Danicamtiv increases myosin recruitment and alters cross-bridge cycling in cardiac muscle
Circulation Research, 2023•Am Heart Assoc
BACKGROUND: Modulating myosin function is a novel therapeutic approach in patients with
cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that
is currently in clinical trials. While it is known that danicamtiv increases force and
cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies
regarding its mode of action are lacking. METHODS: Permeabilized porcine cardiac tissue
and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse …
cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that
is currently in clinical trials. While it is known that danicamtiv increases force and
cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies
regarding its mode of action are lacking. METHODS: Permeabilized porcine cardiac tissue
and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse …
BACKGROUND
Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.
METHODS
Permeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficit.
RESULTS
Danicamtiv increased force and calcium sensitivity via increasing the number of myosins in the ON state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ.
CONCLUSIONS
As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering cross-bridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy.
Am Heart Assoc
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