TY - JOUR
T1 - Sarcomere protein modulation
T2 - The new frontier in cardiovascular medicine and beyond
AU - Morelli, Cristina
AU - Ingrasciotta, Gessica
AU - Jacoby, Daniel
AU - Masri, Ahmad
AU - Olivotto, Iacopo
N1 - Funding Information:
IO has served as PI in the Explorer HCM trial, and is an advisor for Bristol Meier Squibb, Cytokinetics and Amicus and has received grants from Genzyme, Menarini International, Boston Scientific. DJ is a Cytokinetics employee, has received consulting fees for serving on an Advisory Board for Myocardia/BMS and Cytokinetics and he owns the patent: System and Method for Generating Biological Tissue, United States 15/883,381; owns Propria, LLC. AM has received research grants from Pfizer, Ionis, Akcea, Ultromics and the Wheeler Foundation, fees (honoraria or consulting) from Eidos, Pfizer, Ionis, Alnylam, Cytokinetics, Bristol Meier Squibb, Tenaya, and Attralus. The other authors declare they have no conflict of interest.
Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - Over the past decade, the constant progress in science and technologies has provided innovative drug molecules that address specific disease mechanisms thus opening the era of drugs targeting the underlying pathophysiology of the disease. In this scenario, a new paradigm of modulation has emerged, following the development of small molecules capable of interfering with sarcomere contractile proteins. Potential applications include heart muscle disease and various forms of heart failure, although promising targets also include conditions affecting the skeletal muscle, such as degenerative neuromuscular diseases. In cardiac patients, a cardiac myosin stimulator, omecamtiv mecarbil, has shown efficacy in heart failure with reduced systolic function, lowering heart failure related events or cardiovascular death, while two inhibitors, mavacamten and aficamten, in randomized trials targeting hypertrophic cardiomyopathy, have been shown to reduce hypercontractility and left ventricular outflow obstruction improving functional capacity. Based on years of intensive basic and translational research, these agents are the prototypes of active pipelines promising to deliver an array of molecules in the near future. We here review the available evidence and future perspectives of myosin modulation in cardiovascular medicine.
AB - Over the past decade, the constant progress in science and technologies has provided innovative drug molecules that address specific disease mechanisms thus opening the era of drugs targeting the underlying pathophysiology of the disease. In this scenario, a new paradigm of modulation has emerged, following the development of small molecules capable of interfering with sarcomere contractile proteins. Potential applications include heart muscle disease and various forms of heart failure, although promising targets also include conditions affecting the skeletal muscle, such as degenerative neuromuscular diseases. In cardiac patients, a cardiac myosin stimulator, omecamtiv mecarbil, has shown efficacy in heart failure with reduced systolic function, lowering heart failure related events or cardiovascular death, while two inhibitors, mavacamten and aficamten, in randomized trials targeting hypertrophic cardiomyopathy, have been shown to reduce hypercontractility and left ventricular outflow obstruction improving functional capacity. Based on years of intensive basic and translational research, these agents are the prototypes of active pipelines promising to deliver an array of molecules in the near future. We here review the available evidence and future perspectives of myosin modulation in cardiovascular medicine.
KW - Cardiomyopathies
KW - Heart failure
KW - Neuromuscular diseases, therapeutics
KW - Sarcomeres
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U2 - 10.1016/j.ejim.2022.04.020
DO - 10.1016/j.ejim.2022.04.020
M3 - Review article
C2 - 35534374
AN - SCOPUS:85129988749
VL - 102
SP - 1
EP - 7
JO - European Journal of Internal Medicine
JF - European Journal of Internal Medicine
SN - 0953-6205
ER -