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8. Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy.

Author

Luczak, Elizabeth D, Wu, Yuejin, Granger, Jonathan M, Joiner, Mei-Ling A, Wilson, Nicholas R, Gupta, Ashish, Umapathi, Priya, Murphy, Kevin R, Reyes Gaido, Oscar E, Sabet, Amin, Corradini, Eleonora, Tseng, Wen-Wei, Wang, Yibin, Heck, Albert JR, Wei, An-Chi, Weiss, Robert G, and Anderson, Mark E

Subjects
Heart Ventricles, Animals, Mice, Transgenic, Mice, Cardiomyopathy, Dilated, Myocardial Infarction, Calcium, Calcium-Binding Proteins, Mitochondrial Proteins, Signal Transduction, Energy Metabolism, Heart Failure, Calcium-Calmodulin-Dependent Protein Kinase Type 2
Abstract

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. Here, we report increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. By contrast, mice with genetic mitochondrial CaMKII inhibition are protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII overexpression (mtCaMKII) have severe dilated cardiomyopathy and decreased ATP that causes elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We map a metabolic pathway that rescues disease phenotypes in mtCaMKII mice, providing insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase or mitochondrial-targeted CaMKII inhibition.

Published
2020

13. Impact of Utilizing a Composite versus a Symptom-Only Validation Standard in the Development of the Asthma Impairment and Risk Questionnaire.

Author

Chipps, Bradley E, Zeiger, Robert S, Beuther, David A, Wise, Robert A, McCann, William, Reibman, Joan, George, Maureen, Gilbert, Ileen, Eudicone, James M, Coyne, Karin S, Harding, Gale, and Murphy, Kevin R

Subjects
LITERATURE reviews, DISEASE exacerbation, ASTHMATICS, ASTHMA in children, RECEIVER operating characteristic curves
Abstract

This article discusses the development and validation of the Asthma Impairment and Risk Questionnaire (AIRQ®), a tool used to assess asthma control and predict future exacerbation risk. The study found that the AIRQ was effective in differentiating patients with varying levels of current control, lung function, and health-related quality of life. The validation standard for the AIRQ differed from that used for other assessment tools, such as the Asthma Control Test (ACT), and the article explores how the AIRQ's validation standard supported its validity as a measure of both current disease control and future exacerbation risk. The findings of this study will inform the development of future asthma control measures. The article also acknowledges limitations in its generalizability to diverse populations and emphasizes the need for further research in pediatric populations. [Extracted from the article]

Published
2024
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19. Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study

Author

Guilbert, Theresa W, primary, Murphy, Kevin R, additional, Hamelmann, Eckard, additional, Ross, Kristie R, additional, Gupta, Atul, additional, Fiocchi, Alessandro, additional, Xia, Changming, additional, Gall, Rebecca, additional, Ledanois, Olivier, additional, Radwan, Amr, additional, Jacob-Nara, Juby A, additional, Rowe, Paul J, additional, and Deniz, Yamo, additional

Published
2024
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22. Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study

Author

Guilbert,Theresa W, Murphy,Kevin R, Hamelmann,Eckard, Ross,Kristie R, Gupta,Atul, Fiocchi,Alessandro, Xia,Changming, Gall,Rebecca, Ledanois,Olivier, Radwan,Amr, Jacob-Nara,Juby A, Rowe,Paul J, Deniz,Yamo, Guilbert,Theresa W, Murphy,Kevin R, Hamelmann,Eckard, Ross,Kristie R, Gupta,Atul, Fiocchi,Alessandro, Xia,Changming, Gall,Rebecca, Ledanois,Olivier, Radwan,Amr, Jacob-Nara,Juby A, Rowe,Paul J, and Deniz,Yamo

Abstract

Theresa W Guilbert,1 Kevin R Murphy,2 Eckard Hamelmann,3 Kristie R Ross,4 Atul Gupta,5 Alessandro Fiocchi,6 Changming Xia,7 Rebecca Gall,7 Olivier Ledanois,8 Amr Radwan,7 Juby A Jacob-Nara,9 Paul J Rowe,9 Yamo Deniz7 1Cincinnati Children’s Hospital and University of Cincinnati, Cincinnati, OH, USA; 2Boys Town National Research Hospital, Omaha, NE, USA; 3Department of Pediatrics, Children’s Center Bethel, University of Bielefeld, Bielefeld, Germany; 4UH Rainbow Babies and Children’s Hospital, Cleveland, OH, USA; 5King’s College Hospital, London, UK; 6Bambino Gesù Children’s Hospital IRCCS, Rome, Italy; 7Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Sanofi, Paris, France; 9Sanofi, Bridgewater, NJ, USACorrespondence: Theresa W Guilbert, Cincinnati Children’s Hospital and University of Cincinnati, Cincinnati, OH, USA, Tel +1 513-636-6771, Email theresa.guilbert@cchmc.orgBackground: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab.Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥ 150 cells/μL or fractional exhaled nitric oxide ≥ 20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥ 5% or ≥ 10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12– 52, and mean change from baseline in ppFEV1 to Week 12.Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of

Published
2024

23. Development of the Asthma Impairment and Risk Questionnaire (AIRQ): A Composite Control Measure

Author

Kobernick, Aaron K., Mohammad, Acklema, Cherry, Adam T., Fein, Alan, Gaines, Alan, Allison Ramsey, Michaud, Amanda L., Palmer, Amy, Kim, Andrew S., Smith, Andrew M., White, Andrew A., Ricci, Anthony R., Kettelhut, Brett V., Modena, Brian D., Stone, Brian, Rolston, B. Steele, Schnapf, Bruce M., Krajicek, Bryan, Kraft, Cara, Hopkins, Carly, Natalie, Chitra R., Anderson, Christine, Czajkowski, Christine, Arce, Daisy, Hamlin, Danuel, Hill, David G., Mares, David C., Pham, David, Liao, Da-Wei, Simmons, Deborah, Johnson, Derek K., Jhaveri, Devi K., Maselli, Diego J., Kerwin, Edward, Schuman, Edward, Sher, Ellen R., Bleecker, Eugene, Rakowski, Ewa, Ida Hsu, Florence, Averill, Francis J., Barsanti, Franco, Gross, Gary N., Chupp, Geoffrey Lowell, Head, G. Gilbert, Nasir, Hassan, Lee, Howard J., Barjaktarevic, Igor, Cook, J. Paul, Krainson, James P., Pearl, James E., Bellak, Jason M., Perez-Fernandez, Javier, Rehm, Jeffrey, Trevor, Jennifer, Freyer Most, Jessica, Hanson, Jill, Blessing-Moore, Joann, Biller, Jodi H., Gedell, John, Southard, John G., Chancellor, Jon Eric, Ilowite, Jonathan, Romeo, Jonathan R., Manuel Mercado, Jorge, Dominic Fisher, Joseph, Greiwe, Justin, Gregory, Karen L., Nadeau, Kari, Shenoy, Kartik V., Tan, Laren D., Stefanowicz, Leslie A., Humes, Lindsay D., Bowers, Lori A., Edel O’Connor, Maeve, Perez, Mario F., White, Martha V., Hegewald, Matthew, Wilson, Matthew C., Sikora, Maxcie M., Lee Morganroth, Melvin, Smith, Mitchell, Farooqui, Nabeel, James Lesch, Nathan, Jain, Neal, Parikh, Neil, Hartog, Nicholas L., Luthin, Patricia L., Stewart, Patricia H., Rubio O’Connor, Peggy, Schochet, Peter, Goldberg, Pinkus, Patel, Pulin P., Chinthrajah, R. Sharon, Sidhu, Rabinder, Ayinla, Raji M., Brown, Randall, Stadtler, Reneé, Wachs, Richard A., Balkissoon, Ronald C., Duplantier, Rory L., Puente, Rosalba E., Settipane, Russell, Mustafa, S. Shahzad, Surani, Salim, Abdul Jawad, Sami, Adams, Sandra G., Villegas, Sarah, Al-Farra, Sherif, Subramanian, Shyamsunder, Bains, Sonia N., Kelsen, Steven G., Wise, Steven L., Estrella-Eades, Susan, Smith, Susan M., Qureshi, Tabarak, Chen, Taiwen, Kelbel, Theodore E., Miller, Thomas P., Jain, Vipin, Soong, Weily, Soler, Xavier, Mattar, Ziad R., Murphy, Kevin R., Chipps, Bradley, Beuther, David A., Wise, Robert A., McCann, William, Gilbert, Ileen, Eudicone, James M., Gandhi, Hitesh N., Harding, Gale, Coyne, Karin S., and Zeiger, Robert S.

Published
2020
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28. National Asthma Education and Prevention Program 2020 Guidelines: What's Important for Primary Care

Author

Murphy, Kevin R. and Solis, Joel

Subjects
Practice guidelines (Medicine) -- Evaluation, Primary nursing -- Evaluation, Asthma -- Prevention, Health
Abstract

KEY TAKEAWAYS * The 2020 Focused Updates to the Asth ma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group provides updated recommendations for 6 topics related to the management of individuals with asthma. ** For the primary care clinician, key important updated recommendations relate to the use of intermittent inhaled corticosteroids, the use of long-acting muscarinic antagonists in the treatment of patients age [greater than or equal to] 12 years, and a more focused approach to indoor allergen mitigation. * The classification of asthma severity and asthma control, as well as the concept of utilizing a stepwise approach to pharmacologic treatment, were not updated from the Expert Panel Report 3, released in 2007. * However, important updates in preferred therapies for intermittent and persistent asthma at treatment steps 1 through 5 were suggested. * Recommendations regarding biologic therapy were not included in the 2020 update, as only evidence and US Food and Drug Administration approvals through October 2018 were considered. * The most recent 2021 Global Initiative for Asthma guidelines are not included in this review but can be used in a complementary manner to assist primary care clinicians to optimize decisions regarding the care of patients with asthma. FACULTY Kevin R. Murphy, MD, Director, Clinical Research, Allergy, Asthma and Pediatric Pulmonology, Boys Town National Research Hospital, Boys Town, Nebraska. Joel Solis, MD, Valley Medical Arts Clinic, The University of Texas Rio Grande Valley, McAllen, Texas. DISCLOSURES Dr. Murphy discloses that he serves on the advisory board and/or speakers bureau for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron, and Sanofi. Dr. Solis and Gregory Scott, PharmD, have no disclosures to report. ACKNOWLEDGMENT Editorial support was provided by Gregory Scott, PharmD, RPh, at the Primary Care Education Consortium. SPONSORSHIP This activity is sponsored by Primary Care Education Consortium and the Primary Care Respiratory Group and supported by funding from AstraZeneca Pharmaceuticals LP., HISTORICAL OVERVIEW OF NATIONAL ASTHMA EDUCATION AND PREVENTION PROGRAM The National Heart, Lung, and Blood Institute (NHLBI) created the National Asthma Education and Prevention Program (NAEPP) in 1989 to address [...]

Published
2021
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29. CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

Author

Wang, Qinchuan, Hernández-Ochoa, Erick O., Viswanathan, Meera C., Blum, Ian D., Do, Danh C., Granger, Jonathan M., Murphy, Kevin R., Wei, An-Chi, Aja, Susan, Liu, Naili, Antonescu, Corina M., Florea, Liliana D., Talbot, Jr., C. Conover, Mohr, David, Wagner, Kathryn R., Regot, Sergi, Lovering, Richard M., Gao, Peisong, Bianchet, Mario A., Wu, Mark N., Cammarato, Anthony, Schneider, Martin F., Bever, Gabriel S., and Anderson, Mark E.

Published
2021
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31. MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII

Author

Konstantinidis, Klitos, Bezzerides, Vassilios J., Lai, Lo, Isbell, Holly M., Wei, An-Chi, Wu, Yuejin, Viswanathan, Meera C., Blum, Ian D., Granger, Jonathan M., Heims-Waldron, Danielle, Zhang, Donghui, Luczak, Elizabeth D., Murphy, Kevin R., Lu, Fujian, Gratz, Daniel H., Manta, Bruno, Wang, Qiang, Wang, Qinchuan, Kolodkin, Alex L., Gladyshev, Vadim N., Hund, Thomas J., Pu, William T., Wu, Mark N., Cammarato, Anthony, Bianchet, Mario A., Shea, Madeline A., Levine, Rodney L., and Anderson, Mark E.

Subjects
Tachycardia, Actin, Medical research, Amino acids, Heart, Stem cells, Calmodulin, Muscle proteins, Health care industry, Johns Hopkins University, Harvard University. Harvard Stem Cell Institute
Abstract

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining [Ca.sup.2+]/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophilamelanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species., Introduction [Ca.sup.2+]/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase with important roles in cardiovascular physiology and disease (1-4). Despite the critical role of CaMKII in fight-or-flight responses and human [...]

Published
2020
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