Article
Chemistry, Physical
Ananya Chakraborti, Jil C. Tardiff, Steven D. Schwartz
Summary: The study investigated the influence of the positive inotrope Omecamtiv mecarbil (OM) on the recovery stroke of cardiac myosin, as well as its effects in the presence of genetic cardiomyopathic mutations. The study utilized metadynamics and transition path sampling to gain insights into the dynamics and mechanism of ATP hydrolysis in the presence of OM. Understanding the effects of OM is crucial for its potential use in the treatment of cardiac disease.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Pharmacology & Pharmacy
Ashit Trivedi, Cheng-Pang Hsu, Pegah Jafarinasabian, Bianca Terminello, Hanze Zhang, Stephen Flach, Samuel Israel, Ashley Brooks, Hongqi Xue, Borje Darpo, Siddique Abbasi, Sandeep Dutta, Edward Lee
Summary: The study found that Omecamtiv mecarbil (OM) at therapeutic concentrations has no clinically relevant effect on ECG parameters and does not affect the QTc interval significantly up to a plasma concentration of approximately 800 ng/mL. No serious adverse events leading to discontinuation from the study were observed.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Scott D. Solomon, Brian L. Claggett, Zi Michael Miao, Rafael Diaz, G. Michael Felker, John J. McMurray, Marco Metra, Ramon Corbalan, Gerasimos Filippatos, Assen R. Goudev, Viatcheslav Mareev, Pranas Serpytis, Thomas Suter, Mehmet B. Yilmaz, Faiez Zannad, Stuart Kupfer, Stephen B. Heitner, Fady Malik, John R. Teerlink
Summary: In the GALACTIC-HF study, the influence of atrial fibrillation on the effectiveness of omecamtiv mecarbil was explored. The study found that patients with atrial fibrillation derived less benefit from omecamtiv mecarbil treatment, especially those who were also receiving digoxin.
EUROPEAN HEART JOURNAL
(2022)
Article
Biology
Aaron Snoberger, Bipasha Barua, Jennifer L. Atherton, Henry Shuman, Eva Forgacs, Yale E. Goldman, Donald A. Winkelmann, E. Michael Ostap
Summary: The study revealed a novel mechanism, showing that the R712L mutation decreases the working stroke of myosin, while OM is able to rescue this inhibition, providing insights into the pathogenesis of HCM.
Article
Cardiac & Cardiovascular Systems
Arnold Peter Raduly, Attila Toth, Fruzsina Sarkany, Balazs Horvath, Norbert Szentandrassy, Peter P. Nanasi, Zoltan Csanadi, Istvan Edes, Zoltan Papp, Attila Borbely
Summary: This study aimed to compare the effects of different mechanisms of calcium-sensitizing positive inotropic agents (OM, EMD, and Levo) on cardiomyocytes. The results showed that OM exerted its positive inotropic effect by prolonging systolic contraction and increasing calcium sensitivity. In contrast, EMD and Levo exerted positive inotropic effects through different mechanisms. These findings have important implications for the further development of drugs for treating heart failure.
Article
Pharmacology & Pharmacy
Alexander Dashwood, Elizabeth Cheesman, Yee Weng Wong, Haris Haqqani, Nicole Beard, Karen Hay, Melanie Spratt, Wandy Chan, Peter Molenaar
Summary: Omecamtiv mecarbil (OM) is a new drug for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. In human failing heart tissues, OM prolonged time to peak force and 50% relaxation time, reduced time dependent deterioration in contractile strength, and had no significant inotropic effect. Co-administration of (-)-noradrenaline with OM reversed the negative diastolic effects of OM and may limit ischemic side effects from titration of inotropes.
PHARMACOLOGY RESEARCH & PERSPECTIVES
(2021)
Article
Medicine, General & Internal
Gregory D. Lewis, Adriaan A. Voors, Alain Cohen-Solal, Marco Metra, David J. Whellan, Justin A. Ezekowitz, Michael Bohm, John R. Teerlink, Kieran F. Docherty, Renato D. Lopes, Punag H. Divanji, Stephen B. Heitner, Stuart Kupfer, Fady Malik, Lisa Meng, Amy Wohltman, G. Michael Felker
Summary: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo.
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(2022)
Article
Biochemistry & Molecular Biology
Chih-Yu Ting, Chia-Lung Shih, Meng-Cheng Yu, Chao-Liang Wu, Sheng-Nan Wu
Summary: Omecamtiv mecarbil (OM, CK-1827452) is an activator of myosin and has been shown to be beneficial for the treatment of systolic heart failure. However, its effects on ionic currents in electrically excitable cells are not well understood. This study investigated the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells.
Article
Pharmacology & Pharmacy
Ashit Trivedi, Mia Mackowski, Pegah Jafarinasabian, Hanze Zhang, Stephen Flach, Bianca Terminello, Ajay Bhatia, Sandeep Dutta, Edward Lee
Summary: The study aimed to determine the bioavailability of two OM minitablet formulations relative to the adult matrix MR formulation. Results showed that the slow-release and fast-release minitablets demonstrated bioavailability similar to the adult matrix MR formulation.
CLINICAL DRUG INVESTIGATION
(2021)
Article
Physiology
Ranganath Mamidi, Joshua B. Holmes, Chang Yoon Doh, Katherine L. Dominic, Nikhil Madugula, Julian E. Stelzer
Summary: This study investigated the effects of OM on force generation and cross-bridge kinetics in myocardial preparations with reduced cMyBPC phosphorylation. The results showed significant differences in the effects of OM between WT and SA myocardial preparations, suggesting an interplay between OM and XB behavior which may alter the cardiac response to 13-adrenergic stimulation.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Medicine, Research & Experimental
Yusheng Qu, BaoXi Gao, Ziva Arimura, Mei Fang, Hugo M. Vargas
Summary: Omecamtiv mecarbil (OM) is a myosin activator developed for treating heart failure. Studies showed that OM had minimal impact on the heart in a series of experiments, indicating no delay in ventricular repolarization.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2021)
Article
Pharmacology & Pharmacy
Ashit Trivedi, Rajneet K. Oberoi, Pegah Jafarinasabian, Hanze Zhang, Marintan Spring, Stephen Flach, Siddique Abbasi, Sandeep Dutta, Edward Lee
Summary: The study showed that there was no clinically relevant effect of Omecamtiv mecarbil (OM) on the pharmacokinetics of metformin in healthy subjects. Co-administration of OM with metformin did not significantly alter the pharmacokinetic parameters of metformin compared to metformin alone.
CLINICAL DRUG INVESTIGATION
(2021)
Article
Cardiac & Cardiovascular Systems
G. Michael Felker, Scott D. Solomon, Brian Claggett, Rafael Diaz, John J. McMurray, Marco Metra, Inder Anand, Marisa G. Crespo-Leiro, Ulf Dahlstrom, Eva Goncalvesova, Jonathan G. Howlett, Peter MacDonald, Alexander Parkhomenko, Janos Tomcsanyi, Siddique A. Abbasi, Stephen B. Heitner, Thomas Hucko, Stuart Kupfer, Fady Malik, John R. Teerlink
Summary: This study evaluated the efficacy and safety of omecamtiv mecarbil for severe heart failure patients. The results suggest that omecamtiv mecarbil therapy may have clinically meaningful benefits for patients with severe heart failure, supporting its potential role in patients with limited treatment options.
Article
Pharmacology & Pharmacy
Ashit Trivedi, Jan Wahlstrom, Mia Mackowski, Sandeep Dutta, Edward Lee
Summary: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator being developed for the treatment of heart failure, primarily cleared through metabolism by the CYP4 family. The major metabolites recovered in urine and feces were M3 and M4, with high bioavailability of 93.5%.
DRUG METABOLISM AND DISPOSITION
(2021)
Review
Cardiac & Cardiovascular Systems
Arroj Ali, Ramy Abdelmaseih, Ravi Thakker, Mohammed Faluk, Syed Mustajab Hasan
Summary: This article highlights a newer class of medications targeting reduced myocardial contractility in congestive heart failure (HF), despite ongoing morbidity and mortality associated with the condition. Trials have shown promising effects on HF outcomes, emphasizing the potential for improved therapeutic options.
Article
Biology
Justin R. Porter, Artur Meller, Maxwell Zimmerman, Michael J. Greenberg, Gregory R. Bowman
Article
Cardiac & Cardiovascular Systems
Kory J. Lavine, Michael J. Greenberg
Summary: Dilated cardiomyopathy (DCM) should be regarded as a group of diseases with a common left ventricular dilation and systolic dysfunction phenotype, rather than a single entity, and a mechanism-based classification of disease subtypes will revolutionize our understanding and clinical approach towards DCM.
HEART FAILURE REVIEWS
(2021)
Article
Biophysics
Thomas Blackwell, W. Tom Stump, Sarah R. Clippinger, Michael J. Greenberg
Summary: Molecular motors in biological processes perform mechanical work through coupling chemical transitions to conformational changes, and disruption of this coupling can lead to diseases. Optical tweezers with nanometer spatial and millisecond temporal resolution have provided valuable insights, but fluctuations due to Brownian motion can make it difficult to precisely resolve conformational changes. Ensemble averaging of individual trajectories is a powerful analysis technique that has improved the ability to accurately measure mechanochemical coupling in motor proteins.
BIOPHYSICAL JOURNAL
(2021)
Article
Physiology
Michael J. Greenberg, Jil C. Tardiff
Summary: Genetic cardiomyopathies have been studied for decades, revealing that they are more complex than originally thought. Mutations in cardiac genes can cause these diseases, leading to varying clinical phenotypes. Precision medicine approaches may improve patient outcomes by targeting specific underlying biophysical mechanisms.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Physiology
Sarah R. Clippinger, Paige E. Cloonan, Wei Wang, Lina Greenberg, W. Tom Stump, Paweorn Angsutararux, Jeanne M. Nerbonne, Michael J. Greenberg
Summary: Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in sarcomeric proteins and is the leading cause of sudden cardiac death in individuals under 30 years of age. The complex pathogenesis of HCM involves changes in molecular, cellular, and tissue levels of function. Research suggests that molecularly driven changes in mechanical tension are the primary driver of early disease progression in familial HCM.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Immunology
Nicole R. Wong, Jay Mohan, Benjamin J. Kopecky, Shuchi Guo, Lixia Du, Jamison Leid, Guoshuai Feng, Inessa Lokshina, Oleksandr Dmytrenko, Hannah Luehmann, Geetika Bajpai, Laura Ewald, Lauren Bell, Nikhil Patel, Andrea Bredemeyer, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Sachio Morimoto, Peter O. Bayguinov, Max R. Fisher, W. Tom Stump, Michael Greenberg, James A. J. Fitzpatrick, Slava Epelman, Daniel Kreisel, Rajan Sah, Yongjian Liu, Hongzhen Hu, Kory J. Lavine
Summary: Recent studies have revealed that CCR2(-) tissue-resident macrophages play a crucial role in chronic heart failure, essential for maintaining cardiac function. These macrophages interact with cardiomyocytes and are activated through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway, controlling the expression of growth factors.
Article
Cell Biology
Samantha K. Barrick, Lina Greenberg, Michael J. Greenberg
Summary: DCM is a common cause of pediatric heart failure, with mutations in proteins like troponin T affecting cardiac muscle contraction. The R134G variant decreases calcium sensitivity and leads to hypocontractility in cardiomyocytes, demonstrating the importance of multiscale studies and mechanism-based precision medicine approaches for DCM.
MOLECULAR BIOLOGY OF THE CELL
(2021)
Review
Biochemistry & Molecular Biology
Samantha K. Barrick, Michael J. Greenberg
Summary: Cardiac myosin, as a molecular motor, plays an important role in driving heart contraction and is involved in regulating the process. Studies have shown that tension generated by cardiac myosin affects physiological processes beyond muscle contraction. Furthermore, research on cardiac myosin as a target for heart disease treatment is ongoing.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Cardiac & Cardiovascular Systems
Maria Papadaki, Theerachat Kampaengsri, Samantha K. Barrick, Stuart G. Campbell, Dirk von Lewinski, Peter P. Rainer, Samantha P. Harris, Michael J. Greenberg, Jonathan A. Kirk
Summary: The study found that increased glycation of sarcomeric actin in diabetic patients may contribute to the development of HF. This suggests that myofilament glycation could be a promising therapeutic target for preventing HF in diabetics.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Medicine, Research & Experimental
Jennifer McAdow, Shuo Yang, Tiffany Ou, Gary Huang, Matthew B. Dobbs, Christina A. Gurnett, Michael J. Greenberg, Aaron N. Johnson
Summary: Nemaline myopathy, as well as other musculoskeletal disorders, is caused by pathogenic variants in the Tropomyosin 2 gene, leading to muscle development and function issues. Through experiments in Drosophila, mice, and zebrafish models, the pathomechanisms of several TPM2 variants were revealed, and it was found that these variants can cause musculoskeletal defects. These assays suggest that our myogenic experiments can predict the clinical severity of TPM2 variants.
Article
Biochemistry & Molecular Biology
Lindsey A. Lee, Samantha K. Barrick, Artur Meller, Jonathan Walklate, Jeffrey M. Lotthammer, Jian Wei Tay, W. Tom Stump, Gregory Bowman, Michael A. Geeves, Michael J. Greenberg, Leslie A. Leinwand
Summary: MYH7b is a member of the sarcomeric myosin family, and its expression differs between mammals and reptiles. Although the sequence identity of MYH7b is high across species, the motor activity of python MYH7b is slower than human MYH7b, suggesting functional divergence.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biology
Artur Meller, Jeffrey M. Lotthammer, Louis G. Smith, Borna Novak, Lindsey A. Lee, Catherine C. Kuhn, Lina Greenberg, Leslie A. Leinwand, Michael J. Greenberg, Gregory R. Bowman
Summary: The design of compounds that can discriminate between closely related target proteins remains a challenge in drug discovery. This study shows that the probability of pocket opening is an important determinant of the potency of the myosin inhibitor blebbistatin. By using Markov state models, it was found that the probability of pocket opening accurately identifies which isoforms are most sensitive to blebbistatin inhibition and predicts blebbistatin binding affinities.
Article
Biophysics
Sarah R. Clippinger Schulte, Brent Scott, Samantha K. Barrick, W. Tom Stump, Thomas Blackwell, Michael J. Greenberg
Summary: The cardiac cycle is tightly regulated and disruption of this process can lead to various diseases. Cardiac contraction is driven by myosin, but it is unclear how thin-filament regulatory proteins affect the mechanics of the cardiac myosin motor. This study found that thin-filament regulatory proteins gate the calcium-dependent interactions between myosin and the thin filament, but do not affect the mechanics or load-dependent kinetics of cardiac myosin at physiologically relevant ATP concentrations.
BIOPHYSICAL JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Lindsey A. Lee, Samantha K. Barrick, Ada E. Buvoli, Jonathan Walklate, W. Tom Stump, Michael Geeves, Michael J. Greenberg, Leslie A. Leinwand
Summary: For a long time, sarcomeric myosin heavy chain proteins were believed to only exist in striated muscles where they function as molecular motors. However, an evolutionarily ancient member of this myosin family, MYH7b, has been found in mammalian nonmuscle tissues and is linked to hereditary hearing loss. The functional effects of mutations in MYH7b were unknown until now. This study investigates the effects of two hearing loss-associated mutations on the motor activity, structural and assembly properties of MYH7b.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Cardiac & Cardiovascular Systems
Adam L. Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L. Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Emma S. Winkler, Sanja Sviben, Erin Brooks, Ajith P. Nair, Kent A. Heck, Aniket S. Rali, Leo Simpson, Mehrdad Saririan, Dan Hobohm, W. Tom Stump, James A. Fitzpatrick, Xuping Xie, Xianwen Zhang, Pei-Yong Shi, J. Travis Hinson, Weng-Tein Gi, Constanze Schmidt, Florian Leuschner, Chieh-Yu Lin, Michael S. Diamond, Michael J. Greenberg, Kory J. Lavine
Summary: The study provides evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis, leading to severe acute respiratory syndrome coronavirus 2 infection that results in various detrimental effects, including contractile deficits and cell death.
JACC-BASIC TO TRANSLATIONAL SCIENCE
(2021)
