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Cardiac Myosin Inhibitors in the Treatment of Hypertrophic Cardiomyopathy: Clinical Trials and Future Challenges

Biomolecules
Hypertrophic cardiomyopathy (HCM) is a prevalent and often underdiagnosed genetic cardiac disorder characterized by left ventricular hypertrophy and, in many cases, dynamic left ventricular outflow tract obstruction (LVOTO).
Arnold Kukowka, Marek Droździk
doaj   +6 more sources

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans [PDF]

Pharmacology Research & Perspectives
Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten.
Donghong Xu, Punag Divanji, Adrienne Griffith, Rajaa Sukhun, Kathleen Cheplo, Jianlin Li, Polina German   +6 more
doaj   +4 more sources

Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening

Nature Communications, 2023
Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays.
Priyanka Parijat, Seetharamaiah Attili, Zoe Hoare, Michael Shattock, Victor Kenyon, Thomas Kampourakis   +5 more
doaj   +2 more sources

Mechanisms of a novel regulatory light chain–dependent cardiac myosin inhibitor [PDF]

Journal of General Physiology
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins, such as β myosin heavy chain.
Timothy S McMillen, Michael Regnier, Na Sa   +2 more
exaly   +4 more sources

The Central Role of Echocardiography in Mavacamten Therapy for Obstructive Hypertrophic Cardiomyopathy: A Comprehensive Review [PDF]

Cardiology Research and Practice
Mavacamten is a cardiac myosin inhibitor used in adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Echocardiography is central to selecting suitable patients, confirming left ventricular outflow tract (LVOT) obstruction, excluding ...
Ali Nizam, Ibrahim Antoun, Liz Hodson, G. André Ng, Harshil Dhutia   +4 more
doaj   +2 more sources

Left Ventricular Structural, Physiological, and Transcriptomic Abnormalities in a Novel Porcine Hypertrophic Cardiomyopathy Model [PDF]

JACC: Basic to Translational Science
Summary: Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle commonly caused by variants in genes encoding sarcomere-associated proteins. The mechanisms by which these variants lead to the phenotype are uncertain, partly because of the lack of
Eric M. Green, MD, PhD, Carlos del Rio, PhD, Kamel Shibbani, MD, David K. Meyerholz, DVM, PhD, Joshua Gorham, BA, Seong Kim, PhD, Daniel M. DeLaughter, PhD, Marcus P. Henze, PhD, Christopher S. Rogers, PhD, Lindsey M. Gifford, BA, Melissa Kafa, RDCS, Frank Rohret, J. Adam Goeken, Jared M. McLendon, PhD, Ryan L. Boudreau, PhD, Christine E. Seidman, MD, Jessica C. Sieren, PhD, Robert M. Weiss, MD, Jonathan G. Seidman, PhD, Abhay Divekar, MD, Ferhaan Ahmad, MD, PhD   +20 more
doaj   +2 more sources

Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy [PDF]

eLife
This study explores the use of polarized second-harmonic generation (pSHG) to investigate myosin conformation in the relaxed state, differentiating between the actin-available, disordered (ON) state and the energy-conserving, ordered (OFF) state.
Giulia Arecchi, Marica Dente, Weikang Ma, Beatrice Scellini, Nicoletta Piroddi, Marina Scardigli, Jingyuan Yu, Jing Zhao, Riccardo Cicchi, Ryo Kinegawa, Caroline Muellenbroich, Francesco Sera, Corrado Poggesi, Cecilia Ferrantini, Thomas C Irving, Michael Regnier, Leonardo Sacconi, Chiara Tesi   +17 more
doaj   +2 more sources

Novel Use of Mavacamten in RAF1-Associated Noonan Syndrome With Hypertrophic Cardiomyopathy [PDF]

JACC: Case Reports
Background: Mavacamten is a first-in class allosteric inhibitor of cardiac myosin that is shown to reduce left ventricular outflow tract obstruction and improves symptoms in obstructive hypertrophic cardiomyopathy (HCM).
Lubna Ziauddin, MD, Erin Davidson, PharmD, Hannah Spears, MS, PA-C, Erin Coffman, CGC, Markey McNutt, MD, PhD, Nicholas Hendren, MD, Katherine Kearney, MBBS, PhD, Sheila M. Hegde, MD, MPH, Justin L. Grodin, MD, MPH, Natalie Tapaskar, MD   +9 more
doaj   +2 more sources

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy [PDF]

Scientific Reports
Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive ...
Victor N. Rivas, Amanda E. Crofton, Carina E. Jauregui, Jalena R. Wouters, Betty S. Yang, Luke A. Wittenburg, Joanna L. Kaplan, Darren T. Hwee, Anne N. Murphy, Bradley P. Morgan, Fady I. Malik, Samantha P. Harris, Joshua A. Stern   +12 more
doaj   +2 more sources

A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants. [PDF]

JACC Basic To Translational Science, 2022
Malik FI, Robertson LA, Armas DR, Robbie EP, Osmukhina A, Xu D, Li H, Solomon SD.   +7 more
exaly   +2 more sources