100 results on '"Elizabeth A. Braunlin"'
Search Results
2. Unmet Cardiac Clinical Needs in Adult Mucopolysaccharidoses
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Karolina M. Stepien and Elizabeth A. Braunlin
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adult mucopolysaccharidoses ,cardiac ,unmet needs ,therapies ,transition ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
The Mucopolysaccharidoses (MPSs) are a group of heterogenous disorders with complex multisystemic presentations. Although Haematopoietic Cell Transplantation (HCT) and Enzyme Replacement Therapy (ERT) have extended the lifespan of individuals affected with MPS well into adulthood, reversal of pre-existing cardiac, skeletal and neurocognitive deficits does not occur, so there are no truly curative treatments available to these patients at present. The medical and surgical management of cardiovascular problems in adults with MPS is complicated by these pre-existing comorbidities, requiring the involvement of multidisciplinary and multispecialty perioperative teams. This review sets out to describe the unmet cardiac needs in adults with MPS disorders including the lack of effective treatments, monitoring guidelines, and the challenges regarding expertise and training, and psychosocial support.
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- 2022
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3. Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair
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Nathan Grant, Young Bae Sohn, N. Matthew Ellinwood, Ericka Okenfuss, Bryce A. Mendelsohn, Leslie E. Lynch, Elizabeth A. Braunlin, Paul R. Harmatz, and Julie B. Eisengart
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Newborn screening ,Mucopolysaccharidosis type II ,Hunter syndrome ,Enzyme replacement therapy ,Early intervention ,Sibling study ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Hunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504 T > G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling's findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of
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- 2022
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4. The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls
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Raymond Y. Wang, Kyle D. Rudser, Donald R. Dengel, Elizabeth A. Braunlin, Julia Steinberger, David R. Jacobs, Alan R. Sinaiko, and Aaron S. Kelly
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mucopolysaccharidosis ,vascular ,intima ,media ,thickness ,stiffness ,outcome ,treatment ,lysosomal ,structure ,function ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old.
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- 2017
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5. Successful rapid staged hybrid approach for obstructed total anomalous pulmonary venous connection
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Sameh M. Said, Elizabeth A. Braunlin, James Berry, Ashley Loomis, and Gurumurthy Hiremath
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Pulmonary and Respiratory Medicine ,Surgery ,Cardiology and Cardiovascular Medicine - Published
- 2022
6. The double shunt technique as a bridge to heart transplantation in a patient with pulmonary atresia with intact septum and right ventricular-dependent coronary circulation
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Massimo Griselli, Gamal Marey, Sameh M. Said, Ryan T Greene, Gurumurthy Hiremath, Varun Aggarwal, and Elizabeth A. Braunlin
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Pulmonary and Respiratory Medicine ,Heart transplantation ,medicine.medical_specialty ,business.industry ,Congenital: Pulmonary Atresia: Case Report ,medicine.medical_treatment ,medicine.disease ,Bridge (interpersonal) ,Shunt (medical) ,Coronary circulation ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cardiology ,Surgery ,Pulmonary atresia ,business - Published
- 2021
7. Pediatric SubQ-ICD implantation, a single center review of the inter-muscular technique
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Daniel Cortez, Elizabeth A. Braunlin, Jamie L. Lohr, Nathan J. Rodgers, Kari Erickson, Rebecca K. Ameduri, Gurumurthy Hiremath, and Brenda Dugas
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lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Single Center ,Pediatrics ,Sudden death ,Defibrillation threshold ,03 medical and health sciences ,0302 clinical medicine ,Subcutaneous ICD ,Physiology (medical) ,Intermuscular ,medicine ,Mass index ,030212 general & internal medicine ,business.industry ,Surgery ,lcsh:RC666-701 ,Shock (circulatory) ,Cohort ,Original Article ,Median body ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Complication - Abstract
Introduction Pediatric patients with cardiomyopathies are at risk for sudden death and may need implantable cardioverter defibrillators (ICD’s), but given their small size and duration of use, children are at increased risk for complications associated with ICD use. The subcutaneous ICD presents a favorable option for children without pacing indications. Unfortunately, initial pediatric studies have demonstrated a high complication rate, likely due to the 3-incision technique employed. Material and methods Patients with ICD but no pacing indication were retrospectively reviewed after implantation of subcutaneous ICD via the two-incision technique. In half of the patients, 10-J impedance test was also performed to compare with impedance obtained after defibrillation threshold testing with 65-J. Results Twelve patients were included. The median age was 14 years (range 10–16 years) with eight males included (72.7%). The median weight was 55 kg (range 29 kg–75.1 kg). Follow-up had a median of 11.5 months (range 2–27 months). The median body mass index was 18.4 kg/m squared (range 15.5–27.9 kg/m squared). One patient suffered a minor complication after tearing off the incisional adhesive strips early and required a non-invasive repair in clinic. Shock impedance had a median of 55 J (range 48–68 J). There was one appropriate shock/charge and no inappropriate shocks during follow-up. Conclusion The two-incision, intermuscular technique appears to have a lower acute complication rate than prior reports, in our cohort of 12 pediatric patients.
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- 2021
8. Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants
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Marjon van Slegtenhorst, Dean Phelan, Jan D. H. Jongbloed, Christine E. Seidman, Johanna C. Herkert, Francisco Fernández-Avilés, Chloe A Stutterd, Amy E. Roberts, Radhika Agarwal, Paul J. Lockhart, Mary Ella M Pierpont, Ingrid M.B.H. van de Laar, Irene M. van Langen, Ludolf G. Boven, Yolande van Bever, Raquel Yotti, Michael A. Burke, Jonathan G. Seidman, Paul A. James, Judith M.A. Verhagen, Kai'En E. Leong, David J. Amor, Elizabeth A. Braunlin, Ahmet Okay Ḉağlayan, Alireza Haghighi, Neal K. Lakdawala, Lennie van Osch-Gevers, Marian Bulthuis, Ivan Macciocca, Daniela Q.C.M. Barge-Schaapveld, Natasha J Brown, Erwin Birnie, Health Psychology Research (HPR), Reproductive Origins of Adult Health and Disease (ROAHD), Cardiovascular Centre (CVC), Clinical Genetics, and Pediatrics
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Adult ,Cardiomyopathy, Dilated ,Heterozygote ,medicine.medical_specialty ,Heart disease ,Mutation, Missense ,Cardiomyopathy ,Muscle Proteins ,030204 cardiovascular system & hematology ,Gastroenterology ,CLASSIFICATION ,Muscle hypertrophy ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Loss of Function Mutation ,Ventricular hypertrophy ,Internal medicine ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,030212 general & internal medicine ,Age of Onset ,Child ,Chromosomes, Human, Pair 15 ,HYPERTROPHIC CARDIOMYOPATHY ,business.industry ,Hypertrophic cardiomyopathy ,Infant ,Dilated cardiomyopathy ,ASSOCIATION ,Cardiomyopathy, Hypertrophic ,medicine.disease ,PREVALENCE ,Phenotype ,Echocardiography ,Child, Preschool ,CELLS ,Age of onset ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,business ,GENOMICS ,Protein Kinases - Abstract
Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13). Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
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- 2020
9. Pediatric Micra leadless pacemaker implantation via the internal jugular and femoral vein: a single-center, US experience
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John L. Bass, Elizabeth A. Braunlin, Matthew Ambrose, Julia Steinberger, Daniel Cortez, Erick Jimenez, and Hani Siddeek
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medicine.medical_specialty ,Pacemaker, Artificial ,business.industry ,Femoral vein ,Equipment Design ,Femoral Vein ,medicine.disease ,Single Center ,Pericardial effusion ,Surgery ,Pacemaker implantation ,Treatment Outcome ,Pearson marrow-pancreas syndrome ,medicine ,Molecular Medicine ,Humans ,In patient ,Cardiology and Cardiovascular Medicine ,Lead (electronics) ,business ,Child ,Pediatric population ,Retrospective Studies - Abstract
Background: In the pediatric population, conventional transvenous and epicardial pacemaker systems carry complications such as lead distortion due to growth/activity, in addition to other lead/pocket complications. Materials & methods: A retrospective review of pediatric leadless pacing at the University of Minnesota Masonic Children’s Hospital from 2018 to 2020 was performed. Rationale for pacing, demographics of patients, thresholds and longevity of devices were recorded. Results: Seven leadless pacemaker insertions and one removal were performed successfully, in patients weighing between 19 kg and 58 kg. Three patients had Micra implantation via internal jugular vein. One pericardial effusion occurred perioperatively in a 19 kg patient with baseline thrombocytopenia, sideroblastic anemia and Pearson Marrow Pancreas syndrome. Conclusion: Leadless pacemaker implantation/early retrieval is feasible in pediatric patients.
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- 2021
10. Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation
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Lynda E. Polgreen, Elizabeth A. Braunlin, Troy C. Lund, Kyle Rudser, Bradley S. Miller, Paul J. Orchard, Chester B. Whitley, Jakub Tolar, Elise F. Northrop, Julie B. Eisengart, Ellen B. Fung, and Weston P. Miller
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Male ,Time Factors ,Mucopolysaccharidosis I ,Pilot Projects ,Disease ,Pediatrics ,Iduronidase ,0302 clinical medicine ,Child Development ,Lysosomal storage disease ,Hurler syndrome ,Child ,Clinical Research Article ,0303 health sciences ,LARONIDASE ,Hematopoietic Stem Cell Transplantation ,3. Good health ,Treatment Outcome ,Child, Preschool ,Administration ,Public Health and Health Services ,Administration, Intravenous ,Female ,Intravenous ,medicine.medical_specialty ,Adolescent ,Clinical Trials and Supportive Activities ,Drug Administration Schedule ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Humans ,Enzyme Replacement Therapy ,Preschool ,030304 developmental biology ,Transplantation ,Hematopoietic cell ,business.industry ,Adolescent Development ,medicine.disease ,Clinical trial ,Functional Status ,Pediatrics, Perinatology and Child Health ,business ,030217 neurology & neurosurgery - Abstract
Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants
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- 2020
11. Variation in Pharmacologic Management of Patients with Kawasaki Disease with Coronary Artery Aneurysms
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Anji T. Yetman, Patrick Gould, Annette L. Baker, Adriana H. Tremoulet, Tisiana Low, Lillian Lai, Kenny K. Wong, Tanveer H. Collins, Michael R. Carr, Mathew Mathew, Kyle Runeckles, Sean M. Lang, Sam Sabouni, Michael H. Gewitz, Frederic Dallaire, Cedric Manlhiot, Supriya Jain, Nagib Dahdah, Pei-Ni Jone, Claudia Renaud, Kambiz Norozi, Ming-Tai Lin, Geetha Raghuveer, Laurent Desjardins, Sarah D. de Ferranti, Thomas Thomas, Jane W. Newburger, Therese M. Giglia, Michael A. Portman, Elizabeth A. Braunlin, Thomas R. Kimball, Craig Sable, Andrew S. Mackie, Kevin C. Harris, Devin D. Tinker, Brian W. McCrindle, Sunita O’Shea, Karen Texter, Shelby Kutty, Jane C. Burns, Jennifer S. Li, Mei-Hwan Wu, Kevin G. Friedman, Kimberly E. McHugh, Rejane Dillenburg, Nadine Choueiter, Audrey Dionne, Adam A Dempsey, Tapas Mondal, Deepika Thacker, Kevin D. Hill, Elif Seda Selamet Tierney, Simon Lee, William T. Mahle, Sharon Wagner-Lees, S. Kristen Sexson Tejitel, Jacqueline R. Szmuszkovicz, Carolyn A. Altman, Jessica H. Colyer, Anne Fournier, and Ashraf S Harahsheh
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Male ,medicine.medical_specialty ,Pharmacological management ,Mucocutaneous Lymph Node Syndrome ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Abciximab ,Humans ,Immunologic Factors ,Registries ,cardiovascular diseases ,Practice Patterns, Physicians' ,Retrospective Studies ,Coronary artery aneurysm ,Aspirin ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Coronary Aneurysm ,Immunoglobulins, Intravenous ,Infant ,medicine.disease ,Clopidogrel ,Infliximab ,medicine.anatomical_structure ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Kawasaki disease ,business ,medicine.drug ,Artery - Abstract
Objective To evaluate practice variation in pharmacologic management in the International Kawasaki Disease Registry (IKDR). Study design Practice variation in intravenous immunoglobulin (IVIG) therapy, anti-inflammatory agents, statins, beta-blockers, antiplatelet therapy, and anticoagulation was described. Results We included 1627 patients from 30 IKDR centers with maximum coronary artery aneurysm (CAA) z scores 2.5-4.99 in 848, 5.0-9.99 in 349, and ≥10.0 (large/giant) in 430 patients. All centers reported IVIG and acetylsalicylic acid (ASA) as primary therapy and use of additional IVIG or steroids as needed. In 23 out of 30 centers, (77%) infliximab was also used; 11 of these 23 centers reported using it in 20% of patients. Nonsteroidal anti-inflammatory agents were used in >10% of patients in only nine centers. Beta-blocker (8.8%, all patients) and abciximab (3.6%, all patients) were mainly prescribed in patients with large/giant CAAs. Statins (2.7%, all patients) were mostly used in one center and only in patients with large/giant CAAs. ASA was the primary antiplatelet modality for 99% of patients, used in all centers. Clopidogrel (18%, all patients) was used in 24 centers, 11 of which used it in >50% of their patients with large/giant CAAs. Conclusions In the IKDR, IVIG and ASA therapy as primary therapy is universal with common use of a second dose of IVIG for persistent fever. There is practice variation among centers for adjunctive therapies and anticoagulation strategies, likely reflecting ongoing knowledge gaps. Randomized controlled trials nested in a high-quality collaborative registry may be an efficient strategy to reduce practice variation.
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- 2022
12. A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
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Naoko Koyano-Nakagawa, Bhairab N. Singh, Cyprian Weaver, Ivan P. Moskowitz, Satyabrata Das, Wuming Gong, Mary G. Garry, Elizabeth A. Braunlin, Jop H. van Berlo, and Daniel J. Garry
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0301 basic medicine ,Hh signaling ,animal structures ,Science ,General Physics and Astronomy ,Zinc Finger Protein GLI1 ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,GLI1 ,medicine ,Animals ,Humans ,Regeneration ,Mrna transfection ,Hedgehog Proteins ,Myocytes, Cardiac ,lcsh:Science ,Hedgehog ,Cell Proliferation ,N-Myc Proto-Oncogene Protein ,Multidisciplinary ,Biological studies ,biology ,Regeneration (biology) ,Heart ,General Chemistry ,medicine.disease ,Salamandridae ,Cell biology ,030104 developmental biology ,Heart failure ,embryonic structures ,biology.protein ,lcsh:Q ,Function (biology) ,Signal Transduction - Abstract
The mammalian heart has a limited regenerative capacity and typically progresses to heart failure following injury. Here, we defined a hedgehog (HH)-Gli1-Mycn network for cardiomyocyte proliferation and heart regeneration from amphibians to mammals. Using a genome-wide screen, we verified that HH signaling was essential for heart regeneration in the injured newt. Next, pharmacological and genetic loss- and gain-of-function of HH signaling demonstrated the essential requirement for HH signaling in the neonatal, adolescent, and adult mouse heart regeneration, and in the proliferation of hiPSC-derived cardiomyocytes. Fate-mapping and molecular biological studies revealed that HH signaling, via a HH-Gli1-Mycn network, contributed to heart regeneration by inducing proliferation of pre-existing cardiomyocytes and not by de novo cardiomyogenesis. Further, Mycn mRNA transfection experiments recapitulated the effects of HH signaling and promoted adult cardiomyocyte proliferation. These studies defined an evolutionarily conserved function of HH signaling that may serve as a platform for human regenerative therapies., Due to the limited proliferation capacity of adult mammalian cardiomyocytes, the human heart has negligible regenerative capacity after injury. Here the authors show that a Hedgehog-Gli1-Mycn signaling cascade regulates cardiomyocyte proliferation and cardiac regeneration from amphibians to mammals.
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- 2018
13. Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome)
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Julia Steinberger, Aaron S. Kelly, Paul J. Orchard, Elizabeth A. Braunlin, and Todd E. DeFor
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medicine.medical_specialty ,Adolescent ,Mucopolysaccharidosis I ,Mucopolysaccharidosis ,030204 cardiovascular system & hematology ,Gastroenterology ,Young Adult ,03 medical and health sciences ,Mucopolysaccharidosis type I ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Survivors ,Child ,Hurler syndrome ,Metabolic Syndrome ,Transplantation ,business.industry ,Incidence ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Blood pressure ,medicine.anatomical_structure ,Cardiovascular Diseases ,Hypertension ,Metabolic syndrome ,business ,Dyslipidemia ,030215 immunology ,Artery - Abstract
Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome—a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose—is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.
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- 2018
14. Duration of high-dose aspirin therapy does not affect long-term coronary artery outcomes in Kawasaki disease
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Bryce A. Binstadt, Lei Zhang, Karl Migally, and Elizabeth A. Braunlin
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Male ,medicine.medical_specialty ,Minnesota ,Coronary Artery Disease ,Mucocutaneous Lymph Node Syndrome ,030204 cardiovascular system & hematology ,Affect (psychology) ,Drug Administration Schedule ,Article ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Primary outcome ,Internal medicine ,Humans ,Medicine ,030212 general & internal medicine ,Child ,Retrospective Studies ,Inflammation ,Aspirin ,business.industry ,Coronary Aneurysm ,Immunoglobulins, Intravenous ,Infant ,Retrospective cohort study ,medicine.disease ,Coronary Vessels ,3. Good health ,Treatment Outcome ,medicine.anatomical_structure ,Aspirin therapy ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Kawasaki disease ,business ,Artery ,medicine.drug - Abstract
BackgroundHigh-dose aspirin (HDA) is used with intravenous immunoglobulin (IVIg) in Kawasaki disease (KD). Practice regarding HDA varies, and it is unclear whether HDA duration affects the long-term course.MethodsWe retrospectively studied KD patients at our hospital for over 10 years. Patients were categorized as having received HDA for 0, 1-7, or >7 days. Primary outcome was the maximum coronary Z-score at diagnosis and follow-up; secondary outcomes included inflammatory markers.ResultsOne hundred and three patients had HDA duration documented, of which 35 patients had coronary artery abnormalities (CAAs) at diagnosis. There was no difference in demographics or inflammatory markers between the HDA groups, and no difference in HDA duration between patients with or without CAAs. Seventeen patients received no HDA; they had longer illness and defervescence duration before diagnosis, and were less likely to receive IVIg. For CAAs, multivariate regression revealed that HDA duration did not predict the coronary Z-score at 9-15 months. Higher Z-score at diagnosis was associated with higher Z-score at 9-15 months.ConclusionThe only factor associated with coronary Z-score at 9-15 months was the Z-score at diagnosis. At our institution, longer illness and defervescence duration and the lack of IVIg administration were associated with not administering HDA. HDA duration did not affect the clinically relevant outcomes, particularly CAA persistence.
- Published
- 2018
15. Effect of supraphysiological alpha-L-iduronidase (IDUA) expression on skeletal manifestations in mucopolysaccharidosis type I (MPS I) mice following ex vivo lentiviral vector transduction of hematopoietic stem cells
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Troy C. Lund, Hillary Mantone, Avery Huber, Kelly M. Podetz-Pedersen, Elizabeth A. Braunlin, Lalitha R. Belur, Miles Smith, Andrea D. Karlen, R. Scott McIvor, Melissa Bonner, Nicholas A. Robinson, and Hsing-Chen Tsai
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Endocrinology, Diabetes and Metabolism ,Biology ,Biochemistry ,Cell biology ,Viral vector ,Mucopolysaccharidosis type I ,Transduction (genetics) ,Haematopoiesis ,Endocrinology ,Genetics ,Stem cell ,Iduronidase ,Molecular Biology ,Ex vivo - Published
- 2021
16. Curricula components for entrustable professional activities for the subspecialty of pediatric cardiology
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Elizabeth A. Braunlin, Beth F. Printz, Lowell H. Frank, Peter Koenig, Pierre Wong, George McDaniel, Antonio G. Cabrera, Julie S. Glickstein, Troy Alan Johnston, David F.M. Brown, Benjamin E. Reinking, Shubhika Srivastava, and Carol Carraccio
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Medical education ,medicine.medical_specialty ,business.industry ,education ,Subspecialty ,behavioral disciplines and activities ,humanities ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Family medicine ,Pediatrics, Perinatology and Child Health ,Medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Curriculum ,psychological phenomena and processes ,health care economics and organizations ,Pediatric cardiology - Abstract
• Entrustable professional activities define the tasks, knowledge and skills expected of a physician.
- Published
- 2017
17. Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: the 30-year University of Minnesota experience
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Paul J. Orchard, Kyle Rudser, Alexander M. Kaizer, Nathan J. Rodgers, Weston P. Miller, and Elizabeth A. Braunlin
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Male ,0301 basic medicine ,medicine.medical_specialty ,Minnesota ,Mucopolysaccharidosis I ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,National Death Index ,03 medical and health sciences ,Mucopolysaccharidosis type I ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Cumulative incidence ,Hurler syndrome ,Genetics (clinical) ,Retrospective Studies ,Proportional hazards model ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Infant ,Enzyme replacement therapy ,medicine.disease ,Surgery ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Mucopolysaccharidosis IH (MPS IH, Hurler syndrome) naturally leads to death within the first decade of life, primarily from cardiac and pulmonary causes. To determine how hematopoietic stem cell transplantation (HSCT) has altered mortality, we analyzed our institution’s 30-year experience of patients with MPS IH undergoing HSCT. Using chart review and the National Death Index, we determined survival status of 134 patients (males = 69) with MPS IH transplanted between 9/16/1983 and 7/25/2013 on 12/31/2013. Analysis included descriptive statistics, Kaplan-Meier curves, and regression analysis by Cox proportional hazards model. Overall survival (95% CI) at one- and 25-years was 70% (62–78%) and 37% (19–55%), respectively. From 2004 onward, overall survival at one- and 8-years was 84% (73–96%) and 81% (69–94%), respectively, compared to 65% (55–74%) and 57% (47–67%) prior to 2004 (Log-rank p = 0.032). Regardless of era, male survival was significantly better than female (HR 0.40, [95% CI: 0.21–0.74], p = 0.004). The cumulative incidence of death (95% CI) at 25 years was 63% (45–81%); incidence of pulmonary-related death was the highest at 27% (10–41%) compared to 8% (0.3–16%) for cardiac, 12% (6–17%) for infectious disease, and 16% (3–27%) from other complications. HSCT has increased survival in MPS IH beyond the third decade of life and decreased the incidence of cardiac mortality, but deaths after the third year post-HSCT occur in excess of expected US mortality. It is important to determine if improved transplant strategies since 2004 result in better long-term survival in the current patient population.
- Published
- 2017
18. Tele-Pediatric Intensive Care for Critically Ill Children in Syria
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Waseem Ostwani, Elizabeth A. Braunlin, Katherine M. Steffen, Marie E. Steiner, Muhammad Bakr Ghbeis, Gregory J. Beilman, and Jay Dahman
- Subjects
Male ,Emergency Medical Services ,Telemedicine ,Critical Care ,Health Informatics ,Intensive Care Units, Pediatric ,Pediatrics ,Medical care ,Military medicine ,03 medical and health sciences ,0302 clinical medicine ,Health Information Management ,Intensive care ,Humans ,Medicine ,030212 general & internal medicine ,Child ,Referral and Consultation ,health care economics and organizations ,Syria ,Critically ill ,business.industry ,030503 health policy & services ,Infant, Newborn ,Infant ,food and beverages ,General Medicine ,medicine.disease ,Child, Preschool ,War-Related Injuries ,Female ,Medical emergency ,0305 other medical science ,business - Abstract
Armed conflicts can result in humanitarian crises and have major impacts on civilians, of whom children represent a significant proportion. Usual pediatric medical care is often disrupted and trauma resulting from war-related injuries is often devastating. High pediatric mortality rates are thus experienced in these ravaged medical environments.Using simple communication technology to provide real-time management recommendations from highly trained pediatric personnel can provide substantive clinical support and have a significant impact on pediatric morbidity and mortality.We implemented a "Tele-Pediatric Intensive Care" program (Tele-PICU) to provide real-time management consultation for critically ill and injured pediatric patients in Syria with intensive care needs.Over the course of 7 months, 19 cases were evaluated, ranging in age from 1 day to 11 years. Consultation questions addressed a wide range of critical care needs. Five patients are known to have survived, three were transferred, five died, and six outcomes were unknown.Based on this limited undertaking with its positive impact on survival, further development of Tele-PICU-based efforts with attention to implementation and barriers identified through this program is desirable.Even limited Tele-PICU can provide timely and potentially lifesaving assistance to pediatric care providers. Future efforts are encouraged.
- Published
- 2018
19. Cardiac issues in adults with the mucopolysaccharidoses: current knowledge and emerging needs
- Author
-
Elizabeth A. Braunlin and Raymond Y. Wang
- Subjects
medicine.medical_specialty ,Heart Diseases ,Population ,Disease ,030204 cardiovascular system & hematology ,Risk Assessment ,03 medical and health sciences ,Coronary circulation ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,education ,education.field_of_study ,business.industry ,Enzyme replacement therapy ,Mucopolysaccharidoses ,Prognosis ,medicine.disease ,Coronary arteries ,Natural history ,Stenosis ,Phenotype ,medicine.anatomical_structure ,Great vessels ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
The growing availability of innovative treatments for rare genetic diseases with a cardiac component-such as the mucopolysaccharidoses (MPSs)-has changed these syndromes from 'back of the textbook' curiosities of childhood to chronic, but rare, adult cardiac conditions that require both centres of expertise and knowledgeable subspecialists. The MPSs are inherited progressive lysosomal storage diseases, occurring in about 1:25 000 births and resulting from absence of functional hydrolases responsible for the degradation of glycosaminoglycans, naturally occurring complex sugars ubiquitous throughout the body. In the heart, accumulation of glycosaminoglycans occurs within the cardiac valves, the epicardial coronary arteries, the myocytes and cardiac interstitium and the walls of the great vessels. As a consequence, cardiac valve regurgitation and stenosis, diffuse coronary artery stenosis, myocardial dysfunction and aortic root dilation often occur. Haematopoietic cell transplantation and enzyme replacement therapy have changed the previously lethal natural history of the MPSs to one of survival well into adulthood. Despite this improved lifespan, the left-sided cardiac valves continue to show progressive functional involvement and cardiac valve replacement is not uncommon, especially in adults. The risk of any intervention is increased in these patients because of the systemic effects of the disease on the respiratory system and cervical cord. Our current understanding of other cardiac issues in adults with the MPSs, especially with the coronary circulation and myocardium, is meagre and more needs to be known to effectively care for this emerging population of adults. Incorporation of the MPSs, as well as other now-treatable rare diseases, into the educational curriculum of current and future adult subspecialists is an important next step.
- Published
- 2016
20. Cardiopulmonary assessment of adults and adolescents with MPS disorders
- Author
-
Chester B. Whitley and Elizabeth A. Braunlin
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry - Published
- 2020
21. Findings from a first international newborn screening meeting for MPS I
- Author
-
Julie B. Eisengart, Elizabeth A. Braunlin, Susan A. Berry, Amy Gaviglio, Jennifer A. Braun, Ashish Gupta, and Paul J. Orchard
- Subjects
Newborn screening ,medicine.medical_specialty ,Endocrinology ,business.industry ,Obstetrics ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,business ,Molecular Biology ,Biochemistry - Published
- 2020
22. Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2)
- Author
-
Paul J. Orchard, Lindsey Hageman, Weston P. Miller, Troy C. Lund, Mukta Arora, Aman Wadhwa, Anna Sällfors Holmqvist, Michelle Kung, Mariel Parman, Yanjun Chen, Smita Bhatia, Emily Ness, Liton Francisco, Saro H. Armenian, Jessica Wu, and Elizabeth A. Braunlin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Mucopolysaccharidosis I ,Population ,Article ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Risk factor ,education ,Hurler syndrome ,Adrenoleukodystrophy ,Child ,Bone Marrow Transplantation ,Retrospective Studies ,Transplantation ,education.field_of_study ,Hematology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant, Newborn ,Infant ,Leukodystrophy, Metachromatic ,Middle Aged ,medicine.disease ,Metachromatic leukodystrophy ,Survival Rate ,surgical procedures, operative ,Standardized mortality ratio ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,Female ,business ,Busulfan ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.
- Published
- 2018
23. Adding enzyme replacement therapy after hematopoietic stem cell transplantation results in increased metabolic correction in MPS VI
- Author
-
Paul J. Orchard, Elizabeth A. Braunlin, Chester B. Whitley, and Jeanine R. Jarnes-Utz
- Subjects
medicine.medical_specialty ,Creatinine ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Enzyme replacement therapy ,Urine ,Hematopoietic stem cell transplantation ,Biochemistry ,Glycosaminoglycan ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Mole ,Genetics ,medicine ,business ,Molecular Biology ,Normal range ,Liver size - Abstract
Following allogenic bone marrow transplantation with predominance of donor engraftment, patients with Maroteaux-Lamy syndrome (MPS VI) demonstrate several indications of metabolic correction, such as reduction in liver size, and achieve near-normal levels of urine glycosaminoglycan (GAG). Thus it was somewhat surprising that, a single infusion of galsulfase after 20 years of full donor engraftment resulted in a further decline of GAG into the normal range (Whitley and Jarnes-Utz, Mol Genet Metab 101(4): 346-348, 2010). Urine GAG declined from slightly high pre-treatment levels (7.63 mg GAG/mmol creatinine range 7.0-8.5, N=3) progressively declining below the age-specific normal range (
- Published
- 2019
24. The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls
- Author
-
Donald R. Dengel, Kyle Rudser, Raymond Y. Wang, Alan R. Sinaiko, David R. Jacobs, Elizabeth A. Braunlin, Julia Steinberger, and Aaron S. Kelly
- Subjects
0301 basic medicine ,Male ,Carotid arteries ,Mucopolysaccharidosis ,Blood Pressure ,030204 cardiovascular system & hematology ,Carotid Intima-Media Thickness ,lcsh:Chemistry ,stiffness ,0302 clinical medicine ,vascular ,Medicine and Health Sciences ,Medicine ,skin and connective tissue diseases ,Child ,lcsh:QH301-705.5 ,Spectroscopy ,treatment ,Age Factors ,mucopolysaccharidosis ,General Medicine ,diagnosis ,pathology ,physiopathology [Mucopolysaccharidoses] ,3. Good health ,Computer Science Applications ,Cohort ,Cardiology ,outcome ,Female ,Ultrasonography ,Adult ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Young Adult ,Vascular Stiffness ,Internal medicine ,lysosomal ,Humans ,structure ,Physical and Theoretical Chemistry ,Molecular Biology ,Carotid artery distensibility ,function ,business.industry ,Organic Chemistry ,media ,nutritional and metabolic diseases ,Mucopolysaccharidoses ,medicine.disease ,thickness ,Surgery ,Compliance (physiology) ,030104 developmental biology ,Intima-media thickness ,lcsh:Biology (General) ,lcsh:QD1-999 ,Case-Control Studies ,Arterial stiffness ,business ,intima - Abstract
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old.
- Published
- 2017
25. ATP-binding cassette transporter Abcg2 lineage contributes to the cardiac vasculature after oxidative stress
- Author
-
Cindy M. Martin, Qinglu Li, Brian P. Sorrentino, Mary G. Garry, Yi Ren, Elizabeth A. Braunlin, and Travis J. Maher
- Subjects
Paraquat ,animal structures ,Abcg2 ,Physiology ,Angiogenesis ,Vascular Biology and Microcirculation ,Neovascularization, Physiologic ,Oxidative phosphorylation ,In Vitro Techniques ,medicine.disease_cause ,Mice ,Coronary Circulation ,Physiology (medical) ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,Cell Lineage ,Progenitor cell ,Mice, Knockout ,Cardioprotection ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Myocardium ,Transporter ,Coronary Vessels ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,Oxidative Stress ,chemistry ,Models, Animal ,embryonic structures ,biology.protein ,ATP-Binding Cassette Transporters ,sense organs ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,Oxidative stress - Abstract
Due to their specialized location, stem and progenitor cells are often exposed to oxidative stress. Although ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cells have been implicated in cardiac protective mechanisms involving oxidative stress, there remains a lack of understanding regarding the behavior of cardiac Abcg2-expressing cells when exposed to ROS. The aim of the present study was to characterize the response of the cardiac Abcg2 lineage to oxidative stress. In vitro analysis demonstrated that the antioxidant program regulated by Abcg2 is dependent on a functional transporter. Delivery of paraquat dichloride (PQ), a systemic oxidative stress-inducing agent, to mice confirmed that Abcg2 provides a survival benefit. When exposed to PQ, reporter mice showed an increase in the Abcg2 lineage. Transcriptional and immunohistochemical analysis of Abcg2 lineage-positive cells revealed an enhanced vascular commitment after stress. Finally, preconditioning with PQ demonstrated a reduction in scar size and an increase in angiogenesis after permanent left coronary artery ligation. In conclusion, the data suggest that Abcg2 plays a cytoprotective role in response to in vivo oxidative stress. The contribution of the Abcg2 lineage to the vasculature in the heart is increased after PQ delivery.
- Published
- 2014
26. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review
- Author
-
Elizabeth A. Braunlin, Paul J. Orchard, Chester B. Whitley, Robyn C. Reed, J. Carlos Manivel, and Luke Schroeder
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Heart disease ,Biopsy ,Mucopolysaccharidosis I ,Mucopolysaccharidosis ,Coronary Artery Disease ,Severity of Illness Index ,Pathology and Forensic Medicine ,Coronary artery disease ,Mucopolysaccharidosis III ,Young Adult ,Mucopolysaccharidosis type I ,Fatal Outcome ,medicine ,Humans ,Child ,Hurler syndrome ,Glycosaminoglycans ,business.industry ,Hematopoietic Stem Cell Transplantation ,Mucopolysaccharidosis IV ,General Medicine ,medicine.disease ,Coronary Vessels ,Transplantation ,Coronary arteries ,Treatment Outcome ,medicine.anatomical_structure ,Child, Preschool ,Female ,Autopsy ,Cardiology and Cardiovascular Medicine ,business ,Artery - Abstract
Introduction The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other “non-Hurler” phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon. Methods Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy. Results Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation. Conclusions Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases. Summary The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, “non-Hurler” mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive.
- Published
- 2014
27. Carotid intima–media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness
- Author
-
Elizabeth A. Braunlin, Kyle Rudser, Elsa Shapiro, Raymond Y. Wang, Julia Steinberger, Kelly K. Covault, Aaron S. Kelly, Donald R. Dengel, Lynda E. Polgreen, and Andrea M. Metzig
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Mucopolysaccharidosis I ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Coronary Artery Disease ,Carotid Intima-Media Thickness ,Biochemistry ,Article ,Coronary artery disease ,Vascular Stiffness ,Endocrinology ,Internal medicine ,Genetics ,Humans ,Medicine ,Enzyme Replacement Therapy ,Prospective Studies ,cardiovascular diseases ,Child ,Prospective cohort study ,Molecular Biology ,Mucopolysaccharidosis II ,business.industry ,Vascular disease ,Hematopoietic Stem Cell Transplantation ,Enzyme replacement therapy ,medicine.disease ,Recombinant Proteins ,Compliance (physiology) ,Carotid Arteries ,Cross-Sectional Studies ,Treatment Outcome ,Intima-media thickness ,Case-Control Studies ,cardiovascular system ,Arterial stiffness ,Cardiology ,Female ,business - Abstract
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.
- Published
- 2014
28. Natural history of cardiac findings in mucopolysaccharidosis type I: Report from an international registry
- Author
-
Meng Yang, Kristin A. Moy, Luisa Bay, Elizabeth A. Braunlin, Nathalie Guffon, Lorne A. Clarke, and Nicolas Pangaud
- Subjects
Natural history ,Pediatrics ,medicine.medical_specialty ,Mucopolysaccharidosis type I ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,business ,Molecular Biology ,Biochemistry - Published
- 2018
29. Allogeneic hematopoietic stem cell transplant improves outcomes in fucosidosis
- Author
-
Ashish Gupta, Kelly Miettunen, Elizabeth A. Braunlin, Nicole Anderson, Troy C. Lund, Julie B. Eisengart, and Paul J. Orchard
- Subjects
Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,medicine ,Cancer research ,Allogeneic hematopoietic stem cell transplant ,medicine.disease ,business ,Molecular Biology ,Biochemistry ,Fucosidosis - Published
- 2019
30. Consequences of newborn screening: Neuroimaging in infants with severe MPS I ≤6 months of age
- Author
-
David Nascene, Troy C. Lund, Kelly Miettunen, Elizabeth A. Braunlin, Ashish Gupta, and Paul J. Orchard
- Subjects
Pediatrics ,medicine.medical_specialty ,Newborn screening ,Endocrinology ,Neuroimaging ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,medicine ,business ,Molecular Biology ,Biochemistry - Published
- 2019
31. Cardiopulmonary findings with enzyme replacement therapy after hematopoietic cell transplantation for MPS VI
- Author
-
Elizabeth A. Braunlin, Paul J. Orchard, Chester B. Whitley, Jeanine R. Jarnes-Utz, and Nathaniel Gaeckle
- Subjects
Transplantation ,Endocrinology ,Hematopoietic cell ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Cancer research ,Medicine ,Enzyme replacement therapy ,business ,Molecular Biology ,Biochemistry - Published
- 2019
32. Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology
- Author
-
Beau R. Webber, Elizabeth A. Braunlin, Benedikt Hallgrímsson, Ron T. McElmurry, Bruce R. Blazar, Mark J. Osborn, Kyle Rudser, Anna Petryk, Michael Muradian, Jakub Tolar, and Anthony P. DeFeo
- Subjects
Male ,0301 basic medicine ,Cardiac function curve ,Pathology ,medicine.medical_specialty ,Angiotensin receptor ,Heart Diseases ,Mucopolysaccharidosis I ,Aortic Diseases ,030204 cardiovascular system & hematology ,Biology ,Article ,Losartan ,Craniofacial Abnormalities ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,Iduronidase ,Mice ,03 medical and health sciences ,Mucopolysaccharidosis type I ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,Genetics ,medicine ,Lysosomal storage disease ,Animals ,Humans ,Craniofacial ,Genetics (clinical) ,Receptors, Angiotensin ,medicine.disease ,Dilatation ,Blockade ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Cardiovascular Diseases ,Mutation ,Female ,medicine.drug - Abstract
Mucopolysaccharidosis type I (MPS IH) is a lysosomal storage disease (LSD) caused by inactivating mutations to the alpha-L-iduronidase (IDUA) gene. Treatment focuses on IDUA enzyme replacement and currently employed methods can be non-uniform in their efficacy particularly for the cardiac and craniofacial pathology. Therefore, we undertook efforts to better define the pathological cascade accounting for treatment refractory manifestations and demonstrate a role for the renin angiotensin system (RAS) using the IDUA−/− mouse model. Perturbation of the RAS in the aorta was more profound in male animals suggesting a causative role in the observed gender dimorphism and angiotensin receptor blockade (ARB) resulted in improved cardiac function. Further, we show the ability of losartan to prevent shortening of the snout, a common craniofacial anomaly in IDUA−/− mice. These data show a key role for the RAS in MPS associated pathology and support the inclusion of losartan as an augmentation to current therapies.
- Published
- 2016
33. Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA
- Author
-
Ciarán Mc Ardle, Sara M. Hawley, Maisoon Al-Jawad, Elizabeth A. Braunlin, Elizabeth Wright, Christian J. Hendriksz, C. Gail Summers, Rebecca Lawrence, and Kenneth I. Berger
- Subjects
medicine.medical_specialty ,Pediatrics ,Morquio syndrome ,business.industry ,Hearing loss ,Mucopolysaccharidosis ,Mucopolysaccharidosis IV ,Review ,medicine.disease ,Short stature ,Mucopolysaccharidosis Type IVA ,Surgery ,Obstructive sleep apnea ,Tracheomalacia ,Quality of Life ,Genetics ,Humans ,Medicine ,Genetics(clinical) ,sense organs ,medicine.symptom ,business ,Genetics (clinical) - Abstract
Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome is a multisystem disorder caused by galactosamine-6-sulfatase deficiency. Skeletal manifestations, including short stature, skeletal dysplasia, cervical instability, and joint destruction, are known to be associated with this condition. Due to the severity of these skeletal manifestations, the non-skeletal manifestations are frequently overlooked despite their significant contribution to disease progression and impact on quality of life. This review provides detailed information regarding the non-skeletal manifestations and suggests long-term assessment guidelines. The visual, auditory, digestive, cardiovascular, and respiratory systems are addressed and overall quality of life as measured by endurance and other functional abilities is discussed. Impairments such as corneal clouding, astigmatism, glaucoma, hearing loss, hernias, hepatomegaly, dental abnormalities, cardiac valve thickening and regurgitation, obstructive sleep apnea, tracheomalacia, restrictive and obstructive respiratory compromise, and muscular weakness are discussed. Increased awareness of these non-skeletal features is needed to improve patient care. Electronic supplementary material The online version of this article (doi:10.1007/s10545-012-9459-0) contains supplementary material, which is available to authorized users.
- Published
- 2012
34. Cardiac Involvement in the Mucopolysaccharide Disorders
- Author
-
Elizabeth A. Braunlin
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,business ,Surgery - Published
- 2012
35. Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I
- Author
-
Zhenhong Nan, Daniel A. Wolf, Elizabeth A. Braunlin, R S McIvor, Walter C. Low, Chester B. Whitley, Andrew W. Lenander, Pankaj Gupta, and Kelly M. Podetz-Pedersen
- Subjects
media_common.quotation_subject ,Mucopolysaccharidosis ,chemical and pharmacologic phenomena ,03 medical and health sciences ,Mucopolysaccharidosis type I ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Mucopolysaccharidosis I ,Medicine ,030304 developmental biology ,media_common ,0303 health sciences ,Transplantation ,α l iduronidase ,business.industry ,Longevity ,hemic and immune systems ,Hematology ,medicine.disease ,3. Good health ,Ganglioside GM3 ,surgical procedures, operative ,Murine model ,Immunology ,business ,Iduronidase ,030217 neurology & neurosurgery - Abstract
Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I
- Published
- 2011
36. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management
- Author
-
Katherine P. Ponder, Elizabeth A. Braunlin, Howard M. Rosenfeld, Beatriz Furlanetto, Christoph Kampmann, Roberto Giugliani, William C. Roberts, James P. Loehr, Paul Harmatz, and Maurizio Scarpa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Mucopolysaccharidosis ,Clinical Sciences ,Heart Valve Diseases ,Review ,Comorbidity ,Coronary Artery Disease ,Disease ,Muscle hypertrophy ,Coronary artery disease ,Electrocardiography ,Ventricular hypertrophy ,Tachycardia ,Internal medicine ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Age of Onset ,Sinus ,Child ,Preschool ,Genetics (clinical) ,Glycosaminoglycans ,Genetics & Heredity ,medicine.diagnostic_test ,business.industry ,Mitral Valve Insufficiency ,Hypertrophy ,Aortic Valve Stenosis ,Enzyme replacement therapy ,Mucopolysaccharidoses ,Middle Aged ,medicine.disease ,Left Ventricular ,Causality ,Tachycardia, Sinus ,Echocardiography ,Child, Preschool ,Aortic valve stenosis ,Cardiology ,Hypertrophy, Left Ventricular ,Female ,business - Abstract
The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality. The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled. Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.
- Published
- 2011
37. Mechanical circulatory support in patients with heart failure secondary to transposition of the great arteries
- Author
-
Lyle D. Joyce, Paula Kofflin, Elizabeth A. Braunlin, David L. Joyce, Lee A. Pyles, Ranjit John, James D. St. Louis, and Sheri Crow
- Subjects
Pulmonary and Respiratory Medicine ,Transplantation ,medicine.medical_specialty ,Heart disease ,business.industry ,medicine.medical_treatment ,Transposition of the great vessels ,equipment and supplies ,medicine.disease ,Cannula ,Surgery ,medicine.anatomical_structure ,Great arteries ,Ventricular assist device ,Heart failure ,Internal medicine ,Circulatory system ,medicine ,Cardiology ,Moderator band ,Cardiology and Cardiovascular Medicine ,business - Abstract
Advances in palliation of congenital heart disease have resulted in improved survival to adulthood. Many of these patients ultimately develop end-stage heart failure requiring left ventricular assist device implantation (LVAD). However, morphologic differences in the systemic ventricle of these patients require careful attention to cannula placement. We report on the evolution of our surgical technique for implanting LVADs in 3 patients with transposition of the great arteries and congenitally corrected transposition of the great arteries. Applying standard LV cannulation techniques to the systemic ventricle led us too anteriorly in our first patient, creating obstruction by the moderator band. Subsequent use of epicardial and transesophageal echocardiography allowed for intraoperative localization of the intracardiac muscular structures to identify the optimal cannulation site. The acute angle of the inflow cannula on the DeBakey LVAD (MicroMed Technology, Houston, TX) required flipping the device 180°. The HeartMate II device (Thoratec, Pleasanton, CA) could be shifted towards the midline. One patient underwent successful transplant and 2 are home waiting for a donor organ. We conclude from our experience that LVAD surgery can be safely performed in patients with congenital heart disease when implanted under echocardiographic guidance.
- Published
- 2010
38. Pre-transplant risk factors affecting outcome in Hurler syndrome
- Author
-
Elizabeth A. Braunlin, Kendra Bjoraker, John E. Wagner, C. Peters, Paul J. Orchard, Carlos Milla, Jakub Tolar, Bruce R. Blazar, and Todd E. DeFor
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Minnesota ,Mucopolysaccharidosis I ,medicine.medical_treatment ,Risk Factors ,medicine ,Humans ,Transplantation, Homologous ,Intubation ,Enzyme Replacement Therapy ,Hurler syndrome ,Retrospective Studies ,Transplantation ,Reactive airway disease ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant, Newborn ,Infant ,Pneumonia ,Hematology ,Enzyme replacement therapy ,Airway obstruction ,Prognosis ,medicine.disease ,Surgery ,Survival Rate ,Treatment Outcome ,Bronchiolitis ,Child, Preschool ,Female ,business - Abstract
Allogeneic transplantation remains the standard of care for patients with Hurler syndrome. As enzyme replacement therapy (ERT) has become available, controversy has emerged in regards to whether the use of enzyme in the peri-transplant period is appropriate. An analysis was performed on 74 patients with Hurler syndrome transplanted at the University of Minnesota between 1990 and 2003, before our use of ERT associated with transplant, with the intention of determining if patients at higher risk during the transplant can be identified based on evaluations and events before transplantation. Age, the presence of hydrocephalus, a history of cardiovascular issues or upper airway obstruction before transplant was not associated with significant differences in survival. In contrast, patients who had a history of lower airway disease, including reactive airway disease or bronchiolitis, or a history of pneumonia, had a significantly inferior outcome based on OS. The risk for serious respiratory complications was also assessed by evaluating the incidence of intubation. Overall, 31% of these patients were intubated. The risk of intubation was higher in older patients and in those with a history of lower airway disease. These findings have implications for the care of patients with high-risk features.
- Published
- 2009
39. Enhancing Efficacy of Stem Cell Transplantation to the Heart with a PEGylated Fibrin Biomatrix
- Author
-
Qingsong Hu, Ge Zhang, Laura J. Suggs, Jianyi Zhang, and Elizabeth A. Braunlin
- Subjects
medicine.medical_specialty ,Biomedical Engineering ,Apoptosis ,Bioengineering ,Pharmacology ,Biochemistry ,Peripheral blood mononuclear cell ,Ventricular Function, Left ,Fibrin ,Polyethylene Glycols ,Biomaterials ,Mice ,Fibrosis ,In Situ Nick-End Labeling ,medicine ,Animals ,Cell Lineage ,Myocardial infarction ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,biology ,Hepatocyte Growth Factor ,business.industry ,Myocardium ,medicine.disease ,Myocardial Contraction ,Surgery ,Transplantation ,Echocardiography ,biology.protein ,Female ,Hepatocyte growth factor ,Laminin ,Stem cell ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
Bone marrow-derived mononuclear cell (BMNC) transplantation provides the possibility of rescue or regeneration of myocardium lost during acute myocardial infarction (AMI). The extensive death of transplanted cells and the lack of sustained engraftment may limit its application. We investigated whether delivery of BMNCs by an injectable PEGylated fibrin biomatrix that covalently binds hepatocyte growth factor (HGF) would enhance the rate of cell engraftment and improve cardiac function. Balb/C female mice with AMI secondary to left anterior descending coronary ligation were randomly assigned to one of six groups: the Saline control group (n = 8) received a myocardial injection of saline (50 microL); the Cell group (n = 10) received a myocardial injection in the peri-infarct and infarct zones consisting of 500,000 murine BMNCs suspended in 50 microL saline; and the Biomatrix + HGF (n = 9) and Biomatrix + HGF + Cell (n = 9) group hearts received the HGF-loaded injectable biomatrix (identical volume) with or without entrapped BMNCs. Control groups consisting of the biomatrix alone (n = 9) and Biomatrix + Cells (n = 9) without HGF were also included for comparison. The left ventricular (LV) function was measured by echocardiography at days 14 and 28 post-MI. All animals were euthanized 4 weeks after AMI and transplantation for evaluation of angiogenesis, apoptosis, and fibrosis by immunohistochemistry. Cell prevalence rate at 4 weeks increased 15-fold in hearts receiving the Biomatrix + HGF + Cell delivery (p < 0.01), which was accompanied by the lowest levels of apoptosis and the highest LV function recovery among the treated groups.
- Published
- 2008
40. Cardiac Functional and Histopathologic Findings in Humans and Mice with Mucopolysaccharidosis Type I: Implications for Assessment of Therapeutic Interventions in Hurler Syndrome
- Author
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Bruce R. Blazar, Shannon Mackey-Bojack, Li Yan Sun, James M. Berry, Megan J. Riddle, Elizabeth A. Braunlin, Jakub Tolar, Lorne A. Clarke, Angela Panoskaltsis-Mortari, and Ron T. McElmurry
- Subjects
Cardiac function curve ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Heart Diseases ,Mucopolysaccharidosis I ,Cardiomyopathy ,Mice ,Mucopolysaccharidosis type I ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,Hurler syndrome ,Aorta ,Cell Proliferation ,Glycosaminoglycans ,Ultrasonography ,business.industry ,Myocardium ,nutritional and metabolic diseases ,Heart ,Anatomical pathology ,medicine.disease ,Coronary Vessels ,Heart Valves ,Elastin ,Mice, Inbred C57BL ,Coronary arteries ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Circulatory system ,cardiovascular system ,Histopathology ,business ,Pericardium ,Biomarkers - Abstract
Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme alpha-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.
- Published
- 2006
41. Abstract 20451: Hedgehog Signaling and Cardiomyocyte Proliferation
- Author
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Naoko Koyano-Nakagawa, Daniel J. Garry, Elizabeth A. Braunlin, Cyprian Weaver, Stefan M. Kren, Wuming Gong, Bhairab N. Singh, Kathy M. Bowlin, and Mary G. Garry
- Subjects
medicine.medical_specialty ,Cell signaling ,Regeneration (biology) ,Biology ,Hedgehog signaling pathway ,Endocrinology ,PTCH1 ,Downregulation and upregulation ,In vivo ,Physiology (medical) ,Internal medicine ,medicine ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Hedgehog - Abstract
Background: In contrast to adult mammalian heart, lower vertebrates such as newt exhibit a dramatic capacity for regeneration in response to injury. Understanding the underlying mechanisms and signaling pathways in newt could form the basis for regenerative therapies in mammals. In the present study, we explored the role of hedgehog (HH) signaling during cardiac regeneration. Methods and Results: To investigate cardiac regeneration (CR) in vivo, we performed ventricular resection studies in adult newt heart. Whole mount and histochemical studies revealed CR within 30 d of resection injury. Functional assessment by echocardiographic analysis showed improved ejection fraction from 22 ± 5% at 4 d to 42 ± 3% at 30 d of regeneration relative to control (60 ± 3%). Gene clustering and qRT-PCR analysis at 7d post injury indicated enrichment of hedgehog (HH) signaling factors including Shh and ptch1 by 3- and 2-fold respectively, suggesting a critical requirement of HH signaling at early stages of CR. We determined HH signaling is essential as pharmacological inhibition of the HH pathway resulted in complete ablation of CR. Using EdU-labeling and immunohistochemical analyses, we showed that HH signaling regulates proliferation of both epicardial and myocardial cells, as inhibition of the HH pathway reduced EdU-positive nuclei from 15 ± 2% to 5 ± 3%. In contrast, qRT-PCR analysis from murine hearts postnatal day (P) 2 to P14, showed reduced levels of HH signaling factors and cell-cycle associated mRNAs by 3.5-fold with concomitant increase of p21 by 2-fold. This implies HH signals are required for the proliferative process. Consistent with the newt studies, activation of HH in murine neonatal ventricular cardiomyocytes (NVCM) promoted cardiomyocyte proliferation, increasing positive nuclei from 10 ± 2% to 25 ± 3%, while inhibition of HH signaling reduced positivity to 6 ± 3%. qRT-PCR analysis established that activation of HH signaling in NVCM resulted in up regulation of transcripts associated with cardiomyocyte proliferation. Conclusion: These data indicated that HH signaling pathways modulate cardiomyocyte proliferation providing potential therapeutic targets for achieving mammalian cardiac regeneration.
- Published
- 2014
42. Troponin I levels in a hemolytic uremic syndrome patient with severe cardiac failure
- Author
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Varvara Askiti, Alan R. Sinaiko, Elizabeth A. Braunlin, Kristine J. Hendrickson, and Alfred J. Fish
- Subjects
Resuscitation ,medicine.medical_specialty ,Circulatory collapse ,medicine.medical_treatment ,macromolecular substances ,Escherichia coli O157 ,Severity of Illness Index ,Internal medicine ,Troponin I ,medicine ,Humans ,Escherichia coli Infections ,Dialysis ,Heart Failure ,Ejection fraction ,biology ,business.industry ,Infant ,medicine.disease ,Troponin ,Blood pressure ,Nephrology ,Hemolytic-Uremic Syndrome ,Pediatrics, Perinatology and Child Health ,cardiovascular system ,Cardiology ,biology.protein ,Female ,Hemodialysis ,business ,Biomarkers - Abstract
Troponins are highly sensitive and specific biochemical markers of myocardial injury that are released into the circulation during myocardial ischemia. We describe changes in cardiac troponin I (cTnI) prior to and following clinical evidence of severe myocardial dysfunction in a child with hemolytic uremic syndrome (HUS). A previously healthy, 22-month-old girl presented with typical HUS and stool cultures positive for Escherichia coli O157:H7. She required dialysis, blood and platelet transfusions, and insulin for HUS-related diabetes mellitus. On the 6th hospital day she had sudden circulatory collapse with a blood pressure of 70/40 mmHg and an oxygen saturation of 88%. She responded rapidly to emergency resuscitation but had diminished left ventricular function (ejection fraction 18%). Four days after the acute event an echocardiogram showed normal ventricular size and contractility. She underwent hemodialysis for 22 days, and renal function was normal after 33 days. cTnI levels were measured with a microparticle enzyme immunoassay. cTnI was normal (0.4 microg/l) 32 h prior to cardiac collapse, mildly increased (2.1 microg/l) 8 h before the cardiac collapse, severely elevated shortly after the cardiac event (43.1 microg/l), and peaked (140.6 microg/l) at 24 h. It then fell gradually and was normal at discharge. These results suggest that measurement of cTnI may be a useful predictor of cardiac involvement in severely affected children with HUS.
- Published
- 2004
43. Management of fertility and pregnancy in individuals with mucopolysaccharidosis (MPS)
- Author
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Barbara K. Burton, Tracey A. Johnston, Pavan K. Kochhar, Jennifer Semotok, Zlatko Sisic, Susan Hale, Ursula Plöckinger, John J. Mitchell, Elizabeth A. Braunlin, Paul Harmatz, Fiona Stewart, Andrew Bentley, Susanne Gerit Kircher, and Nathalie Guffon
- Subjects
medicine.medical_specialty ,Pregnancy ,Obstetrics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,media_common.quotation_subject ,Fertility ,medicine.disease ,Biochemistry ,Endocrinology ,Genetics ,medicine ,business ,Molecular Biology ,media_common - Published
- 2016
44. A Randomized, Double-Blind Trial of Lisinopril and Losartan for the Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy
- Author
-
Charles E. Canter, John W. Day, Mark D. Parrish, Hugh D. Allen, Craig M. McDonald, Jerry R. Mendell, Igor Dvorchik, Anne M. Connolly, Basil T. Darras, Steven D. Colan, Elizabeth A. Braunlin, Kevin M. Flanigan, Philip T. Thrush, and Han Yin
- Subjects
Angiotensin receptor ,medicine.medical_specialty ,Ejection fraction ,biology ,business.industry ,Duchenne muscular dystrophy ,Lisinopril ,Urology ,Cardiomyopathy ,Medicine (miscellaneous) ,Correction ,Angiotensin-converting enzyme ,medicine.disease ,Losartan ,biology.protein ,medicine ,Experimental Therapeutics ,Prospective cohort study ,business ,medicine.drug - Abstract
Objectives This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD). Background Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD. Methods Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF's were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year. Conclusions Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM. Trial registration ClinicalTrials.gov NCT01982695.
- Published
- 2014
45. Open-lung biopsy guides therapy in children
- Author
-
R. Morton Bolman, Bradley C. Linden, Michael T. Jaklitsch, Elizabeth A. Braunlin, and John E. Foker
- Subjects
Adult ,Lung Diseases ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Adolescent ,Biopsy ,Hypertension, Pulmonary ,medicine.medical_treatment ,Disease ,Predictive Value of Tests ,medicine ,Extracorporeal membrane oxygenation ,Humans ,Hospital Mortality ,Child ,Open lung biopsy ,Lung ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Mortality rate ,Microangiopathy ,Infant, Newborn ,Infant ,medicine.disease ,Survival Analysis ,Pulmonary hypertension ,Surgery ,medicine.anatomical_structure ,Thoracotomy ,Child, Preschool ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background . Open-lung biopsy is uncommon in children. Modern indications and outcomes are unknown. Methods . This is a retrospective review of 64 open-lung biopsies (58 patients) from 1976 to 1996. Open-lung biopsies were used to grade vasculopathy in 8 patients (12% of 64) with pulmonary hypertension and in 10 patients (16% of 64) with combined pulmonary hypertension and lung parenchymal disease. Forty-six biopsies (72%) were obtained to diagnose parenchymal disease. Comparisons were made between biopsies performed from 1976 to 1989 and from 1990 to 1996. Results . In the period 1990 to 1996, there were significantly more infants ( p = 0.03), comorbid disease ( p = 0.009), extracorporeal membrane oxygenation support ( p −4 ), and ventilator dependence ( p = 0.05) and significantly less immunocompromise ( p = 0.04). A definitive diagnosis was made in 43 of 64 cases (67%) and altered workup in 63 of 64 cases (98%). No correlation existed between Heath-Edwards grade of microangiopathy and catheterization data. Definitive diagnosis was most strongly associated with a nonimmunocompromised patient ( p −4 ). Although only one death (1.5%) was related to open-lung biopsy, the procedure was associated with a 30% inhospital mortality rate and an 11% morbidity rate. Of the 19 deaths, 1 patient died from the procedure, 13 died from their diseases, and 5 had support withdrawn. Death was associated with preoperative ventilator dependence ( p −4 ) and extracorporeal membrane oxygenation ( p = 0.007). Conclusions . Pediatric open-lung biopsy commonly alters the diagnostic workup (98%). It is recommended for children who have been supported for 2 weeks by extracorporeal membrane oxygenation and for those with combined pulmonary hypertension and parenchymal lung disease. It is less useful in immunocompromised children.
- Published
- 2001
46. Successful Coil Embolization of a Large Ascending Aortic Pseudoaneurysm Following Explantation of the EXCOR Pediatric Ventricular Assist Device in a Patient With Acute Fulminant Myocarditis
- Author
-
Roosevelt Bryant, Elizabeth A. Braunlin, Nofil Arain, Rebecca K. Ameduri, James D. St. Louis, Daniel H. Gruenstein, and Lyle D. Joyce
- Subjects
medicine.medical_specialty ,Myocarditis ,business.industry ,medicine.medical_treatment ,Fulminant ,General Medicine ,medicine.disease ,Surgery ,Pseudoaneurysm ,Aneurysm ,medicine.artery ,Heart failure ,Internal medicine ,Ventricular assist device ,Pediatrics, Perinatology and Child Health ,Ascending aorta ,cardiovascular system ,Cardiology ,medicine ,Cardiology and Cardiovascular Medicine ,business ,Complication - Abstract
Mechanical ventricular assistance has become a reliable tool for the support of children and infants with heart failure. The devices have shown efficacy both as a bridge to transplantation and as a bridge to recovery. The potential complications that may occur with long-term support have not been fully described. This article reports the occurrence of a large pseudoaneurysm associated with the ascending aorta following explantation of the EXCOR Pediatric ventricular assist device. A management strategy for this potentially lethal complication is described.
- Published
- 2010
47. Human mucopolysaccharidosis IIIA patients do not demonstrate postprandial hypertriglyceridemia, but have increased carotid intima-media thickness
- Author
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Donald R. Dengel, Julia Steinberger, Kyle Rudser, Aaron S. Kelly, Raymond Y. Wang, and Elizabeth A. Braunlin
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Hypertriglyceridemia ,medicine.disease ,Biochemistry ,Endocrinology ,Postprandial ,Intima-media thickness ,Internal medicine ,Genetics ,Cardiology ,Medicine ,business ,Molecular Biology - Published
- 2015
48. Carotid intima-media thickness and arterial stiffness of pediatric mucopolysaccharidosis patients are increased compared to both pediatric and adult populations
- Author
-
Julia Steinberger, Aaron S. Kelly, David R. Jacobs, Raymond Y. Wang, Kyle Rudser, Donald R. Dengel, Alan R. Sinaiko, and Elizabeth A. Braunlin
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,medicine.disease ,Biochemistry ,Endocrinology ,Intima-media thickness ,Internal medicine ,Genetics ,medicine ,Cardiology ,Arterial stiffness ,business ,Molecular Biology - Published
- 2015
49. Cardiac Findings After Enzyme Replacement Therapy for Mucopolysaccharidosis Type I
- Author
-
Elizabeth A. Braunlin, Chester B. Whitley, and James M. Berry
- Subjects
Male ,Cardiac function curve ,medicine.medical_specialty ,Adolescent ,Heart Diseases ,Mucopolysaccharidosis I ,Mucopolysaccharidosis ,Cardiomyopathy ,Left ventricular hypertrophy ,Iduronidase ,Mucopolysaccharidosis type I ,Double-Blind Method ,Ventricular hypertrophy ,Internal medicine ,Humans ,Ventricular Function ,Medicine ,Child ,Infusions, Intravenous ,Glycosaminoglycans ,business.industry ,Myocardium ,Enzyme replacement therapy ,medicine.disease ,Recombinant Proteins ,Treatment Outcome ,Echocardiography ,Child, Preschool ,Heart failure ,cardiovascular system ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Mucopolysaccharidosis type I is a lethal autosomal recessive storage disease caused by a deficiency of lysosomal alpha-L-iduronidase and the consequent systemic accumulation of glycosaminoglycan. Cardiomyopathy and valvar insufficiency occur as glycosaminoglycan accumulates in the myocardium, expands the spongiosa of cardiac valves, and proliferates within the myointima of the epicardial coronary arteries. Congestive heart failure and death occur within the first decade of life in the most severe cases. Allogeneic hematopoietic stem cell transplantation, used in severe forms of the disease, markedly prolongs survival, alleviates ventricular hypertrophy, and preserves cardiac function, but cardiac valves continue to thicken and valvular insufficiency progresses. Enzyme replacement therapy with human recombinant alpha-L-iduronidase has been proposed as an alternativee therapy for patients with mucopolysaccharidosis type I in whom the risk/benefit ratio of hematopoietic stem cell transplantation seems unfavorable. The investigators report the cardiac findings in a small series of 5 children with mucopolysaccharidosis type I who received enzyme replacement therapy for as long as 7 years. No deaths occurred during treatment. Left ventricular hypertrophy, which was present before therapy, resolved in all cases, and myocardial function remained normal. In contrast, the mitral and aortic valves remained thickened and, in some instances, developed progressive thickening and regurgitation. In conclusion, long-term enzyme replacement therapy has some clear benefits for the myocardium, but the cardiac valves appear unresponsive, and the ultimate effect on the coronary vasculature is unknown.
- Published
- 2006
50. Galsulfase (Naglazyme®) therapy in infants with mucopolysaccharidosis VI
- Author
-
Ralph S. Lachman, Celeste Decker, Elizabeth A. Braunlin, Renée Shediac, Linda M. Randolph, Nathalie Guffon, Paul Harmatz, and Paula Garcia
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pediatrics ,N-Acetylgalactosamine-4-Sulfatase ,Drug Administration Schedule ,law.invention ,Randomized controlled trial ,law ,Genetics ,Medicine ,Humans ,Genetics(clinical) ,Enzyme Replacement Therapy ,skin and connective tissue diseases ,Infusions, Intravenous ,Genetics (clinical) ,Mucopolysaccharidosis VI ,Dose-Response Relationship, Drug ,business.industry ,Extramural ,nutritional and metabolic diseases ,Infant ,Enzyme replacement therapy ,Recombinant Proteins ,Surgery ,Clinical trial ,GALSULFASE ,Multicenter study ,Original Article ,business - Abstract
Objective To evaluate the efficacy and safety of two dose levels of galsulfase (Naglazyme®) in infants with MPS VI. Study design This was a phase 4, multicenter, multinational, open-label, two-dose level study. Subjects were randomized 1:1 to receive weekly infusions of 1.0 or 2.0 mg/kg of galsulfase for a minimum of 52 weeks. Progression of skeletal dysplasia was determined by monitoring physical appearance, radiographic changes, and growth. Urinary glycosaminoglycan (GAG) levels, gross and fine motor function, cardiac function, vision, hearing, and health resource utilization were evaluated. Safety assessments were performed. Results Four infants (aged 3.3–12.7 months) participated in the study. Galsulfase was well tolerated at 1.0 and 2.0 mg/kg/week dose levels with no drug-related serious adverse events. Two subjects experienced a total of four possible treatment-related adverse events which were all considered mild. Length and weight remained within age-expected norms. Skeletal abnormalities continued to progress in all subjects. High baseline urinary GAG levels (mean: 870 μg/mg creatinine) decreased by approximately 70 %; these reduced levels were maintained (mean: 220 μg/mg creatinine at week 52) despite the development of anti-galsulfase antibodies. Hearing, cardiac function, hepatosplenomegaly, and facial dysmorphism stabilized or improved, but corneal clouding progressed. There was no clear difference in safety or efficacy between the two doses. Conclusions Galsulfase at two dose levels was safe and well tolerated in infants. Normal growth was maintained but skeletal abnormalities continued to progress. Urinary GAG levels decreased with treatment. Early initiation of galsulfase may prevent or slow progression of some disease manifestations. Electronic supplementary material The online version of this article (doi:10.1007/s10545-013-9654-7) contains supplementary material, which is available to authorized users.
- Published
- 2013
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