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Induction of cardiac alternans in human iPS-derived cardiomyocytes through β-adrenergic receptor stimulation.
Physiol Rep
December 2024
Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
Cardiac alternans (C-ALT) is a phenomenon of alternating strong and weak contractions in the heart and is considered a risk factor for the development of heart failure and arrhythmias. However, no model has been reported that can induce C-ALT in vitro using human cells, and the developmental mechanism of C-ALT has not been studied using human cells. In this study, we successfully induced C-ALT in vitro using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
View Article and Find Full Text PDFDifferential effects of myosin activators on myocardial contractile function in non-failing and failing human hearts.
Am J Physiol Heart Circ Physiol
October 2024
Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States.
The second-generation myosin activator danicamtiv (DN) has shown improved function compared to the first generation myosin activator omecamtiv mecarbil (OM) in non-failing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared to OM persists in remodeled failing myocardium remain unknown. Therefore, this study aimed to investigate the differential contractile response to myosin activators in non-failing and failing myocardium.
View Article and Find Full Text PDFDanicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament.
bioRxiv
October 2024
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-year transplant-free survival rate is only ~50-70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin.
View Article and Find Full Text PDFDynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.
Int J Mol Sci
September 2024
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
The binding of small molecules to sarcomeric myosin can elicit powerful effects on the chemomechanical cycle, making them effective therapeutics in the clinic and research tools at the benchtop. However, these myotropes can have complex effects that act on different phases of the crossbridge cycle and which depend on structural, dynamic, and environmental variables. While small molecule binding sites have been identified crystallographically and their effects on contraction studied extensively, small molecule-induced dynamic changes that link structure-function are less studied.
View Article and Find Full Text PDFMyosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.
Int J Mol Sci
September 2024
Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (β-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of μmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.
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