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3,292 results on '"Neal, K"'

102. Methodology for computing white matter nerve fiber orientation in human histological slices.

Author

Nazaran, Amin, Wisco, Jonathan J, Hageman, Nathan, Schettler, Stephen P, Wong, Anita, Vinters, Harry V, Teng, Chia-Chi, and Bangerter, Neal K

Subjects
Hippocampus, Nerve Fibers, Myelinated, Humans, Histological Techniques, Algorithms, Fourier Analysis, Image Processing, Computer-Assisted, Pattern Recognition, Automated, White Matter, Average orientation, Fiber tracking, Fourier transform, Histology, Nerve fibers, Nerve fibers orientation, Orientation map, White matter, Biomedical Imaging, Neurosciences, Bioengineering, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundThe gold standard for mapping nerve fiber orientation in white matter of the human brain is histological analysis through biopsy. Such mappings are a crucial step in validating non-invasive techniques for assessing nerve fiber orientation in the human brain by using diffusion MRI. However, the manual extraction of nerve fiber directions of histological slices is tedious, time consuming, and prone to human error.New methodThe presented semi-automated algorithm first creates a binary-segmented mask of the nerve fibers in the histological image, and then extracts an estimate of average directionality of nerve fibers through a Fourier-domain analysis of the masked image. It also generates an uncertainty level for its estimate of average directionality.Results and comparison with existing methodsThe average orientations of the semi-automatic method were first compared to a qualitative expert opinion based on visual inspection of nerve fibers. A weighted RMS difference between the expert estimate and the algorithmically determined angle (weighted by expert's confidence in his estimate) was 15.4°, dropping to 9.9° when only cases with an expert confidence level of greater than 50% were included. The algorithmically determined angles were then compared with angles extracted using a manual segmentation technique, yielding an RMS difference of 11.2°.ConclusionThe presented semi-automated method is in good agreement with both qualitative and quantitative manual expert-based approaches for estimating directionality of nerve fibers in white matter from images of stained histological slices of the human brain.

Published
2016

105. Defining the ATPome reveals cross-optimization of metabolic pathways

Author

Neal K. Bennett, Mai K. Nguyen, Maxwell A. Darch, Hiroki J. Nakaoka, Derek Cousineau, Johanna ten Hoeve, Thomas G. Graeber, Markus Schuelke, Emin Maltepe, Martin Kampmann, Bryce A. Mendelsohn, Jean L. Nakamura, and Ken Nakamura

Subjects
Science
Abstract

Energy metabolism and ATP levels are controlled by an interlocking network of pathways. Here, the authors apply a genome-wide CRISPR screen to define genes that increase or decrease ATP levels to define the “ATPome”, a map of pathways that contribute to cellular ATP regulation.

Published
2020
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106. Traceless native chemical ligation of lipid-modified peptide surfactants by mixed micelle formation

Author

Shuaijiang Jin, Roberto J. Brea, Andrew K. Rudd, Stuart P. Moon, Matthew R. Pratt, and Neal K. Devaraj

Subjects
Science
Abstract

Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.

Published
2020
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109. Spontaneous Reconstitution of Functional Transmembrane Proteins During Bioorthogonal Phospholipid Membrane Synthesis

Author

Cole, Christian M, Brea, Roberto J, Kim, Young Hun, Hardy, Michael D, Yang, Jerry, and Devaraj, Neal K

Subjects
Biotechnology, Generic health relevance, Animals, Cattle, Electron Transport Complex IV, Lipid Bilayers, Membrane Proteins, Micelles, Phospholipids, Plasma Membrane Calcium-Transporting ATPases, Proteolipids, membrane proteins, phospholipids, proteoliposomes, self-assembly, synthetic biology, Chemical Sciences, Organic Chemistry
Abstract

Transmembrane proteins are critical for signaling, transport, and metabolism, yet their reconstitution in synthetic membranes is often challenging. Non-enzymatic and chemoselective methods to generate phospholipid membranes in situ would be powerful tools for the incorporation of membrane proteins. Herein, the spontaneous reconstitution of functional integral membrane proteins during the de novo synthesis of biomimetic phospholipid bilayers is described. The approach takes advantage of bioorthogonal coupling reactions to generate proteoliposomes from micelle-solubilized proteins. This method was successfully used to reconstitute three different transmembrane proteins into synthetic membranes. This is the first example of the use of non-enzymatic chemical synthesis of phospholipids to prepare proteoliposomes.

Published
2015

110. Cardiac Sarcoidosis: When and How to Treat Inflammation

Author

Gerard T Giblin, Laura Murphy, Garrick C Stewart, Akshay S Desai, Marcelo F Di Carli, Ron Blankstein, Michael M Givertz, Usha B Tedrow, William H Sauer, Gary M Hunninghake, Paul F Dellaripa, Sanjay Divakaran, and Neal K Lakdawala

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Sarcoidosis is a complex, multisystem inflammatory disease with a heterogeneous clinical spectrum. Approximately 25% of patients with systemic sarcoidosis will have cardiac involvement that portends a poorer outcome. The diagnosis, particularly of isolated cardiac sarcoidosis, can be challenging. A paucity of randomised data exist on who, when and how to treat myocardial inflammation in cardiac sarcoidosis. Despite this, corticosteroids continue to be the mainstay of therapy for the inflammatory phase, with an evolving role for steroid-sparing and biological agents. This review explores the immunopathogenesis of inflammation in sarcoidosis, current evidence-based treatment indications and commonly used immunosuppression agents. It explores a multidisciplinary treatment and monitoring approach to myocardial inflammation and outlines current gaps in our understanding of this condition, emerging research and future directions in this field.

Published
2021
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113. Mavacamten in Obstructive Hypertrophic Cardiomyopathy Patients Referred for Septal Reduction: Health Status Analysis Through Week 56 in VALOR-HCM Trial

Author

Desai, Milind Y., Owens, Anjali, Wolski, Kathy, Geske, Jeffrey B., Saberi, Sara, Wang, Andrew, Sherrid, Mark, Cremer, Paul C., Lakdawala, Neal K., Tower-Rader, Albree, Fermin, David, Naidu, Srihari S., Smedira, Nicholas G., Schaff, Hartzell, McErlean, Ellen, Sewell, Christina, Zhong, Yue, Wyrwich, Kathleen W., Lampl, Kathy L., Sehnert, Amy J., Nissen, Steven E., and Spertus, John A.

Published
2024
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116. Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Author

Yang, Jun, Liang, Yong, Šečkutė, Jolita, Houk, KN, and Devaraj, Neal K

Subjects
Cycloaddition Reaction, Cyclopropanes, Heterocyclic Compounds, Molecular Structure, bioconjugation, bioorthogonal cycloaddition, cyclopropene, density functional calculations, tetrazine, Chemical Sciences, General Chemistry
Abstract

Substituted cyclopropenes have recently attracted attention as stable "mini-tags" that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1-methyl-3-substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels-Alder cycloadditions with 1,2,4,5-tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3-amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1-methyl-3-substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3-amidomethyl substituted methylcyclopropene reacts faster than trans-cyclooctenol with a sterically hindered and extremely stable tert-butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.

Published
2014

117. Outcomes of tricuspid regurgitation after lead extraction.

Author

Shanafelt, Colby, Middour, Thomas G., Ibrahim, Rand, Leal, Miguel, Lloyd, Michael S., Shah, Anand D., Westerman, Stacy B., El‐Chami, Mikhael F., Merchant, Faisal M., and Bhatia, Neal K.

Subjects
TRICUSPID valve, T-test (Statistics), TREATMENT effectiveness, MEDICAL device removal, CHI-squared test, DESCRIPTIVE statistics, PRE-tests & post-tests, MITRAL valve insufficiency, IMPLANTABLE cardioverter-defibrillators, CARDIAC pacing, DATA analysis software, TRICUSPID valve diseases, ELECTROPHYSIOLOGY, ECHOCARDIOGRAPHY
Abstract

Introduction: Transvenous leads have been implicated in tricuspid valve (TV) dysfunction, but limited data are available regarding the effect of extracting leads across the TV on valve regurgitation. The aim of this study is to quantify tricuspid regurgitation (TR) before and after lead extraction and identify predictors of worsening TR. Methods: We studied 321 patients who had echocardiographic data before and after lead extraction. TR was graded on a scale (0 = none/trivial, 1 = mild, 2 = moderate, 3 = severe). A change of >1 grade following extraction was considered significant. Results: A total of 321 patients underwent extraction of a total of 338 leads across the TV (1.05 ± 0.31 leads across the TV per patient). There was no significant difference on average TR grade pre‐ and postextraction (1.18 ± 0.91 vs. 1.15 ± 0.87; p = 0.79). TR severity increased after extraction in 84 patients, but was classified as significantly worse (i.e., >1 grade change in severity) in only 8 patients (2.5%). Use of laser lead extraction was associated with a higher rate of worsening TR postextraction (44.0% vs. 31.6%, p = 0.04). Conclusion: In our single‐center analysis, extraction of leads across the TV did not significantly affect the extent of TR in most patients. Laser lead extraction was associated with a higher rate of worsening TR after extraction. [ABSTRACT FROM AUTHOR]

Published
2024
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118. Control of giant vesicle assemblies by stimuli-responsive lipids.

Author

Lee, Youngjun, Fracassi, Alessandro, and Devaraj, Neal K.

Abstract

We describe a bottom-up synthesis of giant vesicles (GVs) utilizing an artificial stimuli-responsive diazobenzene lipid building block. Controlled by light, the GVs can exhibit dynamic behaviors, including reversible formation, the generation of highly multilamellar assemblies, and vesicle capturing and releasing events. [ABSTRACT FROM AUTHOR]

Published
2024
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120. Complex repolarization dynamics in ex vivo human ventricles are independent of the restitution properties

Author

Iravanian, Shahriar, primary, Uzelac, Ilija, additional, Shah, Anand D, additional, Toye, Mikael J, additional, Lloyd, Michael S, additional, Burke, Michael A, additional, Daneshmand, Mani A, additional, Attia, Tamer S, additional, Vega, John David, additional, El-Chami, Mikhael F, additional, Merchant, Faisal M, additional, Cherry, Elizabeth M, additional, Bhatia, Neal K, additional, and Fenton, Flavio H, additional

Published
2023
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122. Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM

Author

Cresci, Sharon, primary, Bach, Richard G., additional, Saberi, Sara, additional, Owens, Anjali T., additional, Spertus, John A., additional, Hegde, Sheila M., additional, Lakdawala, Neal K., additional, Nilles, Ester Kim, additional, Wojdyla, Daniel M., additional, Sehnert, Amy J., additional, and Wang, Andrew, additional

Published
2023
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124. Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction

Author

Desai, Milind Y., primary, Owens, Anjali, additional, Wolski, Kathy, additional, Geske, Jeffrey B., additional, Saberi, Sara, additional, Wang, Andrew, additional, Sherrid, Mark, additional, Cremer, Paul C., additional, Lakdawala, Neal K., additional, Tower-Rader, Albree, additional, Fermin, David, additional, Naidu, Srihari S., additional, Smedira, Nicholas G., additional, Schaff, Hartzell, additional, McErlean, Ellen, additional, Sewell, Christina, additional, Mudarris, Lana, additional, Gong, Zhiqun, additional, Lampl, Kathy, additional, Sehnert, Amy J., additional, and Nissen, Steven E., additional

Published
2023
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125. Gender differences with leadless pacemakers: Peri-procedural complications, long-term device function, and clinical outcomes

Author

Huang, Jingwen, primary, Bhatia, Neal K., additional, Lloyd, Michael S., additional, Westerman, Stacy, additional, Shah, Anand, additional, Leal, Miguel, additional, Delurgio, David, additional, Patel, Anshul M., additional, Tompkins, Christine, additional, Leon, Angel R, additional, El-Chami, Mikhael F., additional, and Merchant, Faisal M., additional

Published
2023
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127. Outcomes of leadless pacemaker implantation after cardiac surgery and transcatheter structural valve interventions

Author

Huang, Jingwen, primary, Bhatia, Neal K., additional, Lloyd, Michael S., additional, Westerman, Stacy, additional, Shah, Anand, additional, Leal, Miguel, additional, Delurgio, David, additional, Patel, Anshul M., additional, Tompkins, Christine, additional, Leon, Angel R., additional, El‐Chami, Mikhael F., additional, and Merchant, Faisal M., additional

Published
2023
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128. A minimal biochemical route towards de novo formation of synthetic phospholipid membranes

Author

Ahanjit Bhattacharya, Roberto J. Brea, Henrike Niederholtmeyer, and Neal K. Devaraj

Subjects
Science
Abstract

The origin of phospholipids, the primary constituents of cell membranes, is uncertain. Here, the authors develop an in vitro system to synthesize phospholipid molecules from water-soluble single-chain amphiphilic precursors via a reaction catalysed by the mycobacterial ligase FadD10.

Published
2019
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130. Contributors

Author

Al Sulaiman, Dana, primary, Bangerter, Neal K., additional, Boussommier-Calleja, Alexandra, additional, Chandrawati, Rona, additional, Chang, Jason Y.H., additional, Channon, Robert B., additional, del Rio Hernandez, Armando, additional, Delcassian, Derfogail, additional, Elson, Daniel S., additional, Grech-Sollars, Matthew, additional, Islam, Md. Nazmul, additional, Ladame, Sylvain, additional, Ma, Leyuan, additional, Morrell, Glen, additional, Mylonas, George P., additional, Oude Vrielink, Timo Joric Corman, additional, Patel, Asha K., additional, Pavagada, Suraj, additional, Rice, Alistair, additional, Sennoga, Charles A., additional, Silva, Murillo, additional, Steer, Isobel, additional, Tjandra, Angie Davina, additional, Vitiello, Valentina, additional, and Wang, Chensu, additional

Published
2020
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135. Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank

Author

Alfaro-Almagro, Fidel, Jenkinson, Mark, Bangerter, Neal K., Andersson, Jesper L.R., Griffanti, Ludovica, Douaud, Gwenaëlle, Sotiropoulos, Stamatios N., Jbabdi, Saad, Hernandez-Fernandez, Moises, Vallee, Emmanuel, Vidaurre, Diego, Webster, Matthew, McCarthy, Paul, Rorden, Christopher, Daducci, Alessandro, Alexander, Daniel C., Zhang, Hui, Dragonu, Iulius, Matthews, Paul M., Miller, Karla L., and Smith, Stephen M.

Published
2018
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136. Impact of SARS‐Cov‐2 infection in patients with hypertrophic cardiomyopathy: results of an international multicentre registry

Author

Gimeno, Juan R., Olivotto, Iacopo, Isabel Rodriguez, Ana, Ho, Carolyn Y., Fernandez, Adrian, Quiroga, Alejandro, Angeles Espinosa, Mari, Gomez-Gonzalez, Cristina, Robledo, Maria, Tojal-Sierra, Lucas, Day, Sharlene M., Owens, Anjali, Barriales-Villa, Roberto, Maria Larranaga, Jose, Rodriguez-Palomares, Jose, Gonzalez-del-Hoyo, Maribel, Piqueras-Flores, Jesus, Reza, Nosheen, Chumakova, Olga, Ashley, Euan A., Parikh, Victoria, Wheeler, Matthew, Jacoby, Daniel, Pereira, Alexandre C., Saberi, Sara, Helms, Adam S., Villacorta, Eduardo, Gallego-Delgado, Maria, Castro, Daniel, Dominguez, Fernando, Ripoll-Vera, Tomas, Zorio-Grima, Esther, Carlos Sanchez-Martinez, Jose, Garcia-Alvarez, Ana, Arbelo, Elena, Victoria Mogollon, Maria, Eugenia Fuentes-Canamero, Maria, Grande, Elias, Pena, Carlos, Monserrat, Lorenzo, Lakdawala, Neal K., Dilema Int Cardiomyopathy Heart Fa, [Gimeno, Juan R.] Univ Murcia, Dept Med Interns, Ctra Finca Buenavista S-N,Campus Ciencias Salud, Murcia 30120, Spain, [Isabel Rodriguez, Ana] Univ Murcia, Dept Med Interns, Ctra Finca Buenavista S-N,Campus Ciencias Salud, Murcia 30120, Spain, [Gimeno, Juan R.] European Reference Networks Rare Low Prevalence &, Amsterdam, Netherlands, [Isabel Rodriguez, Ana] European Reference Networks Rare Low Prevalence &, Amsterdam, Netherlands, [Castro, Daniel] European Reference Networks Rare Low Prevalence &, Amsterdam, Netherlands, [Dominguez, Fernando] European Reference Networks Rare Low Prevalence &, Amsterdam, Netherlands, [Gimeno, Juan R.] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Angeles Espinosa, Mari] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Gomez-Gonzalez, Cristina] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Barriales-Villa, Roberto] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Maria Larranaga, Jose] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Rodriguez-Palomares, Jose] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Gonzalez-del-Hoyo, Maribel] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Villacorta, Eduardo] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Gallego-Delgado, Maria] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Castro, Daniel] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Dominguez, Fernando] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Zorio-Grima, Esther] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Carlos Sanchez-Martinez, Jose] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Garcia-Alvarez, Ana] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Arbelo, Elena] Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid, Spain, [Olivotto, Iacopo] Careggi Univ Hosp, Cardiomyopathy Unit, Florence, Italy, [Ho, Carolyn Y.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA, [Lakdawala, Neal K.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA, [Fernandez, Adrian] Favaloro Fdn Univ Hosp, Unidad Cardiopatias Familiares, Buenos Aires, DF, Argentina, [Quiroga, Alejandro] Favaloro Fdn Univ Hosp, Unidad Cardiopatias Familiares, Buenos Aires, DF, Argentina, [Angeles Espinosa, Mari] Hosp Gen Univ Gregorio Maranon, Unidad Cardiopatias Familiares, Madrid, Spain, [Gomez-Gonzalez, Cristina] Hosp Gen Univ Gregorio Maranon, Unidad Cardiopatias Familiares, Madrid, Spain, [Robledo, Maria] Hosp Univ Araba Txagorritxu, Alava, Spain, [Tojal-Sierra, Lucas] Hosp Univ Araba Txagorritxu, Alava, Spain, [Day, Sharlene M.] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA, [Owens, Anjali] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA, [Reza, Nosheen] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA, [Barriales-Villa, Roberto] Complexo Hosp Univ A Coruna, Unidad CSUR Cardiopatias Familiares, La Coruna, Spain, [Maria Larranaga, Jose] Complexo Hosp Univ A Coruna, Unidad CSUR Cardiopatias Familiares, La Coruna, Spain, [Rodriguez-Palomares, Jose] Hosp Univ Vall dHebron, Dept Cardiol, Barcelona, Spain, [Gonzalez-del-Hoyo, Maribel] Hosp Univ Vall dHebron, Dept Cardiol, Barcelona, Spain, [Rodriguez-Palomares, Jose] Univ Autonoma Barcelona, Vall dHebron Inst Recerca VHIR, Barcelona, Spain, [Gonzalez-del-Hoyo, Maribel] Univ Autonoma Barcelona, Vall dHebron Inst Recerca VHIR, Barcelona, Spain, [Piqueras-Flores, Jesus] Hosp Gen Univ Ciudad Real, Cardiac Dept, Ciudad Real, Spain, [Chumakova, Olga] Municipal Clin Hosp 17, Moscow, Russia, [Ashley, Euan A.] Stanford Univ, Med Ctr, Ctr Inherited Heart Dis, Stanford, CA 94305 USA, [Parikh, Victoria] Stanford Univ, Med Ctr, Ctr Inherited Heart Dis, Stanford, CA 94305 USA, [Wheeler, Matthew] Stanford Univ, Med Ctr, Ctr Inherited Heart Dis, Stanford, CA 94305 USA, [Jacoby, Daniel] Yale New Haven Hosp, New Haven, CT USA, [Pereira, Alexandre C.] Univ Sao Paulo, Hosp Clin, Sao Paulo, Brazil, [Saberi, Sara] Univ Michigan Hosp, Dept Internal Med, Ann Arbor, MI 48109 USA, [Helms, Adam S.] Univ Michigan Hosp, Dept Internal Med, Ann Arbor, MI 48109 USA, [Villacorta, Eduardo] Complejo Asistencial Univ Salamanca, Serv Cardiol, Unidad Cardiopatias Familiares, Salamanca, Spain, [Gallego-Delgado, Maria] Complejo Asistencial Univ Salamanca, Serv Cardiol, Unidad Cardiopatias Familiares, Salamanca, Spain, [Villacorta, Eduardo] Inst Invest Biomed Salamanca IBSAL, Gerencia Reg Salud Castilla & Leon SACYL, Salamanca, Spain, [Gallego-Delgado, Maria] Inst Invest Biomed Salamanca IBSAL, Gerencia Reg Salud Castilla & Leon SACYL, Salamanca, Spain, [Villacorta, Eduardo] Univ Salamanca, Dept Med, Salamanca, Spain, [Gallego-Delgado, Maria] Univ Salamanca, Dept Med, Salamanca, Spain, [Castro, Daniel] Hosp Univ Puerta Hierro Majadahonda, Unidad CSUR ERN Cardiopatias Familiares, Madrid, Spain, [Dominguez, Fernando] Hosp Univ Puerta Hierro Majadahonda, Unidad CSUR ERN Cardiopatias Familiares, Madrid, Spain, [Ripoll-Vera, Tomas] Hosp Univ Son Llatzer, Unidad Cardiopatias Familiares, Mallorca, Spain, [Zorio-Grima, Esther] Hosp Univ & Politecn La Fe, Unidad Cardiopatias Familiares, Valencia, Spain, [Carlos Sanchez-Martinez, Jose] Hosp Univ & Politecn La Fe, Unidad Cardiopatias Familiares, Valencia, Spain, [Garcia-Alvarez, Ana] Univ Barcelona, Hosp Clin, Cardiol Dept, Arrhythmia Sect, Barcelona, Spain, [Arbelo, Elena] Univ Barcelona, Hosp Clin, Cardiol Dept, Arrhythmia Sect, Barcelona, Spain, [Garcia-Alvarez, Ana] Inst Invest August Pi & Sunyer IDIBAPS, Barcelona, Spain, [Arbelo, Elena] Inst Invest August Pi & Sunyer IDIBAPS, Barcelona, Spain, [Victoria Mogollon, Maria] Hosp San Pedro Alcantara, Cardiac Dept, Caceres, Spain, [Eugenia Fuentes-Canamero, Maria] Badajoz Univ Hosp, Cardiac Dept, Badajoz, Spain, [Grande, Elias] Dilemma Solut SL, La Coruna, Spain, [Pena, Carlos] Dilemma Solut SL, La Coruna, Spain, [Monserrat, Lorenzo] Dilemma Solut SL, La Coruna, SpainHosp Univ Virgen de la Victoria, Unidad Insuficiencia Cardiaca & Cardiopatias Fami, Serv Cardiol, Malaga, SpainHosp Vega Baja, Cardiac Dept, Alicante, SpainHosp Univ Virgen del Rocio, Unidad Cardiopatias Familiares, Seville, SpainUniv Trieste, Azienda Sanitaria Univ Giuliano Isontina ASUGI, Cardiothoracovasc Dept, Trieste, ItalyHosp Univ Infanta Leonor, Cardiac Dept, Madrid, SpainHosp Gen Univ Alicante, Unidad Cardiopatias Familiares, Alicante, SpainHosp Arquitecto Morcide, Cardiac Dept, Ferrol, Spain, Instituto de Salud Carlos III (ICSIII), MyoKardia/Bristol Myers Squibb, Institut Català de la Salut, [Gimeno JR] Departamento de Medicina Interna, Universidad de Murcia, Murcia, Spain. European Reference Networks for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands. Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain. [Olivotto I] Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy. [Rodríguez AI] Departamento de Medicina Interna, Universidad de Murcia, Murcia, Spain. European Reference Networks for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands. [Ho CY] Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA. [Fernández A, Quiroga A] Unidad de Cardiopatías Familiares, Favaloro Foundation University Hospital, Buenos Aires, Argentina. [Rodríguez-Palomares J, González-del-Hoyo M] Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain. Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, Adult, Registry, Cardiology, Heart failure, Miocardi - Malalties - Factors de risc, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Ventricular Dysfunction, Left, Atrial Fibrillation, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Humans, Disease, Registries, Aged, COVID-19 (Malaltia) - Complicacions, SARS-CoV-2, SARS-CoV-2 infection, Cor - Hipertròfia, COVID-19, Cardiovascular Diseases::Heart Diseases::Cardiomyopathies::Cardiomyopathy, Hypertrophic [DISEASES], Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Middle Aged, Cardiomyopathy, Hypertrophic, Prognosis, Classification, Hypertrophic cardiomyopathy, enfermedades cardiovasculares::enfermedades cardíacas::miocardiopatías::miocardiopatía hipertrófica [ENFERMEDADES], Female, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Statement, Cardiology and Cardiovascular Medicine
Abstract

COVID-19; SARS-CoV-2 infection; Heart failure COVID-19; Infección por SARS-CoV-2; Insuficiencia cardiaca COVID-19; Infecció per SARS-CoV-2; Insuficiència cardíaca Aims To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events. Methods and results Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12–4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75–9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16–26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20–49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98–2.91, P = 0.0600). Conclusions Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality. The project was funded by a grant from the Instituto de Salud Carlos III (ICSIII, COV20 00420). We should state that the SHaRe registry has been supported by an unrestricted grant from MyoKardia/Bristol Myers Squibb.

Published
2022

138. Effect of beta‐blocker therapy on the response to mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy

Author

Matthew T. Wheeler, Daniel Jacoby, Perry M. Elliott, Sara Saberi, Sheila M. Hegde, Neal K. Lakdawala, Jonathan Myers, Amy J. Sehnert, Jay M. Edelberg, Wanying Li, and Iacopo Olivotto

Subjects
Cardiology and Cardiovascular Medicine
Abstract

In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VOSubgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium-channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VOMavacamten improved measures of functional capacity, LVOT obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO

Published
2023

139. Plain Language Summary of Publication of the safety and efficacy of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene

Author

Calum A MacRae, Matthew RG Taylor, Luisa Mestroni, John Moses, Euan A Ashley, Matthew T Wheeler, Neal K Lakdawala, Ray E Hershberger, Victor Sandor, Michael E Saunders, Colleen Oliver, Patrice A Lee, and Daniel P Judge

Subjects
Molecular Medicine, Cardiology and Cardiovascular Medicine
Abstract

What is this plain language summary about? This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. What were the results? 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. - After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. - Researchers saw some improvement in KCCQ scores. - Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study ( NCT02057341 ) Phase 2 long-term extension study ( NCT02351856 ) Phase 3 REALM-DCM study ( NCT03439514 )

Published
2023

140. Hypertrophic Cardiomyopathy as an Unexpected Mimic of Inducible Laryngeal Obstruction: The Case for Cardiopulmonary Exercise Testing in Otolaryngology

Author

Neal K. Lakdawala, Bradley M. Wertheim, Thomas L. Carroll, and Sunil Kapur

Subjects
medicine.medical_specialty, Exercise limitation, business.industry, Hypertrophic cardiomyopathy, Cardiopulmonary exercise testing, LPN and LVN, medicine.disease, Article, Laryngeal Obstruction, 030507 speech-language pathology & audiology, 03 medical and health sciences, Speech and Hearing, Laryngopharyngeal reflux, 0302 clinical medicine, Otorhinolaryngology, Internal medicine, medicine, Cardiology, Expiration, 030223 otorhinolaryngology, 0305 other medical science, business, Atrial flutter
Abstract

Summary Introduction Inducible laryngeal obstruction is a common and challenging cause of exertional dyspnea. We report a case of an unanticipated cardiac condition that presented with symptoms suggestive of inducible laryngeal obstruction. Discussion A 55-year-old man was evaluated for progressive exertional dyspnea and throat tightness, unexplained after multiple medical evaluations. Resting laryngeal examination was suspicious for laryngopharyngeal reflux and mild vocal fold adduction during quiet expiration. Given progressive and refractory symptoms, maximal cardiopulmonary exercise testing with intermittent laryngeal examination was performed. This study excluded laryngeal causes of exercise limitation and led to an unexpected diagnosis of persistent atrial flutter and hypertrophic cardiomyopathy. Conclusion Cardiopulmonary exercise testing with laryngeal examination can identify unexpected and life-threatening mimics of inducible laryngeal obstruction that may be missed by unmonitored exercise challenges. Suspicion for inducible laryngeal obstruction at rest may not predict the true nature of exercise limitation on cardiopulmonary exercise testing.

Published
2023

141. Miniaturized Synthetic Palmitoylation Motifs for Small-Molecule Localization in Living Cells

Author

Sachio Suzuki, Masaru Yoshikawa, Shunsuke Sawada, Neal K. Devaraj, and Shinya Tsukiji

Subjects
Pharmacology, Organic Chemistry, Biomedical Engineering, Pharmaceutical Science, Bioengineering, Biotechnology
Abstract

Conjugating small-molecule ligands to synthetic motifs that can localize to specific organelles or membranes in living cells is a practical approach to develop compounds as chimeric tools or drugs that can manipulate biological processes in a subcellular site-specific manner. However, the number of available organelle-targeted synthetic motifs for small-molecule localization is limited. We have recently developed a synthetic myristoyl

Published
2022

142. Communication and quorum sensing in non-living mimics of eukaryotic cells

Author

Henrike Niederholtmeyer, Cynthia Chaggan, and Neal K. Devaraj

Subjects
Science
Abstract

Cells communicate through chemical and mechanical signals but emulating these in non-living mimics has been challenging. Here the authors present a porous mimic with a DNA-hydrogel ‘nucleus’ that can communicate through diffusive protein signals.

Published
2018
Full Text
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144. Optimization of ClpXP activity and protein synthesis in an E. coli extract-based cell-free expression system

Author

Xinying Shi, Ti Wu, Christian M. Cole, Neal K. Devaraj, and Simpson Joseph

Subjects
Medicine, Science
Abstract

Abstract Protein degradation is a fundamental process in all living cells and is essential to remove both damaged proteins and intact proteins that are no longer needed by the cell. We are interested in creating synthetic genetic circuits that function in a cell-free expression system. This will require not only an efficient protein expression platform but also a robust protein degradation system in cell extract. Therefore, we purified and tested the activity of E. coli ClpXP protease in cell-free transcription-translation (TX-TL) systems that used E. coli S30 cell extract. Surprisingly, our studies showed that purified ClpXP added to the TX-TL system has very low proteolytic activity. The low activity of ClpXP was correlated with the rapid consumption of adenosine triphosphate (ATP) in cell extract. We improved the activity of ClpXP in cell extract by adding exogenous ATP and an energy regeneration system. We then established conditions for both protein synthesis, and protein degradation by ClpXP to occur simultaneously in the TX-TL systems. The optimized conditions for ClpXP activity will be useful for creating tunable synthetic genetic circuits and in vitro synthetic biology.

Published
2018
Full Text
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