation. CIRCULATION-HEART FAILURE, 11(4).
• Seckeler, M. D., Thomas, I. D., Andrews, J., Meziab, O., Moe, T., Heller, E., & Klewer, S. E. (2018). Higher Cost of Hospitalizations for Non-cardiac Diagnoses in Adults with Congenital Heart Disease. PEDIATRIC CARDIOLOGY, 39(3), 437-444.
• Seckeler, M. D., White, S. C., Jenkins, J., & Klewer, S. E. (2018). Treatment of tricuspid regurgitation and para-ring leak in tetralogy of Fallot with oversized SAPIEN 3 valve-in-ring implantation. Journal of cardiac surgery, 33(9), 541-544.
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  A 40-year-old female with previously repaired tetralogy of Fallot had recurrent severe tricuspid regurgitation with a para-ring leak after annuloplasty ring placement. Because of multiple prior sternotomies and co-morbidities, she was not felt to be a surgical candidate. Percutaneous placement of an oversized SAPIEN 3 valve-in-ring in the tricuspid position successfully treated the regurgitation and para-ring leak.
• Colombo, J. N., Samson, R. A., Valdes, S. O., Meziab, O., Sisk, D., & Klewer, S. E. (2017). Decreased false-positive adolescent pre-athletic screening with Seattle Criteria-interpreted electrocardiograms. CARDIOLOGY IN THE YOUNG, 27(3), 512-517.
• Seckeler, M. D., Lawson, E., Barber, B. J., & Klewer, S. E. (2017). Percutaneous management of complex acquired aortic coarctation in an adult with tetralogy of Fallot and pulmonary atresia. Annals of pediatric cardiology, 10(3), 295-297.
• Ashfaq, A., Seckeler, M., Pophal, S., Rhee, E., Ryan, J., Rao, R., Klewer, S., & Nigro, J. J. (2016). Integration of Hybrid and Single Ventricle Rehabilitation Techniques to Treat a Neonate After Iatrogenic Mitral Injury. World journal for pediatric & congenital heart surgery, 7(4), 498-501.
• Seckeler, M. D., Thomas, I. D., Andrews, J., Joiner, K., & Klewer, S. E. (2016). A review of the economics of adult congenital heart disease. Expert review of pharmacoeconomics & outcomes research, 16(1), 85-96.
• Seckeler, M. D., Zahedieh, S., Seckeler, M. D., Scherer, K., Klewer, S. E., Daines, C. L., Barber, B. J., & Andrews, J. (2016). Regional and Racial Variation in Hospitalization Costs in Patients with Duchenne Muscular Dystrophy. Pediatrics, 140, 28-28. doi:10.1542/peds.140.1_meetingabstract.28
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  Advances in management for Duchenne muscular dystrophy (DMD) have improved survival. The purpose of this study was to describe hospital outcomes and costs for DMD patients and to identify regional and racial variation. Retrospective review of University Health System Consortium Clinical Data Base/Resource Manager, a …
• Seckeler, M. D., Moe, T. G., Thomas, I. D., Meziab, O., Andrews, J., Heller, E., & Klewer, S. E. (2015). Hospital Resource Utilization for Common Noncardiac Diagnoses in Adult Survivors of Single Cardiac Ventricle. AMERICAN JOURNAL OF CARDIOLOGY, 116(11), 1756-1761.
• Colombo, J. N., Valdes, S. O., Sisk, D., Samson, R. A., Klewer, S. E., & Colombo, J. N. (2014). Abstract 18613: Improved Adolescent Pre-Athletic Screening Sensitivity and Specificity with Seattle Criteria-interpreted ECGs. Circulation, 130.
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  Introduction: Sudden cardiac arrest (SCA) is a rare but devastating cause of death in children and young adults. While electrocardiogram (ECG) can detect many causes of SCA, ECG are not routinely included in pre-athletic screening (PAS) protocols in the United States due, in part, to a high rate of false positive (FP) interpretations in adolescents. Recently, an expert consensus panel developed refined ECG criteria (Seattle Criteria) to improve the specificity for ECG identification of cardiac conditions associated with SCA. Methods: We compared standard ECG criteria with Seattle Criteria in the interpretation of ECGs obtained as part of a youth community SCA screening program. Students completed an AHA-endorsed PAS that included a cardiac specific history and physical exam. A 12 lead ECG was obtained and interpreted by a board certified pediatric cardiologist (PDC). Students found to have a positive PAS screen or abnormal standard ECG completed additional work up with a PDC. All ECGs referred for additional evaluation were interpreted by a PDC using Seattle Criteria in a blinded manner. Results: A total of 1,034 students 11-13 years of age were evaluated. No referrals for additional testing were made based on PAS history alone. There were 72 (7%) ECG abnormalities identified by standard PDC interpretation, while Seattle Criteria identified 21 (2%) ECGs that met criteria for further testing. Formal cardiology evaluation confirmed 4 students at risk for SCA (0.38%); LQTS (n=2), WPW (n=1) and PHTN (n=1); incidental findings isolated RBBB (n=1), MVP (n=1) and PFO (n=1). All students at risk for SCA were identified by both standard pediatric ECG and Seattle Criteria interpretations. Specificity for standard ECG was 93% and for Seattle criteria was 98%. Conclusions: This study demonstrates that inclusion of ECGs in PAS improves the sensitivity for identifying middle school students at risk for SCA compared to history and exam alone. While standard pediatric ECG interpretation yields a 6.5% incidence of FP, application of Seattle Criteria reduces the incidence of FP ECGs in this age group to 1.6% with no adverse effect on sensitivity. This data supports utilizing Seattle Criteria interpretation for community SCA screening programs that include ECG.
• Seckeler, M. D., Seckeler, M. D., Klewer, S. E., Han, L. M., Blank, K. M., & Barber, B. J. (2013). Feasibility of pulse oximetry screening for critical congenital heart disease at 2643-foot elevation.. Pediatric cardiology, 34(8), 1803-7. doi:10.1007/s00246-013-0716-2
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  To evaluate the feasibility of implementing a pulse oximetry screening protocol at a city of mild elevation with a specific focus on the false-positive screening rate. Pulse oximetry screening was performed according to the proposed guidelines endorsed by the American Academy of Pediatrics at a center in Tucson, AZ, at an elevation of 2,643 ft (806 m). During a 10-month period in 2012, 1069 full-term asymptomatic newborns were screened ≥ 24 h after birth. The mean preductal oxygen saturation was 98.5 ± 1.3 % (range 92-100 %), and the mean postductal oxygen saturation was 98.6 ± 1.3 % (range 94-100 %). Of 1,069 patients screened, 7 were excluded secondary to protocol violations, and 1 screened positive. An echocardiogram was performed on the newborn with the positive screen, and it was normal with the exception of right-to-left shunting across a patent foramen ovale. The false-positive rate was 1/1,062 or 0.094 %. The pulse oximetry screening guidelines recommended by the American Academy of Pediatrics are feasible at an elevation of 2,643 ft (806 m) with a low false-positive rate. Adjustments to the protocol are not required for centers at elevations ≤ 2,643 ft. Future studies at greater elevations are warranted.
• Huttemann, M., Erickson, R. P., Grossman, L. I., Larson, D. F., Slack, E. H., Pecinova, A., Pecina, P., Maghsoodi, B., Liu, J., Lee, M., Lee, I., Larson, D. F., Klewer, S. E., Huttemann, M., Grossman, L. I., Erickson, R. P., & Doan, J. W. (2012). Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy.. Mitochondrion, 12(2), 294-304. doi:10.1016/j.mito.2011.11.002
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  Subunit 7a of mouse cytochrome c oxidase (Cox) displays a contractile muscle-specific isoform, Cox7a1, that is the major cardiac form. To gain insight into the role of this isoform, we have produced a new knockout mouse line that lacks Cox7a1. We show that homozygous and heterozygous Cox7a1 knockout mice, although viable, have reduced Cox activity and develop a dilated cardiomyopathy at 6 weeks of age. Surprisingly, the cardiomyopathy improves and stabilizes by 6 months of age. Cox7a1 knockout mice incorporate more of the "liver-type" isoform Cox7a2 into the cardiac Cox holoenzyme and, also surprisingly, have higher tissue ATP levels.
• Meaney, F. J., Donnerstein, R. L., Weinstein, R. S., Lax, D., Krupinski, E. A., Weinstein, R. S., Warda, G., Meaney, F. J., Lopez, A. M., Lax, D., Krupinski, E. A., Klewer, S. E., Haley, J. E., Donnerstein, R. L., & Barber, B. J. (2012). Remote diagnosis of congenital heart disease in southern Arizona: comparison between tele-echocardiography and videotapes.. Telemedicine journal and e-health : the official journal of the American Telemedicine Association, 18(10), 736-42. doi:10.1089/tmj.2012.0037
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  We report our experience with tele-echocardiography and echocardiograms recorded digitally or on videotape (recorded-echos) at The University of Arizona from August 2006 to December 2010 and compare their quality and diagnostic accuracy..Tele-echocardiograms (tele-echos) were transmitted from the Yuma Regional Medical Center to The University of Arizona via a T-1 and aT-3 line at a bandwidth of 768 kilobits per second. Recorded-echos were shipped for interpretation to The University of Arizona by overnight mail. Diagnostic accuracy was assessed by comparing tele- and recorded-echos with electrocardiograms performed by a pediatric cardiologist (PedsCard-echos)..Three hundred forty-six tele-echos in 260 patients and 455 recorded-echos in 406 patients were performed (median age, 6 and 8 days, respectively). Indications included possible congenital heart disease (CHD), patent ductus arteriosus (PDA), and persistent pulmonary hypertension of the newborn. Diagnostic categories included complex CHD, non-critical disease, PDA, and other. PedsCard-echos were available for 27% of the tele-echo and 30% of the recorded-echo patients. Comparisons between tele- and PedsCard-echo yielded no discrepancies in 12 (23%), expected resolution of condition in 26 (49%), and minor in 14 (26%). One (2%) major discrepancy was detected. Comparisons between recorded- and PedsCard-echo showed no discrepancies in 28 (40%), expected resolution of condition in 14 (20%), and minor discrepancies in 28 (40%) patients. No significant difference with respect to discrepancies was detected between tele- and recorded-echos. There was significant (p
• Camenisch, T. D., Runyan, R. B., Runyan, R. B., Lencinas, A., Konieczka, J. H., Klewer, S. E., Camenisch, T. D., Broka, D. M., & Antin, P. B. (2010). Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.. Toxicological sciences : an official journal of the Society of Toxicology, 116(1), 273-85. doi:10.1093/toxsci/kfq086
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  Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An embryonic prototype of EMT is found in the atrioventricular (AV) canal of the developing heart, where endothelia differentiate to form heart valves. Effects of arsenic on this cellular process were examined by collagen gel invasion assay (EMT assay) using explanted AV canals from chicken embryo hearts. AV canals treated with 12.5-500 ppb arsenic showed a loss of mesenchyme at 12.5 ppb, and mesenchyme formation was completely inhibited at 500 ppb. Altered gene expression in arsenic-treated explants was investigated by microarray analysis. Genes whose expression was altered consistently at exposure levels of 10, 25, and 100 ppb were identified, and results showed that 25 ppb in vitro was particularly effective. Three hundred and eighty two genes were significantly altered at this exposure level. Cytoscape analysis of the microarray data using the chicken interactome identified four clusters of altered genes based on published relationships and pathways. This analysis identified cytoskeleton and cell adhesion-related genes whose disruption is consistent with an altered ability to undergo EMT. These studies show that EMT is sensitive to arsenic and that an interactome-based approach can be useful in identifying targets.
• Lax, D., Sorrell, V. L., Lax, D., Klewer, S. E., & Bhatt, R. D. (2010). Are all ventricular septal defects created equal?. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 23(7), 791.e5-7. doi:10.1016/j.echo.2009.12.004
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  The authors report the occurrence of infective endocarditis in a 32-year-old man with a ventricular septal defect and a left ventricular-to-right-atrial shunt who adhered to the revised 2007 American Heart Association guidelines for infective endocarditis. The patient had received antibiotic prophylaxis prior to multiple previous dental procedures. At a recent dental evaluation for fillings, he was informed that he no longer needed prophylaxis. Fatigue and fevers developed 1 week later, and he was treated with an oral course of ciprofloxacin. The symptoms recurred, and blood cultures grew Streptococcus viridans. A 7-mm vegetative mass was seen on the septal leaflet of the tricuspid valve during transesophageal echocardiography. This report raises the concern that patients with ventricular septal defects and left ventricular-to-right-atrial shunts are at higher risk for endocarditis and may require antibiotic prophylaxis.
• Oliveira, L. A., Klewer, S. E., Kitten, G. T., & Baker, R. K. (2010). Expression of beta 2 integrin (CD18) in embryonic mouse and chicken heart.. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 43(1), 25-35. doi:10.1590/s0100-879x2010000100005
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  Integrins are heterodimeric receptors composed of alpha and beta transmembrane subunits that mediate attachment of cells to the extracellular matrix and counter-ligands such as ICAM-1 on adjacent cells. beta2 integrin (CD18) associates with four different alpha (CD11) subunits to form an integrin subfamily, which has been reported to be expressed exclusively on leukocytes. However, recent studies indicate that beta2 integrin is also expressed by other types of cells. Since the gene for beta2 integrin is located in the region of human chromosome 21 associated with congenital heart defects, we postulated that it may be expressed in the developing heart. Here, we show the results from several different techniques used to test this hypothesis. PCR analyses indicated that beta2 integrin and the alphaL, alphaM, and alphaX subunits are expressed during heart development. Immunohistochemical studies in both embryonic mouse and chicken hearts, using antibodies directed against the N- or C-terminal of beta2 integrin or against its alpha subunit partners, showed that beta2 integrin, as well as the alphaL, alphaM, and alphaX subunits, are expressed by the endothelial and mesenchymal cells of the atrioventricular canal and in the epicardium and myocardium during cardiogenesis. In situ hybridization studies further confirmed the presence of beta2 integrin in these various locations in the embryonic heart. These results indicate that the beta2 integrin subfamily may have other activities in addition to leukocyte adhesion, such as modulating the migration and differentiation of cells during the morphogenesis of the cardiac valves and myocardial walls of the heart.
• Sorrell, V. L., Raasch, H., Klewer, S. E., & Kalra, N. (2010). Update on tetralogy of Fallot for the adult cardiologist including a brief historical and surgical perspective.. Congenital heart disease, 5(3), 208-19. doi:10.1111/j.1747-0803.2010.00402.x
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  There has been a steady rise in the prevalence of severe congenital heart disease (CHD) in adults because of improved treatment and survival during childhood. This has resulted in a shift in CHD morbidity and mortality beyond 18 years of age. The healthcare community must be prepared to meet this new challenge. Adult cardiologists need to be aware of common CHD, such as tetralogy of Fallot (TOF), as they will encounter adults with this CHD in their practice. With routine monitoring, cardiac imaging, early intervention, and treatment as highlighted in this report, continued improvement in the long-term fitness and avoidance of late complications for adult TOF patient is anticipated.
• Valdes, S. O., Sorrell, V. L., Klewer, S. E., Barber, B. J., & Abdy, N. A. (2010). Apical hypertrophic cardiomyopathy in an adolescent.. Congenital heart disease, 5(2), 182-7. doi:10.1111/j.1747-0803.2009.00346.x
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  To our knowledge, this is one of the few reported cases of apical hypertrophic cardiomyopathy in an adolescent patient in the United States. We describe a clinical presentation of an adolescent male who presented for cardiac evaluation and was found to have an apical variant of hypertrophic cardiomyopathy.
• Yamada, S., Wisse, L. J., Shiratori, H., Shiota, K., Schoenwolf, G. C., Saijoh, Y., Leppert, M. F., Klewer, S. E., Hunter, J., Hamada, H., Groot, A. C., Chapman, S. C., Bleyl, S. B., & Bax, N. A. (2010). Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms.. Human molecular genetics, 19(7), 1286-301. doi:10.1093/hmg/ddq005
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  Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect inherited via complex genetic and/or environmental factors. We report detailed mapping in extended TAPVR kindreds and mutation analysis in TAPVR patients that implicate the PDGFRA gene in the development of TAPVR. Gene expression studies in mouse and chick embryos for both the Pdgfra receptor and its ligand Pdgf-a show temporal and spatial patterns consistent with a role in pulmonary vein (PV) development. We used an in ovo function blocking assay in chick and a conditional knockout approach in mouse to knock down Pdgfra expression in the developing venous pole during the period of PV formation. We observed that loss of PDGFRA function in both organisms causes TAPVR with low penetrance (approximately 7%) reminiscent of that observed in our human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (approximately 30%), suggesting that TAPVR occurs at one end of a spectrum of defects. We show that the anomalous pulmonary venous connection seen in chick and mouse is highly similar to TAPVR discovered in an abnormal early stage embryo from the Kyoto human embryo collection. Whereas the embryology of the normal venous pole and PV is becoming understood, little is known about the embryogenesis or molecular pathogenesis of TAPVR. These models of TAPVR provide important insight into the pathogenesis of PV defects. Taken together, these data from human genetics and animal models support a role for PDGF-signaling in normal PV development, and in the pathogenesis of TAPVR.
• Samson, R. A., Klewer, S. E., Hainstock, M. R., Gruchala, N. E., Fike, N., & Barber, B. J. (2008). Postural orthostatic tachycardia in a teenager with Klinefelter syndrome.. Congenital heart disease, 3(6), 440-2. doi:10.1111/j.1747-0803.2008.00218.x
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  To our knowledge this is the first reported case of postural orthostatic tachycardia syndrome (POTS) in a patient with Klinefelter syndrome. We describe a classic clinical presentation of POTS in an adolescent male with Klinefelter syndrome. Although the etiology of POTS appears to be multifactorial, there is a strong female predominance that suggests a genetic basis. Our patient with Klinefelter syndrome may further support a link with POTS to the X chromosome.
• Morkin, E., Maitra, N., Klewer, S. E., Hoying, J. B., Greer, K. A., Goldman, S. A., Bahl, J. J., & Adamson, C. (2007). Regulation of gene expression in rats with heart failure treated with the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) and the combination of DITPA and captopril.. Journal of cardiovascular pharmacology, 50(5), 526-34. doi:10.1097/fjc.0b013e318142bdf2
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  We have used an oligonucleotide microarray to identify genes that are affected by congestive heart failure and those influenced by treatment with DITPA and DITPA in combination with captopril using a rat postinfarction model. The most striking result when comparing heart failure to sham operation was that all of the mitochondrial and metabolic enzymes affected were down regulated. When comparing heart failure with DITPA treatment, most of the down regulated metabolic genes were returned toward normal. When comparing heart failure with heart failure animals treated with DITPA and captopril, metabolic enzymes were no longer significantly downregulated. DITPA treatment and the combination of DITPA and captopril show that the metabolic enzymes were no longer down regulated. This represents a substantial improvement in the energy- generating capacity of the heart. These results indicate that the actions of DITPA and the combination of DITPA and captopril in heart failure can be partially explained by differences in gene activation.
• Trivedi, K. R., Sorrell, V. L., Sabbath, A. M., & Klewer, S. E. (2007). Congenital left ventricular splint in an adult patient with unrepaired anomalous left coronary artery from the pulmonary artery.. Congenital heart disease, 2(4), 275-9. doi:10.1111/j.1747-0803.2007.00110.x
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  A 24-year-old woman presented with a recent increase in dyspnea on exertion and development of presyncope. The patient stated that she has reproducible episodes of dizziness and near fainting when she climbs a flight of stairs and activity is limited to a slow gait.
• Camenisch, T. D., Yatskievych, T. A., Stevens, M. V., Pogreba, K., Klewer, S. E., Camenisch, T. D., & Antin, P. B. (2006). Has2 expression in heart forming regions is independent of BMP signaling.. Gene expression patterns : GEP, 6(5), 462-70. doi:10.1016/j.modgep.2005.11.005
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  Heart septation and valve malformations constitute the most common birth defects. These cardiac structures arise from the endocardial cushions through dynamic interactions between cells and the extracellular matrix (cardiac jelly). Targeted deletion of the hyaluronan synthase-2 (Has2) gene in mice results in an absence of cardiac jelly and endocardial cushions, a loss of vascular integrity, and embryonic death at E9.5. Despite the requirements for Has2 and its synthetic product hyaluronan (HA) in the developing cardiovascular system, little is known about the normal expression pattern of Has2 or the factors regulating Has2 gene transcription during development. Bmp signaling is an important regulator of cardiac myogenesis, and is also important for endocardial cushion formation. The current study defines the embryonic expression pattern of Has2 and explores the regulation of Has2 gene expression by Bmp signaling. In situ hybridization studies demonstrate dynamic Has2 expression patterns during myocardial cell development and cardiac tube formation, formation of the cardiac endocardial cushions, and cushion invasion by valve primordial cells. Despite overlapping regional expression of Bmp2 in the late gastrula anterior lateral endoderm and Has2 in the adjacent cardiogenic mesoderm, application of noggin-expressing CHO cells beneath the endoderm failed to perturb normal Has2 expression. Thus, in contrast to many genes expressed in the heart forming region, regulation of Has2 in the cardiogenic mesoderm is independent of Bmp signaling.
• Darnell, D. K., Runyan, R. B., Scholz, M. J., Runyan, R. B., Klewer, S. E., Hubbard, A. D., Greer, K. A., Doyle, S. E., Darnell, D. K., & Antin, P. B. (2006). Latrophilin-2 is a novel component of the epithelial-mesenchymal transition within the atrioventricular canal of the embryonic chicken heart.. Developmental dynamics : an official publication of the American Association of Anatomists, 235(12), 3213-21. doi:10.1002/dvdy.20973
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  Endothelial cells in the atrioventricular canal of the heart undergo an epithelial-mesenchymal transition (EMT) to form heart valves. We surveyed an on-line database (http://www.geisha.arizona.edu/) for clones expressed during gastrulation to identify novel EMT components. One gene, latrophilin-2, was identified as expressed in the heart and appeared to be functional in EMT. This molecule was chosen for further examination. In situ localization showed it to be expressed in both the myocardium and endothelium. Several antisense DNA probes and an siRNA for latrophilin-2 produced a loss of EMT in collagen gel cultures. Latrophilin-2 is a putative G-protein-coupled receptor and we previously identified a pertussis toxin-sensitive G-protein signal transduction pathway. Microarray experiments were performed to examine whether these molecules were related. After treatment with antisense DNA against latrophilin-2, expression of 1,385 genes and ESTs was altered. This represented approximately 12.5% of the microarray elements. In contrast, pertussis toxin altered only 103 (0.9%) elements of the array. There appears to be little overlap between the two signal transduction pathways. Latrophilin-2 is thus a novel component of EMT and provides a new avenue for investigation of this cellular process.
• Krieg, P. A., Runyan, R. B., Runyan, R. B., Person, A. D., Krieg, P. A., Klewer, S. E., & Garriock, R. J. (2005). Frzb modulates Wnt-9a-mediated beta-catenin signaling during avian atrioventricular cardiac cushion development.. Developmental biology, 278(1), 35-48. doi:10.1016/j.ydbio.2004.10.013
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  Normal development of the cardiac atrioventricular (AV) endocardial cushions is essential for proper ventricular septation and morphogenesis of the mature mitral and tricuspid valves. In this study, we demonstrate spatially restricted expression of both Wnt-9a (formerly Wnt-14) and the secreted Wnt antagonist Frzb in AV endocardial cushions of the developing chicken heart. Wnt-9a expression is detected only in AV canal endocardial cells, while Frzb expression is detected in both endocardial and transformed mesenchymal cells of the developing AV cardiac cushions. We present evidence that Wnt-9a promotes cell proliferation in the AV canal and overexpression of Wnt-9a in ovo results in enlarged endocardial cushions and AV inlet obstruction. Wnt-9a stimulates beta-catenin-responsive transcription in AV canal cells, duplicates the embryonic axis upon ventral injections in Xenopus embryos and appears to regulate cell proliferation by activating a Wnt/beta-catenin signaling pathway. Additional functional studies reveal that Frzb inhibits Wnt-9a-mediated cell proliferation in cardiac cushions. Together, these data argue that Wnt-9a and Frzb regulate mesenchymal cell proliferation leading to proper AV canal cushion outgrowth and remodeling in the developing avian heart.
• Runyan, R. B., Runyan, R. B., Person, A. D., & Klewer, S. E. (2005). Cell biology of cardiac cushion development.. International review of cytology, 243, 287-335. doi:10.1016/s0074-7696(05)43005-3
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  The valves of the heart develop in the embryo from precursor structures called endocardial cushions. After cardiac looping, endocardial cushion swellings form and become populated by valve precursor cells formed by an epithelial-mesenchymal transition (EMT). Endocardial cushions subsequently undergo directed growth and remodeling to form the valvular structures and the membranous septa of the mature heart. The developmental processes that mediate cushion formation include many prototypic cellular actions including adhesion, signaling, migration, secretion, replication, differentiation, and apoptosis. Cushion morphogenesis is unique in that these cellular possesses occur in a functioning organ where the cushions act as valves even while developing into definitive valvular structures. Cardiovascular defects are the most common congenital defects, and one of the most common causes of death during infancy. Thus, there is significant interest in understanding the mechanisms that underlie this complex developmental process. In this regard, substantial progress has been made by incorporating an understanding of cardiac morphology and cell biology with the rapidly expanding repertoire of molecular mechanisms gained through human genetics and research using animal models. This article reviews cardiac morphogenesis as it relates to heart valve formation and highlights selected growth factors, intracellular signaling mediators, and extracellular matrix components involved in the creation and remodeling of endocardial cushions into mature cardiac structures.
• Mjaatvedt, C. H., Gourdie, R. G., Klewer, S. E., Wessels, A., Mjaatvedt, C. H., Klewer, S. E., & Gourdie, R. G. (2004). Een geslaagd jubileum! The 10th Weinstein Developmental Cardiovascular Conference in Leiden.. Developmental dynamics : an official publication of the American Association of Anatomists, 231(3), 655-9. doi:10.1002/dvdy.20169
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  The 10th annual Weinstein Conference was held May 13–16, 2004, at Leeuwenhorst Conference Center in the Netherlands outside of Leiden. The Weinstein meeting, founded by Dr. Constance Weinstein and subsequently named in her honor by the attendees, is one of the leading annual gatherings of researchers studying heart development. Basic research scientists and research clinicians were brought together from around the world to share their latest data and concepts of heart development. This year the meeting was sponsored by the Leiden University Medical Center in collaboration with the Medical University of South Carolina in Charleston and was attended by approximately 270 participants. The meeting began Friday evening with a welcoming reception followed by the keynote lecture by Margaret E. Buckingham of the Pasteur Institute. Dr. Buckingham’s lecture entitled, “Programming Cells to Form Muscle: The Cellular Contribution to Cardiogenesis,” reviewed her recently published work on lineage analysis of the anterior heart field in the mouse by a retrospective clonal analysis approach that takes advantage of an infrequent and spontaneous mitotic recombination of an inactivated nlaacZ reporter into an active nlacZ reporter in mouse (Meilhac et al., 2004). The analysis demonstrated that two lineages arise in the heart fields from a common progenitor. These two lineages then contribute unequally to specific regions of the developing heart. The left ventricle and the outflow tract seem to derive from a single lineage, whereas other regions derive from both. During questions and discussion, Roger Markwald proposed that the two lineages are derived at earlier stages from the primitive lateral heart fields and then are sorted into the separate lineages. The observation that some chambers derive from more than one lineage is consistent with earlier concepts that suggested the primitive heart forms initially in a segmental manner, but the mature chambers of the heart result from cellular interactions and remodeling of these primitive segments (Mjaatvedt et al., 1999). The cellular and molecular interactions leading to this specification of precardiac lineages will no doubt be a hot topic of future research in this area. SESSIONS
• Morkin, E., Maitra, N., Klewer, S. E., Hoying, J. B., Greer, K. A., Bahl, J. J., & Adamson, C. (2004). Regulation of gene expression in cardiomyocytes by thyroid hormone and thyroid hormone analogs 3,5-diiodothyropropionic acid and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid].. The Journal of pharmacology and experimental therapeutics, 311(1), 164-71. doi:10.1124/jpet.104.069153
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  The heart is an important target of thyroid hormone actions. Only a limited number of cardiac target genes have been identified, and little is known about their regulation by T(3) (3,3',5-triiodothyronine) and thyroid hormone analogs. We used an oligonucleotide microarray to identify novel cardiac genes regulated by T(3) and two thyroid hormone analogs, 3,5-diidodothyropropionic acid (DITPA) and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid]. DITPA binds with lower affinity than T(3) to thyroid hormone receptor alpha1 and beta1 isoforms, whereas CGS 23425 binds selectively to beta1. Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone ("hypothyroid" control) or treated with T(3), DITPA, and CGS 23425 at concentrations 5 times their respective K(d) values for 48 h. The arrays were scanned and analyzed using an analysis of variance program. Sixty-four genes were identified that were >1.5 times up- or down-regulated by one of the treatments with P < 0.05. The genes regulated by T(3) and DITPA were nearly identical. Thirteen genes were differentially regulated by CGS 23425. Genes encoding contractile proteins, Ca(2+)-ATPase of sarcoplasmic reticulum and several proteins of mitochondrial oxidative phosphorylation, were up-regulated by T(3) and DITPA but not by CGS 23425. These results indicate that some, but not all, of the actions of thyroid hormone analogs can be explained by differences in gene activation.
• Camenisch, T. D., Mcdonald, J. A., Klewer, S. E., Keshet, E., Dor, Y., & Camenisch, T. D. (2003). VEGF modulates early heart valve formation.. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology, 271(1), 202-8. doi:10.1002/ar.a.10026
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  Although hypoxic and/or nutritional insults during gestation are believed to contribute to congenital heart defects, the mechanisms responsible for these anomalies are not understood. Given the role vascular endothelial growth factor (VEGF) plays in response to hypoxia, it is a likely candidate for mediating deleterious effects of embryonic hypoxia. The ectopic or overproduction of endogenous factors such as VEGF may contribute to specific heart defects. Here we compared hypoxia-induced precocious production of VEGF during early heart valve development to normal VEGF production. Mouse prevalvular cardiac endocardial cushions were explanted onto hydrated type I collagen gels under normoxic or hypoxic conditions. The extent of transformation of cardiac endothelium into mesenchyme was inversely correlated with the levels of VEGF during the various culture conditions. A soluble VEGF antagonist confirmed that endogenous production of VEGF was specific for blocking normal cushion mesenchyme formation. We further demonstrated that E10.5 endocardium retains the ability to transform into cardiac mesenchyme in the absence of endogenous VEGF.
• Poelmann, R. E., Oosthoek, P. W., Klewer, S. E., Jongewaard, I. N., Hogers, B., Groot, A. C., Bartram, U., & Bartelings, M. M. (2003). Collagen type VI expression during cardiac development and in human fetuses with trisomy 21.. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology, 275(2), 1109-16. doi:10.1002/ar.a.10126
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  The role played by specific extracellular matrix molecules in normal endocardial cushion differentiation into valves and septa remains to be established. In this respect, type collagen VI is of particular interest because genes encoding the alpha1 and alpha2 chains are located on chromosome 21, and defects involving the atrioventricular (AV) cushions are frequent in trisomy 21. Collagen VI expression was studied in normal human embryonic and fetal hearts (5-18 weeks of development) and compared by immunohistochemistry with results from fetuses (10-16 weeks of development) with trisomy 21. During normal endocardial cushion differentiation (5-8 weeks) there was marked collagen VI expression in the AV cushions, whereas only minor expression was seen in the outflow tract cushions. In the normal fetuses (10-18 weeks), collagen VI in the AV cushions had condensed into a marked zone on the atrial side of the leaflets, as well as subendocardially in other regions of high shear stress. Morphological defects involving the endocardial cushion-derived structures were present in all trisomy 21 cases. An abnormally large membranous septum was observed in three cases. An AV septal defect (AVSD) was present in two, while one had a ventricular septal defect (VSD). Two cases presented with a secondary atrial septal defect (ASDII), and one had an AVSD. Mild to moderate valve dysmorphia was found in all cases. Collagen VI staining in trisomy 21 was more intense than in the normal subjects; however, there were no differences in the spatial expression patterns. We conclude that collagen VI is expressed in the AV cushions and persists during valve differentiation. Collagen VI is more prominent in fetal trisomy 21 hearts than in normal hearts. We hypothesise that collagen VI has a role in the development of heart defects involving endocardial cushion differentiation-specifically in the AV canal, the most common site of malformations affecting children with trisomy 21.
• Camenisch, T. D., Runyan, R. B., Runyan, R. B., Person, A. D., Molin, D. G., Mcdonald, J. A., Klewer, S. E., Groot, A. C., & Camenisch, T. D. (2002). Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis.. Developmental biology, 248(1), 170-81. doi:10.1006/dbio.2002.0731
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  The formation of endocardial cushions in the atrioventricular (AV) canal of the rudimentary heart requires epithelial-to-mesenchymal cell transformation (EMT). This is a complex developmental process regulated by multiple extracellular signals and transduction pathways. A collagen gel assay, long used to examine endocardial cushion development in avian models, is now being employed to investigate genetically engineered mouse models with abnormal heart morphogenesis. In this study, we determine interspecies variations for avian and mouse cultured endocardial cushion explants. Considering these observed morphologic differences, we also define the temporal requirements for TGFbeta2 and TGFbeta3 during mouse endocardial cushion morphogenesis. TGFbeta2 and TGFbeta3 blocking antibodies inhibit endothelial cell activation and transformation, respectively, in avian explants. In contrast, neutralizing TGFbeta2 inhibits cell transformation in the mouse, while TGFbeta3 antibodies have no effect on activation or transformation events. This functional requirement for TGFbeta2 is concomitant with expression of TGFbeta2, but not TGFbeta3, within mouse endocardial cushions at a time coincident with transformation. Thus, both TGFbeta2 and TGFbeta3 appear necessary for the full morphogenetic program of EMT in the chick, but only TGFbeta2 is expressed and obligatory for mammalian endocardial cushion cell transformation.
• Camenisch, T. D., Schroeder, J. A., Mcdonald, J. A., Klewer, S. E., Camenisch, T. D., & Bradley, J. M. (2002). Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors.. Nature medicine, 8(8), 850-5. doi:10.1038/nm742
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  Heart septation and valve malformations constitute the most common anatomical birth defects. These structures arise from the endocardial cushions within the atrioventricular canal (AVC) through dynamic interactions between cushion cells and the extracellular matrix (termed cardiac jelly). Transformation of endothelial cells to mesenchymal cells is essential for the proper development of the AVC and subsequent septation and valve formation. Atrioventricular septal defects can result from incomplete endocardial cushion morphogenesis. We show that hyaluronan-deficient AVC explants from Has2(-/-) embryos, which normally lack mesenchyme formation, are rescued by heregulin treatment, which restores phosphorylation of ErbB2 and ErbB3. These events were blocked using a soluble ErbB3 molecule, as well as with an inhibitor of ErbB2, herstatin. We show further that ErbB3 is activated during hyaluronan treatment of Has2(-/-) explants. These data provide a link between extracellular matrix-hyaluronan and ErbB receptor activation during development of early heart-valve and septal mesenchyme.
• Donnerstein, R. L., Lax, D., Zamora, R., Samson, R. A., Lax, D., Klewer, S. E., Goldberg, S. J., & Donnerstein, R. L. (2002). Comparison of accuracy of diagnosis of congenital heart disease by history and physical examination versus echocardiography.. The American journal of cardiology, 89(11), 1329-31. doi:10.1016/s0002-9149(02)02341-x
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  Cardiol 1984;54:1151–1153. 16. Roberts WC. Aneurysm (redundancy) of the atrial septum (fossa ovale membrane) and prolapse (redundancy) of the mitral valve. Am J Cardiol 1984; 54:1153–1154. 17. Hanley PC, Tajik J, Hynes JK, Edwards WD, Reeder GS, Hagler DJ, Seward JB. Diagnosis and classification of atrial septal aneurysm by two-dimensional echocardiography: report of 80 consecutive cases. J Am Coll Cardiol 1985;6:1370–1382. 18. Mugge A, Daniel WG, Angermann C, Spes C, Khandheria BK, Kronzon I, Freedberg RS, Keren A, Dennig K, Engberding R, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995;91:2785–2792. 19. Pearson AC, Nagelhout D, Castello R, Gomez CR, Labovitz AJ. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991;18:1223–1229. 20. Shirani J, Zafari AM, Roberts WC. Morphologic features of fossa ovalis membrane aneurysm in the adult and its clinical significance. J Am Coll Cardiol 1995;26:466–471.
• Donnerstein, R. L., Samson, R. A., Klewer, S. E., Jolma, C. D., Goldberg, S. J., & Donnerstein, R. L. (2002). Acute cardiac effects of nicotine in healthy young adults.. Echocardiography (Mount Kisco, N.Y.), 19(6), 443-8. doi:10.1046/j.1540-8175.2002.00443.x
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  Nicotine is known to have many physiologic effects. The influence of nicotine delivered in chewing gum upon cardiac hemodynamics and conduction has not been well-characterized..We studied the effects of nicotine in nonsmoking adults (6 male, 5 female; ages 23-36 years) using a double-blind, randomized, cross-over study. Subjects chewed nicotine gum (4 mg) or placebo. After 20 minutes (approximate time to peak nicotine levels), echocardiograms and signal-averaged electrocardiograms (SAECG) were obtained. After 40 minutes, subjects were again given nicotine gum or placebo in cross-over fashion. Standard echocardiographic measurements were made from two-dimensional images. We then calculated end-systolic wall stress (ESWS), shortening fraction (SF), systemic vascular resistance (SVR), velocity for circumferential fiber shortening corrected for heart rate (Vcfc), stroke volume, and cardiac output. P wave and QRS duration were measured from SAECG..Significant differences (P < 0.05) from control or placebo were found for ESWS, mean blood pressure, cardiac output, SVR, heart rate, and P wave duration. No significant changes were seen in left ventricular ejection time (LVET), LV dimensions, SF, contractility (Vcfc), or QRS duration..These results suggest that nicotine chewing gum increases afterload and cardiac output. Cardiac contractility does not change acutely in response to nicotine gum. Heart rate and P wave duration are increased by chewing nicotine gum.
• Patil, S. R., Lauer, R. M., Klewer, S. E., Jongewaard, I. N., & Behrendt, D. A. (2002). Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen.. American journal of medical genetics, 109(4), 298-305. doi:10.1002/ajmg.10413
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  Trisomy 21 (Down syndrome) is a common genetic condition with a high incidence of congenital heart defects (CHD), particularly those involving abnormal development of the embryonic atrioventricular (AV) canal. Type VI collagen (Col VI) is expressed in the developing AV canal extracellular matrix, and has been associated with trisomy 21 AV canal defects in human genetic studies. Although the molecular mechanisms linking Col VI and trisomy 21 AV canal defects are not well understood, a computer model predicts increased cell adhesiveness is responsible for these CHD. We compared integrin-mediated cell adhesive properties for skin fibroblasts isolated from trisomy 21 and non-trisomic individuals on Col VI, fibronectin (FN) and type I collagen (Col I). Cell lines demonstrate similar adhesion profiles to FN and Col I, but all trisomy 21 cells display increased adhesive capacity for Col VI compared to non-trisomic fibroblasts. Cell adhesion to type VI collagen was shown to be GRGDS independent, but beta(1) integrin family dependent. Function-blocking antibodies identified alpha(3)beta(1) as the predominant integrin mediating trisomy 21 and non-trisomic skin fibroblast adhesion on Col VI. Trisomy 21 and non-trisomic fibroblasts display similar expression levels for each of the integrin receptors examined. A beta(1) integrin-activating antibody augments non-trisomic cell adhesion on Col VI, but has no effect upon trisomy 21 fibroblasts. These results demonstrate that beta(1) integrin family members mediate trisomy 21 and non-trisomic skin fibroblast adhesion for Col VI. Altered activation state of the beta(1) integrin is a mechanism responsible for increased trisomy 21 cell adhesion on Col VI.
• Camenisch, T. D., Klewer, S. E., Kubalak, S. W., Spicer, A. P., Mcdonald, J. A., Kubalak, S. W., Klewer, S. E., Camenisch, T. D., Calabro, A., Brehm-gibson, T., Biesterfeldt, J., & Augustine, M. L. (2000). Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.. The Journal of clinical investigation, 106(3), 349-60. doi:10.1172/jci10272
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  We identified hyaluronan synthase-2 (Has2) as a likely source of hyaluronan (HA) during embryonic development, and we used gene targeting to study its function in vivo. Has2(-/-) embryos lack HA, exhibit severe cardiac and vascular abnormalities, and die during midgestation (E9.5-10). Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling. This defect is reproduced by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2(-/-) explants by gene rescue, by administering exogenous HA, or by expressing activated Ras. Conversely, transformation in Has2(-/-) explants mediated by exogenous HA is inhibited by dominant-negative Ras. Collectively, our results demonstrate the importance of HA in mammalian embryogenesis and the pivotal role of Has2 during mammalian development. They also reveal a previously unrecognized pathway for cell migration and invasion that is HA-dependent and involves Ras activation.
• Samson, R. A., Lyon, M. F., Klewer, S. E., Hagiwara, N., Erickson, D. T., & Brilliant, M. H. (2000). Sox6 is a candidate gene for p100H myopathy, heart block, and sudden neonatal death.. Proceedings of the National Academy of Sciences of the United States of America, 97(8), 4180-5. doi:10.1073/pnas.97.8.4180
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  The mouse p locus encodes a gene that functions in normal pigmentation. We have characterized a radiation-induced mutant allele of the mouse p locus that is associated with a failure-to-thrive syndrome, in addition to diminished pigmentation. Mice homozygous for this mutant allele, p(100H), show delayed growth and die within 2 wk after birth. We have discovered that the mutant mice develop progressive atrioventricular heart block and significant ultrastructural changes in both cardiac and skeletal muscle cells. These observations are common characteristics described in human myopathies. The karyotype of p(100H) chromosomes indicated that the mutation is associated with a chromosome 7 inversion. We demonstrate here that the p(100H) chromosomal inversion disrupts both the p gene and the Sox6 gene. Normal Sox6 gene expression has been examined by Northern blot analysis and was found most abundantly expressed in skeletal muscle in adult mouse tissues, suggesting an involvement of Sox6 in muscle maintenance. The p(100H) mutant is thus a useful animal model in the elucidation of myopathies at the molecular level.
• Korenberg, J. R., Barlow, G. M., Person, T., Jongewaard, I. N., Klewer, S. E., & Runyan, R. B. (1999). Betwixt mouse and man A chick model of DS heart disease. American Journal of Human Genetics, 65(4).
• Krob, S. L., Kolker, S. J., Klewer, S. E., & Kitten, G. T. (1998). Expression of type VI collagen in the developing mouse heart.. Developmental dynamics : an official publication of the American Association of Anatomists, 211(3), 248-55. doi:10.1002/(sici)1097-0177(199803)211:3<248::aid-aja6>3.0.co;2-h
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  During development, the embryonic atrioventricular (AV) endocardial cushions undergo a morphogenic process to form mature valve leaflets and the membranous septa in the heart. Several extracellular matrix (ECM) proteins are expressed in the developing AV endocardial cushions, but it remains to be established if any specific ECM proteins are necessary for normal cushion morphogenesis. Abnormal development of the cardiac AV valves is a frequent cause of congenital heart defects, particularly in infants with trisomy 21 (Down syndrome). The genes encoding the alpha1 and alpha2 chains of type VI collagen are located on human chromosome 21 within the region thought to be critical for congenital heart defects in trisomy 21 infants. This suggests that the type VI collagen alpha1(VI) and alpha2(VI) chains may be important in normal AV valve morphogenesis. As a first step in understanding the role of type VI collagen in valve development, the authors examined the normal spatial and temporal expression patterns of mRNA and protein for type VI collagen in the embryonic mouse heart. Ribonuclease protection assay analysis demonstrates cardiac expression of the type VI collagen for alpha1(VI), alpha2(VI), and alpha3(VI) transcripts beginning at embryonic days 11-11.5 of mouse development. In situ hybridization studies demonstrate a coordinated pattern of cardiac expression within the AV valves for each type VI collagen chain from embryonic day 11.5 through the neonatal period. Immunohistochemical studies confirm a concentrated type VI collagen localization pattern in the endocardial cushions from the earliest stages of valve development through the neonatal period. These data indicate that type VI collagen is expressed in the developing AV canal in a pattern consistent with cushion tissue mesenchymal cell migration and proliferation, and suggest that type VI collagen plays a role in the morphogenesis of the developing cardiac AV endocardial cushions into the valve leaflets and membranous septa of the heart.
• Zamora, R., & Klewer, S. E. (1997). Use of a cerebral angiographic catheter facilitates crossing the pulmonary valve in neonates with critical or severe pulmonary valve stenosis.. The American journal of cardiology, 80(9), 1245-7. doi:10.1016/s0002-9149(97)00654-1
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  The inability to cross the pulmonary valve in neonates with severe pulmonary stenosis remains a primary reason for procedural failure. We describe the use of a standard pediatric cerebral angiographic catheter that enables crossing the pulmonary valve in these neonates with relative ease and rapidity.
• Krob, S. L., Kolker, S. J., Klewer, S. E., & Kitten, G. T. (1996). DEVELOPMENTAL EXPRESSION OF TYPE VI COLLAGEN IN THE ATRIO-VENTRICULAR CANAL ENDOCARDIAL CUSHIONS OF THE EMBRYONIC HEART. • 167. Pediatric Research, 39(4), 30-30. doi:10.1203/00006450-199604001-00186
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  The development of the endocardial cushions in the embryonic heart appears to involve the expression of a number of extracellular matrix (ECM) proteins and their receptors. Defects of atrioventricular canal endocardial cushion formation occur most frequently in children with trisomy 21 (Down's syndrome). Genes encoding two of the three chains for type VI collagen, a component of most ECMs, are located on human chromosome 21 within the region thought responsible for the congenital heart defect phenotype associated with trisomy 21. We have examined the expression patterns of type VI collagen in the embryonic mouse heart. An affinity-purified polyclonal type VI collagen antibody was used for immunohistochemical analysis on cryofixed mouse heart sections (d8.0 p.c. to neonatal). Primary antibody was visualized with a FITC-conjugated secondary antibody viewed under fluorescent microscopy. We have determined that type VI collagen is first expressed in the endocardial cushions of the antrioventricular (AV) canal in close association with the endocardium and forming cushion mesenchymal cells. Although type VI collagen is subsequently expressed in other areas of the heart, it remains concentrated in the cushion tissue destined to become the AV valves and membranous septa. This expression pattern is retained in the AV valve leaflets and septa of later stage embryos and neonatal mice. Localization of the three individual type VI collagen chains by in situ hybridization using radiolabeled chain-specific riboprobes on embryonic mouse heart sections correlates well with the observed type VI collagen protein immuno-localization. These data demonstrate that type VI collagen is expressed in the developing AV valves and septa, supporting the molecular genetic studies indicating that type VI collagen is involved in the heart defect phenotype seen in trisomy 21.(Supported by NIH SCOR in Congenital Heart Disease, HL 42266-06).
• Krob, S. L., Kolker, S. J., Klewer, S. E., & Kitten, G. T. (1996). Type VI collagen in the cardiac valves and connective tissue septa during heart development.. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 29(9), 1189-93.
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  A variety of extracellular matrix (ECM) proteins have been shown to be present in the embryonic heart during the morphogenesis of the valves and membranous septa. It is not known if any specific ECM protein is required for the normal morphogenesis of these tissues, but this is of great interest since there is a high incidence of congenital malformations which affect valvular and septal tissues. Interestingly, the alpha 1 and alpha 2 genes of type VI collagen are located within the region of human chromosome 21 thought to be involved in the congenital heart defect phenotype associated with trisomy 21 (Down's syndrome). In this study we examined the distribution and investigated the function of type VI collagen in the cardiac valves and septa of chicken and mouse embryos during various stages of development. Immunohistochemical and in situ hybridization studies revealed a pattern of cardiac expression of type VI collagen which is present from the earliest stages of valve and septum development through the neonatal period. Results from an in vitro bioassay suggest that type VI collagen may play a role in the formation and migration of specific cells in the forming valves and septa. These data support molecular genetic studies which have indicated that type VI collagen is involved in the heart defect phenotype seen in trisomy 21.
• Donnerstein, R. L., Padbury, J. F., Klewer, S. E., Hutter, J. J., Donnerstein, R. L., & Berg, R. A. (1993). Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents.. The Journal of pharmacology and experimental therapeutics, 265(3), 1232-8.
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  Pharmacokinetic and pharmacodynamic data on adrenergic agents in children have revealed wide ranges of plasma clearance rates and hemodynamic responses in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, graded i.v. dobutamine infusions of 0.5, 2.5 and 5.0 micrograms/kg/min were sequentially administered to healthy children and adolescents. Plasma dobutamine concentrations and hemodynamic responses, including echocardiographic measures of systolic and diastolic function, were determined at each infusion rate. Pharmacodynamic data were evaluated by both threshold modeling and mean hemodynamic responses to each infusion rate. Mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. These data establish that the previously published wide variability in dobutamine clearance is not due simply to underlying disease states. Dobutamine clearance was linear over the dosage range evaluated. Dobutamine improved systolic function even at plasma concentrations attained with infusion rates as low as 1 to 2 micrograms/kg/min. The improved systolic function was at least partially due to inotropic effects. In addition, dobutamine improved diastolic function and reduced afterload. Chronotropic effects were observed in only two subjects and only at higher plasma concentrations than the other hemodynamic effects. Individualized threshold modeling effectively described the log-linear relationship between plasma dobutamine concentration and hemodynamic response beyond the threshold concentration.
• Donnerstein, R. L., Klewer, S. E., Hutter, J. J., Goldberg, S. J., Donnerstein, R. L., & Berg, R. A. (1992). Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer.. Journal of the American College of Cardiology, 19(2), 394-401. doi:10.1016/0735-1097(92)90497-b
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  Doxorubicin is an effective anticancer chemotherapeutic agent known to cause acute and chronic cardiomyopathy. To develop a more sensitive echocardiographic screening test for cardiac damage due to doxorubicin, a cohort study was performed using dobutamine infusion to differentiate asymptomatic long-term survivors of childhood cancer treated with doxorubicin from healthy control subjects. Echocardiographic data from the experimental group of 21 patients (mean age 16 +/- 5 years) treated from 1.6 to 14.3 years (median 5.3) before this study with 27 to 532 mg/m2 of doxorubicin (mean 196) were compared with echocardiographic data from 12 normal age-matched control subjects. Graded dobutamine infusions of 0.5, 2.5, 5 and 10 micrograms/kg per min were administered. Echocardiographic Doppler studies were performed before infusion and after 15 min of infusion at each rate. Dobutamine infusion at 10 micrograms/kg per min was discontinued after six studies secondary to a 50% incidence rate of adverse symptoms. The most important findings were that compared with values in control subjects, end-systolic left ventricular posterior wall dimension and percent of left ventricular posterior wall thickening in doxorubicin-treated patients were decreased at baseline study and these findings were more clearly delineated with dobutamine stimulation. End-systolic left ventricular posterior wall dimension at baseline for the doxorubicin-treated group was 11 +/- 1.9 mm versus 13.1 +/- 1.5 mm for control subjects (p less than 0.01). End-systolic left ventricular posterior wall dimension at the 5-micrograms/kg per min dobutamine infusion for the doxorubicin-treated group was 14.1 +/- 2.4 mm versus 19.3 +/- 2.6 mm for control subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
• Donnerstein, R. L., Klewer, S. E., Goldberg, S. J., & Donnerstein, R. L. (1991). Still's-like innocent murmur can be produced by increasing aortic velocity to a threshold value.. The American journal of cardiology, 68(8), 810-2. doi:10.1016/0002-9149(91)90664-7
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  Abstract Still's murmur is a musical or vibratory systolic ejection murmur found in many normal school-aged children and adolescents. Its origin has been attributed to vibration of a cardiac structure during ventricular contraction, turbulent blood flow, or pressure changes across normal valves. 1 We previously related Still's murmur to a small ascending aorta with concomitant high aortic velocity. 2 Functional murmurs are accentuated in high cardiac output states such as fever, exercise and anemia. Dobutamine, a β 1 agonist with primarily inotropic action at low doses, allows study of high cardiac output states. We investigated whether dobutamine infusion could produce a Stills-like murmur in subjects without murmurs at rest and evaluated those factors correlating best with murmur presence.
• Levine, N., Klewer, S. E., & Don, S. A. (1989). Radiofrequency hyperthermia therapy of murine melanoma: a comparison of fractionated versus single-dose treatments.. The Journal of dermatologic surgery and oncology, 15(8), 845-9. doi:10.1111/j.1524-4725.1989.tb01173.x
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  The effects of single and fractionated doses of radiofrequency hyperthermia were investigated in the treatment of cutaneous murine melanoma. S91 murine melanoma cells were implanted into preformed intradermal blister cavities on the backs of DBA/2J mice. Evaluation of treatment response was undertaken after single and fractionated doses of hyperthermia. A single 60-second treatment at 46 degrees C did not result in any complete regressions, while 3 weekly 46 degrees C treatments produced a 40% incidence of tumor regression. Higher temperature therapy was associated with improved cure rates. A single treatment for 60 seconds at 50 degrees C resulted in a 25% complete response rate while 3 weekly 50 degrees C treatments resulted in the eradication of 92% of the treated tumors. In those tumors that responded only partially to hyperthermia, fractionated low- (46 degrees C) and (50 degrees C) high-dose regimens resulted in significantly smaller melanomas than single-treatment schedules at the same temperatures. It is concluded that fractionated hyperthermia is an effective modality in the control of intracutaneous murine melanoma. If other cutaneous malignancies are also sensitive to heat, this may provide a useful nonsurgical means of treating skin cancer.
• Lloyd, T. R., Klewer, S. E., & Goldberg, S. J. (1989). In vivo relation between cineangiographic jet width and jet width imaged by color-coded Doppler.. The American journal of cardiology, 64(19), 1399-401. doi:10.1016/0002-9149(89)90595-x
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  Abstract Measurement of jet velocity distal to a flow obstruction permits estimation of pressure drop, and the resulting value can be used to assess the clinical impact of a cardiac or great vessel lesion. Pressure drop, however, is flow dependent.1 Valve area, which is computed using a flow term derived from catheterization1 or ultrasonic data,2 is probably more desirable information than pressure drop alone. Another approach to computation of valve area might be accurate measurement of jet area. Jets can be imaged by cineangiography and a somewhat similar display can be imaged by color-coded Doppler. With color-coded Doppler, a “jet” imaged distal to an obstruction is displayed as a mosaic or aliased pattern, which has some morphologic characteristics similar to those observed on a cineangiogram. The coefficient of discharge (also called the coefficient of contraction and vena contracta) is the ratio of jet area to obstructive orifice area. Although the coefficient of discharge may assume a range of values, many circumstances have a value approximating 0.7.1 Because color-coded Doppler images a pattern distal to an obstruction that has morphologic characteristics similar to those of a jet, it would be very convenient if that pattern actually represented the jet. If this were true, measurement of this unage and use of the ratio could approximate the area of the obstructive orifice. Yoganathan et al3 reported that the color-coded image of an in vitro jet is an indirect indicator of orifice size, but that the jet, as imaged, is about 20% larger than the true jet. This study examines the in vivo relation between the flow disturbance imaged by color-coded Doppler and the jet width detected by cineangiography. If a relation could be established, Doppler jet width would be a diameter that could be converted to an area [ area = ( width 2 ) 2 · π ] and that area could be used to predict orifice area. Our hypothesis was that width (or area) of the in vivo Doppler jet will exceed width (or area) of the cineangiographic jet.
• Vasquez, J. A., Levine, N., Klewer, S. E., Draelos, Z. K., & Don, S. A. (1989). Radiofrequency hyperthermia and topical retinoic acid therapy in murine melanoma.. The American journal of the medical sciences, 297(5), 285-9. doi:10.1097/00000441-198905000-00003
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  Malignant cells are known to be sensitive to increased temperature. The effects of hyperthermia (HT) on intradermally implanted S91 melanoma cells in syngeneic mice were investigated with a hand-held radiofrequency generator. The possible additive effects of topical retinoic acid (RA) in this system also were studied. Five millimeter diameter melanomas were treated with either HT alone, RA alone, or a combination of HT and RA and were then evaluated after 43 days and 59 days. Eighteen of 20 tumors treated with HT alone and all 20 melanomas treated with HT/RA were eradicated. RA alone caused complete regression in 11 of 19 treated tumors. It is concluded that radiofrequency HT is an effective treatment in intradermal murine melanoma and that the addition of RA does not significantly alter the outcome because of the extreme effectiveness of HT alone.

Proceedings Publications

• Boyer, P., Seckeler, M., Andrews, J., & Klewer, S. (2019, MAR 12). IMPACT OF INSURANCE COVERAGE AND PHYSICIAN COMMUNICATION ON LOSS TO FOLLOW-UP IN ADULTS WITH CONGENITAL HEART DISEASE: RESULTS OF THE CONGENITAL HEART SURVEY TO RECOGNIZE OUTCOMES, NEEDS, AND WELL-BEING (CH STRONG). In JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 73, 570-570.
• Kylathu, R., Kuo, P. H., Barber, B. J., Klewer, S. E., Bernas, M. J., Behan, S., Moedano, L., Mustacich, D., & Witte, M. H. (2019, September). Whole Body Lymphangioscintigraphy and SPECT-CT in Infants and Children with Lymphatic Congestion after Surgical Repair of Complex Congenital Heart Disease. In 27th World Congress of Lymphology Abstract Booklet.
• Myles, R., Kylathu, R., Witte, M. H., Seckeler, M., & Klewer, S. E. (2019, September). The "Failing Fontan" Challenge to the Cardiolymphologist: Case Analysis. In 27th World Congress of Lymphology Abstract Booklet.
• Takamatsu, C., Andrews, J., & Klewer, S. (2019, JAN). REPRODUCTIVE HEALTH OF FEMALES WITH CONGENITAL HEALTH DEFECTS. In JOURNAL OF INVESTIGATIVE MEDICINE, 67, 65-65.
• Parthasarathy, S., Abraham, I. L., Hsu, C., Morgan, W. J., Klewer, S. E., Barber, B. J., Edgin, J. O., & Combs, D. (2018, Fall). Obstructive sleep apnea is a novel risk factor for neurocognitive impairment in children with congenital heart disease. In Circulation, 138(Suppl 1), 14956.
• Seckeler, M., Thomas, I. D., Andrews, J., Meziab, O., Heller, E., Moe, T., & Klewer, S. (2015, MAR 17). HIGH RESOURCE UTILIZATION FOR NON-CARDIAC HOSPITAL ADMISSIONS FOR ADULTS WITH CONGENITAL HEART DISEASE. In JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY.

Presentations

• Seckeler, M., Klewer, S. E., Fox, K., Strah, D., & Yrun-Duffy, M. (2022, May). An unusual congenital aorto-pulmonary shunt in tetralogy of Fallot: Anomalous left innominate artery off the pulmonary artery. The Society for Cardiovascular Angiography and Interventions 2022 Scientific Sessions. Atlanta, GA.
• Seckeler, M., Klewer, S. E., Andrews, J. G., Bernardi, A., & Colombo, J. (2019, November). Marked Decline in Exercise Performance for Adolescents with Fontan Physiology – An Analysis of the Pediatric Heart Network Fontan Public Data Set. American Heart Association 2019 Scientific Sessions. Philadelphia, PA.

Poster Presentations

• Caryl, N., Culbert, H., June, C., Hellinger, R., Hoyer, A., Klewer, S. E., & Seckeler, M. (2022, November). Incidence of Cancer in Hospitalized Adults with Congenital Heart Disease. American Heart Association Scientific Sessions. Chicago, IL: American Heart Association.
• Finn-Downing, K., Nembhard, W., Rose, C., Andrews, J. G., Goudie, A., Klewer, S. E., Oster, M., & Farr, S. (2022, November). Mortality From Birth To Young Adulthood Among Individuals With Congenital Heart Defects: Results From The Congenital Heart Survey To Recognize Outcomes, Needs And, Well-being . American Heart Association Scientific Sessions. Chicago, Il: American Heart Association.
• Seckeler, M., Klewer, S. E., Hoyer, A., Hellinger, R., June, C., Culbert, H., & Caryl, N. (2022, November). Incidence of Cancer in Hospitalized Adults with Congenital Heart Disease. Arizona American College of Cardiology 2022 Annual Meeting. Scottsdale, AZ.
• Combs, D. A., Seckeler, M., Seckeler, M., Fernandez, V., Klewer, S. E., Klewer, S. E., Barber, B. J., Parthasarathy, S., Parthasarathy, S., Morgan, W. J., Andrews, J. G., Andrews, J. G., Hsu, C., Hsu, C., Hsu, C., Andrews, J. G., Morgan, W. J., Morgan, W. J., Parthasarathy, S., , Barber, B. J., et al. (2020, November). Obstructive Sleep Apnea Is Associated with Cardiac Dysfunction In Children With Congenital Heart Disease. 2020 American Heart Association Scientific SessionsAmerican Heart Association.
• Kops, S. A., White, S., Klewer, S. E., Andrews, J. G., & Seckeler, M. (2019, May/Spring). ECMO in Adults with Congenital Heart Disease Analysis of a National Discharge Database. Annual International Symposium on Heart Disease in the Adult. Skamania, WA: OHSU.
• Klewer, S. E., Seckeler, M., White, S., Andrews, J. G., & Gilpatrick, M. (2018, November). Cost of childhood chest pain evaluation is higher in emergency departments with fewer pediatric resources. American Academy of Pediatrics National Conference. New Orleans: American Academy of Pediatrics.
• Zahedieh, S., Seckeler, M., Andrews, J., Klewer, S. E., Scherer, K., Daines, C. L., & Barber, B. J. (2015, Fall). Regional and Racial Variation in Hospitalization Costs in Patients with Duchenne Muscular Dystrophy. American Academy of Pediatrics National Conference and Exhibition. Washington, DC: AAP.