Browsing by Author "Sleeper, Lynn A."

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    Cardiac biomarkers in pediatric cardiomyopathy: Study design and recruitment results from the Pediatric Cardiomyopathy Registry
    (Elsevier, 2019-06-01) Everitt, Melanie D.; Wilkinson, James D.; Shi, Ling; Towbin, Jeffrey A.; Colan, Steven D.; Kantor, Paul F.; Canter, Charles E.; Webber, Steven A.; Hsu, Daphne T.; Pahl, Elfriede; Addonizio, Linda J.; Dodd, Debra A.; Jefferies, John L.; Rossano, Joseph W.; Feingold, Brian; Ware, Stephanie M.; Lee, Teresa M.; Godown, Justin; Simpson, Kathleen E.; Sleeper, Lynn A.; Czachor, Jason D.; Razoky, Hiedy; Hill, Ashley; Westphal, Joslyn; Molina, Kimberly M.; Lipshultz, Steven E.; Pediatrics, School of Medicine
    Background: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. Study Design: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. Results: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. Conclusion: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. Clinical Trial Registration: NCT01873976 https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1
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    Design and Harmonization Approach for the Multi-Institutional Neurocognitive Discovery Study (MINDS) of Adult Congenital Heart Disease (ACHD) Neuroimaging Ancillary Study: A Technical Note
    (MDPI, 2023-09-06) Panigrahy, Ashok; Schmithorst, Vanessa; Ceschin, Rafael; Lee, Vince; Beluk, Nancy; Wallace, Julia; Wheaton, Olivia; Chenevert, Thomas; Qiu, Deqiang; Lee, James N.; Nencka, Andrew; Gagoski, Borjan; Berman, Jeffrey I.; Yuan, Weihong; Macgowan, Christopher; Coatsworth, James; Fleysher, Lazar; Cannistraci, Christopher; Sleeper, Lynn A.; Hoskoppal, Arvind; Silversides, Candice; Radhakrishnan, Rupa; Markham, Larry; Rhodes, John F.; Dugan, Lauryn M.; Brown, Nicole; Ermis, Peter; Fuller, Stephanie; Cotts, Timothy Brett; Rodriguez, Fred Henry; Lindsay, Ian; Beers, Sue; Aizenstein, Howard; Bellinger, David C.; Newburger, Jane W.; Glass Umfleet, Laura; Cohen, Scott; Zaidi, Ali; Gurvitz, Michelle; Pediatric Heart Network MINDS Neuroimaging Ancillary Study Investigators; Radiology and Imaging Sciences, School of Medicine
    Dramatic advances in the management of congenital heart disease (CHD) have improved survival to adulthood from less than 10% in the 1960s to over 90% in the current era, such that adult CHD (ACHD) patients now outnumber their pediatric counterparts. ACHD patients demonstrate domain-specific neurocognitive deficits associated with reduced quality of life that include deficits in educational attainment and social interaction. Our hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits modified by behavioral and environmental enrichment proxies of cognitive reserve (e.g., level of education and lifestyle/social habits). This technical note describes an ancillary study to the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN) “Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD)”. Leveraging clinical, neuropsychological, and biospecimen data from the parent study, our study will provide structural–physiological correlates of neurocognitive outcomes, representing the first multi-center neuroimaging initiative to be performed in ACHD patients. Limitations of the study include recruitment challenges inherent to an ancillary study, implantable cardiac devices, and harmonization of neuroimaging biomarkers. Results from this research will help shape the care of ACHD patients and further our understanding of the interplay between brain injury and cognitive reserve.
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    Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study
    (American Heart Association, 2021-05-04) Ware, Stephanie M.; Wilkinson, James D.; Tariq, Muhammad; Schubert, Jeffrey A.; Sridhar, Arthi; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Webber, Steven A.; Dodd, Debra A.; Everitt, Melanie D.; Kantor, Paul F.; Addonizio, Linda J.; Jefferies, John L.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Chung, Wendy K.; Lee, Teresa; Towbin, Jeffrey A.; Lal, Ashwin K.; Bhatnagar, Surbhi; Aronow, Bruce; Dexheimer, Phillip J.; Martin, Lisa J.; Miller, Erin M.; Sleeper, Lynn A.; Razoky, Hiedy; Czachor, Jason; Lipshultz, Steven E.; Pediatrics, School of Medicine
    Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.
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    Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome
    (Elsevier, 2020-07) Van Driest, Sara L.; Sleeper, Lynn A.; Gelb, Bruce D.; Morris, Shaine A.; Dietz, Harry C.; Forbus, Geoffrey A.; Goldmuntz, Elizabeth; Hoskoppal, Arvind; James, Jeanne; Lee, Teresa M.; Levine, Jami C.; Li, Jennifer S.; Loeys, Bart L.; Markham, Larry W.; Meester, Josephina A.N.; Mital, Seema; Mosley, Jonathan D.; Olson, Aaron K.; Renard, Marjolijn; Shaffer, Christian M.; Sharkey, Angela; Young, Luciana; Lacro, Ronald V.; Roden, Dan M.; Pediatrics, School of Medicine
    Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.