Browsing by Author "Payne, R. Mark"

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    A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice
    (MDPI, 2024-07-27) Snider, Paige L.; Sierra Potchanant, Elizabeth A.; Sun, Zejin; Edwards, Donna M.; Chan, Ka-Kui; Matias, Catalina; Awata, Junya; Sheth, Aditya; Pride, P. Melanie; Payne, R. Mark; Rubart, Michael; Brault, Jeffrey J.; Chin, Michael T.; Nalepa, Grzegorz; Conway, Simon J.; Anatomy, Cell Biology and Physiology, School of Medicine
    Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.
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    Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline–rich protein 1A
    (American Society for Clinical Investigation, 2021-09-22) Aonuma, Tatsuya; Moukette, Bruno; Kawaguchi, Satoshi; Barupala, Nipuni P.; Sepúlveda, Marisa N.; Corr, Christopher; Tang, Yaoliang; Liangpunsakul, Suthat; Payne, R. Mark; Willis, Monte S.; Kim, Il-man; Anatomy, Cell Biology and Physiology, School of Medicine
    MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte–specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline–rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.
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    Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities
    (Elsevier, 2022-07-13) Payne, R. Mark; Pediatrics, School of Medicine
    Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.
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    Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities
    (Elsevier, 2022-12) Payne, R. Mark; Pediatrics, School of Medicine
    Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.
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    The current state of biomarker research for Friedreich's ataxia: a report from the 2018 FARA biomarker meeting
    (Future Science Group, 2019-06-28) Blair, Ian A.; Farmer, Jennifer; Hersch, Steven; Larkindale, Jane; Lynch, David R.; Napierala, Jill; Napierala, Marek; Payne, R. Mark; Subramony, Sub H.; Department of Medicine, IU School of Medicine
    The 2018 FARA Biomarker Meeting highlighted the current state of development of biomarkers for Friedreich's ataxia. A mass spectroscopy assay to sensitively measure mature frataxin (reduction of which is the root cause of disease) is being developed. Biomarkers to monitor neurological disease progression include imaging, electrophysiological measures and measures of nerve function, which may be measured either in serum and/or through imaging-based technologies. Potential pharmacodynamic biomarkers include metabolic and protein biomarkers and markers of nerve damage. Cardiac imaging and serum biomarkers may reflect cardiac disease progression. Considerable progress has been made in the development of biomarkers for various contexts of use, but further work is needed in terms of larger longitudinal multisite studies, and identification of novel biomarkers for additional use cases.
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    Design and Rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial
    (Elsevier, 2018) Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; McCrindle, Brian W.; Menon, Shaji C.; Schumacher, Kurt R.; Payne, R. Mark; Rhodes, Jonathan; McHugh, Kimberly E.; Penny, Daniel J.; Trachtenberg, Felicia; Hamstra, Michelle S.; Richmond, Marc E.; Frommelt, Peter C.; Files, Matthew D.; Yeager, James L.; Pemberton, Victoria L.; Stylianou, Mario P.; Pearson, Gail D.; Paridon, Stephen M.; Pediatrics, School of Medicine
    The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short-term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double blind, placebo controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co., Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.
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    DISHEVELLED-ASSOCIATED ACTIVATOR OF MORPHOGENESIS 1 (DAAM1) IS REQUIRED FOR HEART MORPHOGENESIS
    (2010-02-02T19:55:35Z) Li, Deqiang; Shou, Weinian; Field, Loren J.; Payne, R. Mark; Zhang, Xin
    Dishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, has been implicated in the non-canonical Wnt mediated Planar Cell Polarity (PCP) signaling pathway. Although the studies in Drosophila Daam1 and Xenopus Daam1 generated inconsistent conclusions regarding the function of Daam1, the biological function of mammalian Daam1 was not evaluated. In this study, we used a mouse promoter trap technology to create Daam1 deficient mice to analyze the role of Daam1 in embryonic development and organogenesis. Daam1 is highly expressed in the developing heart. The majority of Daam1 mutant mice died between embryonic day 14.5 and birth, exhibiting a variety of heart defects, which include ventricular noncompaction, ventricular septal defects, and double outlet right ventricle. About 10% mutant mice survive to adulthood, and these survivors do not show significantly compromised heart function based on echocardiographic analyses. However, all of these mutant survivors have ventricular noncompaction with a range of severities. A conditional rescue experiment using a cardiac specific Cre mouse line, Nkx2-5Cre, confirmed that the cardiac defects are the primary cause of death in Daam1 mutants. Both in vivo and ex vivo analyses revealed that Daam1 is essential for regulating non-sarcomeric filamentous actin assembly in cardiomyocytes, which likely contributes to cardiac morphogenesis and ventricular wall maturation. Biochemical studies further suggested that Daam1 is not a key signaling component in regulating the activation of small GTPases, such as RhoA, Rac1 and Cdc42. In conclusion, our studies demonstrated that Daam1 is essential for cardiac morphogenesis likely through its regulation of cytoskeletal architecture in the developing cardiomyocytes.
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    Examination of Adverse Reactions After COVID-19 Vaccination Among Patients With a History of Multisystem Inflammatory Syndrome in Children
    (American Medical Association, 2023-01-03) Elias, Matthew D.; Truong, Dongngan T.; Oster, Matthew E.; Trachtenberg, Felicia L.; Mu, Xiangyu; Jone, Pei-Ni; Mitchell, Elizabeth C.; Dummer, Kirsten B.; Sexson Tejtel, S. Kristen; Osakwe, Onyekachukwu; Thacker, Deepika; Su, Jennifer A.; Bradford, Tamara T.; Burns, Kristin M.; Campbell, M. Jay; Connors, Thomas J.; D'Addese, Laura; Forsha, Daniel; Frosch, Olivia H.; Giglia, Therese M.; Goodell, Lauren R.; Handler, Stephanie S.; Hasbani, Keren; Hebson, Camden; Krishnan, Anita; Lang, Sean M.; McCrindle, Brian W.; McHugh, Kimberly E.; Morgan, Lerraughn M.; Payne, R. Mark; Sabati, Arash; Sagiv, Eyal; Sanil, Yamuna; Serrano, Faridis; Newburger, Jane W.; Dionne, Audrey; Pediatric Heart Network MUSIC Study Investigators; Pediatrics, School of Medicine
    Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, setting, and participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures: COVID-19 vaccination after MIS-C diagnosis. Main outcomes and measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables. Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.
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    Fetal and neonatal echocardiographic analysis of biomechanical alterations for the systemic right ventricle heart
    (Public Library of Science, 2024-09-19) Meyers, Brett A.; Bhattacharya, Sayantan; Brindise, Melissa C.; Loke, Yue-Hin; Payne, R. Mark; Vlachos, Pavlos P.; Mechanical and Energy Engineering, Purdue School of Engineering and Technology
    Background: The perinatal transition's impact on systemic right ventricle (SRV) cardiac hemodynamics is not fully understood. Standard clinical image analysis tools fall short of capturing comprehensive diastolic and systolic measures of these hemodynamics. Objectives: Compare standard and novel hemodynamic echocardiogram (echo) parameters to quantify perinatal changes in SRV and healthy controls. Methods: We performed a retrospective study of 10 SRV patients with echocardiograms at 33-weeks gestation and at day of birth and 12 age-matched controls. We used in-house developed analysis algorithms to quantify ventricular biomechanics from four-chamber B-mode and color Doppler scans. Cardiac morphology, hemodynamics, tissue motion, deformation, and flow parameters were measured. Results: Tissue motion, deformation, and index measurements did not reliably capture biomechanical changes. Stroke volume and cardiac output were nearly twice as large for the SRV compared to the control RV and left ventricle (LV) due to RV enlargement. The enlarged RV exhibited disordered flow with higher energy loss (EL) compared to prenatal control LV and postnatal control RV and LV. Furthermore, the enlarged RV demonstrated elevated vortex strength (VS) and kinetic energy (KE) compared to both the control RV and LV, prenatally and postnatally. The SRV showed reduced relaxation with increased early filling velocity (E) compared prenatally to the LV and postnatally to the control RV and LV. Furthermore, increased recovery pressure (ΔP) was observed between the SRV and control RV and LV, prenatally and postnatally. Conclusions: The novel hydrodynamic parameters more reliably capture the SRV alterations than traditional parameters.
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    Gene therapy for Friedreich ataxia: Too much, too little, or just right?
    (Elsevier, 2022-03-04) Payne, R. Mark; Pediatrics, School of Medicine