Browsing by Author "Lee, Teresa M."

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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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    Cardiac Imaging and Biomarkers for Assessing Myocardial Fibrosis in Children with Hypertrophic Cardiomyopathy
    (Elsevier, 2023) Kirmani, Sonya; Woodard, Pamela K.; Shi, Ling; Hamza, Taye H.; Canter, Charles E.; Colan, Steven D.; Pahl, Elfriede; Towbin, Jeffrey A.; Webber, Steven A.; Rossano, Joseph W.; Everitt, Melanie D.; Molina, Kimberly M.; Kantor, Paul F.; Jefferies, John L.; Feingold, Brian; Addonizio, Linda J.; Ware, Stephanie M.; Chung, Wendy K.; Ballweg, Jean A.; Lee, Teresa M.; Bansal, Neha; Razoky, Hiedy; Czachor, Jason; Lunze, Fatima I.; Marcus, Edward; Commean, Paul; Wilkinson, James D.; Lipshultz, Steven E.; Pediatrics, School of Medicine
    Background: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. Methods: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. Results: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. Conclusions: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.
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    Impact of Genetic Testing for Cardiomyopathy on Emotional Well-Being and Family Dynamics: A Study of Parents and Adolescents
    (American Heart Association, 2021) Ahimaz, Priyanka; Sabatello, Maya; Qian, Min; Wang, Aijin; Miller, Erin M.; Parrott, Ashley; Lal, Ashwin K.; Chatfield, Kathryn C.; Rossano, Joseph W.; Ware, Stephanie M.; Parent, John J.; Kantor, Paul; Yue, Lisa; Wynn, Julia; Lee, Teresa M.; Addonizio, Linda J.; Appelbaum, Paul S.; Chung, Wendy K.; Pediatrics, School of Medicine
    Background: Genetic testing is indicated for children with a personal or family history of hereditary cardiomyopathy to determine appropriate management and inform risk stratification for family members. The implications of a positive genetic result for children can potentially impact emotional well-being. Given the nuances of cardiomyopathy genetic testing for minors, this study aimed to understand how parents involve their children in the testing process and investigate the impact of genetic results on family dynamics. Methods: A survey was distributed to participants recruited from the Children's Cardiomyopathy Foundation and 7 North American sites in the Pediatric Cardiomyopathy Registry. The survey explored adolescent and parent participants' emotions upon receiving their/their child's genetic results, parent-child result communication and its impact on family functionality, using the McMaster Family Assessment Device. Results: One hundred sixty-two parents of minors and 48 adolescents who were offered genetic testing for a personal or family history of cardiomyopathy completed the survey. Parents whose child had cardiomyopathy were more likely to disclose positive diagnostic genetic results to their child (P=0.014). Parents with unaffected children and positive predictive testing results were more likely to experience negative emotions about the result (P≤0.001) but also had better family functioning scores than those with negative predictive results (P=0.019). Most adolescents preferred results communicated directly to the child, but parents were divided about whether their child's result should first be released to them or their child. Conclusions: These findings have important considerations for how providers structure genetic services for adolescents and facilitate discussion between parents and their children about results.
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    The genetic architecture of pediatric cardiomyopathy
    (Elsevier, 2022) Ware, Stephanie M.; Bhatnagar, Surbhi; Dexheimer, Phillip J.; Wilkinson, James D.; Sridhar, Arthi; Fan, Xiao; Shen, Yufeng; Tariq, Muhammad; Schubert, Jeffrey A.; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Bansal, Neha; Webber, Steven A.; Everitt, Melanie D.; Kantor, Paul F.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Lee, Teresa M.; Towbin, Jeffrey A.; Lal, Ashwin K.; Chung, Wendy K.; Miller, Erin M.; Aronow, Bruce; Martin, Lisa J.; Lipshultz, Steven E.; Pediatric Cardiomyopathy Registry Study Group; Pediatrics, School of Medicine
    To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
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    Toward Personalized Medicine: Does Genetic Diagnosis of Pediatric Cardiomyopathy Influence Patient Management?
    (Elsevier, 2015-07-01) Lee, Teresa M.; Ware, Stephanie M.; Department of Pediatrics, IU School of Medicine
    A goal of personalized medicine is to provide increasingly sophisticated, individualized approaches to management and therapy for disease. Genetics is the engine that drives personalized medicine, holding the promise of therapeutics directed toward the unique needs of each patient. The 3(rd) International Conference on Cardiomyopathy in Children provided a forum to discuss the current status of personalized approaches to diagnosis, management, and therapy in the pediatric cardiomyopathy population. This review will focus on the importance of genetic diagnosis in this population as a necessary first step toward understanding the best approach to management and influencing disease outcome. The genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the ability to risk stratify based on genotype, and the impact on cascade screening in family members will be discussed.
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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.